Colloid Science and Biotechnology

**47**

**Chapter 4**

**Abstract**

Functions

inherent to biomimicry.

**1. Introduction**

sterical stabilization, adhesion

Colloid Stability Influences on

*Camillo La Mesa and Gianfranco Risuleo*

the Biological Organization and

It is common to entities having sizes in the nano/micro-scale range be that, real or bio-intended systems, to undergo the action of many different forces, imparting them colloid stability. Ubiquitary electrostatic contributions, sometimes dominant, may overlap with steric stabilization ones; their combination effectively takes place in most cases. The two effects are jointly responsible, for instance, for the control of many phenomena such as: adhesion onto cells of alien agents, cellular separation during morpho-functional evolution, uptake of exogenous materials into cells and tissues. We evidence here, how the combination of these forces operates, and indicate the procedures leading to their effectiveness, when required for purposes

**Keywords:** biological systems, biomimetic systems, surface charge density,

It took a long time before the characteristics peculiar to biological organisms, were considered on the more solid grounds dictated by Physics and Chemistry. It is enough to remind the violent criticism raised by many outstanding scientists against D'Arcy Thompson book "*On growth and form*", dating the second decade of the last century. The successful fate of the book urged biologists to account not only for the taxonomic rules inherent to biological organisms and to focus, much more reasonably, on the physical forces, geometrical, and morphological constraints responsible for biological organization, growth and functions. It is convincingly stated there that "In the growth of a shell, for instance, we can conceive no simpler law than this, that it shall widen and lengthen in the same unvarying proportions: and this simplest of laws is that which Nature tends to follow. The shell, like the creature within it, grows in size but does not change its shape; and the existence of this constant relativity of growth, or constant similarity of form, is of the essence, and may be made the basis of a definition, of the equiangular spiral." [1]. To the best of our knowledge this is the first effort to explain the growth of animal shapes in terms of geometry and topology, and to account for the modes in which organisms self-organize, following the rules dictated by their own genome. With respect to the gene/body shape one should consider the phenomenon of epistasis, i.e., the effect of one gene modulated by the genetic background [2]. Originally this definition meant that the phenotypic effect of one gene is affected by one or more different

#### **Chapter 4**

## Colloid Stability Influences on the Biological Organization and Functions

*Camillo La Mesa and Gianfranco Risuleo*

#### **Abstract**

It is common to entities having sizes in the nano/micro-scale range be that, real or bio-intended systems, to undergo the action of many different forces, imparting them colloid stability. Ubiquitary electrostatic contributions, sometimes dominant, may overlap with steric stabilization ones; their combination effectively takes place in most cases. The two effects are jointly responsible, for instance, for the control of many phenomena such as: adhesion onto cells of alien agents, cellular separation during morpho-functional evolution, uptake of exogenous materials into cells and tissues. We evidence here, how the combination of these forces operates, and indicate the procedures leading to their effectiveness, when required for purposes inherent to biomimicry.

**Keywords:** biological systems, biomimetic systems, surface charge density, sterical stabilization, adhesion

#### **1. Introduction**

It took a long time before the characteristics peculiar to biological organisms, were considered on the more solid grounds dictated by Physics and Chemistry. It is enough to remind the violent criticism raised by many outstanding scientists against D'Arcy Thompson book "*On growth and form*", dating the second decade of the last century. The successful fate of the book urged biologists to account not only for the taxonomic rules inherent to biological organisms and to focus, much more reasonably, on the physical forces, geometrical, and morphological constraints responsible for biological organization, growth and functions. It is convincingly stated there that "In the growth of a shell, for instance, we can conceive no simpler law than this, that it shall widen and lengthen in the same unvarying proportions: and this simplest of laws is that which Nature tends to follow. The shell, like the creature within it, grows in size but does not change its shape; and the existence of this constant relativity of growth, or constant similarity of form, is of the essence, and may be made the basis of a definition, of the equiangular spiral." [1]. To the best of our knowledge this is the first effort to explain the growth of animal shapes in terms of geometry and topology, and to account for the modes in which organisms self-organize, following the rules dictated by their own genome. With respect to the gene/body shape one should consider the phenomenon of epistasis, i.e., the effect of one gene modulated by the genetic background [2]. Originally this definition meant that the phenotypic effect of one gene is affected by one or more different

genetic *loci*. Thus, epistatic mutations have different "combinatorial" rather than individual effects. This was originally a genetics concept but, nowadays, is of common use in biochemistry, computational biology and evolutionary biology. Epistasis stems from interactions between or, reciprocally, within genes and this leads to nonlinear effects. Therefore, it has a dramatic influence on the shape of evolutionary landscapes, which leads to profound consequences for evolution and evolutionary potentials of the phenotypic traits [3].

The statements of D'Arcy Thompson's statement become convincing also if applied to the micro/nanoscale range. Here, the role played by physical forces at short distances comes in full evidence, that is: when the biological organization modes in their lower stage, as in dispersed cells, are considered (however, in a fully organized, functional organism, the role of physical forces may become extremely complex). The stability and, eventually, the organization of such objects is dictated by the overlapping, or dominance, of van der Waals, *vdW*, electrostatic, osmotic, elastic, steric and many other forces. Their combination with what is dictated by gene expression, leads to an optimal topology-ruled shape that a biological system, be it a cell or a tissue, not to speak of a whole organism, assumes. In what follows we put in evidence the role of major contributions when the stabilization in dispersed form is required, or naturally occurs.

To proceed along this line, we discuss separately the physical origins of both electrostatic and steric effects. Examples based on real biological systems, shall be given and the pathways inducing/reducing the onset, or disappearance, of these effects will be discussed. We must be aware that the action of many forces is required to attain a preferred organization mode in cells and tissues, where electrostatic interactions are prevalent, safe the enzyme/substrate where VdW forces are prevalent. We also know that the mentioned forces are dominant, in the terms dictated by energy costs, not considering their modulus (provided the sum of all ΔG terms is <0). This fact, combined with the genetically driven rules, fulfills requirements needed for optimal biological activity and functions. In what follows we describe, in sequence, the quintessential features of both electrostatic and steric forces, which are required to understand how important they are in living systems. In the final part of this chapter we mention some pertinent examples on the role that electrostatic and steric effects may jointly play.

#### **2. Electrostatic aspects**

Sufficiently high electrical potentials, *ψ*, are responsible for the kinetic stability of colloids. These facts avoid the onset of undesired effects, such as sedimentation [4], creaming [5], and/or clustering [6]. The foundations of colloid stability date to the 1940s of the last century and are formalized in DLVO theory, which applies to real dispersions. The original theory combines electrostatics and statistical thermodynamics, and is formalized in the well-known Poisson-Boltzmann, or P-B, equation. The effects considered in that theory are responsible for the stabilization of clays [7], inorganic colloids as Al(OH)3 [8], latexes [9], cells, vesicles, viruses, etc. [10–13]. Note that counter-ion condensation onto DNA, and biopolymers in general, is expressed in terms of the same theory [14, 15].

The balance of attractive vs. repulsive electrostatic forces depends on the sign of their surface potentials, *ψ*'s. On this line, Parsegian and Gingell showed that charged surfaces of the same sign, eventually differing in modulus, may never become attractive. Conversely, particles/surfaces bearing opposite sign attract or repel, depending on experimental conditions [16]. That statement was demonstrated for the surface charge densities of colloid *A* and *B*, termed σ*A* and σ*B*, (with σ*<sup>A</sup>* ≠ σ*B*)

**49**

**Figure 1.**

*Colloid Stability Influences on the Biological Organization and Functions*

among the respective exponentials, that is, exp±(*zeψ/KT*)

are located), and fulfills the law stating

transformation in hyperbolic form reduces the function to [17]

exp+(*ze*/*KT*) − exp−(*ze*/*KT*)

separated by a distance 0 < *x* < l. If the upper and lower limits of the derivative, hereafter indicated as [d(*zeψ/KT*)/d*x*]|*x* = 0 and [d(*zeψ/KT*)/d*x*]|*x* = 1, respectively, differ in sign, the corresponding function must be null somewhere between the integration limits. As a consequence, like-charged surfaces always repel, whatever is *x*, *σ* or *ψ*. The question to be addressed is how to find rational procedures reducing

In what follows, we indicate how to face the problem and to control, or minimize, repulsions. Imagine having two large cells, each characterized by a given *σ*. We suppose that the respective surface charge densities are equal in modulus. The potential that one cell exerts on the other is *ψ*. In the P-B equation, the difference

which is easily linearized if *zeψ* < < *KT*. In words, the Euler-based approximation underlying Eq. (1) holds in linear perturbation regimes. The theory relies on the fact that the effect of *ψ* decreases with distance from the source (i.e., where charges

*ψ* = *ψ° exp*<sup>−</sup>*kx* (2)

Implicit in the equation is the statement that, a distance *x* from a surface of well-defined potential, *ψ* decreases and its decay depends on the number of charges; more properly, on the concentration in excess of positive, or negative, ions. In words, it is as if we were in presence of a double layer, of length 1/*k*, located a distance *x* apart from the source. To reduce the effect of *ψ* on its surroundings, thus,

*Excess concentration of positive ions, (N+—N−), vs. distance, d. dx is the double layer thickness. The surfaces have different charge density. The difference among them, is dσ. The same holds in case of excess negative charges.*

, is considered. Proper

= 2 sinh (*ze*/*KT*) (1)

*DOI: http://dx.doi.org/10.5772/intechopen.88448*

that unescapable fate.

#### *Colloid Stability Influences on the Biological Organization and Functions DOI: http://dx.doi.org/10.5772/intechopen.88448*

*Colloid Science in Pharmaceutical Nanotechnology*

potentials of the phenotypic traits [3].

form is required, or naturally occurs.

that electrostatic and steric effects may jointly play.

general, is expressed in terms of the same theory [14, 15].

**2. Electrostatic aspects**

genetic *loci*. Thus, epistatic mutations have different "combinatorial" rather than individual effects. This was originally a genetics concept but, nowadays, is of common use in biochemistry, computational biology and evolutionary biology. Epistasis stems from interactions between or, reciprocally, within genes and this leads to nonlinear effects. Therefore, it has a dramatic influence on the shape of evolutionary landscapes, which leads to profound consequences for evolution and evolutionary

The statements of D'Arcy Thompson's statement become convincing also if applied to the micro/nanoscale range. Here, the role played by physical forces at short distances comes in full evidence, that is: when the biological organization modes in their lower stage, as in dispersed cells, are considered (however, in a fully organized, functional organism, the role of physical forces may become extremely complex). The stability and, eventually, the organization of such objects is dictated by the overlapping, or dominance, of van der Waals, *vdW*, electrostatic, osmotic, elastic, steric and many other forces. Their combination with what is dictated by gene expression, leads to an optimal topology-ruled shape that a biological system, be it a cell or a tissue, not to speak of a whole organism, assumes. In what follows we put in evidence the role of major contributions when the stabilization in dispersed

To proceed along this line, we discuss separately the physical origins of both electrostatic and steric effects. Examples based on real biological systems, shall be given and the pathways inducing/reducing the onset, or disappearance, of these effects will be discussed. We must be aware that the action of many forces is required to attain a preferred organization mode in cells and tissues, where electrostatic interactions are prevalent, safe the enzyme/substrate where VdW forces are prevalent. We also know that the mentioned forces are dominant, in the terms dictated by energy costs, not considering their modulus (provided the sum of all ΔG terms is <0). This fact, combined with the genetically driven rules, fulfills requirements needed for optimal biological activity and functions. In what follows we describe, in sequence, the quintessential features of both electrostatic and steric forces, which are required to understand how important they are in living systems. In the final part of this chapter we mention some pertinent examples on the role

Sufficiently high electrical potentials, *ψ*, are responsible for the kinetic stability of colloids. These facts avoid the onset of undesired effects, such as sedimentation [4], creaming [5], and/or clustering [6]. The foundations of colloid stability date to the 1940s of the last century and are formalized in DLVO theory, which applies to real dispersions. The original theory combines electrostatics and statistical thermodynamics, and is formalized in the well-known Poisson-Boltzmann, or P-B, equation. The effects considered in that theory are responsible for the stabilization of clays [7], inorganic colloids as Al(OH)3 [8], latexes [9], cells, vesicles, viruses, etc. [10–13]. Note that counter-ion condensation onto DNA, and biopolymers in

The balance of attractive vs. repulsive electrostatic forces depends on the sign of their surface potentials, *ψ*'s. On this line, Parsegian and Gingell showed that charged surfaces of the same sign, eventually differing in modulus, may never become attractive. Conversely, particles/surfaces bearing opposite sign attract or repel, depending on experimental conditions [16]. That statement was demonstrated for the surface charge densities of colloid *A* and *B*, termed σ*A* and σ*B*, (with σ*<sup>A</sup>* ≠ σ*B*)

**48**

separated by a distance 0 < *x* < l. If the upper and lower limits of the derivative, hereafter indicated as [d(*zeψ/KT*)/d*x*]|*x* = 0 and [d(*zeψ/KT*)/d*x*]|*x* = 1, respectively, differ in sign, the corresponding function must be null somewhere between the integration limits. As a consequence, like-charged surfaces always repel, whatever is *x*, *σ* or *ψ*. The question to be addressed is how to find rational procedures reducing that unescapable fate.

In what follows, we indicate how to face the problem and to control, or minimize, repulsions. Imagine having two large cells, each characterized by a given *σ*. We suppose that the respective surface charge densities are equal in modulus. The potential that one cell exerts on the other is *ψ*. In the P-B equation, the difference among the respective exponentials, that is, exp±(*zeψ/KT*) , is considered. Proper transformation in hyperbolic form reduces the function to [17]

$$\exp^{\*\text{(xe\psi/KT)}}\text{ -- }\exp^{-\text{(xe\psi/KT)}}\text{ = 2 }\sinh\left(\text{ze}\,\psi/KT\right)\tag{1}$$

which is easily linearized if *zeψ* < < *KT*. In words, the Euler-based approximation underlying Eq. (1) holds in linear perturbation regimes. The theory relies on the fact that the effect of *ψ* decreases with distance from the source (i.e., where charges are located), and fulfills the law stating

$$
\psi = \psi^p exp^{-kx} \tag{2}
$$

Implicit in the equation is the statement that, a distance *x* from a surface of well-defined potential, *ψ* decreases and its decay depends on the number of charges; more properly, on the concentration in excess of positive, or negative, ions. In words, it is as if we were in presence of a double layer, of length 1/*k*, located a distance *x* apart from the source. To reduce the effect of *ψ* on its surroundings, thus,

#### **Figure 1.**

*Excess concentration of positive ions, (N+—N−), vs. distance, d. dx is the double layer thickness. The surfaces have different charge density. The difference among them, is dσ. The same holds in case of excess negative charges.*

it is enough adding salt in excess. The potential is screened and repulsion between particles substantially minimized. In this way, colloids do not "feel" each other as it was before adding swamping electrolytes.

The problem can be properly addressed discussing the case of surface charge density, *σ*. As a consequence of Eq. (1), *ψ* decreases with distance. On moving from a reference point, *x°*, to *x*, *σ* decreases. The system behaves as a capacitor, and the local, punctual, concentration of ions, *ρ*, decreases with *x*. This is expressed by writing the integral of *σ* from *x°* to the point of interest as

$$
\sigma = -\int \rho d\mathbf{x} \tag{3}
$$

The meaning of Eqs. (2) and (3) is visualized in **Figure 1**. At long, on a molecular scale, distances the value of the integral in Eq. (3) approaches the equilibrium ionic concentration, and electro-neutrality is thus ensured. Therefore, (*N+* —*N−* ) values in the above figure refer to the excess of counter-ions around a given charged body. Swamping electrolytes reduce the effect of potential at long distances and favor coalescence.

In many procedures intended for food chemistry, for instance, salting is by far the preferred route to reduce repulsive forces between entities in the given medium and to induce phase separation [18].

#### **3. Sterical stabilization**

The role that such effect plays in controlling colloid stability, with particular emphasis to biological systems is considered [19]. The concept was originally intended to latexes stabilization, and later extended to bio-systems. The term "*sterical stabilization*" indicates that macromolecules protect particles from flocculation, or coagulation. It applies to systems in which stabilizers are surface bound to the particles in question, which would flocculate if not protected. Sterical stabilization is intended to systems in which binding to a given surface is permanent. When binding is covalent, the drawbacks inherent to depletion [20, 21], which occurs when the stabilizer is weakly bound and may transfer toward the bulk, are missing. In that case, stabilizers partition between the particle surface and the bulk. This favors the onset of osmotic gradients, detaching stabilizers from the particle' surface with coagulation of no longer stabilized colloids. Predicting sterical stabilization is cumbersome if all these effects are not accounted for. As a matter of fact, polymer moieties protruding outward a given particle are solvated, sometimes charged; their state, conformation and degrees of freedom jointly depend on polymer-medium interactions. In other words, entropic contributions are not only due to changes in conformational degrees of freedom, as proposed by van der Waals's school [22, 23]. More precisely, the Gibbs energy, due to entropic and also enthalpy-based terms [24–26], is the result of different contributions.

We consider the following entropic terms

$$
\Delta S\_{tot} = \Delta S\_{conform} + \Delta S\_{solv} + other\ \Delta S\ terms\tag{4}
$$

**51**

*Colloid Stability Influences on the Biological Organization and Functions*

The original hypothesis by van der Waals, which relies only on conformational entropy, is not convincing, since the contribution due to the solvent cannot be null. In fact, the solvent features are responsible for a number of formulation possibili-

To come in more details on the basics of steric stabilization, we report some details describing the first stages of surface anchoring, i.e., polymer wrapping. That process is responsible for macromolecule binding thereon, and not only. We describe below that effect, without entering in much details as to whether binding is covalent or not. Imagine a homo-polymer binding onto a solid surface; in consequence of that, units in the chain face outward, and may bind in a second place. The only physical restriction is that chains cannot enter the particle but may substantially adsorb thereon in many points. The process depends on polymer affinity toward the surface; in words, surface coverage is dictated by thermodynamics. We assume that:

a.polymers and colloidal nano-particles, *NP*s, are mono-disperse;

e.partition between bulk and surface-bound states may occur.

c.wrapping units are much shorter than the fully extended polymer one;

We impose *Xf* to be the overall mole fraction of polymer molecules in the medium; it is either free or interacting with particles. The latter is the sum of wrapping and protruding parts. Interacting polymers are divided in two classes, i.e., wrapped, α, and protruding, ε (=1 − α), states. The equilibrium between such states, Kα,ε, is defined as

As in most classical books on Colloid Chemistry ([27, 28], and references therein), Eq. (5), defines the ratio of wrapped to protruded states, and gives a bind-

where *Pi* refers to a state characterized by a length *li*, and width equal to *a*. We assume the latter to be the cross section of the main chain, **Figure 2**. Terms *w* and *π* are energies per unit volume. Their balance depends on the dominance of attractive/repulsive forces acting on the *NP* surface. *η* is a rotational energy, when the pre-exponential *ki* is a proper weighing factor. *Pi* depends on the balance of all energy terms acting in the first layer around particles. The forces acting in the corona depend on the average local polymer concentration, calculated layer by layer. This statement is due to the fact that the content of polymer sub-units in a layer depends on surface curvature, and/or bulkiness, as well [29]. Expectedly, the solvation is not uniform along the protruding polymer chains. Similar cases occur when polymer coverage is close-grained and does not allow surface adsorption of other species. Thus, poly-oxy-ethylene glycols, PEO's, and structurally related polymers (mostly PEO-PPO-PEO block co-polymers) are widely used to avoid protein adsorption and find application if biomedical-intended NPs must not adsorb albumin or lysozyme, otherwise easily nucleating onto the mentioned NPs [30–32]. This common application is in use, others are mentioned below.

ing probability, *P*, for adsorbed segments. For an *i*th state, it is defined as

*Pi* = *ki* exp−[(*π*+*w*)*ali*/*KT*]

Kα,ε = α/ε = α/ (1 − α) (5)

exp−[η/*KT*] (6)

*DOI: http://dx.doi.org/10.5772/intechopen.88448*

ties, including those intended to bio-systems.

b.polymer size is << *NP*s radius;

d.different parts of the same polymer may wrap;

where the subscripts indicate conformational, solvation, and all other contributions, respectively. We do not consider, in a first stage, terms due to charging/ discharging of polar moieties. Neither shall we consider osmotic repulsion, which is significant when the "coronas" surrounding the nanoparticles are compact. The requirements needed to have effective repulsion between polymer moieties, and in coronas stabilization too, crucially depend on the solvent. It is not casual, thus, that different stabilizers are needed to disperse colloids in polar, or non-polar, media.

*Colloid Stability Influences on the Biological Organization and Functions DOI: http://dx.doi.org/10.5772/intechopen.88448*

The original hypothesis by van der Waals, which relies only on conformational entropy, is not convincing, since the contribution due to the solvent cannot be null. In fact, the solvent features are responsible for a number of formulation possibilities, including those intended to bio-systems.

To come in more details on the basics of steric stabilization, we report some details describing the first stages of surface anchoring, i.e., polymer wrapping. That process is responsible for macromolecule binding thereon, and not only. We describe below that effect, without entering in much details as to whether binding is covalent or not. Imagine a homo-polymer binding onto a solid surface; in consequence of that, units in the chain face outward, and may bind in a second place. The only physical restriction is that chains cannot enter the particle but may substantially adsorb thereon in many points. The process depends on polymer affinity toward the surface; in words, surface coverage is dictated by thermodynamics. We assume that:

a.polymers and colloidal nano-particles, *NP*s, are mono-disperse;

b.polymer size is << *NP*s radius;

*Colloid Science in Pharmaceutical Nanotechnology*

was before adding swamping electrolytes.

σ = −

and to induce phase separation [18].

**3. Sterical stabilization**

writing the integral of *σ* from *x°* to the point of interest as

concentration, and electro-neutrality is thus ensured. Therefore, (*N+*

it is enough adding salt in excess. The potential is screened and repulsion between particles substantially minimized. In this way, colloids do not "feel" each other as it

The problem can be properly addressed discussing the case of surface charge density, *σ*. As a consequence of Eq. (1), *ψ* decreases with distance. On moving from a reference point, *x°*, to *x*, *σ* decreases. The system behaves as a capacitor, and the local, punctual, concentration of ions, *ρ*, decreases with *x*. This is expressed by

∫

The meaning of Eqs. (2) and (3) is visualized in **Figure 1**. At long, on a molecular scale, distances the value of the integral in Eq. (3) approaches the equilibrium ionic

above figure refer to the excess of counter-ions around a given charged body. Swamping electrolytes reduce the effect of potential at long distances and favor coalescence.

In many procedures intended for food chemistry, for instance, salting is by far the preferred route to reduce repulsive forces between entities in the given medium

The role that such effect plays in controlling colloid stability, with particular emphasis to biological systems is considered [19]. The concept was originally intended to latexes stabilization, and later extended to bio-systems. The term "*sterical stabilization*" indicates that macromolecules protect particles from flocculation, or coagulation. It applies to systems in which stabilizers are surface bound to the particles in question, which would flocculate if not protected. Sterical stabilization is intended to systems in which binding to a given surface is permanent. When binding is covalent, the drawbacks inherent to depletion [20, 21], which occurs when the stabilizer is weakly bound and may transfer toward the bulk, are missing. In that case, stabilizers partition between the particle surface and the bulk. This favors the onset of osmotic gradients, detaching stabilizers from the particle' surface with coagulation of no longer stabilized colloids. Predicting sterical stabilization is cumbersome if all these effects are not accounted for. As a matter of fact, polymer moieties protruding outward a given particle are solvated, sometimes charged; their state, conformation and degrees of freedom jointly depend on polymer-medium interactions. In other words, entropic contributions are not only due to changes in conformational degrees of freedom, as proposed by van der Waals's school [22, 23]. More precisely, the Gibbs energy, due to entropic and also

enthalpy-based terms [24–26], is the result of different contributions.

where the subscripts indicate conformational, solvation, and all other contributions, respectively. We do not consider, in a first stage, terms due to charging/ discharging of polar moieties. Neither shall we consider osmotic repulsion, which is significant when the "coronas" surrounding the nanoparticles are compact. The requirements needed to have effective repulsion between polymer moieties, and in coronas stabilization too, crucially depend on the solvent. It is not casual, thus, that different stabilizers are needed to disperse colloids in polar, or non-polar, media.

Δ *Stot* = Δ *Sconform* + Δ *Ssolv* + *other* Δ*S terms* (4)

We consider the following entropic terms

*dx* (3)

—*N−*

) values in the

**50**

c.wrapping units are much shorter than the fully extended polymer one;

d.different parts of the same polymer may wrap;

e.partition between bulk and surface-bound states may occur.

We impose *Xf* to be the overall mole fraction of polymer molecules in the medium; it is either free or interacting with particles. The latter is the sum of wrapping and protruding parts. Interacting polymers are divided in two classes, i.e., wrapped, α, and protruding, ε (=1 − α), states. The equilibrium between such states, Kα,ε, is defined as

$$\mathbf{K}\_{\alpha,\varepsilon} = \alpha/\varepsilon = \alpha/(\mathbf{1}-\alpha) \tag{5}$$

As in most classical books on Colloid Chemistry ([27, 28], and references therein), Eq. (5), defines the ratio of wrapped to protruded states, and gives a binding probability, *P*, for adsorbed segments. For an *i*th state, it is defined as

$$P\_i = k\_i \exp^{-\left[\left(\pi \ast w\right)ali/KT\right]} \exp^{-\left[\eta/KT\right]} \tag{6}$$

where *Pi* refers to a state characterized by a length *li*, and width equal to *a*. We assume the latter to be the cross section of the main chain, **Figure 2**. Terms *w* and *π* are energies per unit volume. Their balance depends on the dominance of attractive/repulsive forces acting on the *NP* surface. *η* is a rotational energy, when the pre-exponential *ki* is a proper weighing factor. *Pi* depends on the balance of all energy terms acting in the first layer around particles. The forces acting in the corona depend on the average local polymer concentration, calculated layer by layer. This statement is due to the fact that the content of polymer sub-units in a layer depends on surface curvature, and/or bulkiness, as well [29]. Expectedly, the solvation is not uniform along the protruding polymer chains. Similar cases occur when polymer coverage is close-grained and does not allow surface adsorption of other species. Thus, poly-oxy-ethylene glycols, PEO's, and structurally related polymers (mostly PEO-PPO-PEO block co-polymers) are widely used to avoid protein adsorption and find application if biomedical-intended NPs must not adsorb albumin or lysozyme, otherwise easily nucleating onto the mentioned NPs [30–32]. This common application is in use, others are mentioned below.

#### **Figure 2.**

*Polymer adsorption for loops sizes << NP diameter. The surface adsorption term, has energy = w. Polymerpolymer interactions at the NP surface, π, are attractive or repulsive. At saturation wrapping has reached its maximum value. Above that threshold, w and π energies balance.*

#### **Figure 3.**

*Reconstructed liposomes with DNA compacted on the outer surface. The lower left arrow indicates lipid head groups; the upper one random coils represents compacted DNA. Protruding whips indicate PEO chains anchored to the bilayer. Such chains are hydrated, elastic, densely packed, and do not allow other species to come in contact with liposomes.*

**Figure 3** describes how to get the stabilization of synthetic liposomes against coalescence and is widely used in transfection technologies.

#### **4. Biological implications**

Physics and Chemistry allow to clarify some items of biology, despite substantial problems, due to a terrific increase in complexity inherent to living systems. As a matter of fact, these consist of many parts substantially differing from each other, in reciprocal relation. A first glance to a biological sample allows to observe some organization details. Understanding the hierarchy of active forces, packing modes, and processes taking place in bio-systems is discouraging, unless systematic efforts are stricken out. Therefore, most attempts to relate cell complexity to a number of forces acting therein are not trivial. Such attempts require going from simplicity to complexity, and to focus only on the essential modes of interaction. To focus only on the electrostatic and steric effects is a promising starting hypothesis. The first accounts for forces decaying with distance in a predictable way, irrespective of the medium [33]. The second conveys the impression that the geometry dictated by an arrangement of springs, or semi-rigid protrusions, facing outward the particle surface implies repulsion [34]. This fact is more convincing if we account for the additional role of osmotic forces [35], quite often associated to steric stabilization.

Cells always systematically trigger surface charges, acting as a physical barrier against the entry of exogenous material. Passive diffusion is not enough [36], unless it is substantially assisted by other transfer pathways. Imagine having the necessity to insert a nucleic acid in the cell. It is absolutely necessary to make use of chaperons, capable to overcome the protecting action of electric barriers [37]. This action relies on

**53**

**5. Final remarks**

*Colloid Stability Influences on the Biological Organization and Functions*

transfection technologies capable to neutralize/invert the charge of hosts to be transferred through membranes, thus favoring uptake. For instance, DNA is neutralized, or adsorbed on oppositely charged vesicles, and transferred into the hosting cells [38–42]. Attraction between cells and transfectants is electrostatic in nature, and its action favors fusion with the cell membrane. It is a phenomenon comparable to the behavior met when viruses enter a cell [43–45]. This mimicry overlaps with other physical effects, due

to membrane curvature elasticity [46, 47], its fluid state [48], and so forth [49]. It is known that steric stabilization has a large effect on macrophage uptake in vitro [50]. This effect is tuned by the fixed thickness of aqueous layers, at least in lipid-based chaperones. To ensure long-lasting circulation to immuno-liposomes (and avoid their biodegradation), combination of sterical stabilization with a superior targetability is attained by attaching monoclonal antibodies. These are formed directly on the distal ends of liposome-grafted PEO chains [51, 52]. Similar effects are attained when the more rigid poly-l-lysine is used as sterical stabilizer. In this case, electrostatic effects, due to pH-sensitive charging/discharging of the peptide moieties, are significant. The coupling of antibodies to membranes allow anchorage even in mild basic conditions without the need for antibody derivatization. On the same line, lipo-plexes sterically stabilized with PEO derivatives are used [53]. Relevant are some reports on doxorubicin-loaded liposomes, previously stabilized by adsorption of heparin; these systems show a marked antitumor activity. Heparin is also a coating material stabilizing and protecting liposomes against adverse immune reactions [54], or, in presence of adjuvants, induces drug accumulation at the tumor site [55]. The above list is far from being exhaustive and indicates that steric stabilization, in conjunction with other contributions, is responsible for advanced applica-

tions in most fields of bio-medicine and molecular medicine [56–60].

The "visions" of nature have been different throughout the development of natural sciences. Often physicists, chemists and biologists had a different, sometimes conflicting, way of looking at nature and investigating natural phenomena. One example for all: physical and chemical phenomena (reactions) were considered essentially irreversible in the "classical" history of natural sciences. On the contrary, biological phenomena were considered reversible, and fluidity, change of shape and behavior were dominant. It is not a coincidence that one of the masterpieces of theoretical biology written by J. Monod (1910–1976), one of the most authoritative biologists of last century is entitled "*Chance and necessity*" [61]. As the title suggests, chance seems to rule the biological phenomena: how life arose, the "plasticity" of many biological events. But, necessity is the driving force; a sort of constraint, impeding the same phenomena to escape the stringent laws permitting the completion of a fully functional living organism. Indeed, these strict laws are often represented by physico-chemical (essentially weak) interactions that give a determinant contribution to biological organization and functions. In other words, one could confidently conclude that Occam razor in its popular acceptation, once again, holds true: if there are competing ideas, the simplest one is possibly the correct one. This formulation is not actually the Occam's razor, but rather the law of maximum parsimony. Occam's razor states that in the case of competing hypotheses making the same predictions, the solution with the fewest assumptions is most likely to be true, provided that hypotheses predicting different solutions are not discarded by default. Ockham stated this principle in various ways, but the most popular version, "Entities are not to be multiplied without necessity" (originally "Non sunt multiplicanda entia sine necessitate.") was formulated by the Irish Franciscan philosopher John Punch.

*DOI: http://dx.doi.org/10.5772/intechopen.88448*

#### *Colloid Stability Influences on the Biological Organization and Functions DOI: http://dx.doi.org/10.5772/intechopen.88448*

transfection technologies capable to neutralize/invert the charge of hosts to be transferred through membranes, thus favoring uptake. For instance, DNA is neutralized, or adsorbed on oppositely charged vesicles, and transferred into the hosting cells [38–42]. Attraction between cells and transfectants is electrostatic in nature, and its action favors fusion with the cell membrane. It is a phenomenon comparable to the behavior met when viruses enter a cell [43–45]. This mimicry overlaps with other physical effects, due to membrane curvature elasticity [46, 47], its fluid state [48], and so forth [49].

It is known that steric stabilization has a large effect on macrophage uptake in vitro [50]. This effect is tuned by the fixed thickness of aqueous layers, at least in lipid-based chaperones. To ensure long-lasting circulation to immuno-liposomes (and avoid their biodegradation), combination of sterical stabilization with a superior targetability is attained by attaching monoclonal antibodies. These are formed directly on the distal ends of liposome-grafted PEO chains [51, 52]. Similar effects are attained when the more rigid poly-l-lysine is used as sterical stabilizer. In this case, electrostatic effects, due to pH-sensitive charging/discharging of the peptide moieties, are significant. The coupling of antibodies to membranes allow anchorage even in mild basic conditions without the need for antibody derivatization. On the same line, lipo-plexes sterically stabilized with PEO derivatives are used [53]. Relevant are some reports on doxorubicin-loaded liposomes, previously stabilized by adsorption of heparin; these systems show a marked antitumor activity. Heparin is also a coating material stabilizing and protecting liposomes against adverse immune reactions [54], or, in presence of adjuvants, induces drug accumulation at the tumor site [55]. The above list is far from being exhaustive and indicates that steric stabilization, in conjunction with other contributions, is responsible for advanced applications in most fields of bio-medicine and molecular medicine [56–60].

#### **5. Final remarks**

*Colloid Science in Pharmaceutical Nanotechnology*

*maximum value. Above that threshold, w and π energies balance.*

**Figure 3** describes how to get the stabilization of synthetic liposomes against

*Reconstructed liposomes with DNA compacted on the outer surface. The lower left arrow indicates lipid head groups; the upper one random coils represents compacted DNA. Protruding whips indicate PEO chains anchored to the bilayer. Such chains are hydrated, elastic, densely packed, and do not allow other species to* 

*Polymer adsorption for loops sizes << NP diameter. The surface adsorption term, has energy = w. Polymerpolymer interactions at the NP surface, π, are attractive or repulsive. At saturation wrapping has reached its* 

Physics and Chemistry allow to clarify some items of biology, despite substantial problems, due to a terrific increase in complexity inherent to living systems. As a matter of fact, these consist of many parts substantially differing from each other, in reciprocal relation. A first glance to a biological sample allows to observe some organization details. Understanding the hierarchy of active forces, packing modes, and processes taking place in bio-systems is discouraging, unless systematic efforts are stricken out. Therefore, most attempts to relate cell complexity to a number of forces acting therein are not trivial. Such attempts require going from simplicity to complexity, and to focus only on the essential modes of interaction. To focus only on the electrostatic and steric effects is a promising starting hypothesis. The first accounts for forces decaying with distance in a predictable way, irrespective of the medium [33]. The second conveys the impression that the geometry dictated by an arrangement of springs, or semi-rigid protrusions, facing outward the particle surface implies repulsion [34]. This fact is more convincing if we account for the additional role of osmotic forces [35], quite often associated to steric stabilization. Cells always systematically trigger surface charges, acting as a physical barrier against the entry of exogenous material. Passive diffusion is not enough [36], unless it is substantially assisted by other transfer pathways. Imagine having the necessity to insert a nucleic acid in the cell. It is absolutely necessary to make use of chaperons, capable to overcome the protecting action of electric barriers [37]. This action relies on

coalescence and is widely used in transfection technologies.

**4. Biological implications**

*come in contact with liposomes.*

**Figure 3.**

**Figure 2.**

**52**

The "visions" of nature have been different throughout the development of natural sciences. Often physicists, chemists and biologists had a different, sometimes conflicting, way of looking at nature and investigating natural phenomena. One example for all: physical and chemical phenomena (reactions) were considered essentially irreversible in the "classical" history of natural sciences. On the contrary, biological phenomena were considered reversible, and fluidity, change of shape and behavior were dominant. It is not a coincidence that one of the masterpieces of theoretical biology written by J. Monod (1910–1976), one of the most authoritative biologists of last century is entitled "*Chance and necessity*" [61]. As the title suggests, chance seems to rule the biological phenomena: how life arose, the "plasticity" of many biological events. But, necessity is the driving force; a sort of constraint, impeding the same phenomena to escape the stringent laws permitting the completion of a fully functional living organism. Indeed, these strict laws are often represented by physico-chemical (essentially weak) interactions that give a determinant contribution to biological organization and functions. In other words, one could confidently conclude that Occam razor in its popular acceptation, once again, holds true: if there are competing ideas, the simplest one is possibly the correct one. This formulation is not actually the Occam's razor, but rather the law of maximum parsimony. Occam's razor states that in the case of competing hypotheses making the same predictions, the solution with the fewest assumptions is most likely to be true, provided that hypotheses predicting different solutions are not discarded by default. Ockham stated this principle in various ways, but the most popular version, "Entities are not to be multiplied without necessity" (originally "Non sunt multiplicanda entia sine necessitate.") was formulated by the Irish Franciscan philosopher John Punch.

*Colloid Science in Pharmaceutical Nanotechnology*

#### **Author details**

Camillo La Mesa1 \* and Gianfranco Risuleo2

1 Department of Chemistry, Sapienza Università di Roma, Rome, Italy

2 Department of Biology and Biotechnologies, Sapienza Università di Roma, Rome, Italy

\*Address all correspondence to: camillo.lamesa@uniroma1.it

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

**55**

*Colloid Stability Influences on the Biological Organization and Functions*

Molecular mechanisms of tolerance in tardigrades: New perspectives for preservation and stabilization of biological material. Biotechnology Advances. 2009;**27**:348-352

Carpenter JF, Wistrom CA. Stabilization

[11] Crowe JH, Crowe LM,

Journal. 1987;**242**:1-10

of dry phospholipid bilayers and proteins by sugars. The Biochemical

[12] Kostarelos K, Luckham PF, Tadros TF. Steric stabilization of phospholipid vesicles by block copolymers. Vesicle flocculation and osmotic swelling caused by monovalent

and divalent cations. Journal of the Chemical Society, Faraday Transactions. 1998;**94**:2159-2168

[13] Jung M, Hubert DHW, Bomans PHH, Frederik PM, Meuldijk J, van Herk AM, et al. New vesicle-polymer hybrids: The parachute architecture. Langmuir.

[14] Bloomfield VA. DNA condensation by multivalent cations. Biopolymers.

[15] Bloomfield VA. DNA condensation. Current Opinion in Structural Biology.

[16] Parsegian VA, Gingell D. On the electrostatic interaction across a salt solution between two bodies bearing unequal charges. Biophysical Journal.

[17] Fogolari F, Brigo A, Molinari HJ. The

[18] Vauthier C, Bouchemal K. Methods for the preparation and manufacture

Poisson-Boltzmann equation for biomolecular electrostatics: A tool for structural biology. Journal of Molecular

Recognition. 2002;**15**:377-392

of polymeric nanoparticles.

1997;**13**:6877-6880

1997;**44**:269-282

1996;**6**:334-341

1972;**12**:1192-1204

*DOI: http://dx.doi.org/10.5772/intechopen.88448*

[1] Thompson D'AW. On Growth and Form. Cambridge University Press; 1917

Tenaillon O. The evolution of epistasis and its links with genetic robustness, complexity and drift in a phenotypic model of adaptation. Genetics.

[3] Rieger R, Michaelis A, Green MM. A Glossary of Genetics and Cytogenetics: Classical and Molecular. New York: Springer-Verlag; 1968. ISBN

Caldwell KD, Giddings C. Sedimentation field-flow fractionation of colloidal particles in river water. International Journal of Environmental Analytical

[5] Robins MM. Emulsions—Creaming phenomena. Current Opinion in Colloid & Interface Science. 2000;**5**:265-272

[6] Yasrebi M, Shih WY, Aksay IA. Clustering of binary colloidal suspensions: Experiment. Journal of Colloid and Interface Science.

[7] Bell FG. Lime stabilization of clay minerals and soil. Engineering Geology.

[8] Luo Q, Campbell DR, Babu SV. Stabilization of alumina slurry for chemical-mechanical polishing of copper. Langmuir. 1996;**12**:3563-3566

[9] Thompson KL, Armes SP, York DW, Burdis JA. Synthesis of stericallystabilized latexes using well-defined poly(glycerol monomethacrylate) macromonomers. Macromolecules.

[10] Schill RO, Mali B, Dandekar T, Schnölzer M, Reuter D, Frohme M.

[2] Gros PA, Le Nagard H,

2009;**182**:277-293

9780387076683

[4] Karaiskakis G, Graff KA,

Chemistry. 1982;**12**:1-15

1991;**142**:357-368

1996;**42**:223-237

2010;**43**:2169-2177

**References**

*Colloid Stability Influences on the Biological Organization and Functions DOI: http://dx.doi.org/10.5772/intechopen.88448*

#### **References**

*Colloid Science in Pharmaceutical Nanotechnology*

**54**

Italy

**Author details**

Camillo La Mesa1

\* and Gianfranco Risuleo2

\*Address all correspondence to: camillo.lamesa@uniroma1.it

provided the original work is properly cited.

1 Department of Chemistry, Sapienza Università di Roma, Rome, Italy

2 Department of Biology and Biotechnologies, Sapienza Università di Roma, Rome,

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

[1] Thompson D'AW. On Growth and Form. Cambridge University Press; 1917

[2] Gros PA, Le Nagard H, Tenaillon O. The evolution of epistasis and its links with genetic robustness, complexity and drift in a phenotypic model of adaptation. Genetics. 2009;**182**:277-293

[3] Rieger R, Michaelis A, Green MM. A Glossary of Genetics and Cytogenetics: Classical and Molecular. New York: Springer-Verlag; 1968. ISBN 9780387076683

[4] Karaiskakis G, Graff KA, Caldwell KD, Giddings C. Sedimentation field-flow fractionation of colloidal particles in river water. International Journal of Environmental Analytical Chemistry. 1982;**12**:1-15

[5] Robins MM. Emulsions—Creaming phenomena. Current Opinion in Colloid & Interface Science. 2000;**5**:265-272

[6] Yasrebi M, Shih WY, Aksay IA. Clustering of binary colloidal suspensions: Experiment. Journal of Colloid and Interface Science. 1991;**142**:357-368

[7] Bell FG. Lime stabilization of clay minerals and soil. Engineering Geology. 1996;**42**:223-237

[8] Luo Q, Campbell DR, Babu SV. Stabilization of alumina slurry for chemical-mechanical polishing of copper. Langmuir. 1996;**12**:3563-3566

[9] Thompson KL, Armes SP, York DW, Burdis JA. Synthesis of stericallystabilized latexes using well-defined poly(glycerol monomethacrylate) macromonomers. Macromolecules. 2010;**43**:2169-2177

[10] Schill RO, Mali B, Dandekar T, Schnölzer M, Reuter D, Frohme M. Molecular mechanisms of tolerance in tardigrades: New perspectives for preservation and stabilization of biological material. Biotechnology Advances. 2009;**27**:348-352

[11] Crowe JH, Crowe LM, Carpenter JF, Wistrom CA. Stabilization of dry phospholipid bilayers and proteins by sugars. The Biochemical Journal. 1987;**242**:1-10

[12] Kostarelos K, Luckham PF, Tadros TF. Steric stabilization of phospholipid vesicles by block copolymers. Vesicle flocculation and osmotic swelling caused by monovalent and divalent cations. Journal of the Chemical Society, Faraday Transactions. 1998;**94**:2159-2168

[13] Jung M, Hubert DHW, Bomans PHH, Frederik PM, Meuldijk J, van Herk AM, et al. New vesicle-polymer hybrids: The parachute architecture. Langmuir. 1997;**13**:6877-6880

[14] Bloomfield VA. DNA condensation by multivalent cations. Biopolymers. 1997;**44**:269-282

[15] Bloomfield VA. DNA condensation. Current Opinion in Structural Biology. 1996;**6**:334-341

[16] Parsegian VA, Gingell D. On the electrostatic interaction across a salt solution between two bodies bearing unequal charges. Biophysical Journal. 1972;**12**:1192-1204

[17] Fogolari F, Brigo A, Molinari HJ. The Poisson-Boltzmann equation for biomolecular electrostatics: A tool for structural biology. Journal of Molecular Recognition. 2002;**15**:377-392

[18] Vauthier C, Bouchemal K. Methods for the preparation and manufacture of polymeric nanoparticles.

Pharmaceutical Research. 2009;**26**: 1025-1058

[19] Allen TM, Cullis PR. Liposomal drug delivery systems: From concept to clinical applications. Advanced Drug Delivery Reviews. 2013;**65**:36-48

[20] Tardani F, La Mesa C. Attempts to control depletion in the surfactantassisted stabilization of single-walled carbon nanotubes. Colloids and Surfaces A: Physicochemical and Engineering Aspects. 2014;**443**:123-128

[21] De Gennes PG. Polymer solutions near an interface. Adsorption and depletion layers. Macromolecules. 1981;**14**:1637-1643

[22] Mackor EL. A theoretical approach of the colloid-chemical stability of dispersions in hydrocarbons. Journal of Colloid Science. 1951;**6**:492-495

[23] Mackor EL, van der Waals JH. The statistics of the adsorption of rodshaped molecules in connection with the stability of certain colloidal dispersions. Journal of Colloid Science. 1952;**7**:535-550

[24] Napper DH. Flocculation studies of sterically stabilized dispersions. Journal of Colloid and Interface Science. 1970;**32**:106-114

[25] Napper DH, Netsehey A. Studies of the steric stabilization of colloidal particles. Journal of Colloid and Interface Science. 1971;**37**:528-535

[26] Evans R, Napper DH. Steric stabilization. Comparison of theories with experiment. Kolloid-Zeitschrift und Zeitschrift für Polymere. 1973;**251**:409-414

[27] Vold RD, Vold MJ. Colloid and Interface Chemistry. Reading, Mass: Addison-Wesley; 1983. pp. 134-148, and references therein

[28] Adamson AW. Physical Chemistry of Surfaces. Vth ed. New York: Wiley; 1990. pp. 421-449, and references therein

[29] Chithrani BD, Ghazani AA, Chan WCW. Determining the size and shape dependence of gold nanoparticle uptake into mammalian cells. Nano Letters. 2006;**6**:4662-4668

[30] Gref R, Luck M, Quellec P, Marchand M, Dellacherie E, Harnish S, et al. Stealth corona-core nanoparticles surface modified by polyethylene glycol (PEG): Influences of the corona (PEG chain length and surface density) and of the core composition on phagocytic uptake and plasma protein adsorption. Colloids and Surfaces B: Biointerfaces. 2000;**18**:301-313

[31] Malmsten M, Linse P, Cosgrove T. Adsorption of PEO-PPO-PEO block copolymers at silica. Macromolecules. 1992;**25**:2474-2481

[32] Docter D, Westmeier D, Markiewicz M, Stolte S, Knauer SK, Stauber RH. The nanoparticle biomolecule corona: Lessons learned— Challenge accepted? Chemical Society Reviews. 2015;**44**:6094-6121

[33] More correctly, the whole process is controlled by the medium permittivity, *ε*

[34] Liufu S, Xiao H, Li Y. Adsorption of poly(acrylic acid) onto the surface of titanium dioxide and the colloidal stability of aqueous suspensions. Journal of Colloid and Interface Science. 2005;**281**:155-163

[35] Kim S-H, Park J-G, Choi TM, Manoharan VN, Weitz DA. Osmoticpressure-controlled concentration of colloidal particles in thin-shelled capsules. Nature Communications. 2014;**5**:3068

[36] Di L, PerArtursson P, Avdeef A, Ecker GF, Faller B, Fischer H, et al.

**57**

*Colloid Stability Influences on the Biological Organization and Functions*

[43] Du X, Wang J, Zhou Q, Zhang L, Wang S, Zhang Z, et al. Advanced physical techniques for gene delivery based on membrane perforation. Drug

[44] Garcia-Guerra A, Dunwell TL, Trigueros S. Nano-scale gene delivery systems. Current technology, obstacles, and future directions. Current Medicinal

[45] van der Schaar HH, Rust MJ, Chen Chen C, van der Ende-Metselaar H, Wilschut J, Xiaowei ZX, et al. Dissecting the cell entry pathway of dengue virus by single-particle tracking in living cells. PLoS Pathogens. 2008;**4**:e1000244

[46] Temin HM. On the origin of RNA tumor viruses. Annual Review of

curvature elasticity of fluid membranes: A catalogue of vesicle shapes. Journal de

[48] Winterhalter M, Helfrich W. Effect of surface charge on the curvature elasticity of membranes. The Journal of Physical Chemistry. 1988;**92**:6865-6867

[49] Losa DA, Murata N. Membrane fluidity and its roles in the perception of environmental signals. Biochimica et Biophysica Acta—Biomembranes.

[50] Barbetta A, Pucci C, Tardani F, Andreozzi P, La Mesa C. Size and charge modulation of surfactant-based vesicles. The Journal of Physical Chemistry. B.

[51] Zeisig R, Shimada K, Hirota S, Arndt D. Effect of sterical stabilization on macrophage uptake in vitro and on thickness of the fixed aqueous layer of liposomes made from alkylphosphocholines. Biochimica et Biophysica Acta. 1996;**1285**:237-245

2004;**1666**:142-157

2011;**115**:12751-12758

[47] Deuling HJ, Helfrich W. The

Physique. 1976;**37**:1335-1345

Genetics. 1974;**8**:155-177

Chemistry. 2018;**25**:2448-2464

Delivery. 2018;**25**:1516-1525

*DOI: http://dx.doi.org/10.5772/intechopen.88448*

Evidence-based approach to assess passive diffusion and carrier-mediated drug transport. Drug Discovery Today.

[37] Valenzano KJ, Benjamin ER, René P, Bouvier M. Pharmacological chaperones: Potential for the treatment of hereditary diseases caused by mutations in G protein-coupled receptors. In: Gilchrist A, editor. CPCR Molecular Pharmacology and Drug Targeting: Shifting Paradigms and New Directions. Wiley; 2010. pp. 460-500

[38] Barbetta A, La Mesa C, Muzi L, Pucci C, Risuleo G, Tardani F. Chapt. VII: Cat-anionic vesicle-based systems as potential carriers in nanotechnologies. In: Ahmed W, Phoenix DA, editors. Nanobiotechnology. UK: One Central

Press; 2014. pp. 152-179

2019;**11**:745-780

2019;**558**:250-260

2007;**8**:1824-1829

[39] Rai R, Alwani S, Badea I. Polymeric nanoparticles in gene therapy: New avenues of design and optimization for delivery applications. Polymers.

[40] Shende P, Ture N, Gaud RS, Trotta F. Lipid- and polymer-based plexes as therapeutic carriers for bioactive molecules. International

Journal of Pharmaceutics.

[41] Bonincontro A, La Mesa C, Proietti C, Risuleo G. A biophysical investigation on the binding and controlled DNA release in a cetyltrimethylammonium bromidesodium octyl sulfate cat-anionic vesicle system. Biomacromolecules.

[42] Bonincontro A, Falivene M, La Mesa C, Risuleo G, Ruiz

Langmuir. 2008;**24**:1973-1978

Pena M. Dynamics of DNA adsorption on and release from SDS-DDAB catanionic vesicles: A multitechnique study.

2012;**17**:905-912

*Colloid Stability Influences on the Biological Organization and Functions DOI: http://dx.doi.org/10.5772/intechopen.88448*

Evidence-based approach to assess passive diffusion and carrier-mediated drug transport. Drug Discovery Today. 2012;**17**:905-912

*Colloid Science in Pharmaceutical Nanotechnology*

[28] Adamson AW. Physical Chemistry of Surfaces. Vth ed. New York: Wiley; 1990. pp. 421-449, and references

[29] Chithrani BD, Ghazani AA, Chan WCW. Determining the size and shape dependence of gold nanoparticle uptake into mammalian cells. Nano

Letters. 2006;**6**:4662-4668

2000;**18**:301-313

[31] Malmsten M, Linse P,

[32] Docter D, Westmeier D,

Reviews. 2015;**44**:6094-6121

2005;**281**:155-163

Cosgrove T. Adsorption of PEO-PPO-PEO block copolymers at silica. Macromolecules. 1992;**25**:2474-2481

Markiewicz M, Stolte S, Knauer SK, Stauber RH. The nanoparticle

biomolecule corona: Lessons learned— Challenge accepted? Chemical Society

[33] More correctly, the whole process is controlled by the medium permittivity, *ε*

[34] Liufu S, Xiao H, Li Y. Adsorption of poly(acrylic acid) onto the surface of titanium dioxide and the colloidal stability of aqueous suspensions.

Journal of Colloid and Interface Science.

[35] Kim S-H, Park J-G, Choi TM, Manoharan VN, Weitz DA. Osmoticpressure-controlled concentration of colloidal particles in thin-shelled capsules. Nature Communications. 2014;**5**:3068

[36] Di L, PerArtursson P, Avdeef A, Ecker GF, Faller B, Fischer H, et al.

[30] Gref R, Luck M, Quellec P,

Marchand M, Dellacherie E, Harnish S, et al. Stealth corona-core nanoparticles surface modified by polyethylene glycol (PEG): Influences of the corona (PEG chain length and surface density) and of the core composition on phagocytic uptake and plasma protein adsorption. Colloids and Surfaces B: Biointerfaces.

therein

Pharmaceutical Research. 2009;**26**:

[19] Allen TM, Cullis PR. Liposomal drug delivery systems: From concept to clinical applications. Advanced Drug Delivery Reviews. 2013;**65**:36-48

[20] Tardani F, La Mesa C. Attempts to control depletion in the surfactantassisted stabilization of single-walled carbon nanotubes. Colloids and Surfaces A: Physicochemical and Engineering

[21] De Gennes PG. Polymer solutions near an interface. Adsorption and depletion layers. Macromolecules.

[22] Mackor EL. A theoretical approach of the colloid-chemical stability of dispersions in hydrocarbons. Journal of

[23] Mackor EL, van der Waals JH. The statistics of the adsorption of rodshaped molecules in connection with the stability of certain colloidal dispersions. Journal of Colloid Science.

[24] Napper DH. Flocculation studies of sterically stabilized dispersions. Journal of Colloid and Interface Science.

[25] Napper DH, Netsehey A. Studies of the steric stabilization of colloidal particles. Journal of Colloid and Interface Science. 1971;**37**:528-535

[26] Evans R, Napper DH. Steric stabilization. Comparison of theories with experiment. Kolloid-Zeitschrift und Zeitschrift für Polymere.

[27] Vold RD, Vold MJ. Colloid and Interface Chemistry. Reading, Mass: Addison-Wesley; 1983. pp. 134-148, and

Colloid Science. 1951;**6**:492-495

Aspects. 2014;**443**:123-128

1981;**14**:1637-1643

1952;**7**:535-550

1970;**32**:106-114

1973;**251**:409-414

references therein

1025-1058

**56**

[37] Valenzano KJ, Benjamin ER, René P, Bouvier M. Pharmacological chaperones: Potential for the treatment of hereditary diseases caused by mutations in G protein-coupled receptors. In: Gilchrist A, editor. CPCR Molecular Pharmacology and Drug Targeting: Shifting Paradigms and New Directions. Wiley; 2010. pp. 460-500

[38] Barbetta A, La Mesa C, Muzi L, Pucci C, Risuleo G, Tardani F. Chapt. VII: Cat-anionic vesicle-based systems as potential carriers in nanotechnologies. In: Ahmed W, Phoenix DA, editors. Nanobiotechnology. UK: One Central Press; 2014. pp. 152-179

[39] Rai R, Alwani S, Badea I. Polymeric nanoparticles in gene therapy: New avenues of design and optimization for delivery applications. Polymers. 2019;**11**:745-780

[40] Shende P, Ture N, Gaud RS, Trotta F. Lipid- and polymer-based plexes as therapeutic carriers for bioactive molecules. International Journal of Pharmaceutics. 2019;**558**:250-260

[41] Bonincontro A, La Mesa C, Proietti C, Risuleo G. A biophysical investigation on the binding and controlled DNA release in a cetyltrimethylammonium bromidesodium octyl sulfate cat-anionic vesicle system. Biomacromolecules. 2007;**8**:1824-1829

[42] Bonincontro A, Falivene M, La Mesa C, Risuleo G, Ruiz Pena M. Dynamics of DNA adsorption on and release from SDS-DDAB catanionic vesicles: A multitechnique study. Langmuir. 2008;**24**:1973-1978

[43] Du X, Wang J, Zhou Q, Zhang L, Wang S, Zhang Z, et al. Advanced physical techniques for gene delivery based on membrane perforation. Drug Delivery. 2018;**25**:1516-1525

[44] Garcia-Guerra A, Dunwell TL, Trigueros S. Nano-scale gene delivery systems. Current technology, obstacles, and future directions. Current Medicinal Chemistry. 2018;**25**:2448-2464

[45] van der Schaar HH, Rust MJ, Chen Chen C, van der Ende-Metselaar H, Wilschut J, Xiaowei ZX, et al. Dissecting the cell entry pathway of dengue virus by single-particle tracking in living cells. PLoS Pathogens. 2008;**4**:e1000244

[46] Temin HM. On the origin of RNA tumor viruses. Annual Review of Genetics. 1974;**8**:155-177

[47] Deuling HJ, Helfrich W. The curvature elasticity of fluid membranes: A catalogue of vesicle shapes. Journal de Physique. 1976;**37**:1335-1345

[48] Winterhalter M, Helfrich W. Effect of surface charge on the curvature elasticity of membranes. The Journal of Physical Chemistry. 1988;**92**:6865-6867

[49] Losa DA, Murata N. Membrane fluidity and its roles in the perception of environmental signals. Biochimica et Biophysica Acta—Biomembranes. 2004;**1666**:142-157

[50] Barbetta A, Pucci C, Tardani F, Andreozzi P, La Mesa C. Size and charge modulation of surfactant-based vesicles. The Journal of Physical Chemistry. B. 2011;**115**:12751-12758

[51] Zeisig R, Shimada K, Hirota S, Arndt D. Effect of sterical stabilization on macrophage uptake in vitro and on thickness of the fixed aqueous layer of liposomes made from alkylphosphocholines. Biochimica et Biophysica Acta. 1996;**1285**:237-245

[52] Bendas G, Krause A, Bakowsky U, Vogel J, Rothe U. Targetability of novel immunoliposomes prepared by a new antibody conjugation technique. International Journal of Pharmaceutics. 1999;**181**:79-93

[53] Sanders NN, De Smedt SC, Cheng SH, Demeester J. Pegylated GL67 lipoplexes retain their gene transfection activity after exposure to components of CF mucus. Gene Therapy. 2002;**9**:363-371

[54] Duehrkop C, Leneweit G, Heyder C, Fromell K, Edwards K, Ekdahl KN, et al. Development and characterization of an innovative heparin coating to stabilize and protect liposomes against adverse immune reactions. Colloids and Surfaces B: Biointerfaces. 2016;**141**:576-583

[55] Park J, Hwang SR, Choi JU, Alam F, Byun Y. Self-assembled nanocomplex of PEGylated protamine and heparinsuramin conjugate for accumulation at the tumor site. International Journal of Pharmaceutics. 2018;**535**:38-46

[56] Merino M, Zalba S, Garrido MJ. Immunoliposomes in clinical oncology: State of the art and future perspectives. Journal of Controlled Release. 2018;**275**:162-176

[57] Rasenack N, Müller BW. Micronsize drug particles: Common and novel micronization techniques. Pharmaceutical Development and Technology. 2004;**9**:1-13

[58] Salem HF, Eid K, Sharaf MA. Formulation and evaluation of silver nanoparticles as antibacterial and antifungal agents with a minimal cytotoxic effect. International Journal of Drug Delivery. 2011;**3**:293-304

[59] Bakowsky H, Richter T, Kneuer C, Hoekstra D, Rothe U, Bendase G, et al. Adhesion characteristics and stability assessment of lectin-modified

liposomes for site-specific drug delivery. Biochimica et Biophysica Acta. 2008;**1778**:242-249

Chapter 5

Abstract

surfactant

59

1. Introduction

Self-Microemulsifying System

Oral route is preferred for drug administration; however according to the recent scenario 40% of new drug candidates have poor water solubility and low bioavailability. One of the biggest challenges in drug delivery science is to improve low oral bioavailability problem which is associated with the hydrophobic drugs due to their unprecedented potential as a drug deliver with the broad range of application. Self-emulsifying systems have been proved as highly useful technological innovations to vanquish such bioavailability problem by virtue of their diminutive globule size, higher solubilization tendency for hydrophobic drugs, robust formulation advantages, and easy to scale up. Self-microemulsifying systems are isotropic mixers of oil, surfactant, drug and co-emulsifier or solubilizer, which spontaneously form transparent micro-emulsions with oil droplets ranging between 100 and 250 nm. Micro emulsified drug can be easily absorbed through the lymphatic pathway and it bypasses the hepatic first-pass effect. Self-microemulsifying system is a thermodynamically stable system and overcomes the drawback of layering of emulsions after sitting for a long period of time. The present literature gives exhaustive information on the formulation design and characterization of

Keywords: self-micro emulsifying systems, bioavailability, lipid base formulation,

An advance in in-vitro screening methods such as conjunctional chemistry is leading to publicizing of many potential chemical components with high therapeutic activity. Such rapid identification of highly potent pharmaceutical lead com-

biopharmaceutical characteristics [1]. Most of the drugs are lipophilic in nature and has poor water solubility. Such low water solubility becomes the major challenge in successful development of their oral formulation. Also several drug compounds has low oral bioavailability which further enhances the challenge for the formulator scientist [2, 3]. More than 40% of drugs are lipophilic in nature with poor water solubility. To resolve such challenges, many approaches have been reported to improve the solubility and enhance the oral bioavailability which includes the formation of cyclodextrin complex, lipid based drug delivery system, solid dispersions, micronization, etc. [4, 5]. Among these methods, self-emulsifying systems is one of the most optimistic approaches to enhance the oral bioavailability of poorly water-soluble drugs since it maintains the drug in a solubilized state in the gastrointestinal tract [6]. A stable self-micro emulsifying system consists of mixture of drug, oil, surfactant and co-surfactant. Upon dilution with water it results into fine

pounds has optimized pharmacodynamic properties but sub-optimal

Mansi Shah and Anuj G. Agrawal

self-microemulsifying systems.

[60] Xu X, Ho W, Zhang X, Bertrand N, Farokhzad O. Cancer nanomedicine: From targeted delivery to combination therapy. Trends in Molecular Medicine. 2015;**21**:223-232

[61] Monod J. Chance and Necessity: An Essay on the Natural Philosophy of Modern Biology. New York: Alfred A. Knopf; 1971. ISBN: 0-394-46615-2

## Chapter 5 Self-Microemulsifying System

Mansi Shah and Anuj G. Agrawal

#### Abstract

*Colloid Science in Pharmaceutical Nanotechnology*

liposomes for site-specific drug

2008;**1778**:242-249

2015;**21**:223-232

0-394-46615-2

delivery. Biochimica et Biophysica Acta.

[60] Xu X, Ho W, Zhang X, Bertrand N, Farokhzad O. Cancer nanomedicine: From targeted delivery to combination therapy. Trends in Molecular Medicine.

[61] Monod J. Chance and Necessity: An Essay on the Natural Philosophy of Modern Biology. New York: Alfred A. Knopf; 1971. ISBN:

[52] Bendas G, Krause A, Bakowsky U, Vogel J, Rothe U. Targetability of novel immunoliposomes prepared by a new antibody conjugation technique. International Journal of Pharmaceutics.

[53] Sanders NN, De Smedt SC,

of CF mucus. Gene Therapy.

of an innovative heparin coating to stabilize and protect liposomes against adverse immune reactions. Colloids and Surfaces B: Biointerfaces.

Pharmaceutics. 2018;**535**:38-46

Journal of Controlled Release.

Technology. 2004;**9**:1-13

2018;**275**:162-176

[56] Merino M, Zalba S, Garrido MJ. Immunoliposomes in clinical oncology: State of the art and future perspectives.

[57] Rasenack N, Müller BW. Micronsize drug particles: Common and novel micronization techniques. Pharmaceutical Development and

[58] Salem HF, Eid K, Sharaf MA. Formulation and evaluation of silver nanoparticles as antibacterial and antifungal agents with a minimal cytotoxic effect. International Journal of

Drug Delivery. 2011;**3**:293-304

[59] Bakowsky H, Richter T, Kneuer C, Hoekstra D, Rothe U, Bendase G, et al. Adhesion characteristics and stability assessment of lectin-modified

Cheng SH, Demeester J. Pegylated GL67 lipoplexes retain their gene transfection activity after exposure to components

[54] Duehrkop C, Leneweit G, Heyder C, Fromell K, Edwards K, Ekdahl KN, et al. Development and characterization

[55] Park J, Hwang SR, Choi JU, Alam F, Byun Y. Self-assembled nanocomplex of PEGylated protamine and heparinsuramin conjugate for accumulation at the tumor site. International Journal of

1999;**181**:79-93

2002;**9**:363-371

2016;**141**:576-583

**58**

Oral route is preferred for drug administration; however according to the recent scenario 40% of new drug candidates have poor water solubility and low bioavailability. One of the biggest challenges in drug delivery science is to improve low oral bioavailability problem which is associated with the hydrophobic drugs due to their unprecedented potential as a drug deliver with the broad range of application. Self-emulsifying systems have been proved as highly useful technological innovations to vanquish such bioavailability problem by virtue of their diminutive globule size, higher solubilization tendency for hydrophobic drugs, robust formulation advantages, and easy to scale up. Self-microemulsifying systems are isotropic mixers of oil, surfactant, drug and co-emulsifier or solubilizer, which spontaneously form transparent micro-emulsions with oil droplets ranging between 100 and 250 nm. Micro emulsified drug can be easily absorbed through the lymphatic pathway and it bypasses the hepatic first-pass effect. Self-microemulsifying system is a thermodynamically stable system and overcomes the drawback of layering of emulsions after sitting for a long period of time. The present literature gives exhaustive information on the formulation design and characterization of self-microemulsifying systems.

Keywords: self-micro emulsifying systems, bioavailability, lipid base formulation, surfactant

#### 1. Introduction

An advance in in-vitro screening methods such as conjunctional chemistry is leading to publicizing of many potential chemical components with high therapeutic activity. Such rapid identification of highly potent pharmaceutical lead compounds has optimized pharmacodynamic properties but sub-optimal biopharmaceutical characteristics [1]. Most of the drugs are lipophilic in nature and has poor water solubility. Such low water solubility becomes the major challenge in successful development of their oral formulation. Also several drug compounds has low oral bioavailability which further enhances the challenge for the formulator scientist [2, 3]. More than 40% of drugs are lipophilic in nature with poor water solubility. To resolve such challenges, many approaches have been reported to improve the solubility and enhance the oral bioavailability which includes the formation of cyclodextrin complex, lipid based drug delivery system, solid dispersions, micronization, etc. [4, 5]. Among these methods, self-emulsifying systems is one of the most optimistic approaches to enhance the oral bioavailability of poorly water-soluble drugs since it maintains the drug in a solubilized state in the gastrointestinal tract [6]. A stable self-micro emulsifying system consists of mixture of drug, oil, surfactant and co-surfactant. Upon dilution with water it results into fine

oil-in-water emulsion with a droplets diameter less than 50 nm [7, 8]. The microemulsion droplet of self-micro emulsifying systems entraps the drug molecule completely with 100% efficacy, thus self-micro emulsifying systems shows high potential to deliver low water soluble drug [9]. Rapid emulsion formation helps to keep the drug in a dissolved form and small droplet size offers a considerably larger interfacial surface area which further accelerates the absorption rate of drug with limited solubility. Moreover, the droplets can be rapidly dispersed in blood as well as lymph and the lymphatic drug transport can avoid the first-pass effect [10]. This feature makes self-micro emulsifying systems a significant choice for oral delivery of lipophilic, low bioavailable drugs having ample of lipid solubility [11–14]. Selfemulsifying systems is a broad term which produces emulsions with a droplet size ranging from a few nanometers to several microns. A self-micro emulsifying system indicates the formulations forming transparent micro-emulsions with oil droplets ranging between 100 and 250 nm. Term self-nano emulsifying system is used to characterize the system which results into emulsion with globule size less than 100 nm [15, 16].

coarse dispersion and is not readily dispersible. Initial digestibility by pancreatic lipase/co-lipase to engender more amphiphilic species is a pivotal necessity for their oral absorption. For potent drugs or drugs with high oil solubility, Type I formula-

water it developed emulsion which is opaque in nature.

co-solvents. Oil is absent in this type of formulation.

BCS class Hurdles overcome by SES

Class II Solubility and bioavailability.

SES as a solution to various problems to different classes of drugs.

Class I Gut wall efflux, Enzymatic degradation.

Class III Enzymatic degradation, bioavailability and gut wall efflux. Class IV Solubility, bioavailability, Enzymatic degradation, gut wall efflux.

Type II: These formulation contain drug with oil and water insoluble surfactants (Hydrophilic lipophilic balance <12), and are also called as self-emulsifying systems. Self-emulsification is mainly acquired at the surfactant concentration above 25% w/w. Surfactant greater than 60% w/w that is at higher Concentration, there is formation of liquid crystalline gel phases at the o/w interface because emulsification is impeded. Such systems generate droplets size above 300 nm, when dispersed in

Type III: Type III formulations consist of drug, oil, surfactants, and co-solvents for both water-soluble and water insoluble. Ethanol, polyethylene glycol and propylene glycols are selected as co-solvents. Such systems generate droplets size below 300 nm, when dispersed in water and are called as self-micro emulsifying systems. The obtained emulsion is either optically clear or somewhat opalescent dispersion. Type IV: Type IV formulations consist of drug, water soluble surfactants, and

Drugs that belong to the Class II and Class IV of biopharmaceutical classification system offer potential platform to enhance the oral bioavailability. Log P of the drug indicates the potential utility of lipid based formulation. Maintenance of drug solubility in gastrointestinal tract is the foremost challenges to oral formulation and especially the increased drug solubility at the absorption site of the gut [19]. Lipophilic drug composite that manifest dissolution rate limited absorption, selfemulsifying systems can provide an improvement in absorption in terms of rate and extent, that results in consistent blood time profiles [7, 20]. Problem of poor solubility and low bioavailability of drug across all categories of biopharmaceutical classification system can be resolved by formulating into self-emulsifying system,

For an oral absorption Lipinski's rule of five has been widely proposed as a qualitative predictive model. In the discovery setting, the 'rule of five' predicts that if there are more than five H– bond donors, it shows poor absorption or poor

Whether solubility and log P are sufficient to identify probable drug candidates for such formulations that question arises and also it is noted that biopharmaceutical classification system and Lipinski's rule of five classification system are useful, particularly at inceptive screening stage, they have some constraint. For recognize the suitable lipid based formulation approach aqueous solubility and log P alone are improbable enough because they do not adequately predict potential in- vivo

2.2 Suitable drug candidate identification for self-emulsifying systems

tions are preferable.

Self-Microemulsifying System

DOI: http://dx.doi.org/10.5772/intechopen.88603

as shown in Table 2 [21].

permeation [22].

effects.

Table 2.

61

#### 2. Self-micro emulsifying systems

#### 2.1 Classification of lipidic formulations

Lipidic formulations are classified as Type I, II, III, and IV based upon excipients used. Type I formulations are non-self-emulsifying whereas Type II, III, and IV formulations are self-emulsifying. Type of emulsion formed after dilution of selfemulsifying system with water, depends upon the excipients used in formulation. Digestibility of lipidic compositions is also affected by these ingredients. Elements of lipidic systems are represented in the proceeding portion [17, 18]. Classification system of lipid formulation is shown in Table 1.

Type I: Drug with tri-, di- or monoglyceride in lipid based compositions is called as type I formulations. Dilution of type I formulations with aqueous media creates


#### Table 1.

The Lipid Formulation Classification System: characteristic features, pros and cons of the four essential types of 'lipid' formulations.

#### Self-Microemulsifying System DOI: http://dx.doi.org/10.5772/intechopen.88603

oil-in-water emulsion with a droplets diameter less than 50 nm [7, 8]. The microemulsion droplet of self-micro emulsifying systems entraps the drug molecule completely with 100% efficacy, thus self-micro emulsifying systems shows high potential to deliver low water soluble drug [9]. Rapid emulsion formation helps to keep the drug in a dissolved form and small droplet size offers a considerably larger interfacial surface area which further accelerates the absorption rate of drug with limited solubility. Moreover, the droplets can be rapidly dispersed in blood as well as lymph and the lymphatic drug transport can avoid the first-pass effect [10]. This feature makes self-micro emulsifying systems a significant choice for oral delivery of lipophilic, low bioavailable drugs having ample of lipid solubility [11–14]. Selfemulsifying systems is a broad term which produces emulsions with a droplet size ranging from a few nanometers to several microns. A self-micro emulsifying system indicates the formulations forming transparent micro-emulsions with oil droplets ranging between 100 and 250 nm. Term self-nano emulsifying system is used to characterize the system which results into emulsion with globule size less than

Lipidic formulations are classified as Type I, II, III, and IV based upon excipients used. Type I formulations are non-self-emulsifying whereas Type II, III, and IV formulations are self-emulsifying. Type of emulsion formed after dilution of selfemulsifying system with water, depends upon the excipients used in formulation. Digestibility of lipidic compositions is also affected by these ingredients. Elements of lipidic systems are represented in the proceeding portion [17, 18]. Classification

Type I: Drug with tri-, di- or monoglyceride in lipid based compositions is called as type I formulations. Dilution of type I formulations with aqueous media creates

> Simple, Compatibility is excellent for capsule.

Unlikely to lose solvent capacity on dispersion

clear or almost clear dispersion; drug absorption without digestion

Formulation has good solvent capacity for many

drugs

Formulation has poor solvent capacity unless drug is highly lipophilic.

Turbid o/w dispersion (particlesize0.25–

Possible loss of solvent capacity on dispersion; less easily digested

Likely loss of solvent capacity On dispersion; might not be digestible

2 mm)

Formulation Excipients Properties Pros Cons

Not dispersing, it needs digestion.

SES formed without watersoluble components

SES/SMES formed with water-soluble components

Formulation disperses typically to forma micellar solution

The Lipid Formulation Classification System: characteristic features, pros and cons of the four essential types of

100 nm [15, 16].

2. Self-micro emulsifying systems

2.1 Classification of lipidic formulations

Colloid Science in Pharmaceutical Nanotechnology

system of lipid formulation is shown in Table 1.

surfactants (e.g. tri-,diand mono glycerides)

Type I Oils lacking of

Type II Oils and water-insoluble surfactants.

Type III Oils, surfactants and co

Type IV Water-soluble

Table 1.

60

'lipid' formulations.

solvents (both water insoluble and watersoluble excipients)

surfactants and Co solvents(no oils)

coarse dispersion and is not readily dispersible. Initial digestibility by pancreatic lipase/co-lipase to engender more amphiphilic species is a pivotal necessity for their oral absorption. For potent drugs or drugs with high oil solubility, Type I formulations are preferable.

Type II: These formulation contain drug with oil and water insoluble surfactants (Hydrophilic lipophilic balance <12), and are also called as self-emulsifying systems. Self-emulsification is mainly acquired at the surfactant concentration above 25% w/w. Surfactant greater than 60% w/w that is at higher Concentration, there is formation of liquid crystalline gel phases at the o/w interface because emulsification is impeded. Such systems generate droplets size above 300 nm, when dispersed in water it developed emulsion which is opaque in nature.

Type III: Type III formulations consist of drug, oil, surfactants, and co-solvents for both water-soluble and water insoluble. Ethanol, polyethylene glycol and propylene glycols are selected as co-solvents. Such systems generate droplets size below 300 nm, when dispersed in water and are called as self-micro emulsifying systems. The obtained emulsion is either optically clear or somewhat opalescent dispersion.

Type IV: Type IV formulations consist of drug, water soluble surfactants, and co-solvents. Oil is absent in this type of formulation.

#### 2.2 Suitable drug candidate identification for self-emulsifying systems

Drugs that belong to the Class II and Class IV of biopharmaceutical classification system offer potential platform to enhance the oral bioavailability. Log P of the drug indicates the potential utility of lipid based formulation. Maintenance of drug solubility in gastrointestinal tract is the foremost challenges to oral formulation and especially the increased drug solubility at the absorption site of the gut [19]. Lipophilic drug composite that manifest dissolution rate limited absorption, selfemulsifying systems can provide an improvement in absorption in terms of rate and extent, that results in consistent blood time profiles [7, 20]. Problem of poor solubility and low bioavailability of drug across all categories of biopharmaceutical classification system can be resolved by formulating into self-emulsifying system, as shown in Table 2 [21].

For an oral absorption Lipinski's rule of five has been widely proposed as a qualitative predictive model. In the discovery setting, the 'rule of five' predicts that if there are more than five H– bond donors, it shows poor absorption or poor permeation [22].

Whether solubility and log P are sufficient to identify probable drug candidates for such formulations that question arises and also it is noted that biopharmaceutical classification system and Lipinski's rule of five classification system are useful, particularly at inceptive screening stage, they have some constraint. For recognize the suitable lipid based formulation approach aqueous solubility and log P alone are improbable enough because they do not adequately predict potential in- vivo effects.


Table 2.

SES as a solution to various problems to different classes of drugs.

#### 2.3 Choice of self-microemulsifying excipients for formulations

Self-emulsifying formulation produces dispersion in gastrointestinal tract by using different excipients. Isotropic mixtures of oils, surfactants, solvents, and cosolvents/surfactants comprise self-emulsifying formulation and it emulsifies in gastrointestinal tract under a gentle agitation [23].

2.3.3 Surfactants

Self-Microemulsifying System

DOI: http://dx.doi.org/10.5772/intechopen.88603

2.3.4 Co-surfactants/co-solvents

narrated by

Table 3.

63

The self-emulsifying system demand incorporation of comparatively large amounts of surfactant in addition to the oil, to convey drug in the formulation. Permeability of the intestinal membrane and affinity between lipids and intestinal membrane will be improved due to effect of surfactant. Surfactants improve the permeability by partitioning into the cell membrane and disrupting the structural organization of the lipid bilayer dominates to permeation enhancement [30]. The two major affairs that command the selection of a surfactant enclose first safety and second hydrophilic lipophilic balance. To formulate self-emulsifying systems, Hydrophilic lipophilic balance of surfactant provides important information. High emulsifying performance is achieved if the emulsifier used in formulation of selfemulsifying systems has high hydrophilicity and hydrophilic lipophilic balance. Therefore, for effective absorption at the site, drug is present in solubilized form for a longer period of time and prevents precipitation of drug substance in gastrointestinal tract lumen [31]. Generally single alkyl chains are more penetrative, so surfactants such as polysorbates and triglyceride ethoxylates are found to be less toxic. Usually the surfactant concentration ranges between 30 and 60% of the total for-

mulation in order to form stable self-micro emulsifying systems [32].

and results into precipitation of drug (Table 3) [34, 35].

2.4 Mechanism of self-emulsifying systems

Stress of interface is decrease in the presence of co-surfactant and it allows the interfacial film sufficient flexibility to take up different curvatures required to form self-micro emulsifying systems over a wide range of composition [33]. The mixture with higher surfactant and co-surfactant: oil ratio assists the formation of self-micro emulsifying systems. Disadvantage of alcohol and other volatile cosolvents is that they get evaporated through the shell of soft or hard gelatin capsules

The mechanism by which self-emulsification occurs is not yet well understood. The entropy change of dispersion is greater than the energy required to increase the surface area of the dispersion at that time self-emulsification is occurring. In a conventional emulsion formulation, a free energy is an energy that required developing a new surface between the two phases i.e. oil and water and it can be

co-solvent

Ethanol

Oils Surfactants Co-surfactants/

Sunflower oil Polyethylene glycol

Peanut oil Lauroglycol Sesame oil Isopropyl alcohol

Cotton seed oil Polysorbate 20 (Tween 20) Span 20 Soybean oil Polysorbate 80 (Tween 80) Span 80 Corn oil Polyoxy 35 castor oil (Cremophor RH40) Capryol 90

Castor oil D-alpha Tocopheryl polyethylene glycol 1000 succinate

(TPGS)

Example of Oil, Surfactant and Co-surfactant/Co-solvent.

Depending upon the type of dispersion produced after dilution with water phase, self-emulsifying formulations are further classified as self-emulsifying systems, self-micro emulsifying systems and self-nano emulsifying systems. Emulsion which is slightly hazy, opalescent or opaque colloidal coarse dispersion is called as self-emulsifying systems. Micro-emulsion which is clear or pellucid, slightly hazy, opalescent, non-opaque colloidal dispersion with droplet size below 150 nm are called as self-micro emulsifying systems. Nano-emulsion which clear or pellucid, slightly hazy, opalescent, non-opaque or substantially non-opaque colloidal dispersion with droplet size below 20 nm in diameter called as self-nano emulsifying systems [24]. For the formulation, excipient should be chosen from the list of generally regarded as safe "GRAS" excipients published by USFDA or from other inactive ingredients approved and published by regulatory agencies.

#### 2.3.1 Active pharmaceutical ingredient

Active Pharmaceutical Ingredient should be soluble in oil phase as this have an impact on the self-micro emulsifying systems to maintain the active pharmaceutical ingredient solubility. Drugs with the low solubility in aqueous media or lipids are strenuous to convey through self-micro emulsifying systems. Exceedingly good solubility in one of the components of self-micro emulsifying systems is require preferably oil phase, if very high dose of drug liked to be administered. For selfmicro emulsifying systems, high melting point of drug with log P value around 2 is not appropriate and for self-micro emulsifying systems, lipophilic drugs with the log P values more than 5 are good candidate [19, 25].

#### 2.3.2 Lipids/oils

In self-emulsifying formulations, oil represents the most important constituent as it solubilizes prominent amounts of the lipophilic drug. Oil promotes selfemulsification and extends the fragment of lipophilic drug transported through the intestinal lymphatic system. Absorption of lipophilic drug from the gastrointestinal tract is enhanced depending upon the molecular nature of the triglyceride used in formulation [26, 27]. Regardless of the noteworthy potential that these lipid excipients have, very few of lipid based formulations has reached to the pharmaceutical market. This may be due to the insufficient data concerning the relatively composite physical chemistry of lipids and scrutinize about formulated drug chemical and physical stability. Incorporation to these studies, its impact on drug absorption is also essential and which depends on interaction of a lipid-based formulation with the gastrointestinal tract environment [28]. Natural edible oils, comprising medium-chain triglycerides, are not commonly preferred in this regard owing to their poor ability to dissolve large amounts of lipophilic drugs [29]. For designing of self-emulsifying systems, varying degrees of saturated and hydrolyzed long and medium chain triglycerides are used. These semi synthetic derivatives form good emulsification systems when used with a large number of solubility enhancing surfactants approved for oral administration. There is polarity deference between the long chain triglyceride and medium-chain triglyceride, a wide micro-emulsion area has been achieved in phase diagram if medium chain triglyceride is used. More is hydrophobic long chain triglyceride, more difficult it becomes to emulsify.

#### 2.3.3 Surfactants

2.3 Choice of self-microemulsifying excipients for formulations

inactive ingredients approved and published by regulatory agencies.

trointestinal tract under a gentle agitation [23].

Colloid Science in Pharmaceutical Nanotechnology

2.3.1 Active pharmaceutical ingredient

2.3.2 Lipids/oils

62

log P values more than 5 are good candidate [19, 25].

Self-emulsifying formulation produces dispersion in gastrointestinal tract by using different excipients. Isotropic mixtures of oils, surfactants, solvents, and cosolvents/surfactants comprise self-emulsifying formulation and it emulsifies in gas-

Depending upon the type of dispersion produced after dilution with water phase, self-emulsifying formulations are further classified as self-emulsifying systems, self-micro emulsifying systems and self-nano emulsifying systems. Emulsion which is slightly hazy, opalescent or opaque colloidal coarse dispersion is called as self-emulsifying systems. Micro-emulsion which is clear or pellucid, slightly hazy, opalescent, non-opaque colloidal dispersion with droplet size below 150 nm are called as self-micro emulsifying systems. Nano-emulsion which clear or pellucid, slightly hazy, opalescent, non-opaque or substantially non-opaque colloidal dispersion with droplet size below 20 nm in diameter called as self-nano emulsifying systems [24]. For the formulation, excipient should be chosen from the list of generally regarded as safe "GRAS" excipients published by USFDA or from other

Active Pharmaceutical Ingredient should be soluble in oil phase as this have an impact on the self-micro emulsifying systems to maintain the active pharmaceutical ingredient solubility. Drugs with the low solubility in aqueous media or lipids are strenuous to convey through self-micro emulsifying systems. Exceedingly good solubility in one of the components of self-micro emulsifying systems is require preferably oil phase, if very high dose of drug liked to be administered. For selfmicro emulsifying systems, high melting point of drug with log P value around 2 is not appropriate and for self-micro emulsifying systems, lipophilic drugs with the

In self-emulsifying formulations, oil represents the most important constituent

as it solubilizes prominent amounts of the lipophilic drug. Oil promotes selfemulsification and extends the fragment of lipophilic drug transported through the intestinal lymphatic system. Absorption of lipophilic drug from the gastrointestinal tract is enhanced depending upon the molecular nature of the triglyceride used in formulation [26, 27]. Regardless of the noteworthy potential that these lipid excipients have, very few of lipid based formulations has reached to the pharmaceutical market. This may be due to the insufficient data concerning the relatively composite physical chemistry of lipids and scrutinize about formulated drug chemical and physical stability. Incorporation to these studies, its impact on drug absorption is also essential and which depends on interaction of a lipid-based formulation with the gastrointestinal tract environment [28]. Natural edible oils, comprising medium-chain triglycerides, are not commonly preferred in this regard owing to their poor ability to dissolve large amounts of lipophilic drugs [29]. For designing of self-emulsifying systems, varying degrees of saturated and hydrolyzed long and medium chain triglycerides are used. These semi synthetic derivatives form good emulsification systems when used with a large number of solubility enhancing surfactants approved for oral administration. There is polarity deference between the long chain triglyceride and medium-chain triglyceride, a wide micro-emulsion area has been achieved in phase diagram if medium chain triglyceride is used. More is hydrophobic long chain triglyceride, more difficult it becomes to emulsify.

The self-emulsifying system demand incorporation of comparatively large amounts of surfactant in addition to the oil, to convey drug in the formulation. Permeability of the intestinal membrane and affinity between lipids and intestinal membrane will be improved due to effect of surfactant. Surfactants improve the permeability by partitioning into the cell membrane and disrupting the structural organization of the lipid bilayer dominates to permeation enhancement [30]. The two major affairs that command the selection of a surfactant enclose first safety and second hydrophilic lipophilic balance. To formulate self-emulsifying systems, Hydrophilic lipophilic balance of surfactant provides important information. High emulsifying performance is achieved if the emulsifier used in formulation of selfemulsifying systems has high hydrophilicity and hydrophilic lipophilic balance. Therefore, for effective absorption at the site, drug is present in solubilized form for a longer period of time and prevents precipitation of drug substance in gastrointestinal tract lumen [31]. Generally single alkyl chains are more penetrative, so surfactants such as polysorbates and triglyceride ethoxylates are found to be less toxic. Usually the surfactant concentration ranges between 30 and 60% of the total formulation in order to form stable self-micro emulsifying systems [32].

#### 2.3.4 Co-surfactants/co-solvents

Stress of interface is decrease in the presence of co-surfactant and it allows the interfacial film sufficient flexibility to take up different curvatures required to form self-micro emulsifying systems over a wide range of composition [33]. The mixture with higher surfactant and co-surfactant: oil ratio assists the formation of self-micro emulsifying systems. Disadvantage of alcohol and other volatile cosolvents is that they get evaporated through the shell of soft or hard gelatin capsules and results into precipitation of drug (Table 3) [34, 35].

#### 2.4 Mechanism of self-emulsifying systems

The mechanism by which self-emulsification occurs is not yet well understood. The entropy change of dispersion is greater than the energy required to increase the surface area of the dispersion at that time self-emulsification is occurring. In a conventional emulsion formulation, a free energy is an energy that required developing a new surface between the two phases i.e. oil and water and it can be narrated by


Table 3. Example of Oil, Surfactant and Co-surfactant/Co-solvent.

$$
\Delta \mathbf{G} = \Sigma \mathbf{N} \pi \mathbf{2} \sigma \tag{1}
$$

method is generally used to performed these type of studies. In these studies excess amount of drug is added to the excipient and then flask is shaken for 48 hours in water bath shaker at room temperature. After 48 hours samples are subjected to centrifugation, then filtered through 0.45 μm filters and drug content is examined [40, 41]. The objective of these solubility studies is to choose oil, surfactant, and co-surfactant that show maximum solubility to the drug. Another objective is accomplishment of optimal drug loading with minimized entire volume of the

To check the emulsification ability, screening of surfactant and co-surfactant is done by mixing known amount of surfactants with equal portion of selected oil and surfactant, and homogenized. The idea about ease of emulsification is obtained when the mixture is added to double distilled water and the number of flask inversions required to form homogenous emulsion is noted [43]. Then, the obtained dilution is tested for turbidity, percentage transmittance and clarity. The surfactant that shows high percentage transmittance at lower flask inversions with high emulsification efficiency is generally selected. Similarly, co-surfactants representing higher emulsification efficiency are selected for self-emulsifying formulation [44].

Micro-emulsion is formed by the spontaneous emulsification method and can be depicted with the help of phase diagrams. Construction of phase diagram is a useful approach to study the complex series of interactions that can occur when different components are mixed ternary phase diagram is used to study the phase behavior of three components. Ternary phase diagram represents the system with three components oil, water, and surfactant. But in case of self-micro emulsifying systems, the additional component like co-surfactant/co-solvent addition is most common. Ternary diagram contains three corners that correspond to the 100% of the particular component. In case of addition of fourth component, the ternary diagram can be termed as pseudoternary phase diagram [45]. For building of pseudoternary phase diagram, components of micro-emulsion are examined for emulsification efficiency at various compositions. Emulsions, micro-emulsions, micelles, inverted micelle structures may be form and the degree of formation of these structures can be determined with the formation of ternary phase diagram [46, 47]. The fixed ratio is typically formed by the fusion of surfactant and cosurfactant and it may be the mixture of oil and surfactant. This is mixed with the specific volume of the third phase like oil or co-surfactant; then the other component i.e. water is added in a gradual amounts and with every addition the solution is tested for the clarity, dispersibility, time for self-emulsification, and flowability.

The total concentration of all components in each mixture is 100%. In

indicates the good emulsification efficiency [48, 49].

at point O can be known by the following procedure [50].

65

pseudoternary phase diagram, the samples which formed clear solution is denoted by suitable symbols in the phase diagram. The area that is formed when these points are joined indicates the mono-physic micro-emulsion existing area and wide area

an easy way. The three corners of the typical ternary diagram represent three components, that is, A, B, and C. The arrow towards BA indicates increase in proportion of A from 0% concentration (at point B) to 100% concentration (at point A), the arrow towards AC indicates the increase in proportion of C from 0% concentration (at point A) to 100% concentration (at point C), and similarly the arrow towards CB indicates the increase in proportion of B from 0% concentration (at point C) to 100% concentration (at point B). It shows in Figure 1, composition

The following points may be useful to read and to understand ternary diagram in

formulation [42].

Self-Microemulsifying System

DOI: http://dx.doi.org/10.5772/intechopen.88603

2.5.2 Construction of pseudoternary phase diagram

where G is free energy, N is the droplets number, r is globules radius, and σ is the interfacial energy [22, 26]. The oil and water phase of the emulsion separates upon reduction in the interfacial area and free energy of the system. Conventional emulsifying agent stabilizes the emulsion by forming a monolayer around the emulsion droplets and reduces the interfacial energy, thereby provides a barrier to coalescence. For the formulation self-emulsifying systems free energy requires is either very low or positive or negative then, the emulsion process occurs irrepressible. Very low energy requires for emulsification, it involves destabilization through diminution of interfacial regions. It is necessary to not have any resistance to the surface shearing of the interfacial structure to occur the emulsification. Through the emulsification water penetrates into the various liquid crystals or phases. As soon as binary mixture of oil/non-ionic surfactant comes in contact with aqueous phase, formation of interface between the oil and aqueous phases occurs. Aqueous phase penetrates through this interface and starts solubilizing with oil phase till the limit of solubilization is reached at the interface. There is relationship between the emulsification properties of the surfactant and phase inversion behavior of the system.

Upon mild agitation of self-micro emulsifying systems, water penetration occurs quickly and leads to the interference of interface and droplets will be formed as micro-emulsions are thermodynamically stable; equilibrium exists within the system although there is continuous exchange of matter between the different phases [36]. Interchanging of matter usually occurs in two different ways like amalgamation of small droplets followed by the parting of larger droplet into small droplets and fragmentation of droplets which later coagulate with other droplets [37].

Self-emulsifying drug delivery system also poses accountability in contempt of its many assets namely


#### 2.5 Formulation design

Formulation of self-micro emulsifying systems involves the following steps.


#### 2.5.1 Screening of excipients

Selection of the most satisfactory excipients that can be used in the preparation of self-micro emulsifying systems depends on the solubility studies. Solubility of the drug is tested in various oils, surfactants, and co-surfactants [39]. Shake flask

#### Self-Microemulsifying System DOI: http://dx.doi.org/10.5772/intechopen.88603

ΔG ¼ ΣNπr2σ (1)

where G is free energy, N is the droplets number, r is globules radius, and σ is the interfacial energy [22, 26]. The oil and water phase of the emulsion separates upon reduction in the interfacial area and free energy of the system. Conventional emulsifying agent stabilizes the emulsion by forming a monolayer around the emulsion droplets and reduces the interfacial energy, thereby provides a barrier to coalescence. For the formulation self-emulsifying systems free energy requires is either very low or positive or negative then, the emulsion process occurs irrepressible. Very low energy requires for emulsification, it involves destabilization through diminution of interfacial regions. It is necessary to not have any resistance to the surface shearing of the interfacial structure to occur the emulsification. Through the emulsification water penetrates into the various liquid crystals or phases. As soon as binary mixture of oil/non-ionic surfactant comes in contact with aqueous phase, formation of interface between the oil and aqueous phases occurs. Aqueous phase penetrates through this interface and starts solubilizing with oil phase till the limit of solubilization is reached at the interface. There is relationship between the emulsification properties of the surfactant and phase inversion behavior of the system. Upon mild agitation of self-micro emulsifying systems, water penetration occurs quickly and leads to the interference of interface and droplets will be formed as micro-emulsions are thermodynamically stable; equilibrium exists within the system although there is continuous exchange of matter between the different phases [36]. Interchanging of matter usually occurs in two different ways like amalgamation of small droplets followed by the parting of larger droplet into small droplets and fragmentation of droplets which later coagulate with other droplets [37].

Self-emulsifying drug delivery system also poses accountability in contempt of

ii. Large amount of surfactant used in formulation causes irritancy in

iii. Precipitation of lipophilic drugs take place when volatile co-solvent is

Formulation of self-micro emulsifying systems involves the following steps.

Selection of the most satisfactory excipients that can be used in the preparation of self-micro emulsifying systems depends on the solubility studies. Solubility of the drug is tested in various oils, surfactants, and co-surfactants [39]. Shake flask

its many assets namely

i. Drug chemical instability

Colloid Science in Pharmaceutical Nanotechnology

gastrointestinal tract

incorporated [38].

1.Screening of excipients.

2.5.1 Screening of excipients

64

2.Establishment of pseudoternary phase diagram.

3.Development of self-micro emulsifying systems.

4.Characterization of self-micro emulsifying systems.

2.5 Formulation design

method is generally used to performed these type of studies. In these studies excess amount of drug is added to the excipient and then flask is shaken for 48 hours in water bath shaker at room temperature. After 48 hours samples are subjected to centrifugation, then filtered through 0.45 μm filters and drug content is examined [40, 41]. The objective of these solubility studies is to choose oil, surfactant, and co-surfactant that show maximum solubility to the drug. Another objective is accomplishment of optimal drug loading with minimized entire volume of the formulation [42].

To check the emulsification ability, screening of surfactant and co-surfactant is done by mixing known amount of surfactants with equal portion of selected oil and surfactant, and homogenized. The idea about ease of emulsification is obtained when the mixture is added to double distilled water and the number of flask inversions required to form homogenous emulsion is noted [43]. Then, the obtained dilution is tested for turbidity, percentage transmittance and clarity. The surfactant that shows high percentage transmittance at lower flask inversions with high emulsification efficiency is generally selected. Similarly, co-surfactants representing higher emulsification efficiency are selected for self-emulsifying formulation [44].

#### 2.5.2 Construction of pseudoternary phase diagram

Micro-emulsion is formed by the spontaneous emulsification method and can be depicted with the help of phase diagrams. Construction of phase diagram is a useful approach to study the complex series of interactions that can occur when different components are mixed ternary phase diagram is used to study the phase behavior of three components. Ternary phase diagram represents the system with three components oil, water, and surfactant. But in case of self-micro emulsifying systems, the additional component like co-surfactant/co-solvent addition is most common. Ternary diagram contains three corners that correspond to the 100% of the particular component. In case of addition of fourth component, the ternary diagram can be termed as pseudoternary phase diagram [45]. For building of pseudoternary phase diagram, components of micro-emulsion are examined for emulsification efficiency at various compositions. Emulsions, micro-emulsions, micelles, inverted micelle structures may be form and the degree of formation of these structures can be determined with the formation of ternary phase diagram [46, 47]. The fixed ratio is typically formed by the fusion of surfactant and cosurfactant and it may be the mixture of oil and surfactant. This is mixed with the specific volume of the third phase like oil or co-surfactant; then the other component i.e. water is added in a gradual amounts and with every addition the solution is tested for the clarity, dispersibility, time for self-emulsification, and flowability. The total concentration of all components in each mixture is 100%. In pseudoternary phase diagram, the samples which formed clear solution is denoted by suitable symbols in the phase diagram. The area that is formed when these points are joined indicates the mono-physic micro-emulsion existing area and wide area indicates the good emulsification efficiency [48, 49].

The following points may be useful to read and to understand ternary diagram in an easy way. The three corners of the typical ternary diagram represent three components, that is, A, B, and C. The arrow towards BA indicates increase in proportion of A from 0% concentration (at point B) to 100% concentration (at point A), the arrow towards AC indicates the increase in proportion of C from 0% concentration (at point A) to 100% concentration (at point C), and similarly the arrow towards CB indicates the increase in proportion of B from 0% concentration (at point C) to 100% concentration (at point B). It shows in Figure 1, composition at point O can be known by the following procedure [50].

the formulation contains water soluble co-solvents then precipitation is common outcome and it can be avoided by enhancing the concentration of surfactant

This is a crucial factor in self-emulsification performance because it determines the rate and extent of drug release, as well as the stability of the emulsion [57]. The droplet size is mainly dependent on the nature and concentration of surfactant. Photon correlation spectroscopy, microscopic techniques or a coulter nanosizer are

mainly used for the determination of the emulsion droplet size [58, 59].

This recognizes efficient self-emulsification by determine the dispersion reaching equilibrium quickly in a consistent time [60]. Orbeco-Helle turbidity meter is most commonly used for turbidity measurements. This turbidity meter is connected to dissolution equipment and emulsification time, optical clarity of nano or micro-emulsion formed is recorded after every 15 second. Turbidity can also be discovered in expression of spectroscopic characterization of optical clarity [61].

This is used to identify the charge of the droplets. In conventional self-micro emulsifying systems, the charge on an oil droplet surface is negative because of the presence of free fatty acids. Zeta potential is generally measured by zeta potential analyzer or zeta meter system [11]. Value of zeta potential indicates the stability of emulsion after appropriate dilution. Higher zeta potential indicates the good

Viscosity of diluted self-micro emulsifying systems formulation is determined by rheometers like brookfield, cone and plate rheometers fitted with cone spindle or rotating spindle brookfield viscometer. During titration, the initial increase in viscosity with subsequent decrease with the increase in water volume attributes to water percolation threshold. This indicates the formation of o/w micro-emulsion from w/o micro-emulsion with intermediate bi-continuous phase [64]. Microemulsion can be determined by the graph plotted between shear stress and shear rate. The Newtonian behavior indicates the presence of droplets of small and

Efficiency of emulsification of various compositions of medium chain triglyceride systems is determined by using a rotating paddle to assist emulsification in a crude nephelometer [65]. This empowers an assessment of the time taken for

Cloud point is generally determined by gradually increasing the temperature of water bath in which the formulation is placed and measured spectrophotometrically.

[55, 56].

2.5.4.2 Droplet size

Self-Microemulsifying System

DOI: http://dx.doi.org/10.5772/intechopen.88603

2.5.4.3 Turbidity measurement

2.5.4.4 Zeta potential measurement

stability of formulation [62, 63].

2.5.4.6 Determination of emulsification time

2.5.4.7 Cloud point determination

2.5.4.5 Viscosity measurement

spherical shape.

emulsification.

67

Figure 1. Typical ternary diagram indicating the composition of A, B, and C at point O.


#### 2.5.3 Preparation method of self-micro emulsifying systems

Self-micro emulsifying systems is prepared by adding drug into the mixture of oil, surfactant, and co-surfactant and then vortexed. In some methods, first drug is dissolved in one of the excipients and later on other excipients are added to this prepared solution. Then, the solution is appropriately mixed and turbidity measured. After 48 hours at climatic condition, the solution is heated if required for the development of clear solution [51, 52].

#### 2.5.4 Characterization of self-micro emulsifying systems

#### 2.5.4.1 Visual inspection

The assessment of self-emulsification is possible by visual evaluation. After dilution of self-micro emulsifying systems with water, the opaque and milky white appearance indicates the formation of macro emulsion whereas the clear, isotropic, transparent solution indicates the formation of micro-emulsion [53, 54]. Precipitation of drug in diluted self-micro emulsifying systems is evaluated by visual inspection. The stable formulation is obtained when drug precipitation is not noticeable. If the formulation contains water soluble co-solvents then precipitation is common outcome and it can be avoided by enhancing the concentration of surfactant [55, 56].

#### 2.5.4.2 Droplet size

This is a crucial factor in self-emulsification performance because it determines the rate and extent of drug release, as well as the stability of the emulsion [57]. The droplet size is mainly dependent on the nature and concentration of surfactant. Photon correlation spectroscopy, microscopic techniques or a coulter nanosizer are mainly used for the determination of the emulsion droplet size [58, 59].

#### 2.5.4.3 Turbidity measurement

This recognizes efficient self-emulsification by determine the dispersion reaching equilibrium quickly in a consistent time [60]. Orbeco-Helle turbidity meter is most commonly used for turbidity measurements. This turbidity meter is connected to dissolution equipment and emulsification time, optical clarity of nano or micro-emulsion formed is recorded after every 15 second. Turbidity can also be discovered in expression of spectroscopic characterization of optical clarity [61].

#### 2.5.4.4 Zeta potential measurement

This is used to identify the charge of the droplets. In conventional self-micro emulsifying systems, the charge on an oil droplet surface is negative because of the presence of free fatty acids. Zeta potential is generally measured by zeta potential analyzer or zeta meter system [11]. Value of zeta potential indicates the stability of emulsion after appropriate dilution. Higher zeta potential indicates the good stability of formulation [62, 63].

#### 2.5.4.5 Viscosity measurement

i. A line is drawn parallel to CB from point O towards AB. The point where this line intersects with AB indicates the percent composition of A at point O (X).

ii. Then, percent composition of B at point O can be known by drawing a line that is parallel to AC towards BC. The point where this line intersects with

Self-micro emulsifying systems is prepared by adding drug into the mixture of oil, surfactant, and co-surfactant and then vortexed. In some methods, first drug is dissolved in one of the excipients and later on other excipients are added to this prepared solution. Then, the solution is appropriately mixed and turbidity measured. After 48 hours at climatic condition, the solution is heated if required for the

The assessment of self-emulsification is possible by visual evaluation. After dilution of self-micro emulsifying systems with water, the opaque and milky white appearance indicates the formation of macro emulsion whereas the clear, isotropic, transparent solution indicates the formation of micro-emulsion [53, 54]. Precipitation of drug in diluted self-micro emulsifying systems is evaluated by visual inspection. The stable formulation is obtained when drug precipitation is not noticeable. If

BC indicates the percent composition of B at point O (Y).

drawing a line that is parallel to AB towards AC (Z).

Typical ternary diagram indicating the composition of A, B, and C at point O.

Colloid Science in Pharmaceutical Nanotechnology

2.5.3 Preparation method of self-micro emulsifying systems

2.5.4 Characterization of self-micro emulsifying systems

development of clear solution [51, 52].

2.5.4.1 Visual inspection

66

Figure 1.

iii. Similarly, the percent composition of C, at point O can be known by

Viscosity of diluted self-micro emulsifying systems formulation is determined by rheometers like brookfield, cone and plate rheometers fitted with cone spindle or rotating spindle brookfield viscometer. During titration, the initial increase in viscosity with subsequent decrease with the increase in water volume attributes to water percolation threshold. This indicates the formation of o/w micro-emulsion from w/o micro-emulsion with intermediate bi-continuous phase [64]. Microemulsion can be determined by the graph plotted between shear stress and shear rate. The Newtonian behavior indicates the presence of droplets of small and spherical shape.

#### 2.5.4.6 Determination of emulsification time

Efficiency of emulsification of various compositions of medium chain triglyceride systems is determined by using a rotating paddle to assist emulsification in a crude nephelometer [65]. This empowers an assessment of the time taken for emulsification.

#### 2.5.4.7 Cloud point determination

Cloud point is generally determined by gradually increasing the temperature of water bath in which the formulation is placed and measured spectrophotometrically. The point where percentage transmittance decreases signifies the cloud point that is the temperature above which the transparent solution changes to cloudy solution. As the body temperature is 37°C, formulations should exhibit the cloud point more than body temperature to retain its self-emulsification property. Phase separation and decrease in drug solubilization are commonly observed at higher temperature than the cloud point due to the susceptibility of surfactant to dehydration. Cloud point is influenced by drug lipophilicity and other formulation components [66].

formulation. Dilution of self-micro emulsifying systems will owe to decrease solvent capacity of the surfactant or co-surfactant. An equilibrium solubility measurement is

Drug release from the self-micro emulsifying systems is mainly affected by the polarity of the lipid phase. The polarity of the droplet is governed by the hydrophilic lipophilic balance, the chain length and degree of unsaturation of the fatty acid, the molecular weight of the hydrophilic portion and the concentration of the emulsifier. Affinity of drug towards solvent is indicated by polarity. Rapid release of

1.Self-micro emulsifying systems have the same advantage as emulsions, of facilitating the solubility of hydrophobic drugs. Macro-emulsions undergo creaming over a period of time, whereas self-micro emulsifying systems being

2.Most of the self-micro emulsifying systems formulations are in capsule or tablet dosage forms, thus occupying smaller volume, easy to administer and

3. Self-micro emulsifying systems are advantageous over self-emulsifying systems as the former is less dependent on bile salts for the formation of

5.Self-micro emulsifying systems have the ability to facilitate rapid oral absorption of the drug, which results in quick onset of action [75].

6.Absorption of drug from self-micro emulsifying systems formulation is not affected by food. The lipophilic contents of fatty diet, aids in absorption of

7.Self-micro emulsifying systems can be easily manufactured at large scale as it requires simple and economical manufacturing facilities, such as simple mixer

reported to increase the permeability of the drug when administered along with the formulation due to the loosening effect of these on tight junctions [78].

1. In gastrointestinal tract fluid, diluted self-micro emulsifying systems undergo precipitation of drug. An essential for the lipid formulations is that they should allow keeping the drug in the solubilized form in the gastrointestinal tract. Advantage of lipid-based formulation is abolished due to the precipitation of

with an agitator and volumetric liquid filling equipment [77].

2.8 Challenges in self-micro emulsifying systems formulation

8. Surfactants of high hydrophilic lipophilic balance like polysorbate 80 are

4.Drugs which have propensity to be degraded by the chemical and enzymatic means in gastrointestinal tract can be protected by the formulation of selfmicro emulsifying systems as the drug will be presented to the body in oil

carried out to predict the potential cases of precipitation in the gut region.

the drug in the aqueous phase is high if the polarity is high.

thermodynamically stable can be stored easily [22].

2.7 Significance of self-micro emulsifying systems

hence improved patient compliance [72].

2.6.3 Polarity of lipid phase

Self-Microemulsifying System

DOI: http://dx.doi.org/10.5772/intechopen.88603

droplets [73].

droplets [74].

69

drug from these systems [76].

#### 2.5.4.8 Cryo-transmission electron microscopy studies

Transmission electron microscope is used to characterize the sample. In this sample is taken on copper grid. Filter paper is used to form the thin liquid film on the grid. The grid is extinguished in liquid ethane at 180°C and transferred to liquid nitrogen at 196°C [67, 68].

#### 2.5.4.9 Percent transmission

This test gives the indication of transparency of diluted self-micro emulsifying systems formulation. It is determined spectrophotometrically after dilution of formulation with water, keeping water as blank. The percentage transmittance value near to 100% indicates clear and transparent micro-emulsion formation [69].

#### 2.5.4.10 Small-angle neutron scattering

Size and shape of the droplets is determined using small angle neutron scattering. Small-angle neutron scattering experiments use the interference effect of wave lets scattered from different materials in a sample with the different scattering length densities.

#### 2.5.4.11 Thermodynamic stability study

These studies are useful to evaluate the consequence of temperature change on formulation. Formulation is diluted with aqueous phase and subjected to centrifugation at 15,000 rpm for 15 min or at 3500 rpm for 30 min. The samples in which the phase separation is not observed further subjected to freeze thaw cycles (20 and 40°C temperature, respectively) and observed visually. The thermodynamically stable formulations does not show any changes in visual description [70, 71].

#### 2.6 Factors influencing formulation of self-micro emulsifying systems

#### 2.6.1 Drug dose

Drugs with a very high dose are not acceptable for self-micro emulsifying systems unless they exhibit very good solubility in one of the excipients of self-micro emulsifying systems, mostly in a lipophilic phase. The drugs having a little solubility in water and lipids (log P values of approximately 2) are very difficult to deliver by self-micro emulsifying systems.

#### 2.6.2 Drug solubility

Solubility of the drug in oil phase is important parameter in self-micro emulsifying systems formulation to maintain the drug solubility. A chance of precipitation is probably higher if contribution of surfactant and co-surfactant is greater in

formulation. Dilution of self-micro emulsifying systems will owe to decrease solvent capacity of the surfactant or co-surfactant. An equilibrium solubility measurement is carried out to predict the potential cases of precipitation in the gut region.

#### 2.6.3 Polarity of lipid phase

The point where percentage transmittance decreases signifies the cloud point that is the temperature above which the transparent solution changes to cloudy solution. As the body temperature is 37°C, formulations should exhibit the cloud point more than body temperature to retain its self-emulsification property. Phase separation and decrease in drug solubilization are commonly observed at higher temperature

Transmission electron microscope is used to characterize the sample. In this sample is taken on copper grid. Filter paper is used to form the thin liquid film on the grid. The grid is extinguished in liquid ethane at 180°C and transferred to

This test gives the indication of transparency of diluted self-micro emulsifying systems formulation. It is determined spectrophotometrically after dilution of formulation with water, keeping water as blank. The percentage transmittance value near to 100% indicates clear and transparent micro-emulsion formation [69].

Size and shape of the droplets is determined using small angle neutron scattering. Small-angle neutron scattering experiments use the interference effect of wave lets scattered from different materials in a sample with the different scattering

These studies are useful to evaluate the consequence of temperature change on formulation. Formulation is diluted with aqueous phase and subjected to centrifugation at 15,000 rpm for 15 min or at 3500 rpm for 30 min. The samples in which the phase separation is not observed further subjected to freeze thaw cycles (20 and 40°C temperature, respectively) and observed visually. The thermodynamically stable formulations does not show any changes in visual description [70, 71].

Drugs with a very high dose are not acceptable for self-micro emulsifying systems unless they exhibit very good solubility in one of the excipients of self-micro emulsifying systems, mostly in a lipophilic phase. The drugs having a little solubility in water and lipids (log P values of approximately 2) are very difficult to deliver by

Solubility of the drug in oil phase is important parameter in self-micro emulsifying

systems formulation to maintain the drug solubility. A chance of precipitation is probably higher if contribution of surfactant and co-surfactant is greater in

2.6 Factors influencing formulation of self-micro emulsifying systems

than the cloud point due to the susceptibility of surfactant to dehydration. Cloud point is influenced by drug lipophilicity and other formulation

2.5.4.8 Cryo-transmission electron microscopy studies

Colloid Science in Pharmaceutical Nanotechnology

liquid nitrogen at 196°C [67, 68].

2.5.4.10 Small-angle neutron scattering

2.5.4.11 Thermodynamic stability study

2.5.4.9 Percent transmission

length densities.

2.6.1 Drug dose

2.6.2 Drug solubility

68

self-micro emulsifying systems.

components [66].

Drug release from the self-micro emulsifying systems is mainly affected by the polarity of the lipid phase. The polarity of the droplet is governed by the hydrophilic lipophilic balance, the chain length and degree of unsaturation of the fatty acid, the molecular weight of the hydrophilic portion and the concentration of the emulsifier. Affinity of drug towards solvent is indicated by polarity. Rapid release of the drug in the aqueous phase is high if the polarity is high.

#### 2.7 Significance of self-micro emulsifying systems


#### 2.8 Challenges in self-micro emulsifying systems formulation

1. In gastrointestinal tract fluid, diluted self-micro emulsifying systems undergo precipitation of drug. An essential for the lipid formulations is that they should allow keeping the drug in the solubilized form in the gastrointestinal tract. Advantage of lipid-based formulation is abolished due to the precipitation of

the drug. The precipitation tendency of the drug on dilution is higher due to the dilution effect of the hydrophilic solvent. It thereby requires incorporation of polymers to minimize drug precipitation in-vivo [79, 80].

3. Conclusion

Self-Microemulsifying System

DOI: http://dx.doi.org/10.5772/intechopen.88603

in market.

Conflict of interest

publication of this paper.

Author details

India

71

Mansi Shah<sup>1</sup> and Anuj G. Agrawal<sup>2</sup>

provided the original work is properly cited.

Self-micro emulsifying systems drug delivery systems are effective approach for increase the bioavailability of poor water soluble drug. Currently, several formulations have been developed to produce modified emulsified formulations as alternatives to conventional self-emulsifying systems, which provide faster and enhanced drug release. Versatility of self-micro emulsifying systems could be proved if issues like method to predict solubilization state of the drug in-vivo, interaction of lipid systems with components of capsule shell and basic mechanism of transport of selfmicro emulsifying systems through gastrointestinal tract are adequately addressed. Further research in developing self-micro emulsifying systems with surfactants of low toxicity and to develop in-vitro methods to better understand the in-vivo fate of these formulations can maximize the availability of self-micro emulsifying systems

The authors declare that there is no conflict of interests regarding the

\*

2 Netsurf Research Lab Pvt. Ltd., Pune, Maharashtra, India

\*Address all correspondence to: royalanuj@yahoo.co.in

1 Parul Institute of Pharmacy and Research, Parul University, Vadodara, Gujarat,

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,


#### 2.9 Patented conventional self-micro emulsifying systems of lipophilic drugs


Self-micro emulsifying systems patent are shown in Table 4 [83–86].

Table 4. Patented conventional SMES of lipophilic drugs.

#### 3. Conclusion

the drug. The precipitation tendency of the drug on dilution is higher due to the dilution effect of the hydrophilic solvent. It thereby requires incorporation

2.Liquid self-micro emulsifying systems are difficult during handling, storage and stability. Therefor formulating solid self-micro emulsifying systems seems

formulations is the lack of good established in-vitro models for the assessment

potentially are dependent on digestion of lipid in the gut, earlier to release of the drug. In-vitro model replicating the digestive processes of the duodenum has been developed to mimic the condition [81]. This model also needs more clarification and validation before its strength are examined. Further,

to be a logical solution for these problems [81]. Another hurdle in the development of self-micro emulsifying systems and other lipid-based

3.Conventional dissolution methods do not work, as these formulations

4.Lipid excipients containing unsaturated fatty acids and its derivatives are prone to lipid oxidation [81]. Inclusion of Lipid soluble antioxidant in

2.9 Patented conventional self-micro emulsifying systems of lipophilic drugs

Sr. no Summary of invention Application Patent number

Poorly water soluble compounds Taxoids having high molecular weight, and slightly lipophilic. This patent enhances oral bioavailability of taxoids through self-emulsification.

Increases bioavailability of poorly soluble drugs of paclitaxel and docetaxel.

Improves bioavailability of poorly soluble drugs such as cyclosporine, tacrolimus, ibuprofen, ketoprofen, nifedipine, amlodipine, and simvastatin.

The invention provides the SMES of mitotane, which overcomes the issue of its low solubility and low bioavailability.

EP1498143A1

EP1340497A1

EP2062571A1

EP2435022A2

Self-micro emulsifying systems patent are shown in Table 4 [83–86].

formulation of capsule [82]. Polymorphism associated with thermo-softening lipid excipients requires specific process control in their application, in order

development can be based on in vitro–in-vivo correlations.

to minimize polymorphic changes of the excipient matrix.

of polymers to minimize drug precipitation in-vivo [79, 80].

of the formulations [79].

Colloid Science in Pharmaceutical Nanotechnology

1 Self-microemulsifying formulation containing taxoid, surfactant, and Cosurfactant [22].

2 The self-micro emulsifying

3 Self-emulsifying pharmaceutical

4 Formulation containing mitotane, propylene glycol monocaprylate, propylene glycol dicaprate, and polyoxyethylene sorbitanmonooleate [74].

Patented conventional SMES of lipophilic drugs.

Table 4.

70

Formulation consisting of poorly soluble or insoluble drug, vitamin E, a co-solvent, bile salt(s), TPGS, and a surfactant [72].

Composition containing a lipophilic drug, surfactant(s), and hydrophilic carrier(s) [73].

Self-micro emulsifying systems drug delivery systems are effective approach for increase the bioavailability of poor water soluble drug. Currently, several formulations have been developed to produce modified emulsified formulations as alternatives to conventional self-emulsifying systems, which provide faster and enhanced drug release. Versatility of self-micro emulsifying systems could be proved if issues like method to predict solubilization state of the drug in-vivo, interaction of lipid systems with components of capsule shell and basic mechanism of transport of selfmicro emulsifying systems through gastrointestinal tract are adequately addressed. Further research in developing self-micro emulsifying systems with surfactants of low toxicity and to develop in-vitro methods to better understand the in-vivo fate of these formulations can maximize the availability of self-micro emulsifying systems in market.

#### Conflict of interest

The authors declare that there is no conflict of interests regarding the publication of this paper.

### Author details

Mansi Shah<sup>1</sup> and Anuj G. Agrawal<sup>2</sup> \*

1 Parul Institute of Pharmacy and Research, Parul University, Vadodara, Gujarat, India

2 Netsurf Research Lab Pvt. Ltd., Pune, Maharashtra, India

\*Address all correspondence to: royalanuj@yahoo.co.in

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

### References

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[9] Amri A, Le-Clanche S, Therond P, Bonnefont-Rousselot D, Borderie D, Lai-Kuen R. Resveratrol selfemulsifying system increases the uptake by endothelial cells and improves protectionagainst oxidative stressmediated death. European Journal of Pharmaceutics and Biopharmaceutics. 2014;86(3):418-426. DOI: 10.1016/j. ejpb.2013.10.015

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[12] Qureshi MJ, Chitneni MK, Kian WG. Enhancement of solubility and therapeutic potential of poorly soluble lovastatin by SMEDDS formulation adsorbed on directly compressed spray dried magnesium aluminometasilicate liquid loadable

Self-Microemulsifying System DOI: http://dx.doi.org/10.5772/intechopen.88603

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Colloid Science in Pharmaceutical Nanotechnology

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s13205-019-1630-y

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10.1016/j.addr.2018.07.001

2016;1:1-39. DOI: 10.1615/

S149717

0280-y

72

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Markandeywar TS. Systems (SEDDSS) to enhance the bioavailability of poorly water-soluble drugs. Critical Reviews in Therapeutic Drug Carrier Systems.

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addr.2018.10.014

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228-234. DOI: 10.1016/j.ijpharm.2019. 01.039

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2008;69(2):553-562. DOI: 10.1016/j. ejpb.2007.12.020

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603-611. DOI: 10.1080/ 03639040802488089

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75

Sharma T, Singh B. QbD-based development of cationic self-

10.1208/s12249-007-9014-8

Self-Microemulsifying System

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[39] Borhade V, Nair H, Hegde D. Design and evaluation of selfmicroemulsifying drug delivery system Self-Microemulsifying System DOI: http://dx.doi.org/10.5772/intechopen.88603

(SMEDDS) of tacrolimus. AAPS PharmSciTech. 2008;9(1):13-21. DOI: 10.1208/s12249-007-9014-8

2008;69(2):553-562. DOI: 10.1016/j.

Colloid Science in Pharmaceutical Nanotechnology

emulsions. Current Opinion in Colloid & Interface Science. 2005;10(3–4): 102-110. DOI: 10.1016/j.cocis.2005.

[33] Mercuri A, Belton PS, Royall PG.

Pharmacology. 2012;9(9):2658-2668.

[34] Singh B, Singh R, Bandyopadhyay S. Optimized nano-emulsifying systems with enhanced bioavailability of carvedilol. Colloids and Surfaces. B, Biointerfaces. 2013;101:465-474. DOI: 10.1016/j.colsurfb.2012.07.017

[35] Reiss H. Entropy-induced dispersion of bulk liquids. Journal of Colloid and Interface Science. 1975;53(1):61-70. DOI: 10.1016/0021-9797(75)90035-1

[36] Bagwe RP, Kanicky JR, Palla BJ, Patanjali PK, Shah DO. Improved drug delivery using micro-emulsions: Rationale, recent progress, and new horizons. Critical Reviews in Therapeutic Drug Carrier Systems.

[37] Chakraborty S, Shukla D, Mishra B, Singh S. Lipid – An emerging platform for oral delivery of drugs with poor bioavailability. European Journal of Pharmacology. 2009;73(1):1-15. DOI:

[38] Pouton CW. Lipid formulations for oral administration of drugs: Nonemulsifying, self-emulsifying and "selfmicroemulsifying" drug delivery systems. European Journal of

Pharmaceutical Sciences. 2000;11(2): S93-S98. DOI: 10.1016/S0928-0987(00)

[39] Borhade V, Nair H, Hegde D. Design and evaluation of self-

microemulsifying drug delivery system

2001;18(1):77-140

00167-6

10.1016/j.ejpb.2009.06.001

Identification and molecular interpretation of the effects of drug incorporation on the self-emulsification process using spectroscopic, micro polarimetric and microscopic measurements. Molecular

DOI: 10.1155/2013/848043

06.004

Pharmaceutics and Biopharmaceutics. 2000;50(1):179-188. DOI: 10.1016/

Bioavailability of Poorly Water Soluble Drugs in Drugs and Pharmaceutical Sciences. 1st ed. Vol. 170. NC USA: Informa Healthcare. 2007. pp. 1-339

[26] Gershanik T, Benita S. Selfdispersing lipid formulations for improving oral absorption of lipophilic

drugs. European Journal of

S0939-6411(00)00089-8

[27] Hauss DJ. Oral Lipid Based Formulations Enhancing the

[28] Odeberg JM, Kaufmann P, Kroon KG, Höglund P. Lipid drug delivery and rational formulation design for lipophilic drugs with low oral bioavailability, applied to cyclosporine. European Journal of Pharmaceutical Sciences. 2003;20:375-382. DOI: 10.1016/j.ejps.2003.08.005

[29] Swenson ES, Milisen WB, Curatolo W. Intestinal permeability enhancement: Efficacy, acute local

Pharmaceutical Research. 1994;11(8):

[30] Shah NH, Carvajal MT, Patel CI,

toxicity, and reversibility.

1132-1142. DOI: 10.1023/A:

Infeld MH, Malick AW. Selfemulsifying drug delivery systems (SEDDS) with polyglycolyzed glycerides for improving in vitro dissolution and oral absorption of lipophilic drugs. International Journal of Pharmaceutics. 1994;106(1):15-23. DOI:

10.1016/0378-5173(94)90271-2

efficiency of emulsification.

0378-5173(85)90081-X

74

[31] Pouton CW. Self-emulsifying drug delivery systems: Assessment of the

International Journal of Pharmaceutics. 1985;27(2–3):335-348. DOI: 10.1016/

[32] Solans C, Izquierdo P, Nolla J, Azemar N, Garcia-Celma MJ. Nano-

1018984731584

ejpb.2007.12.020

[40] Wang Y, Sun J, Zhang T, Liu H, He F, He Z. Enhanced oral bioavailability of tacrolimus in rats by self- microemulsifying drug delivery systems. Drug Development and Industrial Pharmacy. 2011;37(10): 1225-1230. DOI: 10.3109/ 03639045.2011.565774

[41] AboulFotouh K, Allam A, El-Badry M, El-Sayed AM. Self-emulsifying drug– delivery systems modulate Pglycoprotein activity: Role of excipients and formulation aspects. Nanomedicine. 2018. DOI: 10.2217/nnm-2017-0354

[42] Basalious EB, Shawky N, Badr-Eldin SM. SNEDDS containing bio enhancers for improvement of dissolution and oral absorption of lacidipine: Development and optimization. International Journal of Pharmaceutics. 2010;391(1–2): 203-211. DOI: 10.1016/j.ijpharm.2010. 03.008

[43] Lawrence MJ, Rees GD. Microemulsion-based media as novel drug delivery systems. Advanced Drug Delivery Reviews. 2000;45(1):89-121. DOI: 10.1016/S0169-409X(00)00103-4

[44] Cui SX, Nie SF, Li L, Wang CG, Pan WS, Sun JP. Preparation and evaluation of self-microemulsifying drug delivery system containing vinpocetine. Drug Development and Industrial Pharmacy. 2009;35(5): 603-611. DOI: 10.1080/ 03639040802488089

[45] Narang AS, Delmarre D, Gao D. Stable drug encapsulation in micelles and micro-emulsions. International Journal of Pharmaceutics. 2007;345 (1–2):9-25. DOI: 10.1016/j. ijpharm.2007.08.057.I

[46] Beg S, Kaur R, Khurana RK, Rana V, Sharma T, Singh B. QbD-based development of cationic selfnanoemulsifying drug delivery systems of paclitaxel with improved biopharmaceutical attributes. AAPS PharmSciTech. 2019;20(3):118. DOI: 10.1208/s12249-019-1319-x

[47] Lupo N, Jalil A, Nazir I, Gust R, Bernkop-Schnürch A. In vitro evaluation of intravesical mucoadhesive self-emulsifying drug delivery systems. International Journal of Pharmaceutics. 2019;564:180-187. DOI: 10.1016/j. ijpharm.2019.04.035

[48] Eleftheriadis GK, Mantelou P, Karavasili C, Chatzopoulou P, Katsantonis D, Irakli M, et al. Development and characterization of a self-nano emulsifying drug delivery system comprised of rice bran oil for poorly soluble drugs. AAPS PharmSciTech. 2019;20(2):78. DOI: 10.1208/s12249-018-1274-y

[49] Elnaggar YSR, El-Massik MA, Abdallah OY. Self-nano emulsifying drug delivery systems of tamoxifen citrate: Design and optimization. International Journal of Pharmaceutics. 2009;380(1–2):133-141. DOI: 10.1016/j. ijpharm.2009.07.015

[50] Xu X, Cao M, Ren L, Qian Y, Chen G. Preparation and optimization of rivaroxaban by self-nanoemulsifying drug delivery system (SNEDDS) for enhanced oral bioavailability and no food effect. AAPS PharmSciTech. 2018; 19:1847-1859

[51] Parveen R, Baboota S, Ali J, Ahuja A, Vasudev S, Ahmad S. Oil based nano carrier for improved oral delivery of silymarin: In vitro-in vivo studies. International Journal of Pharmaceutics. 2011;413(1–2):245-253. DOI: 10.1016/j. ijpharm.2011.04.041

[52] Kohli K, Chopra S, Dhar D, Arora S, Khar RK. Self-emulsifying drug delivery systems: An approach to enhance oral bioavailability. Drug Discovery Today. 2010;15(21–22):958-965. DOI: 10.1016/j. drudis.2010.08.007

[53] Nazari-Vanani R, Azarpira N, Heli H. Development of selfnanoemulsifying drug delivery systems for oil extracts of Citrus aurantium L. blossoms and Rose damascena and evaluation of anticancer properties. Journal of Drug Delivery Science and Technology. 2018;47:330-336. DOI: 10.1016/j.jddst.2018.08.003

[54] Patel AR, Vavia PR. Preparation and in vivo evaluation of SMEDDS (selfmicroemulsifying drug delivery system) containing fenofibrate. The AAPS Journal. 2007;9(3):E344-E352. DOI: 10.1208/aapsj0903041

[55] Goddeeris C, Cuppo F, Reynaers H, Bouwman WG. Light scattering measurements on micro-emulsions: Estimation of droplet sizes. International Journal of Pharmaceutics. 2006;312(1–2):187-195. DOI: 10.1016/j. ijpharm.2006.01.037

[56] Akhtartavan S, Karimi M, Karimian K, Azarpira N, Khatami M, Heli H. Evaluation of a selfnanoemulsifying docetaxel delivery system. Biomedicine & Pharmacotherapy. 2019;109:2427-2433. DOI: 10.1016/j.biopha.2018.11.110

[57] Abdulkarim M, Sharma PK, Gumbleton M. Self-emulsifying drug delivery system: Mucus permeation and innovative quantification technologies. Advanced Drug Delivery Reviews. 2019. DOI: 10.1016/j. addr.2019.04.001

[58] Gursoy N, Garrigue JS, Razafindratsita A, Lambert G, Benita S. Excipient effects on in vitro cytotoxicity of a novel paclitaxel self-emulsifying drug delivery system. Journal of Pharmaceutical Sciences. 2003;92(12): 2411-2418. DOI: 10.1002/jps.10501

[59] Subramanian N, Ray S, Ghosal SK, Bhadra R, Satya P. Formulation design of self-microemulsifying drug delivery systems for improved oral bioavailability of celecoxib. Biological & Pharmaceutical Bulletin. 2004;27(12): 1993-1999. DOI: 10.1248/bpb.27.1993

exemestane from self-microemulsifying drug delivery system (SMEDDS). AAPS PharmSciTech. 2009;10(3):906-916. DOI: 10.1208/s12249-009-9281-7

DOI: http://dx.doi.org/10.5772/intechopen.88603

of itraconazole in healthy volunteers. European Journal of Pharmaceutical Sciences. 2008;33:59-65. DOI: 10.1016/j.

magnesium aluminometasilicate tablets

PharmSciTech. 2009;10:1388-1395. DOI:

[76] Chen ZQ, Liu Y, Zhao JH. Improved oral bioavailability of poorly watersoluble indirubin by a supersaturable self-microemulsifying drug delivery system. International Journal of Nanomedicine. 2012;7:1115-1125. DOI:

[74] Sander C, Holm P. Porous

as carrier of a cyclosporine selfemulsifying formulation. AAPS

[75] Buyukozturk F, Benneyan JC, Carrier RL. Impact of emulsion-based drug delivery systems on intestinal permeability and drug release kinetics. Journal of Controlled Release. 2010; 142(1):22-30. DOI: 10.1016/j.

10.1208/s12249-009-9340-0

jconrel.2009.10.005

10.2147/IJN.S28761

[77] Porter CJH, Trevaskis NL, Charman WN. Lipids and lipid based formulations: Optimizing the oral delivery of lipophilic drugs. Nature Reviews. Drug Discovery. 2007;6: 231-238. DOI: 10.1038/nrd2197

[78] Tang B, Cheng G, Gu JC, Xu CH. Development of solid self-emulsifying drug delivery system; preparation techniques and dosage forms. Drug Discovery Today. 2008;13:606-612. DOI: 10.1016/j.drudis.2008.04.006

[79] Zhang P, Liu Y, Xu J. Preparation and evaluation of self-emulsifying drug

International Journal of Pharmaceutics. 2008;355:269-276. DOI: 10.1016/j.

[80] Dahan A, Hoffman A. Rationalizing the selection of oral lipid based drug delivery system by an in vitro lipolysis model for improved oral bioavailability of poorly water soluble drugs. Journal of

delivery system of oridonin.

ijpharm.2007.12.026

ejps.2007.11.001

emulsification dynamics and stability of self-emulsifying drug delivery systems. European Journal of Pharmaceutics and Biopharmaceutics. 2018;123:1-8. DOI:

[68] Shafiq S, Shakeel F, Talegaonkar S,

[69] Khan AW, Kotta S, Ansari SH. Potentials and challenges in self-nano emulsifying drug delivery systems. Expert Opinion on Drug Delivery. 2012; 9:1305-1317. DOI: 10.1517/17425247.

[70] Morozowich W. Development of super saturable self-emulsifying drug delivery system formulations for improving the oral absorption of poorly soluble drugs. Expert Opinion on Drug Delivery. 2006;3:97-110. DOI: 10.1517/

Ambade KW, Kadam VJ. Applications of micro-emulsion based drug delivery system. Current Drug Delivery. 2006;

[72] Taha E, Ghorab D, Zaghloul AA. Bioavailability assessment of vitamin a self-nano emulsified drug delivery systems in rats: a comparative study. Medical Principles and Practice. 2007; 16:355-359. DOI: 10.1159/000104808

[73] Woo JS, Song YK, Hong JY. Reduced food-effect and enhanced bioavailability of a self-microemulsifying formulation

[67] Vasconcelos T, Marques S, Sarmento B. Measuring the

Self-Microemulsifying System

10.1016/j.ejpb.2017.11.003

Ahmad FJ, Khar RK, Ali M. Development and bioavailability assessment of ramipril nano emulsion formulation. European Journal of Pharmaceutics and Biopharmaceutics. 2007;66(2):227-243. DOI: 10.1016/j.

ejpb.2006.10.014

2012.719870

17425247.3.1.97

77

[71] Jadhav KR, Shaikh IM,

3(3):267-273. DOI: 10.2174/ 156720106777731118

[60] Gershanik T, Benita S. Positively charged self-emulsifying oil formulation for improving the oral bioavailability of progestrone. Pharmaceutical Development and Technology. 1996; 1(2):147-157. DOI: 10.3109/ 10837459609029889

[61] Usmani A, Mishra A, Arshad M, Jafri A. Development and evaluation of doxorubicin self nanoemulsifying drug delivery system with Nigella Sativa oil against human hepatocellular carcinoma. Artificial Cells, Nanomedicine, and Biotechnology. 2019;47(1):933-944. DOI: 10.1080/ 21691401.2019.1581791

[62] Araújo LM, Thomazine JA, Lopez RF. Development of microemulsions to topically deliver 5 aminolevulinic acid in photodynamic therapy. European Journal of Pharmaceutics and Biopharmaceutics. 2010;75(1):48-55. DOI: 10.1016/j. ejpb.2010.01.008

[63] Pouton CW. Formulation of selfemulsifying drug delivery system. Advanced Drug Delivery Reviews. 1997; 25:47-58. DOI: 10.1016/S0169-409X(96) 00490-5

[64] Agrawal A, Kumar A, Gide P. Formulation of solid selfnanoemulsifying drug delivery systems using N-methyl pyrrolidone as cosolvent. Drug Development and Industrial Pharmacy. 2015;41(4): 594-604. DOI: 10.3109/03639045.2014. 886695

[65] Agrawal A, Kumar A, Gide P. Selfemulsifying drug delivery system for enhanced solubility and dissolution of glipizide. Colloids and Surfaces B: Biointerfaces. 2014;126:553-560. DOI: 10.1016/j.colsurfb.2014.11.022

[66] Singh AK, Chaurasiya A, Awasthi A. Oral bioavailability enhancement of

Self-Microemulsifying System DOI: http://dx.doi.org/10.5772/intechopen.88603

exemestane from self-microemulsifying drug delivery system (SMEDDS). AAPS PharmSciTech. 2009;10(3):906-916. DOI: 10.1208/s12249-009-9281-7

[53] Nazari-Vanani R, Azarpira N, Heli H. Development of self-

10.1016/j.jddst.2018.08.003

10.1208/aapsj0903041

nanoemulsifying drug delivery systems for oil extracts of Citrus aurantium L. blossoms and Rose damascena and evaluation of anticancer properties. Journal of Drug Delivery Science and Technology. 2018;47:330-336. DOI:

Colloid Science in Pharmaceutical Nanotechnology

Pharmaceutical Bulletin. 2004;27(12): 1993-1999. DOI: 10.1248/bpb.27.1993

[60] Gershanik T, Benita S. Positively charged self-emulsifying oil formulation for improving the oral bioavailability of

Development and Technology. 1996;

[61] Usmani A, Mishra A, Arshad M, Jafri A. Development and evaluation of doxorubicin self nanoemulsifying drug delivery system with Nigella Sativa oil

progestrone. Pharmaceutical

1(2):147-157. DOI: 10.3109/ 10837459609029889

against human hepatocellular carcinoma. Artificial Cells,

[62] Araújo LM, Thomazine JA, Lopez RF. Development of microemulsions to topically deliver 5 aminolevulinic acid in photodynamic

therapy. European Journal of

ejpb.2010.01.008

00490-5

886695

Pharmaceutics and Biopharmaceutics. 2010;75(1):48-55. DOI: 10.1016/j.

[63] Pouton CW. Formulation of selfemulsifying drug delivery system. Advanced Drug Delivery Reviews. 1997; 25:47-58. DOI: 10.1016/S0169-409X(96)

[64] Agrawal A, Kumar A, Gide P.

nanoemulsifying drug delivery systems using N-methyl pyrrolidone as cosolvent. Drug Development and Industrial Pharmacy. 2015;41(4): 594-604. DOI: 10.3109/03639045.2014.

[65] Agrawal A, Kumar A, Gide P. Selfemulsifying drug delivery system for enhanced solubility and dissolution of glipizide. Colloids and Surfaces B: Biointerfaces. 2014;126:553-560. DOI: 10.1016/j.colsurfb.2014.11.022

[66] Singh AK, Chaurasiya A, Awasthi A. Oral bioavailability enhancement of

Formulation of solid self-

21691401.2019.1581791

Nanomedicine, and Biotechnology. 2019;47(1):933-944. DOI: 10.1080/

[54] Patel AR, Vavia PR. Preparation and in vivo evaluation of SMEDDS (selfmicroemulsifying drug delivery system) containing fenofibrate. The AAPS Journal. 2007;9(3):E344-E352. DOI:

[55] Goddeeris C, Cuppo F, Reynaers H,

International Journal of Pharmaceutics. 2006;312(1–2):187-195. DOI: 10.1016/j.

Bouwman WG. Light scattering measurements on micro-emulsions:

Estimation of droplet sizes.

[56] Akhtartavan S, Karimi M, Karimian K, Azarpira N, Khatami M,

Heli H. Evaluation of a self-

system. Biomedicine &

nanoemulsifying docetaxel delivery

[57] Abdulkarim M, Sharma PK, Gumbleton M. Self-emulsifying drug delivery system: Mucus permeation and innovative quantification

Reviews. 2019. DOI: 10.1016/j.

[58] Gursoy N, Garrigue JS,

systems for improved oral

76

addr.2019.04.001

Pharmacotherapy. 2019;109:2427-2433. DOI: 10.1016/j.biopha.2018.11.110

technologies. Advanced Drug Delivery

Razafindratsita A, Lambert G, Benita S. Excipient effects on in vitro cytotoxicity of a novel paclitaxel self-emulsifying drug delivery system. Journal of Pharmaceutical Sciences. 2003;92(12): 2411-2418. DOI: 10.1002/jps.10501

[59] Subramanian N, Ray S, Ghosal SK, Bhadra R, Satya P. Formulation design of self-microemulsifying drug delivery

bioavailability of celecoxib. Biological &

ijpharm.2006.01.037

[67] Vasconcelos T, Marques S, Sarmento B. Measuring the emulsification dynamics and stability of self-emulsifying drug delivery systems. European Journal of Pharmaceutics and Biopharmaceutics. 2018;123:1-8. DOI: 10.1016/j.ejpb.2017.11.003

[68] Shafiq S, Shakeel F, Talegaonkar S, Ahmad FJ, Khar RK, Ali M. Development and bioavailability assessment of ramipril nano emulsion formulation. European Journal of Pharmaceutics and Biopharmaceutics. 2007;66(2):227-243. DOI: 10.1016/j. ejpb.2006.10.014

[69] Khan AW, Kotta S, Ansari SH. Potentials and challenges in self-nano emulsifying drug delivery systems. Expert Opinion on Drug Delivery. 2012; 9:1305-1317. DOI: 10.1517/17425247. 2012.719870

[70] Morozowich W. Development of super saturable self-emulsifying drug delivery system formulations for improving the oral absorption of poorly soluble drugs. Expert Opinion on Drug Delivery. 2006;3:97-110. DOI: 10.1517/ 17425247.3.1.97

[71] Jadhav KR, Shaikh IM, Ambade KW, Kadam VJ. Applications of micro-emulsion based drug delivery system. Current Drug Delivery. 2006; 3(3):267-273. DOI: 10.2174/ 156720106777731118

[72] Taha E, Ghorab D, Zaghloul AA. Bioavailability assessment of vitamin a self-nano emulsified drug delivery systems in rats: a comparative study. Medical Principles and Practice. 2007; 16:355-359. DOI: 10.1159/000104808

[73] Woo JS, Song YK, Hong JY. Reduced food-effect and enhanced bioavailability of a self-microemulsifying formulation

of itraconazole in healthy volunteers. European Journal of Pharmaceutical Sciences. 2008;33:59-65. DOI: 10.1016/j. ejps.2007.11.001

[74] Sander C, Holm P. Porous magnesium aluminometasilicate tablets as carrier of a cyclosporine selfemulsifying formulation. AAPS PharmSciTech. 2009;10:1388-1395. DOI: 10.1208/s12249-009-9340-0

[75] Buyukozturk F, Benneyan JC, Carrier RL. Impact of emulsion-based drug delivery systems on intestinal permeability and drug release kinetics. Journal of Controlled Release. 2010; 142(1):22-30. DOI: 10.1016/j. jconrel.2009.10.005

[76] Chen ZQ, Liu Y, Zhao JH. Improved oral bioavailability of poorly watersoluble indirubin by a supersaturable self-microemulsifying drug delivery system. International Journal of Nanomedicine. 2012;7:1115-1125. DOI: 10.2147/IJN.S28761

[77] Porter CJH, Trevaskis NL, Charman WN. Lipids and lipid based formulations: Optimizing the oral delivery of lipophilic drugs. Nature Reviews. Drug Discovery. 2007;6: 231-238. DOI: 10.1038/nrd2197

[78] Tang B, Cheng G, Gu JC, Xu CH. Development of solid self-emulsifying drug delivery system; preparation techniques and dosage forms. Drug Discovery Today. 2008;13:606-612. DOI: 10.1016/j.drudis.2008.04.006

[79] Zhang P, Liu Y, Xu J. Preparation and evaluation of self-emulsifying drug delivery system of oridonin. International Journal of Pharmaceutics. 2008;355:269-276. DOI: 10.1016/j. ijpharm.2007.12.026

[80] Dahan A, Hoffman A. Rationalizing the selection of oral lipid based drug delivery system by an in vitro lipolysis model for improved oral bioavailability of poorly water soluble drugs. Journal of Controlled Release. 2008;129:1-10. DOI: 10.1016/j.jconrel.2008.03.021

[81] Wasylaschuk WR, Harmon PA, Wagner G. Evaluation of hydro peroxides in common pharmaceutical excipients. Journal of Pharmaceutical Sciences. 2007;96:106-116. DOI: 10.1002/jps.20726

[82] Bowtle W. Materials, process, and manufacturing considerations for lipidbased hard- capsule formats. In: Hauss DJ, editor. Oral Lipid Based Formulations Enhancing the Bioavailability of Poorly Water Soluble Drugs. Vol. 170. New York: Informa Healthcare; 2007

[83] Cote S, Gaudel G, Peracchia MT. Self-emulsifying and selfmicroemulsifying formulations for the oral administration of taxoids. EP1498143A12005

[84] Benita S, Garrigue, JS, Gursoy N, Lambert G, Razafindratsita A, Yang S. Self-emulsifying drug delivery systems for poorly soluble drugs. EP1340497A1. 2003

[85] Hao WH, Hsu CS, Wang JJ. Self-emulsifying pharmaceutical composition with enhanced bioavailability. EP2062571A1. 2012

[86] Battung F, Sansoë L, Hassan E. Self-microemulsifying mitotane composition. EP2435022A2. 2012

**79**

**Chapter 6**

**Abstract**

controlled release

**1. Introduction**

Cyclodextrin Nanosponges:

A Promising Approach for

Modulating Drug Delivery

Nanotechnology showed great promise and impact on administration of therapeutic agents owing to its advantages over contemporary delivery systems. Nanoscale carriers like nanosponges represent a novel category of hyper crosslinked polymer structures with nanosized cavities which can be filled with variety of active moieties (hydrophilic as well as hydrophobic). These nanocarriers can circulate around the body until they found the specific target site and adhere on the surface and release the active moiety in a predictable and controlled manner, resulting in more effective delivery of a given dosage. Nanosponge technology helps to reduce drug associated side effects, improve stability, increase elegance and improve the flexibility of formulations, administered orally, parenterally and topically. Among nanosponges, *cyclodextrin-based nanosponges (CDNS)* are smart versatile carriers studied widely for drug delivery applications. Statistically, it have presented that approximately 40% of active moieties marketed currently and about 90% of active moieties in their preliminary phase confront problems regarding to solubility. In the past decade, the number of studies describing CDNS has dramatically increased. In the present chapter, scientists working in arena of nanotechnology can get an idea of fabrication, characterization and therapeutic utilities of nanosponges.

**Keywords:** drug targeting, solubility enhancement, porosity, nanocarrier,

The development of new active moiety is very expensive and time consuming. Currently, it is estimated the bringing a new portion of active moiety through discovery, development, clinical trials and regulatory approval will take a decade and cost approximately \$120 million. Therefore, an attempt has been made to improve the safety efficacy relationship of established drugs using a variety of methods, such as individualized drug therapy, therapeutic drug monitoring and dose titration. The delivery of active moieties at controlled rate and targeted delivery have attracted the attention of research community and hence, pursued vigorously [1–4]. Further, effective and safe delivery of therapeutic drug molecules has always posed challenge for formulation scientists. For this purpose, numerous nanocarriers have been fabricated and explored. Nanoformulations are highly multifunctional delivery systems possessing a range of applications such as enhanced solubility, stability, specific targeting, on-demand release and degradation within suitable period of time [5].

*Sunil Kumar, Pooja Dalal and Rekha Rao*

#### **Chapter 6**

Controlled Release. 2008;129:1-10. DOI:

Colloid Science in Pharmaceutical Nanotechnology

[81] Wasylaschuk WR, Harmon PA, Wagner G. Evaluation of hydro peroxides in common pharmaceutical excipients. Journal of Pharmaceutical Sciences. 2007;96:106-116. DOI:

[82] Bowtle W. Materials, process, and manufacturing considerations for lipid-

Bioavailability of Poorly Water Soluble Drugs. Vol. 170. New York: Informa

[83] Cote S, Gaudel G, Peracchia MT.

microemulsifying formulations for the

[84] Benita S, Garrigue, JS, Gursoy N, Lambert G, Razafindratsita A, Yang S. Self-emulsifying drug delivery systems for poorly soluble drugs. EP1340497A1.

based hard- capsule formats. In: Hauss DJ, editor. Oral Lipid Based Formulations Enhancing the

10.1016/j.jconrel.2008.03.021

10.1002/jps.20726

Healthcare; 2007

EP1498143A12005

2003

78

Self-emulsifying and self-

oral administration of taxoids.

[85] Hao WH, Hsu CS, Wang JJ. Self-emulsifying pharmaceutical composition with enhanced bioavailability. EP2062571A1. 2012

[86] Battung F, Sansoë L, Hassan E. Self-microemulsifying mitotane composition. EP2435022A2. 2012

## Cyclodextrin Nanosponges: A Promising Approach for Modulating Drug Delivery

*Sunil Kumar, Pooja Dalal and Rekha Rao*

#### **Abstract**

Nanotechnology showed great promise and impact on administration of therapeutic agents owing to its advantages over contemporary delivery systems. Nanoscale carriers like nanosponges represent a novel category of hyper crosslinked polymer structures with nanosized cavities which can be filled with variety of active moieties (hydrophilic as well as hydrophobic). These nanocarriers can circulate around the body until they found the specific target site and adhere on the surface and release the active moiety in a predictable and controlled manner, resulting in more effective delivery of a given dosage. Nanosponge technology helps to reduce drug associated side effects, improve stability, increase elegance and improve the flexibility of formulations, administered orally, parenterally and topically. Among nanosponges, *cyclodextrin-based nanosponges (CDNS)* are smart versatile carriers studied widely for drug delivery applications. Statistically, it have presented that approximately 40% of active moieties marketed currently and about 90% of active moieties in their preliminary phase confront problems regarding to solubility. In the past decade, the number of studies describing CDNS has dramatically increased. In the present chapter, scientists working in arena of nanotechnology can get an idea of fabrication, characterization and therapeutic utilities of nanosponges.

**Keywords:** drug targeting, solubility enhancement, porosity, nanocarrier, controlled release

#### **1. Introduction**

The development of new active moiety is very expensive and time consuming. Currently, it is estimated the bringing a new portion of active moiety through discovery, development, clinical trials and regulatory approval will take a decade and cost approximately \$120 million. Therefore, an attempt has been made to improve the safety efficacy relationship of established drugs using a variety of methods, such as individualized drug therapy, therapeutic drug monitoring and dose titration. The delivery of active moieties at controlled rate and targeted delivery have attracted the attention of research community and hence, pursued vigorously [1–4]. Further, effective and safe delivery of therapeutic drug molecules has always posed challenge for formulation scientists. For this purpose, numerous nanocarriers have been fabricated and explored. Nanoformulations are highly multifunctional delivery systems possessing a range of applications such as enhanced solubility, stability, specific targeting, on-demand release and degradation within suitable period of time [5].

Nanoformulations and nanoparticles have already been applied as carriers of active moieties with great success; and they have an even greater potential for many applications, like gene therapy, anti-tumor therapy, radiotherapy and AIDS therapy, in the delivery of virostatics, antibiotics, proteins and vaccines [6]. Among the various novel forms of drug delivery nanovehicle, colloidal systems like nanosponges have emerged as promising and potential carrier for promising drug delivery of tough molecules in the past few decades [5] because other novel carrier systems have their own drawbacks enlisted in **Table 1.**

Nanosponges are a new class of structures based on hyper reticulated polymers that have cavities in the nanorange [7, 8]. Nanosponge technology offers pay load of active moieties and thought to help in reducing side effects, increase elegance, improve formulation flexibility and stability. These are non-mutagenic, non-irritating, non-toxic and non-allergenic. In comparison with other nanostructres, NS are insoluble in organic solvents and water. NS are non-toxic, porous, biodegradable and highly stable (up to 300°C) [9]. These nanostructures are able to transport both hydrophilic and lipophilic moieties and improve the solubilization efficacy of drugs. Nanosponge based drug delivery system is used to improve the performance of drugs administered orally, parenterally, pulmonary and topically [10]. Many active moieties with different pharmacological activities, structures and solubility have been encapsulated in NSs, including camptothecin, paclitaxel, doxorubicin, dexamethasone, 5-fluorouracil, itraconazole, nelfinavir mesylate, progesterone, tamoxifen and resveratrol [11]. Further, we acknowledge some excellent reviews that have been published earlier on nanosponges [8, 12–15]. Some of the well-known nanosponges are titanium based NS, silicon NS and cyclodextrin NS [16]. Nanosponges possess various attractive features [17] like


Despite of these advantages, nanosponges have some limitations also. Only small molecules can be entrapped which depend on loading capacities [18]. Cyclodextrin nanosponges can be categorized into four successive generations, on the basis their chemical configuration and features (**Table 2**).

**81**

**Table 2.**

**Table 1.**

**2. Architecture of nanosponges**

*Evolution of cyclodextrin based nanosponges.*

Second Modified

Fourth Molecularly

nanosponges

*Novel drug carrier systems with their limitations.*

imprinted nanosponges

mer cross linking agent and drug moiety [44]**.**

Typically, nanosponges have been constructed from cyclodextrin cross-linked with organic carbonates. Nanosponges mainly comprise of three components- poly-

nanosponges

**Generation Category Sub category References**

ether nanosponges, cyclodextrin-based carbonate nanosponges, ester nanosponges

**Limitations References**

Challenging large-scale up, polymer toxicity, [21, 22]

entrapment of active molecules, Expeditiously taken

Insufficient stability and reproducibility, problematic

up by reticular endothelial system (RES)

stability during storage, rapid drug leakage,

Fluorescent carbonate nanosponges, fluorescent carboxylated nanosponges, electrically charged CD-NSs, hydrophobic NSs

hydrogels, glutathione-responsive NSs, aminocyclodextrin nanosponges

Molecularly imprinted polymers based CD

[33–36]

[19]

[20]

[23]

[20, 27]

[37, 38]

[39–41]

[42, 43]

First Plain nanosponges Cyclodextrin-based urethane nanosponges

Thirrd Stimuli nanosponges pH responsive cross-linked CD based

Nature and type of polymer used can impact the formulation and the performance of NS. The selection of polymer relies on the nature of drug and purpose for which drug is encapsulated. For drug targeting the polymer should possess

*Cyclodextrin Nanosponges: A Promising Approach for Modulating Drug Delivery*

1 Microspheres Premature release of active molecules, deficient

8 Liposome Weak load capacity, poor chemical and physical

2 Liposphere Weak loading capacity, limited chemical and physical

sterilization, low payload

 Niosome Less skin penetration [28] Transferosome Chemically unstable, very expensive [29] Sphingosome Low entrapment efficacy, high cost of sphingolipids [30] Ethosome Poor yield [31] Phytosomes Low stability [32]

5 Nanolipid Carriers Sterilization difficulties [23, 24] 6 Micelle Not good for hydrophilic drugs [25] 7 Dendrimers Polymer dependent biocompatibility [26]

stability on storage, rapid drug leakage,

*DOI: http://dx.doi.org/10.5772/intechopen.90365*

**carrier systems**

Nanoparticle

Nanoparticle

**S. No. Novel drug** 

3 Polymeric

4 Solid lipid


*Cyclodextrin Nanosponges: A Promising Approach for Modulating Drug Delivery DOI: http://dx.doi.org/10.5772/intechopen.90365*

#### **Table 1.**

*Colloid Science in Pharmaceutical Nanotechnology*

own drawbacks enlisted in **Table 1.**

features [17] like

solids

• Targeted site specific drug delivery.

with healthy tissue).

• Simple method production

• Gives predictable release.

chemical configuration and features (**Table 2**).

polymer.

• Easy to scale-up.

in these, after mixing with cross-linker.

Nanoformulations and nanoparticles have already been applied as carriers of active moieties with great success; and they have an even greater potential for many applications, like gene therapy, anti-tumor therapy, radiotherapy and AIDS therapy, in the delivery of virostatics, antibiotics, proteins and vaccines [6]. Among the various novel forms of drug delivery nanovehicle, colloidal systems like nanosponges have emerged as promising and potential carrier for promising drug delivery of tough molecules in the past few decades [5] because other novel carrier systems have their

Nanosponges are a new class of structures based on hyper reticulated polymers that have cavities in the nanorange [7, 8]. Nanosponge technology offers pay load of active moieties and thought to help in reducing side effects, increase elegance, improve formulation flexibility and stability. These are non-mutagenic, non-irritating, non-toxic and non-allergenic. In comparison with other nanostructres, NS are insoluble in organic solvents and water. NS are non-toxic, porous, biodegradable and highly stable (up to 300°C) [9]. These nanostructures are able to transport both hydrophilic and lipophilic moieties and improve the solubilization efficacy of drugs. Nanosponge based drug delivery system is used to improve the performance of drugs administered orally, parenterally, pulmonary and topically [10]. Many active moieties with different pharmacological activities, structures and solubility have been encapsulated in NSs, including camptothecin, paclitaxel, doxorubicin, dexamethasone, 5-fluorouracil, itraconazole, nelfinavir mesylate, progesterone, tamoxifen and resveratrol [11]. Further, we acknowledge some excellent reviews that have been published earlier on nanosponges [8, 12–15]. Some of the well-known nanosponges are titanium based NS, silicon NS and cyclodextrin NS [16]. Nanosponges possess various attractive

• Can be employed to mask unpleasant flavors and to turn liquid substances to

• Being suitable aqueous solubility, the hydrophobic drugs can be encapsulated

• Less harmful side effects (since small amount of the active moiety is in contact

• The drug profile can be tailored from fast, medium to slow release as per need.

Despite of these advantages, nanosponges have some limitations also. Only small molecules can be entrapped which depend on loading capacities [18]. Cyclodextrin nanosponges can be categorized into four successive generations, on the basis their

• Particle size can be varied by using different proportion of cross-linker to

**80**

*Novel drug carrier systems with their limitations.*


**Table 2.**

*Evolution of cyclodextrin based nanosponges.*

#### **2. Architecture of nanosponges**

Typically, nanosponges have been constructed from cyclodextrin cross-linked with organic carbonates. Nanosponges mainly comprise of three components- polymer cross linking agent and drug moiety [44]**.**

Nature and type of polymer used can impact the formulation and the performance of NS. The selection of polymer relies on the nature of drug and purpose for which drug is encapsulated. For drug targeting the polymer should possess

the capacity to bind with specific ligands. The capacity of the polymer to be crosslinked depends on its active and functional groups to be substituted [44]**.** Polymers used for architecting the NS are include polyvinyl alcohol (PVA), ethyl cellulose, polymethylmethacrylate, hyper connected polystyrenes, cyclodextrins and their derivatives like methyl beta cyclodextrins, alkyloxycarbonylcyclodextrins [45]**.** Among these, cyclodextrins (CDs) have been the most popularly employed for fabrication of nanosponges. These cone-shaped truncated cyclic oligosaccharides are comprised of glucopyranose units aligned around the hydrophobic cavity that may lodge guest moieties owing to inclusion complexes formation [46]. The basic physicochemical features of CD have been discovered in the early 1950s and since then they have been applied to improve the pharmaceutical and physicochemical properties, like stability, solubility and bioavailability of active moieties [47]. Conventionally, these nanosponges have been applied for decontamination of water [48]. However, nowadays they have been investigated and employed as nanocarriers for drug delivery in the field of pharmaceuticals.

Cyclodextrin complexes prepared with biocompatible hydrophilic polymers have been reported to enhance the solubility of encapsulated categories in aqueous media. Recently, it has been described that, by reacting cyclodextrins with crosslinkers, a new hyper-crosslinked nanostructured material can be obtained; these are termed as nanosponges [49].

Selection of crosslinker depends on the structure of polymer employed and active moiety to be incorporated [44]. Efficient crosslinkers help to transform molecular nanocavities into three-dimensional nanoporous products. By varying the degree of crosslinking, either hydrophobic or hydrophilic matrix can be formulated and possesses ability to entrap targeted moieties. By taking epichlorohydrin as a crosslinker, hydrophilic nanosponges can be developed, which can modify the amount of active moiety release, increase the absorption of active moiety through biological barriers and act as a potential system for immediate release formulations. Other cross-linking agents, like pyromellitic anhydride, diphenyl carbonate, diisocyanates, diarylcarbonates, glutarldehyde, carbonyldiimidazoles, 2,2 bis(acrylamido) acetic acid and carboxylic acid dianhydrides result in hydrophobic nanosponges [16, 50].

#### **3. Engineering of cyclodextrin based nanosponges**

Nanosponges are synthesized depending on type of delivery system, polymer and nature of drug and solvents [14]. Various approaches used for formation of nanosponges are (**Table 3**).

#### **3.1 Techniques for synthesis of cyclodextrin based nanosponges**

Several techniques have been reported for synthesis of nanosponges, however melt method and solvent evaporation techniques have been widely reported in literature for preparation of these porous colloidal nanostructures (**Figure 1**).

An account of various methods that have been proposed is presented below:

#### *3.1.1 Melt method*

In brief way, the cross-linking agent is melted with CD and all components are homogenized and heated at 100°C with stirring magnetically for 5 hrs. Then, above matrix is allowed to cool. Frequent bathing is done to eliminate by-products and unreacted components [47].

**83**

**Types of nanosponge**

Cyclodextrin carbonate nanosponges Cyclodextrin carbomate nanosponges Cyclodextrin anhydride

Anhydride

Pyromellitic dianhydride,

Ethylenediaminetetraacetic acid

dianhydride

cross-linkers

nanosponges

Epichlorohydrin

Epichlorohydrin

Epichlorohydrin

Solvent method

Creatinine, cilazapril captopril and enalapril

[67, 68]

cross linkers

cyclodextrin

nanosponges

**Table 3.** *Engineering of cyclodextrin based nanosponges.*

Diisocyanate cross-linkers

Hexamethylene diisocyanate and Toluene diisocyanate

Carbonyl cross-linkers

**Crosslinkers**

**Example of crosslinkers**

Diphenyl carbonate, Carbonyl diimidazole, Dimethyl carbonate

Solvent extraction, Thermal desorption

Solvent method

Solvent method

L-DOPA, erlotinib, quercetin, telmisartan, curcumin, reservertol, tamoxifen, paclitaxel, Itraconazole, Camptothecin,

Dextromethorphan, Steroids, Dyes and Naringin

Ibuprofen, doxorubicin, meloxicam, acetylsalicylic

[36, 39,

64–66]

acid and strigolactones

[60–63]

**Method**

**Encapsulated drugs**

*Cyclodextrin Nanosponges: A Promising Approach for Modulating Drug Delivery*

*DOI: http://dx.doi.org/10.5772/intechopen.90365*

**References**

[43, 51–59]


#### *Cyclodextrin Nanosponges: A Promising Approach for Modulating Drug Delivery DOI: http://dx.doi.org/10.5772/intechopen.90365*

**Table 3.**

*Engineering of cyclodextrin based nanosponges.*

*Colloid Science in Pharmaceutical Nanotechnology*

for drug delivery in the field of pharmaceuticals.

termed as nanosponges [49].

nanosponges [16, 50].

nanosponges are (**Table 3**).

unreacted components [47].

*3.1.1 Melt method*

the capacity to bind with specific ligands. The capacity of the polymer to be crosslinked depends on its active and functional groups to be substituted [44]**.** Polymers used for architecting the NS are include polyvinyl alcohol (PVA), ethyl cellulose, polymethylmethacrylate, hyper connected polystyrenes, cyclodextrins and their derivatives like methyl beta cyclodextrins, alkyloxycarbonylcyclodextrins [45]**.** Among these, cyclodextrins (CDs) have been the most popularly employed for fabrication of nanosponges. These cone-shaped truncated cyclic oligosaccharides are comprised of glucopyranose units aligned around the hydrophobic cavity that may lodge guest moieties owing to inclusion complexes formation [46]. The basic physicochemical features of CD have been discovered in the early 1950s and since then they have been applied to improve the pharmaceutical and physicochemical properties, like stability, solubility and bioavailability of active moieties [47]. Conventionally, these nanosponges have been applied for decontamination of water [48]. However, nowadays they have been investigated and employed as nanocarriers

Cyclodextrin complexes prepared with biocompatible hydrophilic polymers have been reported to enhance the solubility of encapsulated categories in aqueous media. Recently, it has been described that, by reacting cyclodextrins with crosslinkers, a new hyper-crosslinked nanostructured material can be obtained; these are

Selection of crosslinker depends on the structure of polymer employed and active moiety to be incorporated [44]. Efficient crosslinkers help to transform molecular nanocavities into three-dimensional nanoporous products. By varying the degree of crosslinking, either hydrophobic or hydrophilic matrix can be formulated and possesses ability to entrap targeted moieties. By taking epichlorohydrin as a crosslinker, hydrophilic nanosponges can be developed, which can modify the amount of active moiety release, increase the absorption of active moiety through biological barriers and act as a potential system for immediate release formulations. Other cross-linking agents, like pyromellitic anhydride, diphenyl carbonate,

diisocyanates, diarylcarbonates, glutarldehyde, carbonyldiimidazoles, 2,2-

**3. Engineering of cyclodextrin based nanosponges**

**3.1 Techniques for synthesis of cyclodextrin based nanosponges**

bis(acrylamido) acetic acid and carboxylic acid dianhydrides result in hydrophobic

Nanosponges are synthesized depending on type of delivery system, polymer and nature of drug and solvents [14]. Various approaches used for formation of

Several techniques have been reported for synthesis of nanosponges, however melt method and solvent evaporation techniques have been widely reported in literature for preparation of these porous colloidal nanostructures (**Figure 1**). An account of various methods that have been proposed is presented below:

In brief way, the cross-linking agent is melted with CD and all components are homogenized and heated at 100°C with stirring magnetically for 5 hrs. Then, above matrix is allowed to cool. Frequent bathing is done to eliminate by-products and

**82**

**Figure 1.**

*Various techniques for fabrication of nanosponges.*

#### *3.1.2 Solvent evaporation technique*

In solvent evaporation method, the fusion step is avoided and solvents like dimethylsulfoxide (DMSO) or dimethylformamide (DMF) are employed to solubilize the cross-linking agent. Polymer is mixed with solvent (polar aprotic) and the mixture obtained is put in solution of cross-linker and refluxed for 1–48 hrs. By adding cold solution to a large surplus of distilled water, the product is achieved. Finally, filtration is done to recover of the final product and is purified using Soxhlet extraction for prolonged periods. The product achieved is spherical and solid nanostructures with high water solubility either by non-inclusion or inclusion mechanism. The size of NS can be reduced by high pressure homogenization where water suspension of prepared nanosponges is homogenized at constant speed for 10 min [48, 49, 69].

#### *3.1.3 Ultrasound-assisted synthesis*

In ultrasound-assisted fabrication, in first, cyclodextrins are reacted with crosslinking agents under ultrasound without solvents. Anhydrous β-CD and DPC are taken in a vial and put in an ultrasound bath, pre-filled with water (at 90°C) and sonicated for 5 hrs. Furthermore, crystallization and purification steps are same as in solvent evaporation and melt technique [70].

#### *3.1.4 Microwave assisted synthesis*

It is the simplest method for synthesizing of CDNS using microwave irradiation, remarkably retards the reaction time. The resultant NS possess higher degree of crystallization. In comparison to common melt method, microwave assisted fabrication had exhibited four time reduction in reaction time. The process led to production of particle homogeneous distribution and crystallinity [52].

**85**

*Cyclodextrin Nanosponges: A Promising Approach for Modulating Drug Delivery*

Crystal structure of the active moiety acts as one of the important criteria that determine its complex efficiency with CD and nanosponges. Paracrystalline and crystalline NS vary in the drug loading capacities. When compared, crystalline NS result in higher drug pay load the paracrystalline NS [47, 58, 71]. The porous crosslinked blank NS have numerous interactive sites for inclusion of drug moieties than parent CD. Further, these possess numerous mesh polarities owing to hydrophobic channels of CD which are enclosed by hydrophilic nanocavities of the polymeric matrix, allowing for large interactions with guests of variable lipophilicities and structures [72]. The resultant polymeric network of NS may be responsible for NS protection and solubilization compared to original CD as shown in **Figure 2** [58, 71]. The active moieties are entrapped into nanopores of blank nanosponges by dispersing them within drug dispersion and consequently freeze drying. The solvent evaporation is one another method reported for loading active moieties into NS using organic solvents suitable for dissolving the active moiety. Finally, NS are added to the prepared active moiety dispersion and triturated until the solvent

Spectroscopic analytical tools represent a complementary tool to evaluate nanosponges. The variation in properties such as fluorescence intensity, wave number, absorbance and NMR shift of NS can be investigated by different spectroscopic

To analyze NS in solution (liquid medium), UV–Visible spectrophotometry is a fast, simple, valuable and economic tool. The solubilization efficacy of various molecules such as telmisartan (296 nm) [53], acetyl salicyclic acid (234 nm) [65], resveratrol (303 nm) [55], repaglinide (283 nm) [75], quercetin (372 nm) [76] and efavirenz (286 nm) [73] entrapped in NS have been analyzed using this tool.

Anandam and Selvamuthukumar checked payload, stability assay in simulated intestinal fluid, *in vitro* release, metal chelating and photostability investigation for

quercetin NS via this spectrophotometeric tool (λmax 372 nm) [76].

*DOI: http://dx.doi.org/10.5772/intechopen.90365*

**3.2 Drug loading into blank NS**

*Schematic representation of engineering of cyclodextrin based nanosponges.*

**Figure 2.**

evaporates [47, 73, 74].

analytical tools.

**4.1 Spectroscopic techniques**

*4.1.1 Ultraviolet: Visible spectrophotometry*

**4. Analytical techniques to characterize nanosponges**

*Cyclodextrin Nanosponges: A Promising Approach for Modulating Drug Delivery DOI: http://dx.doi.org/10.5772/intechopen.90365*

**Figure 2.**

*Colloid Science in Pharmaceutical Nanotechnology*

*3.1.2 Solvent evaporation technique*

*Various techniques for fabrication of nanosponges.*

**Figure 1.**

*3.1.3 Ultrasound-assisted synthesis*

*3.1.4 Microwave assisted synthesis*

in solvent evaporation and melt technique [70].

In solvent evaporation method, the fusion step is avoided and solvents like dimethylsulfoxide (DMSO) or dimethylformamide (DMF) are employed to solubilize the cross-linking agent. Polymer is mixed with solvent (polar aprotic) and the mixture obtained is put in solution of cross-linker and refluxed for 1–48 hrs. By adding cold solution to a large surplus of distilled water, the product is achieved. Finally, filtration is done to recover of the final product and is purified using Soxhlet extraction for prolonged periods. The product achieved is spherical and solid nanostructures with high water solubility either by non-inclusion or inclusion mechanism. The size of NS can be reduced by high pressure homogenization where water suspension of prepared nanosponges is homogenized at constant speed for 10 min [48, 49, 69].

In ultrasound-assisted fabrication, in first, cyclodextrins are reacted with crosslinking agents under ultrasound without solvents. Anhydrous β-CD and DPC are taken in a vial and put in an ultrasound bath, pre-filled with water (at 90°C) and sonicated for 5 hrs. Furthermore, crystallization and purification steps are same as

It is the simplest method for synthesizing of CDNS using microwave irradiation, remarkably retards the reaction time. The resultant NS possess higher degree of crystallization. In comparison to common melt method, microwave assisted fabrication had exhibited four time reduction in reaction time. The process led to

production of particle homogeneous distribution and crystallinity [52].

**84**

*Schematic representation of engineering of cyclodextrin based nanosponges.*

#### **3.2 Drug loading into blank NS**

Crystal structure of the active moiety acts as one of the important criteria that determine its complex efficiency with CD and nanosponges. Paracrystalline and crystalline NS vary in the drug loading capacities. When compared, crystalline NS result in higher drug pay load the paracrystalline NS [47, 58, 71]. The porous crosslinked blank NS have numerous interactive sites for inclusion of drug moieties than parent CD. Further, these possess numerous mesh polarities owing to hydrophobic channels of CD which are enclosed by hydrophilic nanocavities of the polymeric matrix, allowing for large interactions with guests of variable lipophilicities and structures [72]. The resultant polymeric network of NS may be responsible for NS protection and solubilization compared to original CD as shown in **Figure 2** [58, 71]. The active moieties are entrapped into nanopores of blank nanosponges by dispersing them within drug dispersion and consequently freeze drying. The solvent evaporation is one another method reported for loading active moieties into NS using organic solvents suitable for dissolving the active moiety. Finally, NS are added to the prepared active moiety dispersion and triturated until the solvent evaporates [47, 73, 74].

#### **4. Analytical techniques to characterize nanosponges**

#### **4.1 Spectroscopic techniques**

Spectroscopic analytical tools represent a complementary tool to evaluate nanosponges. The variation in properties such as fluorescence intensity, wave number, absorbance and NMR shift of NS can be investigated by different spectroscopic analytical tools.

#### *4.1.1 Ultraviolet: Visible spectrophotometry*

To analyze NS in solution (liquid medium), UV–Visible spectrophotometry is a fast, simple, valuable and economic tool. The solubilization efficacy of various molecules such as telmisartan (296 nm) [53], acetyl salicyclic acid (234 nm) [65], resveratrol (303 nm) [55], repaglinide (283 nm) [75], quercetin (372 nm) [76] and efavirenz (286 nm) [73] entrapped in NS have been analyzed using this tool.

Anandam and Selvamuthukumar checked payload, stability assay in simulated intestinal fluid, *in vitro* release, metal chelating and photostability investigation for quercetin NS via this spectrophotometeric tool (λmax 372 nm) [76].

#### *4.1.2 Fourier-transform infrared spectroscopy*

It is major employed technique for characterization of nanosponges. In general, measurements of FTIR absorption are carried out on dry samples, in the range 400–4000 cm<sup>−</sup><sup>1</sup> [77]. In case of nanosponges, during the reticulation (cross linking), the vibrational modes of cross-linkers, polymers and moieties are displayed from parent positions, broadening or disappearance of the prominent peaks of the molecule, polymer and cross-linkers [78, 79]**.**

In FTIR spectra of the placebo NS, bands that varies from 1700 to 1750 cm<sup>−</sup><sup>1</sup> evidences the carbonate bond. Although, the parent polymer for NS fabrication, β-CD does not show peak at 1750 cm<sup>−</sup><sup>1</sup> in FTIR spectrum [76]**.** Cavalli and his colleagues explored the occurrence of carbonate bond (1700 cm<sup>−</sup><sup>1</sup> ) in NS [80]**.**

#### *4.1.3 Raman spectroscopy (RS)*

Nowadays, it is suggested as a useful analytical tool to study drug entrapment in NS [81]. Not only this, it can be employed together with FTIR to provide a better image to investigate interactions of active moiety and NS. Swaminathan and his colleagues performed RS to investigate dexamethasone and nanosponge interaction. On complexation with nanosponges, the prominent bands of the dexamethasone at 1620, 1480, 1440, 950 and 680 cm<sup>−</sup><sup>1</sup> in Raman spectra of the active moiety were substantially masked or displaced, advocating the inclusion phenomenon [82].

#### *4.1.4 Nuclear magnetic resonance*

It is based on the principle of radiofrequency radiation absorption by atomic nuclei having non zero spins in a high magnetic field [83]. Olteanu and co-workers performed the physicochemical characterization of NS using 1H-NMR. High alteration in the chemical shift (0.47–0.24 ppm) of repaglinide A ring protons was observed. It was envisioned that inclusion in hydrophobic pores of CD and steric hinderance owing to CD substitution, have been considered responsible for interaction phenomenon [75].

#### **4.2 Differential scanning calorimetry**

It is a thermoanalytical technique to measure the change in physical or chemical properties of nanostructures and their fabricating materials owing to alteration in temperature. In general, thermal processes (both exothermic and endothermic) are evidenced by the peak direction [84]. This tool explored the exothermic and endothermic processes at the temperature range from −120 to 600°C [85–88]. The thermal behavior of the various drugs (dexamethasone, furbiprofen, doxorubicin [80], Itraconazole [59], camptothecin [58], resverarol [55], amino salicylic acid [65], gamma-oryzanol [89], telmisartan [53], curcumin [54], acyclovir [37], quercetin [76] and meloxicam [64]) entrapped in the NS was examined by DSC.

The complete disappearance of the therapeutic molecule fusion peak in graph of the NS complex is commonly considered as a confirmatory evidence of the encapsulation of therapeutic molecule within the NS cavity [90]. This may be due to conversion of the crystalline nature to amorphous ones [91]. Other evidence for confirming NS fabrication reported by research scientists include alterations in temperature peak and shape of cyclodextrins, alongwith disappearance of active moiety fusion peak and appearance of new peaks [92].

**87**

prepared [37].

*Cyclodextrin Nanosponges: A Promising Approach for Modulating Drug Delivery*

is widespread approach to solid-state characterization of nanosponges.

Thermogravimetric analysis (TGA) is crucial for supply of fundamental data for NS characterization. Due to its very simplicity, relative reliability and rapidity, TGA

TGA chart of dexamethasone, quercetin, silibinin, apple polyphenols NS have been explored. In drug loaded NS thermograms, endotherms of the pure drug disappeared fully, evidencing the potential encapsulation of these molecules in

It gives detailed information on phases, texture, structures and other structural parameters (crystallinity, crystal defects and deformation) [95]. Unlikely thermal techniques, sample does not suffer any physical or chemical changes during analysis. Furthermore, XRPD studies can support the results of thermal methods. The complete amorphization of the sample in DSC analysis, can be validated by this

Crystalline and paracrystalline nature of NS and porosity can be revealed using this technique. A number of molecules (acetyl salicylic acid [65], camptothecin [58], telmisartan [53], resveratrol [55], acyclovir [37], quercetin [76], meloxicam [64], curcumin [54], and dexamethasone [82]) encapsulated in nanosponges have

Microscopy can be used as an imaging analytical technique for qualitative analysis of NS with respect to their aggregation, size and shape. This section provides information on the microscopic methods like AFM, SEM, TEM, and CLSM that are

Scanning electron microscopy is used for observation of surface processes and

A nanoscale imaging tool, TEM is used to visualize and characterize various types of nanoparticles [99, 100]. It is relatively expensive and slow technique. Surface morphology via TEM has also been performed for several NS such as ibuprofen [36], quercetin [76], acyclovir [37], paclitaxel [57], dexamethasone [82],

Recently developed microscopic technique with high resolution, atomic force microscopy (AFM) is used for viewing atoms and molecules [101]. AFM has been applied to image the molecular nature of β-CDNS in the distilled water and to investigate their mechanical properties. The paracrystalline NS presented spherical colloidal structures (nearly 600 nm), whereas the crystalline NS presented the

Confocal laser scanning microscopy (CLSM) is recently emerging tool to improve the optical contrast and resolution of sample graph [102]. Lembo and his co-workers examined carboxylated NS loaded with acyclovir for cellular uptake of nanopreparation through CLSM. For this, fluorescent carboxylated NS were

camptothecin [58], resveratrol [55], acetyl salicylic acid [65].

spectacular crystal planes (nearby 500 nm) [82].

is capable of obtaining images of bulky samples with a greater depth. It is also employed in solid state evaluation of nanosponges [97]. The topographic changes (related to the interactions of the polymer, active moiety and cross-linking agent) are provided [98]. Various pharmacological active molecules like resveratrol [55], telmisartan [53], dexamethasone [82], and meloxicam [64] have been explored

*DOI: http://dx.doi.org/10.5772/intechopen.90365*

**4.3 Thermogravimetric analysis**

nanostructures [82, 93, 94].

technique.

**4.4 X-ray diffraction techniques**

been evaluated using this technique.

properly used for NS characterization [96].

**4.5 Microscopic techniques**

microscopically using SEM.

#### **4.3 Thermogravimetric analysis**

*Colloid Science in Pharmaceutical Nanotechnology*

*4.1.2 Fourier-transform infrared spectroscopy*

molecule, polymer and cross-linkers [78, 79]**.**

explored the occurrence of carbonate bond (1700 cm<sup>−</sup><sup>1</sup>

dexamethasone at 1620, 1480, 1440, 950 and 680 cm<sup>−</sup><sup>1</sup>

does not show peak at 1750 cm<sup>−</sup><sup>1</sup>

*4.1.3 Raman spectroscopy (RS)*

*4.1.4 Nuclear magnetic resonance*

phenomenon [82].

tion phenomenon [75].

examined by DSC.

**4.2 Differential scanning calorimetry**

moiety fusion peak and appearance of new peaks [92].

400–4000 cm<sup>−</sup><sup>1</sup>

It is major employed technique for characterization of nanosponges. In general,

[77]. In case of nanosponges, during the reticulation (cross link-

in FTIR spectrum [76]**.** Cavalli and his colleagues

) in NS [80]**.**

in Raman spectra of the

evi-

measurements of FTIR absorption are carried out on dry samples, in the range

ing), the vibrational modes of cross-linkers, polymers and moieties are displayed from parent positions, broadening or disappearance of the prominent peaks of the

In FTIR spectra of the placebo NS, bands that varies from 1700 to 1750 cm<sup>−</sup><sup>1</sup>

dences the carbonate bond. Although, the parent polymer for NS fabrication, β-CD

Nowadays, it is suggested as a useful analytical tool to study drug entrapment

in NS [81]. Not only this, it can be employed together with FTIR to provide a better image to investigate interactions of active moiety and NS. Swaminathan and his colleagues performed RS to investigate dexamethasone and nanosponge interaction. On complexation with nanosponges, the prominent bands of the

active moiety were substantially masked or displaced, advocating the inclusion

It is based on the principle of radiofrequency radiation absorption by atomic nuclei having non zero spins in a high magnetic field [83]. Olteanu and co-workers performed the physicochemical characterization of NS using 1H-NMR. High alteration in the chemical shift (0.47–0.24 ppm) of repaglinide A ring protons was observed. It was envisioned that inclusion in hydrophobic pores of CD and steric hinderance owing to CD substitution, have been considered responsible for interac-

It is a thermoanalytical technique to measure the change in physical or chemical properties of nanostructures and their fabricating materials owing to alteration in temperature. In general, thermal processes (both exothermic and endothermic) are evidenced by the peak direction [84]. This tool explored the exothermic and endothermic processes at the temperature range from −120 to 600°C [85–88]. The thermal behavior of the various drugs (dexamethasone, furbiprofen, doxorubicin [80], Itraconazole [59], camptothecin [58], resverarol [55], amino salicylic acid [65], gamma-oryzanol [89], telmisartan [53], curcumin [54], acyclovir [37], quercetin [76] and meloxicam [64]) entrapped in the NS was

The complete disappearance of the therapeutic molecule fusion peak in graph of the NS complex is commonly considered as a confirmatory evidence of the encapsulation of therapeutic molecule within the NS cavity [90]. This may be due to conversion of the crystalline nature to amorphous ones [91]. Other evidence for confirming NS fabrication reported by research scientists include alterations in temperature peak and shape of cyclodextrins, alongwith disappearance of active

**86**

Thermogravimetric analysis (TGA) is crucial for supply of fundamental data for NS characterization. Due to its very simplicity, relative reliability and rapidity, TGA is widespread approach to solid-state characterization of nanosponges.

TGA chart of dexamethasone, quercetin, silibinin, apple polyphenols NS have been explored. In drug loaded NS thermograms, endotherms of the pure drug disappeared fully, evidencing the potential encapsulation of these molecules in nanostructures [82, 93, 94].

#### **4.4 X-ray diffraction techniques**

It gives detailed information on phases, texture, structures and other structural parameters (crystallinity, crystal defects and deformation) [95]. Unlikely thermal techniques, sample does not suffer any physical or chemical changes during analysis. Furthermore, XRPD studies can support the results of thermal methods. The complete amorphization of the sample in DSC analysis, can be validated by this technique.

Crystalline and paracrystalline nature of NS and porosity can be revealed using this technique. A number of molecules (acetyl salicylic acid [65], camptothecin [58], telmisartan [53], resveratrol [55], acyclovir [37], quercetin [76], meloxicam [64], curcumin [54], and dexamethasone [82]) encapsulated in nanosponges have been evaluated using this technique.

#### **4.5 Microscopic techniques**

Microscopy can be used as an imaging analytical technique for qualitative analysis of NS with respect to their aggregation, size and shape. This section provides information on the microscopic methods like AFM, SEM, TEM, and CLSM that are properly used for NS characterization [96].

Scanning electron microscopy is used for observation of surface processes and is capable of obtaining images of bulky samples with a greater depth. It is also employed in solid state evaluation of nanosponges [97]. The topographic changes (related to the interactions of the polymer, active moiety and cross-linking agent) are provided [98]. Various pharmacological active molecules like resveratrol [55], telmisartan [53], dexamethasone [82], and meloxicam [64] have been explored microscopically using SEM.

A nanoscale imaging tool, TEM is used to visualize and characterize various types of nanoparticles [99, 100]. It is relatively expensive and slow technique. Surface morphology via TEM has also been performed for several NS such as ibuprofen [36], quercetin [76], acyclovir [37], paclitaxel [57], dexamethasone [82], camptothecin [58], resveratrol [55], acetyl salicylic acid [65].

Recently developed microscopic technique with high resolution, atomic force microscopy (AFM) is used for viewing atoms and molecules [101]. AFM has been applied to image the molecular nature of β-CDNS in the distilled water and to investigate their mechanical properties. The paracrystalline NS presented spherical colloidal structures (nearly 600 nm), whereas the crystalline NS presented the spectacular crystal planes (nearby 500 nm) [82].

Confocal laser scanning microscopy (CLSM) is recently emerging tool to improve the optical contrast and resolution of sample graph [102]. Lembo and his co-workers examined carboxylated NS loaded with acyclovir for cellular uptake of nanopreparation through CLSM. For this, fluorescent carboxylated NS were prepared [37].

#### **4.6 Measurement of zeta potential**

The zeta potential (ZP) is employed to measure the electrokinetic potential of nanomedicines. Simply, it is used for quantifying the charge [103]. To investigate the charge on the nanostructures, ZP must be carried out by suspending them in distilled water or suspension medium [104]. CDNS have been evaluated via the electrophoretic light scattering technique [53, 80, 105]. In practice, ZP predicts surface charge and colloidal stability of nanomaterials.

#### **5. Nanosponges in drug delivery**

Owing to their versatile, biocompatible and nanoporous nature, nanosponges have variety of applications in pharmaceuticals, cosmetics, agriculture, environment, food and polymer industry [55, 80, 106–108]. Among these, they have been predominantly studied for drug delivery. Numerous active molecules including lipophilic and hydrophilic actives and volatile oils can be conventionally entrapped in these multifaceted nanostructures for solubility and stability enhancement and for controlled delivery [7]. Hence, these novel carriers have attracted much interest of formulation scientists as they hold promise in addressing other challenges like poor bioavailability, permeation and therapeutic activity [69]. Cyclodextrin nanosponges have also been explored for drug delivery and drug targeting for cancer management [40, 109, 110]. In the following sections, information regarding their applications in pharmaceutical field has been summarized (**Table 4**).


**89**

*Cyclodextrin Nanosponges: A Promising Approach for Modulating Drug Delivery*

Gamma-oryzanol Antioxidant Topical Improved antioxidant

Telmisartan Antihypertensive Oral Improved intrinsic

Efavirenz Anti HIV Oral Bioavailability

Lysozyme Antihypcaalcemic Oral Inhibit depletion

inflammatory and analgesic

Quercetin Antioxidant — Enhanced

Tazarotene Anti acne topical Improved bioavailability

Strigolactones Anti-cancer — Targeted delivery to

Rilpinavir Anti-retroviral Oral Increased in

Lansoprazole Antiulcer Oral Prolonged drug release [113]

Anti-cancer — Dual drug delivery [114]

**administration**

**Remarks References**

[89]

[93]

[53]

[73]

[105]

[76]

[115]

[43]

[117]

[118]

[66]

[119]

[74]

[120]

potential and photostability

Oral Solubility enhancement [75]

solubility and bioavailability

enhancement

of calcium in antibiotic associated hypocalcemic condition

Oral Controlled release [64]

photostability and anti-oxidant activity; Improved dissolution

and skin retention of

profile

drug

enhancement

enhancement

Oral Enhancement of stability

activity

prostate cancer cells

and hypoglycemic

intestinal permeation and antibacterial activity

Bioavailability

Oral Prolonged release of drug

Insect Repellent Topical Prolong the persistence [116]

Oral Bioavailability

Oral Bioavailability

Oral Enhancement in

Topical High degree of retention and protection

*DOI: http://dx.doi.org/10.5772/intechopen.90365*

Repaglinide Hypoglycemic

Apple polyphenols (Rutin, phloridzin and chlorogenic

acid)

Tamoxifen and quercetin

Meloxicam Anti-

Levodopa Anti Parkinson's

Norfloxacin fluoroquinolone

N,N Diethyl-Meta-Toluamide

Rosuvastatin Anti-

Atorvastatin Calcium

*Salvia officinalis* essential oil

disease

Antihyperlipidemic

hyperlipidemic

Hypoglycemic activity

antibiotic

**Drug candidate Category Route of** 

agent

Antioxidant antiaging and anti-inflammatroy


*Colloid Science in Pharmaceutical Nanotechnology*

surface charge and colloidal stability of nanomaterials.

The zeta potential (ZP) is employed to measure the electrokinetic potential of nanomedicines. Simply, it is used for quantifying the charge [103]. To investigate the charge on the nanostructures, ZP must be carried out by suspending them in distilled water or suspension medium [104]. CDNS have been evaluated via the electrophoretic light scattering technique [53, 80, 105]. In practice, ZP predicts

Owing to their versatile, biocompatible and nanoporous nature, nanosponges have variety of applications in pharmaceuticals, cosmetics, agriculture, environment, food and polymer industry [55, 80, 106–108]. Among these, they have been predominantly studied for drug delivery. Numerous active molecules including lipophilic and hydrophilic actives and volatile oils can be conventionally entrapped in these multifaceted nanostructures for solubility and stability enhancement and for controlled delivery [7]. Hence, these novel carriers have attracted much interest of formulation scientists as they hold promise in addressing other challenges like poor bioavailability, permeation and therapeutic activity [69]. Cyclodextrin nanosponges have also been explored for drug delivery and drug targeting for cancer management [40, 109, 110]. In the following sections, information regarding their

**administration**

**Remarks References**

[80, 82]

[80]

[80]

[59]

[56]

[55]

[57, 111]

[54, 112]

[58]

[37]

solubility

solubility

solubility

efficiency

of drug

potential

pharmacokinetic activity

stability and cytotoxicity against HCPC-1 cells

migration of tumor cells

anticancer activity

Enhanced antiviral activity against HSV-1 (clinical isolates)

applications in pharmaceutical field has been summarized (**Table 4**).

Dexamethasone Anti-inflammatory Oral, Parenteral Improved aqueous

Flurbiprofen Anti-inflammatory Oral Improved aqueous

Doxorubicin Antineoplastic Parenteral Enhanced aqueous

Tamoxifen Antiestrogen Oral Enhanced

Itraconazole Antifungal Oral, Topical Improved solubilization

Resveratrol Antioxidant Oral, Topical Enhanced permeation,

Paclitaxel Antineoplastic Parenteral *In vitro* enhancement of

Camptothecin Antineoplastic Parenteral Inhibits the adhesion and

Acetylsalicylic acid Analgesic Oral Controlled release [65]

parenteral

Curcumin Anti-cancer Oral Higher solubilization

Acyclovir Antiviral Oral, topical,

**Drug candidate Category Route of** 

**4.6 Measurement of zeta potential**

**5. Nanosponges in drug delivery**

**88**


#### **Table 4.**

*Active molecules encapsulated in cyclodextrin based nanosponges.*

#### **5.1 Improved stability**

Cyclodextrin nanosponges can prevent degradation of drug molecules which are susceptible to degradation when exposed to water, oxygen (air), heat or radiation. Such interactions are being widely studied in nanosponges. The nanosponges safeguard the drug molecules from oxidation, hydrolysis, racemization, polymerization and enzyme hydrolysis [126, 127]. A number of molecules including L-DOPA, resveratrol, camptothecin and γ-oryzanol and have been encapsulated in nanosponges are reported for stability enhancement and reported [43, 55, 58, 89]. Anandam and Selvamuthukumar found that phototability of anti-oxidant drug quercetin increased on incorporating into nanosponges. The main hindrance in its utility is its photodegradation. In addition, dissolution rate of the biomolecule was also remarkably enhanced in quercetin nanosponges.

#### **5.2 Enhanced solubility**

Poor solubility of BCS (Biopharmaceutical Classification System) class II drugs possesses a challenge in their formulation. However, these drugs can be successfully incorporated into cyclodextrin nanosponges with better efficacy. These nanocarriers improve their aqueous solubility *via* formation of inclusion complexes by enhancing their wetting and solubility in water. The drug dissolution enhancement consequently enhances their bioavailability. Curcumin is a upcoming herbal active drug having potential for treatment of various fatal diseases including cancer. Though, it has higher efficacy and safety profile, its poor solubility and low bioavailability limit its therapeutic application. Darandale and Vavia fabricated cyclodextrin based nanosponges of curcumin to increase solubility and control its release. These nanosponges were obtained using dimethyl carbonate as linking agent. The prepared nanoformulation showed enhanced solubility, prolonged drug release and reduced cytotoxicity against MCF-7 cells. Besides this, other drug moieties which have been successfully encapsulated in cyclodextrin nanosponges for improved dissolution include doxorubicin [80], itraconazole [59], flurbiprofen, dexamethasone [80], telmisartan [53], tamoxifen [56], repaglinide [75] and paclitaxel [111].

#### **5.3 Reduction in volatility of essential oil and material handling benefits**

Nanosponges have been reported to protect volatile oils against lost by evaporation. These nanosponges can have resulted in long lasting effect due to slow release

**91**

*Cyclodextrin Nanosponges: A Promising Approach for Modulating Drug Delivery*

ment in solubility also led to improve *in vitro* release behavior [64].

of chief volatile components of oils [72]. Further, volatile oil liquids (at room temperature) can be difficult to handle and hence needed to be formulate into stable solid formulations. Nanosponges may help to convert these substances into amorphous or microcrystalline powders which are convenient to handle [49].

Judicious loading of therapeutic actives into nanosponges ensures a tailored drug release. Developing controlled drug delivery systems is the topic of interest for research community while maintaining therapeutic effectiveness of drug. Employing these nanocarriers ensures optimal drug use with improved patient compliance owing to reduced frequency of administration. Nanosponges showed strong potential for providing sustained drug release in a controlled fashion. Shende et al.*,* prepared meloxicam loaded cyclodextrin nanosponges to enhance solubility and stability and to prolong its release. *In vitro* and *in vivo* results demonstrated controlled release of meloxicam from the nanocarrier for 24 hrs. It was discussed that slow release of drug might have been due to large degree of cross linking that permitted the entrapment of drug as inclusion complex in the nanosponges. Decrease in crystallinity and enhance-

Besides enhancing effectiveness of drug, drug targeting also helps in reducing its adverse effects on healthy cells. By using nanosponges for drug delivery, drug is released at the specific site preventing its circulation throughout the body. A limited number of research papers were found on drug targeting using nanosponges. Harth and Diaz have widely explored nanosponges for targeted drug delivery. Polyester nanosponges were fabricated using special chemical "linkers" for delivery of anti-cancer drugs. These linkers ensure that nanosponge bound selectively to tumor cells, on injection. These nanosponges stick to the surface of tumor cells and release

Oral drug delivery has been well-established route of administration having high patient compliance. However, delivery of molecules *via* this route poses challenges owing to poor solubility, presystemic activation and inefficient intestinal permeability. Cyclodextrin based nanosponges have emerged as potential carriers for oral delivery without any compromise on safety issues. An excellent mini review on cyclodextrin nanosystems for oral delivery of drugs have been recently published by

Zidan et al., have developed atorvastatin calcium for oral drug delivery by encapsulating it in β- cyclodextrin nanosponges cross linked with carbonyldiimidazole. The prepared nanosponges were found to increase bioavailability of drug up to 2.13-folds in comparison to its suspension. In addition, pharmacokinetic studies revealed remarkable decrease in total cholesterol, LDL-C (Low Density Lipoprotein

Nanosponges can also be incorporated in cream and gels for topical delivery

Cholesterol) and triglyceride and improved level of HDL-C (High Density Lipoprotein Cholesterol) leading to improvement of liver steatosis [117].

of drugs. Although least explored, nanosponges may prove very promising

*DOI: http://dx.doi.org/10.5772/intechopen.90365*

**5.4 Modulated drug release**

**5.5 Drug targeting**

the drug in a controlled fashion [128].

Adeoye and Cabral-Marques [129].

**5.7 Topical drug delivery**

**5.6 Oral drug delivery**

of chief volatile components of oils [72]. Further, volatile oil liquids (at room temperature) can be difficult to handle and hence needed to be formulate into stable solid formulations. Nanosponges may help to convert these substances into amorphous or microcrystalline powders which are convenient to handle [49].

#### **5.4 Modulated drug release**

*Colloid Science in Pharmaceutical Nanotechnology*

Ellagic acid Antioxidant,

**Drug candidate Category Route of** 

Anticancer

*Active molecules encapsulated in cyclodextrin based nanosponges.*

Doxirubicin Anti-cancer Oral Site specific drug

Imiquimod Anti-cancer Toipcal Enhanced skin retention

Babchi oil Anti-psoriatic Topical Enhanced

**5.1 Improved stability**

**Table 4.**

**5.2 Enhanced solubility**

Cyclodextrin nanosponges can prevent degradation of drug molecules which are susceptible to degradation when exposed to water, oxygen (air), heat or radiation. Such interactions are being widely studied in nanosponges. The nanosponges safeguard the drug molecules from oxidation, hydrolysis, racemization, polymerization and enzyme hydrolysis [126, 127]. A number of molecules including L-DOPA, resveratrol, camptothecin and γ-oryzanol and have been encapsulated in nanosponges are reported for stability enhancement and reported [43, 55, 58, 89]. Anandam and Selvamuthukumar found that phototability of anti-oxidant drug quercetin increased on incorporating into nanosponges. The main hindrance in its utility is its photodegradation. In addition, dissolution rate of the biomolecule was

**administration**

Oral Enhancement in oral

bioavailability

and permeation

photostability, solubility and anti psoriatic efficacy

delivery

**Remarks References**

[121]

[122]

[125]

[123, 124]

Poor solubility of BCS (Biopharmaceutical Classification System) class II drugs possesses a challenge in their formulation. However, these drugs can be successfully incorporated into cyclodextrin nanosponges with better efficacy. These nanocarriers improve their aqueous solubility *via* formation of inclusion complexes by enhancing their wetting and solubility in water. The drug dissolution enhancement consequently enhances their bioavailability. Curcumin is a upcoming herbal active drug having potential for treatment of various fatal diseases including cancer. Though, it has higher efficacy and safety profile, its poor solubility and low bioavailability limit its therapeutic application. Darandale and Vavia fabricated cyclodextrin based nanosponges of curcumin to increase solubility and control its release. These nanosponges were obtained using dimethyl carbonate as linking agent. The prepared nanoformulation showed enhanced solubility, prolonged drug release and reduced cytotoxicity against MCF-7 cells. Besides this, other drug moieties which have been successfully encapsulated in cyclodextrin nanosponges for improved dissolution include doxorubicin [80], itraconazole [59], flurbiprofen, dexamethasone [80],

telmisartan [53], tamoxifen [56], repaglinide [75] and paclitaxel [111].

**5.3 Reduction in volatility of essential oil and material handling benefits**

Nanosponges have been reported to protect volatile oils against lost by evaporation. These nanosponges can have resulted in long lasting effect due to slow release

also remarkably enhanced in quercetin nanosponges.

**90**

Judicious loading of therapeutic actives into nanosponges ensures a tailored drug release. Developing controlled drug delivery systems is the topic of interest for research community while maintaining therapeutic effectiveness of drug. Employing these nanocarriers ensures optimal drug use with improved patient compliance owing to reduced frequency of administration. Nanosponges showed strong potential for providing sustained drug release in a controlled fashion. Shende et al.*,* prepared meloxicam loaded cyclodextrin nanosponges to enhance solubility and stability and to prolong its release. *In vitro* and *in vivo* results demonstrated controlled release of meloxicam from the nanocarrier for 24 hrs. It was discussed that slow release of drug might have been due to large degree of cross linking that permitted the entrapment of drug as inclusion complex in the nanosponges. Decrease in crystallinity and enhancement in solubility also led to improve *in vitro* release behavior [64].

#### **5.5 Drug targeting**

Besides enhancing effectiveness of drug, drug targeting also helps in reducing its adverse effects on healthy cells. By using nanosponges for drug delivery, drug is released at the specific site preventing its circulation throughout the body. A limited number of research papers were found on drug targeting using nanosponges. Harth and Diaz have widely explored nanosponges for targeted drug delivery. Polyester nanosponges were fabricated using special chemical "linkers" for delivery of anti-cancer drugs. These linkers ensure that nanosponge bound selectively to tumor cells, on injection. These nanosponges stick to the surface of tumor cells and release the drug in a controlled fashion [128].

#### **5.6 Oral drug delivery**

Oral drug delivery has been well-established route of administration having high patient compliance. However, delivery of molecules *via* this route poses challenges owing to poor solubility, presystemic activation and inefficient intestinal permeability. Cyclodextrin based nanosponges have emerged as potential carriers for oral delivery without any compromise on safety issues. An excellent mini review on cyclodextrin nanosystems for oral delivery of drugs have been recently published by Adeoye and Cabral-Marques [129].

Zidan et al., have developed atorvastatin calcium for oral drug delivery by encapsulating it in β- cyclodextrin nanosponges cross linked with carbonyldiimidazole. The prepared nanosponges were found to increase bioavailability of drug up to 2.13-folds in comparison to its suspension. In addition, pharmacokinetic studies revealed remarkable decrease in total cholesterol, LDL-C (Low Density Lipoprotein Cholesterol) and triglyceride and improved level of HDL-C (High Density Lipoprotein Cholesterol) leading to improvement of liver steatosis [117].

#### **5.7 Topical drug delivery**

Nanosponges can also be incorporated in cream and gels for topical delivery of drugs. Although least explored, nanosponges may prove very promising

for treatment of skin disorders *via* this route. Besides drug targeting nanosponges also improved drug delivery from topical gel, if entrapped successfully. Nanosponges for topical delivery of drugs have been mentioned for resveratrol, γ-oryzanol, diclofenac sodium and babchi oil in literature [55, 89, 106, 124]. In addition, this nanoformulation also helps to alleviate local irritation problem associated with topical drugs. Conte et al., developed cyclodextrin nanosponges with pyromellitic dianhydride as cross linker and loaded them in semi-solid formulations for skin delivery. Skin permeation studies in diclofenac sodium loaded nanosponge gel and cream gels significantly retarded the drug permeation through skin while enhancing its concentration in viable epidermis and stratum corneum, confirming the localization of highly penetrating drugs in external layers of skin [11].

#### **5.8 Pulmonary drug delivery**

The pulmonary route is an alternative option to parenteral drug delivery, however, for delivery *via* this route, the drug must be in the form of aerosol. The nanosponges possess the advantage of reduced interparticle attraction forces and better flow characteristics. Further, they possess low bulk density and small narrow dynamic diameter resulting in their greater deposition in lower pulmonary area. For pulmonary delivery, nanosponges of sodium cromoglicate, budesinide, bendroflumethazide using sugar excipients like trehalose and raffinose have been reported [130–133].

Additionally, nanosponges have also been used for protein encapsulation, enzyme immobilization and stabilization. The enzymes like isomerase, hydrolase, oxidoreductase, ligase, and transferase has been studied. Bovine serum albumin when encapsulated as nanosponges resulted in prolonged release [13]. NS can also be employed as carrier of gases like carbondioxide and oxygen. Oxygen loaded NS can be used to supply oxygen to hypoxic tissues in different disorders [134].

#### **6. Conclusion**

Cyclodextrin nanosponges are colloidal nanoparticles made from inexpensive, biodegradable materials and can be used for internal or external administration. As such, these offer a versatile platform to address challenges like solubility, stability and toxicity for therapeutically effective drugs. Cyclodextrin nanosponges are developing rapidly in the field of nanotechnology possessing several applications in drug targeting, delivery and research, as well as in other fields. Due to their unique porous nature and size-dependent properties, they present the possibility to develop new therapeutic options. Their ability to entrap drugs and controlled release features offer a new mode in drug delivery resulting in higher levels of drug targeting. Therefore, cyclodextrin nanosponges are a great promise to achieve the goal of site specific and controlled delivery aspects and can open new perspectives in the management of complex diseases, in coming future.

#### **Acknowledgements**

The author Mr. Sunil Kumar is thankful to the Indian Council of Medical Research, New Delhi for providing Senior Research Fellowship (Letter No: 45/44/2018-Nan/BMS on dated 14/05/2018).

**93**

**Author details**

Sunil Kumar, Pooja Dalal and Rekha Rao\*

provided the original work is properly cited.

\*Address all correspondence to: rekhaline@gmail.com

and Technology, Hisar, Haryana, India

Department of Pharmaceutical Sciences, Guru Jambheshwar University of Science

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

*Cyclodextrin Nanosponges: A Promising Approach for Modulating Drug Delivery*

The authors have no conflict of interest to declare and are responsible for the

*DOI: http://dx.doi.org/10.5772/intechopen.90365*

content and writing of the manuscript.

**Conflict of interest**

*Cyclodextrin Nanosponges: A Promising Approach for Modulating Drug Delivery DOI: http://dx.doi.org/10.5772/intechopen.90365*

#### **Conflict of interest**

*Colloid Science in Pharmaceutical Nanotechnology*

layers of skin [11].

[130–133].

disorders [134].

**6. Conclusion**

**Acknowledgements**

**5.8 Pulmonary drug delivery**

for treatment of skin disorders *via* this route. Besides drug targeting nanosponges also improved drug delivery from topical gel, if entrapped successfully. Nanosponges for topical delivery of drugs have been mentioned for resveratrol, γ-oryzanol, diclofenac sodium and babchi oil in literature [55, 89, 106, 124]. In addition, this nanoformulation also helps to alleviate local irritation problem associated with topical drugs. Conte et al., developed cyclodextrin nanosponges with pyromellitic dianhydride as cross linker and loaded them in semi-solid formulations for skin delivery. Skin permeation studies in diclofenac sodium loaded nanosponge gel and cream gels significantly retarded the drug permeation through skin while enhancing its concentration in viable epidermis and stratum corneum, confirming the localization of highly penetrating drugs in external

The pulmonary route is an alternative option to parenteral drug delivery, however, for delivery *via* this route, the drug must be in the form of aerosol. The nanosponges possess the advantage of reduced interparticle attraction forces and better flow characteristics. Further, they possess low bulk density and small narrow dynamic diameter resulting in their greater deposition in lower pulmonary area. For pulmonary delivery, nanosponges of sodium cromoglicate, budesinide, bendroflumethazide using sugar excipients like trehalose and raffinose have been reported

Additionally, nanosponges have also been used for protein encapsulation, enzyme immobilization and stabilization. The enzymes like isomerase, hydrolase, oxidoreductase, ligase, and transferase has been studied. Bovine serum albumin when encapsulated as nanosponges resulted in prolonged release [13]. NS can also be employed as carrier of gases like carbondioxide and oxygen. Oxygen loaded NS can be used to supply oxygen to hypoxic tissues in different

Cyclodextrin nanosponges are colloidal nanoparticles made from inexpensive, biodegradable materials and can be used for internal or external administration. As such, these offer a versatile platform to address challenges like solubility, stability and toxicity for therapeutically effective drugs. Cyclodextrin nanosponges are developing rapidly in the field of nanotechnology possessing several applications in drug targeting, delivery and research, as well as in other fields. Due to their unique porous nature and size-dependent properties, they present the possibility to develop new therapeutic options. Their ability to entrap drugs and controlled release features offer a new mode in drug delivery resulting in higher levels of drug targeting. Therefore, cyclodextrin nanosponges are a great promise to achieve the goal of site specific and controlled delivery aspects and can open new perspectives

The author Mr. Sunil Kumar is thankful to the Indian Council of Medical Research, New Delhi for providing Senior Research Fellowship (Letter No:

in the management of complex diseases, in coming future.

45/44/2018-Nan/BMS on dated 14/05/2018).

**92**

The authors have no conflict of interest to declare and are responsible for the content and writing of the manuscript.

#### **Author details**

Sunil Kumar, Pooja Dalal and Rekha Rao\* Department of Pharmaceutical Sciences, Guru Jambheshwar University of Science and Technology, Hisar, Haryana, India

\*Address all correspondence to: rekhaline@gmail.com

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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[108] Seglie L, Spadaro D, Trotta F, Devecchi M, Gullino ML, Scariot V. Use of 1-methylcylopropene in cyclodextrinbased nanosponges to control grey mould caused by Botrytis cinerea on Dianthus caryophyllus cut flowers. Postharvest Biology and Technology. 2012;**64**(1):55-57

[109] Minelli R, Cavalli R, Ellis L, Pettazzoni P, Trotta F, Ciamporcero E, et al. Nanosponge-encapsulated camptothecin exerts anti-tumor activity in human prostate cancer cells. European Journal of Pharmaceutical Sciences. 2012;**47**(4):686-694

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*Cyclodextrin Nanosponges: A Promising Approach for Modulating Drug Delivery*

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Sallam MA. Carboxylate cross-linked cyclodextrin: A nanoporous scaffold for enhancement of rosuvastatin oral bioavailability. European Journal of Pharmaceutical Sciences. 2018;**111**:1-12

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2018;**31**(5):2069-2076

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[123] Kumar S, Trotta F,

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Rao R. Encapsulation of Babchi oil in cyclodextrin-based nanosponges: Physicochemical characterization, photodegradation, and in vitro cytotoxicity studies. Pharmaceutics. 2018;**10**(4):169. DOI: 10.3390/ pharmaceutics10040169

Afouna MI, Ibrahim EA. In vitro and in vivo evaluation of cyclodextrinbased nanosponges for enhancing oral bioavailability of atorvastatin calcium. Drug Development and Industrial Pharmacy. 2018;**44**(8):1243-1253

*DOI: http://dx.doi.org/10.5772/intechopen.90365*

[111] Mognetti B, Barberis A, Marino S, Berta G, De Francia S, Trotta F, et al. In vitro enhancement of anticancer activity of paclitaxel by a Cremophor free cyclodextrin-based nanosponge formulation. Journal of Inclusion Phenomena and Macrocyclic Chemistry.

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2016;**8**(4):579-601

2012;**74**(1-4):201-210

[112] Pushpalatha R, Selvamuthukumar S, Kilimozhi D. Cross-linked, cyclodextrin-based nanosponges for curcumin delivery-physicochemical characterization, drug release, stability and cytotoxicity. Journal of Drug Delivery Science and Technology. 2018;**45**:45-53

[113] Penjuri SC, Ravouru N,

[114] Lockhart JN, Stevens DM, Beezer DB, Kravitz A, Harth E. Dual drug delivery of tamoxifen and quercetin: Regulated metabolism for anticancer treatment with nanosponges.

Journal of Controlled Release.

[115] Aggarwal G, Nagpal M, Kaur G. Development and comparison of nanosponge and niosome based gel for the topical delivery of tazarotene. Pharmaceutical nanotechnology.

[116] Peila R, Scordino P, Shanko DB, Caldera F, Trotta F, Ferri A. Synthesis and characterization of β-cyclodextrin nanosponges for N, N-diethyl-metatoluamide complexation and their application on polyester fabrics. Reactive and Functional Polymers.

2016;**13**(3):304-310

2015;**220**:751-757

2016;**4**(3):213-228

2017;**119**:87-94

Damineni S, Bns S, Formulation PSR. Evaluation of lansoprazole loaded nanosponges. Turkish Journal of Pharmaceutical Sciences.

#### *Cyclodextrin Nanosponges: A Promising Approach for Modulating Drug Delivery DOI: http://dx.doi.org/10.5772/intechopen.90365*

A versatile platform for cancer nanotherapeutics development. Wiley Interdisciplinary Reviews. Nanomedicine and Nanobiotechnology. 2016;**8**(4):579-601

*Colloid Science in Pharmaceutical Nanotechnology*

[103] Kutscher HL, Chao P,

rigid microparticles in rats.

2010;**402**(1-2):64-71

Deshmukh M, Rajan SS, Singh Y, Hu P, et al. Enhanced passive pulmonary targeting and retention of PEGylated

International Journal of Pharmaceutics.

[104] Radomska-Soukharev A. Stability

nanoparticles. Advanced Drug Delivery

[105] Deshmukh K, Tanwar YS, Sharma S, Shende P, Cavalli R. Functionalized nanosponges for controlled antibacterial

Na-diclofenac β-cyclodextrin inclusion complex on cotton wound dressing. The Journal of The Textile Institute.

[107] Seglie L, Martina K, Devecchi M, Roggero C, Trotta F, Scariot V. The effects of 1-MCP in cyclodextrin-based nanosponges to improve the vase life of Dianthus caryophyllus cut flowers. Postharvest Biology and Technology.

[108] Seglie L, Spadaro D, Trotta F, Devecchi M, Gullino ML, Scariot V. Use of 1-methylcylopropene in cyclodextrinbased nanosponges to control grey mould caused by Botrytis cinerea on Dianthus caryophyllus cut flowers. Postharvest Biology and Technology.

[109] Minelli R, Cavalli R, Ellis L, Pettazzoni P, Trotta F, Ciamporcero E, et al. Nanosponge-encapsulated camptothecin exerts anti-tumor activity in human prostate cancer cells. European Journal of Pharmaceutical Sciences. 2012;**47**(4):686-694

[110] Swaminathan S, Cavalli R, Trotta F. Cyclodextrin-based nanosponges:

of lipid excipients in solid lipid

Reviews. 2007;**59**(6):411-418

and antihypocalcemic actions. Biomedicine and Pharmacotherapy.

[106] Montazer M, Mehr EB.

2016;**84**:485-494

2010;**101**(5):373-379

2011;**59**(2):200-205

2012;**64**(1):55-57

[95] Bunaciu AA, UdriŞTioiu EG, Aboul-Enein HY. X-ray diffraction: Instrumentation and applications. Critical Reviews in Analytical Chemistry. 2015;**45**(4):289-299

[96] Luykx DM, Peters RJ, van Ruth SM, Bouwmeester H. A review of analytical methods for the identification and characterization of nano delivery systems in food. Journal of Agricultural and Food Chemistry. 2008;**56**(18):8231-8247

[97] Fraunhofer W, Winter G. The use of asymmetrical flow field-flow fractionation in pharmaceutics and biopharmaceutics. European Journal of Pharmaceutics and Biopharmaceutics.

[98] Maestrelli F, Cecchi M, Cirri M, Capasso G, Mennini N, Mura P. Comparative study of oxaprozin complexation with natural and chemically-modified cyclodextrins in solution and in the solid state. Journal of Inclusion Phenomena and Macrocyclic

Chemistry. 2009;**63**(1-2):17-25

[99] Williams DB, Carter CB. The transmission electron microscope. In: Transmission Electron Microscopy. Boston, MA: Springer; 1996. pp. 3-17

[100] Wang ZL. Transmission electron microscopy of shape-controlled nanocrystals and their assemblies. The Journal of Physical Chemistry B.

[102] Jonkman J, Brown CM. Any way you slice it—A comparison of confocal microscopy techniques. Journal of Biomolecular Techniques: JBT.

2004;**58**(2):369-383

2000;**104**:1153-1175

2005;**25**(1):81-89

2015;**26**(2):54

[101] Ruozi B, Tosi G, Forni F, Fresta M, Vandelli MA. Atomic force microscopy and photon correlation spectroscopy: Two techniques for rapid characterization of liposomes. European Journal of Pharmaceutical Sciences.

**100**

[111] Mognetti B, Barberis A, Marino S, Berta G, De Francia S, Trotta F, et al. In vitro enhancement of anticancer activity of paclitaxel by a Cremophor free cyclodextrin-based nanosponge formulation. Journal of Inclusion Phenomena and Macrocyclic Chemistry. 2012;**74**(1-4):201-210

[112] Pushpalatha R, Selvamuthukumar S, Kilimozhi D. Cross-linked, cyclodextrin-based nanosponges for curcumin delivery-physicochemical characterization, drug release, stability and cytotoxicity. Journal of Drug Delivery Science and Technology. 2018;**45**:45-53

[113] Penjuri SC, Ravouru N, Damineni S, Bns S, Formulation PSR. Evaluation of lansoprazole loaded nanosponges. Turkish Journal of Pharmaceutical Sciences. 2016;**13**(3):304-310

[114] Lockhart JN, Stevens DM, Beezer DB, Kravitz A, Harth E. Dual drug delivery of tamoxifen and quercetin: Regulated metabolism for anticancer treatment with nanosponges. Journal of Controlled Release. 2015;**220**:751-757

[115] Aggarwal G, Nagpal M, Kaur G. Development and comparison of nanosponge and niosome based gel for the topical delivery of tazarotene. Pharmaceutical nanotechnology. 2016;**4**(3):213-228

[116] Peila R, Scordino P, Shanko DB, Caldera F, Trotta F, Ferri A. Synthesis and characterization of β-cyclodextrin nanosponges for N, N-diethyl-metatoluamide complexation and their application on polyester fabrics. Reactive and Functional Polymers. 2017;**119**:87-94

[117] Zidan MF, Ibrahim HM, Afouna MI, Ibrahim EA. In vitro and in vivo evaluation of cyclodextrinbased nanosponges for enhancing oral bioavailability of atorvastatin calcium. Drug Development and Industrial Pharmacy. 2018;**44**(8):1243-1253

[118] Gabr MM, Mortada SM, Sallam MA. Carboxylate cross-linked cyclodextrin: A nanoporous scaffold for enhancement of rosuvastatin oral bioavailability. European Journal of Pharmaceutical Sciences. 2018;**111**:1-12

[119] Nait Bachir Y, Nait Bachir R, Hadj-Ziane-Zafour A. Nanodispersions stabilized by β-cyclodextrin nanosponges: Application for simultaneous enhancement of bioactivity and stability of sage essential oil. Drug Development and Industrial Pharmacy. 2019;**45**(2):333-347

[120] Mendes C, Meirelles GC, Barp CG, Assreuy J, Silva MA, Ponchel G. Cyclodextrin based nanosponge of norfloxacin: Intestinal permeation enhancement and improved antibacterial activity. Carbohydrate Polymers. 2018;**195**:586-592

[121] Mady FM, Ibrahim M, Ragab S. Cyclodextrin-based nanosponge for improvement of solubility and oral bioavailability of ellagic acid. Pakistan Journal of Pharmaceutical Sciences. 2018;**31**(5):2069-2076

[122] Singh P, Ren X, Guo T, Wu L, Shakya S, He Y, et al. Biofunctionalization of β-cyclodextrin nanosponges using cholesterol. Carbohydrate Polymers. 2018;**190**:23-30

[123] Kumar S, Trotta F, Rao R. Encapsulation of Babchi oil in cyclodextrin-based nanosponges: Physicochemical characterization, photodegradation, and in vitro cytotoxicity studies. Pharmaceutics. 2018;**10**(4):169. DOI: 10.3390/ pharmaceutics10040169

[124] Kumar S, Singh KK, Rao R. Enhanced anti-psoriatic efficacy and regulation of oxidative stress of a novel topical babchi oil (*Psoralea corylifolia*) cyclodextrin-based nanogel in a mouse tail model. Journal of Microencapsulation. 2019;**36**(2):140-155. DOI: 10.1080/02652048.2019.1612475

[125] Argenziano M, Haimhoffer A, Bastiancich C, Jicsinszky L, Caldera F, Trotta F, et al. In vitro enhanced skin permeation and retention of imiquimod loaded in β-cyclodextrin nanosponge hydrogel. Pharmaceutics. 2019;**11**(3):138. DOI: 10.3390/ pharmaceutics11030138

[126] Loftsson T, Brewster ME. Pharmaceutical applications of cyclodextrins. 1. Drug solubilization and stabilization. Journal of Pharmaceutical Sciences. 1996;**85**(10):1017-1025

[127] Challa R, Ahuja A, Ali J, Khar RK. Cyclodextrins in drug delivery: An updated review. AAPS PharmSciTech. 2005;**6**(2):E329-E357

[128] Harth E, Diaz R. Nanosponge Drug Delivery System More Effective Than Direct Injection. Nanotechnology Now [Internet]. 2010. Available from: https://news.vanderbilt. edu/2010/06/01/nanosponge-drugdelivery-system-more-effective-thandirect-injection-116839/ [Accessed: May 11, 2019]

[129] Adeoye O, Cabral-Marques H. Cyclodextrin nanosystems in oral drug delivery: A mini review. International Journal of Pharmaceutics. 2017;**531**(2):521-531

[130] Healy AM, McDonald BF, Tajber L, Corrigan OI. Characterisation of excipient-free nanoporous microparticles (NPMPs) of bendroflumethiazide. European Journal of Pharmaceutics and Biopharmaceutics. 2008;**69**(3):1182-1186

[131] Nolan LM, Li J, Tajber L, Corrigan OI, Healy AM. Particle engineering of materials for oral inhalation by dry powder inhalers. II—Sodium cromoglicate. International Journal of Pharmaceutics. 2011;**405**(1-2):36-46

[132] Nolan LM, Tajber L, McDonald BF, Barham AS, Corrigan OI, Healy AM. Excipient-free nanoporous microparticles of budesonide for pulmonary delivery. European Journal of Pharmaceutical Sciences. 2009;**37**(5):593-602

[133] Ógáin ON, Li J, Tajber L, Corrigan OI, Healy AM. Particle engineering of materials for oral inhalation by dry powder inhalers. I— Particles of sugar excipients (trehalose and raffinose) for protein delivery. International Journal of Pharmaceutics. 2011;**405**(1-2):23-35

[134] Indira B, Bolisetti SS, Samrat C, Reddy SM, Reddy NS. Nanosponges: A new era in drug delivery. Journal of Pharmacy Research. 2012;**5**(12):5293-5296

**103**

**Chapter 7**

**Abstract**

poorly soluble drugs

**1. Introduction**

application [1–3].

Effect of Cyclodextrin

Efficacy of Drugs

Derivatization on Solubility and

Cyclodextrins (CDs) possess cyclic structure having (α-1,4)-linked glucopyranose units making them less vulnerable to enzymatic degradation as than the linear dextrins. Commonly used natural CDs are α-CD, β-CD, and ɣ-CD with truncated cone-like appearance having lipophilic central cavity and hydrophilic exterior surface. The problem of low aqueous solubility of natural CDs can be addressed by reacting them with various reagents to produce water-soluble derivatives. CD derivatives can be categorized in many ways depending upon their substituents, biological activity, polarity, and size. The derivatization of natural CDs produces noncrystalline and amorphous forms with higher water solubility that are physically and microbiologically stable for prolonged time period. Variety of methods can be used to determine average degree of substitution for a modified CD. Dissociation by dilution is considered as major release mechanism of drugs from complex. It is essential to optimize the amount of CDs for a given preparation because they can

*Syed Haroon Khalid, Mehreen Bashir, Sajid Asghar,* 

either retard or promote drug delivery through biological membrane.

**Keywords:** natural cyclodextrins, cyclodextrin derivatives, inclusion complex,

Cyclodextrins (CDs), first isolated by Antoine in 1891, are categorized as cyclic oligosaccharides in which glucose units are repeatedly connected through α-1,4 glycosidic linkages. Their unique property is the availability of various hydroxyl groups that serve as active site to form a variety of derivatives and linkages. CDs possess the capability of forming inclusion complexes with various molecules by incorporating them in their inner hydrophobic cavity, which not only alters the biological and physicochemical properties but also expands their magnitude of

Inclusion complexation is basically the formation of hydrogen bonds and Van der Waals' and hydrophobic interactions along with removal of water molecules [4, 5]. CDs are getting popular as food additives, owing to their solubilizing and protecting properties; they can be effectively used for incorporating vitamins, flavors, fragrances, essential oils, and dyes. They not only provide the controlled

*Tauqeer Hussain Mallhi and Ikram Ullah Khan*

#### **Chapter 7**

*Colloid Science in Pharmaceutical Nanotechnology*

[131] Nolan LM, Li J, Tajber L, Corrigan OI, Healy AM. Particle engineering of materials for oral inhalation by dry powder inhalers.

II—Sodium cromoglicate.

[132] Nolan LM, Tajber L,

2011;**405**(1-2):36-46

2009;**37**(5):593-602

2011;**405**(1-2):23-35

2012;**5**(12):5293-5296

A new era in drug delivery. Journal of Pharmacy Research.

[133] Ógáin ON, Li J, Tajber L, Corrigan OI, Healy AM. Particle engineering of materials for oral inhalation by dry powder inhalers. I— Particles of sugar excipients (trehalose and raffinose) for protein delivery. International Journal of Pharmaceutics.

[134] Indira B, Bolisetti SS, Samrat C, Reddy SM, Reddy NS. Nanosponges:

International Journal of Pharmaceutics.

McDonald BF, Barham AS, Corrigan OI, Healy AM. Excipient-free nanoporous microparticles of budesonide for pulmonary delivery. European Journal of Pharmaceutical Sciences.

Microencapsulation. 2019;**36**(2):140-155. DOI: 10.1080/02652048.2019.1612475

[125] Argenziano M, Haimhoffer A, Bastiancich C, Jicsinszky L, Caldera F, Trotta F, et al. In vitro enhanced skin

imiquimod loaded in β-cyclodextrin nanosponge hydrogel. Pharmaceutics.

cyclodextrins. 1. Drug solubilization and stabilization. Journal of Pharmaceutical

[127] Challa R, Ahuja A, Ali J, Khar RK. Cyclodextrins in drug delivery: An updated review. AAPS PharmSciTech.

[128] Harth E, Diaz R. Nanosponge Drug Delivery System More Effective Than Direct Injection. Nanotechnology

Now [Internet]. 2010. Available from: https://news.vanderbilt. edu/2010/06/01/nanosponge-drugdelivery-system-more-effective-thandirect-injection-116839/ [Accessed:

[129] Adeoye O, Cabral-Marques H. Cyclodextrin nanosystems in oral drug delivery: A mini review.

[130] Healy AM, McDonald BF,

of excipient-free nanoporous microparticles (NPMPs) of bendroflumethiazide. European Journal of Pharmaceutics and Biopharmaceutics. 2008;**69**(3):1182-1186

International Journal of Pharmaceutics.

Tajber L, Corrigan OI. Characterisation

permeation and retention of

2019;**11**(3):138. DOI: 10.3390/ pharmaceutics11030138

[126] Loftsson T, Brewster ME. Pharmaceutical applications of

Sciences. 1996;**85**(10):1017-1025

2005;**6**(2):E329-E357

May 11, 2019]

2017;**531**(2):521-531

[124] Kumar S, Singh KK, Rao R. Enhanced anti-psoriatic efficacy and regulation of oxidative stress of a novel topical babchi oil (*Psoralea corylifolia*) cyclodextrin-based nanogel in a mouse tail model. Journal of

**102**

## Effect of Cyclodextrin Derivatization on Solubility and Efficacy of Drugs

*Syed Haroon Khalid, Mehreen Bashir, Sajid Asghar, Tauqeer Hussain Mallhi and Ikram Ullah Khan*

#### **Abstract**

Cyclodextrins (CDs) possess cyclic structure having (α-1,4)-linked glucopyranose units making them less vulnerable to enzymatic degradation as than the linear dextrins. Commonly used natural CDs are α-CD, β-CD, and ɣ-CD with truncated cone-like appearance having lipophilic central cavity and hydrophilic exterior surface. The problem of low aqueous solubility of natural CDs can be addressed by reacting them with various reagents to produce water-soluble derivatives. CD derivatives can be categorized in many ways depending upon their substituents, biological activity, polarity, and size. The derivatization of natural CDs produces noncrystalline and amorphous forms with higher water solubility that are physically and microbiologically stable for prolonged time period. Variety of methods can be used to determine average degree of substitution for a modified CD. Dissociation by dilution is considered as major release mechanism of drugs from complex. It is essential to optimize the amount of CDs for a given preparation because they can either retard or promote drug delivery through biological membrane.

**Keywords:** natural cyclodextrins, cyclodextrin derivatives, inclusion complex, poorly soluble drugs

#### **1. Introduction**

Cyclodextrins (CDs), first isolated by Antoine in 1891, are categorized as cyclic oligosaccharides in which glucose units are repeatedly connected through α-1,4 glycosidic linkages. Their unique property is the availability of various hydroxyl groups that serve as active site to form a variety of derivatives and linkages. CDs possess the capability of forming inclusion complexes with various molecules by incorporating them in their inner hydrophobic cavity, which not only alters the biological and physicochemical properties but also expands their magnitude of application [1–3].

Inclusion complexation is basically the formation of hydrogen bonds and Van der Waals' and hydrophobic interactions along with removal of water molecules [4, 5]. CDs are getting popular as food additives, owing to their solubilizing and protecting properties; they can be effectively used for incorporating vitamins, flavors, fragrances, essential oils, and dyes. They not only provide the controlled

release of drugs and other incorporated molecules but also mask the obnoxious taste and odor [6–9].

The order of water solubility for commonly used cyclodextrins is as follows: β-CD (18.5 gL<sup>−</sup><sup>1</sup> ) < α-CD (145gL<sup>−</sup><sup>1</sup> ) < γ-CD (232 gL<sup>−</sup><sup>1</sup> ). The crystal state of natural CDs indicates strong molecular bonding (high crystal lattice energy) which in turn results in low aqueous solubility. β-CD has limited application as a solubilizing agent due to its low aqueous solubility, despite low cost, ease of availability, and appropriate cavity size. The most likely justification of lower solubility of β-CD is inadequate hydration by water molecule due to intramolecular hydrogen bond interaction offered by optimally arranged secondary hydroxyl groups [10]. Another possible elucidation of low aqueous solubility is the formation of aggregates that leads to unfavorable interactions with the hydrogen bonded structure of water molecule as proposed by Colman and coworkers [11]. β-CD shows Bs-type behavior in phase solubility graph when added to the aqueous drug solution or suspension due to precipitation of respective CD inclusion complex.

The solubilizing power of parent CDs can be enhanced by adopting many different strategies, but the most interesting of them is the derivatization of CDs. The hydroxyl groups of CDs can be substituted to yield a variety of derivatives with significantly high aqueous solubility [12–14]. This chapter discusses the various strategies to functionalize the CDs and the resultant improvement in the aqueous solubility of formed complexes.

#### **2. Functionalized CDs**

Parent CDs can be modified through structural modifications by incorporating hydrophilic moieties that will ultimately result in significant increase in aqueous solubility. Furthermore, the inclusion complexes formed by modified CDs have higher complexation efficiencies than that of parent CDs. Rekharsky and Inoue reported various examples of thermodynamic parameters of inclusion complexes involving derivatized CDs [5].

It is noteworthy that derivatization of CDs does not always enhance the complexation. The inhibition and promotion of complexation solely depends upon the type of substituents. Although the strong electrostatic force of attraction between the cationic substituents and organic anion was predicted to promote complexation, paradoxical effect was observed when the complexation of 2-naphthalene sulfonate was reduced with polyamine derivatives of β-CD. An unfavorable entropic effect may be involved that results in decrease in complexation [15]. On the other hand, a favorable electrostatic interaction occurs that leads to formation of zwitterionic corona by substituting both cationic and anionic groups at the primary face that will ultimately enhance the complexation of amino acids [16].

The interdependence of numerous molecular parameters including type of substituent at the CDs, contribution of hydrophobic, and charge character of the guest moiety and competitive self-complexation (possible inclusion complexation of substituent moiety inside the core of CD) was discussed in detail by Kean and his coworkers [17]. While dealing with ionic species, electrostatic effects are usually dominated which exert a paradoxical effect. Based on this status quo, the inclusion complexation of charged CD with organic ions must be evaluated on the basis of electrostatic interactions. The properties of modified CDs are governed by the location of hydroxyl groups on the parent CDs that are going to be substituted. Three different hydroxyl groups that exert different reactivities are located on the glucose repeating unit of a CD molecule, including one primary hydroxyl group attached to

**105**

**Figure 1.**

*Synthesis of methyl β-CD [21].*

*Effect of Cyclodextrin Derivatization on Solubility and Efficacy of Drugs*

Most common derivatives of CDs are discussed in this section.

C6 (at the narrow side) and two secondary hydroxyl groups attached to C2 and C3

There is variety of ways to perform methylation of native cyclodextrins: Formerly methyl derivatives were synthesized by using either methyl iodide or dimethyl sulfate [18]. These two reagents are highly toxic and unsafe so may be detrimental to the environment as well as human being. Based on this status quo, it is mandatory to seek new and novel synthetic method to replace these toxic

Dimethyl carbonate being eco-friendly could be an attractive alternate in this scenario [19]. The synthesis involves addition of β-CD in dimethylformamide solution followed by stirring until clear solution is obtained. Potassium carbonate is added as catalyst followed by dropwise addition of dimethyl carbonate, and mixture is allowed to stir for the next 48 hours. The catalyst and dimethyl carbonate are removed to produce syrupy consistency. At the end, this concentrate is treated with acetone followed by its removal by filtration. Finally, the product is treated with ether two to three times, and after filtration white powdered product is

An important feature of methyl β-CD is its degree of substitution that has marked effect on drug solubilization, so it must be carefully investigated [20]. **Table 1** gives the use of methyl derivatives of β-CD with effect on solubility and

This pharmaceutically significant methylated derivative of β-CD has the

The replacement of hydroxyl groups of CD by 2-hydroxypropyl moiety can be done by the reaction of CD with propylene oxide in an alkaline aqueous solution (**Figure 2a**) [31]. An isopropylene (oligomeric hydroxypropylene) side chain is

• Easy availability (as dry powder/aqueous solution 50%)

• High inclusion capacity for hydrophobic drugs

formed for high degree of substitution (**Figure 2b**).

*DOI: http://dx.doi.org/10.5772/intechopen.90364*

**2.1 Methyl derivatives of CDs**

obtained as indicated in **Figure 1**.

efficacy of various drugs.

• Good water solubility

following advantages:

• Cost-effective

**2.2 Hydroxypropyl CDs**

(at wider side).

chemicals.

C6 (at the narrow side) and two secondary hydroxyl groups attached to C2 and C3 (at wider side).

Most common derivatives of CDs are discussed in this section.

#### **2.1 Methyl derivatives of CDs**

*Colloid Science in Pharmaceutical Nanotechnology*

) < α-CD (145gL<sup>−</sup><sup>1</sup>

precipitation of respective CD inclusion complex.

solubility of formed complexes.

**2. Functionalized CDs**

involving derivatized CDs [5].

of amino acids [16].

taste and odor [6–9].

β-CD (18.5 gL<sup>−</sup><sup>1</sup>

release of drugs and other incorporated molecules but also mask the obnoxious

The order of water solubility for commonly used cyclodextrins is as follows:

CDs indicates strong molecular bonding (high crystal lattice energy) which in turn results in low aqueous solubility. β-CD has limited application as a solubilizing agent due to its low aqueous solubility, despite low cost, ease of availability, and appropriate cavity size. The most likely justification of lower solubility of β-CD is inadequate hydration by water molecule due to intramolecular hydrogen bond interaction offered by optimally arranged secondary hydroxyl groups [10]. Another possible elucidation of low aqueous solubility is the formation of aggregates that leads to unfavorable interactions with the hydrogen bonded structure of water molecule as proposed by Colman and coworkers [11]. β-CD shows Bs-type behavior in phase solubility graph when added to the aqueous drug solution or suspension due to

The solubilizing power of parent CDs can be enhanced by adopting many different strategies, but the most interesting of them is the derivatization of CDs. The hydroxyl groups of CDs can be substituted to yield a variety of derivatives with significantly high aqueous solubility [12–14]. This chapter discusses the various strategies to functionalize the CDs and the resultant improvement in the aqueous

Parent CDs can be modified through structural modifications by incorporating hydrophilic moieties that will ultimately result in significant increase in aqueous solubility. Furthermore, the inclusion complexes formed by modified CDs have higher complexation efficiencies than that of parent CDs. Rekharsky and Inoue reported various examples of thermodynamic parameters of inclusion complexes

It is noteworthy that derivatization of CDs does not always enhance the complexation. The inhibition and promotion of complexation solely depends upon the type of substituents. Although the strong electrostatic force of attraction between the cationic substituents and organic anion was predicted to promote complexation, paradoxical effect was observed when the complexation of 2-naphthalene sulfonate was reduced with polyamine derivatives of β-CD. An unfavorable entropic effect may be involved that results in decrease in complexation [15]. On the other hand, a favorable electrostatic interaction occurs that leads to formation of zwitterionic corona by substituting both cationic and anionic groups at the primary face that will ultimately enhance the complexation

The interdependence of numerous molecular parameters including type of substituent at the CDs, contribution of hydrophobic, and charge character of the guest moiety and competitive self-complexation (possible inclusion complexation of substituent moiety inside the core of CD) was discussed in detail by Kean and his coworkers [17]. While dealing with ionic species, electrostatic effects are usually dominated which exert a paradoxical effect. Based on this status quo, the inclusion complexation of charged CD with organic ions must be evaluated on the basis of electrostatic interactions. The properties of modified CDs are governed by the location of hydroxyl groups on the parent CDs that are going to be substituted. Three different hydroxyl groups that exert different reactivities are located on the glucose repeating unit of a CD molecule, including one primary hydroxyl group attached to

) < γ-CD (232 gL<sup>−</sup><sup>1</sup>

). The crystal state of natural

**104**

There is variety of ways to perform methylation of native cyclodextrins:

Formerly methyl derivatives were synthesized by using either methyl iodide or dimethyl sulfate [18]. These two reagents are highly toxic and unsafe so may be detrimental to the environment as well as human being. Based on this status quo, it is mandatory to seek new and novel synthetic method to replace these toxic chemicals.

Dimethyl carbonate being eco-friendly could be an attractive alternate in this scenario [19]. The synthesis involves addition of β-CD in dimethylformamide solution followed by stirring until clear solution is obtained. Potassium carbonate is added as catalyst followed by dropwise addition of dimethyl carbonate, and mixture is allowed to stir for the next 48 hours. The catalyst and dimethyl carbonate are removed to produce syrupy consistency. At the end, this concentrate is treated with acetone followed by its removal by filtration. Finally, the product is treated with ether two to three times, and after filtration white powdered product is obtained as indicated in **Figure 1**.

An important feature of methyl β-CD is its degree of substitution that has marked effect on drug solubilization, so it must be carefully investigated [20]. **Table 1** gives the use of methyl derivatives of β-CD with effect on solubility and efficacy of various drugs.

This pharmaceutically significant methylated derivative of β-CD has the following advantages:


#### **2.2 Hydroxypropyl CDs**

The replacement of hydroxyl groups of CD by 2-hydroxypropyl moiety can be done by the reaction of CD with propylene oxide in an alkaline aqueous solution (**Figure 2a**) [31]. An isopropylene (oligomeric hydroxypropylene) side chain is formed for high degree of substitution (**Figure 2b**).

**Figure 1.** *Synthesis of methyl β-CD [21].*


#### **Table 1.**

*Effect of methyl derivatives of β-CD on solubility and efficacy of drugs.*

The characterization of finally synthesized hydroxypropyl derivatives involves determination of average number of substituents on the cyclodextrin molecule (degree of substitution). According to latest US and European pharmacopoeias, the acceptable range for DS is 2.8–10.5 for HPβCD. Degree of substitution can be measured by a variety of techniques including near-infrared reflectance spectroscopy, nuclear magnetic resonance (NMR), microcalorimetric titration [33], mass spectrometry (MS), differential scanning calorimetry (DSC) [34], and reductivecleavage and methylation analysis.

Encapsin™ and Molecusol™ are the trade names of commercially available form of hydroxyalkyl derivative (2-hydroxypropyl-β-CD). Various clinical trials have been performed with this derivative besides its use in technological, toxicological, and pharmaceutical experiments [35]. Being the most thoroughly studied derivative, FDA has approved Sporanox™ by Janssen using the same derivatives as molecular carrier. The hydroxypropyl derivative of β-CD and ɣ-CD have been widely used for solubility enhancement and leading to increase in efficacy of various drugs as illustrated in **Tables 2** and **3**.

#### **2.3 Sulfoalkylated CDs**

Almost more than 180 articles had focused on the preparation and use of charged (anionic) CD derivatives by the end of July 1998.The glucopyranose unit present in the native CD ring could be directly substituted with charged moiety, or a neutral spacer group may be used for the insertion [49]. Such functional groups can be inserted at different degrees of substitution (DS) and have variable sizes, so the final product of modified CD derivative may be influenced by electronic and steric factors.

The sulfopropyl and sulfobutyl derivatives of beta-CDs are produced by reacting native CD with propane sultone and butane sultone, respectively, in an alkaline aqueous solution as shown in **Figure 3**.

**107**

**Figure 2.**

[36]

[37]

Kaur et al. 2004

Chowdary et al.

El-Maradny et al. [38]

Manali Shah et al. [39]

Asbahr et al. [40]

Mummidi and Jayanthi [41]

Pacheco et al. [42]

Jadhav and Pore

*Effects of HPβCD on solubility and efficacy of drugs.*

[43]

**Table 2.**

*Effect of Cyclodextrin Derivatization on Solubility and Efficacy of Drugs*

*DOI: http://dx.doi.org/10.5772/intechopen.90364*

*Reaction scheme for HPβCD synthesis: (a) low DS, (b) high DS [32].*

**Author Drug Other additives** 

Acetazolamide PVA, PVP,

Celecoxib PVP, HPMC,

Isradipine PVP, HPMC,

**(if present)**

HPMC, Carbopol 940

PEG

PEG

**Effects**

complexation

oral bioavailability

dosage forms

complexes

dissolution rate

complex

Meloxicam PVP, L-ARG Improved solubility, quick pain relieving

Etoricoxib PVP, L-ARG Enhanced dissolution profile, improved

Finasteride PVP, chitosan Positive effect on drug solubility, inc. in

Albendazole PVA Enhanced solubility, improved intrinsic

Bosentan Arginine (ARG) Enhanced solubility and dissolution profile

Improved solubility, effective drug permeation, improved corneal transport

Improved solubility, higher CE by ternary

effect, faster drug release with ternary

bulk of formulation so can be used in solid

Marked increase in solubilizing efficiency, improved dissolution with ternary

*Effect of Cyclodextrin Derivatization on Solubility and Efficacy of Drugs DOI: http://dx.doi.org/10.5772/intechopen.90364*

*Colloid Science in Pharmaceutical Nanotechnology*

Schipper et al. [22]

Schipper et al. [23]

Sigurdsson et al.

Soares-Sobrinho et al. [25]

Mathiron et al.

Terauchi et al. [30]

**Table 1.**

[24]

[26]

**Author Drug Additives** 

Benznidazole PVP,

cleavage and methylation analysis.

Rassu et al. [29] Deferoxamine

mesylate

*Effect of methyl derivatives of β-CD on solubility and efficacy of drugs.*

ous drugs as illustrated in **Tables 2** and **3**.

aqueous solution as shown in **Figure 3**.

**2.3 Sulfoalkylated CDs**

The characterization of finally synthesized hydroxypropyl derivatives involves determination of average number of substituents on the cyclodextrin molecule (degree of substitution). According to latest US and European pharmacopoeias, the acceptable range for DS is 2.8–10.5 for HPβCD. Degree of substitution can be measured by a variety of techniques including near-infrared reflectance spectroscopy, nuclear magnetic resonance (NMR), microcalorimetric titration [33], mass spectrometry (MS), differential scanning calorimetry (DSC) [34], and reductive-

**(if used)**

HPMC

Vieira et al. [28] Efavirenz PVP Improved dissolution profile, increased

Chao et al. [27] Ofloxacin — Significant increase in solubility,

Insulin — Improved nasal absorption

Salmon calcitonin — Enhanced nasal penetration

Dexamethasone — Localized drug delivery to anterior eye

Midazolam — Improved solubility, protective effect on

Simvastatin — Improved solubility, effective bone

**Effects**

segment

stability

drug degradation

— Improved bioavailability, avoidance of systemic exposure

regeneration therapy

Enhanced solubility, reduced toxicity

improved pharmacological efficacy

Encapsin™ and Molecusol™ are the trade names of commercially available form of hydroxyalkyl derivative (2-hydroxypropyl-β-CD). Various clinical trials have been performed with this derivative besides its use in technological, toxicological, and pharmaceutical experiments [35]. Being the most thoroughly studied derivative, FDA has approved Sporanox™ by Janssen using the same derivatives as molecular carrier. The hydroxypropyl derivative of β-CD and ɣ-CD have been widely used for solubility enhancement and leading to increase in efficacy of vari-

Almost more than 180 articles had focused on the preparation and use of charged (anionic) CD derivatives by the end of July 1998.The glucopyranose unit present in the native CD ring could be directly substituted with charged moiety, or a neutral spacer group may be used for the insertion [49]. Such functional groups can be inserted at different degrees of substitution (DS) and have variable sizes, so the final product of modified CD derivative may be influenced by electronic and steric factors. The sulfopropyl and sulfobutyl derivatives of beta-CDs are produced by reacting native CD with propane sultone and butane sultone, respectively, in an alkaline

**106**

**Figure 2.** *Reaction scheme for HPβCD synthesis: (a) low DS, (b) high DS [32].*


#### **Table 2.**

*Effects of HPβCD on solubility and efficacy of drugs.*


#### **Table 3.**

*Effects of HP*ɣ*CD on solubility and efficacy of drugs.*

**Figure 3.** *Synthesis of SBE-β-CD [50].*

Sulfobutylated β-CD with seven substituents is considered as suitable derivative and is commercially available under the trade name of Captisol™ by CyDex. Resveratrol is complexed with sulfobutylether derivatives of β-CD and increased the anticancer activity with increase in solubility of resveratrol as well [51].

#### **2.4 Sulfated CDs**

A class of water-soluble CD derivatives having anti-angiogenic, biological, and anticancer properties is sulfated CDs. As the tumor growth is dependent on angiogenesis, the use of these derivatives could be a unique approach for the treatment of solid tumors, as reported by Folkman et al. in early 1970 [52]. In addition to these properties, they also possess antilipemic, antiviral, and anti-inflammatory effects [53].

Reaction of CD in absolute dimethylformamide with pyridine sulfur trioxide gives better yield of sulfated derivatives of CDs [54]. Besides their use as solubility enhancers, these derivatives also provide protection against gentamicin-induced nephrotoxicity and have no hemolytic properties, so can be effectively used in clinical studies [55]. **Figure 4** presents the scheme of preparation of sulfated β-CD.

**109**

**3. Conclusion**

*Effect of Cyclodextrin Derivatization on Solubility and Efficacy of Drugs*

**2.5 Guidelines regarding synthesis of CD derivatives**

medium [57].

*Synthesis of sulfated β-CD [56].*

**Figure 4.**

cose residues [35].

the cavity of CDs [58].

properties in functionalized CDs.

The following guidelines should be strictly followed during the synthesis of CD

• Although the substituents at primary hydroxyl side may influence other uses, they do not exert much effect on the complexation. The pH of the medium is decisive that either the secondary hydroxyl side or primary side will be substituted. Moderately basic medium will favor secondary hydroxyl substitution, whereas primary hydroxyl side will get substituted in strong basic

• To avoid the deformation of cavity shape, avoid the bulky substitution which may crowd each other. Although the CD torus is made of anhydroglucose repeating units which are quite rigid, they are connected to each other through single glycosidic bonds. As torus is stabilized by hydrogen bonds between the secondary hydroxyls on adjacent glucose unit, the stabilizing effect of hydrogen bonding is diminished by secondary hydroxyl substitution. Finally, the anhydroglucose units may tilt out the defined torus shape due to introduction of steric strain between substituting units present on the adjacent anhydroglu-

• The water-soluble CDs are used either in solid form or in concentrated solution state. Some substituting groups have the tendency to incorporate in the core of CDs, so they compete with active drug molecules for inclusion complexation. Therefore, it is mandatory to select those substituents that are unable to fit in

• A glucopyranose unit of cyclodextrin ring contains how many substituted hydroxyl groups are defined as its degree of substitution. One mole of glucopyranose unit contains three reactive hydroxyl groups so the maximum possible numbers of substituents are 18, 21, and 24 for α-, β-, and γ- CDs, respectively. Controlling the degree of substitution is important in producing the desired

Using different functional groups, modified CDs could play a pivotal role in improving limited drug stability and boosting aqueous solubility and dissolution behavior of drugs with poor water solubility. In order to use full potential of CDs as

derivatives in order to get the better solubility and complexing ability:

*DOI: http://dx.doi.org/10.5772/intechopen.90364*

*Effect of Cyclodextrin Derivatization on Solubility and Efficacy of Drugs DOI: http://dx.doi.org/10.5772/intechopen.90364*

**Figure 4.** *Synthesis of sulfated β-CD [56].*

*Colloid Science in Pharmaceutical Nanotechnology*

**Author Drug Other** 

ursolic acid

Soica et al. [45] Oleanolic acid,

*Effects of HP*ɣ*CD on solubility and efficacy of drugs.*

Misiuk and Jasiuk 2014 [46]

Misiuk et al. [47]

Wathoni et al. [48]

**Table 3.**

**Figure 3.**

Sulfobutylated β-CD with seven substituents is considered as suitable derivative and is commercially available under the trade name of Captisol™ by CyDex. Resveratrol is complexed with sulfobutylether derivatives of β-CD and increased the anticancer activity with increase in solubility of resveratrol as well [51].

**additives (if present)**

Zhou et al. [44] Baicalein — Higher drug absorption, better stability,

Bupropion — Improved release, rapid absorption,

Ceftazidime — Improved aqueous solubility, improved

Curcumin — Increased solubility, enhanced antioxidant activity

**Effects**

enhanced release profile

enhanced encapsulation efficiency

stability as suggested by NMR study

— Enhanced aqueous solubility, marked antiproliferative activity

A class of water-soluble CD derivatives having anti-angiogenic, biological, and anticancer properties is sulfated CDs. As the tumor growth is dependent on angiogenesis, the use of these derivatives could be a unique approach for the treatment of solid tumors, as reported by Folkman et al. in early 1970 [52]. In addition to these properties, they also possess antilipemic, antiviral, and anti-inflammatory

Reaction of CD in absolute dimethylformamide with pyridine sulfur trioxide gives better yield of sulfated derivatives of CDs [54]. Besides their use as solubility enhancers, these derivatives also provide protection against gentamicin-induced nephrotoxicity and have no hemolytic properties, so can be effectively used in clinical studies [55]. **Figure 4** presents the scheme of preparation of sulfated

**108**

β-CD.

**2.4 Sulfated CDs**

*Synthesis of SBE-β-CD [50].*

effects [53].

#### **2.5 Guidelines regarding synthesis of CD derivatives**

The following guidelines should be strictly followed during the synthesis of CD derivatives in order to get the better solubility and complexing ability:


#### **3. Conclusion**

Using different functional groups, modified CDs could play a pivotal role in improving limited drug stability and boosting aqueous solubility and dissolution behavior of drugs with poor water solubility. In order to use full potential of CDs as a drug delivery carrier, the nature and degree of functionalization play an important role. However, the future research should focus on the use of green chemistry for CDs' functionalization, and the attention should also be paid to the toxicokinetic profiling of the modified CDs to establish their safety and efficacy at the same time.

#### **Conflict of interest**

There is no conflict of interest among the listed authors.

### **Author details**

Syed Haroon Khalid1 \*, Mehreen Bashir1 , Sajid Asghar1 , Tauqeer Hussain Mallhi2 and Ikram Ullah Khan1

1 Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, Government College University, Faisalabad, Pakistan

2 Department of Clinical Pharmacy, Jouf University, Sakaka, Kingdom of Saudi Arabia

\*Address all correspondence to: haroonkhalid80@gmail.com and syedharoonkhalid@gcuf.edu.pk

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

**111**

*Effect of Cyclodextrin Derivatization on Solubility and Efficacy of Drugs*

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[10] Miyazawa I, Ueda H, Nagase H, Endo T, Kobayashi S, Nagai T. Physicochemical properties and inclusion complex formation of δ-cyclodextrin. European Journal of Pharmaceutical Sciences. 1995;**3**:153-162. DOI: 10.1016/0928-0987(95)00006-Y

[11] Coleman AW, Nicolis I, Keller N, Dalbiez JP. Aggregation of cyclodextrins:

An explanation of the abnormal solubility of β-cyclodextrin. Journal of Inclusion Phenomena and Molecular Recognition in Chemistry. 1992;**13**:139-

143. DOI: 10.1007/BF01053637

[12] Szejtli J. The properties and potential uses of cyclodextrin derivatives. Journal of Inclusion

[13] Uekama K. Pharmaceutical uses of cyclodextrin derivatives. In: High Performance Biomaterials. A Comprehensive Guide to Medical and Pharmaceutical Applications. Szycher M, editor. Technomic: Lancaster, PA; 1991. pp. 789-806

[14] Szejtli J. Introduction and general overview of cyclodextrin chemistry. Chemical Reviews. 1998;**98**:1743-1754.

[15] Inoue Y, Liu Y, Tong LH, Shen BJ, Jin DS. Calorimetric titration of inclusion complexation with modified.

Beta.-cyclodextrins. Enthalpyentropy compensation in host-guest complexation: From ionophore to cyclodextrin and cyclophane. Journal of the American Chemical Society. 1993;**115**:10637-10644. DOI: 10.1021/

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*DOI: http://dx.doi.org/10.5772/intechopen.90364*

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*Effect of Cyclodextrin Derivatization on Solubility and Efficacy of Drugs DOI: http://dx.doi.org/10.5772/intechopen.90364*

#### **References**

*Colloid Science in Pharmaceutical Nanotechnology*

a drug delivery carrier, the nature and degree of functionalization play an important role. However, the future research should focus on the use of green chemistry for CDs' functionalization, and the attention should also be paid to the toxicokinetic profiling of the modified CDs to establish their safety and efficacy at the same

There is no conflict of interest among the listed authors.

**110**

**Author details**

time.

**Conflict of interest**

Syed Haroon Khalid1

and Ikram Ullah Khan1

Kingdom of Saudi Arabia

College University, Faisalabad, Pakistan

and syedharoonkhalid@gcuf.edu.pk

provided the original work is properly cited.

\*, Mehreen Bashir1

2 Department of Clinical Pharmacy, Jouf University, Sakaka,

\*Address all correspondence to: haroonkhalid80@gmail.com

, Sajid Asghar1

1 Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, Government

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

, Tauqeer Hussain Mallhi2

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[3] Del Valle EM. Cyclodextrins and their uses: A review. Process Biochemistry. 2004;**39**:1033-1046. DOI: 10.1016/ S0032-9592(03)00258-9

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*Colloid Science in Pharmaceutical Nanotechnology*

formulations. Pharmaceutical Research. 1993;**10**:682-686. DOI: 10.1023/A:1018999414088

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Calcified Tissue International. 1995;**56**:280-282. DOI: 10.1007/

BF00318047

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[24] Sigurdsson HH, Konráðsdóttir F, Loftsson T, Stefansson E. Topical and systemic absorption in delivery of dexamethasone to the anterior and posterior segments of the eye. Acta Ophthalmologica Scandinavica. 2007;**85**:598-602. DOI: 10.1111/j.1600-0420.2007.00885.x

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[26] Mathiron D, Marçon F, Dubaele JM, Cailleu D, Pilard S, DjedaÏni-pilard F. Benefits of methylated cyclodextrins in the development of midazolam pharmaceutical formulations. Journal of Pharmaceutical Sciences. 2013;**102**:2102-2111. DOI: 10.1002/

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polymers for the delivery of Efavirenz. Carbohydrate Polymers. 2015;**130**:133- 140. DOI: 10.1016/j.carbpol.2015.04.050

carbpol.2012.02.042

jps.23558

[16] Tabushi I, Kuroda Y, Mizutani T. Artificial receptors for amino acids in water. Local environmental effect on polar recognition by 6A-amino-6B-carboxyand 6B-amino-6A-carboxy-. Beta. cyclodextrins. Journal of the American Chemical Society. 1986;**108**:4514-4518.

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DOI: 10.1021/ja00275a043

10.1039/A806488A

seppur.2008.06.021

DOI: 10.1021/ar010076f

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2008;**63**:701-705. DOI: 10.1016/j.

[19] Tundo P, Selva M. The chemistry of dimethyl carbonate. Accounts of Chemical Research. 2002;**35**:706-716.

[20] Gan Y, Zhang Y, Xiao C, Zhou C, Zhao Y. A novel preparation of methylβ-cyclodextrin from dimethyl carbonate and β-cyclodextrin. Carbohydrate Research. 2011;**346**:389-392. DOI: 10.1016/j.carres.2010.05.028

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[34] Novák C, Pokol G, Sztatisz J, Szente L, Szejtli J. Determination of the degree of substitution of hydroxypropylated β-cyclodextrins by differential scanning calorimetry. Analytica Chimica Acta. 1993;**282**:313-316. DOI: 10.1016/0003-2670(93)80216-8

[35] Szente L, Szejtli J. Highly soluble cyclodextrin derivatives: Chemistry,

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[37] Chowdary KP, Srinivas SV. Influence of hydrophilic polymers on celecoxib complexation with hydroxypropyl β-cyclodextrin. AAPS PharmSciTech. 2006;**7**:E184-E189. DOI: 10.1208/pt070

[38] El-Maradny H, Mortada S, Kamel O, Hikal A. Characterization of ternary complexes of meloxicam-HPβCD and PVP or L-arginine prepared by the spray-drying technique. Acta Pharmaceutica. 2008;**58**:455-466. DOI: 10.2478/v10007-008-0029-9

[39] Shah M, Karekar P, Sancheti P, Vyas V, Pore Y. Effect of PVP K30 and/ or L-arginine on stability constant of etoricoxib–HPβCD inclusion complex: Preparation and characterization of etoricoxib–HPβCD binary system. Drug Development and Industrial Pharmacy. 2009;**35**:118-129. DOI: 10.1080/03639040802220292

[40] Asbahr AC, Franco L, Barison A, Silva CW, Ferraz HG, Rodrigues LN. Binary and ternary inclusion complexes of finasteride in HPβCD and polymers: Preparation and characterization. Bioorganic & Medicinal Chemistry. 2009;**17**:2718-2723. DOI: 10.1016/j. bmc.2009.02.044

[41] Mummidi V, Jayanthi V. Effect of hydrophilic polymers on isradipine complexation with hydroxypropyl β-cyclodextrin. Drug Development and Industrial Pharmacy. 2013;**39**:970-977. DOI: 10.3109/03639045.2012.686508

[42] Pacheco PA, Rodrigues LN, Ferreira JF, Gomes AC, Veríssimo CJ, Louvandini H, et al. Inclusion complex and nanoclusters of cyclodextrin to increase the solubility and efficacy of albendazole. Parasitology Research. 2018;**117**:705-712. DOI: 10.1007/s0043

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[47] Misiuk W. Investigation of inclusion complex of HP-γ-cyclodextrin with ceftazidime. Journal of Molecular Liquids. 2016;**224**:387-392. DOI: 10.1016/j.molliq.2016.10.009

[48] Wathoni N, Motoyama K, Higashi T, Okajima M, Kaneko T, Arima H. Enhancement of curcumin wound healing ability by complexation with 2-hydroxypropyl-γ-cyclodextrin in sacran hydrogel film. International Journal of Biological Macromolecules.

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[51] Venuti V, Cannavà C, Cristiano MC, Fresta M, Majolino D, Paolino D, et al. A characterization study of resveratrol/

Joullie MM, Li WW, Ewing WR. Control of angiogenesis with synthetic heparin substitutes. Science. 1989;**243**:1490- 1493. DOI: 10.1126/science.2467380

sulfobutyl ether-β-cyclodextrin inclusion complex and in vitro anticancer activity. Colloids and Surfaces. B, Biointerfaces. 2014;**115**:22- 28. DOI: 10.1016/j.colsurfb.2013.11.025

[52] Folkman J, Weisz PB,

[53] Anand R, Nayyar S, Pitha J, Merril CR. Sulphated sugar alpha-cyclodextrin sulphate, a uniquely potent anti-HIV agent, also exhibits marked synergism with AZT, and lymphoproliferative activity. Antiviral Chemistry and Chemotherapy. 1990;**1**:41-46. DOI: 10.1177/095632029000100107

[54] Pitha J, Mallis LM, Lamb DJ, Irie T, Uekama K. Cyclodextrin sulfates: Characterization as polydisperse and amorphous mixtures. Pharmaceutical Research. 1991;**8**:1151-1154. DOI:

[55] Shiotani K, Irie T, Uekama K, Ishimaru Y. Cyclodextrin sulfates in parenteral use: Protection against gentamicin nephrotoxicity in the rat. European Journal of Pharmaceutical

10.1023/A:1015854402122

ijbiomac.2017.01.144

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[44] Zhou Q, Zhong L, Wei X, Dou W, Chou G, Wang Z. Baicalein and

hydroxypropyl-γ-cyclodextrin complex in poloxamer thermal sensitive hydrogel for vaginal administration. International Journal of Pharmaceutics. 2013;**454**:125- 134. DOI: 10.1016/j.ijpharm.2013.07.006

[45] Soica C, Oprean C, Borcan F, Danciu C, Trandafirescu C, Coricovac D, et al. The synergistic biologic activity of oleanolic and ursolic acids in complex with hydroxypropyl-γcyclodextrin. Molecules. 2014;**19**:4924- 4940. DOI: 10.3390/molecules19044924

[46] Misiuk W, Jasiuk E. Study of the inclusion interaction of HP-γcyclodextrin with bupropion and its analytical application. Journal of Molecular Structure. 2014;**1060**:272-279. DOI: 10.1016/j.molstruc.2013.12.056

[47] Misiuk W. Investigation of inclusion complex of HP-γ-cyclodextrin with ceftazidime. Journal of Molecular Liquids. 2016;**224**:387-392. DOI: 10.1016/j.molliq.2016.10.009

[48] Wathoni N, Motoyama K, Higashi T, Okajima M, Kaneko T, Arima H. Enhancement of curcumin wound healing ability by complexation with 2-hydroxypropyl-γ-cyclodextrin in sacran hydrogel film. International Journal of Biological Macromolecules.

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### *Edited by Selcan Karakuş*

This book presents studies on colloidal particle/nanoparticle systems and their applications. Some of the topics covered are include nanoparticle-based drug design, theranostic nanoparticles for cancer therapy, market perspectives of colloidal particles, and stability of nanoparticles. The authors focus on recent findings, applications, and new technological developments of the fundamental properties of colloidal particle systems.

Published in London, UK © 2020 IntechOpen © d1sk / iStock

Colloid Science in Pharmaceutical Nanotechnology

Colloid Science in

Pharmaceutical

Nanotechnology

*Edited by Selcan Karakuş*