**2. Nanoemulsion based delivery system: types and properties**

#### **2.1. Self emulsifying formulations (SEFs)**

2

**Figure 2.** Negative stain TEM image of a silicate particle-stabilized oil in water nanoemulsion. Obtained via: http://

www.vironova.com/nanoemulsions-casebody. Accessed on April 27, 2014.

**Figure 1.** A silicate particle-stabilized oil in water nanoemulsion imaged using negative stain TEM (left panel) and cryo TEM (right panel). Nanoemulsions courtesy of the Chemical, Materials and Surfaces unit at SP Technical Research Institute of Sweden (former YKI, Institute for Surface Chemistry). Obtained via:

**Figure 1.** A silicate particle-stabilized oil in water nanoemulsion imaged using negative stain TEM (left panel) and cryo

Nanoemulsions courtesy of the Chemical, Materials and Surfaces unit at SP Technical Research Institute of Sweden (former YKI, Institute for Surface Chemistry). Obtained via: http://www.vironova.com/nanoemulsions-casebody. Ac‐

http://www.vironova.com/nanoemulsions-casebody. Accessed on April 27, 2014.

cessed on April 27, 2014.

78 Application of Nanotechnology in Drug Delivery

TEM (right panel).

consisting of emulsified oil and water systems with mean droplet diameters ranging from 50 to 1000 nm. Usually, the average droplet size is between 100 and 500 nm and can exist as oil-inwater (o/w) or water-in-oil (w/o) form, where the core of the particle is either oil or water, respectively. Nanoemulsions (Figs. 1 and 2) are made from pharmaceutical surfactants that are generally regarded as safe (GRAS). The surfactant type and concentration in the aqueous phase are chosen to provide good stability against coalescence. Several types of oils- natural, semisynthetic and synthetic are used in the formulation of nanoemulsions. The capacity of nanoemulsions to dissolve large quantities of low soluble drugs along with their mutual compatibility and ability to protect the drugs from hydrolysis and enzymatic degradation make them ideal drug delivery vectors [1]. The major advantages of nanoemulsions as drug delivery carriers include increased drug loading, enhanced drug solubility and bioavailability, reduced patient variability, controlled drug release, and protection from enzymatic degradation [2].

> Self-emulsifying formulations (SEFs) are mixtures of oil, surfactant, co-surfactant, and cosolvents (absence of external phase water) and forms a transparent isotropic solution, which emulsify under gentle agitation similar to those which would be encountered in gastro intestinal tract (GIT). It has been recognized that this formulation when administered orally undergo spontaneous emulsification in aqueous GI fluids [6]. This emulsified oil (triglycerides) stimulates bile secretion and drug containing oil droplets are further emulsified by bile salts. Lipid droplets are then metabolized by lipases and co lipases, secreted from the salivary gland, gastric mucosa and pancreas, which also hydrolyze the triglycerides into di-and monoglycer‐ ides and free fatty acids. Further, solubilization of these molecules occurs during the passage through the GI tract and eventually forms a range of emulsion droplets, vesicular structures

and mixed micelles containing bile salts, phospholipids and cholesterol [6]. Upon mixing with water the system SEFs have an ability to form fine colloidal droplets with very high surface area. In many cases, this accelerates the digestion of the lipid formulation, improves absorp‐ tion, and reduces food effect and inter-subject variability [7]. Self emulsifying formulations distribute readily in the GI tract, the digestive motility of the stomach and the intestines provides sufficient agitation enough for the spontaneous formation of emulsions [8,9].

SEFs prepared using surfactants of HLB < 12 possess high stability and improved dissolution (for poorly soluble drugs) due to enhancement in surface area on dispersion [6]. Therefore, their absorption is independent of bile secretion and ensures a rapid transport of poorly soluble drugs into the blood [6].

According to Reiss [10], self emulsification occurs when the entropy changes that favor dispersion is greater than the energy required to increase the surface area of the dispersion [10]. The free energy of the conventional emulsion is a direct function of the energy required to create a new surface between the oil and water phase and can be described by the equation:

$$
\Delta \mathbf{G} = \sum \mathbf{N}\_i \mathbf{4} \pi r\_i^2 \sigma \tag{1}
$$

have been transformed into solid dosage forms using techniques such as melt granulation, where the lipid excipient acts as a binder and solid granules are produced on cooling. Solvents or supercritical fluids can be used with semisolid excipients, which are solubilized and then the solvent evaporated to produce a waxy powder. Spraying techniques can be used to produce powder formulations. These techniques enable the production of granules or powders that can then be compressed into a tablet form or filled into capsules. In all cases, the lipid excipients

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Self-emulsifying drug delivery system (SEDDS) is a strategy that has drawn wide research interest, basically due to its distinct capacity to solubilize and improve the bioavailability of hydrophobic drugs. This it does by ensuring aqueous solubility of the lipophilic drug [19]. The presence of oil makes SEDDS unique and distinguishes them from ordinary surfactant dispersions of drugs [20]. SEDDS are isotropic combination of drug, lipid/oil, cosolvents and surfactants [19]. On dilution by an aqueous phase they form fine stable oil-in-water (o/w) emulsions or fine lipid droplets which is the characteristic feature of these systems. When such a formulation is released into the lumen of the GIT, it disperses to form a fine emulsion generally o/w emulsion. SEDDS are generally formulated with triglyceride oils and ethoxy‐ lated nonionic surfactants. In general, the concentration of surfactant is greater than 25% in

the formulation. The size of droplets ranges approximately less than 100 nm [19].

SEDDS are believed to be superior compared with lipid solutions due to the presence of surfactants in the formulations leading to a more uniform and reproducible bioavailability [7]. Advantages of SEDDS include more consistent drug absorption, selective targeting of drug(s) toward specific absorption window in GIT, protection of drug(s) from the gut environment, control of delivery profiles, reduced variability including food effects, enhanced oral bioa‐ vailability enabling reduction in dose and high drug loading efficiency [21]. Self emulsifying formulations spread readily in the gastrointestinal tract (GIT), and the digestive motility of the stomach and intestine provide the agitation necessary for self emulsification. These systems advantageously present the drug in dissolved form and the small droplet size provides a large interfacial area for the drug absorption. SEDDSs typically produce emulsions with turbid appearance, and droplet size between 200 nm to 5 μm while self micro emulsifying drug delivery systems (SMEDDSs) form translucent micro-emulsions with droplet size of less than 200 nm. However, self nano emulsifying drug delivery systems (SNEDDS) produces clear or transparent emulsion with droplets size less than 100 nm [22,23]. When compared with emulsions, which are sensitive and metastable dispersed forms, SEFs are physically stable formulations that are easy to manufacture. Thus, for lipophilic drug compounds that exhibit dissolution rate-limited absorption, these systems may offer an improvement in the rate and extent of absorption and result in more reproducible blood time profiles [17]. SEDDS are prepared in two forms: Liquid and solid SEDDS (S-SEDDS). S-SEDDS are prepared by solidification of liquid self-emulsifying components into powder. This powder is then used to produce various solid dosage forms, for example self-emulsifying pellets, self-emulsifying tablets etc [19]. S-SEDDS do not suffer with the problems like liquid SEDDS (L-SEDDS). It has

used must be semi‐solid at room temperature [18].

*2.1.1. Self emulsifying drug delivery systems (SEDDS)*

where, ΔG is the free energy associated with the process, ri is the radius of droplets, Ni is the number of droplets, σ is the interfacial energy [11]. The two phases of the emulsion tend to separate with time to reduce the interfacial area and thus, minimize the free energy of the system(s). The conventional emulsifying agents stabilize emulsions resulting from aqueous dilution by forming a monolayer around the emulsion droplets, reducing the interfacial energy and forming a barrier to coalescence. On the other hand, emulsification occurs spontaneously with SEDDS, as the free energy required to form the emulsion is low, whether positive or negative [12]. For emulsification to take place, it is vital for the interfacial structure to offer negligible or no resistance against surface shearing [13]. The ease of emulsification has been suggested to be related to the ease of water penetration into various liquid crystals or gel phases formed on the surface of the droplet [14-16]. The interface between the oil and aqueous continuous phases is formed upon addition of a binary mixture (oil/non-ionic surfactant) to water [14]. This is followed by solubilization within the oil phase, as a result of aqueous penetration through the interface. Invariably, this tends to occur until the solubilization limit is attained close to the interphase. Further, aqueous penetration will lead to the formation of the dispersed liquid crystal phase. Ultimately, everything that is in close proximity with the interface will be liquid crystal, the actual amount of which depends upon the emulsifier concentration in the binary mixture. Hence, following gentle agitation of the self-emulsifying system, water rapidly penetrates into the aqueous cores leading to interface disruption and droplet formation [16].

When compared with emulsions, which are sensitive and metastable dispersed forms, SEFs are physically stable formulations that are easy to manufacture. Thus, for lipophilic drugs that exhibit dissolution rate-limited absorption, these systems may offer an improvement in the rate and extent of absorption and result in more reproducible blood time profiles [17]. SEFs have been transformed into solid dosage forms using techniques such as melt granulation, where the lipid excipient acts as a binder and solid granules are produced on cooling. Solvents or supercritical fluids can be used with semisolid excipients, which are solubilized and then the solvent evaporated to produce a waxy powder. Spraying techniques can be used to produce powder formulations. These techniques enable the production of granules or powders that can then be compressed into a tablet form or filled into capsules. In all cases, the lipid excipients used must be semi‐solid at room temperature [18].

#### *2.1.1. Self emulsifying drug delivery systems (SEDDS)*

and mixed micelles containing bile salts, phospholipids and cholesterol [6]. Upon mixing with water the system SEFs have an ability to form fine colloidal droplets with very high surface area. In many cases, this accelerates the digestion of the lipid formulation, improves absorp‐ tion, and reduces food effect and inter-subject variability [7]. Self emulsifying formulations distribute readily in the GI tract, the digestive motility of the stomach and the intestines provides sufficient agitation enough for the spontaneous formation of emulsions [8,9].

SEFs prepared using surfactants of HLB < 12 possess high stability and improved dissolution (for poorly soluble drugs) due to enhancement in surface area on dispersion [6]. Therefore, their absorption is independent of bile secretion and ensures a rapid transport of poorly soluble

According to Reiss [10], self emulsification occurs when the entropy changes that favor dispersion is greater than the energy required to increase the surface area of the dispersion [10]. The free energy of the conventional emulsion is a direct function of the energy required to create a new surface between the oil and water phase and can be described by the equation:

> p s

number of droplets, σ is the interfacial energy [11]. The two phases of the emulsion tend to separate with time to reduce the interfacial area and thus, minimize the free energy of the system(s). The conventional emulsifying agents stabilize emulsions resulting from aqueous dilution by forming a monolayer around the emulsion droplets, reducing the interfacial energy and forming a barrier to coalescence. On the other hand, emulsification occurs spontaneously with SEDDS, as the free energy required to form the emulsion is low, whether positive or negative [12]. For emulsification to take place, it is vital for the interfacial structure to offer negligible or no resistance against surface shearing [13]. The ease of emulsification has been suggested to be related to the ease of water penetration into various liquid crystals or gel phases formed on the surface of the droplet [14-16]. The interface between the oil and aqueous continuous phases is formed upon addition of a binary mixture (oil/non-ionic surfactant) to water [14]. This is followed by solubilization within the oil phase, as a result of aqueous penetration through the interface. Invariably, this tends to occur until the solubilization limit is attained close to the interphase. Further, aqueous penetration will lead to the formation of the dispersed liquid crystal phase. Ultimately, everything that is in close proximity with the interface will be liquid crystal, the actual amount of which depends upon the emulsifier concentration in the binary mixture. Hence, following gentle agitation of the self-emulsifying system, water rapidly penetrates into the aqueous cores leading to interface disruption and

When compared with emulsions, which are sensitive and metastable dispersed forms, SEFs are physically stable formulations that are easy to manufacture. Thus, for lipophilic drugs that exhibit dissolution rate-limited absorption, these systems may offer an improvement in the rate and extent of absorption and result in more reproducible blood time profiles [17]. SEFs

(1)

is the

<sup>2</sup> Δ 4 *G Nr i i* <sup>=</sup> å

where, ΔG is the free energy associated with the process, ri is the radius of droplets, Ni

drugs into the blood [6].

80 Application of Nanotechnology in Drug Delivery

droplet formation [16].

Self-emulsifying drug delivery system (SEDDS) is a strategy that has drawn wide research interest, basically due to its distinct capacity to solubilize and improve the bioavailability of hydrophobic drugs. This it does by ensuring aqueous solubility of the lipophilic drug [19]. The presence of oil makes SEDDS unique and distinguishes them from ordinary surfactant dispersions of drugs [20]. SEDDS are isotropic combination of drug, lipid/oil, cosolvents and surfactants [19]. On dilution by an aqueous phase they form fine stable oil-in-water (o/w) emulsions or fine lipid droplets which is the characteristic feature of these systems. When such a formulation is released into the lumen of the GIT, it disperses to form a fine emulsion generally o/w emulsion. SEDDS are generally formulated with triglyceride oils and ethoxy‐ lated nonionic surfactants. In general, the concentration of surfactant is greater than 25% in the formulation. The size of droplets ranges approximately less than 100 nm [19].

SEDDS are believed to be superior compared with lipid solutions due to the presence of surfactants in the formulations leading to a more uniform and reproducible bioavailability [7]. Advantages of SEDDS include more consistent drug absorption, selective targeting of drug(s) toward specific absorption window in GIT, protection of drug(s) from the gut environment, control of delivery profiles, reduced variability including food effects, enhanced oral bioa‐ vailability enabling reduction in dose and high drug loading efficiency [21]. Self emulsifying formulations spread readily in the gastrointestinal tract (GIT), and the digestive motility of the stomach and intestine provide the agitation necessary for self emulsification. These systems advantageously present the drug in dissolved form and the small droplet size provides a large interfacial area for the drug absorption. SEDDSs typically produce emulsions with turbid appearance, and droplet size between 200 nm to 5 μm while self micro emulsifying drug delivery systems (SMEDDSs) form translucent micro-emulsions with droplet size of less than 200 nm. However, self nano emulsifying drug delivery systems (SNEDDS) produces clear or transparent emulsion with droplets size less than 100 nm [22,23]. When compared with emulsions, which are sensitive and metastable dispersed forms, SEFs are physically stable formulations that are easy to manufacture. Thus, for lipophilic drug compounds that exhibit dissolution rate-limited absorption, these systems may offer an improvement in the rate and extent of absorption and result in more reproducible blood time profiles [17]. SEDDS are prepared in two forms: Liquid and solid SEDDS (S-SEDDS). S-SEDDS are prepared by solidification of liquid self-emulsifying components into powder. This powder is then used to produce various solid dosage forms, for example self-emulsifying pellets, self-emulsifying tablets etc [19]. S-SEDDS do not suffer with the problems like liquid SEDDS (L-SEDDS). It has the advantages like low manufacturing cost, more stability and is more patient compliance, because they are available as solid dosage form in tablets or pellet form. In many studies it have been reported that SEDDS are used for delivering and targeting hydrophobic drugs such as coenzyme Q10, halofantrine, vitamin E and cyclosporine-A [19]. The solid SEDDS focus on the incorporation of liquid/semisolid ingredients into powders employing diverse solidifica‐ tion techniques like spray drying, melt granulation, moulding, melt extrusion, and nanopar‐ ticle technology. The powders can then be formulated as solid dosage forms like selfemulsifying tablets and self-emulsifying pellets [16]. Alternative approaches for the development of solid SEDDS comprise adsorption by solid carriers like microcrystalline cellulose, colloidal silica and various viscosity grades of HPMC, and use of high melting point solid excipients like Lutrol® and Gelucire® [16]. The idea of blending the potential SEDDS with that of the pellets through the inclusion of a self-emulsifying mixture into microcrystalline cellulose, and the production of pellets using extrusion-spheronization was first introduced by Newton *et al* [24].

ed formulation, suggesting increased adhesion of the droplets to the cell surface due to

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Different dosage forms of S-SEDDS include the dry emulsions, self-emulsifying capsules, selfemulsifying sustained/controlled-release tablets, self-emulsifying sustained/controlledrelease pellets, self-emulsifying solid dispersions, self-emulsifying beads, self-emulsifying sustained-release microspheres, self-emulsifying nanoparticles, self-emulsifying supposito‐

**•** Improvement and reduction in the variability of GI absorption of poorly water soluble,

**•** Possible reduction in, or elimination of, a number of development and processing steps (e.g., salt selection or identification of a stable crystalline form of the drug, coating, taste masking, and reduced need for containment and clean-up requirements during manufacture of

**•** The dose ranging from less than 25 mg to greater than 2000 mg can be administered by using

**•** These systems enhance oral bioavailability due to bypass of hepatic metabolism and delivers

**•** Inhibition of p-glycoprotein mediated drug efflux and pre-absorptive metabolism by gut

**•** They enhance absorption of lipophilic drugs by stimulating pancreatic and biliary secretions

**•** Food does not interfere with the absorption of drug by use of such systems.

**•** Relative ease of manufacture using readily available equipment.

electrostatic attraction [16].

*2.1.1.1. Advantages of SEDDS*

lipophilic drugs.

these systems.

**•** High drug payloads.

**•** Liquid or solid dosage forms.

**•** Control of delivery profile

*2.1.1.2. Disadvantages of SEDDS*

ries and self-emulsifying implant [29 – 34].

highly-potent or cytotoxic drug products).

drug directly into systemic circulation.

membrane bound cytochrome enzyme.

**•** Reduced energy requirement for emulsion formation.

**•** Protection of sensitive drug substances

**•** Promotion of lymphatic drug transport.

Disadvantages of SEDDS include [11, 35]:

and by prolongation of gastric residence time.

SEDDS possess the following advantages among others [11]:

High levels of surfactant typically present in SEDDS formulations can invariably lead to severe GI side-effects. Hence, a new class of SEDDS formulations, i.e., supersaturable SEDDS (S-SEDDS) has been designed to reduce the amount of surfactant by incorporating a water soluble polymeric precipitation inhibitor (PPI) [25] Such formulations have been developed specifi‐ cally to reduce the surfactant side-effects and achieve rapid absorption of poorly soluble drugs [16]. The system is intended to generate and maintain a metastable supersaturated state *in vivo* by preventing or minimizing the precipitation of the drug through the use of a suitable PPI. Supersaturation is intended to increase the thermodynamic activity of the drug beyond its solubility limit, and therefore, to result in an increased driving force for transit into and across the biological barrier [26]. The S-SEDDS formulations have been demonstrated to improve both the rate and extent of the oral absorption of poorly water-soluble drugs quite effectively [25, 27, 28]. The inclusion of cellulosic polymers in the S-SEDDS formulation tends to effectively suppress the precipitation of drugs [29]. Various viscosity grades of hydroxy‐ propyl methylcellulose (HPMC) are well-recognized for their ability to inhibit crystallization and, thereby, generate and maintain their supersaturated state for extended time periods [16]. *In vitro* dilution of the S-SEDDS formulation results in the formation of a microemulsion, followed by slow crystallization of the drug on standing indicating that the supersaturated state of the system is prolonged by HPMC in the formulations. In the absence of HPMC, the SEDDS formulation undergoes rapid precipitation, yielding a lower drug concentration [25]. The significantly reduced amount of surfactant used in the S-SEDDS formulation approach significantly reduces toxicity and improves safety profile over the conventional SEDDS formulations [16].

Positively charged SEDDS have also been produced; many physiological studies have proved that the apical potential of absorptive cells, as well as that of all other cells in the body, is negatively charged with respect to the mucosal solution in the lumen [16]. The drug exposure of the positively charged SEDDS has been found to be higher as well as the conventional formulations especially for bioavailability enhancement. The binding of the cationic SEDDS has been found to be much higher compared with the anionically charg‐ ed formulation, suggesting increased adhesion of the droplets to the cell surface due to electrostatic attraction [16].

Different dosage forms of S-SEDDS include the dry emulsions, self-emulsifying capsules, selfemulsifying sustained/controlled-release tablets, self-emulsifying sustained/controlledrelease pellets, self-emulsifying solid dispersions, self-emulsifying beads, self-emulsifying sustained-release microspheres, self-emulsifying nanoparticles, self-emulsifying supposito‐ ries and self-emulsifying implant [29 – 34].

#### *2.1.1.1. Advantages of SEDDS*

the advantages like low manufacturing cost, more stability and is more patient compliance, because they are available as solid dosage form in tablets or pellet form. In many studies it have been reported that SEDDS are used for delivering and targeting hydrophobic drugs such as coenzyme Q10, halofantrine, vitamin E and cyclosporine-A [19]. The solid SEDDS focus on the incorporation of liquid/semisolid ingredients into powders employing diverse solidifica‐ tion techniques like spray drying, melt granulation, moulding, melt extrusion, and nanopar‐ ticle technology. The powders can then be formulated as solid dosage forms like selfemulsifying tablets and self-emulsifying pellets [16]. Alternative approaches for the development of solid SEDDS comprise adsorption by solid carriers like microcrystalline cellulose, colloidal silica and various viscosity grades of HPMC, and use of high melting point solid excipients like Lutrol® and Gelucire® [16]. The idea of blending the potential SEDDS with that of the pellets through the inclusion of a self-emulsifying mixture into microcrystalline cellulose, and the production of pellets using extrusion-spheronization was first introduced

High levels of surfactant typically present in SEDDS formulations can invariably lead to severe GI side-effects. Hence, a new class of SEDDS formulations, i.e., supersaturable SEDDS (S-SEDDS) has been designed to reduce the amount of surfactant by incorporating a water soluble polymeric precipitation inhibitor (PPI) [25] Such formulations have been developed specifi‐ cally to reduce the surfactant side-effects and achieve rapid absorption of poorly soluble drugs [16]. The system is intended to generate and maintain a metastable supersaturated state *in vivo* by preventing or minimizing the precipitation of the drug through the use of a suitable PPI. Supersaturation is intended to increase the thermodynamic activity of the drug beyond its solubility limit, and therefore, to result in an increased driving force for transit into and across the biological barrier [26]. The S-SEDDS formulations have been demonstrated to improve both the rate and extent of the oral absorption of poorly water-soluble drugs quite effectively [25, 27, 28]. The inclusion of cellulosic polymers in the S-SEDDS formulation tends to effectively suppress the precipitation of drugs [29]. Various viscosity grades of hydroxy‐ propyl methylcellulose (HPMC) are well-recognized for their ability to inhibit crystallization and, thereby, generate and maintain their supersaturated state for extended time periods [16]. *In vitro* dilution of the S-SEDDS formulation results in the formation of a microemulsion, followed by slow crystallization of the drug on standing indicating that the supersaturated state of the system is prolonged by HPMC in the formulations. In the absence of HPMC, the SEDDS formulation undergoes rapid precipitation, yielding a lower drug concentration [25]. The significantly reduced amount of surfactant used in the S-SEDDS formulation approach significantly reduces toxicity and improves safety profile over the conventional SEDDS

Positively charged SEDDS have also been produced; many physiological studies have proved that the apical potential of absorptive cells, as well as that of all other cells in the body, is negatively charged with respect to the mucosal solution in the lumen [16]. The drug exposure of the positively charged SEDDS has been found to be higher as well as the conventional formulations especially for bioavailability enhancement. The binding of the cationic SEDDS has been found to be much higher compared with the anionically charg‐

by Newton *et al* [24].

82 Application of Nanotechnology in Drug Delivery

formulations [16].

SEDDS possess the following advantages among others [11]:


#### *2.1.1.2. Disadvantages of SEDDS*

Disadvantages of SEDDS include [11, 35]:


SNEDDS offer a reduction in bioavailability and can offer reproducibility in plasma profiles of drugs. The ability of the SNEDDS in improving Cmax and oral bioavailability or therapeutic effect has been established for various hydrophobic drugs. The improvement in bioavailability can be translated into reduction in the drug dose and dose-related side effects of many hydrophobic drugs, such as antihypertensive and antidiabetic drugs [37]. Transretinol acetate SNEDDS emulsion, anti hyperlipidemic, probucol, estrogen receptor antagonist, tamoxifen citrate, calcium channel blocker, felodipine,and beta blocker, carvedilol have been formulated as SNEDDS [36]. SNEDDS are used for enhancing the solubility of anti-inflammatory drugs such as indomethacin [38]. Fibrinolytic drugs such as simvastatin, atorvastatin, valsartan, gemfibrozil were also formulated as SNEDDS for improved bioavailability. Super-SNEDDS of simvastatin show increased bioavailability compared to the conventional SNEDDS due to the increased drug loading [39]. Solid SNEDDS of valsartan enhanced the bioavailabilty potential due to the presence of porous carriers and also showed stability for about six months which is an important factor [40]. Hormones such as ondasteron hydrochloride and insulin were also delivered orally by using SNEDDS. Solid SNEDDS of ondasteron showed increased bioavailbility than the pure drug [41]. Insulin was formulated into SNEDDS by first forming insulin-phospholipid complex (IPC) and this was used as oil phase in the formulation. This showed good hypoglycemic effect in diabetic Wistar rats for oral administration. Hence IPC

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Anti-cancer drugs were also formulated as SNEDDS. They include raloxifene hydrochloride, cyclosporine A, paclitaxel, flutamide. In raloxifene, the uptake of the drug by endocrine organs was assessed by administering the SNEDDS in alkalinized and non-alkalinized form to Wistar rats. Non-alkalinized form showed good uptake by the endocrine organs than the alkalinized form [43]. SNEDDS pellets of cyclosporine A were formulated by fluid bed coating technique and this improved the *in vivo* performance of the drug [44]. The drug release profile of paclitaxel was improved by SNEDDS [45] and the dissolution rate was also faster compared

SNEDDS are given in the form of soft or hard gelatin capsules. They reach the gastro intestinal tract and the GI motility of the stomach provides the agitation for self-emulsification. Because of this self-emulsification the drug is given as small droplets with size less than 5μm for improved solubility. After administering orally, lingual and pancreatic lipases act on the oily phase of the SNEDDS that result in the formation of emulsified mono-glycerides, di-glycerides and fatty acids. This in the presence of bile acids leads to the formation of intestinal mixed micelles. When these mixed micelles pass through the enterocytes, it leads to the formation of chylomicrons. These drain the drug into the lymphatic vessels and not in the blood vessels

thus bypassing the first pass effect. Thus the oral bioavailability gets increased [37].

**•** Selective targeting of drug(s) toward specific absorption window in GIT.

can be used for the oral delivery of insulin [42].

to that of the pure drug in flutamide [37, 46].

*2.1.2.1. Advantages of SNEDDS*

Advantages of SNEDDS include [36]:

**•** Protection of sensitive drug substances.


#### *2.1.2. Self nano emulsifying drug delivery systems (SNEDDSs)*

Self-nano emulsifying drug delivery systems (SNEDDS) are isotropic mixtures of oil, surfac‐ tant, co-surfactant and drug that form fine oil-in-water nanoemulsion when introduced into aqueous phases under gentle agitation. SNEDDS spread readily in the gastrointestinal tract, and the digestive motility of the stomach and the intestine provide the agitation necessary for self-emulsification [36]. SEDDSs typically produce emulsions with turbid appearance, and droplet size between 200 nm to 5 μm, while self micro emulsifying drug delivery systems (SMEDDSs) form translucent micro-emulsions with droplet size of less than 200 nm. However, self nano-emulsifying drug delivery systems (SNEDDS) produce clear or transparent emulsion with droplets size less than 100 nm [22, 23].

Successful formulation of SNEDDS depends on the thorough understanding of the spontane‐ ous nano-emulsification process and also on the physicochemical and biological properties of the components used for the fabrication of SNEDDS. The factors influencing the phenomenon of self nano-emulsification are:


These factors should receive attention while formulating SNEDDS. In addition, the accepta‐ bility of the SNEDDS components for the desired route of administration is also very important while formulating SNEDDS [36].

SNEDDS offer a reduction in bioavailability and can offer reproducibility in plasma profiles of drugs. The ability of the SNEDDS in improving Cmax and oral bioavailability or therapeutic effect has been established for various hydrophobic drugs. The improvement in bioavailability can be translated into reduction in the drug dose and dose-related side effects of many hydrophobic drugs, such as antihypertensive and antidiabetic drugs [37]. Transretinol acetate SNEDDS emulsion, anti hyperlipidemic, probucol, estrogen receptor antagonist, tamoxifen citrate, calcium channel blocker, felodipine,and beta blocker, carvedilol have been formulated as SNEDDS [36]. SNEDDS are used for enhancing the solubility of anti-inflammatory drugs such as indomethacin [38]. Fibrinolytic drugs such as simvastatin, atorvastatin, valsartan, gemfibrozil were also formulated as SNEDDS for improved bioavailability. Super-SNEDDS of simvastatin show increased bioavailability compared to the conventional SNEDDS due to the increased drug loading [39]. Solid SNEDDS of valsartan enhanced the bioavailabilty potential due to the presence of porous carriers and also showed stability for about six months which is an important factor [40]. Hormones such as ondasteron hydrochloride and insulin were also delivered orally by using SNEDDS. Solid SNEDDS of ondasteron showed increased bioavailbility than the pure drug [41]. Insulin was formulated into SNEDDS by first forming insulin-phospholipid complex (IPC) and this was used as oil phase in the formulation. This showed good hypoglycemic effect in diabetic Wistar rats for oral administration. Hence IPC can be used for the oral delivery of insulin [42].

Anti-cancer drugs were also formulated as SNEDDS. They include raloxifene hydrochloride, cyclosporine A, paclitaxel, flutamide. In raloxifene, the uptake of the drug by endocrine organs was assessed by administering the SNEDDS in alkalinized and non-alkalinized form to Wistar rats. Non-alkalinized form showed good uptake by the endocrine organs than the alkalinized form [43]. SNEDDS pellets of cyclosporine A were formulated by fluid bed coating technique and this improved the *in vivo* performance of the drug [44]. The drug release profile of paclitaxel was improved by SNEDDS [45] and the dissolution rate was also faster compared to that of the pure drug in flutamide [37, 46].

SNEDDS are given in the form of soft or hard gelatin capsules. They reach the gastro intestinal tract and the GI motility of the stomach provides the agitation for self-emulsification. Because of this self-emulsification the drug is given as small droplets with size less than 5μm for improved solubility. After administering orally, lingual and pancreatic lipases act on the oily phase of the SNEDDS that result in the formation of emulsified mono-glycerides, di-glycerides and fatty acids. This in the presence of bile acids leads to the formation of intestinal mixed micelles. When these mixed micelles pass through the enterocytes, it leads to the formation of chylomicrons. These drain the drug into the lymphatic vessels and not in the blood vessels thus bypassing the first pass effect. Thus the oral bioavailability gets increased [37].

#### *2.1.2.1. Advantages of SNEDDS*

**•** Lack of good predicative *in vitro* models for assessment of the formulations.

digestion prior to release of the drug.

84 Application of Nanotechnology in Drug Delivery

imately 30-60%) may irritate GIT.

of the hydrophilic solvent.

the precipitation of the lipophilic drugs.

with droplets size less than 100 nm [22, 23].

or co surfactant or solubilizer (if included)

**•** The ratio of the components, especially oil-surfactant ratio

of self nano-emulsification are:

while formulating SNEDDS [36].

polarity.

**•** *In vitro* model needs further development and validation.

*2.1.2. Self nano emulsifying drug delivery systems (SNEDDSs)*

**•** Traditional dissolution methods do not work, because formulations are independent on

**•** Different prototype lipid based formulations needs to be developed and tested *in vivo*.

**•** Chemical instabilities of drugs and high surfactant concentrations in formulations (approx‐

**•** Volatile co solvents may migrate into the shells of soft or hard gelatin capsules, resulting in

**•** The precipitation tendency of the drug on dilution may be higher due to the dilution effect

Self-nano emulsifying drug delivery systems (SNEDDS) are isotropic mixtures of oil, surfac‐ tant, co-surfactant and drug that form fine oil-in-water nanoemulsion when introduced into aqueous phases under gentle agitation. SNEDDS spread readily in the gastrointestinal tract, and the digestive motility of the stomach and the intestine provide the agitation necessary for self-emulsification [36]. SEDDSs typically produce emulsions with turbid appearance, and droplet size between 200 nm to 5 μm, while self micro emulsifying drug delivery systems (SMEDDSs) form translucent micro-emulsions with droplet size of less than 200 nm. However, self nano-emulsifying drug delivery systems (SNEDDS) produce clear or transparent emulsion

Successful formulation of SNEDDS depends on the thorough understanding of the spontane‐ ous nano-emulsification process and also on the physicochemical and biological properties of the components used for the fabrication of SNEDDS. The factors influencing the phenomenon

**•** The physicochemical nature and concentration of oily phase, surfactant and co-emulsifier

**•** The temperature and pH of the aqueous phase where nano-emulsification would occur

**•** Physicochemical properties of the drug, such as hydrophilicity/lipophilicity, pKa and

These factors should receive attention while formulating SNEDDS. In addition, the accepta‐ bility of the SNEDDS components for the desired route of administration is also very important

**•** Formulations containing several components become more challenging to validation.

Advantages of SNEDDS include [36]:


properties of active pharmaceutical ingredients, such as solubility, heat stability and

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The simplest technique to convert liquid SNEDDS to solid SNEDDS is by adsorption onto the surface of carriers or by granulation using liquid SNEDDS as a binder. This technique is uncomplicated, cost effective, easily optimized and industrially scalable. It can be used for heat-and moisture-sensitive molecules, thus providing an advantage over other techniques, such as spray drying and freeze drying. Various excipients utilized for the preparation of solid oral dosage forms can be employed for adsorption. The excipients should possess large surface

The ability of different excipients, such as dibasic calcium phosphate, lactose, microcrystalline cellulose, colloidal silicon dioxide and Neusilin, to adsorb cefpodoxime proxetil SNEDDS have been studied [47]. Solidification techniques for converting liquid/semisolid SEDDS/SNEDDS

**• Capsule filling with liquid and semisolid self-emulsifying formulations:** Capsule filling is the simplest and the most common technology for the encapsulation of liquid or semi solid SE formulations for the oral route. The advantages of capsule filling are simplicity of manufacturing, suitability for low-dose highly potent drugs and high drug loading up to

**• Spray drying:** This technique involves the preparation of a formulation by mixing lipids, surfactants, drug, solid carriers, and solubilization of the mixture before spray drying. The solubilized liquid formulation is then atomized into a spray of droplets. The droplets are introduced into a drying chamber, where the volatile phase (e.g. the water contained in an emulsion) evaporates, forming dry particles under controlled temperature and airflow

**• Spray cooling:** Spray cooling also referred to as spray congealing is a process whereby the molten formula is sprayed into a cooling chamber. Upon contact with the cooling air, the molten droplets congeal and re-crystallize into spherical solid particles that fall to the bottom of the chamber and subsequently collected as fine powder. The fine powder may then be used for development of solid dosage forms, tablets or direct filling into hard shell capsules. Many types of equipment are available to atomize the liquid mixture and to generate

**• Adsorption to solid carriers:** SEDDS can be adsorbed at high levels (up to 70% (w/w)) onto suitable carriers. Solid carriers can be microporous inorganic substances, high surface area colloidal inorganic adsorbent substances, cross-linked polymers or nanoparticle adsorbents (i.g., silica, silicates, magnesium trisilicate, magnesium hydroxide, talcum, crospovidone, cross-linked sodium carboxymethyl cellulose and crosslinked polymethyl methacrylate). The adsorption technique has been successfully applied to gentamicin and erythropoietin with caprylocaproyl polyoxylglycerides (Labrasol) formulations that maintained their

conditions. Such particles can be further prepared into tablets or capsules [48].

droplets: rotary pressure, two-fluid or ultrasonic atomizers [49, 50].

bioavailability enhancing effect after adsorption on carriers [51-53].

areas to adsorb sticky and sometimes viscous oily SNEDDS formulation [47].

compatibility with other ingredients [47].

to solids include:

50% (w/w) potential [48].

**•** As compared with oily solutions, they provide a large interfacial area for partitioning of the drug between oil and water [36].

#### *2.1.2.2. Disadvantages of SNEDDS*

Disadvantages of SNEDDS include [36]:


#### *2.1.2.3. Factors affecting SNEDDS*

There are many factors that affect SNEDDS viz:


#### *2.1.3. Solid self-nanoemulsifying drug delivery systems (SSNEDDSs)*

Solid SNEDDS was developed in order to eliminate the disadvantages associated with liquid SNEDDS handling, manufacturing and stability. Solid SNEDDS in the form of dry, solid powders would help in overcoming the limitations associated with liquid SNEDDS. Solid dosage forms are most stable and are convenient for handling; therefore, attempts are made to convert the liquid systems into solid SNEDDS. Various techniques, such as spray drying, freeze drying and adsorption on carriers, can be employed to convert liquid SNEDDS into solid SNEDDS compressed into tablets. The selection of a particular process for prepara‐ tion of solid SNEDDS would depend on the content of oily excipient of the formulation, properties of active pharmaceutical ingredients, such as solubility, heat stability and compatibility with other ingredients [47].

**•** Enhanced oral bioavailability enabling reduction in dose.

between bulk drug substance and the gut wall.

drug between oil and water [36].

Disadvantages of SNEDDS include [36]:

*2.1.2.2. Disadvantages of SNEDDS*

a suitable animal model

to deliver by SNEDDS.

*2.1.2.3. Factors affecting SNEDDS*

There are many factors that affect SNEDDS viz:

*2.1.3. Solid self-nanoemulsifying drug delivery systems (SSNEDDSs)*

**•** It can be easily stored since it belongs to a thermodynamics stable system.

**•** Fine oil droplets would pass rapidly and promote wide distribution of the drug throughout the GIT, thereby minimizing the irritation frequently encountered during extended contact

**•** As compared with oily solutions, they provide a large interfacial area for partitioning of the

**•** Lack of good predicative *in vitro* models for assessment of the formulations because traditional dissolution methods do not work, because these formulations potentially are dependent on digestion prior to release of the drug. To mimic this, an *in vitro* model

**•** Need of different prototype lipid based formulations to be developed and tested *in vivo* in

**•** Drugs which are administered at very high dose are not suitable for SNEDDS, unless they exhibit extremely good solubility in at least one of the components of SNEDDS, preferably lipophillic phase. The drugs exhibit limited solubility in water and lipids are most difficult

**•** The ability of SNEDDS to maintain the drug in solubilized form is greatly influenced by the solubility of the drug in oily phase. If the surfactant or co-surfactant is contributing to a greater extent for drug solubilization, then there could be a risk of precipitation, as dilution of SNEDDS will lead to lowering of solvent capacity of surfactant or co-surfactant [36].

Solid SNEDDS was developed in order to eliminate the disadvantages associated with liquid SNEDDS handling, manufacturing and stability. Solid SNEDDS in the form of dry, solid powders would help in overcoming the limitations associated with liquid SNEDDS. Solid dosage forms are most stable and are convenient for handling; therefore, attempts are made to convert the liquid systems into solid SNEDDS. Various techniques, such as spray drying, freeze drying and adsorption on carriers, can be employed to convert liquid SNEDDS into solid SNEDDS compressed into tablets. The selection of a particular process for prepara‐ tion of solid SNEDDS would depend on the content of oily excipient of the formulation,

simulating the digestive processes of the duodenum has been developed.

**•** High drug payloads.

86 Application of Nanotechnology in Drug Delivery

The simplest technique to convert liquid SNEDDS to solid SNEDDS is by adsorption onto the surface of carriers or by granulation using liquid SNEDDS as a binder. This technique is uncomplicated, cost effective, easily optimized and industrially scalable. It can be used for heat-and moisture-sensitive molecules, thus providing an advantage over other techniques, such as spray drying and freeze drying. Various excipients utilized for the preparation of solid oral dosage forms can be employed for adsorption. The excipients should possess large surface areas to adsorb sticky and sometimes viscous oily SNEDDS formulation [47].

The ability of different excipients, such as dibasic calcium phosphate, lactose, microcrystalline cellulose, colloidal silicon dioxide and Neusilin, to adsorb cefpodoxime proxetil SNEDDS have been studied [47]. Solidification techniques for converting liquid/semisolid SEDDS/SNEDDS to solids include:


**• Melt granulation:** Melt granulation or pelletization is a one step-process allowing the transformation of a powder mix (containing the drug) into granules or spheronized pellets. The technique needs high shear mixing in presence of a meltable binder. This is referred to as "pump-on" technique. Alternatively, the binder may be blended with the powder mix in its solid or semi-solid state and allowed to melt (partially or completely) by the heat generated from the friction of particles during high shear mixing referred to as "melt-in" process. The melted binder forms liquid bridges with the powder particles that shape into small agglomerates (granules) which can, by further mixing under controlled conditions transform to spheronized pellets [48].

may be sufficient. Nanoemulsions are usually formulated with surfactants, which are

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**•** Nanoemulsions can be applied for delivery of fragrance, which may be incorporated in many personal care products. This could also be applied in perfumes, which are desirable

**•** Nanoemulsions may be applied as a substitute for liposomes and vesicles (which are much less stable) and it is possible in some cases to build lamellar liquid crystalline phases around

**•** Nanoemulsions can be formulated in numerous dosage foam such as creams, liquids, sprays

**•** They do not damage healthy human and animal cells, so nanoemulsions are suitable for

**•** Increase the rate of absorption, increases bioavailability and eliminates variability in

**•** Better uptake of oil-soluble supplements in cell cultures. Improve growth and vitality of

**•** Nanoemulsions could enhance the stability of chemically unstable compounds by protect‐

**•** Possibilities of controlled drug release and drug targeting, and the incorporation of a great

Although nanoemulsions provide great advantages as a delivery system, however they suffer

**•** The formulation of nanoemulsions is an expensive process due to size reduction of droplets is very difficult as it required a special kind of instruments and process methods. For example, homogenizer (instrument required for the nanoemulsions formulation) arrange‐ ment is an expensive process. More ever micro-fluidization and ultrasonication (manufac‐

**•** One problem associated with nanoemulsion is their stability. Although it is generally accepted that these systems could remain stable even by years, however, due to the small droplet size, it has been reported that the Oswald ripening could damage nanoemulsions, causing their application to be limited. Therefore, in most cases, nanoemulsions are required

**•** Helps solubilize lipophilic drug and masks unpleasant taste of some drugs

cultured cells. It allows toxicity studies of oil-soluble drugs in cell cultures.

ing them from oxidative degradation and degradation by light.

for some major challenges and limitations which include [56-58]:

turing process) require large amount of financial support.

to be prepared shortly before their use.

**•** Various routes like topical, oral and intravenous can be used to deliver the product.

approved for human consumption (GRAS), they can be taken by enteric route.

to be formulated alcohol free.

the nanoemulsion droplets.

variety of therapeutic actives.

**3.1. Major challenges**

human and veterinary therapeutic purposes [56].

and foams.

absorption

**• Melt extrusion/Extrusion spheronization:** It is a solvent-free process that allows high drug loading (60%) as well as content uniformity. Applying extrusion-spheronization, SE pellets of diazepam and progesterone and bi-layered cohesive SE pellets have been prepared [54, 55].
