**10. Novel technologies for dermal and transdermal application**

Nanoparticles for dermatological applications such liposomes and other vesicular systems as well as other types of nanosized drug carriers such as solid lipid nanoparticles, nanostruc‐ tured lipid carriers, polymer-based nanoparticles and magnetic nanoparticles have been developed. These have in one way or the other, addressed the shortcoming of the tradition‐ al TDDS such as ointments, gels etc. Different carrier systems have been proposed in an attempt to favor the transport of drugs through the skin, enabling drug retention and in some cases allowing a controlled release [6]. Skin penetration is essential to a number of current concerns, e.g. contamination by microorganisms and chemicals, drug delivery to skin (dermatological treatments) and through skin (transdermal treatments), and skin care and protection (cosmetics) [6].

Physicochemical properties of nanocarrier systems determine the interaction with biological systems and nanocarrier cell internalization. The main physicochemical properties that affect cellular uptake are size, shape, rigidity, and charge in the surface of nanoparticles. The most used and investigated nanocarriers for dermal/transdermal drug delivery in the pharmaceut‐ ical field include liposomes, transfersomes, ethosomes, niosomes, dendrimers, nanoparticleslipid and polymer nanoparticles, and nanoemulsions. In general, the advantages and limitations of using nanocarriers for transdermal drug delivery are their tiny size, their high surface energy, their composition, their architecture, and their attached molecules. Table 2 summarizes the advantages and disadvantages of common transdermal nanocarriers.

#### **10.1. Microemulsions**

**9.13. Spreadability**

208 Application of Nanotechnology in Drug Delivery

between two parallel plates:

**9.14. Rheology**

Pharmaceutical semisolid preparations include ointments, pastes, creams, emulsions, gels, and rigid foams. Their common property is the ability to cling to the application surface for a reasonable period of time before they are washed off or worn off [61]. They usually serve as vehicles for topically applied drugs, as emollients, or as protective or occlusive dressings, or they may be applied to the skin and membranes such as the rectal, buccal, nasal, and vaginal mucosa, urethral membrane, external ear lining, or the cornea [62]. These preparations are widely used as a means of altering the hydration state of the substrate (i.e., the skin or the mucous membrane) and for delivering the drugs (topical or systemic) by means of the topical– mucosal route. Nanoparticles for transdermal application could be formulated as gels, creams, emulsions, foams etc, or dispersed in ointment bases. This makes the spreadability character‐

The efficacy of topical therapy depends on the patient spreading the formulation in an even layer to deliver a standard dose. The optimum consistency of such a formulation helps ensure that a suitable dose is applied or delivered to the target site. This is particularly important with formulations of potent drugs. A reduced dose would not deliver the desired effect, and an excessive dose may lead to undesirable side effects. The delivery of the correct dose of the drug depends highly on the spreadability of the formulation. Spreadability, in principle, is related to the contact angle of the drop of a liquid or a semisolid preparation on a standardized substrate and is a measure of lubricity, which is directly related to the coefficient of friction

shear during spreading, *γ* s-1, is calculated using the following equation for plane laminar flow

in which *v* is the relative velocity of the plates (cm s-1) and *d* is the distance between them (cm);

To assess the spreadability of a topical or a mucosal semisolid preparation, the important factors to consider include hardness or firmness of the formulation, the rate and time of shear produced upon smearing, and the temperature of the target site [64]. The rate of spreading also depends on the viscosity of the formulation, the rate of evaporation of the solvent, and

Rheology is the science that studies how materials deform and flow under the influence of external forces. Characterization of the rheological properties of the system is important not only in the design of the product and its application, but during its processing and to ensure long shelf-life [66]. It is thus necessary to explore the rheological changes that our formulations would experience when subjected to external forces during manufacture and in use. To that effect, measurements of the shear stress, strain, viscosity are done on the formulations. This

*<sup>γ</sup>* <sup>=</sup> *<sup>v</sup>*

the rate of increase in viscosity with concentration that results from evaporation [65].

to 105

*<sup>d</sup>* (1)

s-1. The rate of

istics of the formulation very pertinent in achieving the desired objective.

[63]. Spreadability is subjectively assessed at shear rates varying from 102

that is, a measure of thickness of the film between the skin surfaces [64].

Microemulsions are dispersions with droplet size from 10 to 100 nm and do not have the tendency to coalesce [67-69]. Microemulsions form spontaneously with appropriate amounts of a lipophilic and a hydrophilic ingredient, as well as a surfactant and a co-surfactant [70]. Microemulsions have several specific physicochemical properties such as transparency, optical isotropy, low viscosity and thermodynamic stability [70,71]. As efficient drug carriers, microemulsions have been widely employed in both transdermal and dermal delivery of drugs [72,73].

Most of the microemulsions have very low viscosity, which may restrict their application to the transdermal delivery field due to inconvenient use [74]. The main mechanisms to explain the advantages of microemulsions for the transdermal delivery of drugs include the high solubility potential for hydrophilic drugs of microemulsion systems, permeation enhancing effect of the ingredients of microemulsions, and the increased thermodynamic activity of the drug in the carriers [68,70,71].

#### **10.2. Nanoemulsions**

Nanoemulsions are isotropic dispersed systems of two nonmiscible liquids, normally consist‐ ing of an oily system dispersed in an aqueous system, or an aqueous system dispersed in an oily system but forming droplets or other oily phases of nanometric sizes. They are thermo‐ dynamically unstable systems, in contrast to microemulsions, because some nanoemulsions need high energy to produce them. They are susceptible to Oswald ripening, and as a conse‐ quence susceptible to creaming, flocculation, and other physical instability problems associ‐ ated with emulsions. Despite this, they can be stable (metastable) for long periods due to their extremely small size and the use of adequate surfactants. Hydrophobic and hydrophilic drugs can be formulated in nanoemulsions. They are nontoxic and nonirritant systems, and they can be used for skin or mucous membranes and parenteral and non-parenteral administration in general, and they have been utilized in the cosmetic field. Nanoemulsions can be prepared by three methods mainly: high-pressure homogenization, microfluidization, and phase-inversion temperature. Transdermal delivery using nanoemulsions has decreased due to the stability problems inherent to this dosage form. Some examples of drugs using nanoemulsions for transdermal drug delivery are gamma tocopherol, caffeine, plasmid DNA, aspirin, methyl salicylate, insulin and nimesulide [75].

Presently, transdermal nanoemulsion formulations are not developed as much as nanoparti‐ cles or liposomes due to the stability problems inherent to this dosage form. Nevertheless, gamma tocopherol, caffeine, plasmid DNA, aspirin, methyl salicylate, insulin, and nimesulide have been included in nanoemulsions. The use of these nanocarriers to deliver analgesics, corticosteroids, anticancer agents, etc, is very important, as these drugs are able to act imme‐ diately because they do not need to cross extra barriers [76-82].

phospholipid-association bodies and the leak of their encapsulated ingredients. As a result, their ability to transport active ingredients to deep skin is not likely good. For this reason, the use of flexible liposomes (transformable liposomes or transfersomes) has emerged as an invaluable strategy to reach the objective of drug delivery via the transdermal route. Examples of drugs delivered throughout the skin by using liposomes are melatonin, indinavir, metho‐ trexate, amphotericin B, ketoprofen, estradiol, clindamicyn hydrochloride, and lignocaine, while examples of transdermal drug delivery using transformable liposomes (transfersomes) are diclofenac, insulin, tetanus toxoid, corticosteroids, superoxide dismutase, DNA, triamci‐

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**Figure 5.** Structure of a liposome (http://en.wikipedia.org/wiki/Liposome. Downloaded on April 26, 2014)

These are non-ionic surfactant vesicular novel drug delivery system in which the medication is encapsulated in a vesicle. Niosomes are unilamellar or multilamellar vesicles capable of entrapping hydrophilic and hydrophobic solutes. From a technical point of view, niosomes are promising drug carriers as they possess greater stability and lack of many disadvantages associated with liposomes, such as high cost and the variable purity problems of phospholipids [95]. Another advantage is the simple method for the routine and large scale production of niosomes without the use of unacceptable solvents. One alternative of phospholipids is the hydrated mixture of cholesterol and non-ionic surfactants such as alkyl ethers, alkyl esters or alkyl amides [95,96]. This type of vesicle formed from the above mixture has been known as niosomes or non-ionic surfactant vesicles. Niosome surfactants are biodegradable, biocom‐

Niosomes are versatile carrier systems that can be administered through various routes, including transdermal delivery [97,98]. Particular efforts have been aimed at using niosomes

nolone-acetonide, ketoprofen, interleukin-2, and ketotifen fumarate [88-94].

*10.3.2. Niosomes*

patible and non-immunogenic.

#### **10.3. Vesicular systems**

#### *10.3.1. Liposomes*

Liposomes (Fig. 5) are spherical, self closed vesicles of colloidal dimensions, in which phos‐ pholipid bilayer sequesters part of the solvent, in which they freely float, into their interior [83]. Their advantage, with respect to pharmaceutical application as drug carriers, is the wide variety of drugs to be incorporated as well as the biocompatibility, inherently connected with natural phospholipids. Regarding the penetration behavior of liposomes it is still under discussion if such objects might penetrate intact skin [84-87].

Liposomes have become one of the pharmaceutical nanocarriers of choice for many applica‐ tions. Currently, many liposome-based drugs and biomedical products have been approved for use in clinic. They were used to study membrane processes and membrane-bound proteins. Liposomes were also proposed as drug carriers that reduce toxicity and increase efficacy. The nature of liposomes makes them one of the best alternatives for drug delivery because they are nontoxic and remain inside the bloodstream for a long time. They are being successfully used in cancer therapy and in skin melanoma [6]. However, to date many liquid-type nano‐ cosmetic carriers, such as liposomes, are structurally unstable. Specifically, when passing through the skin, they adhere to the inside walls of the skin cells, causing the collapse of

**Figure 5.** Structure of a liposome (http://en.wikipedia.org/wiki/Liposome. Downloaded on April 26, 2014)

phospholipid-association bodies and the leak of their encapsulated ingredients. As a result, their ability to transport active ingredients to deep skin is not likely good. For this reason, the use of flexible liposomes (transformable liposomes or transfersomes) has emerged as an invaluable strategy to reach the objective of drug delivery via the transdermal route. Examples of drugs delivered throughout the skin by using liposomes are melatonin, indinavir, metho‐ trexate, amphotericin B, ketoprofen, estradiol, clindamicyn hydrochloride, and lignocaine, while examples of transdermal drug delivery using transformable liposomes (transfersomes) are diclofenac, insulin, tetanus toxoid, corticosteroids, superoxide dismutase, DNA, triamci‐ nolone-acetonide, ketoprofen, interleukin-2, and ketotifen fumarate [88-94].

#### *10.3.2. Niosomes*

**10.2. Nanoemulsions**

210 Application of Nanotechnology in Drug Delivery

salicylate, insulin and nimesulide [75].

**10.3. Vesicular systems**

*10.3.1. Liposomes*

diately because they do not need to cross extra barriers [76-82].

discussion if such objects might penetrate intact skin [84-87].

Nanoemulsions are isotropic dispersed systems of two nonmiscible liquids, normally consist‐ ing of an oily system dispersed in an aqueous system, or an aqueous system dispersed in an oily system but forming droplets or other oily phases of nanometric sizes. They are thermo‐ dynamically unstable systems, in contrast to microemulsions, because some nanoemulsions need high energy to produce them. They are susceptible to Oswald ripening, and as a conse‐ quence susceptible to creaming, flocculation, and other physical instability problems associ‐ ated with emulsions. Despite this, they can be stable (metastable) for long periods due to their extremely small size and the use of adequate surfactants. Hydrophobic and hydrophilic drugs can be formulated in nanoemulsions. They are nontoxic and nonirritant systems, and they can be used for skin or mucous membranes and parenteral and non-parenteral administration in general, and they have been utilized in the cosmetic field. Nanoemulsions can be prepared by three methods mainly: high-pressure homogenization, microfluidization, and phase-inversion temperature. Transdermal delivery using nanoemulsions has decreased due to the stability problems inherent to this dosage form. Some examples of drugs using nanoemulsions for transdermal drug delivery are gamma tocopherol, caffeine, plasmid DNA, aspirin, methyl

Presently, transdermal nanoemulsion formulations are not developed as much as nanoparti‐ cles or liposomes due to the stability problems inherent to this dosage form. Nevertheless, gamma tocopherol, caffeine, plasmid DNA, aspirin, methyl salicylate, insulin, and nimesulide have been included in nanoemulsions. The use of these nanocarriers to deliver analgesics, corticosteroids, anticancer agents, etc, is very important, as these drugs are able to act imme‐

Liposomes (Fig. 5) are spherical, self closed vesicles of colloidal dimensions, in which phos‐ pholipid bilayer sequesters part of the solvent, in which they freely float, into their interior [83]. Their advantage, with respect to pharmaceutical application as drug carriers, is the wide variety of drugs to be incorporated as well as the biocompatibility, inherently connected with natural phospholipids. Regarding the penetration behavior of liposomes it is still under

Liposomes have become one of the pharmaceutical nanocarriers of choice for many applica‐ tions. Currently, many liposome-based drugs and biomedical products have been approved for use in clinic. They were used to study membrane processes and membrane-bound proteins. Liposomes were also proposed as drug carriers that reduce toxicity and increase efficacy. The nature of liposomes makes them one of the best alternatives for drug delivery because they are nontoxic and remain inside the bloodstream for a long time. They are being successfully used in cancer therapy and in skin melanoma [6]. However, to date many liquid-type nano‐ cosmetic carriers, such as liposomes, are structurally unstable. Specifically, when passing through the skin, they adhere to the inside walls of the skin cells, causing the collapse of

These are non-ionic surfactant vesicular novel drug delivery system in which the medication is encapsulated in a vesicle. Niosomes are unilamellar or multilamellar vesicles capable of entrapping hydrophilic and hydrophobic solutes. From a technical point of view, niosomes are promising drug carriers as they possess greater stability and lack of many disadvantages associated with liposomes, such as high cost and the variable purity problems of phospholipids [95]. Another advantage is the simple method for the routine and large scale production of niosomes without the use of unacceptable solvents. One alternative of phospholipids is the hydrated mixture of cholesterol and non-ionic surfactants such as alkyl ethers, alkyl esters or alkyl amides [95,96]. This type of vesicle formed from the above mixture has been known as niosomes or non-ionic surfactant vesicles. Niosome surfactants are biodegradable, biocom‐ patible and non-immunogenic.

Niosomes are versatile carrier systems that can be administered through various routes, including transdermal delivery [97,98]. Particular efforts have been aimed at using niosomes as effective dermal and transdermal drug-delivery systems [99,100]. In particular, niosomes are considered an interesting drug-delivery system in the treatment of dermatological disorders. Examples of transdermal drug delivery using niosomes are minoxidil and ellagic acid. Niosomes have been reported to enhance the residence time of drugs in the stratum corneum and epidermis, while reducing the systemic absorption of the drug, and improve penetration of the trapped substances across the skin. In addition, these systems have been reported to decrease side effects and to give a considerable drug release [101]. Niosomes formed from sorbitan monoesters (Spans) with cholesterol molar ratios of 1:1 are a promising approach for the topical delivery of minoxidil in hair-loss treatment [102]. Junyaprasert et al demonstrated that the Span 60 and Tween 60 niosomes may be a potential carrier for dermal delivery of ellagic acid [103].

tions, due to the high alcohol content. The size decreased as alcohol increased from 20 to 45 % [39]. This reduction in size was attributed to the conferment of a net negative charge on the vesicle surface by ethanol. Other excipients usually added in ethosome formula‐ tion include cholesterol, for vesicle membrane stabilization; permeation enhancers, mark‐ er dyes (if required) such as rhodamine, for characterization study. The stabilizing effect of cholesterol is due to prevention of vesicle aggregation and enlargement during storage [111]. The small size and malleability of ethosomes enable them to pass through the skin or membrane barrier and also influence the extent of transdermal permeation. The smaller

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Ethosomes permeate through the stratum corneum barrier and posses significantly high transdermal flux unlike classical liposomes. These effects of combined phospholipids and high concentration of ethanol in vesicular formulations have been suggested to be responsible for deeper distribution and penetration in the skin lipid bilayers [110]. Application of ethosomes in drug delivery has numerous advantages [112-114]: simplicity of the technology, noninvasive means of application (e.g., topical), enhanced transdermal drug delivery, and avoidance of first-pass effect. Non-invasiveness enhances patient's compliance hence, better therapeutic outcome. Ethosomes have been shown to exhibit high encapsulation efficiency for a wide range of molecules including lipophilic drugs due to the multilamellarity of the vesicles as well as the presence of ethanol, which allows for better solubility of many drugs [39,115]. Unlike liposomes and transfersomes, ethosomes were able to improve skin delivery of drugs

The application of transformable liposomes, which are prepared using alcohol (ethosomes) in the lipid bilayer of stratum corneum, able to deform and penetrate throughout the skin when pressure is applied, has been increased. For example, tacrolimus-loaded ethosomes may be useful as a therapeutic agent for atopic dermatitis [120]. Skin permeation of ethosomal formulations assessed by confocal microscopy revealed enhanced permeation of Rhodamine 123-loaded formulation in comparison to the hydroalcoholic solution. Another ethosomal formulation has proved to be a potentially useful vehicle for transdermal delivery of ketopro‐ fen [121]. Furthermore, an ethosomal carrier (phosphatidylethanolamine) is an optional treatment for psoriasis that provides long-term therapeutic effects, is nontoxic, and has better compliance with patients. Application of ethosomal carriers with 5-aminolevulinic acid (ALA) in hyperproliferative murine skin can improve the penetration of ALA and the formation of protoporphyrin IX and significantly reduce tumor necrosis factor in this disordered skin

Ethosomes were used efficiently to enhance the anti-inflammatory activity of ammonium glycyrrhizinate compared to the ethanolic or aqueous solutions of this drug [123]. Moreover, the ethosomal system dramatically enhanced the skin permeation of minoxidil *in vitro* compared with either ethanolic or hydroethanolic solution or phospholipid ethanolic micellar solution of minoxidil. In addition, the transdermal delivery of testosterone from an ethosomal patch was greater both *in vitro* and *in vivo* than from commercially available patches [124]. Examples of transdermal drug delivery using ethosomes are tacrolimus [120], clotrimazole

the size, the greater the extent of penetration [108].

compared to an ALA aqueous solution [122].

both under occlusive [117] and non-occlusive conditions [111,118,119].

[125], trihexyphenidyl HCl [126], ketoprofen [121] and testosterone.

#### *10.3.3. Transfersomes*

Transfersomes have been defined as specially designed vesicular particles, consisting of at least one inner aqueous compartment surrounded by a lipid bilayer with appropriately tailored properties. Accordingly, transfersomes resemble lipid vesicles, liposomes, in mor‐ phology but, functionally, transfersomes are sufficiently deformable to penetrate pores much smaller than their own size [104].

They are metastable, which makes the vesicle membrane ultraflexible, and, thus, the vesicles are highly deformable. It is chiefly the unusually strong membrane adaptability that allows the transfersomes vesicles to accommodate to a confining pore and thus trespass such a pore. Typical transfersomes are, therefore, characterized by at least one order of magnitude more elastic membrane than that of conventional lipid vesicles, liposomes. In order to change liposomes into transfersomes, one can incorporate one or more edge-active substance(s) into the vesicular membrane, surfactants were suggested as examples of such edge-activators [105-107]. Another specific difference between transfersomes and liposomes is the higher hydrophilicity of the former, which allows transfersome membrane to swell more than conventional lipid vesicle bilayers.

#### *10.3.4. Ethosomes*

Ethosomes are lipid vesicular carriers embodying ethanol in relatively high concentrations for enhanced skin permeation of drugs [108]. They are composed mainly of phospholipids, ethanol and water. The high concentration of ethanol, which essentially differentiates ethosomes from other vesicular carriers, acts to enhance skin permeation in order to release the entrapped drug particles into deeper layers and systemic circulation. Ethosome was developed by Touitou in 1996, in the course of studying the use of lipid vesicles in drug delivery systems for skin treatment [109].

Structurally, an ethosomal vesicle is composed a phospholipid bilayer and an aqueous inner core containing the entrapped active ingredient. They are soft and malleable. The size of an ethosome vesicle lies within the nanometer range [110]. In addition, the size of etho‐ some vesicle is smaller than that of a liposome when prepared under the same condi‐ tions, due to the high alcohol content. The size decreased as alcohol increased from 20 to 45 % [39]. This reduction in size was attributed to the conferment of a net negative charge on the vesicle surface by ethanol. Other excipients usually added in ethosome formula‐ tion include cholesterol, for vesicle membrane stabilization; permeation enhancers, mark‐ er dyes (if required) such as rhodamine, for characterization study. The stabilizing effect of cholesterol is due to prevention of vesicle aggregation and enlargement during storage [111]. The small size and malleability of ethosomes enable them to pass through the skin or membrane barrier and also influence the extent of transdermal permeation. The smaller the size, the greater the extent of penetration [108].

as effective dermal and transdermal drug-delivery systems [99,100]. In particular, niosomes are considered an interesting drug-delivery system in the treatment of dermatological disorders. Examples of transdermal drug delivery using niosomes are minoxidil and ellagic acid. Niosomes have been reported to enhance the residence time of drugs in the stratum corneum and epidermis, while reducing the systemic absorption of the drug, and improve penetration of the trapped substances across the skin. In addition, these systems have been reported to decrease side effects and to give a considerable drug release [101]. Niosomes formed from sorbitan monoesters (Spans) with cholesterol molar ratios of 1:1 are a promising approach for the topical delivery of minoxidil in hair-loss treatment [102]. Junyaprasert et al demonstrated that the Span 60 and Tween 60 niosomes may be a potential carrier for dermal

Transfersomes have been defined as specially designed vesicular particles, consisting of at least one inner aqueous compartment surrounded by a lipid bilayer with appropriately tailored properties. Accordingly, transfersomes resemble lipid vesicles, liposomes, in mor‐ phology but, functionally, transfersomes are sufficiently deformable to penetrate pores much

They are metastable, which makes the vesicle membrane ultraflexible, and, thus, the vesicles are highly deformable. It is chiefly the unusually strong membrane adaptability that allows the transfersomes vesicles to accommodate to a confining pore and thus trespass such a pore. Typical transfersomes are, therefore, characterized by at least one order of magnitude more elastic membrane than that of conventional lipid vesicles, liposomes. In order to change liposomes into transfersomes, one can incorporate one or more edge-active substance(s) into the vesicular membrane, surfactants were suggested as examples of such edge-activators [105-107]. Another specific difference between transfersomes and liposomes is the higher hydrophilicity of the former, which allows transfersome membrane to swell more than

Ethosomes are lipid vesicular carriers embodying ethanol in relatively high concentrations for enhanced skin permeation of drugs [108]. They are composed mainly of phospholipids, ethanol and water. The high concentration of ethanol, which essentially differentiates ethosomes from other vesicular carriers, acts to enhance skin permeation in order to release the entrapped drug particles into deeper layers and systemic circulation. Ethosome was developed by Touitou in 1996, in the course of studying the use of lipid vesicles in drug delivery systems for skin

Structurally, an ethosomal vesicle is composed a phospholipid bilayer and an aqueous inner core containing the entrapped active ingredient. They are soft and malleable. The size of an ethosome vesicle lies within the nanometer range [110]. In addition, the size of etho‐ some vesicle is smaller than that of a liposome when prepared under the same condi‐

delivery of ellagic acid [103].

212 Application of Nanotechnology in Drug Delivery

smaller than their own size [104].

conventional lipid vesicle bilayers.

*10.3.4. Ethosomes*

treatment [109].

*10.3.3. Transfersomes*

Ethosomes permeate through the stratum corneum barrier and posses significantly high transdermal flux unlike classical liposomes. These effects of combined phospholipids and high concentration of ethanol in vesicular formulations have been suggested to be responsible for deeper distribution and penetration in the skin lipid bilayers [110]. Application of ethosomes in drug delivery has numerous advantages [112-114]: simplicity of the technology, noninvasive means of application (e.g., topical), enhanced transdermal drug delivery, and avoidance of first-pass effect. Non-invasiveness enhances patient's compliance hence, better therapeutic outcome. Ethosomes have been shown to exhibit high encapsulation efficiency for a wide range of molecules including lipophilic drugs due to the multilamellarity of the vesicles as well as the presence of ethanol, which allows for better solubility of many drugs [39,115]. Unlike liposomes and transfersomes, ethosomes were able to improve skin delivery of drugs both under occlusive [117] and non-occlusive conditions [111,118,119].

The application of transformable liposomes, which are prepared using alcohol (ethosomes) in the lipid bilayer of stratum corneum, able to deform and penetrate throughout the skin when pressure is applied, has been increased. For example, tacrolimus-loaded ethosomes may be useful as a therapeutic agent for atopic dermatitis [120]. Skin permeation of ethosomal formulations assessed by confocal microscopy revealed enhanced permeation of Rhodamine 123-loaded formulation in comparison to the hydroalcoholic solution. Another ethosomal formulation has proved to be a potentially useful vehicle for transdermal delivery of ketopro‐ fen [121]. Furthermore, an ethosomal carrier (phosphatidylethanolamine) is an optional treatment for psoriasis that provides long-term therapeutic effects, is nontoxic, and has better compliance with patients. Application of ethosomal carriers with 5-aminolevulinic acid (ALA) in hyperproliferative murine skin can improve the penetration of ALA and the formation of protoporphyrin IX and significantly reduce tumor necrosis factor in this disordered skin compared to an ALA aqueous solution [122].

Ethosomes were used efficiently to enhance the anti-inflammatory activity of ammonium glycyrrhizinate compared to the ethanolic or aqueous solutions of this drug [123]. Moreover, the ethosomal system dramatically enhanced the skin permeation of minoxidil *in vitro* compared with either ethanolic or hydroethanolic solution or phospholipid ethanolic micellar solution of minoxidil. In addition, the transdermal delivery of testosterone from an ethosomal patch was greater both *in vitro* and *in vivo* than from commercially available patches [124]. Examples of transdermal drug delivery using ethosomes are tacrolimus [120], clotrimazole [125], trihexyphenidyl HCl [126], ketoprofen [121] and testosterone.

#### **10.4. Dendrimers**

Dendrimers are nonpeptidic fractal 3-D structures made of numerous small molecules. The structure of these molecules results in relatively uniform shapes, sizes, and molecular weights. The permeability of dendrimers through the skin depends on physicochemical characteristics like generation size, molecular weight, surface charge, composition, and concentration. These nanocarriers have been used to transport photosensitizers for photochemical therapy and antifungal molecules.

**Nanocarrier Advantages Disadvantages**

• Dendrimers also act like solubility enhancers, increasing the permeation of lipophilic drugs.

• They can encapsulate both hydrophilic and

• Ability to target organs for drug delivery. • Extremely high flexibility of their membrane.

**Table 2.** Advantages and disadvantages of nanocarrier systems for transdermal drug delivery [6, 75].

Lipid nanoparticles include solid lipid nanoparticles (SLN), nanostructured lipid carriers, lipid drug conjugates and are colloidal drug carrier systems [135-137]. They are very much like nanoemulsions, differing in lipid nature. The liquid lipid used in emulsions is replaced by a lipid solid at room temperature in SLN including high-melting point glycerides or waxes [136,138,139]. Lipid nanoparticles are good candidates for transdermal delivery. They can be prepared in different sizes and it is possible to modify surface polarity in order to improve skin penetration. From the upper skin, nanoparticles can reach deeper skin regions because

NLC are colloidal carriers characterized by a solid lipid core consisting of a mixture of solid and liquid lipids, and having a mean particle size in the nanometer range. They consist of a

Dendrimers • They increase stability of therapeutic agents. • They have shown cellular toxicity.

• High drug loads.

lipophilic moieties.

**10.5. Lipid nanoparticles**

they exhibit mechanical flexion [6].

*10.5.1. Nanostructured lipid carriers (NLC)*

Niosomes, transfersomes, ethosomes

• High biocompatibility. • Lipid crystallization leads to a lot of

• Simple manufacture. • Variable kinetics of distribution processes. • Protein carriers increase their stability. • They are susceptible to physical instability.

• They are easily prepared and functionalized. • Elimination and metabolism could be a

• They increase bioavailability of drugs. • Their synthesis costs are higher than other

• Biodegradable and low toxicity. • Predisposition to oxidative degradation.

• They covalently associate drugs. • Hemolytic effects can be found.

• Easy to prepare. • Purity of natural phospholipids. • Softness, malleability. • Formulations may be expensive.

polymorphic issues.

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materials.

nanocarriers.

drugs.

problem depending on the generation and

• They are not good carriers for hydrophilic

Dendrimers have been utilized for transdermal drug delivery, as shown in Table 1. The main problems with this kind of transdermal carrier are their poor biodegradation and inherent cytotoxicity [127]. The main advantage of dendrimers is that they have multivalency [128] and it is possible to precisely control the functional groups on the surface [129]. Due to their form and size, these molecules can carry drugs, imaging agents, etc. Dendrimers interact with lipids present in membranes, and they show better permeation in cell cultures and intestinal membranes. Dendrimers also act like solubility enhancers, increasing the permeation of lipophilic drugs. However, they are not good carriers for hydrophilic drugs. Examples of drugs delivered throughout the skin by using dendrimers are tamsulosin [130], indomethacin [131], ketoprofen, diflunisal [132], 5-fluorouracil [133] and peptides [134].



**Table 2.** Advantages and disadvantages of nanocarrier systems for transdermal drug delivery [6, 75].

#### **10.5. Lipid nanoparticles**

**10.4. Dendrimers**

214 Application of Nanotechnology in Drug Delivery

antifungal molecules.

Dendrimers are nonpeptidic fractal 3-D structures made of numerous small molecules. The structure of these molecules results in relatively uniform shapes, sizes, and molecular weights. The permeability of dendrimers through the skin depends on physicochemical characteristics like generation size, molecular weight, surface charge, composition, and concentration. These nanocarriers have been used to transport photosensitizers for photochemical therapy and

Dendrimers have been utilized for transdermal drug delivery, as shown in Table 1. The main problems with this kind of transdermal carrier are their poor biodegradation and inherent cytotoxicity [127]. The main advantage of dendrimers is that they have multivalency [128] and it is possible to precisely control the functional groups on the surface [129]. Due to their form and size, these molecules can carry drugs, imaging agents, etc. Dendrimers interact with lipids present in membranes, and they show better permeation in cell cultures and intestinal membranes. Dendrimers also act like solubility enhancers, increasing the permeation of lipophilic drugs. However, they are not good carriers for hydrophilic drugs. Examples of drugs delivered throughout the skin by using dendrimers are tamsulosin [130], indomethacin [131],

• Not enough toxicological assessment has

• Some processes are difficult to scale up.

• Sometimes, the size they reach is not enough to avoid the immune system.

• They are susceptible to Oswald ripening.

used, decreased stability of high molecular

been done.

method for drug delivery.

• There are many ways to prepare them. • It is difficult to develop an analytical

• They are nontoxic and nonirritant. • Surface charge has a marked effect on

• Easily applied to skin and mucous membranes. • Variable kinetics of distribution processes

Liposomes • Control release based on natural lipids. • When high-pressure homogenization is

stability.

and clearance.

weight molecules.

ketoprofen, diflunisal [132], 5-fluorouracil [133] and peptides [134].

**Nanocarrier Advantages Disadvantages**

• They can include antibodies in their surface to

• Both hydrophilic and hydrophobic drugs can be

• They are able to avoid the immune system due to

Nanoparticles • They can be made of a lot of biodegradable

reach target organs.

loaded in ananoparticle.

Nanoemulsions • They can be formulated as foams, liquids, creams,

materials.

their size.

and sprays.

Lipid nanoparticles include solid lipid nanoparticles (SLN), nanostructured lipid carriers, lipid drug conjugates and are colloidal drug carrier systems [135-137]. They are very much like nanoemulsions, differing in lipid nature. The liquid lipid used in emulsions is replaced by a lipid solid at room temperature in SLN including high-melting point glycerides or waxes [136,138,139]. Lipid nanoparticles are good candidates for transdermal delivery. They can be prepared in different sizes and it is possible to modify surface polarity in order to improve skin penetration. From the upper skin, nanoparticles can reach deeper skin regions because they exhibit mechanical flexion [6].

#### *10.5.1. Nanostructured lipid carriers (NLC)*

NLC are colloidal carriers characterized by a solid lipid core consisting of a mixture of solid and liquid lipids, and having a mean particle size in the nanometer range. They consist of a lipid matrix with a special nanostructure [140]. This nanostructure improves drug loading and firmly retains the drug during storage. NLC system minimizes some problems associated with SLN such as low payload for some drugs; drug expulsion on storage and high water content of SLN dispersions.

The conventional method for the production of NLC involves mixing of spatially very different lipid molecules, i.e. blending solid lipids with liquid lipids (oils). The resulting matrix of the lipid particles shows a melting point depression compared with the original solid lipid but the matrix is still solid at body temperature. Depending on the method of production and the composition of the lipid blend, different types of NLC are obtained. The basic idea is that by giving the lipid matrix a certain nanostructure, the payload for active compounds is increased and expulsion of the compound during storage is avoided. Ability to trigger and even control drug release should be considered while mixing lipids to produce NLC. Newer methods of generating NLC have been developed [141].

#### *10.5.2. Solid lipid nanoparticles*

Solid lipid nanoparticles (SLN) are formed by a matrix of lipids which are biodegradable raw materials that are physiologically well tolerated [142]. The main advantages of these systems include protection of labile substances from chemical degradation, control of the release of substances due to the solid state of the lipid matrix, and formation of films over the skin showing occlusive properties [140]. Additional features are the avoidance of organic solvents during the preparation and amenability to large scale production and sterilization. Further‐ more, the great ability of SLNs to facilitate the contact of active substances with the stratum corneum, because of the small size of the particles and consequently the high surface area, leads to the high permeation of the carried substances through the viable skin [143].

(http://www.skin-care-forum.basf.com/en/author-articles/strategies-for-skin-penetration-enhancement/ 2004/08/12?id=5b9a9164-6148-4d66-bd84-6df76bd6d111&mode=Detail. Downloaded April 26, 2014).

Polymeric nanoparticles are prepared from biocompatible and biodegradable polymers with size between 10-1000 nm, where the drug is dissolved, entrapped, encapsulated or attached to a polymer nanoparticle matrix. The penetration and transport extent of these systems through the skin depends on the ingredients' chemical composition, the encapsulation mechanism influencing the drug release, the size of nanoparticles and on the viscosity of the formulations. The polymeric nanoparticles are able to modify the activity of drugs, delay and control the drug release, and increase the drug adhesivity or its time of permanence in the skin. Briefly, the nanoparticles can be useful as reservoirs of lipophilic drugs to deliver them in the stratum corneum becoming an important strategy to control their permeation into the skin [145].

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Carbon nanotubes are stable carbon nanoparticles with potential anti-oxidant ability and cytoprotective effect. Carbon nanotubes (Fig. 7) have extremely small mean diameters (<100 nm). Their large inner volume allows the loading of small biomolecules while their outer surface can be chemically modified to render themselves various novel features that can be used to load proteins and genes for effective drug delivery [146], even through the skin.

Fullerenes (Fig. 7) are 1-nm scale carbon spheres of 60 carbon atoms. Although fullerenes are hydrophobic, they can be organically functionalized by attaching hydrophilic moiety and become water-soluble and capable of carrying genes, proteins and other biomolecules for delivery purposes [146]. Their small size, spherical shape and hollow interior all provide

**Figure 6.** Structure of lipid nanodispersed vehicle systems

**10.7. Carbon nanotubes (CNT) and fullerenes**

**10.6. Polymeric nanoparticles**

The degree of crystallinity of lipid nanoparticles has a great impact on the extent of occlusion by the formulation. With increasing crystallinity, the occlusion factor increases as well [142]. This explains why liquid nanoemulsions in contrast to SLNs do not show an occlusive effect and why the extent of occlusion by nanostructured lipid carrier (NLC) compared to SLN is reduced. Other parameters influencing the occlusion factor are the particle size and the number of particles. The occlusion factor decreases with increase in particle size but increases with increase in number of particles. The occlusive effect leads to reduced water loss and increased skin hydration. Highly crystalline SLNs can be used for physical sun protection due to scattering and reflection of the ultra violet (UV) radiation by the particles. A high crystallinity was found to enhance the effectiveness and was also synergistic with UV absorbing substances used in conventional sunscreens. Similarly, synergism was observed on the sun protection factor and UV-A protection factor exhibited by the incorporation of the inorganic sunscreen, titanium-dioxide in NLC of carnauba wax and decyloleate [144]. Fig. 6 shows the structures of some lipid nanodispersed vehicle systems.

(http://www.skin-care-forum.basf.com/en/author-articles/strategies-for-skin-penetration-enhancement/ 2004/08/12?id=5b9a9164-6148-4d66-bd84-6df76bd6d111&mode=Detail. Downloaded April 26, 2014).

#### **10.6. Polymeric nanoparticles**

lipid matrix with a special nanostructure [140]. This nanostructure improves drug loading and firmly retains the drug during storage. NLC system minimizes some problems associated with SLN such as low payload for some drugs; drug expulsion on storage and high water content

The conventional method for the production of NLC involves mixing of spatially very different lipid molecules, i.e. blending solid lipids with liquid lipids (oils). The resulting matrix of the lipid particles shows a melting point depression compared with the original solid lipid but the matrix is still solid at body temperature. Depending on the method of production and the composition of the lipid blend, different types of NLC are obtained. The basic idea is that by giving the lipid matrix a certain nanostructure, the payload for active compounds is increased and expulsion of the compound during storage is avoided. Ability to trigger and even control drug release should be considered while mixing lipids to produce NLC. Newer methods of

Solid lipid nanoparticles (SLN) are formed by a matrix of lipids which are biodegradable raw materials that are physiologically well tolerated [142]. The main advantages of these systems include protection of labile substances from chemical degradation, control of the release of substances due to the solid state of the lipid matrix, and formation of films over the skin showing occlusive properties [140]. Additional features are the avoidance of organic solvents during the preparation and amenability to large scale production and sterilization. Further‐ more, the great ability of SLNs to facilitate the contact of active substances with the stratum corneum, because of the small size of the particles and consequently the high surface area,

leads to the high permeation of the carried substances through the viable skin [143].

The degree of crystallinity of lipid nanoparticles has a great impact on the extent of occlusion by the formulation. With increasing crystallinity, the occlusion factor increases as well [142]. This explains why liquid nanoemulsions in contrast to SLNs do not show an occlusive effect and why the extent of occlusion by nanostructured lipid carrier (NLC) compared to SLN is reduced. Other parameters influencing the occlusion factor are the particle size and the number of particles. The occlusion factor decreases with increase in particle size but increases with increase in number of particles. The occlusive effect leads to reduced water loss and increased skin hydration. Highly crystalline SLNs can be used for physical sun protection due to scattering and reflection of the ultra violet (UV) radiation by the particles. A high crystallinity was found to enhance the effectiveness and was also synergistic with UV absorbing substances used in conventional sunscreens. Similarly, synergism was observed on the sun protection factor and UV-A protection factor exhibited by the incorporation of the inorganic sunscreen, titanium-dioxide in NLC of carnauba wax and decyloleate [144]. Fig. 6 shows the structures

of SLN dispersions.

216 Application of Nanotechnology in Drug Delivery

generating NLC have been developed [141].

of some lipid nanodispersed vehicle systems.

*10.5.2. Solid lipid nanoparticles*

Polymeric nanoparticles are prepared from biocompatible and biodegradable polymers with size between 10-1000 nm, where the drug is dissolved, entrapped, encapsulated or attached to a polymer nanoparticle matrix. The penetration and transport extent of these systems through the skin depends on the ingredients' chemical composition, the encapsulation mechanism influencing the drug release, the size of nanoparticles and on the viscosity of the formulations. The polymeric nanoparticles are able to modify the activity of drugs, delay and control the drug release, and increase the drug adhesivity or its time of permanence in the skin. Briefly, the nanoparticles can be useful as reservoirs of lipophilic drugs to deliver them in the stratum corneum becoming an important strategy to control their permeation into the skin [145].

#### **10.7. Carbon nanotubes (CNT) and fullerenes**

Carbon nanotubes are stable carbon nanoparticles with potential anti-oxidant ability and cytoprotective effect. Carbon nanotubes (Fig. 7) have extremely small mean diameters (<100 nm). Their large inner volume allows the loading of small biomolecules while their outer surface can be chemically modified to render themselves various novel features that can be used to load proteins and genes for effective drug delivery [146], even through the skin.

Fullerenes (Fig. 7) are 1-nm scale carbon spheres of 60 carbon atoms. Although fullerenes are hydrophobic, they can be organically functionalized by attaching hydrophilic moiety and become water-soluble and capable of carrying genes, proteins and other biomolecules for delivery purposes [146]. Their small size, spherical shape and hollow interior all provide therapeutic opportunities and have been proposed for use in cosmetic products like sunscreens, moisturizers, long lasting makeup, etc.

and less dense [150]. The vesicles then squeeze through the intercellular spaces into the deeper layers of skin. It has been shown that drug particles are concentrated more on the inside wall than in the core of vesicles [151]. In this position, release of the vesicular content is thermody‐ namically favored. Owing to the increased affinity, due to its lipid content, the vesicle fuses with the lipid contents of the skin layers and releases its content which then diffuses into deeper layers of the skin or membrane and into systemic circulation. Other mechanisms, such as the

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**Figure 8.** Mechanism of drug delivery from ethosomal vesicular carriers through the skin [46,115]. Note the initial flu‐

Safety and toxicological issues are the most important issues for a drug delivery system. Safety is an obvious concern for the fast growth of nanoparticles mediated drug delivery [152]. Governmental regulatory agencies such as the United States Food and Drug Agency (USFDA) have established guidelines describing the kind of safety tests that should be conducted in animals in order to have a new drug approved for use in clinical trials and in order to get approval of a new drug application (NDA) for marketing. The rationale and circumstances for conducting reproductive, mutagenicity, carcinogenicity, irritation, and sensitization studies have already been mentioned. The requirements for acute, subacute, and chronic toxicity

**12. Regulations on dermal and transdermal delivery systems**

free drug diffusion, may be involved in penetration.

idization of the skin architecture.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3853888/figure/F4/#108;93 A; http://www.ncbi.nlm.nih.gov/pmc/ articles/PMC3853888/figure/F5/#117.75;90.75 B

**Figure 7.** Carbon nanotube (A) and fullerene (B)
