**9. Characterization of dermal and transdermal delivery systems and their performance**

Dermal and transdermal delivery systems are characterized using different methods.

#### **9.1. Drug solubility determination**

**•** The other advantage of transdermal delivery is that multiple dosing, on-demand or variablerate delivery of drugs is possible with the latest programmable systems, adding more

**•** The general acceptability of transdermal products by patients is very high, which is also

**•** Transdermal route permits the use of a relatively potent drug with minimal risk of system

Even though dermal and transdermal delivery systems have a lot of advantages over conven‐ tional topical formulation, it still suffer from a lot of limitations. The disadvantages of dermal

**•** Drugs or drug formulation may cause sensitization or irritation which must be evaluated

**•** The manufacture requires specialized equipments which results in the formulation being more expensive to manufacture than conventional dosage forms thus the formulation will

**•** There is always a lag time for drug to penetrate through the skin to the systemic circulation,

**•** There is a requirement for low dose/high permeable drug. In general a drug with molecular weight less than 400, logPo/w=2-3 and dose less than 10 mg will be the best candidate for

**9. Characterization of dermal and transdermal delivery systems and their**

Dermal and transdermal delivery systems are characterized using different methods.

therefore TDDS is not suitable for drugs requiring rapid onset of action.

**•** In case of toxicity, the transdermal patch can easily be removed by the patient [37].

**8. Disadvantages of dermal and transdermal delivery systems**

and transdermal delivery systems according to Ranade and Cannon [38] are that:

benefits to the conventional patch dosage forms.

**•** Not all drugs are suitable for transdermal delivery.

fairly early in the development process.

not be economical for most patients.

transdermal delivery.

**performance**

**•** The patches may/can be uncomfortable to wear.

**•** Drugs that require high blood levels cannot be administered.

**•** The adhesive used may not adhere well to all types of skin.

toxicity [35,36].

202 Application of Nanotechnology in Drug Delivery

evident from the increasing market for transdermal products.

The determination of solubility of the drug in the transdermal/dermal matrix early in the formulation process can avoid crystallization problem, which is one of the instabilities in transdermal drug delivery systems (TDDS). This instability in the matrix which could be due to supersaturation makes the formulation metastable and upon storage results in changes in the liberation/release rate of the drug from the formulation.

#### **9.2. Micromeritic measurements**

#### *9.2.1. Particle-size, shape and zeta potential analysis*

Light scattering is an important way of characterizing colloidal and macromolecular disper‐ sions and could be useful in assessing properties of particulate TDDS e.g. ethosomes. The particle size and size distribution are primarily measured using wet laser diffraction sizing otherwise called dynamic light scattering (DLS) [39]. Size of formulation can also be deter‐ mined using dynamic light scattering (e.g. using a Zetasizer). This is necessary to ascertain the possible effect of the size on drug release and penetration across barriers in transdermal and dermal delivery as well as to monitor stability over time. The zeta potential of a formulation is very important. It is determined using Zetsizer or by other means, and gives information on the charge of the particles and the tendency of the particles in a formulation to aggregate or to remain discrete.

#### *9.2.2. Specific surface area*

An important parameter of bulk powders is the specific surface area expressed per unit weight. The specific surface area measurement includes the cracks, crevices, nooks, and crannies present in the particles. To include these features in the surface-area measurement, methods have been developed to probe these convoluted surfaces through adsorption by either a gas or a liquid [40-42]. The most widely used surface area measurement technique is the adsorption of a monolayer of gas, typically krypton or nitrogen as the adsorbate gas in helium as an inert diluent, using the method developed by Brunauer, Emmett, and Teller known as the BET method. Surface area affects spreading and occlusivity of TDDS.

#### **9.3. Visualization by transmission electron microscopy**

A combination of transmission electron microscopy (TEM) and freeze fracturing otherwise referred to as freeze fracture electron microscopy (FFEM) could be used to visualize skin structures and certain perturbations in the skin. A micrograph image is generated by trans‐ mitting a beam of electrons through a specimen appropriately treated to enhance the visuali‐ zation of skin structural details. High resolution of TEM makes it possible to visualize both structures and transition processes in the epidermis. Using different techniques, epidermal granules [43], Langerhans cells [44] and the lipids in stratum corneum and epidermis [45], amongst others, have been observed. Samples preparation in FFTEM involves freezing the sample and subsequent longitudinal fracturing approximately parallel to the original skin surface under high vacuum [46]. Further treatment could be done on the sample after which the fracture is viewed under high voltage. This visualization method can provide information on the interaction between the nanoparticle formulation and the skin. Since the fracture will always run along the plane of least resistance, FFEM micrographs of treated stratum corneum often show the lipid coated surfaces of corneocytes or the lipid lamellae.

All components in a mixture spend more or less the same time in the mobile phase in order to

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The combination of high-pressure liquid chromatography (HPLC) with monitoring by UV/ Visible detection provides an accurate, precise and robust method for quantitative analysis of pharmaceutical products and is the industry standard method for this purpose. The two principal mechanisms which produce retardation of a compound passing through a column are straight-phase packing where adsorption of polar groups of a molecule onto the polar groups of a stationary phase occur and reverse-phase packing which is due to partitioning of

Mass spectrometry in conjunction with liquid chromatography provides a method for characterizing impurities in drugs and formulation excipients [53]. It provides highly sensitive and specific methods for determining drugs and their metabolities in biological fluids and

FTIR spectroscopic properties are used to determine the chemical stability of the drug in a TDDS. FTIR spectra of formulations, the starting materials and pure drug sample are normally obtained at a range of 4000-400 cm-1 and the spectra obtained on infrared spectrophotometer

Detailed insights into the organization of the stratum corneum can be gained through the study of the vibrations of amide, amine and carboxylic groups and the frequencies of the methylene stretching, scissoring and rocking vibrations. FTIR is used to study the lateral lipid organiza‐ tion of the intercellular lipid matrix in stratum corneum, which is essential for the barrier function of stratum corneum, as more densely organized membranes are less permeable to substances. The stretching vibrations are used to determine whether lipids are in an ordered (hexagonal or orthorhombic lateral packing) or disordered packing (liquid phase), while the scissoring and rocking vibration provide detailed information on the presence of orthorhombic phases. By performing measurements at different temperatures, also the thermotropic

Attenuated total reflectance FTIR (ATR-FTIR) is a modification of FTIR. In this technique, IR radiation is not transmitted through the sample but reflected by the sample. With this technique, it is possible to perform measurements on stratum corneum *in vivo*, because the skin can be placed on the ATR crystal. The IR radiation beam penetrates only to a limited extent into stratum corneum. In order to detect substances in the stratum corneum, it is necessary to remove stratum corneum layers, by tape-stripping, which makes it also possible to generate a penetration profile of an applied substance in stratum corneum [54-56]. ATR-FTIR has been used to determine effects of topically applied substances on the lipid organization in the

exit the column. The column effluent can be monitored with a variety of detectors.

the lipophilic portion of a molecule into the stationary phase.

**9.6. Liquid chromatography–mass spectrometry (LC/MS)**

**9.7. Fourier Transform infra red (FTIR) spectroscopy**

using potassium bromide of spectroscopic grade.

behaviour of the lipids can be determined.

**9.8. Attenuated Total Reflectance FTIR (ATR-FTIR)**

tissues.

#### **9.4. Stability**

Physical and chemical instabilities of carrier systems often limit their widespread use in medical applications [47]. Instabilities in ethosomes and other nanocarrier formulations are caused by hydrolysis or oxidation of the phospholipid molecules and are indicated by leakage of the encapsulated drug and alterations in vesicle size due to fusion and aggregation [48,49]. Changes in size and size distribution, entrapment efficiency and aggregation of vesicles are very important parameters in monitoring stability. These parameters can be assessed by EM or DLS repeatedly over time at varying storage conditions. It has recently been found that although multilamellar and large unilamellar benzocaine-loaded ethosome vesicles remained substantially stable with time, in terms of drug entrapment yield and particle dimensions, small unilamellar vesicles showed high tendency to form aggregates due to increased surface area exposed to the medium [10]. Such vesicle aggregation indicates instability. In addition, changes in storage conditions led to marked decrease in particle dimensions and drugentrapping yield with less regular morphology for frozen-and-thawed multilamellar etho‐ some dispersions, while the untreated multilamellar and unilamellar vesicular dispersions remained homogenous and stable with regard to those parameters assessed over the period [50]. Temperature of formulation and storage conditions affect physical stability of nanopar‐ ticle preparations [10,51].

Optical characteristics, viscosity and physical changes such as cracking or creaming are also important in assessing stability of ethosomes. Ethosomes are colloidal disperse systems therefore, cracking and creaming may be observed during storage as in water-in-oil emulsions. The use of an innovative optical analyzer, Turbiscan Lab® Expert, in studying the influence of optical characteristics on long-term stability of vesicular colloidal delivery systems has been advocated [52]. The principle of this measurement is based on the variation of the droplet volume fraction (migration) or mean size (coalescence), thus resulting in the variation of backscattering and transmission signals as a function of time. No variation of particle size occurs when the backscattering profile is within the interval ± 2 %. Variations greater than 10 % either as a positive or negative value in the graphical scale of backscattering are represen‐ tative of an unstable formulation.

#### **9.5. High-pressure liquid chromatography (HPLC)**

It is used to monitor the stability of pure drug substance and drugs in formulation with quantitation of degradation product. A liquid mobile phase is pumped under pressure through a stainless steel column containing particles of stationary phase with a diameter of 3-10 μm. The analyte is loaded onto the head of the column via a loop valve and separation of a mixture occurs according to the relative lengths of time spent by its components in the stationary phase. All components in a mixture spend more or less the same time in the mobile phase in order to exit the column. The column effluent can be monitored with a variety of detectors.

The combination of high-pressure liquid chromatography (HPLC) with monitoring by UV/ Visible detection provides an accurate, precise and robust method for quantitative analysis of pharmaceutical products and is the industry standard method for this purpose. The two principal mechanisms which produce retardation of a compound passing through a column are straight-phase packing where adsorption of polar groups of a molecule onto the polar groups of a stationary phase occur and reverse-phase packing which is due to partitioning of the lipophilic portion of a molecule into the stationary phase.

#### **9.6. Liquid chromatography–mass spectrometry (LC/MS)**

surface under high vacuum [46]. Further treatment could be done on the sample after which the fracture is viewed under high voltage. This visualization method can provide information on the interaction between the nanoparticle formulation and the skin. Since the fracture will always run along the plane of least resistance, FFEM micrographs of treated stratum corneum

Physical and chemical instabilities of carrier systems often limit their widespread use in medical applications [47]. Instabilities in ethosomes and other nanocarrier formulations are caused by hydrolysis or oxidation of the phospholipid molecules and are indicated by leakage of the encapsulated drug and alterations in vesicle size due to fusion and aggregation [48,49]. Changes in size and size distribution, entrapment efficiency and aggregation of vesicles are very important parameters in monitoring stability. These parameters can be assessed by EM or DLS repeatedly over time at varying storage conditions. It has recently been found that although multilamellar and large unilamellar benzocaine-loaded ethosome vesicles remained substantially stable with time, in terms of drug entrapment yield and particle dimensions, small unilamellar vesicles showed high tendency to form aggregates due to increased surface area exposed to the medium [10]. Such vesicle aggregation indicates instability. In addition, changes in storage conditions led to marked decrease in particle dimensions and drugentrapping yield with less regular morphology for frozen-and-thawed multilamellar etho‐ some dispersions, while the untreated multilamellar and unilamellar vesicular dispersions remained homogenous and stable with regard to those parameters assessed over the period [50]. Temperature of formulation and storage conditions affect physical stability of nanopar‐

Optical characteristics, viscosity and physical changes such as cracking or creaming are also important in assessing stability of ethosomes. Ethosomes are colloidal disperse systems therefore, cracking and creaming may be observed during storage as in water-in-oil emulsions. The use of an innovative optical analyzer, Turbiscan Lab® Expert, in studying the influence of optical characteristics on long-term stability of vesicular colloidal delivery systems has been advocated [52]. The principle of this measurement is based on the variation of the droplet volume fraction (migration) or mean size (coalescence), thus resulting in the variation of backscattering and transmission signals as a function of time. No variation of particle size occurs when the backscattering profile is within the interval ± 2 %. Variations greater than 10 % either as a positive or negative value in the graphical scale of backscattering are represen‐

It is used to monitor the stability of pure drug substance and drugs in formulation with quantitation of degradation product. A liquid mobile phase is pumped under pressure through a stainless steel column containing particles of stationary phase with a diameter of 3-10 μm. The analyte is loaded onto the head of the column via a loop valve and separation of a mixture occurs according to the relative lengths of time spent by its components in the stationary phase.

often show the lipid coated surfaces of corneocytes or the lipid lamellae.

**9.4. Stability**

204 Application of Nanotechnology in Drug Delivery

ticle preparations [10,51].

tative of an unstable formulation.

**9.5. High-pressure liquid chromatography (HPLC)**

Mass spectrometry in conjunction with liquid chromatography provides a method for characterizing impurities in drugs and formulation excipients [53]. It provides highly sensitive and specific methods for determining drugs and their metabolities in biological fluids and tissues.

#### **9.7. Fourier Transform infra red (FTIR) spectroscopy**

FTIR spectroscopic properties are used to determine the chemical stability of the drug in a TDDS. FTIR spectra of formulations, the starting materials and pure drug sample are normally obtained at a range of 4000-400 cm-1 and the spectra obtained on infrared spectrophotometer using potassium bromide of spectroscopic grade.

Detailed insights into the organization of the stratum corneum can be gained through the study of the vibrations of amide, amine and carboxylic groups and the frequencies of the methylene stretching, scissoring and rocking vibrations. FTIR is used to study the lateral lipid organiza‐ tion of the intercellular lipid matrix in stratum corneum, which is essential for the barrier function of stratum corneum, as more densely organized membranes are less permeable to substances. The stretching vibrations are used to determine whether lipids are in an ordered (hexagonal or orthorhombic lateral packing) or disordered packing (liquid phase), while the scissoring and rocking vibration provide detailed information on the presence of orthorhombic phases. By performing measurements at different temperatures, also the thermotropic behaviour of the lipids can be determined.

#### **9.8. Attenuated Total Reflectance FTIR (ATR-FTIR)**

Attenuated total reflectance FTIR (ATR-FTIR) is a modification of FTIR. In this technique, IR radiation is not transmitted through the sample but reflected by the sample. With this technique, it is possible to perform measurements on stratum corneum *in vivo*, because the skin can be placed on the ATR crystal. The IR radiation beam penetrates only to a limited extent into stratum corneum. In order to detect substances in the stratum corneum, it is necessary to remove stratum corneum layers, by tape-stripping, which makes it also possible to generate a penetration profile of an applied substance in stratum corneum [54-56]. ATR-FTIR has been used to determine effects of topically applied substances on the lipid organization in the stratum corneum [54,57]. ATR-FTIR can be combined with tape-stripping to determine the penetration profile of hydrophilic and lipophilic substances in stratum corneum in addition to the water profile of the stratum corneum.

wiped off. The skin reactions are scored at 24 and 72 h after the initial application according

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**Skin reaction Value**

No erythema 0 Very slight erythema (barely perceptible) 1 Well-defined erythema 2 Moderate to severe erythema 3 Severe erythema (beet redness) to slight eschar formation (injuries in depth) 4

No edema 0 Very slight edema (barely perceptible) 1 Slight edema (edges of area well defined by definite raising) 2 Moderate edema (raised approximately 1 mm) 3 Severe edema (raised more than 1 mm and extending beyond the area of exposure) 4

The mean values of the six rabbits for erythema and eschar formation at 24 and 72 h for both intact and abraded skin (four values) are added. The mean values of the six rabbits for edema at 24 and 72 h (four values) are also added. The total of eight values is divid‐ ed by 4 to give the primary irritation index. Values of 5 or greater are considered indica‐

It is usually the aim of cosmetic chemists to maintain the skin's softness and freshness and it is considered important to retain moisture in the stratum corneum. The degree to which a formulation retains or promotes the loss of moisture from the stratum corneum is termed the occlusivity. The occlusivity of formulations for topical application is determined *in vivo* by measuring the suppression of transepidermal water loss (TEWL) of the skin. The occlusive effect of the formulation also depends on the characteristics of the skin such as the lipid level and prevailing environmental condition. The occlusivity of films formed by nanoparticles varies with time, type of formulation, coating amount, physical form, size of particles etc. It is necessary to determine the occlusivity of a nanoparticle formulation for topical application as it directly affects liberation and penetration of the encapsulated drug. Under occlusive

conditions, the skin is more hydrated and transport of drug could be higher.

to a scheme such as that listed in Table 1.

**Erythema and eschar formation**

**Table 1.** Dermal irritation scoring system

tive of a positive irritant [60].

**9.12. Occlusivity**

**Edema formation**

#### **9.9. Differential scanning calorimetry (DSC)**

This technology is used to evaluate the degree of perturbation of the skin lipids as a result of penetration of a formulation or drug through skin. The free intercellular lipid bilayers of the stratum corneum have a unique composition compared to other epithelial lipid bilayers and consist of ceramides (50%), cholesterol (25%), and fatty acids (10-20%, highly enriched in linoleic acid). These common skin lipids are detected at different transition temperatures when the skin is subjected to DSC studies.

#### **9.10. Small angle X-ray diffraction (SAXD)**

This technique is used to analyse the long range order of the crystalline structure of lipids. Stratum corneum is a very thin layer of about 10 μm and composed of corneocytes and an intercellular lipid matrix. The ordered structure of the intercellular lipid matrix plays an important role in skin barrier function. Structural analyses of intercellular lipids in mammalian stratum corneum by X-ray diffraction have shown more detailed lipid structure models. The X-ray pattern of a lamellar phase is characterized by a series of sequential maxima, which are positioned at equal interpeak distances at increasing scattering angle [58]. The sequential peaks are referred to as the 1st order (positioned at distance Q1), the 2nd order (Q2), the 3rd order (Q3), etc, in which Q is directly related to the scattering angle. The repeat distance (d) of a lamellar phase can be directly calculated from the peak positions d=2*π*/Q1=4 *π* /Q2=6 *π* /Q3, etc. In skin research SAXD is used to study the lamellar organization of the lipids in the intercellular matrix of stratum corneum of humans and other mammals. Furthermore, SAXD measurements using lipid mixtures of ceramides, cholesterol and free fatty acids have revealed the role of the various lipid classes in the lamellar phases. Additionally, it has been used to study effects of topically applied substances [59] or physical stratum corneum perturbation methods [54]. SAXD is also used to study the effects of hydrophilic and lipophilic agents like nanoparticles on the lamellar organization of isolated stratum corneum.

#### **9.11. Dermal irritation assay**

If a new drug is intended to be applied to the skin or eyes, one of the first tests to be conducted would be to determine if the drug, or the formulation containing the drug, will cause irritation of the skin or eyes. Even if a drug is intended only for dermal application, eye irritation testing may also be required because of the possibility of inadvertent exposure to the eyes. The test is conducted as follows: Six male albino rabbits are to be clipped free of hair on the back. One area of skin is left intact, whereas another is abraded in a tic-tac-toe pattern with the point of a hypodermic needle so as to incise the superficial epidermis layer without causing bleeding. The test material, 0.5 ml of liquid or 0.5 g of solid or semisolid is applied to each site under a 1 × 1 inch gauze pad. The entire trunk of the animal is wrapped with an impervious material and held in place with tape for 24 h. The patches are then removed and excessive material wiped off. The skin reactions are scored at 24 and 72 h after the initial application according to a scheme such as that listed in Table 1.


**Table 1.** Dermal irritation scoring system

The mean values of the six rabbits for erythema and eschar formation at 24 and 72 h for both intact and abraded skin (four values) are added. The mean values of the six rabbits for edema at 24 and 72 h (four values) are also added. The total of eight values is divid‐ ed by 4 to give the primary irritation index. Values of 5 or greater are considered indica‐ tive of a positive irritant [60].

#### **9.12. Occlusivity**

stratum corneum [54,57]. ATR-FTIR can be combined with tape-stripping to determine the penetration profile of hydrophilic and lipophilic substances in stratum corneum in addition

This technology is used to evaluate the degree of perturbation of the skin lipids as a result of penetration of a formulation or drug through skin. The free intercellular lipid bilayers of the stratum corneum have a unique composition compared to other epithelial lipid bilayers and consist of ceramides (50%), cholesterol (25%), and fatty acids (10-20%, highly enriched in linoleic acid). These common skin lipids are detected at different transition temperatures when

This technique is used to analyse the long range order of the crystalline structure of lipids. Stratum corneum is a very thin layer of about 10 μm and composed of corneocytes and an intercellular lipid matrix. The ordered structure of the intercellular lipid matrix plays an important role in skin barrier function. Structural analyses of intercellular lipids in mammalian stratum corneum by X-ray diffraction have shown more detailed lipid structure models. The X-ray pattern of a lamellar phase is characterized by a series of sequential maxima, which are positioned at equal interpeak distances at increasing scattering angle [58]. The sequential peaks are referred to as the 1st order (positioned at distance Q1), the 2nd order (Q2), the 3rd order (Q3), etc, in which Q is directly related to the scattering angle. The repeat distance (d) of a lamellar phase can be directly calculated from the peak positions d=2*π*/Q1=4 *π* /Q2=6 *π* /Q3, etc. In skin research SAXD is used to study the lamellar organization of the lipids in the intercellular matrix of stratum corneum of humans and other mammals. Furthermore, SAXD measurements using lipid mixtures of ceramides, cholesterol and free fatty acids have revealed the role of the various lipid classes in the lamellar phases. Additionally, it has been used to study effects of topically applied substances [59] or physical stratum corneum perturbation methods [54]. SAXD is also used to study the effects of hydrophilic and lipophilic agents like

If a new drug is intended to be applied to the skin or eyes, one of the first tests to be conducted would be to determine if the drug, or the formulation containing the drug, will cause irritation of the skin or eyes. Even if a drug is intended only for dermal application, eye irritation testing may also be required because of the possibility of inadvertent exposure to the eyes. The test is conducted as follows: Six male albino rabbits are to be clipped free of hair on the back. One area of skin is left intact, whereas another is abraded in a tic-tac-toe pattern with the point of a hypodermic needle so as to incise the superficial epidermis layer without causing bleeding. The test material, 0.5 ml of liquid or 0.5 g of solid or semisolid is applied to each site under a 1 × 1 inch gauze pad. The entire trunk of the animal is wrapped with an impervious material and held in place with tape for 24 h. The patches are then removed and excessive material

nanoparticles on the lamellar organization of isolated stratum corneum.

to the water profile of the stratum corneum.

206 Application of Nanotechnology in Drug Delivery

**9.9. Differential scanning calorimetry (DSC)**

the skin is subjected to DSC studies.

**9.11. Dermal irritation assay**

**9.10. Small angle X-ray diffraction (SAXD)**

It is usually the aim of cosmetic chemists to maintain the skin's softness and freshness and it is considered important to retain moisture in the stratum corneum. The degree to which a formulation retains or promotes the loss of moisture from the stratum corneum is termed the occlusivity. The occlusivity of formulations for topical application is determined *in vivo* by measuring the suppression of transepidermal water loss (TEWL) of the skin. The occlusive effect of the formulation also depends on the characteristics of the skin such as the lipid level and prevailing environmental condition. The occlusivity of films formed by nanoparticles varies with time, type of formulation, coating amount, physical form, size of particles etc. It is necessary to determine the occlusivity of a nanoparticle formulation for topical application as it directly affects liberation and penetration of the encapsulated drug. Under occlusive conditions, the skin is more hydrated and transport of drug could be higher.

#### **9.13. Spreadability**

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

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 [63]. Spreadability is subjectively assessed at shear rates varying from 102 to 105 s-1. The rate of shear during spreading, *γ* s-1, is calculated using the following equation for plane laminar flow between two parallel plates:

$$
\gamma = \frac{v}{\pi} \tag{1}
$$

property can also be used to assess the stability of the formulation over time. To obtain information about viscous and elastic behaviour as well as microstructure of the topical gels,

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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

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.

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

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

flow viscometry, oscillatory rheometry, and transient measurements are conducted.

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

and protection (cosmetics) [6].

**10.1. Microemulsions**

delivery of drugs [72,73].

drug in the carriers [68,70,71].

in which *v* is the relative velocity of the plates (cm s-1) and *d* is the distance between them (cm); that is, a measure of thickness of the film between the skin surfaces [64].

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

#### **9.14. Rheology**

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 property can also be used to assess the stability of the formulation over time. To obtain information about viscous and elastic behaviour as well as microstructure of the topical gels, flow viscometry, oscillatory rheometry, and transient measurements are conducted.
