**5. Dermatopharmacokinetics**

Dermatopharmacokinetics describe the pharmacokinetics of topically applied drugs in the stratum corneum with pharmacodynamic effects. The smart techniques (tape stripping and microdialysis) use in dermatopharmacokinetic methodology assesses the cutaneous drug concentration at the site of application. Various studies have shown dermatopharmacokinetics to be a reliable and reproducible method for determining bioequivalence, and have indicated that it is applicable for all topical dermatological drug products. Dermatopharmacokinetics refer to the determination of stratum corneum concentration-time curves for topical actives. This is analogous to plasma/urine concentration-time curves for systemically or orally administered drugs, and the concept is clearly adaptable to microdialysis, where drug is determined in the skin compartment in which the microdialysis fibre is positioned (Fig. 4).

Although, this procedure is invasive, it is a method of great potential offering information of high value and relevance. There could be sampling in a compartment within the skin. It is a technically demanding procedure, however, requiring experimental dexterity of high order. The potential for use on diseased skin is a unique and considerable advantage over other techniques, but real challenges remain with respect to reproducibility, sensitivity, applicable drugs, etc.

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

Stratum corneum tape-stripping is a minimally invasive method for determining drug levels in human stratum corneum *in vivo.* It involves repeated application of adhesive tapes on a site that has been treated with a topical formulation and determination of drug levels in stratum corneum collected on tape strips.

The dermatopharmacokinetics approach suggested by the Food and Drug Administration (FDA) proposes to evaluate the level of a topically applied drug in the stratum corneum during its uptake and clearance so as to calculate classic pharmacokinetic parameters [18]. The assumption is that stratum corneum concentration-time curves are directly related to concen‐ tration-time curves in the epidermis and dermis.

When applied to diseased skin, topical drug products induce one or more therapeutic responses, where onset, duration, and magnitude depend on the relative efficiency of three sequential processes, namely:

**•** the release of the drug from the dosage form

Nanoparticles show a high affinity for cellular membrane mainly due to electrostatic interac‐ tions [12]. It is known that cell membranes have large negatively charged domains, which should repel negatively charged nanoparticles. The high cellular uptake of negatively charged nanoparticles is related first to the non-specific process of nanoparticles adsorption on the cell membrane and second to formation of nanoparticle clusters [13]. The adsorption of the negatively charged particles at the positively charged sites via electrostatic interaction can lead to localized neutralization and a subsequent bending of the membrane favouring in turn endocytosis for cellular uptake [14]. Thus the formulation of nanoparticles with different surface properties can influence their cellular uptake and intracellular distribution and it is possible to localize the nanoparticles to specific intracellular targets (lysosomes, mitochondria,

There are some investigations that showed the effect of surface charge, for example polymer charge density of dendrimers was found to significantly impact membrane permeability. The most densely charged polymer facilitates the transport of dye molecule across the membrane [16]. Other investigation showed that lipid coating of ionically charged nanoparticles was able to increase endothelial cell layer crossing 3 or 4 fold compared with uncoated particles, whereas nanoparticles coating of neutral particles did not significantly alter their permeation charac‐ teristics across the endothelial cell monolayer [13]. Transdermal drug administration systems have been limited to certain drugs of a range of molecular weight and lipophilicity, and of certain charge preference. For instance, cationic compounds have a positive effect on skin permeation, since the skin carries a negative surface charge due to phosphatidylcholine [17] and carbohydrates found in mammalian cells contain negatively charged groups. Therefore, nanoparticles with predominant positive charge would promote transdermal permeation.

Dermatopharmacokinetics describe the pharmacokinetics of topically applied drugs in the stratum corneum with pharmacodynamic effects. The smart techniques (tape stripping and microdialysis) use in dermatopharmacokinetic methodology assesses the cutaneous drug concentration at the site of application. Various studies have shown dermatopharmacokinetics to be a reliable and reproducible method for determining bioequivalence, and have indicated that it is applicable for all topical dermatological drug products. Dermatopharmacokinetics refer to the determination of stratum corneum concentration-time curves for topical actives. This is analogous to plasma/urine concentration-time curves for systemically or orally administered drugs, and the concept is clearly adaptable to microdialysis, where drug is determined in the skin compartment in which the microdialysis fibre is positioned (Fig. 4). Although, this procedure is invasive, it is a method of great potential offering information of high value and relevance. There could be sampling in a compartment within the skin. It is a technically demanding procedure, however, requiring experimental dexterity of high order. The potential for use on diseased skin is a unique and considerable advantage over other techniques, but real challenges remain with respect to reproducibility, sensitivity, applicable

cytoplasm, etc) by modifying their surface charge [15].

198 Application of Nanotechnology in Drug Delivery

**5. Dermatopharmacokinetics**

drugs, etc.


Because topical products deliver the drug directly to or near the intended site of action, measurement of the drug uptake into and drug elimination from the stratum corneum can provide a dermatopharmacokinetics means of assessing the bioequivalence of two topical drug products [19,20]. Presumably, two formulations that produce comparable stratum corneum concentration-time curves may be bioequivalence, just as two oral formulations are judged bioequivalent if they produce comparable plasma concentration-time curves. Even though the target site for topical dermatologic drug products in some instances may not be the stratum corneum, the topical drug must still pass through the stratum corneum, except in instances of damage, to reach deeper sites of action [21]. In certain instances, the stratum corneum itself is the site of action. For example, in fungal infections of the skin, fungi reside in the stratum corneum and therefore dermatopharmacokinetic measurement of an antifungal drug in the stratum corneum represents direct measurement of drug concentration at the site of action [22]. In instances where the stratum corneum is disrupted or damaged, *in vitro* drug release may provide additional information toward the bioequivalent assessment. In this context, the drug release rate may reflect drug delivery directly to the dermal skin site without passage through the stratum corneum. For antiacne drug products, target sites are the hair follicles and sebaceous glands. In this setting, the drug diffuses through the stratum corneum, epidermis, and dermis to reach the site of action. The drug may also follow follicular pathways to reach the sites of action. The extent of follicular penetration depends on the particle size of the active ingredient if it is in the form of a suspension [21, 23-25]. Under these circumstances, the dermatopharmacokinetic approach is still expected to be applicable because studies indicate a positive correlation between the stratum corneum and follicular concentrations. Although the exact mechanism of action for some dermatological drugs is unclear, the dermatopharma‐ cokinetic approach may still be useful as a measure of bioequivalence because it has been demonstrated that the stratum corneum functions as a reservoir, and stratum corneum concentration is a predictor of the amount of drug absorbed [26].

the transdermal drug market. Besides great potency, the physicochemical drug characteristics often evoked as favourable for percutaneous delivery include moderate lipophilicity and low molecular weight [28]. However, a large number of pharmaceutical agents do not fulfill these criteria. This is especially true for macromolecules, such as insulin, human growth hormone or cyclosporine, which are very challenging from the drug delivery point of view. The

Nanoparticles for Dermal and Transdermal Drug Delivery

http://dx.doi.org/10.5772/58672

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**•** Affinity for both lipophilic and hydrophilic phases. Extreme partitioning characteristics not

Overcoming low skin permeability to xenobiotics can be achieved by a variety of approaches, and is an active field of research. Their effectiveness and applicability will vary from drug to drug depending on the physicochemical nature of the compound. New drug discovery is still a complicated process and generally requires substantial time and monetary investment. Technologies for formulation change provide the benefit of improving pharmaceutical product efficacy and safety as well as patient convenience; these technologies provide a relatively simple approach to creating new pharmaceuticals compared with new drug discovery because the active compounds used in the formulation have already been approved [29-31]. Nnamani *et al* [32] developed and evaluated the antimicrobial activities of an alternative non-invasive, convenient and cost-effective transdermal drug delivery system (TDDS) containing gentami‐ cin in biodegradable polyester-based matrices. Other drugs which have been formulated for dermal and transdermal delivery are nitroglycerin, nicotine, scopolamine, clonidine, fentanyl, 17-β-estradiol, testosterone, Boswellic acid (*Boswellia serrata*) and curcumin (*Curcuma longa*).

Transdermal delivery provides convenient and pain-free self-administration for patients. It eliminates frequent dosing administration and plasma level peaks and valleys associated with oral dosing and injections to maintain constant drug concentrations, and a drug with a short half-life can be delivered easily. All this leads to enhanced patient compliance, especially when long-term treatment is required, as in chronic pain treatment and smoking cessation therapy

**•** Avoidance of hepatic first-pass metabolism and the gastrointestinal (GI) tract for poorly bioavailable drugs is another advantage of transdermal delivery. Elimination of the firstpass effect allows the amount of drug administered to be lower, and hence, safer in hepato-

**•** Transdermal systems are generally inexpensive when compared with other therapies on a

monthly cost basis, as patches are designed to deliver drugs from 1 to 7 days.

physicochemical properties of ideal drug for transdermal delivery include:

**•** Molecular weight less than approximately 1000 Daltons.

**•** Should be potent, with short half life and be non-irritating.

**7. Advantages of dermal and transdermal drug delivery**

compromised patients, resulting in the reduction of adverse effects.

ideal.

[3,33,34].

**•** Low melting point.

For reasons thus cited, dermatopharmacokinetic principles should be generally applicable to all topical dermatological drug products including antifungal, antiviral, antiacne, antibiotic, corticosteroid, and vaginally applied drug products. The dermatopharmacokinetic approach can thus be the primary means to document bioavailability/bioequivalence. Generally, bioequivalence determinations using dermatopharmacokinetic studies are performed in healthy subjects because skin where disease is present demonstrates high variability and changes over time. Use of healthy subjects is consistent with similar use in bioequivalence studies for oral drug products.

A dermatopharmacokinetic approach is not generally applicable when:

