**4. Main factors for nano-based delivery system**

#### **4.1. Particle size, size distribution and zeta potential**

Particle size and shape affect drug release, physical stability and cellular uptake of the nanoparticulate materials. The yield and size distribution of each system are affected by certain

**Figure 3.** Structure of the skin showing routes of penetration: (1) across the intact horny layer, (2) through the hair follicles with the associated sebaceaous glands, or (3) via the sweat glands (http://www.skin-careforum.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).

in-process operations and conditions such as stirring rate, temperature, type and amount of dispersing agent as well as the viscosity of the organic and aqueous phases [9,10]. Zeta potential of a dispersion is necessary for dispersion stability [11].

#### **4.2. Surface properties**

layers of such molecules [7]. The hydrophilic molecules diffuse predominantly "laterally" along surfaces of the less abundant water-filled interlamellar spaces or through such volumes; polar molecules can also use the free space between a lamella and a corneocyte outer membrane

Intracellular macromolecular matrix within the stratum corneum abounds in keratin, which does not contribute directly to the skin diffusive barrier but supports mechanical stability and thus intactness of the stratum corneum. Transcellular diffusion is practically unimportant for transdermal drug transport [8]. The narrow aqueous transepidermal pathways have been observed using confocal laser scanning microscopy. Here, regions of poor cellular and intercellular lipid packing coincide with wrinkles on skin surface and are simultaneously the sites of lowest skin resistance to the transport of hydrophilic entities. This lowest-resistance pathway leads between clusters of corneocytes at the locations where such cellular groups show no lateral overlap. The contribution to transdermal drug transport can increase with pathway widening or multiplication, e.g., that which is caused by exposing the stratum corneum to a strong electrical (electroporation/iontophoresis), mechanical (sonoporation/

Recently, follicular penetration has become a major focus of interest due to the fact that drug targeting to the hair follicle is of great interest in the treatment of skin diseases. However, follicular orifices occupy only 0.1% of the total skin surface area. For this reason, it was assumed to be a nonimportant route for drug penetration. But a variety of studies have shown that hair follicles could be an interesting option for drug penetration through the skin [6]. Such follicular pathways have also been proposed for topical administration of polystyrene nanoparticles. They were investigated in porcine skin (*ex vivo*) and human skin (*in vivo*). Surface images revealed that polystyrene nanoparticles accumulated preferentially in the follicular openings. This distribution was increased in a time-dependent manner, and the follicular localization was favored by the smaller particle size. The study also confirmed similarity in the penetration between both membranes (porcine and human skin). In other investigations, the influence of microparticle size in skin penetration has been shown by differential stripping. Nanoparticles can act as efficient drug carriers through the follicle or can be utilized as follicle blockers to

Particle size and shape affect drug release, physical stability and cellular uptake of the nanoparticulate materials. The yield and size distribution of each system are affected by certain

sonophoresis), or thermal stimulus, or suitable skin penetrants.

stop the penetration of topically applied substances.

**4. Main factors for nano-based delivery system**

**4.1. Particle size, size distribution and zeta potential**

to the same end.

**3.2. The transcellular route**

196 Application of Nanotechnology in Drug Delivery

**3.3. Follicular penetration**

The attachment of nanoparticles to cell membrane is affected by the surface charge of the particles. Variation of the particle surface charge could potentially control binding to the tissue and direct nanoparticles to cellular compartments both *in vitro* and *in vivo*. Cellular surfaces are dominated by negatively charged sulphated proteoglycans molecules that play pivotal roles in cellular proliferation, migration and motility [12]. Cell surface proteoglyans consist of a core protein anchored to the membrane and linked to one or more glycosaminoglycan side chains (heparan, dermatan, keratan or chondrotine sulfates) to produce a structure that extends away from the cell surface.

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

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.

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

**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.

Nanoparticles for Dermal and Transdermal Drug Delivery

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

199

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‐

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

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

corneum collected on tape strips.

Downloaded April 26, 2014)

sequential processes, namely:

tration-time curves in the epidermis and dermis.

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

**•** penetration of the drug through the skin barrier, and

**•** generation of the desired pharmacological effect.
