Enhancement of skin permeability

Enhancement of Skin Permeability of Various Drugs by Different Types of Enhancers3 ... 

Ongpipattanakul, B., The perturbation of stratum comeum lipids by perdeuter-ated oleic acid and its implication for the enhancement of skin permeability. Ph.D. thesis. School of Pharmacy. University of Wisconsin Press Madison, 1991. 

In a recent systematic study of the dependence of 20 kHz sonophoresis on ultrasound parameters, Mitragotri et al. showed that the enhancement of skin permeability varies linearly with ultrasound intensity and ultrasound on-time (for pulsed ultrasound, ultrasound on-time equals the product of total ultrasound application time and duty cycle), while is independent of the ultrasound duty cycle. Based on those findings, fhe authors reported that there is a threshold energy dose for ultrasound induced transdermal drug transport. Once the threshold value is crossed, the enhancement of skin permeability varies linearly with the ultrasound energy dose (J/cm ), which is calculated as the product of ultrasound intensity and ultrasound on-time. This result indicates that ultrasound energy dose can be used as a predictor of the effect of 20 kHz sonophoresis. The authors also indicated that it is important to determine the threshold energy dose for each individual sonophoresis system, for example, the real in vivo situation, because it may vary from system to system. Specifically, it may vary between different skin models, as well as with the ultrasound frequency and the distance of the transducer from the skin surface, etc. 

The main cells of the viable epidermis are keratinocytes. They get their growth factors and nutrients by passive diffusion via the interstitial fluid, which is estimated to represent about 15% of the total volume of the epidermis and drains into the lymphatic system. The viable epidermis also contains melanocytes, Langerhans cells, migrant macrophages, and lymphocytes. The top two layers of the viable epidermis, the stratum lucidum and the stratum granulosum, are physiologically very important. Removal of these three epidermal layers results in water loss and an enhancement of skin permeability [8],... 

Permeation of a model solute across skin in presence of an enhancer is dependent not only on the inherent capacity of the enhancer to permeabi-lize skin but also on the physicochemical interactions of the enhancer with the model solute. An end point used to characterize the effect of an enhancer on skin permeability should be able to decouple these two effects. This assures the generality of the results. 

A new generation of transdermal drug delivery (TDD) system was developed to contain one or more skin permeation enhancers in the surface adhesive coating layers. This TDD system has been found, experimentally, to release the enhancers to the surface of stratum corneum to modify the skin s barrier properties, prior to the controlled delivery of the active drug. The extent of enhancement in skin permeability appears to be dependent upon the chemical structure of drug to be delivered transdermally as well as the type and the concentration of enhancer used. The mechanism of skin permeation enhancement have been explored and are analyzed in this report. 

In addition to the esters of saturated and unsaturated fatty acids, azone and decylmethyl sulfoxide are also very effective in enhancing the skin permeability of drugs (Table II and Figure 6). Results appear to suggest the possible existence of a relationship between the skin permeability enhancement of a drug, molecular structure of the drug, as well as the type of enhancer used. The skin permeability can be further improved by incorporating... 

Table III Effect of the Location of Skin Permeation Enhancer3 on the Enhancement of Progesterone Permeability...

Unlike iontophoresis, which acts on the transporting molecules and ions, US has been shown to act on the skin barrier itself The effects of sonophoresis depend on the "quality" of the barrier that is subject to US treatment thus, barriers which are intrinsically more permeable will be more liable to physical perturbation by US and vice versa. This may explain why the most successful attempts at the US-assisted extraction of glucose across the skin involved the use of a surfactant or chemical enhancer to better "normalize" the increased transport effects observed. One of the challenges in pretreatment-type sonophoresis is that the degree of skin permeability must be determined prior to drug placement. 

A variety of chemical penetration enhancers with or without protease inhibitors or colloidal vehicles (liposomes) have been investigated for their potential to enhance the skin permeability of peptides and pro-teins, but these approaches have only been limited to animal models or in vitro or in vivo models of human skin and have not progressed to human clinical studies. A notable exception is the use of so-called Transferosomes , ultraflexible liposomes, containing a mixture of soybean phosphatidylcholine and sodium... 

The main barrier against percutaneous uptake of solvents are structures of the stratum comeum, especially intercellular lipids and fibrous keratin. Removal of lipids by polar solvents such as ethanol or hydration in the stratum comeum is associated with an increase of skin permeability. Defects or lack of stratum comeum that may occur in skin diseases, at particular skin locations such as hair folhcles or glandula regions enhance the percutaneous movement of solvents. The absorption through mucosa membranes is facilitated because of the lack of the stratum comeum. 

H. Rachmawati, C.A. Edityaningrum, and R. Mauludin, Molecular inclusion complex of curcumin-P-cyclodextrin nanoparticle to enhance curcumin skin permeability from hydrophilic matrix gel, AAPS PharmSaTech, 14 (4), 1303-1312,2013. 

Exercise also increases skin circulation and perspiration, which both enhance dermal penetration of compounds into the body. Furthermore, skin lesions, such as wounds and dermatitis, can increase the permeability of the skin to chemicals. Also, exposure of the skin to solvents and removal of skin fat increase dermal penetration of a number of compounds. Compounds penetrate the skin more readily in places where the skin is thin, like the face, hands and scrotum. Increased dermal blood flow due to exercise facilitates the penetration of the skin by chemicals. 

The properties of a formulation and its composition affect skin permeability. For example, the pH of formulations was shown to have an effect on skin permeability. Using experimental data a predictive model could be established [86], A mechanistic understanding of this effect is still missing—as well as a purely computational model. Various substances are known to enhance... 

Using a similar approach, Notman et al. [81], determined the free energy for pore formation in bilayers composed of ceramide, as a model for the stratum corneum of the skin, both in the presence and in the absence of DMSO. Without DMSO, the bilayer was in the gel phase, and interestingly, a hydrophobic pore was observed with a high free-energy barrier ( 60 kj/mol). In the presence of DMSO, the bilayer was more fluid, and the more typical hydrophilic pore was observed, with a much smaller activation energy of 20kJ/mol. This work provided a thermodynamic and structural explanation for the enhanced permeability of skin by DMSO. 

INSIGHT uses the fundamental correlation between the electrical and permeability properties of skin. Skin permeability shows a strong correlation with skin impedance, as shown in Figure 4B. Figure 4B shows 150 independent and simultaneous measurements of mannitol skin permeability and skin impedance for six different enhancer formulations. The relationship between skin impedance and permeability to hydrophilic solutes confirms that the former can be used as a surrogate measure for the later. Skin conductance is quick and easy to obtain and does not require additional sample handling and analysis. 

Figure 8 (A) In vitro permeability of candidate drug molecules in the presence of synergistic combinations of penetration enhancers (SCOPE) formulations. Open circles indicate passive skin permeability and closed circles indicate skin permeability in the presence of SCOPE formulations as a function of the molecular weight of the solute. (B) In vivo delivery of leuprolide acetate, a synthetic analogue of LHRH in hairless rat model, y-axis shows blood plasma concentration of leuprolide acetate as a function of time for control formulation (open circles) and SCOPE formulation (closed circles). Abbreviation-. LHRH, luteinizing hormone-releasing hormone.

Sonophoresis is defined as the transport of drugs through intact skin under the influence of an ultrasound. Ultrasound at various frequencies in the range of 20 kHz to 16 MHz has been used to enhance skin permeability [1-3]. This chapter attempts to present sonophoresis, experimental variables, possible mechanisms of action, and clinical applications. 

---