Chemical skin permeation enhancers

He N, et al. Mechanistic study of chemical skin permeation enhancers with different polar and lipophilic functional groups. J Pharm Sci 2004 93 1415-1430. 

Warner, K.S., et al. 2003. Structure-activity relationship for chemical skin permeation enhancers Probing the chemical microenvironment of the site of action. J Pharm Sci 92 1305. 

Warner, K.S. Li, S.K. Ftiguchi, W.I. Influences of alkyl group chain length and polar head group on chemical skin permeation enhancement. J. Pharm. Sci. 2001, 90, 1143-1153. 

The use of skin permeation enhancers in combination for synergistic effects has been studied in the transdermal literature (70). Such synergistic methods can be grouped in three categories (i) combination of two physical methods, e.g., ultrasound and iontophoresis (71-75) (ii) combination of a physical method with a chemical enhancer, e.g., use of ultrasound with sodium lauryl sulfate or isopropyl myristate (76-80) and (iii) combination of two chemicals, e.g., terpenes and propylene glycol (46,81-88). Numerous studies have been published on using combination of two physical methods or use of a physical method in conjunction with a chemical enhancer. Use of a physical method, by itself or in combination with another physical method, increases application cost for delivery purposes as mentioned before. In addition, there are unexplored safety and membrane recovery issues associated with these methods. A few reports have also been published on the use of a mixture of chemical enhancers for enhancing transdermal delivery. Typically, such studies use... 

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. 

Brain, K.R. Walters, K.A. Molecular modeling of skin permeation enhancement by chemical agents. In Pharmaceutical Skin Penetration Enhancement Walters, K.A., Hadgraft, J., Eds. Marcel Dekker, Inc. New York, 1993 389 16. 

On the other hand, SEPA (2-n-nonyl-l,3-dioxolane) has been shown to be a more versatile penetration enhancer in terms of its ease of formulation, chemical stability and its ability to enhance the skin penetration of a wide variety of compounds of varying physicochemical characteristics. Permeants that have been evaluated include indomethacin, ibuprofen, minoxidil, acyclovir, caffeine, econazole, papaverine, progesterone and estradiol. The degree of skin penetration enhancement using SEPA is dependent on the physicochemical characteristics of the permeant. For example, following application of indomethacin in a simple ethanol-propylene glycol vehicle to human skin in vitro, cumulative absorption over 24 h amounted to 0.7 percent of the applied dose. The addition of 2 percent SEPA to the vehicle increased the 24 h absorption value to 23 percent of the applied dose (Marty et al. 1989). Furthermore, in comparative studies between SEPA and Azone, SEPA was shown to be a more effective human skin permeation enhancer for indomethacin (Figure 14.6, Marty et al. 1989). 

In the design of TDDS, the skin permeability often needs to be enhanced by various approaches including the use of skin permeation enhancers to reduce the barrier property of the skin. In the absence of permeation enhancers, systemic delivery of most drugs through the skin is limited, primarily because of the barrier function of the stratum corneum. Certain enhancers including some terpenes have a tendency to form eutectics when mixed with certain chemical entities. Terpenes are a group of chiral skin penetration enhancers that are derived from plant essential oils and are widely used as pharmaceutical excipients with various drugs. Terpenes are... 

The lack of significant impact of CPEs on transdermal delivery vehicles is related to the inherent nonspecific activity of CPEs in the different strata of the skin, as discussed earlier. This limitation may be overcome by utilization of mixtures of CPEs. Research has already shown that binary mixtures of CPEs provide increased permeation enhancement as well as increased safety compared to single enhancers. Such unique chemical combinations, called synergistic combinations of penetration enhancers or SCOPE formulations, offer new opportunities in transdermal drug delivery (46). 

Use of consistent thermodynamic conditions for enhancer formulations Permeation enhancement efficacy of a CPE is a function of its chemical potential, temperature, pressure, and cosolvent amongst other thermodynamic parameters. These thermodynamic conditions need to be standardized for all the enhancers that are being tested to create direct comparison of their efficacies in increasing skin permeation. 

Care has to be taken when considering simple concentrations of the permeant since the driving force for diffusion is really the chemical potential gradient. As stated above the maximum flux should occur for a saturated solution of the permeant. However, if supersaturated solutions are applied to the skin, it is possible to obtain enhanced fluxes [27]. This can only be true if the outer skin lipids are capable of sustaining a supersaturated state of the diffusant. Figure 4.4 shows the linear increase in skin permeation with degree of supersaturation, and Fig. 4.5 demonstrates... 

The systematic study of polar permeant permeation served to confirm the existence of a porous permeation pathway through the HEM. It also led to the characterization of important properties of this pathway. The results of this study demonstrated that the diffusion of polar permeants through skin is limited by the low effective porosity of the HEM and by hindrance effects due to restrictive pore dimensions. Effectively enhancing the transport of polar drugs in the MW range of many therapeutic peptides may require increasing the effective Rp of the HEM as well as the effective porosity/tortuosity ratio. Perhaps novel combinations of chemical permeation enhancers and physical means such as an applied electrical field or ultrasound may be necessary to achieve this objective. 

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