Dermal penetration enhancers

In connection with studies on structure-property relationships with dermal penetration enhancers, substituted azepinone derivatives (e.g., 74, R = Me and 75, R = Me) were made by Kim et al. from the 3-aminoazepanone 71 via 72 and 73 using standard functional group manipulations (Scheme 8) <2001MI183>. 

Infrared microscopic imaging provides the significant advantages of direct spatially resolved concentration and molecular structure information for sample constituents. Raman microscopy (not further discussed in this chapter) possesses the additional benefit of confocal acquisition of this information and a 10-fold increase in spatial resolution at the expense of reduced signal-to-noise ratios compared with IR. The interested reader is urged to check the seminal studies of the Puppels group in Rotterdam,38 0 as well as our own initial efforts in this direction.41 The current section describes the initial applications of IR microspectroscopic imaging to monitor the permeation and tissue distribution of the dermal penetration enhancer, DMSO, in porcine skin as well as to track the extent of permeation of phospholipid vesicles. 

Michniak, B.B., et al. 1993. In-vitro evaluation of a series of azone analogs as dermal penetration enhancers. Int.]. Pharmaceutics 91 85-93. 

Phillips, C. A., and B. Michniak. 1996. Transdemal delivery of drugs with differing lipophilicities using Azone analogs as dermal penetration enhances./. Pharm. Sci. 84 1427-1433. 

Phillips, C.A. Michniak, B.B. Transdermal delivery of drugs with differing lipophilicities using azone analogs as dermal penetration enhancers. J.Pharm.ScL, 1995, 84, 1427-1433... 

Mirejovsky, D. and Takruri, H. (1986). Dermal penetration enhancement profile of hexame-thylenelauramide and its homologues in vitro versus in vivo behavior of enhancers in the penetration of hydrocortisone, J. Pharm. Scl, 75 1089-1093. 

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. 

Because skin exhibits many of the properties of a lipid membrane, dermal penetration can often be enhanced by increasing a molecule s lipophilicity. Preparation of an ester of an alcohol is often used for this purpose since this stratagem simultaneously time covers a hydrophilic group and provides a hydrophobic moiety the ready cleavage of this function by the ubiquitous esterase enzymes assures availability of the parent drug molecule. Thus acylation of the primary alcohol in flucinolone (65) with propionyl chloride affords procinonide (66) the same transform... 

Under normal conditions, the transcellular route is not considered as the preferred way of dermal invasion, the reason being the very low permeability through the corneocytes and the obligation to partition several times from the more hydrophilic corneocytes into the lipid intercellular layers in the stratum corneum and vice versa. The transcellular pathway can gain in importance when a penetration enhancer is used, for example, urea, which increases the permeability of the corneocytes by altering the keratin structure. 

Kadir, R., and B.W. Barry. 1991. a-Bisabolol, a possible safe penetration enhancer for dermal and transdermal therapeutics. Int J Pharm 70 87. 

Some fatty acids, especially unsaturated fatty acids, are well-known skin penetration enhancers. The addition of PC to dermal dosage forms has been reported to increase percutaneous absorption. Lipid disperse systems (LDSs) containing polar lipids, such as PC and glycosylceramide, are also useful for increasing the percutaneous permeation of drug through rat abdominal skin in both in vitro and in vivo systems. 

Other cosolvents, such as DMSO, demonstrate skin penetration enhancement properties for a number of compounds. Although this could be a highly desirable property for many drugs, the use of DMSO as a solvent for dermal application has not been approved. 

Walters, K.A. Penetration enhancers and their use in trans-dermal therapeutic systems. In Transdermal Drug Delivery Hadgraft, J., Guy, R.H., Eds. Drugs and the Pharmaceutical Sciences Marcel Dekker, Inc. New York, 1989 Vol. 35, 197-246. 

In another dermal penetration study, it was shown that the absorption of the insecticide carbaryl was enhanced by the solvent acetone and the surfactant sodium lauryl sulfate. The synergist PO significantly increased the absorption of carbaryl when added to the acetone-carbaryl rnixJ31 This study points out both the enhanced absorption of pesticide by individual inert additives as well as the further enhanced mixture effect. 

The crotonic acid (Figure 25.14) that it contains is an irritant that accelerates epidermal lysis and enhances the cutaneous penetration of the phenol. Some authors maintain that a phenol peel will only produce good results if croton oil is present. The croton oil enhances dermal penetration and epidermal protein coagulation, and thus lower concentrations of phenol can be used. We have seen, however, that many phenol peel formulations do not contain croton oil. 

Kenneth A. Walters, PhD, is director of An-eX Analytical Services Ltd and an honorary lecturer in pharmaceutical chemistry at the Welsh School of Pharmacy. His research interests are biological membrane penetration enhancement and retardation, particularly with respect to skin. He has experience at Fisons Pharmaceuticals, Eastman Pharmaceuticals (a division of Eastman Kodak Company) and Controlled Therapeutics Ltd. (Scotland). Dr. Walters has published many articles and reviews and has co-edited two volumes on skin penetration enhancement and dermal toxicity. He is a charter member of the American Association of Pharmaceutical Scientists and also a member of the Society of Investigative Dermatology, the Controlled Release Society, the Society of Toxicology and the Society of Cosmetic Scientists. 

There is a paucity of published data on in vitro studies of dermal penetration in food animals. In one study comparing the effects of freezing on human and cow skin (27), it is alluded to that the follicular route of penetration predominates in the cow. These authors have also written an excellent review on topical drug delivery to cattle and sheep which should be consulted for further details (2S). In this work, studies on the dermal application of twenty four different substances are reviewed. Some interesting data on differential effects of dermal enhancers in different species underlines the problems inherent to interspecies extrapolations. One conclusion of this study was that "the barrier properties of sheep and cattle skin are not well understood." This situation has not improved in the intervening years. 

In Vivo Efficacy and Dermal Toxicity of Terpenes Used as Penetration Enhancers... 

Williams, A.C. and Barry, B.W., Chemical penetration enhancement, in Dermal Absorption and Toxicity Msessment (M.S. Roberts and K.A. Walters, eds.). New York Dekker, pp. 297-312, 1998. 

The natural function of the skin is the protection of the body against the loss of endogenous substances such as water and undesired influences from the environment caused by exogenous substances. This implies that the skin acts as a barrier for diffusion of substances through the underlying tissue. Overcoming this natural barrier is the main problem in dermal/transdermal administration of drugs. Methods to decrease the diffusional barrier include the use of penetration enhancers. 

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