Transdermal penetration

Cyclic sulfoxides, lactones, lactams, and other heterocycles as transdermal penetration enhancers 99CLY107. 

Transdermal delivery of certain APIs is now common for the treatment of some medical conditions, and there are several excipients that are promoted as transdermal penetration enhancers. One of the earlier materials developed was laurocapram (Azone ). There is a detrimental interaction between laurocapram and mineral oil (liquid paraffin) whereby when both are included in the same formulation, the skin penetration-enhancing properties of laurocapram are lost. Such interactions have implications for extemporaneous mixing of different cream and ointment formulations in the pharmacy. 

Karande P, Jain A, Mitragotri S. Discovery of transdermal penetration enhancers by high throughput screening. Nature Biotechnol 2004 22 192-197. 

Finnin B, Morgan T. Transdermal penetration enhancers applications, limitations, and potential. J Pharm Sci 1999 88 955-958. 

Sasaki H, Kojima M, Nakamura J, Shibasaki J. Acute toxicity and skin irritation of pyr-rolidone derivatives as transdermal penetration enhancers. Chem Pharm Bull 1990 38 2308-2310. 

Ogiso, T., M. Iwaki, and T. Paku. 1995. Effect of various enhancers on transdermal penetration of indomethacin and urea, and relationship between penetration parameters and enhancement factors. J Pharm Sci 84 482. 

Wong, O., et al. 1989. Unsaturated cyclic ureas as new non-toxic biodegradable transdermal penetration enhancers. II. Evaluation study. Int J Pharm 52 191. 

Vanbever, R., M. Leroy, and V. Preat. 1998. Transdermal penetration of neutral molecules by skin electroporation. J Control Release 54 243. 

Chemical PEs have recently been studied for increasing transdermal delivery of ASOs or other polar macromolecules [35]. Chemically induced transdermal penetration results from a transient reduction in the barrier properties of the stratum corneum. The reduction may be attributed to a variety of factors such as the opening of intercellular junctions due to hydration [36], solubilization of the stratum corneum [37, 38], or increased lipid bilayer fluidization [39, 40]. Combining various surfactants and co-solvents can be used to achieve skin penetration, purportedly resulting in therapeutically relevant concentrations of ASO in the viable epidermis and dermis [41]. In summary, it appears feasible to deliver ASO to the skin using a number of different delivery techniques and formulations. 

Vitamins are essential nutrients, which must be supplied exogenously. They are organic compounds with indispensable biological activities as coenzymes in a multitude of cellular metabolic processes. Vitamin A, retinoids (vitamin A-derivatives), carotenoids, vitamin D, vitamin E, and vitamin K are fat-soluble, vitamin C and vitamins of the B-complex are water-soluble. This is of importance for gastrointestinal absorption in oral supplementation as well as the transdermal penetration for topical applications. 

There are some well-described deficiency syndromes, the well-established therapeutic use of vitamin K antagonists as oral anticoagulants and the well-known positive effects of pantothenic acid on skin hydration/moisturization and wound healing, which apparently lacks scientific solid base. Apart from that there are not many studies available on the treatment of dermatological disorders with these vitamins, either systemically or topically. Even less is known about transdermal penetration, stability, and formulation dependencies of possible topical applications. 

Krautheim, A. and Gollnick, H., Transdermal penetration of topical drugs used in the treatment of acne, Clin. Pharmacokinet., 42, 1287, 2003. 

The ability to test the transdermal penetration of compounds in vitro has been investigated extensively over the last decade. Hundreds of studies have shown that the permeation rate of compounds can be accurately measured using several available in vitro diffusion cells and various types of skin models [17]. 

The hydrosilylation of acetyl-protected allylglucoside with a Si-H-ended telechelic polysiloxane, followed by deprotection has also been described by Nagase et al. for the preparation of glyco-oligodimethylsiloxanes as transdermal penetration enhancers (Fig. 10) [16-18]. The status of the siloxane chain after deprotection has been checked by size exclusion chromatography (SEC). When they used MeOH/K COj for deprotection, they observed by SEC the formation of two peaks... 

T. Akimoto, K. Kawahara, Y. Nagase, T. Aoyagi, Macromol. Chem. Phys., 2000, 201(18), 2729-2734. Preparation of oligodimethylsiloxanes with sugar moiety at a terminal group as a transdermal penetration enhancer . 

Ogiso, T., Paku, T., Masahiro, I. and Tanino, T. Mechanism of the enhancement effect of n-octyUP-D-thioglucoside on the transdermal penetration of fluorescein isothiocyanate-labeled dextrans and the molecular weight dependence of water-... 

Azone (l-Dodecylazacycloheptan-2-one) and related compounds have been studied as transdermal penetration and oral absorption enhancers. Although some efficacy has been shown, an emulsifying agent appears to be necessary for azone to penetrate the intestinal mucosal membrane in order to promote drug absorption. One study reported the absence of gross morphological damage after exposure of mucosa to azone but additional information on the effect of azone on overall mucosa structure is not avalable. 

Wong, O. Huntington, A. Nishihata, T. Rytting, J.H. New alkyl V V-Dialkyl-substituted amino acetates as transdermal penetration enhancers. Pharm. Res. 1989, 6, 286-295. 

Riviere, J.E. Chang, S.K. Transdermal penetration and metabolism of organophosphate insecticides. 

Kravchenko lA, Golovenko NY, Larionov VB, et al. Effect of lauric acid on transdermal penetration of phenazepam in vivo. Bull Exp Biol Med 2003 136(6) 579-581. 

Stearyl alcohol is used in cosmetics and topical pharmaceutical creams and ointments as a stiffening agent. By increasing the viscosity of an emulsion, stearyl alcohol increases its stability. Stearyl alcohol also has some emollient and weak emulsifying properties and is used to increase the water-holding capacity of ointments, e.g. petrolatum. In addition, stearyl alcohol has been used in controlled-release tablets, " suppositories, and microspheres. It has also been investigated for use as a transdermal penetration enhancer. ... 

Magee, P.S. (1998). Some Novel Approaches to Modeling Transdermal Penetration and Reactivity with Epidermal Proteins. In Comparative QSAR (Devillers, J., ed.), Taylor Francis, Washington (DC), pp. 137-168. [R]... 

When the transdermal penetration of a drug is inadequate to achieve and maintain a plasma concentration above the minimum therapeutic concentration required to produce the desired effect, a lipophilic prodrug that will be metabolized in the epidermis to the active drug could be used in the development of a controlled-release transdermal delivery system. This approach has been applied to estradiol esters (diacetate and valerate) which are rapidly converted by esterases in the skin tissue to estradiol (Chien et al, 1985). The prodrug serves to increase the transdermal bioavailability of the active drug to which it is converted by metabolism (generally ester hydrolysis) during the percutaneous absorption process. 

Riviere, J.E. Chang, S.K. (1992) Transdermal penetration and metabolism of organo-phosphate insecticides. In Organophosphates Chemistry, Fate and Effects. Academic Press, New York. 

Brand RM, Mueller C. Transdermal penetration of atrazine, alachlor and tri-fluralin Effect of formulation. Toxicol Sci 2002 68(1) 18-23. 

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