Date of Award

1991

Embargo Period

8-1-2024

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Pharmaceutical Sciences

College

College of Graduate Studies

First Advisor

Paul J. Niebergall

Second Advisor

James E. Wynn

Third Advisor

Robert E. Notari

Fourth Advisor

Edward Sumner

Fifth Advisor

Gilbert Schmidt

Sixth Advisor

Farid Sadik

Abstract

Current transdermal drug delivery systems are limited to delivery, via passive diffusion, of a few substances exhibiting natural skin penetrability. These substances are low molecular weight, highly potent agents possessing a certain degree of hydrophilicity as well as lipophilicity. These limitations are dictated by the outermost layer of the skin, the stratum corneum, which acts as a barrier. The stratum corneum consists mostly of the protein keratin. The barrier strength of keratin is attributed to its extensive disulfide bond cross-linking. In order to expand the spectrum of transdermal drug candidates this keratin barrier must be overcome. Low molecular weight primary aliphatic thiol compounds reduce disulfide linkages of cystine units in the keratin protein forming sulfhydryl-terminated cysteine units and thus diminishes the number of cross-links between polypeptide chains. This has been shown to increase the permeability of the skin to a variety of drugs by opening up the stratum corneum for facile diffusion most probably through increased diffusivity. This validates the use of low molecular weight primary aliphatic thiol compounds as transdermal permeation enhancers. One of the major requirements of any pharmaceutical applied topically is lack of significant irritation that would render the formulation unacceptable to the user. An acute non-invasive dermal toxicity study on both animals and humans has shown most of the enhancers to be well tolerated.

Rights

All rights reserved. Copyright is held by the author.

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