EXCEED THE SPACE PROVIDED. Transdermal drug delivery has several potential advantages over other parenteral drug administration methods. Apart from the convenience and non-invasiveness, the skin also provides a 'reservoir' that can sustain delivery over a long period. Furthermore, the skin offers multiple sites to avoid local irritation and toxicity, and yet can also offer the option to concentrate drugs at local areas to avoid undesirable systemic effects. However, at present, the clinical use of transdermal delivery is limited by the fact that only small sized drugs can currently be delivered transdermally at a viable rate. The skin forms an efficient barrier for most molecules, and very few non-invasive methods were known to significantly enhance transport through the skin. Our studies have shown that anionic lipids like 1,2-diacyl-sn-3-phosphatidylserine (PS) can very significantly increase the lifetime of the pathways created by electroporation and that this increase in lifetime can be used to delivery the required doses of drugs. Preliminary studies indicate that electroporation in the presence of PS alters the structure of the stratum corneum, the outer most layer of the skin, and also increases its hydration. The modified stratum corneum can allow the passage of larger drugs like insulin. The main aim of this proposal is to use the knowledge that we have gained during the preceding grant period to (a) better define the mechanistic role of anionic lipids in enhancing transdermal transport by electroporation, and (b) to apply this new found knowledge in preclinical studies to deliver drugs that are currently administered by injection. We will investigate the pharmacokinetics and the pharmacodynamics of insulin and two drugs that are used for the treatment of osteoporosis, calcitonin and teriparatide. The results of the proposed study will be a significant first step towards the development of feasible transdermal drug delivery system using anionic lipid enhanced electroporation pathways to deliver therapeutic drugs in clinical trials. PERFORMANCE SITE ========================================Section End===========================================
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