EFFECT OF ENHANCEMENT TECHNOLOGIES ON TRANSDERMAL DELIVERY OF SINGLE AND CO-ADMINISTERED MOLECULES ACROSS NORMAL AND COMPROMISED SKIN

Abstract

Topical and transdermal delivery uses skin as a route for non-invasive administration of various pharmaceutical active ingredients. Topical and transdermal delivery thus offers a sustained and controlled release of drugs with avoidance of first-pass metabolism, thereby increasing patient compliance. However, the unique structure of skin favors permeation of only small (molecular weight <500 Da), unionized, and moderately lipophilic molecules (log P- 1 to 3), posing a challenge in exploring this route of administration for most drugs. Therefore, various physical and chemical enhancement strategies are investigated to aid drug delivery via skin. Our goal was to understand the effect of some of these technologies on transdermal delivery of single and co-administered molecules across normal and compromised skin. Our study used physical enhancement strategies such as microneedles and iontophoresis to administer potential anti-psoriatic candidate – tofacitinib citrate. We observed that a therapeutic drug dose could be delivered using microneedles alone and in combination with iontophoresis. We also tested the effect of these physical enhancement techniques alone and in combination to deliver model drug diclofenac sodium across normal and compromised skin from marketed formulations. We observed increased absorption of diclofenac sodium into and across compromised skin, indicating potential increased systemic exposure. In addition, we tested the feasibility of simultaneous administration of two novel antidotes, N-acetylcysteine and 4-phenylbutryic acid, via skin for the first time. Considering different lipophilicities of these molecules, we screened various chemical enhancers to deliver these antidotes alone and in combination. These showed significant enhancement in delivery of the antidotes into and across skin. We developed a foam formulation based on these preliminary studies to deliver the antidotes. Our last aim was to test this foam formulation for the antidotes' short- and long-term delivery along with decontamination. The developed foam formulation achieved simultaneous decontamination and short-term delivery of 4-phenylbutyric acid within 5 minutes of application on skin. The same foam formulation achieved long-term delivery of up to 24 hours for both antidotes upon re-application of foam following decontamination.