Audra Stinchcomb - Ph.D.

Research Focus
Dr. Stinchcomb's major research interest is percutaneous absorption. Research investigations include transdermal and topical drug delivery, dermal metabolism, and risk assessment involving dermal absorption of toxic chemicals. The transdermal and topical drug delivery focus has been on efforts to improve delivery of drugs by altering their physicochemical properties, i.e. via prodrugs and codrugs. Her specific therapeutic areas of interest include cannabinoid therapies and treatments for opiate, tobacco and alcohol abuse.

Transdermal delivery of naltrexone is desirable for opioid addicts and alcoholics in order to help reduce side effects associated with oral therapy and improve compliance. Naltrexone itself does not have the essential physicochemical properties that would allow a therapeutic dose of the drug to cross the human skin barrier.

Prodrugs are being designed and synthesized to improve the transdermal delivery rate of naltrexone, in order to make a therapeutically successful drug delivery system. These prodrugs make excellent research tools for investigating quantitative structure-permeability relationships (QSPRs) for transdermal flux and concurrent metabolism. Correlation of in vitro data with the in vivo models (guinea pig and swine) will aid in the creation of a reliable QSPR database, as well as help to identify the most promising prodrug for eventual human use.

The overall objective of the transdermal codrug project is two-fold: 1) to improve pharmacotherapy for alcohol and tobacco addiction recovery by creating a transdermal codrug dosage form and 2) to increase understanding of the transdermal codrug as a viable drug-delivery option for other therapies. A codrug or mutual prodrug consists of two synergistic drugs chemically linked together, in order to improve the drug delivery properties of one or both drugs.

This codrug approach has not been used in a transdermal dosage form to date. Transdermal prodrugs and drug combination patches are extensively studied, and a practical augmentation of these two delivery options is the transdermal codrug.

Transdermal delivery of cannabinoids is extremely desirable for treatment of chronic pain, lack of appetite, and cancer chemotherapy nausea. Limited clinical studies indicate that cannabinoid combination therapy may have significant therapeutic advantages over single cannabinoid treatments.

The hypothesis for this project is that therapeutic transdermal delivery rates of the cannabinoids can be achieved through human skin, and that by characterizing the important pharmacokinetic and pharmacodynamic drug interactions a non-invasive drug delivery system with enhanced patient compliance can be developed. The paucity of information about cannabinoid combination therapy dictates a systematic investigation in order to take advantage of this promising treatment in cancer patients.

Selected Publications/Presentations

• Near infrared spectrometry for the quantification of human dermal absorption of econazole nitrate and estradiol. Medendorp J, Paudel K, Lodder RA, Stinchcomb AL. Pharm. Research. 24(1):186-193 (2007).
• Enhancement of transdermal delivery of 6-beta-naltrexol via a codrug linked to hydroxybupropion. Kiptoo PK, Hamad MO, Crooks PA, Stinchcomb AL. Journal of Controlled Release. 113(2):137-145 (2006).
• Human skin permeation for branched chain 3-O-alkyl ester and carbonate prodrugs of naltrexone. Vaddi HK, Hamad MO, Chen J, Banks SL, Crooks PA, Stinchcomb AL. Pharmaceutical Research. 22(5):758-765 (2005).
• In Vivo Evaluation of 3-O-Alkyl Ester Transdermal Prodrugs of Naltrexone in Hairless Guinea Pigs. S. Valiveti, D.C. Hammell, K.S. Paudel, M.O. Hamad, P.A. Crooks, A.L. Stinchcomb. Journal of Controlled Release. 102(2):509-520 (2005).
• Intranasal Delivery of Recombinant Human Parathyroid Hormone [hPTH (1-34)], Teriparatide in Rats. R.U. Agu, S. Valiveti, D.C. Earles, M. Klausner, P.J. Hayden, D.P. Wermeling, A.L. Stinchcomb. Endocrine Research. 3(30):455-467 (2004).
• A Duplex "Gemini" Prodrug of Naltrexone for Transdermal Delivery. D.C. Hammell, M. Hamad, H.K. Vaddi, P.A. Crooks, A.L. Stinchcomb. Journal of Controlled Release. 97:283-290 (2004).
• Transdermal Delivery of the Synthetic Cannabinoid WIN 55,212-2: In Vitro/In Vivo Correlation. S. Valiveti, D.C. Hammell, D.C. Earles, A.L. Stinchcomb. Pharmaceutical Research. 21(7):1137-1145 (2004).
• LC-MS Quantitation of ?9-Tetrahydrocannabinol and Two Metabolites in Pharmacokinetic Plasma Samples. S. Valiveti and A.L. Stinchcomb. Journal of Chromatography B. 803(2):243-248 (2004).
• Straight-chain naltrexone ester prodrugs: diffusion and concurrent esterase biotransformation in human skin. A.L. Stinchcomb, P.W. Swaan, O. Ekabo, K.K. Harris, J. Browe, D.C. Hammell, T. A. Cooperman, M. Pearsall. Journal of Pharmaceutical Sciences. 91(12):2571-2578 (2002).
• Characterization of the permeability barrier of human skin in vivo. F. Pirot, Y.N. Kalia, A.L. Stinchcomb, G. Keating, A.L. Bunge, R.H. Guy. Proc. Natl. Acad. Sci. 94: 1562-1567 (1997).