Use of Topical Co-drugs for the Treatment of Psoriasis: Formulation, Stability and Targeted Drug Delivery in the Skin.
Loading...
Issue Date
2017
Authors
Jadhav, Ankita '17
Degree
MS in Pharmaceutical Sciences
Advisor
Hass, Martha A.
Committee Members
Zheng, HaiAn
Musteata, Marcel
Musteata, Marcel
Journal Title
Journal ISSN
Volume Title
Abstract
Psoriasis is a chronic autoimmune disease characterized by extensive epidermal keratinocyte proliferation and inflammation. In order to target the hyperproliferation and inflammation, our lab previously synthesized the co-drugs, \316\261-MTX-IBU and \316\263-MTX-IBU, from the parent compounds, methotrexate (MTX) and ibuprofen (IBU). The objective of this project was to formulate these co-drugs into stable microemulsions (ME) for topical delivery, to evaluate their hydrolytic stability in the ME formulations, to monitor accumulation and hydrolysis in the skin and to assess their in vitro efficacy. To assess stability of the formulated co-drugs, \316\261- MTX-IBU and \316\263-MTX-IBU were formulated into ME composed of Capmul (oil), Tween 20 and PEG400 (surfactants) and water. After designated time intervals, co-drugs were extracted from the ME formulation and analysed by HPLC to evaluate hydrolytic stability. Formulated co-drugs were applied to intact, porcine skin and allowed to penetrate for 24h. After 24h, co-drugs were extracted from the skin, quantified, and the efficacy of the co-drug (and/or released MTX) that accumulated in the viable skin layers was evaluated for inhibition of DHFR. Stability studies revealed that both \316\261-MTX-IBU and \316\263 -MTX-IBU were unstable in the ME formulation at all of the time points monitored. Hydrolysis of approximately 13% for \316\261-MTX- IBU and 26% for \316\263-MTX- IBU was observed. Hydrolysis of both co-drugs was observed at the earliest time point and did not change over the 24h period. Results of the penetration and enzyme inhibition experiments showed that both co-drugs, in their intact 2 and hydrolysed forms (MTX + IBU), penetrated into viable layers of the skin. \316\261-MTX-IBU and MTX extracted from skin after 24h penetration weakly inhibited DHFR (1.5%) and \316\263- MTX-IBU and MTX showed 15% inhibition. For \316\261-MTX-IBU, approximately 0.84% of the applied co-drug accumulated in the skin and 8.4% of the isolated co-drug was hydrolyzed. The percent hydrolysis of \316\263-MTX-IBU isolated from the skin was 71.4% with only 0.06% of the applied co-drug accumulating in the skin. Approximately the same amount of MTX was released from both co-drugs in the skin, however \316\263-MTX-IBU greater inhibition of DHFR (15%) than \316\261-MTX-IBU (1.5%). The higher inhibitory activity observed for \316\263-MTX-IBU may be due to the inhibitory activity of the intact co-drug. Overall, co-drugs were shown to be unstable in the ME formulation. Hydrolysis of the diesters occurred in the ME, presumably because of the high water content (42%). Despite the hydrolytic instability of the co-drugs, \316\261-MTX-IBU and \316\263-MTX-IBU in the ME formulation, and released MTX were shown to penetrate into the viable skin layers in concentrations sufficient to weakly inhibit DHFR. ME formulations in which the co-drugs are hydrolytically stable, with lower water content or simple oil formulations will be explored in the future.
Citation
Jadhav, A. Use of Topical co-drugs for the Treatment of psoriasis : formulation, stability and targeted drug delivery in the skin. Ann Arbor (MI): Proquest LLC; 2017. 66 p.
ACPHS Research Commons URI
Description
Click on the Resource Link to find this item in the ACPHS Library catalog.