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Title

In Vitro Percutaneous Penetration Of Methotrexate

Date of Award

1981

Document Type

Dissertation - Pacific Access Restricted

Abstract

This research project was designed to investigate the effects of various physical and chemical parameters on percutaneous penetration of methotrexate. The potential of propylene glycol in water as a vehicle for topical delivery of methotrexate has been examined. A detailed examination of solubility, partition coefficient and pH parameters in the range of 2 to 6 pH units has been conducted with the goal of correlating their effects on skin penetration of methotrexate. The importance of physiochemical parameters such as solubility and partition coefficient and their aid in the development of a suitable delivery system for topical application has been explained. In vitro percutaneous absorption of methotrexate was examined across suitably characterized human cadaver skin samples. The results of this investigation suggested that the stratum corneum formed the main effective barrier for penetration of topically applied methotrexate. The analysis of the penetration data revealed relatively high lag times even at the most optimal pH, indicative of the low amounts of drug penetrating during the initial hours. These observations might explain the successful clinical results seen with topical methotrexate. At low pH values between 1 and 3, the protonation of the nitrogens possibly of the pteridine nucleus and also at the 10 position was found to retard skin penetration. Between pH values 3 and 5, the concentration of the unionized species present was optimal, contributing to penetration by passive diffusion. This was consistent with the improved rate of penetration and comparatively low values for lag times in this pH range. Relatively low drug solubility in this pH range in the vehicle examined might account for lower rate and extent of penetration than those observed in the pH range 5 to 6. Beyond pH 5, the concentration of unionized drug was very low, yet the lag times, and rate and extent of penetration were the highest observed. Relatively high drug solubility and gradually increasing contribution of shunt pathways probably accounted for this. The results of this investigation emphasize the particular importance of in vitro skin penetration studies which should precede clinical trials. Based on the results of this investigation, it is suggested that optimal conditions for topical delivery of methotrexate should include a vehicle system with a pH of about 4 capable of dissolving the drug to the extent of 0.4% w/v or more while still retaining good partitioning characteristics for the skin.

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