Transdermal Delivery of Progesterone

Abstract

Background and Aims: Vasomotor hot flushes are one of the most common and troublesome symptoms of menopause. The current available therapeutic options for management of hot flushes are associated with either severe adverse effects or lack of therapeutic efficacy. Bioidentical progesterone is considered a safer alternative to its synthetic counterparts. However, transdermal penetration of progesterone is poor and variable due to the physical and enzymatic barriers of the skin. The objective of this thesis is to evaluate the efficacy of Self Microemulsifying Drug Delivery Systems (SMEDDS) together with inhibition of progesterone metabolism across the skin, for enhanced transdermal permeation. Method: SMEDDS were characterised in terms of their water solubilisation capacity, the ability to form microemulsion, and thermal stability. In vitro diffusion studies across porcine skin was then carried out to measure the penetration rate of progesterone from SMEDDS and selected commercial formulations. Microscopic evaluation of the skin surface together with infrared spectroscopy was used to investigate the mechanism of action of SMEDDS. In the pilot clinical study, the effect of enzyme inhibitor dutasteride on the bioavailability of progesterone was investigated in postmenopausal women. Results and Discussion: Systems based on Tween 85 and Cremophor EL as the surfactant, Imwitor 308 as the cosurfactant, and Myritol and Isopropyl Myristate as the oil phase were able to solubilise over 70% water. Water in oil microemulsion could solubilise 20-30% water and remained stable at 32°C. Subsequent in vitro studies showed that saturated SMEDDS significantly enhanced the penetration rate of progesterone across the skin when compared to control and commercial creams. The mode of action of SMEDDS was through their penetration enhancing ability rather than supersaturation. Inhibition of 5α-reductase enzymes did not increase the bioavailability of transdermal progesterone. Conclusion: This thesis explored novel approaches to enhance the transdermal permeation of bioidentical progesterone. In addition to the generation of physiochemical data, the permeation rate of progesterone was significantly improved through development of a novel SMEDDS. The formulations developed could be applied to other steroidal hormones and the data generated provides the background information for further research on SMEDDS as topical or transdermal delivery systems. This thesis also demonstrated that 5α-reductase enzymes do not affect the transdermal bioavailability of progesterone.