Development of a Transdermal Delivery System for Progesterone using Supercritical Carbon Dioxide

Abstract

BACKGROUND: Millions of postmenopausal women globally have diminishing bone density, higher rates of ovarian cancers, hot flushes and sweating, insomnia, and postmenopausal depression. The associated costs to the healthcare systems weigh heavily and current treatments prove ineffective or carry significant adverse effects. The use of hormone replacement therapy (HRT) is one of the most popular method for controlling postmenopausal signs and symptoms. Bio- identical progesterone (PGN) is an endogenous-like steroid that is capable of averting many of the postmenopausal related conditions and has lower rates and severity of adverse effects. Unfortunately, the oral administration of PGN results in very low bioavailability due to PGN‘s poor aqueous solubility, physical barriers, and extensive first pass metabolism. Alternatively, transdermal delivery of PGN is a favourable option. AIM: The aim of this thesis is to investigate the transdermal delivery potential of PGN in unique dispersion systems prepared using a novel supercritical fluid (SCF) method known as particles from gas saturated suspension (PGSS). METHODS: The preformulation phase on PGN included a high performance liquid chromatography (HPLC) method development and validation, x-ray powder diffraction (XRPD), infrared (IR) spectral identification, melting behaviour, saturation solubility, and in vitro dissolution studies. Three excipients were selected as dispersion matrices for PGN primarily based on solubility parameters and saturation solubility, which showed that Gelucire 44/14, a polyethylene glycols (PEG) 400/4000 mixture, and d-α-tocopheryl PEG 1000 succinate (TPGS) were promising. In order to formulate PGN dispersion systems in the selected excipients, a SCF unit was designed, constructed, and developed to perform the PGSS method using supercritical carbon dioxide (SC-CO2). A factorial design study was used to optimise the PGSS process by identifying significant variables that affected the process yield, in vitro dissolution extent after 20 minutes (E20), and t1/2 of PGN release. A non-linear dual first order model was employed to elucidate the mechanisms of PGN release which was found to be dominated by both erosion and diffusion. The dual first order was then compared to conventional release models such as zero and first order, Krosmeyer-Peppas, and Higuchi. The permeability of PGN across nude mouse skin from the dispersion systems prepared by various methods was determined using a Franz diffusion cell. In addition, a SCF-prepared formulation was manufactured with TPGS, an oil (myritol 318), and a penetration enhancer (transcutol P) which was compared with oil and enhancer free SCF prepared systems, conventionally prepared dispersions, and two controls: an aqueous PGN suspension and a commercial cream. RESULTS and DISCUSSION: Improvement in the aqueous dissolution of PGN was observed using the selected excipients, thus Gelucire 44/14, TPGS, and PEG were employed to manufacture PGN dispersion systems using SC-CO2 and PGSS method. The PGSS unit was built and operated successfully to form various dispersion systems, and pilot results using TPGS or Gelucire 44/14 systems produced at 124 bar and 59°C showed promising results in improving the aqueous dissolution of PGN. The factorial experimental design study showed that higher pressure (186 bar), higher temperature (60°C), and longer processing time (30 minutes) all had positive effects on the yield and E20 dissolution. On the other hand, the higher pressure and temperature along with a shorter processing time of 10 minutes significantly affected t1/2 (p-value < 0.05). The higher loading amount of 9 g and longer sonication time of 10 minutes significantly affected E20, while the larger orifice diameter (1/4‖) during expansion only affected t1/2. The permeability results showed that the SCF formulation in the presence of myritol 318 and transcutol P was significantly different from the controls (p-value < 0.05). Histological examination showed that the enhanced PGN permeability was explained by the dispersion system‘s ability to disrupt the SC bilayer and improve the diffusion of PGN into the skin. CONCLUSION: Uniform dispersion systems of PGN with Gelucire 44/14, TPGS, and PEG can be formed using the PGSS method. Raman and FTIR spectroscopy, DSC, and XRD were able to successfully characterise the PGN dispersions. The dispersion systems were then optimised using a factorial design study, and the mechanism of PGN release was found to be occurring by the dual processes of erosion and diffusion. TPGS/myritol 318/transcutol P-based systems increased the permeability of PGN across the skin by 2-fold compared to the commercial cream. A transdermal delivery system of PGN has been established using SC-CO2 processing and could be used as a platform to optimise the delivery of other steriods.