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Context: Supercritical fluid methods offer an alternative to conventional mixing methods, particularly for heat sensitive drugs and where an organic solvent is undesirable. Objective: To design, develop and construct a unit for the particles from a gas-saturated suspension/solution (PGSS) method and form endogenous progesterone (PGN) dispersion systems using SC-CO2. Materials and methods: The PGN dispersions were manufactured using three selected excipients: polyethylene glycol (PEG) 400/4000 (50:50), Gelucire 44/14 and D-α-tocopheryl PEG 1000 succinate (TPGS). Semisolid dispersions of PGN prepared by PGSS method were compared to the conventional methods; comelting (CM), cosolvent (CS) and physical mixing (PM). The dispersion systems made were characterized by Raman and Fourier transform infrared (FTIR) spectroscopies, X-ray powder diffraction (XRPD), scanning electron microscopy (SEM), PGN recovery, uniformity and in vitro dissolution, analyzed by high-performance liquid chromatography (HPLC). Results: Raman spectra revealed no changes in the crystalline structure of PGN treated with SC-CO2 compared to that of untreated PGN. XRPD and FTIR showed the presence of peaks and bands for PGN confirming that PGN has been incorporated well with each individual excipient. All PGN dispersions prepared by the PGSS method resulted in the improvement of PGN dissolution rates compared to that prepared by the conventional methods and untreated PGN after 60 min ( p value < 0.05). Conclusion: The novel PGN dispersions prepared by the PGSS method offer the great potential to enhance PGN dissolution rate, reduce preparation time and form stable crystalline dispersion systems over those prepared by conventional methods. [ABSTRACT FROM AUTHOR]

The aim of this study was to investigate the permeability of unique dispersion systems prepared by supercritical fluid (SCF) processing, to deliver bioidentical progesterone (PGN) across mouse skin. Semisolid dispersions of PGN were made up of either polyethylene glycol (PEG) 400/4000, Gelucire 44/14, d-α-tocopheryl PEG 1000 succinate (TPGS), tanscutol P or myritol 318. SCF dispersion systems were compared with various control formulations; a market cream, aqueous suspension, and three conventionally prepared dispersions - comelted, cosolvent and physically mixed systems. The permeability coefficient in the absence or presence of a permeation enhancer was evaluated using ex vivo mouse skin. The permeation study results for the TPGS/myritol/transcutol P dispersion system prepared using supercritical carbon dioxide (SC-CO2) had a two-fold improvement in transdermal permeation over 24 h compared to the control formulation, 245.7 and 126 µg cm−2, respectively ( p value < 0.05). In this study, the skin integrity and morphology was also investigated for changes due to the formulation constituents using histological examination and Fourier transform infrared spectroscopy. The particles from the gas-saturated suspension method and SC-CO2 together with TPGS/myritol/transcutol P may offer potential advantages over the available cream on the market based on the vastly improved lag time and flux of PGN across the skin. [ABSTRACT FROM AUTHOR]

Purpose: Bioavailability of transdermal progesterone is low and variable. This may be attributed to transdermal metabolism by the 5α-reductase enzymes or the direct transport to the saliva. The objective of the current study was to evaluate the effect of enzyme inhibition on the bioavailability of transdermal progesterone. Serum and salivary progesterone levels were evaluated to gain a better insight into the mechanism progesterone transport across the skin., Method: Twenty postmenopausal women with a Follicle Stimulating Hormone > 40IU/L were recruited to take part in the study. The subjects were randomly allocated to either dutasteride (n=10) or placebo (n=10). Each group applied either 500 mg of non ionic cream or dutasteride cream (2mg/g) to the right arm for 2 weeks. This was followed by applying 500 mg of progesterone or progesterone dutasteride cream (equivalent to 40 mg of progesterone) for a further 2 weeks. On day 30 blood and saliva were collected for over 12 hours and progesterone concentration was measured., Results: The baseline progesterone concentration on day zero was 0.1 ng/ml. On day 30 baseline progesterone levels increased significantly (p <0.05) to 1.40 ng/ml and 1.15 ng/ml in the progesterone and dutasteride groups, respectively. Salivary progesterone concentrations were increased by seven fold, from 0.40 ng/ml to 2.9 ng/ml. On average, salivary progesterone concentration was four times the serum levels., Conclusion: The average serum and salivary progesterone concentration, Cmax, and the AUC were slightly higher in the dutasteride group, but no significant difference could be noted. Metabolism by the 5α-reductase enzyme is unlikely to affect the bioavailability of progesterone.