Water soluble progesterone-hydroxypropyl-β-cyclodextrin complex for injectable formulations

The use of cyclodextrin to increase the water solubility of progesterone (P) was described by Pitha as a complex with beta-cyclodextrin and derivates to obtain a water soluble formulation (Pitha, J.: US patent n. 4,727,064). Hydroxypropyl-beta-cyclodextrin (HPBCD) has a high water solubility which allows the solubilization of high quantity of P. Considering a 1:2 guess/host complex stoichiometry it is possible to obtain up to 50 mg/ml of P concentration, which is a considerable dosage for drug development in the progesterone therapy. In our drug development the P/HPBCD complex in water showed the formation of a light precipitate during stability ICH conditions. A precipitate formation was described already by Choi (J. Korean Pharm. Sci. 31(3), 151, 2001) and also by Pitha (US patent n. 4,727,064) but the chemical structure was not elucidated. In our case the precipitate was purified and it turned out to contain progesterone and residual unmodified beta-cyclodextrin. We have developed a production process in which the residual unreacted beta-cyclodextrin is separated from the HPBCD by the formation of the insoluble inclusion complex (Zoppetti et al.: European Patent deposit n. 05108494.5). The resulting P/HPBCD contains up to 0.1% of residual beta-cyclodextrin and does not produce precipitate during the stability study. The complex stoichiometry and the complex constant were calculated by the phase solubility study according to Higuchi and Connors (Adv. Anal. Chem. Instrum. 4, 117, 1965) and the presence of the inclusion complex was demonstrated by DSC, NMR, X-ray, FTIR. The formulation prepared at pilot scale as injectable form compared with the commercial oil formulation demonstrated a favourable kinetic in humans.