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Zoppetti G.(1), Puppini N.(1), Pizzutti M.(1), Fini, A.(2), Giavani T(3) and Comini S.(4).
(1) IBSA SA Pambio-Noranco (Ch),
(2) Istituto di Scienze Chimiche, University of Bologna (I),
(3) Institute for Chemical and Biochemical research “G. Ronzoni” Milano (I),
(4) Roquette Frères, Lestrem (F).
Introduction
Progesterone (P) is a natural hormone utilized as a drug to control reproductive function and for postmenopausal therapy. The current administration routes are oral by soft gel caspules, vaginal by soft gel capsules or cream and intramuscolar oily solution or water suspension injections. Oral and vaginal routes have low bioavailability and, in addition oral route has a limited usefulness because of its short half-life and extensive degradation after absorption.
Therefore the injection route should be the preferred choice , but the oily solution and the water suspension allow only intramuscular administration with a considerable pain during the treatment. This encourage the research of new injectable pharmaceutical form with increased patient compliance.
A water soluble P could be a good solution because it could be administered also by subcutaneous route, therefore allowing the automedication and less pain during the treatment is expected. The use of Cyclodextrin to increase the water solubility of Progesterone (P) was described by Pitha et al as a complex with β-cyclodextrin andderivatives to obtain a water soluble formulation.
The evidence of the inclusion complex formation of progesterone with β-cyclodextrin and derivatives is described by other authors using different physico-chemical methods. Among the cyclodextrins tested hydroxypropyl-β-cyclodextrin (HPBCD) is the preferred choice for a formulation with therapeutic amount of P.
The therapeutic dosage of P by injection vary from 5 to 200 mg. in function of the specific pathology. HPBCD has a high water solubility(48% P/V), which allow the solubilisation of high quantity of P . Considering a 1:2 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 understability ICH conditions. A precipitate formation was already noticed by Choi et al and also by Pitha et al but the chemical structure was not elucidated.
This work describes a method to obtain a P/HPBCD without insoluble particles and the physico-chemical characterization of the precipitate and the purified inclusion complex.
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