Controlled release of contraceptive steroids from biodegradable poly (ortho esters).

Abstract

The synthesis of poly (ortho esters) by the condensation of diols and diketene acetals and the in vitro drug release from devices containing norethindrone or levonorgestrel and either Na2C03 or Na2S04 is described. Drug release kinetics are rationalized in terms of an osmotically driven water imbibition and release of the steroid from the swollen polymer. No polymer erosion occurs when Na2C03 is used. When Na2S04 is used, polymer erosion does take place but lags drug release. As expected from the known acid lability of ortho ester linkages, drug release is strongly dependent on the pH of the external environment and a dramatic increase occurs between pH 5.5 and 5.0. The glass transition temperature of the poly (ortho esters) can be continuously and predictably varied between 115 and 20 degrees Celsius by using an appropriate ratio of 1,6-hexanediol, and trans-cyclohexanedimethanol in the condensation reaction with the diketene acetal. Polymer hydrophilicity can be varied by the incorporation of varying amounts of the hydrophilic diol diethylene glycol into the polymer. Molecular weight control can be readily achieved by skewing the stoichiometry, and polymers with weight average molecular weights between 20,000 and in excess of 100,000 have been produced. Hydrolytic degradation of the poly (ortho esters) produces the expected products.