Capronor--a biodegradable delivery system for levonorgestrel.

Pitt CG; Schindler A
In: Long-acting contraceptive delivery systems, edited by Gerald I. Zatuchni, Alfredo Goldsmith, James D. Shelton and John J. Sciarra. Philadelphia, Pennsylvania, Harper & Row, 1984. 48-63.

Capronor is a biodegradable polymer system for the sustained subdermal delivery of contraceptive steroids. The polyesters, as a class, are very attractive for in vivo use, partly because of their long history of use and partly because of the lack of toxicity of polylactic acid, polyglycolic acid, and copolymers as biodegradable sutures. Poly(epsilon-caprolactone) (PCL) was selected to test because of its availability, permeability, biodegradability, and biocompatability, PCL is conveniently prepared by ring-opening polymerization of neat epsilon-caprolactone, catalyzed by stannous octoate (200-1000 ppm) at 140 degrees Centigrade. The permeability of PCL to a number of different steroids has been quantitated by determining the diffusion coefficients using a standard cell and measuring lagtimes or the steady-state diffusion rate. The solubility of the steroid in the polymer was determined from the product of the aqueous solubility and the partition coefficient. The biodegradation of PCL, polylactic acid, and their copolymers is characterized by a long induction period before weight loss. On subdermal implantation there is a continual decrease in the molecular weight of the polymer resulting from cleavage of the ester linkages. The first phase of PCL's biodegradation is consistent with a mechanism that involves random chain scission by hydrolytic cleavage of ester groups. The second stage of the ciodegradation process has been examined by implanting tritium-labeled PCL that has been predegraded under accelerated in vitro conditions to a molecular weight of 3000, in rats. The observation of substantial induction periods before bioerosion, coupled with the high permeability of PCL and its copolymers, opens the way for developing reservoir devices (capsules) that provide sustained and constant drug release by a diffusion mechanism and that erode only after the drug has been exhausted. A 90 day toxicology trial in female rats and guinea pigs revealed no toxic effects associated with subdermal Capronor. 2 limited clinical trials of Capronor have been conducted, 1 at Duke University Medical Center and a World Health Organization study in London, Bangkok, and Rome. Only the Duke study in complete. No side effects beyond the usual ones associated with minidoses of a progestogen were found--for example, mood swings, mild breast tenderness, and increased appetite. No subjects had intermenstrual bleeding, but test cycles were shorter than preceding cycles. Wide variations in serum levels of levonorgestrel existed; ovulation suppression occurred at a plasma level of 300 pg/ml or greater. (author's modified)

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