Release of contraceptive progestogens from biodegradable systems

Abstract

Hormonal contraceptives remain the most widely utilized form of female fertility regulation. Progress in the field has been achieved through the search for a lower dose regimen to avoid adverse reactions such as thromboembolic complications. Introduction of hormonal contraceptives into the developing world has led to the development of preparations of long acting formulations or the synthesis of long acting derivatives of steroids that could be injected and would provide protection against pregnancy without added estrogen. 2 drugs are utilized: medroxyprogesterone acetate in a depot mycrocrystalline formulation and a heptanoic acid ester of norethisterone. Unfortunately longterm injectable progestogens expose the body to unnecessarily high plasma concentrations not required for the contraceptive effect. Sustained release derivatives producing release profiles close to zero order can be prepared however a certain degree of cycle disturbance is unavoidable. Polymeric drug delivery systems have been developed which include capsules rods and pellets placed under the skin; microcapsules for intramuscular injection; and various devices for delivery to the vagina uterus and fallopian tubes. Biodegradable polymers have been investigated for infusion controlled devices the most successful have been the polyesters. Attempts have also been made to use the rate of erosion of the polymer in the body as the controlling mechanism. Both systems however are dependent on the specific drug used. The use of polymers for the intramuscular route of administration primarily has been with microspheres. Poly(lactic acid) has been the polymer of choice. Reasonable approximations of zero order release have been obtained with microcapsules containing norethisterone. The use of polypeptides is another approach to sustained drug delivery which could be used intramuscularly. Polysiloxane rings releasing steroids for delivery through the vagina have been prepared. Devices have been tested using synthetic progestogen with naturally occurring estrogen and progestogen only. The rationale for using low doses of progestogen is to maintain a more normal endocrine profile and menses through interference with the reproductive processes at a level peripheral to the ovary as opposed to inhibiting ovulation. Local delivery at the site of action is also possible and has been achieved with devices such as IUDs which release progestogens. Sustained release systems can usefully be applied to the delivery of androgen-progestogen combinations. Testicular steroid production is more uniform with time making a zero order system an ideal tool for the delivery of contraceptive steroid combinations.