A new long-acting injectable microcapsule system for the administration of progesterone.

A long-acting injectable microcapsule system for the controlled-release systemic administration of progesterone (P4) is described. The system consists of microcapsules made of the biodegradable polymer, d,l-polylactic acid, which contain crystalline P4. Following injection, P4 is released from the microcapsules by diffusion and biodegradation of the polymer matrix. The rate of P4 release from the prototype microcapsule system in vivo is 1.3 microgram of P4/day/mg of microcapsules, and the duration of release is 30 days. Vaginal estrous cycles in rats and cyclic ovarian function in baboons were inhibited for 1 month following a single injection of P4 microcapsules. The effects of continuous progesterone therapy on reproductive function in both rats and baboons are dose-dependent. The utility of the system as a once-a-month injectable contraceptive is established in the baboon model.

PIP: A longacting injectable microcapsule system for the controlled-release systemic administration of progesterone is described and photographed. The microcapsules are made of biodegradable polymer which contain crystalline progesterone. After injection, the progesterone is released over time from the microcapsules by diffusion and biodegradation of the polymer matrix. Rats and baboons were used to evaluate the in vivo rates of progesterone release from different capsule preparations. Results are graphed and tabulated. Tests showed that 50% of the progesterone is available for quick release while the other 50% remains to be released at a slower rate. Smaller microcapsules released the progesterone at a greater rate and a shorter duration. By using larger microcapules, it should be possible to extend the useful duration of the microcapsule system. Vaginal estrus cycles in rats and cyclic ovarian function in baboons were inhibited for 1 month following injection of the progesterone microcapsules. This method of delivery has the advantages that it obviates cyclic overdosing and underdosing and it can be delivered both locally and systemically.

Long-acting steroidal contraceptive systems.

PIP: This is a general discussion of the development of long-acting steroidal contraceptive systems. This is believed to be an important solution to the problems of effectiveness, safety, and acceptability of steroidal contraceptives, especially in developing countries. Since side effects from hormones are known to be dose-dependent, the aim is to develop a contraceptive with a great enough amount of hormone to prevent pregnancy but not so great as to cause side effects. There are 2 different approaches to the delivery of fertility control: the pharmacologic and the systems engineering approaches. The pharmacologic approach is typified by an injectable steroid while the systems engineering approach involves inert drug carriers which control the release of the hormone. Delivery of long-acting substances can either be made locally or systemically. The state of the art regarding long-acting contraception is reviewed with a thorough discussion of the process of development, dosage requirements, and method of delivery of the following types of contraceptives: 1) injectable depot formulations; 2) subdermal implants; 3) medical intrauterine systems; 4) medicated intravaginal systems; 5) medicated intracervical systems; and 6) biodegradable systems.^ieng

Clinical evaluation of injectable biodegradable contraceptive system.

A new long-acting injectable contraceptive system was tested in 24 women. The system consists of microspheres made of biodegradable d,l-polylactic acid in which micronized crystals of norethisterone (NET) are homogeneously dispersed. In previous animal studies we showed that NET is slowly released from the microspheres for 6 months, and after the drug is released, the microspheres biodegrade into lactic acid by the process of hydrolysis. The serum levels of NET, estrogen, and progesterone were monitored by radioimmunoassay, and the effects of treatment on ovarian function and menstrual bleeding were evaluated. The doses ranged from 29 to 370 mg of microspheres containing 7.25 to 94.5 mg of NET or 0.134 to 2.30 mg of NET/kg of body weight. The duration of the NET release was 6 months, and the serum NET profiles in women were similar to those previously described in subhuman primates. Following a small burst, there was a gradual decline in the serum levels of NET over 6 months after treatment. The serum levels of NET varied in proportion to the dose. Doses less than 0.267 mg of NET/kg had no discernible effect on either ovarian function or menstrual bleeding. Doses ranging from 0.419 to 2.30 mg had variable effects on ovarian function and menstrual bleeding. Higher doses caused suppression of ovarian function for longer periods of time, increased the interval between episodes of menstrual bleeding, and decreased the quantity of blood loss during each episode. The treatment was well tolerated by all subjects, and, with the exception of spotting and irregular menstrual cycles, there were no adverse side effects. Based on this initial study, it was determined that doses ranging from 1.33 to 3.45 mg of NET/kg are necessary to suppress ovulation for 6 months. Additional studies with the use of higher doses are currently under way.

New long-acting injectable microcapsule contraceptive system.

A new long-acting, injectable contraceptive which provides continuous controlled release of the steroid norethisterone (NET) for a precise period of 6 months following a single intramuscular injection is described. The prototype system consists of microcapsules made of the biodegradable polymer d, l-polylactic acid, in which micronized crystals of NET are homogeneously dispersed. NET is slowly released from the microcapsules following intramuscular injection at a rate of 0.90 microgram NET/day/mg of microcapsule by diffusion of the steroid from the polymer matrix. Three different doses of a standard preparation of microcapsules were tested in normally cycling female babbons (4 to 5 baboons/group). Following injection of either 300, 200, or 100 mg of microcapsules containing 75, 50, or 25 mg of NET, blood samples were collected at selected intervals and analyzed for NET, estrogen, and progesterone by radioimmunoassay. All three doses provided continuous NET release for 6 months following injection. The NET serum profiles for the different doses are parallel, and ovulation was inhibited in all baboons for 6 months following treatment.

PIP: A new, long-acting, injectable contraceptive system which uses a biodegradable polymer (d,1-polylactic acid) in the form of microspheres for controlled delivery of norethisterone is described. The continuous controlled release is designed to last exactly 6 months after a single intramuscular injection. System fabrication has yielded a prototype: Microcapsules of the biodegradable polymer containing homogeneously dispersed micronized crystals of norethisterone are injected, and the steroid is released slowly at a rate of .9 mcg of norethisterone/day/mg of microcapsule by diffusion of the drug through the polymer matrix. Pharmacokinetics of the injectable system of norethisterone were tested in normally cycling female baboons. 3 different doses of a standard preparation were tested (4-5 animals/group). After injection of either 300, 200, or 100 mg of microcapsules of 75, 50, or 25 mg of norethisterone, blood samples were collected and analyzed for the steriod, estrogen, and progesterone; radioimmunoassay of samples collected at selected intervals was carried out. For 6 months after injection, all 3 doses were parallel. Ovulation was inhibited in all baboons for 6 months after treatment; each animal resumed normal ovarian function within 1-2 weeks after the norethisterone blood level fell below the level of detection of the assay system (10-25 pg/ml).

Poly(DL-lactide-co-glycolide)/norethisterone microcapsules: an injectable biodegradable contraceptive.

Microcapsules made from a biocompatible, biodegradable polymeric excipient, poly(DL-lactide-co-glycolide) (DL-PLGA) that contained 22 weight percent (wt %) norethisterone (NET), were prepared by a solvent-evaporation microencapsulation process. The effects of changing both the lactide-to-glycolide ratio of the DL-PLGA and the size of the microcapsules on the rate of NET release and the rate of excipient biodegradation were determined in vivo. NET release rates were determined in baboons after injecting the microcapsule formulations intramuscularly. Serum samples obtained at various times following treatment were analyzed for NET, progesterone, and estrogen by radioimmunoassay (RIA). Biodegradation kinetics were determined by injecting NET microcapsules made from radiolabeled DL-PLGA intramuscularly into the hind legs of rats. Residual radioactivity at the injection site was determined at various times after treatment by combustion analysis of the muscle tissue. Changing the ratio of the comonomers to include more glycolide (DL-lactide:glycolide-96:4, 92:8, 87:13, 74:26) increased the rate of NET release and accelerated the biodegradation of the copolymer excipient. Decreasing the size of the microcapsules increased the rate of NET release. On the basis of these studies a NET microcapsule formulation has been identified for clinical testing which releases NET for 3 months and biodegrades completely within 6 months.