Donald R. Cowsar

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.

[8] Poly(lactide-co-glycolide) microcapsules for controlled release of steroids

Publisher Summary This chapter addresses long-acting, drug-delivery systems comprising steroidal drugs microencapsulated in aliphatic polyester resins. Because the aliphatic polyesters slowly degrade, owing to hydrolysis of ester linkages, when they are exposed to water they disappear from the tissues soon after (or during) drug release. Many drug and biologic substances, other than the steroids, can be microencapsulated in the biodegradable polyesters to produce injectable controlled-release doses. The specific copolymer resins and the appropriate microencapsulation processes must be chosen carefully, however, to achieve the rates and durations of drug release desired. When steroid hormones are microencapsulated in the biodegradable copolyesters in which the drug is homogeneously dispersed within the resin matrix to form a monolithic microcapsule and the microcapsules are injected either intramuscularly or subcutaneously, the drugs are slowly released into the tissues principally by a diffusion mechanism. The microcapsules are designed to release norethisterone at a nearly constant rate for 3 months. The 85:15 poly(DL-lactide-co-glycolide) resin is selected as the biodegradable excipient because the onset of resin fragmentation occurs at about 50 days postinjection. Total resorption of the resin by the tissues is complete in about 180 days.

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.

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.

Biodegradable Polyamides Based on 4,4′-Spirobibutyrolactone

This paper describes the synthesis, structure, and some properties of a new family of biodegradable poly(amides) based on 4,4′-spirobibutyrolactone (SBBL). The polymers were synthesized using melt polymerization techniques similar to those used to prepare nylon 6,6. Both homopolymers (SBBL + diamine) and block copolymers (SBBL + diamine + nylon salt) were prepared. The homopolymer and copolymer backbones contain lactam and spirolactam groups in addition to the expected secondary amide groups. Homopolymers were found to degrade completely in neutral phosphate buffer, while the block copolymers degraded only partially in vitro and in vivo. The copolymers evoked only a mild tissue response when implanted subcutaneously in rabbits. Other properties of this unusual family of polymers are discussed.

Drug Delivery Systems: Design Criteria

In the context of the current state of the art, a controlled release drug delivery system is a combination of drug and excipient, commonly a polymeric material, arranged to allow delivery of the drug to the target at controlled rates over a specified time. The polymeric material may be either biodegradable or nonbiodegradable, and the drug may be released by diffusion of the drug through the encapsulating polymer matrix, by erosion of the polymer matrix, by a combination of diffusion and erosion, or by an alternative physical phenomenon such as capillary flow through wicks of fluid-filled devices and displacement by physiological fluids. The physical forms of the controlled release doses can vary considerably and currently include macrocapsules or pellets that are implanted via incision or trocar, microcapsules or micro-particles that are injected via a syringe; envelopes, films, or laminates that are placed in the cul-de-sac of the eye or in the oral cavity, or are implanted subcutaneously; various ring- and T-shaped intravaginal and intrauterine devices; and bandages for topical and transdermal delivery.

Controlled Release: Benefits vs. Risks

During the decade of the 1970s, new controlled-release technology continued to emerge from research laboratories around the world. A few controlled-release formulations and devices have already reached the market place, and many others are currently undergoing premarketing trials. One might say that controlled release has transgressed from its infancy through its childhood, and it is rapidly maturing to occupy a vital position in many important industries. The future of controlled release appears bright indeed.