Lee R. Beck

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.

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.

Clinical evaluation of an improved injectable microcapsule contraceptive system

Pharmacokinetics and pharmacodynamics of a long-acting injectable microcapsule, poly(DL-lactide-co-glycolide), delivery system were tested in 10 women. Two doses (75 or 100 mg of norethindrone) were administered by intramuscular injection. Treatment suppressed ovarian function and inhibited ovulation for 3 months in all subjects. Levels of norethindrone in subjects who received the 100 mg dose were proportionately higher than those in subjects who received the 75 mg dose. Subsequent to the injection, there was a rapid rise in the serum levels of norethindrone followed by a gradual decline until 8 to 10 weeks. Between 10 and 20 weeks after treatment, there was a secondary rise and fall in the serum levels of norethindrone. Treatment caused suppression of the endometrium for 3 months, and, except for spotting and irregular menstrual cycles, there were no adverse side effects. Treatment had no significant effect on serum lipids.

The comparative anatomy histology and morphology of the mammalian oviduct.

Literature on the comparative anatomy histology and morphology of the mammalian oviduct is reviewed. Structural aspects of the oviduct including the supporting mesenteries blood vessels lymphatic system and nerves the histologic characteristics of the tunica serosa tunica muscularis and tunica mucosa and the morphology of the oviduct supporting mesenteries and the uterotubal junction are reviewed.

Controlled-release delivery systems for hormones. A review of their properties and current therapeutic use.

SummaryBiomedical engineering approaches used to develop controlled-release delivery systems for hormones are here reviewed regarding system design and therapeutic applications.The biomedical engineering approach uses a system of non-drug components to control the rate and duration of hormone delivery. The non-drug components vary from system to system, but generally include: a reservoir for the hormone; a barrier or regulator to contain the hormone within the reservoir and to control its release; an energy source to remove the hormone from the reservoir; and a pathway for egress of the hormone from the system. Controlled-release delivery systems for hormones discussed in this review include mechanical and osmotic pumps; intraocular, intravaginal and intrauterine platform devices; biodegradable and non-biodegradable subcutaneous implants; and small particulate systems including microcapsules, microspheres and liposomes. Examples of the therapeutic application of the various systems are given along with a discussion of design factors and pharmacological aspects relevant to their clinical use.

Larger animal testing of an injectable sustained release fertility control system.

Abstract Results are reported of the testing in four female baboons of an injectable fertility control system. This system, an injectable powder of 90–180μ particle size, contained 20% by weight of carbon-14 labeled norethisterone (NET) in a biodegradable tritium labeled polymer matrix. The polymer was synthesized from 90 parts by weight L-lactide and 10 parts glycolide to a molecular weight of 200,000. Results of the baboon tests indicate a uniform release with a pronounced but not dramatic early “burst” and an approximate system lifetime of two months. Concomitant release of polymer and drug was observed as measured by tritium and carbon-14 in the excreta. These data, the first for this injectable formulation in a large animal, were correlated with earlier results from smaller animals. Release rates were found to be strongly dependent on the quantity of drug injected. Based on this correlation it may now be projected that an injection of 150 mg NET will provide an average release of approximately 800 μg NET/day for 90 days.

Fibrous Polymers for the Delivery of Contraceptive Steroids to the Female Reproductive Tract

Research and development on the application of controlled-release technology to fertility regulation was initiated in the late 1960s and has been accelerated in recent years.1’2 Since sustained-release doses obviate the problem of cyclic overdosing and underdosing associated with the conventional administration of steroids, the technology, in principle, affords a means of effecting an optimum pharmacological response with a minimum dose of exogenous steroid.3 Depending upon the half-life of the drug in plasma, the duration of the dose regimen, and the route of administration, the total dose can be reduced to 1/100 or less for continuous versus intermittant delivery.

SP-1 secretion by baboon embryos in vitro

Baboon embryos cultured to postimplantation stages have been shown to secrete the placental protein SP-I into the culture medium in quantities of up to almost 5 micrograms/day, based on a rhesus monkey standard. Twelve embryos, for which spent media samples have been assayed, have been shown to secrete this protein, with measurable quantities usually being present on day four following attachment of the zonaless embryo to the culture dish. Secretion has continued for up to 14 days, with over 26 micrograms total SP-I secretion from one embryo. These observations further enhance the utility of the baboon embryo culture system as a model for studying early placental development in the primate.

The baboon as a primate model for the study of endometrium

A series of transcervical uterine biopsy specimens were obtained at various stages of the menstrual cycle from a colony of 11 normally cycling female baboons, Papio anubis and Papio cynocephalus. Morphologically, baboon endometrium appeared to be similar to human endometrium. Alkaline phosphatase activity was maximal throughout the preovulatory phase and during the late postovulatory period. During the preovulatory phase acid phosphatase was not demonstrable but increased after ovulation to reach maximal activity prior to menstruation. While differences exist between human and baboon endometria, the overall morphologic and histochemical changes are similar. In addition, the baboons endometrium is readily accessible by transcervical uterine biopsy, thus making these animals valuable primate models for study of human reproductive problems.