Pharmacokinetics of once-a-month injectable contraceptives.

The addition of a short- or medium-acting estrogen ester to the long-acting progestins depot-medroxyprogesterone acetate (DMPA) and norethisterone enanthate (NET-EN) to produce "combined" injectable formulations has proved a successful strategy in the development of once-a-month injectable contraceptives. Recent clinical pharmacokinetic studies undertaken on once-a-month injectable contraceptives in various WHO Collaborating Centers have guided the selection of the estrogen-progestogen combinations, ratios and dose schedules. At least three combined once-a-month injectable preparations exhibit acceptable pharmacokinetic and pharmacodynamic profiles; however, further improvement in the design of optimal estrogen/progestin injectables are expected during this decade.

PIP: The World Health Organization [WHO] Special Programme of Research, Development and Research Training in Human Reproduction has coordinated the developmental strategy of combined once-a-month injectable contraceptives. The strategy consists of the selection, based on pharmacokinetic data, of appropriate long-acting progestin-estrogen combinations to develop at least 2 sustained-release formulations; assessment of safety and effectiveness of these formulations in clinical research facilities; and their evaluation at field level through service facilities of national family planning programs. WHO Collaborating Centers were involved in selecting the estrogen-progestogen combinations, ratios, and dose schedules. Research has found at least 3 combined once-a-month injectable contraceptives that demonstrate acceptable pharmacokinetic and pharmacodynamic profiles. 2 safe and effective once-a-month contraceptive formulations (Cyclofem and Mesigyna) can join the existing choice of contraceptive methods. WHO expects more improvement in the design of optimal estrogen/progestin injectables in the 1990s.

Contraceptive vaccines.

PIP: Researchers are developing vaccines to control fertility by inducing antibody and/or cell-mediated immune response against either a hormone or an antigen associated with gametes. The beta-human chorionic gonadotropin (hCG) vaccine, delivered with the tetanus toxoid vaccine, is reversible and causes only minimal side effects. It causes a large variability of antibody response. An improved version uses the beta-hCG linked with the alpha-subunit of another species (hetrospecies dimer). It is more immunogenic and produces antibodies at higher titres than does the beta-hCG-TT vaccine. It does not affect menstrual regularity. Researchers have formulated Praneem VILCI (vaccine-inducing local cell-mediated immunity) with purified extracts from Azardichta indica, an ancient Indian tree, to prevent pregnancy during the 1st 3 months. It is administered into the uterus and may be a feasible compatible approach with the hCG vaccine. Praneem VILCI does not affect ovarian function or sexual drive. The follicle-stimulating hormone vaccine has caused oligospermia and reduced fertilizing capacity of the sperm in monkeys. Contraceptive vaccines need to induce an effective and sustained immune response over a designated period in virtually all acceptors. Improved and more potent and safe adjuvants are probably needed to achieve such a response. Carriers with T cell epitopes with no suppressor T cell determinants can overcome variation in the immune response due to MCH-restriction in human populations with dissimilar immunogenetic background. Future vaccines may be polyvalent with various antigens prohibiting fertility at more than 1 point in the reproductive process. Contraceptive vaccines need to deliver multiple doses of the vaccine at 1 contact point. Biodegradable polymer microspheres can deliver antigens periodically. Live recombinant vaccines using engineered vectors can effect immunization with 1 or more doses. They would be cost effective and producible in large amounts, which would make them affordable for developing countries.^ieng

Subdermal progestin implant contraception.

Sustained-release progestin contraceptives are a new approach to meeting a worldwide need for more effective and acceptable birth control. These contraceptive systems provide low, stable levels of synthetic progestins for periods of months to several years. Unlike earlier injectable and oral contraceptives, they do not cause peaks in progestin levels beyond those required for effective contraception, nor do they employ estrogens. For these reasons, sustained-release progestin systems are without some of the health risks attributed to birth control pills, and they are more effective, as well as easy to use, and completely reversible. They share common side effects, the most frequent of which is irregular menstrual bleeding caused by the erratic shedding of hypotrophic endometrium. Despite this and other minor side effects, most users find the sustained-release systems acceptable alternatives to other methods of contraception. Permanent or biodegradable subdermal implants, injections, intrauterine and intracervical devices, and vaginal rings are all employed as delivery systems for contraceptive progestins. The Norplant (Wyeth Ayerst, Radnor, PA) system, consisting of six silastic tubes filled with levonorgestrel and implanted under the skin, was recently approved by the US Food and Drug Administration and is already used by more than a half million women worldwide. The other sustained-release systems are in various stages of development, at least several years away from general use. When these new methods complete clinical trials, women will be able to choose from among implants, injections, or pellets with various durations of action, all providing convenient, highly effective contraception with low risk to health.

PIP: Sustained released progestin-containing subdermal implants, the first new contraceptives to be released in 30 years, have the advantages of being easy to use, completely reversible, highly effective, and free of some of the health risks associated with combined oral contraceptives. The Norplant implant system, consisting of 6 levonorgestrel-filled silastic capsules, is being used by more than 500,000 women around the world and was approved for use in the US in late-1990. Because Norplant does not contain estrogen, it can be used safely by women with elevated blood pressure or a history of thromboembolic disease. Clinical trials have revealed first-year continuation rates of 76-90% compared with 50% for the pill. The most common reasons for requesting removal of Norplant are menstrual irregularity (prolonged menstrual bleeding, spotting between periods, or amenorrhea), headache, and weight gain. Plasma levonorgestrel concentrations are below contraceptive levels within 48 hours of removal, and most women resume normal ovulatory cycles during the first month after method discontinuation. Studies of carbohydrate metabolism, liver function, blood coagulation, immunoglobulin levels, serum cortisol levels, and blood chemistries have failed to reveal significant alterations in Norplant acceptors. Although some studies have recorded reductions in cholesterol, and triglyceride levels, lipoprotein levels return to pretreatment values by the end of the first year of use. Biodegradable implants that eliminate the need for surgical removal and implants that provide contraceptive protection for only 1-2 years could further increase the affordability and acceptability of this method. Under development are the Capronor and norethindrone/cholesterol pellet systems, both of which are shorter term and biodegradable.

Long-acting steroid contraceptive technology.

PIP: Long-acting steroid contraceptive technologies that have either been recently approved or are currently under study are reviewed and the status of contraceptive research in the US is noted. The benefits and drawbacks, as well as the duration and possible cost, of each method are discussed. Approved by the Food and Drug Administration on December 10, 1990, Norplant is reportedly the first new contraceptive technology available to women in the US since the 1960s. This implant delivery system, which lasts up to 5 years, is cheaper than the pill and nearly as effective as sterilization. Study is currently under way on other multiyear, nonbiodegradable and biodegradable implants. Although already used by 4 million women worldwide, the long-acting injectable Depo-Provera has yet to be approved for use in the US. 5 new types of injectables are being developed. Steroid-containing IUDs have been in the market for some time, and current research is attempting to increase their contraceptive life beyond 1 year. Contraceptive developers are also exploring transdermal delivery systems, vaginal rings, and buccal and sublingual delivery. It is considered misleading to call Norplant the first new contraceptive introduced since the pill. Over the past 20 years, virtually every contraceptive has been significantly improved, developments that have enhanced the contraceptive options of couples. Because new contraceptive technologies are increasingly complex, their development is much slower. Consequently, it is concluded that in the foreseeable future, the demand for more acceptable contraceptives will be met through improvements of currently available technologies.^ieng

Contraception with progestogens and progesterone during lactation.

The growth and development of breastfed infants whose mothers used the contraceptive implants Norplant containing levonorgestrel and the injectable containing norethisterone enanthate were studied. Each group comprised of 120 women who initiated the use during the 5th to 7th week postpartum and were compared with a similar number of IUD using mothers. The breastfeeding performance did not differ between groups. The infants of the three groups performed similarly as regards their physical growth and health as well as the time of acquisition of the various milestones of psychomental development. A vaginal ring releasing 10 mg of the "natural" progesterone per 24 h was tested in breastfeeding mothers. The continuous use of the ring produced a serum level of progesterone around 4 ng/ml. This was effective in augmenting lactational infertility even through the later phases of breastfeeding when such an effect starts to wane off. The use of the ring proved to be acceptable and had no ill-effect on breastfeeding or infant growth or health. Using the natural progesterone as a contraceptive adds a new measure of safety, since the amount of the steroid secreted in the mother's milk will not be effectively absorbed from the infant's gut. These studies suggest the possibility of using two new methods for breastfeeding mothers; Norplant and the progesterone vaginal contraceptive ring. These can be initiated early postpartum, whenever this is considered needed.

PIP: Weight gain and psychomotor development of breastfed infants of Egyptian mothers using Norplant, Cu T-380A IUDs, norethisterone enanthate injectables (NET-EN), Depo Provera and a levonorgestrel minipill were compared in 2 trials. First, groups of 120 women using Norplant and NET-EN were compared to a control group using IUDs, beginning 5-7 weeks postpartum. There were no differences in infant weight gain, mid-arm circumference, triceps-skin-fold thickness, or timing of motor milestones. The mean growth curve of all 3 groups were close to that of the 50th percentile for Egyptian infants. While timing of initiation of supplements was similar in the 3 groups, complete weaning occurred first in the IUD group, second in the Norplant group, and last in the NET-EN users. A second trail compared progesterone implants injected with a trocar that resulted in a blood level of 3 ng/ml for 5 months, with Population Council vaginal rings releasing 10 progesterone/24 hours, and CuT-380A IUDs. Serum progesterone in the ring users averaged 5.2 ng/ml for the 1st 2 weeks, then leveled off at about 4 ng/ml for about 2 months, falling to about 3 ng/ml for the last 3 weeks of use. Each women used 4 rings per year. Evidence of ovulation by ultrasonic vaginal probe and assay of estradiol and progesterone was apparent in 25% of vaginal ring users, compared to 55.9% of controls in the 2nd 6 months postpartum. There was 1 pregnancy in a ring users. The continuation rates were 66.6% for rings and 85.5% for IUDs. The reasons for discontinuation in vaginal ring continuation were logistical problems and unfamiliarity.

Contraceptive development lags in U.S.

PIP: Contraceptive development in the US has been halted by all but one company Ortho Pharmaceuticals. The reasons for this are complex and the problem is very serious. Legal and regulatory pressures have taken away the incentive to do research. There are 3 million unwanted pregnancies each year in this country. If contraceptive use were more widespread and the technology was constantly being improved by a highly competitive market, then this number would be much lower. There are several new forms of birth control being studies for use in the US, such as injectables using microspheres or microcapsules which can last for 1, 3, or 6 months, biodegradable pellets that are inserted under the skin of the hip or upper arm slowly release hormones, the vaginal ring which is saturated with time-released hormones and is worm around the opening of the uterus like a diaphragm, transdermal patches which are changed weekly for 3 weeks with a placebo patch to allow menstruation, osmotic pills which gradually release hormones on a lower and less frequent schedule, and vaccines which can immunize women against hormones in the placenta, egg or from sperm. This research is at an early stage. Luteinizing hormone-releasing hormone (LHRH) analogues suppress ovulation by affecting the pituitary gland. This method has the side effect of blocking ovarian production of estrogen and progesterone. Male methods like Inhibit inhibit the production of follicle-stimulating hormone (FSH). Gossypol has been used in China, but one side effect is that it is sometimes irreversible. Outside the US the injectables Depo-Provera and Noristerat are approved in 90 and 40 countries respectively. Norplant is a progesterone releasing implant, made in Finland, that lasts up to 5 years; it was recommended for approval in 1989 by the FDA's Fertility and Maternal Health Drug Advisory Committee RU-486 prevents the cells in the uterus from receiving progesterone, was developed in France. The Filshie clip is a titanium and silicone rubber barrier that blocks the fallopian tubes. Ovablock is a silicone plug that blocks the fallopian tubes and increase reversibility.^ieng

Contraceptive efficacy of norethindrone encapsulated in injectable biodegradable poly-dl-lactide-co-glycolide microspheres: phase II clinical study.

Contraceptive efficacy of injectable norethindrone (NET) microspheres of 90 day duration was evaluated for 6 months: nine women received two injections of 65 mg each and eight received two injections of 100 mg each with 90 days between each injection. Average serum NET levels were 5 to 9 ng/mL on the day after injection and subsequently remained at 1 to 3 ng/mL. With 65 and 100 mg doses, respectively, 36% and 25% of cycles had normal bleeding patterns, 36% and 48% were amenorrheic, and the remaining 28% and 27% had prolonged bleeding. Also, 56% and 40% of cycles showed increased spotting for the 65 mg and 100 mg dose, respectively. There was no incidence of pregnancy or serious side effects. The mean serum NET concentration returned to RIA nonspecific basal levels 100 days after the second injection. Women returned to ovulatory cycles between days 100 to 115 after the second injection.

A comparative evaluation of the safety and contraceptive effectiveness of 65 mg and 100 mg of 90-day norethindrone (NET) injectable microspheres: a multicenter study.

The first of a second generation of slow-release injectable contraceptives is the norethindrone (NET) microspheres with a 90-day duration of action. It was evaluated at 65-mg and 100-mg doses for safety and contraceptive effectiveness in two randomized, single-blind trials among 131 women: 94 women for 12 months and 37 women for 6 months. The 6-month trial included additional evaluations of ovarian function and serum NET values. In the 6-month trial, no indication of ovulation was detected in the 100-mg dose group, while 3 of the 19 women in the 65-mg group showed signs of ovulation (progesterone greater than 3 ng/ml). No pregnancies were reported in the 100-mg group and one pregnancy in the 65-mg group resulted in a life-table pregnancy rate for that dose of 2.6 per 100 woman-years (95% confidence interval, 0 to 7.5). Days of vaginal bleeding were analyzed for 30 days before treatment and in 90-day reference periods after treatment. The mean number of vaginal bleeding and spotting days increased initially after the first injection in both dose groups, but decreased to below baseline in both dose groups after 6 months. The two doses appear comparable in clinical safety, side effects, vaginal bleeding patterns, and laboratory measures. With the preliminary estimate of efficacy, the 65-mg dose would be the minimally effective dose for the NET 90-day injectable contraceptive.

Long-acting steroidal contraception: an update.

Long-acting, injectable contraceptives first became available in the 1960s. It is currently estimated that almost 3.5 million women are now using depo-medroxyprogesterone acetate (DMPA); 800,000 are using norethindrone enanthate (NET-EN), and another few hundred thousand are using a variety of once-a-month injectables comprised of progestin plus estrogen. The advantages of injectable contraceptives are that they are highly effective, independent of coitus, easily administered, and they ensure regular contact with health services personnel. The last factor may be considered a disadvantage by some, since contact is more frequent than would be required for routine health services. The major disadvantage of the progestin-only formulations is disruption of normal menses, giving rise to unpredicted episodes of bleeding and spotting. With the once-a-month formulation, on the other hand, there are few discontinuations due to disruption of menses. For a long-acting method to be used longer than 6 months, it is desirable to choose an implant, since the method can be discontinued at will. The first implant system to be developed was Norplant, a set of six rubber capsules filled with levonorgestrel and implanted under the skin. The implant releases sufficient levels of medication to protect against pregnancy. For the first 5 years, the average failure rate was four or five per thousand users per year. The failure rate for women using standard oral contraceptives is approximately 20 to 50 per thousand. The most common side effect of the implant method is the disruption of the menstrual cycle, an effect that is particularly marked in the first month of use.(ABSTRACT TRUNCATED AT 250 WORDS)

Subtracting injury from insult: ethical issues in the use of pharmaceutical implants.

PIP: Implantable drug delivery systems are devices that release a drug into the body in a controlled manner over a long time period. Examples are insulin diffusion systems and Norplant, the implantable contraceptive device developed by the Population Council. The advantages of these systems are many: they are noninvasive; they are reversible; they are efficient because, through "organ-targeting," the dosage and therefore the side effects can be reduced; and they are profitable because the ratio of development time to patent protection is lower than it is in new drug development. Superficially, it would appear that implantable drug delivery systems should not be subject to the same ethical constraints as psychosurgery, gene surgery, and surgical sterilization, which are invasive and irreversible. However, the question remains whether implantable devices which accomplish the same ends as the invasive, irreversible technics may not be equally reprehensible.^ieng

Long-acting steroids provide new options.

PIP: New injectable and implantable contraceptives that provide a slow, steady dose of hormone over long periods of time promise convenient, trouble-free contraception not related to intercourse. Like oral progestagen-only contraceptives, they prevent fertilization by impeding sperm penetration through the cervical mucus, and, also like oral progestagens, their major side effects are menstrual disorders. Injectable contraceptives have the advantage that they can be administered by trained health workers and the disadvantage that they cannot be removed. New 90-day injectables that do not release initial high levels of progestagens are being developed. Family Health International is conducting Phase III clinical trials of the NET 90-day injectable, which releases .66 mg progestagen a day. Other 90-day injectables include a levonorgestrel and a progesterone injectable being developed by Stolle, a norgestimate injectable being tested by Ortho Pharmaceutical, and steroid ester injectables being developed by the World Health Organization and the US National Institute of Child Health and Human Development. Combined estrogen-progesterone monthly injectables are used by millions of women in Mexico, Latin America, and China; and 2 monthly combined injectables, HRP112 and HRP102, are being tested by the World Health Organization. 2 injectables, Upjohn's Depo-Provera and Schering's Noristerat, have been available for over a decade. Both are extremely effective, with pregnancy rates of less than 2/100 woman-years of use. Depo-Provera has been approved for use in the UK and West Germany but not in the US, due to the development of breast and endometrial tumors in experimental animals. The longest acting steroid contraceptives are the implantables. Family Health International is conducting Phase III clinical trials of the biodegradable NET pellets, containing 85% norethindrone and 15% cholesterol, developed by Endocon, Inc. Capronor, a biodegradable capsule containing levonorgestrel, developed by the Research Triangle Institute, is currently being tested in animals. The Population Council's Norplant consists of 36 mg levonorgestrel in 6 silicon elastomer capsules, which are not biodegradable. Norplant is effective for 5 years, after which the capsules must be removed. Norplant is highly effective, with a pregnancy rate of less than 1/100 woman-years of use. Its advantages are the lack of estrogen-related side effects and a swift return to fertility. Disadvantages are a higher initial cost and the need for insertion and removal by trained personnel.^ieng

Future developments in contraception.

PIP: Research in the improvement of current contraceptive methods includes the development of longacting, biodegradable steroid delivery systems; antiviral spermicides; and condoms made of better materials than latex rubber. At the forefront of research are the development of male contraceptive pills and contraceptive vaccines. Progestagens cannot be used to suppress spermatogenesis without suppressing libido unless they are accompanied by replacement androgen therapy. Moreover, it is extremely difficult to inhibit spermatogenesis completely, so antispermatogenic substances must also render surviving spermatozoa infertile. The zona-free hamster egg penetration test has been developed to test antispermatozoal agents, and a combination of Depo-Provera and testosterone enanthate is being tested in Scotland. Gossypol has been found to suppress male fertility in China, but it has toxic side effects. Another Chinese antifertility agent is the plant Tripterygium wilfordii, but its active component has not yet been identified. The drug sulfasalazine has also been found to induce reversible infertility in men, but it also has toxic side effects. Efforts to develop an antifertility vaccine have concentrated on immunizing women against the surface antigens of the spermatozoa or against the surface antigens of the zona pellucida, which surrounds the ovum. A 3rd approach would be to immunize women against the human chorionic gonadotropin and thus prevent implantation of the blastocyst.^ieng

Norethisterone contraceptive microspheres.

Two formulations of polylactic and polyglycolic acid microcapsules containing 75 and 100 mg of NET respectively were studied for a 90-day period of anticipated contraceptive effect in two groups of five women. A 200 mg dose of NET preparation was also studied for a 180-day period of anticipated contraceptive effect in 19 women. Alteration in menstrual cycle, with tendency to short bleeding episodes, spotting days, and amenorrhea were the most important collateral effects. In the majority of cases, ovulation was inhibited. No cases of pregnancy were presented. The obtained NET circulating levels were very stable during the period of anticipated contraceptive effect.

PIP: At the Institute of Scientific Investigation of Juarez University of Durango State in Mexico, clinical researchers compared three delivery systems of norethisterone (NET) contraceptive microspheres (biodegradable polymers [e.g., polyglycolic or polylactic acid] containing micronized crystals of NET). In the 6-month system, they injected 800 mg of microspheres containing 200 mg NET intramuscularly into 19 women and then monitored the women for various effects and side effects. Soon after injection, the mean NET level in serum rose to a peak value of about 3 ng/ml and then fell gradually until it was below 0.5 ng/ml at 25 weeks. No pregnancies occurred during this period. Estradiol levels remained well below 100 pg/ml, suggesting inhibition of follicular activity. However, one patient showed an elevation in estradiol at week 16. By 24 weeks, 4 of the 19 women showed signs of the return of follicular activity. Rises in progesterone levels, indicative of ovulation, were not seen in most women during the 6-month period. However, 4 women showed progesterone peaks followed by menstruation in weeks 4, 7, 17, and 23, suggesting that their cycles had begun to return before the end of the 6-month period. 35% of women reported dizziness and nausea. 26% reported nausea. A more serious concern was the disruption seen in the menstrual pattern. 13 women had bleeding and spotting, which continued for 8-30 days in 8 women. In the 3-month system, microspheres containing either 75 or 100 mg NET were injected, each into 5 women. NET levels rose to between 1 and 2 ng/ml and fell to 0.5 ng/ml by week 15. At week 25, they were undetectable. Levels of estradiol remained low for at least 15 weeks as did serum progesterone. No pregnancies occurred. One woman ovulated in week 17. Although no headache, dizziness, and nausea were reported, many of the same disruptions in the menstrual cycle reported in the 6-month study were observed, particularly prolonged cycles, amenorrhea, and spotting. Based on these findings, the researchers deemed the 100 mg for 3 months to be the most safe and effective formulation.

Poly(ortho ester) biodegradable polymer systems.

PIP: 1 approach to developing bioerodible drug delivery systems is to prepare hydrolytically labile polymers into which a drug can be physically dispersed under relatively mild conditions and in which release of the drug is controlled by the hydrolytic erosion of the matrix. Focus is on devices in which the hydrolytic erosion process is confined to the surface of a solid device. In such devices, and for a constant rate of polymer hydrolysis, rate of drug release is directly proportional to drug loading, and lifetime of the device is directly proportional to the physical dimensions of the device. Due to the fact that the rate of drug release is directly proportional to the total surface area of the device, as the physical dimensions of the device decrease because of the erosion process, the rate of drug release also will decrease. There are 2 possible approaches to the achievement of controlled surface erosion: the interior of the matrix is stabilized so that only the outer layers can erode; and development of a highly hydrophobic polymer that contains linkages in the polymer backbone whose rates of hydrolysis are pH dependent and to incorporate into the polymer excipients that, in contact with water, produce a pH that induces the desired polymer hydrolysis rate. 1 such polymer system is the poly(ortho esters). This chapter describes some work done on polymer synthesis and the use of various excipients to achieve controlled drug release of various therapeutic agents physically dispersed in these polymers. It contains a review of drug release studies, which covers the use of basic or neutral water-soluble excipients, the use of acidic excipients, the use of calcium lactate, and the use of anhydrides. Poly(ortho ester) bioerodible polymers are suitable materials for the topical administration of a wide variety of therapeutic agents; varying the nature and amounts of excipients physically incorporated into the polymer will vary the erosion rates from a few hours to many months. With this range of control, delivery systems for short-term applications such as oral 12-24 hour tablets, intermediate ophthalmic products lasting 1 week, or implants lasting as long as 1 year can be produced. No extensive toxicological studies have been performed as yet. In vivo release rate experiments performed over many months have not shown any adverse tissue reactions beyond the expected encapsulation.^ieng

The use of biodegradable norethisterone implants as a 6-month contraceptive system.

The effects of a 6-month contraceptive system of biodegradable norethisterone (NET) implants on the menstrual cycle, estradiol and progesterone levels, the presence of side effects, its contraceptive effectiveness, and the NET levels achieved were studied in a group of nine women. There was practically no disruption of the menstrual cycle and no important side effects. Ovulation was inhibited in four subjects, and another four subjects remained ovulatory. In all the subjects a cyclic secretion of estradiol was maintained. No pregnancies occurred. The circulatory levels of NET were very stable throughout the 6-month period of implant use.

Biodegradable polymers in controlled drug delivery.

Erosion mechanisms are divided into three types and drug release within each type is described. Type I erosion involves hydrolysis of hydrogels and these are useful in the controlled release of macromolecules entangled within their network structure. Type II erosion involves solubilization of water-insoluble polymers by reactions involving groups pendant from the polymer backbone. Of particular interest are polymers that solubilize by ionization of carboxylic acid groups, and the utilization of those systems is described. Type III erosion involves cleavage of hydrolytically labile bonds within the polymer backbone and four distinct polymer systems within this category are under development. One system involves the diffusion of drugs from a reservoir through a bioerodible membrane, another system utilizes microcapsules, a third system utilizes monolithic devices, and the fourth system utilizes drugs chemically bound to a bioerodible polymer.

PIP: Controlled-release methodologies can be classified on the basis of the mechanism that controls the release of the active agent from the delivery device diffusion, osmosis, or polymer erosion. This paper presents an extensive review of the research on erosional devices. The various polymer erosion mechanisms are of 3 basic types. Type I erosion refers to water-soluble polymers that have been insolubilized by covalent cross-links and that solubilize as the cross-links (type IA) or backbone (type IB) undergo a hydrolytic cleavage. In type II erosion, polymers that are initially water insoluble are solubilized by hydrolysis, ionization, or pronation of a pendant group. In type III erosion, hydrophobic polymers are converted to small water-soluble molecules by backbone cleavage. The choice of a particular erosion mechanism is dictated by the specific application. In addition, there are 2 mechanisms of polymer release from bioerodible polymers: one approach involves surrounding the drug core with a rate-controlling bioerodible membrane, while the other involves dispersing the drug within a polymer to form a bioerodible monolithic device. The use of biodegradable systems for the sustained release of fertility-regulating agents is based on type III erosion. Polymer erosion tends to lead drug release, and there is some indication that drug release from the implant is controlled by rate of solubilization of the highly water-insoluble steroid.

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 effect of a biodegradable contraceptive capsule (Capronor) containing levonorgestrel on gonadotropin, estrogen, and progesterone levels.

Eight ovulatory women participated in the preliminary evaluation of a new method of contraception. The technique consisted of subdermal implantation of a biodegradable capsule capable of controlled release of levonorgestrel. The study spanned five menstrual cycles: three observation cycles to confirm ovulation, a cycle with the capsule implanted, and a follow-up observation cycle after its removal. All subjects who were sexually active relied on barrier contraception during the study. Basal body temperature determinations were made throughout all five cycles, and the last three cycles included serum assays of luteinizing hormone, follicle-stimulating hormone, estradiol, progesterone, and levonorgestrel on days 5, 8 to 18, and 22. All subjects except one experienced suppression of ovulation while the capsule was in place. No serious adverse effects were encountered. These results would seem to justify a larger clinical trial to assess the actual efficacy of this contraceptive method.

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.

Implantable controlled release systems.

PIP: A controlled release system utilizes a polymer matrix or pump as a rate-controlling device to deliver the drug in a fixed, predetermined pattern for a desired time period. These systems have the following advantages compared to other methods of administration: 1) plasma drug levels are continuously maintained in a therapeutically desirable range, 2) harmful side effects from systemic administration can be reduced or eliminated by local administration from a controlled release system, 3) drug administration may be improved and facilitated in underpriviledged areas where good medical supervision is not available, 4) administration of drugs that have short in vivo half lives may be greatly facilitated, 5) continuous small amounts of drug may be less painful than several large doses, 6) patient compliance may be improved, and 7) this method is relatively less expensive and less wasteful of the drug. Disadvantages include possible toxicity, need for surgery to implant the system, possible pain, and difficulty in shutting off release if necessary. Two types of diffusion-controlled systems have been developed. The reservoir is a core of drug surrounded with a polymer film. The 2nd type, the matrix, is one in which the drug is uniformly distributed through a polymer. In chemically controlled systems, the rate of drug release is regulated by a chemical reaction with the polymer. In solvent activated systems a swelling or osmotic mechanism is involved. Pharmaceutical applications have been made in ocular disease with the Ocusert, a reservoir system for glaucoma therapy and which is not widely used, and in contraception with 4 systems. These systems are: 1) subdermal implants of nonbiodegradable polymers such as Norplant, 6 capsules of 36 mg levonorgestrel; 2) subdermal implant of biodegradable polymers; 3) steroid releasing IUD; and 4) vaginal rings, which are silicone-coated. Other applications have been made in the areas of dentistry, immunization, anticoagulation, cancer, narcotic antogonists, and insulin delivery. Transdermal delivery involves placing a polymeric system containing a contact adhesive on the skin.^ieng