WO1998030171A1

WO1998030171A1 - Opiate antagonist implant and process of preparation therefor

Info

Publication number: WO1998030171A1
Application number: PCT/US1998/000510
Authority: WO
Inventors: Lance L. Gooberman; George J. Malmberg; Alan R. Tripp
Original assignee: Gooberman Lance L; Malmberg George J; Tripp Alan R
Priority date: 1997-01-13
Filing date: 1998-01-13
Publication date: 1998-07-16
Also published as: AU5913098A; CA2278137A1

Abstract

The present invention provides an opiate antagonist implant which is an admixture of an opiate antagonist, in either acid or base form, and a pharmaceutically acceptable carrier. The admixture is uniformly compressed into a subcutaneously implantable pellet which is effective to release levels of the opiate antagonist over desired amounts of time when subcutaneously implanted in a patient to effectively inhibit the effects of a number of addictive drugs.

Description

OPIATE ANTAGONIST IMPLANT AND PROCESS OF PREPARATION THEREFOR

Field of the Invention

The present invention relates to an opiate antagonist implant in which the active ingredient antagonist is effective as a self-sustaining delivery mechanism for its own dissolution and delivery for desired extended periods of time and, more particularly, to an implantable pellet produced in a novel compression method to form a concentrated implantable antagonist which when subcutaneously inserted in a patient will deliver an effective and desired level of an opiate antagonist in the patient's bloodstream, preferably in excess of thirty days or more.

Background of the Invention Heroin addiction is a growing health care problem in the United States. The United States Department of Health and Human Services ' Substance Abuse Branch issued a report in December of 1994 stating that the number of emergency department visits directly related to heroin use rose from 48,000 in 1992 to 63,000 in 1993, a 31% increase. The rate of heroin-related episodes per 100,000 people rose 81%, from 15 to 28 per 100,000, between 1990 and 1993. Upon breaking down the heroin-using population into ethnic groups and age groups, it has been demonstrated that all subsets have increased rates of use for this time period.

Human opiate detoxification has been in use for some time. More than 31,000 individuals of the Empire Blue Cross and Blue Shield subscriber base in New York were hospitalized at least once for opiate dependency between 1982 and 1992. The majority of these individuals were working adults, and their principal reason for hospitalization was addiction treatment. Drug detoxification accounted for 96% of the admissions, and the length of stay ranged between five and ten days . In cases where individuals have been recently "detoxed" there is a high incident of relapse and re- addiction. While these former addicts are often strongly motivated to seek treatment and relapses often produce guilt and depression, they are still unable to resist giving in to the intense craving for heroin or pressure from drug dealers. In recognition of the foregoing, opiate antagonists have been administered to such detoxified addicts. Opiate antagonists are defined as chemical compounds which block the effects of opiate drugs by blocking the opiate receptors in a patient. By blocking the effects of agonist opiates, opiate antagonists also prevent the development of physical dependence and tolerance to opiate drugs, such as heroin.

It should be noted that while opiate antagonists do not produce symptoms when they are used in the treatment of heroin dependence, they will precipitate an abstinence syndrome in individuals who are physically dependent on an opiate drug. By virtue of their affinity for the opiate receptors, they will compete with and oftentimes displace opiate agonists from the receptor sites. Accordingly, a heroin addict must be detoxified before he can be treated with an opiate antagonist. Once completely free of opiate drugs, however, no symptoms will be produced by the administration of the opiate antagonist. One preferred antagonist used in the treatment of former heroin addicts is naltrexone (N-cyclopropylmethylnoroxy morphone) . Naltrexone, such as some opiate antagonists, provides no euphoric effects and there are no observable pharmacological consequences when a patient stops taking the drug. For naltrexone treatment to be effective, sufficient levels of the drug must be maintained in the patient for a substantial period of time. This typically requires the patient to self-administer dosages of the drug several times a week. A major problem with the use of opiate antagonists, such as naltrexone, in the treatment of opiate addiction has been patient compliance. This is frequently due to the patient ' s strong desire to experience the euphoric feeling which would otherwise be prevented by the presence of the opiate antagonist in his or her bloodstream. One solution for improving patient compliance is the time-lapsed release of an antagonist such as naltrexone over a desirably long period of time . Several methods for implantable antagonists in animals for purposes other than to successfully treat opiate- addicted humans have been reported. For example, in PECHNICK et al., Neuropharmacology, 26 (11) : 1589-1593 (1987), male rats injected with pentobarbital showed sleeping time to be increasingly antagonized after naltrexone administration by injection, but not in subjects implanted with a pellet of naltrexone. This study concluded that potentiation of pentobarbital sleeping time produced by opiates is mediated by opiate receptors, but did not show any development of tolerance. No indication of how the naltrexone pellets are made or their composition is provided in this study, except that the naltrexone pellets were obtained from the National Institute on Drug Abuse. While no clinical treatment program for humans is suggested, the article concludes with suggestion that the use of barbiturates by individuals chronically using opiates may have profound adverse consequences .

In BARDO et al . , Pharmacology, Biochemistry & Behavior, 28:267-273(1987), rats implanted with a naltrexone pellet were shown to be devoid of morphine-induced conditioned place preference (CPP) . Pellets of naltrexone freebase used in this study were also obtained from the National Institute on Drug Abuse. Nothing is mentioned as to pellet composition or method of manufacture. It was concluded that chronic naltrexone exposure produces behavioral supersensitivity to morphine-induced reinforcement and hyperactivity, and that the reinforcing efficacy of heroin is potentiated following chronic naltrexone administration. It was also concluded that up-regulation of opiate receptors following chronic naltrexone enhances opiate reward and that chronic naltrexone also potentiated morphine-induced hyperactivity in rats.

BARDO et al., Neuropharmacology 27 (11) : 1103-1109 (1988) also discusses rats implanted with naltrexone pellets for short time intervals (from one to ten days in this study) . As in other references pellets were obtained from the National Institute on Drug Abuse, but nothing is mentioned as to methods of pellet manufacture or pellet composition. As shown in this study, one-day after pellet removal naltrexone-treated animals displayed an enhanced response of the synthesis of ' dopamine (DA) , and that naltrexone removal after ten days showed no effect on morphine-induced changes to DA synthesis and locomotor activity to indicate that supersensitivity to morphine is transient.

GREELY et al . , Psyche-pharmacology, 96:36-39 (1988) also examined the effects of pellet implantation of opiate antagonists naloxone and naltrexone, and of chronic administration of naloxone by subcutaneous injections in rats. In this study, 50 mg pellets of naloxone and naltrexone were employed containing 10 mg naloxone or naltrexone as base (significantly low compared to human dosages of 1000 mg or more) . Procedures for manufacturing these pellets or their exact composition were not revealed. The results of this study were said to show that repeated painful stimulation results in analgesia in rats treated with an opiate antagonist.

In YAMAGUCHI et al . , Journal of Controlled Release, 19:299-314 (1992), a study was performed with subcutaneous implantation of naltrexone sustained release preparations such as naltrexone-containing beads and microspheres in rats and rabbits to evaluate tissue rejection. As in other references discussed herein, the beads and microspheres were obtained from the National Institute of Drug Abuse and are said to based on a matrix of poly- (L (+) -lactic-co-glycolic acid, a composition found unacceptable for use in humans by CHIANG, infra . This study concluded that all of the tested implantable materials caused inflammatory responses .

In another rat-based study, HEMENDRA et al . , Gen . Pharmac , 25 (1) : 149-155 (1994), showed the effects of pellets containing 10 or 30 mg of naltrexone base implanted for up to seven days on the development of tolerance and physical dependence on morphine in rats. Again, naltrexone pellets used in this study were obtained from the National Institute on Drug Abuse, but the reference is silent as to method for pellet production and composition. As concluded in this study, when left intact, naltrexone pellet implantation prevents naltrexone-induced decrease in body temperature, and increase in fecal and urinary output and inhibits body weight loss during abrupt withdrawal. The results are said to show that a single pellet of 10 mg of naltrexone can effectively block morphine tolerance and physical dependence in rats, and that such a procedure may be useful in studying biochemical, endocrinological, and immunological mechanisms involved in opiate addiction processes.

Other animal-based studies are REUNING et al . , J. of Pharmakinetics and Biopharmaceutics, 11 (4) : 369-387 (1983) (naltrexone-containing lactic acid/glycolic acid copolymer beads subcutaneously implanted in monkeys); SHARON et al . , Research Monograph 28, National Institute on Drug Abuse (1980) (polylactic-co-glycolic acid bead-containing naltrexone implanted in mice); and HARRIGAN et al . , Naltrexone Research Monograph 28, National Institute on Drug Abuse (1980) (naltrexone 75/25 dipalmitin/tripalmitin matrix rods, naltrexone/disodium carbonate/chronomer rods, and naltrexone lactic acid glycolic acid and copolymer beads implanted in monkeys ) . None of the aforementioned studies, however, provide any teaching or guidance for the expectation of successful treatment of opiate-addicted humans with a subcutaneously implantable antagonist-containing pellet. Indeed, studies undertaken with subcutaneous administration of naltrexone-containing beads in opiate- addicted humans have been shown to be unacceptable for clinical treatment. In CHIANG et al . , "Clinical Evaluation of a Naltrexone Sustained-Release Preparation", Drug and Alcohol Dependence, 16:1-8 (1985), beads composed of copolymers of lactic acid and glycolic acids containing 70% naltrexone were administered (30 or more at a time) for periods of from 2-4 weeks in male humans. To minimize tissue reactions, the beads were dispersed in a circle of 2 inches in diameter of the implantation site. As concluded in this study, the results were thought to indicate that a sustained-release dosage which is capable of maintaining a constant naltrexone plasma level for one month can be clinically useful if sufficient plasma levels of naltrexone are sustained. Unfortunately, however, it was also concluded that the use of the lactic acid-glycolic acid bead dosage form was precluded from clinical usefulness in humans due to the incidence of tissue irritations of the naltrexone-containing beads. As further projected, it was thought that the results of this study would be useful in the development of an as yet unidentified, improved delivery system which is biocompatible and suitable for clinical use for the treatment of narcotic addiction.

See also, for example, CHIANG et al . , "Implantable Narcotic Antagonists : A Possible New Treatment for Narcotic Addiction", Psychopharmacology Bulletin 21 (3 ): 672-675 (1985), also reporting the results of implantable naltrexone- containing beads or spheres composed of copolymers of lactic acid and glycolic acid, and which also concludes that the incidence of tissue irritation excludes clinical use of this bead dosage form. In a recent CHIANG et al . study, "Medications development for the treatment of pregnant addicts and their infants", NIDA Research Monograph 149 (1995), bioerodible polymer technology involving implantable/injectable matrices to administer drugs are discussed. Again, despite attempts by several earlier studies (see ATKINS et al . , "An injectable 30-day naltrexone delivery system", Proc . Intern Symp . Control Rel . Bioact Mater 19:54 (1992); CHIANG et al . (1985) supra ; MAA et al . , "Controlled release of naltrexone pamoate from linear poly (ortho) esters", J. Controlled Rel . 14:21-28 (1990); ROSKOS et al . , "A Morphine-Triggered Delivery System in the Treatment of Heroin Addiction", Clin . Mat . 13:109-119 (1993); and HELLER et al . , "Recent developments in the synthesis and utilization of poly (ortho) esters " , J^". Control Release 16:3-14 (1991) ) , and others currently working on 30-day naltrexone delivery systems, none are clinically useful, and more research is necessary before a bioerodible drug delivery system for drug addiction can be commercialized.

The disappointing results of the CHIANG et al . studies ending in non-clinically useful subcutaneous dosage forms are not surprising in that adverse reactions of naltrexone leading to limited acceptance of the drug as a treatment for opiate-dependent persons had been earlier predicted. See HOLLISTER et al., "Adverse effects of Naltrexone in Subjects Not Dependent on Opiates", Drug and Alcohol Dependence, 8:37-41 (1981).

The CHIANG et al . naltrexone bead implants are further undesirable in that their manufacture is relatively complex and excessively costly. Recently, U.S. Patent No. 5,486,362 has disclosed a subcutaneous implantable drug delivery system said to useful for treating nicotine-addicted individuals which consists of a physical constraint modulation system ("PCMS") containing a drug substitute such as lobeline, a substituted piperidine compound obtained from dried leaves of the Indian tobacco herb Lobelia inflata . Lobeline is said to produce physiological effects similar to nicotine and thus is an effective nicotine substitute which assists individuals in lessening addiction to nicotine, albeit with some undesirable side effects. Other drug substitutes said to be deliverable include the opiate antagonist naltrexone. The PCMS system which contains and delivers the drug substitute is a biodegradable polymer suitable for subcutaneous injections, preferably microparticles suspended in a pharmaceutically acceptable vehicle just prior to subcutaneous injection to avoid the undesirable release of significant amounts of the drug substitute into the vehicle. Examples of polymers said to be preferred for use in the delivery system include poly (lactic/glycolic) and copolymers, which as shown above, have been found to be unacceptable forms for clinical delivery of naltrexone in the CHIANG studies.

In view of the above, an important need therefore exists for a time-lapse release of an antagonist which can be subcutaneously implanted in humans to provide therapeutic levels of antagonist to patients over extended periods of time to successfully treat various addictions.

Summary of the Invention

One aspect of the present invention comprises the placement of a subcutaneously implantable opiate antagonist in a patient in which the antagonist is effective as a self- sustaining delivery mechanism for its own dissolution and for delivery over a desired extended period of time to effectively block the effects of heroin and/or other opiates, thus eliminating the craving response of addicts, and preventing re-addiction. The inventive implant is also useful in blocking the positive reinforcement from a number of other addictive substances including cocaine, alcohol, and nicotine. The inventive opiate antagonist implant is effective to maintain sufficiently high levels of an opiate antagonist in a detoxified patient for an extended period of time, preferably at least about thirty days and more, in order to prevent a former addict from relapsing.

The implant, which comprises an admixture of an opiate antagonist and a pharmaceutically acceptable carrier, is manufactured by compressing the admixture, preferably uniformly, into a subcutaneously implantable pellet containing antagonist in concentrated form, wherein such compressed admixture is effective to deliver therapeutically effective levels of an opiate antagonist when subcutaneously implanted over an extended period of time in a patient, for example, up to thirty days and longer.

This invention will be more fully described in the following detailed description of preferred embodiments, and accompanying examples.

Detailed Description of the Preferred Embodiments

The present invention provides an opiate antagonist implant in the form of a pellet in which the active ingredient antagonist is present in concentrated form as a self- sustaining delivery mechanism for its own dissolution and for delivering an effective amount of an opiate antagonist over a prolonged or extended period of time, preferably in excess of thirty days or more . The implant is adapted to be implanted subcutaneously. The opiate antagonist implant comprises an admixture of an opiate antagonist and a pharmaceutically acceptable carrier, and is prepared by compressing the admixture into a subcutaneously implantable pellet containing antagonist in concentrated form as more fully described hereinbelow. While implanted in a patient, the pellet dissolves, releasing amounts of opiate antagonist effective to block the effects of opiates on the human nervous system, and is effective in inhibiting the effects of endogenous, exogenous, synthetic and natural opiates, and is also effective in inhibiting the effects of a number of other addictive substances including cocaine, alcohol and nicotine.

The present inventive implants, which are comprised of compressed antagonist compounds and a pharmaceutically acceptable carrier or filler, advantageously avoids the use of conventional complex copolymer delivery systems, polymer matrices, encapsulating agents and other expensive and complex time-release agents, which have been found to produce unacceptable complications in humans in earlier studies. The inventive implants are easily manufactured with active ingredient antagonist in concentrated form for direct subcutaneous implantation in humans to treat addiction and to prevent various re-addiction.

A variety of opiate antagonists can be utilized in the implants of this invention. Representative examples of such opiate antagonists include, but are not limited to, naltrexone, naloxone, cyclazocine, diprenorphine , metazocine, levalorphan, metazocine, nalorphine, nalmefene, and salts thereqf . The preferred opiate antagonist is naltrexone, which has received FDA approval for use in humans and has been shown to be free of severe side-effects. Naltrexone is neither addicting nor habit forming.

Any pharmaceutically acceptable carrier or filler may be used in accordance with this invention, including without limitation, magnesium stearate, stearic acid, starch, and cellulose. The preferred carrier is magnesium stearate which is often used as both a lubricant and a binder in tablets .

The respective amounts of antagonist and binder may vary from about 0.01% antagonist/99.9% binder to 99.9% antagonist/0.01% binder, with the preferred antagonist range being from about 45% wt to about 95% wt with the remainder carrier or filler material binder.

A preferred embodiment for manuf cturing the inventive opiate antagonist implant, illustrating naltrexone as the opiate antagonist and magnesium stearate as the carrier, is described in Example I below. It is to be understood however, that this Example is for illustrative purposes only and is not intended to limit the scope of this invention or the claims in any way.

EXAMPLE I: PREPARATION A quantity of naltrexone hydrochloric acid is mixed with purified water in the ratio of 1 gram of naltrexone HCL for every 3 ml of water in order to obtain a slurry. A 10% sodium hydroxide solution is then added to and mixed with the slurry in a ratio of 1.06 ml for every gram of naltrexone HCL in the slurry.

Thereafter, the liquid from the slurry is filtered off using conventional filtering techniques to obtain a solid residue of naltrexone. The residue is then placed between layers of filter paper. The layers of filter paper are pressed in order to absorb excess moisture from the residue. The thus obtained naltrexone product is then dried by heating the same for approximately 24 hours at a constant temperature of approximately 50°C (120°F) to obtain a partially dried naltrexone cake. The naltrexone cake is then broken into smaller pieces and subjected to further drying by heating the same for an additional 24 to 48 hours at a constant temperature of approximately 50°C (120°F) . In an alternative embodiment, naltrexone base can be employed initially instead of converting naltrexone HCL to the naltrexone base. The dried naltrexone is then triturated in order to reduce the particle size. Magnesium stearate carrier is then mixed with the naltrexone in a ratio of 1 mg of magnesium stearate for every 15 mg of naltrexone. The resultant mixture is then dried by heating the same for 24 hours at a constant temperature of 50°C (120°F) and then triturated to obtain a homogenous mixture .

Once dried, the naltrexone and magnesium stearate mixture is uniformly compressed into pellets of equal density. This is preferably accomplished by using a hand operated pellet press such as the Parr Pellet Press, Model # Parr. To obtain a pellet of one preferred size, approximately 1.079 grams of the naltrexone/magnesium stearate 15:1 mix is weighed out and then pressed using a 1/2" die and punch. The pellet press used preferably applies approximately 1000 psi of pressure on the punch which causes a firm pellet having a homogenous density to be formed. The resulting implantable pellet is preferably cylindrical in shape, has a diameter of approximately 13 mm, has a length of 8 mm, weighs approximately 1.04 grams, has a naltrexone content of approximately 1.006 grams and has a hardness in the range of about 12.5 to about 14.0 kiloponds. In accordance with a preferred embodiment of the invention, a pellet having such properties is expected to deliver therapeutically effective amounts of naltrexone in a patient in which the pellet has been subcutaneously implanted for approximately one month or longer to effectively inhibit the effects of a number of addictive drugs including heroin, cocaine, alcohol, and nicotine . Once the pellet is removed from the press, it is preferably placed in a 7.5 cm (3") x 10 cm (4") Mylar pouch which is then heat sealed.^' The pellet is then preferably gamma irradiated at a minimum of 3 kilogray and a maximum of 6 kilogray of radiation.

EXAMPLE II: CLINICAL USE

In use, the pelletized opiate antagonist can be subcutaneously implanted in an addict as part of a detoxification program or once a patient has completed a detoxification program. Once implanted, opiate antagonist will be released into the patient's bloodstream for an extended period of time.

Such time will depend on the size of the pellet inserted in addition to the type and the percentage of the opiate antagonist contained therein. For example, a pellet comprising approximately 95% naltrexone, which is approximately 8 mm long and has a diameter of approximately 13 mm, will supply therapeutic amounts of the opiate antagonist for up to one month or longer. The delivery of sufficient levels of the opiate antagonist in the patient eliminates the mood-altering effects of any opiate that the patient takes, and will help to maintain sobriety while the patient seeks counseling. It has also been discovered that the implant is also useful in eliminating the mood-altering effects of cocaine, alcohol, and nicotine. To increase the period of time in which naltrexone will be effectively delivered into a patient's bloodstream and to effectively block the positive reinforcement from the particular drug, larger pellets may be manufactured and implanted.

The following Table I summarizes the effect of therapeutically effective blocking normally lethal does of 5 cc of Fetanyl IV on eight patients subcutaneously implanted with a compressed a pelletized opiate antagonist composition of the present invention.

TABLE I : Fentanyl Challenges Post -Implant

EXAMPLE III: RELAPSE STUDIES

Relapse is common after detoxification. Naltrexone maintenance therapy has been used to decrease the incidence of relapse but requires (1) a period of abstinence after detoxification and (2) compliance with the medical regimen. Detoxification under general anesthesia eliminates the need for a period of abstinence. This study evaluates the effectiveness of the inventive depot naltrexone preparation to eliminate non-compliance with the medical regimen after detoxification under general anesthesia.

Two randomly selected sequential groups of opiate addicts were chose from a population of 952 patients (mean age 36, 75% male) who underwent opiate reversal under general anesthesia (ORGA) with immediate initiation of naltrexone maintenance therapy. The first group (ONM) received naltrexone maintenance therapy by oral administration of 50 mgs of naltrexone per day. The second group (DNM) received naltrexone maintenance through a depot naltrexone preparation containing 1000 mgs of naltrexone per month, via a pellet implant used in Table I.

There were 434 patients in the ONM group and 199 patients in the DNM populations with respect to age, sex, type of opiate use or amount of use.

Telephone follow-up was attempted for 633 patients. Because a large number of the total populations were not available for follow-up, comparative analysis of those using opiates for the two populations (DNM versus ONM) were made in three ways with the following results; namely (1) excluding those who could not be contacted -- 19% versus 44% with x2 = 14.06 (very significant); (2) assuming all those not contacted were using at one month after opiate reversal -- 50% versus 54% with x2 = 0.76 (not significant), and (3) assuming all those not contacted were clean one month after opiate reversal -- 9% versus 14% with x2 = 18.5 (very significant) . The results of this study show that the subcutaneously implantable naltrexone-containing pellets of this invention decreased relapse significantly immediately post-detoxification from opiates.

The present invention may be embodied in other specific forms without departing from the spirit or essential attributes thereof. Accordingly, reference should be made to the appended claims rather than the foregoing specification as indicating the scope of the invention.

Claims

CLAIMSWhat is claimed is :

1. An opiate antagonist implant comprising an admixture of an opiate antagonist and a pharmaceutically acceptable carrier, said admixture being compressed into a subcutaneously implantable pellet, wherein said implantable pellet is effective to release said opiate antagonist over time when subcutaneously implanted in humans in need thereof.

2. The opiate antagonist implant of claim 1 wherein said implant is effective to release levels of said opiate antagonist over an extended period of time when subcutaneously implanted in humans in need thereof.

3. The opiate antagonist implant of claim 2 where said extended period of time is at least approximately 30 days .

4. The opiate antagonist of claim 1 wherein said opiate antagonist is selected from the group consisting of an endogenous, exogenous, synthetic and natural opiate antagonist .

5. The opiate antagonist implant of claim 1 wherein said opiate antagonist is selected from the group consisting of naltrexone, naloxone, nalmefene, cyclazocine, diprenorphine, metazocine, levalorphan, metazocine, nalorphine, and salts thereof.

6. The opiate antagonist implant of claim 1 wherein said pharmaceutically acceptable carrier is magnesium stearate .

7. The opiate antagonist implant of claim 1 wherein said subcutaneously implantable pellet is cylindrical in shape, is approximately 8 mm long and has a diameter of approximately 13 mm.

8. The opiate antagonist implant of claim 1 wherein said opiate antagonist comprises from about 0.01% to about 99.9% of the implant by weight.

9. The opiate antagonist implant of claim 1 wherein said opiate antagonist comprises from about 45% to about 95% of the implant by weight.

10. The opiate antagonist implant of claim 1 wherein said subcutaneously implantable pellet has a hardness of in the range of about 12 to about 15 kiloponds .

11. A process of manufacturing an opiate antagonist implant comprising compressing a therapeutically effective amount of an opiate antagonist with a pharmaceutically acceptable carrier.

12. The process of claim 11 wherein the amount of said compression produces an implant which is effective to release said opiate antagonist in therapeutically effective amounts for at least about 30 days or longer.

13. The process of claim 11 wherein said implant has a moisture content which is effective to release said opiate antagonist in therapeutically effective amounts for at least about 30 days or longer.

14. A process of manufacturing a naltrexone implant comprising the steps of:

(a) providing a quantity of naltrexone;

(b) providing a pharmaceutically acceptable carrier;

(c) admixing said pharmaceutically acceptable carrier and said naltrexone in a ratio of approximately 15 grams of said naltrexone for approximately every one gram of said pharmaceutically acceptable carrier;

(d) triturating the admixture of step (c) ;

(e) applying uniform pressure to the triturated admixture of step (d) in order to obtain a naltrexone implant in the form of a firm pellet.

15. A process for detoxifying opioid-addicted humans in need thereof comprising detoxifying said opioid-addicted humans, followed by administering opioid antagonist by inserting the opiate antagonist implant of claim 1.

16. The method of claim 14 wherein approximately 1000 psi of pressure is applied to the triturated admixture of step (d) .

17. The method of claim 14 wherein said triturated admixture of step (d) is dried for approximately 24 hours at a constant temperature of approximately 50┬░C (120┬░F).

18. A process of manufacturing a naltrexone implant comprising the steps of:

(a) providing a quantity of naltrexone HCL;

(b) providing a quantity of water; (c) admixing said quantity of water with said quantity of naltrexone HCL in a ratio of approximately 3 ml of water for approximately every one gram of naltrexone HCL until a slurry is obtained; (d) providing a quantity of 10% sodium hydroxide solution;

(e) admixing said quantity of 10% sodium hydroxide solution to said slurry of step (c) in the ratio of approximately 1 ml of sodium hydroxide for approximately every one gram of naltrexone HCL;

(f) filtering off any liquid from said slurry to obtain a solid residue of naltrexone;

(g) drying said residue of naltrexone for approximately 24 to approximately 72 hours at a constant temperature of 50┬░C (120┬░F) ;

(h) providing a pharmaceutically acceptable carrier;

(i) admixing said pharmaceutically acceptable carrier and said naltrexone in a ratio of approximately 15 grams of said naltrexone for approximately every one gram of said pharmaceutically acceptable carrier;

(j) triturating said admixture of step (i), and (k) applying uniform pressure to said triturated admixture of step (j) in order to obtain a naltrexone implant in the form of a firm pellet.

19. The method of claim 18 wherein approximately 1000 psi of pressure is applied to the triturated admixture of step ( j ) .

20. A method for administering predetermined, effective amounts of an opiate antagonist from an implant to a human which comprises subcutaneously implanting the implant of claim 1 in a human so that the human receives controlled amounts of said opiate antagonist for an extended period of time .

21. The method of claim 20 wherein said implant comprises said opiate antagonist in an amount of approximately 95% by weight and said pharmaceutically acceptable carrier in an amount of approximately 5% by weight.

22. The method of claim 20 wherein said opiate antagonist is selected from the group consisting of naltrexone, naloxone, nalmefene, cyclazocine, diprenorphine , etazocine, levalorphan, metazocine, nalorphine, and salts thereof.

23. The method of claim 20 wherein said pharmaceutically acceptable carrier is magnesium stearate.

24. The method of claim 20 wherein said extended period of time is at least approximately 30 days.

25. A method of treating an opiate addicted patient for opiate addiction comprising administering subcutaneously an opiate antagonist implant comprising an opiate antagonist implant comprising an admixture of an opiate antagonist and a pharmaceutically acceptable carrier, said admixture being compressed into a subcutaneously implantable pellet, wherein said implantable pellet is effective to release levels of said opiate antagonist over time when subcutaneously implanted in a patient .

26. A method of using an opiate antagonist implant comprising an opiate antagonist implant comprising an admixture of an opiate antagonist and a pharmaceutically acceptable carrier, said admixture being compressed into a subcutaneously implantable pellet, wherein said implantable pellet is effective to release levels of said opiate antagonist over time when subcutaneously implanted in a patient by subcutaneously implanting said implant in a patient in need thereof .

27. A method for detoxifying opioid-addicted humans comprising, detoxifying said opioid-addicted humans followed by, administering opioid antagonist by inserting the opioid antagonist implant of claim 1.

28. A method of maintaining an abstinent state in a human from substance addiction or dependence comprising subcutaneous administration of an opioid antagonist implant of claim 1 to said human.