Injectable naltrexone microsphere compositions and their use...

Details Injectable naltrexone microsphere compositions and their use... Injectable naltrexone microsphere compositions and their use...

2000-04-07

2001-10-23

Fubara, Blessing (Department: 1615)

Drug, bio-affecting and body treating compositions

Preparations characterized by special physical form

Implant or insert

C424S400000, C424S486000, C424S489000, C514S872000, C514S811000, C514S772300, C514S812000, C514S964000

Reexamination Certificate

active

06306425

ABSTRACT:

INTRODUCTION
Background
The disease of substance abuse remains a scourge on society. As it becomes more evident that there is a substantial genetic contribution to becoming addicted, helping addicted individuals to terminate their dependency or at least achieve a level of becoming a functional member of society, rather than treating substance abuse as a moral issue, has become increasingly accepted policy. Various programs have been put in place in the public and private sectors. In the private sectors, there are such organizations as Alcoholics Anonymous and Narcotics Anonymous, which play an important role in psycho-social support. In addition there are many private clinics which serve to provide both psycho-social support and medicinal support, using the somewhat limited repertoire of drugs which are available. In the public arena, there are the extensive programs to bring to the attention of young people and parents the hazards of substance abuse and discourage the young people from embarking on drug use. Also, there are the methadone programs, which are primarily public supported.
The number of substance abusing subjects in the United States is quite staggering. There are estimated to be about 15 million people who abuse alcohol, about 1.3 million who abuse cocaine in its many manifestations, about 0.8 million who abuse amphetamines and about 0.5-0.8 million who abuse heroin, in addition to the use of other drugs, such as the psychedelic drugs. Efforts to reduce the numbers of scheduled substances and alcohol users have been continuous and relatively unavailing. Those subjects who have entered programs have had a dismal record of relapse, so that only a small proportion of the people who do enter programs and are retained in the programs remain clean long after the completion of the program.
One significant factor in lack of retention and relapse is compliance. A repetitive act, such as taking a pill daily, is not a simple matter, even where the subject has no qualms about taking the pill. With the substance abuser, who may have physiological and emotional needs for the abused substance, the sustaining of the therapeutic routine is substantially more difficult. Therapeutic techniques, which require perseverance on the part of the subject, decrease the likelihood of success of the treatment. It is therefore of great importance to be able to reduce the level of involvement of the subject where medicinal treatments are involved, particularly treatments, which may involve frequent scheduling, monitoring of compliance, and sustaining a particular regimen.
In order to reduce the vicissitudes of compliance, there have been efforts to provide sustained-release methodologies. These have involved pumps, patches, depots and the like. Where the release implement is accessible to the subject, there is always the temptation to remove the implement during a craving episode. This opportunity, which may be an indication of will power, nevertheless, puts the subject at risk that succumbs to the temptation. By providing for a slow-release medicament, which is introduced into the body, the temptation is avoided and the drug is released in accordance with a predetermined schedule over an arranged period of time. One can have implantable rods, which are introduced surgically and must be removed surgically or microspheres, which are injectable and are devised to release the drug over an extended period of time in a controlled manner.
Various slow-release microspheres (or microparticles) have been developed for a variety of drugs, a few have been commercialized. There are many constraints on a satisfactory slow-release injectable formulation: the release of the drug must be over an extended period of time; during the time of treatment, the level of drug maintained in the subject must be an effective level, without reaching any hazardous level; the drug must be released slowly without a catastrophic dumping of the drug; the polymeric matrix used for the microspheres must be biocompatible and biodegradable; any residual chemicals must be below the maximum acceptable level; the microspheres must be small and capable of being delivered by a syringe with a needle which is acceptable to patients; the results must be reproducible, which requires that the process can be accurately controlled and is not unduly sensitive to minor changes in conditions; the injectable formulation must be capable of being sterilized; the metabolites that are produced must be acceptable levels; as well as other characteristics which may be general or specific to the particular medicament. The properties of the microspheres are sensitive to many properties of the drug and matrix, as well as the selection of the process and the conditions under which the microspheres are prepared and subsequently processed.
BRIEF DESCRIPTION OF THE PRIOR ART
Krantzler, et al., Alcoholism: Clin and Exp Res 1998, 22:1074-1079 report the treatment of alcoholics with a slow-release naltrexone particle injectable formulation. A number of studies were carried out by Reuning's laboratory concerning naltrexone and its use in a slow-release form: Reuning, et al., NIDA Re: Monograph Series, January 1976, (4) p43-5; Reuning et al., J. Pharmacokinet Biopharm, August 1983, 11 (4), p369-87; Reuning, et al., Drug Metab Dispos November-December 1989, 17(6) p583-9; MacGregor et al., J. Pharm Pharmacol, January 1983, 35(1) p38-42; Reuning et al., NIDA Res Monograph Series 1980, 28, p172-84. See also, Schwope et al., NIDA Res Monograph Series, 1975, (4), p13-8; Yolles et al., J Pharm Sci Febuary 1975, 64(2) p348-9; Thies, NIDA Res Monograph Series, 1975 (4), p19-20; Schwope et al., NIDA Res Monograph Series, January 1976, 4, p13-18; Chiang et al., Clin Pharmacol Ther Nov. 1984 36(5) p704-8; Pitt et al., NIDA Res Monograph Series 1981, 28, p232-53; Chiang et al., Drug Alcohol Depend (SWITZERLAND), September 1985, 16 (1) p1-8; Yoburn et al., J. Pharmacol Exp Ther, April 1986, 237 (1) p126-130; Cha and Pitt, J. Control Release, 1989, 8(3), p259-265; Yamaguchi and Anderson, J. Control Release, 1992, 19(1-3), p299-314.
The use of naltrexone in the treatment of alcoholism is described in O'Malley et al., Psychiatric Annals, November 1995, 11, p681-688, as well as numerous other publications.
Patents of interest include U.S. Pat. Nos. 4,568,559; 4,623,588; 4,897,267; and 5,486,362. U.S. Pat. No. 5,407,609 describes a process applicable to the process employed in the subject invention.
The use of polylactide in the preparation of drug containing microspheres is described in Benita et al., J Pharm Sci, December 1984, 73(12) p1271-4; Speniehauer et al., ibid, August 1986, 75(8), p 750-5; and Nihant et al., October 1994, 11(10), p1479-84.
SUMMARY OF THE INVENTION
Injectable, slow-release naltrexone formulations are provided comprising a therapeutically effective amount of naltrexone released over an extended period of time and a matrix consisting of the polymer poly(D,L-lactide). The microspheres are under 100 &mgr;m in diameter and can be readily injected intramuscularly. Different release profiles are obtained depending upon the molecular weight of the polymer, molecular-weight homogeneity of the polymer, matrix size of the microspheres, and the weight percentage of naltrexone. The microspheres are prepared by solvent extraction of a oil-in-water emulsion, the dispersed oil phase being an organic solution of naltrexone and the polymer.
DESCRIPTION OF THE SPECIFIC EMBODIMENTS
Injectable, slow-release naltrexone formulations are provided for use in the treatment of alcoholics and heroin addicts and such other indications for which naltrexone has been found to be efficacious. Small sterilized particles, microspheres, are provided which can pass through a syringe needle and be administered intramuscularly and remain at the site of injection for an extended period of time, while continuously releasing and maintaining a therapeutically effective amount of naltrexone for at least about 28 days. The release profile is found to be sensitive to the amount of naltrexone

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