Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Implant or insert
Reexamination Certificate
1998-10-09
2001-03-20
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Implant or insert
C424S423000, C424S426000, C514S255030, C514S282000, C514S812000, C514S953000, C514S965000
Reexamination Certificate
active
06203813
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to pharmaceutical delivery device in which the active ingredient is a pharmaceutically active substance and is effective as a self-sustaining delivery mechanism for its own dissolution and delivery for desired extended periods of time. More particularly, this invention relates to a subcutaneously implantable pellet produced in a novel compression method to form a concentrated implantable pharmaceutically active substance, and when subcutaneously inserted in a patient will deliver an effective and desired level of pharmaceutically active substance in the patient's bloodstream, preferably in excess of thirty days or more, and more preferably up to and exceeding ninety days.
The invention further relates to a pharmaceutical delivery device in the form of 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 the desired extended periods of time. The invention also relates to such an implant in the form of a pellet produced by an inventive compression method to form an antagonist-containing subcutaneously implantable pellet which is capable of delivering an effective and desired level of antagonist in a patients bloodstream over desired extended period, preferably exceeding ninety days and longer.
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 quilt 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. Thus, it has been said that rehabilitation of the patient is the first target. (Brewer,
Addiction Biology:
2, 291-303 (1997)).
One solution for improving patient compliance and concomitant rehabilitation 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.,
Psychopharmacology,
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
Channavajjala Lakshmi
Lerner David Littenberg Krumholz & Mentlik LLP
Page Thurman K.
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