Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Web – sheet or filament bases; compositions of bandages; or...
Reexamination Certificate
2001-02-08
2004-04-06
Russel, Jeffrey E. (Department: 1654)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Web, sheet or filament bases; compositions of bandages; or...
C604S304000, C604S890100
Reexamination Certificate
active
06716449
ABSTRACT:
BACKGROUND OF THE INVENTION
Opioids, also known as opioid agonists, are a group of drugs that exhibit opium or morphine-like properties. Opioid agonists are known in the literature and to those skilled in the art (Merck Manual, 16th Ed. (1992)). Because of their analgesic efficacy, opioid agonists have been used to provide pain relief to patients. Side effects are also associated with the use of opioid analgesics. For example, it has been reported that administration of opioid agonists such as morphine are associated with side effects, including nausea, vomiting, pruritis, urinary retention, and respiratory depression. Gan, et al.
Anesthesiology,
vol. 87, No. 5, 1075-1081 (1997). Chronic use of morphine has also been reported to increase physical dependence and increase tolerance of the drug, Shen et al.,
Brain Res.,
Vol. 597, 74-83 (1992), and to induce constipation.
Attempts to reduce the side effects of opioid agonists, without affecting its analgesic efficacy, have also been reported. For example, Gan, et al.
Anesthesiology,
vol. 87, No. 5, 1075-1081 (1997) report that the administration of 0.25 &mgr;g.kg-
1
.h-
1
or 1 &mgr;g.kg-
1
.h-
1
naloxone (opioid antagonist) by infusion concomitantly with intravenous morphine, was effective in reducing certain potential side effects of morphine (e.g., the incidence of nausea, vomiting and prurities).
OBJECTS AND SUMMARY OF THE INVENTION
It is an object of the invention to promote patient compliance and thereby increase the efficacy of opioid agonist treatment in patients who are being treated with opioid agonist.
It is a further object of the invention to reduce the side effects associated with opioid agonist treatment.
It is also an object of the invention to provide agonist therapy in which the analgesically effective blood levels of the opioid agonist are maintained during an extended period of time, while also maintaining the pharmacologically effective blood levels of the antagonist for reducing the side effects associated with the opioid treatment.
It is also an object of the invention to enhance the analgesic potency of an opioid agonist in controlled release form and simultaneously attenuate development of physical dependence, tolerance and other undesirable side effects caused by the chronic administration of the opioid agonist.
It is also an object of the invention to provide agonist therapy in which analgesically effective blood levels of the opioid agonist are maintained over an extended period of time, while also selectively enhancing the analgesic potency of the opioid agonist. Preferably, the selective enhancement of analgesic potency of the opioid agonist occurs while simultaneously attenuating development of physical dependence, tolerance and other undesirable side effects caused by the chronic administration of the opioid agonist.
In view of the above-mentioned objects and others, the invention is directed to a controlled release oral dosage form comprising opioid agonist and opioid antagonist, wherein the dosage form releases the opioid agonist and the antagonist in a controlled-release manner.
The invention is further directed to a controlled-release dosage form comprising an opioid agonist and the opioid antagonist, wherein the opioid agonist or the opioid antagonist, before it is combined with the other, is treated to modify its release rate, such that when combined into the controlled-release dosage form, the opioid agonist and the antagonist are released from the dosage form at appropriately similar times.
The invention is further directed to a controlled-release dosage form comprising opioid agonist and opioid antagonist, wherein the opioid agonist is present in an amount that is analgesically effective when administered to a human, and wherein the opioid antagonist is present in an amount which does not cause a reduction in the level of analgesia provided by the dosage form to a non-therapeutic level. In certain embodiments, the opioid antagonist is also present in an amount that is effective in reducing opioid-related side effects.
In certain embodiments of the present invention, the controlled release dosage form comprises a transdermal delivery system, an oral mucosal delivery system, a composition for intranasal administration, an injectable composition, and a solid oral composition.
In certain preferred embodiments, the present invention comprises a controlled release dosage form that delivers an opioid agonist and an opioid antagonist over an extended period of time. In these oral embodiments, the dosage form includes an amount of an oploid agonist, preferably a bimodally-acting opioid agonist, and an amount of an opioid antagonist, and upon administration the dosage form delivers an analgesic or sub-analgesic amount of the oploid agonist over the dosing interval, along with an amount of the opioid antagonist effective to enhance the analgesic potency of the opioid agonist and attenuate the anti-analgesia, hyperalgesia, hyperexcitability, physical dependence and/or tolerance effects of the opioid agonist.
Certain embodiments of the invention are directed to controlled-release dosage forms comprising an opioid agonist and the opioid antagonist, wherein the opioid agonist or the opioid antagonist, before it is combined with the other, is treated to modify its release rate, such that when combined into the controlled-release dosage form, the opioid agonist and the antagonist are released from the dosage form at appropriately similar times.
The present invention is also directed to the use of the above-mentioned controlled release formulations for maintenance treatment of previously detoxified opiate addicts.
In certain preferred embodiments, the opioid agonist is selected from the group consisting of hydromorphone, oxycodone, hydrocodone, morphine, pharmaceutically acceptable salts thereof and mixtures thereof.
In certain preferred embodiments, the opioid agonist is a bimodally-acting opioid agonist selected from, e.g., morphine, codeine, fentanyl analogs, pentazocine, buprenorphine, methadone, enkephalins, dynorphins, endorphins, and similarly acting opioid alkaloids and opioid peptides.
In certain preferred embodiments, the opioid antagonist is selected from the group consisting of naltrexone, naloxone, nalmefene, pharmaceutically acceptable salt thereof and mixtures thereof.
DETAILED DESCRIPTION OF THE INVENTION
The present invention is directed to controlled-release dosage forms comprising an opioid agonist and an opioid antagonist, the dosage form providing controlled-release of the opioid agonist and controlled-release of the opioid antagonist. In preferred embodiments, the release rate of the agonist and the antagonist from the dosage form are controlled to maintain an analgesically effective amount of the agonist in the blood throughout the dosing period and to maintain the concentration of the opioid antagonist throughout the dosing period sufficient for decreasing the side effects associated with the opioid agonist but not sufficient to negate the analgesic efficacy of the agonist. In preferred embodiments, the invention is directed to controlled release solid dosage forms that release an opioid agonist and an opioid antagonist over an extended period of time. In these oral embodiments, the dosage form includes an amount of an opioid agonist, preferably a biomodally-acting opioid agonist, and an amount of an opioid antagonist, and upon oral administration the dosage form releases an analgesic or sub-analgesic amount of the opioid agonist over the dosing interval, along with an amount of the opioid antagonist effective to enhance the analgesic potency of the opioid agonist and attenuate the anti-analgesia, hyperalgesia, hyperexcitability, physical dependence and/or tolerance effects of the opioid agonist.
The present invention is further directed to a controlled-release solid oral dosage form comprising an opioid agonist and an opioid antagonist, the dosage form providing controlled-release of the opioid agonist and controlled-release of the opioid antagonist, the dosage form, when adm
Oshlack Benjamin
Wright Curtis
Davidson Davidson & Kappel LLC
Euro-Celtique S.A.
Russel Jeffrey E.
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