Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Nitrogen containing other than solely as a nitrogen in an...
Reexamination Certificate
2000-03-03
2002-11-12
Dees, Jose G. (Department: 1616)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Nitrogen containing other than solely as a nitrogen in an...
C424S451000, C424S457000, C424S458000, C424S464000, C424S468000, C424S472000, C514S406000, C514S569000, C514S570000, C514S576000, C514S577000, C514S608000, C514S617000, C514S646000, C514S709000, C514S716000, C514S717000, C514S721000, C514S964000
Reexamination Certificate
active
06479551
ABSTRACT:
FIELD OF THE INVENTION
The present invention is directed to compositions comprising metoclopramide and a second drug, particularly an analgesic. These compositions may be used as a treatment for migraine and other disorders.
BACKGROUND
Migraine is a painful syndrome characterized by unilateral, pulsating headaches, nausea, vomiting, and sensitivity to light and sound. Approximately 23 million Americans presently suffer from this disorder. Drugs that have been used in an attempt to treat migraine include: ergotamine and ergotamine-like agents; serotonin agonists; and caffeine with ergots or other pharmacologic agents (see e.g., Silberstein, S. D.,
Curr. Opinion Neurology
7:258-263 (1994); Welch, K. M. A.,
New Engl J. Med
. 329:1476-1483 (1993); Kumar, K. L.,
J. Gen. Int. Med
. 9:339-348 (1994); Saadah, H.,
Headache
32:95-97 (1992); and Becker,
Arzneimittelforshung
42(4):552-555 (1992)). All of these drugs are thought to initially relieve migraine-associated pain by causing vasoconstriction. Unfortunately, this leads to numerous side effects such as chest pain or pressure, flushing, generalized tingling sensations, nausea, vomiting, pain in the legs and arms, asthenia, drowsiness, and dizziness. Acute ergotism is a particularly pernicious side effect of ergot drugs and is characterized by severe central and peripheral vasoconstriction, nausea, vomiting, diarrhea, colic, headache, vertigo, paresthesia, and possibly convulsive seizures.
Patients have, on occasion, found total or partial relief for some forms of migraine through the use of non-prescription analgesics. As outlined by Welch (
New Engl J. Med
. 329: 1476-1483 (1993)), the initial dosages of such analgesics are typically: aspirin, 500-650 mg; acetaminophen, 500 mg; naproxen sodium, 750-825 mg; tolfenamic acid, 200-400 mg; and, ibuprofen 200 mg. After oral dosing, peak plasma concentrations in normal subjects usually occur at about 1 hour for aspirin and acetaminophen, and between 1 and 2 hours for naproxen sodium, tolfenamic acid, and ibuprofen. However, the absorption of these and other agents during a migraine attack has been shown to be impaired, apparently due to gastric stasis.
Ideally a migraine drug formulation should be nonaddictive and free of vasoactive agents (i.e. agents causing the constriction or dilation of blood vessels). This requires the exclusion of ergots, serotonin agonists such as sumatriptan (including related 5 HT agonist heterocyclic compounds as described in U.S. Pat. No. 4,816,470) and caffeine. The formulation should relieve pain, reduce gastric stasis, reduce nausea, and allow for a faster rate of drug absorption.
Metoclopramide is a drug known to relieve migraine-associated nausea when administered at a minimum oral dose of 10 mg. Poyser et al. have described a formulation in which aspirin is uniformly intermixed with metoclopramide (U.S. Pat. No. 4,380,540). One drawback of this formulation is that it undergoes unacceptable degradation in a matter of two to three weeks at ambient temperatures. In addition, aspirin is known to have a very short plasma half life. New formulations of metoclopramide that are effective in treating migraine headache and that avoid the disadvantages of this and other previously disclosed preparations would represent a clear advance in the art.
SUMMARY OF THE INVENTION
The present invention is based upon the discovery of improved formulations for the treatment of migraine headache. The formulations contain a combination of metoclopramide and one or more analgesics (preferably NSAIDs) and are prepared in such a manner as to avoid the loss of activity that has been observed to sometimes accompany such formulations. In particular, it has been discovered that loss of activity occurs when an acidic analgesic is in prolonged contact with metoclopramide. Thus, compositions that utilize non-acidic analgesics (i.e., analgesics having a pK
a
of 7 or above when dissolved in water) or in which metoclopramide and analgesic are separated offer substantial advantages. In addition, new dosage forms have been developed that have improved therapeutic characteristics. Specifically, improved absorption of drug has been accomplished using “coordinated” dosage forms in which metoclopramide and NSAID are sequentially delivered. Improved characteristics may also be obtained by using long-acting analgesics or analgesics that are formulated to be long acting.
In its first aspect, the present invention is directed to a pharmaceutical composition in unit dosage form suitable for oral administration in the treatment of migraine headache. The dosage form contains metoclopramide in an amount effective to increase gastric motility in a patient suffering from a migraine attack and a non-acidic analgesic (preferably a non-acidic NSAID) in an amount effective to reduce or eliminate headache pain. Preferably, the dosage form should be either a tablet or capsule and should be free from vasoactive agents, including 5 HT agonist vasoactive agents. The dosage form may be coordinated for the sequential delivery of drugs and may incorporate long-acting NSAIDs, including cyclooxygenase-2 inhibitors. Alternatively, the dosage form may contain analgesics formulated to be long acting. The most preferred non-acidic NSAID is Celecoxib (Celebrex®), typically in an amount of between 25 and 250 mg. It is desirable that sufficient metoclopramide be present to reduce or eliminate the nausea associated with migraine headache. Typically, a dosage form will have between 1 mg and 100 mg of metoclopramide.
In a second aspect, the invention is directed to a pharmaceutical composition in unit dosage form that has been acid-base storage stabilized. Metoclopramide and one or more analgesics (preferably NSAIDs) are present in an amount such that their combination is effective in reducing or eliminating headache pain. Acid-base storage stabilization is accomplished by constructing dosage forms in a manner that eliminates or minimizes contact between the drugs during storage. For example, tablets or capsules may be made in which either metoclopramide or analgesic is barrier coated. Alternatively, metoclopramide and analgesic may be in separate layers of a multilayer tablet. Dosage forms should typically be free of vasoactive agents, may be coordinated and may contain either long-acting NSAIDs or NSAIDs formulated to be long acting. Typical NSAIDs that may be used include: acetaminophen; ibuprofen; flurbiprofen; ketoprofen; naproxen; oxaprozin; etodolac; indomethacin; ketorolac; nabumetane; piroxicam; celecoxib; rofecoxib; meloxicam; JTE-522; L-745,337; NS398; and pharmaceutically acceptable salts thereof. The most preferred analgesic is naproxen. This should be present at between 50 mg and 1500 mg and preferably at between 200 and 600 mg. Although any form of naproxen is compatible with the invention, naproxen sodium is generally preferred.
More generally, the present invention encompasses pharmaceutical compositions in unit dosage form that contain at least one analgesic (preferably an NSAID) in combination with metoclopramide and which are either coordinated or in which at least one analgesic is long acting or formulated to be long acting. In all cases, the combination of drugs should be effective to reduce or eliminate headache pain. Long acting NSAIDs suitable for use in the dosage forms include: ibuprofen; flurbiprofen; ketoprofen; oxaprozin; etodolac; indomethacin; ketorolac; nabumetane; piroxicam; celecoxib; rofecoxib; meloxicam; JTE-522; L-745,337; NS398; or pharmaceutically acceptable salts thereof When naproxen, the preferred analgesic, is used, it should be present in an amount of between 50 and 1500 mg and preferably between 200 and 600 mg. The sodium salt of naproxen is generally preferred. Analgesics that may be formulated to be long acting include ibuprofen, aspirin and acetaminophen. Methods for making appropriate long acting formulations for these and other analgesics are well known in the art (see, e.g.,
Remington's Pharmaceutical Sciences
, 16th ed., A. Oslo editor, Easton Pa. (1980); Control
Chowhan Zakauddin T.
Plachetka John R.
Choi Frank
Dees Jos,e G.
Fitch Even Tabin & Flannery
Pozen Inc.
Sanzo Michael A.
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