Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Radical -xh acid – or anhydride – acid halide or salt thereof...
Reexamination Certificate
2000-02-22
2002-03-26
Criares, Theodore J. (Department: 1617)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Radical -xh acid, or anhydride, acid halide or salt thereof...
Reexamination Certificate
active
06362227
ABSTRACT:
1. FIELD OF THE INVENTION
The invention relates to methods of treating neuropathic pain, tinnitus, and other disorders, and to pharmaceutical compositions useful in the treatment of neuropathic pain and tinnitus.
2. BACKGROUND OF THE INVENTION
2.1. Ketoprofen and its Isomers
Chemically, ketoprofen is 2-(3-benzoylphenyl)-propionic acid, and has the following structure:
Racemic ketoprofen (a mixture of the R(−) and S(+) enantiomers) is sold under the tradenames Orudis® and Oruvail® for the treatment of inflammation.
Physicians Desk Reference
52
nd
Ed., p. 3092 (1998). Generally, ketoprofen is considered to be a nonsteroidal anti-inflammatory agent (“NSAID”). NSAIDs are believed to exhibit activity as COX-1 or COX-2 enzyme inhibitors. Most NSAIDs are believed to cause gastrointestinal irritation.
The S(+) enantiomer of ketoprofen has long been thought to possess most, if not all, of the pharmacological activity of the racemate. See, e.g., Yamaguchi et al.,
Nippon Yakurigaku Zasshi.
90:295-302 (1987); Abas et al.,
J. Pharinacol. Exp. Ther.,
240:637-641 (1987); and Caldwell et al.,
Biochem. Pharrnacol.
37:105-114 (1988). Indeed, U.S. Pat. Nos. 4,868,214, 4,962,124, and 4,927,854 each allege that the analgesic activity of ketoprofen resides exclusively in the S(+) enantiomer.
However, U.S. Pat. No. 5,331,000 discloses the use of the optically pure R(−) enantiomer as an antipyretic and analgesic agent to treat, with reduced gastrointestinal irritancy.
2.2. Neuropathic Pain
The effective treatment of pain requires an understanding of its physiology. It is well known, however, that stimuli which activate pain receptors in one tissue may not activate pain receptors in another. For example, pricking or cutting which causes pain in skin tissue does not cause pain in the stomach or intestine. The causes of pain in skeletal muscle, joints, and arteries can also differ.
Principles of Neurology,
6
th
ed., Adams, R. D., et al., eds. (McGraw-Hill: 1997), pp. 133-134. Consequently, methods useful for relieving one type of pain are often less effective, or even ineffective, when applied to the alleviation of others.
In general, neuropathic pain is persistent and is characterized by burning, gnawing, aching, shooting, or lancinating sensations. It is frequently associated with hyperesthesia, hyperalgesia, allodynia, and hyperpathia, and in some cases by sensory deficit or autonomic dysfunction. Unfortunately, and unlike other types of pain, neuropathic-pain tends to respond poorly to analgesic medication.
Principles of Neurology,
6
th
ed., Adams, R. D., et al., eds. (McGraw-Hill: 1997), p. 140.
Depending on the particular nerves involved, a particular instance of neuropathic pain can be classified as a central or peripheral neuropathy. Central neuropathies arise from spinal cord, brainstem, thalamic, and cerebral damage or disease, while peripheral neuropathies arise from damage or disease of peripheral nerves. Specific peripheral neuropathies include, but are not limited to: thoracic outlet obstruction syndromes; compression and entrapment neuropathies such as ulnar nerve palsey, carpal tunnel syndrome, peroneal nerve palsey, radial nerve palsey; and Guillain-Barré syndrome. The
Merck Manual,
16th ed., 1518-1522 (1992).
Neuropathic, or neurogenic, pain arises from the direct stimulation of nervous tissue. Neuropathic pain encompasses a wide variety of disorders involving single and multiple nerves. These include, but are not limited to, trigeminal neuralgia and disorders due to herpes zoster, diabetes, and trauma (including causalgia); spinal arachnoiditis and spinal cord injuries; and the thalamic pain syndrome of Déjerine-Roussy.
Principles of Neurology,
6
th
ed., Adams, R. D., et al., eds. (McGraw-Hill: 1997), p. 140.
Neuropathic pain is caused by a variety of factors including, but not limited to: trauma caused by injury or surgical operation; tumors; bony hyperostosis; casts; crutches; prolonged cramped postures; hemorrhage into a nerve; exposure to cold or radiation; collagen-vascular disorders; metabolic diseases such as diabetes; infectious diseases such as Lyme disease and HIV; toxins such as emetine, hexobarbital, barbital, chlorobutanol, sulfonamides, phenytoin, nitrofurantoin, the vinca alkaloids, heavy metals, carbon monoxide, triorthocresylphosphate, orthodinitrophenol, and other solvents and industrial poisons; autoimmune reactions; nutritional deficiency, and vitamin B deficiency in particular; and metabolic disorders such as hypothyroidism, porphyria, sarcoidosis, amyloidosis, uremia and diabetes.
The Merck Manual,
16th ed., 1518 (1992).
Because so many causes of neuropathic pain exist, and because it tends to respond poorly to analgesic medication, the discovery of drugs that safely and effectively aid in its relief has been difficult.
2.3. Tinnitus
Like neuropathic pain, tinnitus is often thought of as a subjective disorder; numerous causes have thus been postulated for it. A patient with tinnitus typically perceives a sound in the head or the ears without an evident external stimulus. Such sounds often have a buzzing, ringing, roaring, whistling, or hissing quality, or may be more complex and vary over time. Vesterager, V.,
BMJ,
314:728-31(1997).
Tinnitus can result from nearly all ear disorders, including, but not limited to: obstruction of the external auditory canal; infectious processes such as external otitis, myrignitis, otitis media, labyrinthitis, petrositis, syphilis and meningitis; eustachian tube obstruction; otosclerosis; middle ear neoplasms such as the glomus tympanicum and glomus jugulare tumors; Meniere's disease; arachnoiditis; cerebellopontine angle tumors; cardiovascular diseases such as hypertension, arteriosclerosis and aneurysms; anemia; hypothyroidism; hereditary sensorineural or noise-induced hearing loss; and acoustic trauma.
The Merck Manual,
16th ed., 2324 (1992). Tinnitus can also result from ototoxicity caused by acute intoxication or long-term administration or exposure to salicylates, quinine and its synthetic analogues, aminoglycoside antibiotics, diuretics, carbon monoxide, heavy metals, and other drugs or toxins. Seligmann, H., et al.,
Drug Safety
14(3):198-212 (1996). Psychological causes have also been suggested. Vesterager, V.,
BMJ,
314:728-31 (1997).
The biological mechanism which causes or relates to tinnitus remains unclear. Some researchers have suggested that it may result from a decrease of the normal GABAergic inhibitory influence of neurons in the inferior colliculus. Møller, A. R.,
Am. J. Otology,
18:577-585 (1997). Others have argued that the disorder results from pathological changes of neurons within the inner ear. See, e.g., Ehrenberger, K., and Felix, D.,
Acta Otolaryngol
(
Stockh
), 115:236-240 (1995). It has also been suggested that tinnitus generation might be similar to the “gate theory” of pain. See, e.g., Murai, Kazuo, et al.,
Am. J. Otology
13(5):454-464 (1992); Sahley, T. L., et al.,
Ear
&
Hearing
17:341-353 (1996); and Sahley, T. L., et al.,
Ear
&
Hearing
17:552-558 (1996).
Because its mechanism is poorly understood, the discovery of drugs that are effective in the treatment of tinnitus has been slow. Some researchers have alleged that administration of the local anesthetic lidocaine can reduce symptoms of the disorder, but its alleged effectiveness is of short duration. Lyttkens, L.,
Scand. Audiol. Suppl.
(
Sweden
) 26:27-31 (1986); and Murai, Kazuo, et al.,
Am. J. Otology
13(5):454-464 (1992). Other drugs alleged to be somewhat effective in the treatment of tinnitus include oxazepam, clonazepam, glutamic acid, streptomycin, and eperisone hydrochloride. Murai, Kazuo, et al.,
Am. J. Otology
13(5):454-464 (1992). Unfortunately, these and other drugs are allegedly effective in only a few patients. More important, those drugs that are reportedly the most effective (e.g., lidocaine, oxazepam and clonazepam) can cause a wide variety of adverse effects. These include, but are not limited to, numbness, tingling, light-headedness, blurred spee
Jerussi Thomas P.
Rubin Paul D.
Criares Theodore J.
Kim Jennifer
Pennie & Edmonds LLP
Sepracor Inc.
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