MXPA00011648A - Compositions comprising gaba analogs and caffeine - Google Patents

Abstract

Compositions that comprise a GABA analog, such as gabapentin or pregabalin in combination with caffeine are disclosed. The compositions are used to treat pain in mammals.

Description

COMPOSITIONS THAT COMPRISE ANALOGS GABA AND CAFFEINE BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to compositions comprising analogues of glutamic acid and gamma-aminobutyric acid (GABA) in combination with a central nervous system stimulant (CNS). The present invention is also related to a method for using these compositions to treat pain. 2. Prior art GABA analogs are known agents useful for anticonvulsant therapies for disorders of the central nervous system such as epilepsy, Huntington's chorea, cerebral ischemia, parkinson's disease, tardive dyskinesia and spasticity. It has also been suggested that the compounds can be used as antidepressants, angiolytics, and antipsychotics. See WO 92/09560 (U.S. Patent Serial Number 618,692 filed November 27, 1990) and WP 93/23383 (U.S. Patent Serial Number 886,080 filed May 20, 1992). WO 97/33858 teaches that compounds related to gabapentin are useful for treating epilepsy, fainting fits, hypokinesia, cranial disorders, neurodegenerative disorders, depression, anxiety, panic, pain, and neuropathological disorders. WO 97/33858 does not specify what forms of pain it treats. Additionally, GABA analogs are known for the treatment of neuropathic pain. For example, see Rosner H; Rubin L; Kestenbaum A., Gabapentin adjunctive therapy in neuropathic pain states. Clin J Pain, 1996 Mar, 12: 1, 56-8; Segal AZ; Rordorf G., Gabapentin as a novel treatment for postherpetic neuralgia. Neurology, 1996 Apr, 46: 4, 1175-6; Wetzel CH; Connelly JF., Use of gabapentin in pain management. Ann Pharmacother, 1997 Sep, 31: 9, 1082-3; Zapp JJ., Postpoliomyelitis pain treated with gabapentin [letter]. Am Fam Physician, 1996 Jun, 53: 8, 2442, 2445; Cheville A, et al., Neuropathic pain, myelopathy case report. Program book, American Pain Society (14th Annual Scientific Meeting). Abstract # 95823, p.A-115; Sist T; Filadora V; Miner M; Lemma M., Gabapentin for idiopathic trigeminal neuralgia: report of two cases. Neurology, 1997 May, 48: 5, 1467; Waldman SD, Tutorial 28: Evaluation and Treatment of Trigeminal Neuralgia. Pain Digest (1997) 7: 21-24; Mellick LB; Mellick GA., Successful treatment of reflex sympathetic dystrophy with gabapentin [letter]. Am J Emerg Med, 1995 Jan, 13: 1, 96; Mellick GA; Seng Ml. The use of gabapentin in the treatment or reflex sympathetic distrophy and a phobic disorder. Am J Pain Manage 1995; 5: 7-9; Mellick GA; Mellicy LB, Mellick LB., Gabapentin in the management or reflex sympathetic dystrophy [letter]. J Pain Sympton Manage, 1995 May, : 4, 265-6; Mellick GA; Mellick LB., Reflex sympathetic dystrophy treated with gabapentin. Arch Phys Med Rehabil, 1997 Jan, 78: 1, 98: 105 and Mackin GA., Medical and pharmacologic management of upper limb neuropathic pain syndromes. J Hand Ther, 1997 Apr-Jun, 10: 2, 96-109. Caffeine, or 3,7-dihydro-1,3,7-trimethyl-1 H-purine-2,6-dione, has the structural formula: Caffeine is a central nervous system stimulant that has been used, either alone or in combination with other drugs, in the treatment of headaches. Compositions containing one or more of analgesic aspirin, acetaminophen and phenacetin in combination with varying amounts of caffeine have been marketed in the past. In several cases, such products with the combination of analgesic / non-narcotic caffeine have also included one of narcotic analgesic codeine, propoxyphene or oxycodone. Examples of these combinations include the products known commercially as Excedrin® SK-65® Compound, Darvon® Compound, Anacin®, A.P.C., and A.P.C. with Codeine, Tabloid® Brand.

The caffeine that is used in the treatment of headaches has a long history. The FDA Advisory Panel, in its report on caffeine [Federal Register, 1997, 42 (131): 35482-35485] argued that the known biochemical effect of caffeine in small blood vessels provides a plausible explanation for its effectiveness in treating headaches associated with cerebral blood vessels. Sechzer [Curr. Therapy Research, 1979, 26 (4)] found that intravenous administration of caffeine sodium benzoate rapidly provided an improvement in the majority of patients experiencing headaches resulting from dural puncture or spinal anesthesia. The author, referring to the literature on the mechanism of action of caffeine in cerebral blood flow and cerebral vascular tone, argues from the opposite perspective of the panel that the analgesic improvement obtained implies that an intracranial vascular component is the main factor in such headaches. Changes in mood and in the overall sense of "well-being" after the administration of caffeine have been widely reported in the literature. Beginning at the beginning of this century, Hollingsworth (Arch. Psychol., 1912, 22: 1) reported beneficial motor and mental effects from 65 to 130 mg of caffeine, and muscle tremor, poor motor performance and insomnia caused by 390 mg of caffeine. . Many studies in the last 70 years have confirmed these discoveries. The review articles on xanthines [Ritchie, J.M., "Central nervous system stimulants." 2. The xanthines, "Goodman, L. S. &; Gilman, A. (Eds) The pharmacological basis of therapeutics, 4th Ed., New York: Macmillian Co., 1970; Stephenson, P. E., "Physiology and psychotropic effects of caffeine on man," J. Amer. Diet Assoc, 1977, 71 (3): 240-247] report that doses of 50 to 200 mg of caffeine result in a more alert person, decreased dizziness and less fatigue. Doses in the range of 200 to 500 mg can cause headaches, muscle tremor, nervousness and irritability. After extensively reviewing the relevant literature, the FDA advisory panel in 1977 concluded that caffeine when used as an analgesic adjuvant was safe, but that insufficient data existed to show that caffeine contributed in some way to the action of the analgesic [ Federal Register, 1997, 42 (131): 35482-35485]. The panel stated: Unfortunately, the information and data presented do not conclusively show that caffeine in combination is the effective ingredient as an analgesic, antipyretic and / or antirheumatic. The panel finds that there is little evidence to show that this ingredient still contributes to these pharmacological effects in a clinical situation. This remains as the official position in question to date. Consequently, many of the previously available analgesic / caffeine combination products are no longer on the market.

US Pat. No. 4656,177 discloses combinations of analgesic / non-spheroidal non-narcotic anti-inflammatory drugs and / or caffeine and narcotic analgesics. The compositions result in a more potent and faster analgesic response than if the medication were provided on its own. U.S. Patent No. 5,248,678 teaches a method for increasing the alertness of comatose patients or neacomatose patients comprising administering to patients effective amounts of an adenosine receptor antagonist, such as caffeine, and a GABA agonist, such as gabapentin. It has been discovered that a new class of drugs, which are not chemically related to aspirin, phenacetin, ibuprofen, other NSAIDS analgesics or narcotics can provide improved efficacy when combined with caffeine or other central nervous system stimulants. This invention provides a composition for treating pain including a combination of an effective amount of a given analog and caffeine. The GABA analog is a cyclic amino acid compound of Formula I H2N ~ CH2 or 7-C-CH2C02R? < CH,) " wherein R-i is hydrogen or lower alkyl and n is an integer from 4 to 6, and pharmaceutically acceptable salts thereof. An especially preferred embodiment uses a compound of Formula I wherein R-i is hydrogen and n is 4. This compound is acetic acid 1- (aminomethyl) -cyclohexane, known generically as gabapentin. In another embodiment, the invention is directed to a composition for treating pain comprising a compound of Formula II. * 2 II Wherein R2 is a linear or branched alkyl having from 1 to 6 carbon atoms, phenyl, or cycloalkyl having from 3 to 6 carbon atoms; R3 is hydrogen or methyl; and R 4 is hydrogen, methyl, or carboxyl; or an individual enantiomeric isomer thereof; or a pharmaceutically acceptable salt thereof, in a dosage unit form, for a mammal in need of such treatment; in combination with caffeine. Preferred compounds of Formula II are those wherein R and R3 are hydrogen, and R2 is - (CH2) or-2-i C4H9 as an (R), (S), or (R, S) isomer. The most preferred compounds of Formula II are (S) -3- (aminomethyl) -5-methylhexanoic acid and 3-aminomethyl-5-methyl-hexanoic acid, now known generically as pregabalin.

The present invention also includes a method of treating pain comprising administering effective amounts of the compositions described above. DETAILED DESCRIPTION OF THE PREFERRED MODALITIES The compositions of this invention utilize any GABA analog. A GABA analog is any compound derived from or based on gamma-aminobutyric acid. The compounds are readily available, either commercially, or by a synthetic methodology well known to those skilled in the art of organic chemistry. The preferred GABA analogs to be used in the method of this invention are cyclic amino acids of Formula I. These are described in US Pat. No. 4,024,175, which is incorporated herein by reference. Another preferred method uses the GABA analogs of Formula II, and these are described in US Patent 5,563,175, which is incorporated herein by reference. All that is required to practice the method of this invention is to administer the combination of a GABA analog and caffeine in an amount that is effective to treat a mammal, especially humans, suffering from pain. The amount of GABA analogue in the composition will generally be from about 1 to about 300 per kg of body weight of the subject. Typical doses will be from about 10 to about 5000 mg per day for an adult subject of normal weight. It is expected that the common doses that can be administered are 100 mg three times a day up to 600 mg four times a day. Commercially available capsules of 100 mg can be administered, 300 mg and 400 mg of gabapentin. Alternative forms include liquids and film-coated tablets. If a compound of Formula II, such as pregabalin, is used, the dose level is one sixth of that of gabapentin. The dose range for pregabalin is from about 0.15 mg to about 50 mg per kg per day of the subject's body weight. Typical doses for pregabalin will be from about 1.6 mg to about 840 mg per day with individual doses ranging from about 0.15 mg to about 65 mg per dose. The GABA analogs of the present invention can form pharmaceutically acceptable salts with both acids and organic and inorganic bases. For example, the acid addition salts of the basic compounds are prepared either by dissolving the free base in an aqueous solution of alcohol or an aqueous solution or other suitable solvents containing the appropriate acid and dissolving the salt by evaporating the solution. Examples of the pharmaceutically acceptable salts are hydrochlorides, hydrobromides, hydrosulfates, etc., as well as sodium, potassium and magnesium salts, etc. The compounds of Formula II may contain one or more asymmetric carbon atoms. The invention includes individual diastereomers or enantiomers, and mixtures thereof. The individual diastereomers or enantiomers can be prepared or isolated by methods known in the art. The term "caffeine" as used herein is intended to encompass not only caffeine as the anhydrous powder, but any salt or derivative of caffeine or any compound mixture thereof which is non-toxic, pharmaceutically acceptable and which is capable of accelerating and improving an analgesic or anti-inflammatory response when employed as described herein. See, for example, The Merck Index, ninth edition, Merck &; Co., Inc. Rahway N. J. (1976), pp. 207-208, for a description of mixtures, derivatives and caffeine salts that may prove useful in the compositions of the present invention. However, caffeine as the anhydrous powder base is currently preferred and where specific amounts of caffeine are then established, such amounts are provided in milligrams of the anhydrous base. The amount of caffeine in the composition will be sufficient to further improve the analgesia or to accelerate its onset. In humans, this amount will typically be from about 60 to about 200 mg (preferably 65 to 150 mg), an amount generally sufficient both to accelerate its onset and to improve analgesia. The daily dose of caffeine once again will generally not exceed 1000 mg. Of course, larger amounts can be used if tolerated by the patient. An additional advantage when using caffeine in the compositions and methods of the present invention is to compensate for the feeling of dizziness or sedation experienced by about one fifth of the users of the GABA analogues. A dosage unit form of the GABA analogue / caffeine analogue combination used in this invention may also comprise other compounds useful in the treatment of pain. While the compositions of the invention are preferably for oral use, they can also be formulated and administered by other known methods for the administration of analgesics, for example, as suppositories. Also, the preferred human dose levels indicated above are for use in adults; the pediatric compositions would contain in proportion less of the active ingredients. The compositions of the present invention are very conveniently administered to mammals by any suitable administration route for the GABA analog or selected, for example, oral or rectal. Preferably, the combination is formulated with any suitable non-toxic pharmaceutically acceptable inert carrier material. Such carrier materials are well known to those skilled in the art of pharmaceutical formulations. For those without skill in the art, reference is made to the text entitled "REMINGTONS PHARMACEUTICAL SCIENCES" (Fourteenth Edition), 1970. In a typical preparation for oral administration, for example, tablet or capsule, the GABA analog selected in an effective amount and caffeine in an amount sufficient to improve the effect of the GABA analogue or to accelerate its onset, combine with any inert non-toxic pharmaceutically acceptable inert carrier such as lactose, starch (pharmaceutical grade), dicalcium phosphate, calcium sulfate, kaolin, mannitol and powdered sugar. The pharmaceutical compositions of the compound of the present invention or its salts are produced by formulating the active compound in a dosage unit form with a pharmaceutical carrier. Some examples of dosage unit forms are tablets, capsules, pills, powders, aqueous and non-aqueous oral solutions and suspensions, and parenteral solutions packaged in containers containing either one or a greater number of dose units that are capable of subdivision. in individual doses. Additionally, when required, suitable binders, lubricants, disintegrating agents and coloring agents may also be included. Typical binders include starch, gelatin, sugars such as sucrose, melase and lactose, natural and synthetic gums such as acacia gum, sodium alginate, ireland moss extract, carboxymethyl cellulose, methyl cellulose, polyvinyl pyrrolidone, polyethylene glycol, ethyl cellulose and waxes. Typical lubricants for use in these dosage forms may include, but are not limited to, boric acid, sodium benzoate, sodium acetate, sodium chloride, leucine and polyethylene glycol. Suitable disintegrators may include, but are not limited to, starch, methylcellulose, agar, bentonite, cellulose, wood products, alginic acid, guar gum, citris pulp, carboxymethylcellulose, and sodium lauryl sulfate. If desired, a conventional pharmaceutically acceptable dye can be incorporated in the unit dosage form, ie, any of the standard FD &; C. Sweetening and flavoring and preservative agents may also be included, particularly when formulating a liquid dosage form, for example, an elixir, suspension or syrup. Also when the dosage form is a capsule, it may contain, in addition to the materials of the aforementioned t a liquid carrier such as a fatty oil. Other materials may be present as coatings or otherwise modify the physical form of the dosage unit. For example, tablets, pills or capsules may be coated with shellac, sugar or both. The compositions preferably should contain at least 0.1% of the active components; generally the active ingredients will be between about 2% to about 60% by weight of the dose unit. The compositions may, if desired, also contain other therapeutic agents. The percentage of active ingredients in the above compositions may vary within wide limits, but for practical purposes preferably they should be present in a concentration of at least 10% in a solid composition and at least 2% in a primary liquid composition. The most satisfactory compositions are those in which a much higher proportion of the active ingredient is present. The advantages of using the compounds of Formula I and II, especially gabapentin and pregabalin, in the present invention include the relatively non-toxic nature of the compounds, the ease of preparation, the fact that the compounds are well tolerated, and the ease of the administration of IV drugs. Gabapentin has few interactions with the major classes of drugs because they are not metabolized in the liver, but are excreted without body changes. In addition, drugs are not metabolized in the body. The subjects treated with the method of the present invention are mammals, including humans.

Claims (36)

1. CLAIMS 1. A method for producing an improved analgesic response in a mammal, characterized in that it comprises administering to the mammal a pharmaceutical composition comprising: (a) an analgesically effective amount of a GABA analogue; and (b) an effective amount of caffeine.
2. 2. The method according to claim 1, characterized in that the GABA analog is the compound according to Formula I: wherein Ri is hydrogen or a lower alkyl and n is an integer from 4 to 6, and pharmaceutically acceptable salts thereof.
3. 3. The method according to claim 2, characterized in that the Formula I comprises gabapentin.
4. 4. The method according to claim 1, characterized in that it comprises from about 60 mg to about 200 mg of caffeine.
5. 5. The method according to claim 4, characterized in that it comprises from about 65 mg to about 150 mg of caffeine.
6. 6. The method according to claim 2, characterized in that it comprises from about 10 mg to about 400 mg of Formula 1.
7. 7. The method according to claim 3, characterized in that it comprises from about 10 mg to about 400 mg of gabapentin.
8. The method according to claim 1, characterized in that it comprises from about 10 mg to about 400 mg of GABA analog and from about 60 mg to about 200 mg of caffeine.
9. The method according to claim 2, characterized in that it comprises from about 10 mg to about 400 mg of the compound according to Formula I and from about 60 mg to about 200 mg of caffeine.
10. The method according to claim 3, characterized in that it comprises from about 10 mg to about 400 mg of gabapentin and from about 60 mg to about 200 mg of caffeine.
11. 11. The method according to claim 1, characterized in that the GABA analog is a compound according to Formula II: R * II wherein R2 is a linear or branched alkyl of 1 to 6 carbon atoms, phenyl, or cycloalkyl having from 3 to 6 carbon atoms; R3 is hydrogen or methyl; and R 4 is hydrogen, methyl or carboxyl.
12. 12. The method according to claim 11, characterized in that Formula II comprises pregabalin.
13. The method according to claim 11, characterized in that it comprises from about 60 mg to about 200 mg of caffeine.
14. The method according to claim 13, characterized in that it comprises from about 65 mg to about 150 mg of caffeine.
15. 15. The method according to claim 11, characterized in that it comprises from about 0.15 mg to about 65 mg of Formula II.
16. 16. The method according to claim 12, characterized in that it comprises from about 0.15 to about 0.15 mg of pregabalin.
17. The method according to claim 11, characterized in that it comprises from about 0.15 mg to about 65 mg of the compound according to Formula II and from about 60 mg to about 200 mg of caffeine.
18. 18. The method according to claim 12, characterized in that it comprises from about 0.15 mg to about 65 mg of gabapentin and from about 60 mg to about 200 mg of caffeine.
19. 19. A composition for producing an improved analgesic response in a mammal characterized in that it comprises: (a) an analgesically effective amount of a GABA analogue; and (b) an effective amount of caffeine.
20. The composition according to claim 19, characterized in that the GABA analog is a compound according to Formula I: wherein R-i is hydrogen or a lower alkyl and n is an integer from 4 to 6, and pharmaceutically acceptable salts thereof.
21. 21. The method of the composition according to claim 20, characterized in that the Formula I comprises gabapentin.
22. 22. The composition in accordance with the claim 19, characterized in that it comprises from about 60 mg to about 200 mg of caffeine.
23. 23. The composition according to claim 22, characterized in that it comprises from about 65 mg to about 150 mg of caffeine.
24. 24. The composition in accordance with the claim 20, characterized in that it comprises from about 10 mg to about 400 mg of Formula I.
25. 25. The composition according to claim 21, characterized in that it comprises from about 10 mg to about 400 mg of gabapentin.
26. 26. The composition in accordance with the claim 19, characterized in that it comprises from about 10 mg to about 400 mg of the GABA analog and from about 60 mg to about 200 mg of caffeine.
27. 27. The composition in accordance with the claim 20, characterized in that it comprises from about 10 mg to about 400 mg of the compound according to Formula I and from about 60 mg to about 200 mg of caffeine.
28. 28. The composition in accordance with the claim 21, characterized in that it comprises from about 10 mg to about 400 mg of gabapentin and from about 60 mg to about 200 mg of caffeine.
29. 29. The composition according to claim 19, characterized in that the GABA analog is a compound according to Formula II: II wherein R2 is a linear or branched alkyl of 1 to 6 carbon atoms, phenyl or cycloalkyl having from 3 to 6 carbon atoms; R3 is a hydrogen or methyl; and R4 is hydrogen, methyl, or carboxyl.
30. 30. The composition according to claim 29, characterized in that Formula II comprises pregabalin.
31. 31. The composition in accordance with the claim 29, characterized in that it comprises from about 60 mg to about 200 mg of caffeine.
32. 32. The composition according to claim 31, characterized in that it comprises from about 65 mg to about 150 mg of caffeine.
33. 33. The composition according to claim 29, characterized in that it comprises from about 0.15 mg to about 65 mg of Formula II.
34. 34. The composition according to claim 30, characterized in that it comprises from about 0.14 mg to about 65 mg of pregabalin.
35. 35. The composition in accordance with the claim 29, characterized in that it comprises from about 0.15 mg to about 65 mg of the compound according to Formula II and from about 60 mg to about 200 mg of caffeine.
36. 36. The composition in accordance with the claim 30, characterized in that it comprises from about 0.15 mg to about 65 mg of pregabalin and from about 60 mg to about 200 mg of caffeine. SUMMARY Compositions comprising a GABA analog are described, such as gabapentin or pregabalin in combination with caffeine. The compositions are used to treat pain in mammals.