KR20010074682A - Compositions Comprising GABA Analogs and a Decongestant to Relieve Sinus Headache Pain - Google Patents

Abstract

The present invention relates to compositions comprising analogs of glutamic acid and gamma-aminobutyric acid with decongestants and methods of treating sinus headache or sinus pain.

Description

Compositions Comprising GABA Analogs and Decongestants to Relieve Sinus Headaches

GABA analogs are known agents that are useful in anticonvulsant therapies for central nervous system diseases such as epilepsy, Huntington's chorea, cerebral ischemia, Parkinson's disease, pancreatic dyskinesia and convulsions. It has been suggested that the compounds can be used as antidepressants, anti-anxiety agents and antipsychotics. See WO 92/09560 (US Patent Application No. 618,692, filed November 27, 1990) and WP 93/23383 (US Patent Application No. 886,080, filed May 20, 1992).

WO 97/33858 teaches that compounds related to gabapentin are useful for treating epilepsy, fainting seizures, dyskinesia, brain diseases, neurodegenerative disorders, depression, anxiety, panic, pain and neuropathological diseases. WO 97/33858 does not specify what form of pain is treated.

In addition, compounds of the invention are known for the treatment of neuropathic pain (e.g., 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 Apr: 1175-6; Wetzel CH; Connelly JF., Use of gabapentin in pain management. 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 in radiation myelopathy: a case report.Program book, American Pain Society (14th Annual Scientific Meeting) .Abstract # 95823, p.A-115; Sist T; Filadora V; Miner M; Lema 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; Melli ck LB; Mellick GA., Successful treatment of reflex sympathetic dystrophy with gabapentin [letter]. Am J Emerg Med, 1995 Jan, 13: 1, 96; Mellick GA; Seng MI., The use of gabapentin in the treatment of reflex sympathetic dystrophy and a phobic disorder. Am J Pain Manage 1995; 5: 7-9; Mellick GA; Mellicy LB; Mellicy LB., Gabapentin in the management of reflex sympathetic dystrophy [letter]. J Pain Symptom Manage, 1995 May, 10: 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 extremity neuropathic pain syndromes. J Hand Ther, 1997 Apr-Jun, 10: 2, 96-109).

Sinus headaches are caused by inflammation of the sinuses causing sinus pressure and pain. Sinus headache is common in adults over 35 years of age and is often promoted by cold or allergic rhinitis. Common treatments include analgesics and decongestants.

Prior to the present invention, the use of GABA analogues, originally used to treat epilepsy that is neurological disorders, in combination with decongestants and other sinus medications to relieve sinus headache or sinus pain, and also to treat neuropathy or nervous system pain There was no report of.

Summary of the Invention

The present invention provides a method for treating sinus headache comprising administering an GABA analog with an effective amount of decongestant to a subject suffering from a sinus headache. Preferred GABA analogs use the cyclic amino acid compounds of formula (I) and their pharmaceutically acceptable salts.

In formula, R <_1> is hydrogen or lower alkyl, n is an integer of 4-6.

A particularly preferred embodiment uses a compound of formula (I) wherein R ₁ is hydrogen and n is 4, wherein the compound is 1- (aminomethyl) -cyclohexane acetic acid with the common name gabapentin.

Decongestants useful in the present invention include various sympathetic drugs such as pseudoephedrine, ephedrine, phenylephrine and pharmaceutically acceptable salts thereof. Another decongestant useful in the present invention is ephedra, a supplemental medicament, whose decongestant properties are known. These decongestants are known to those skilled in the art as effective therapeutics for the relief of nasal congestion.

In another embodiment, the present invention provides a sinus with a unit dosage form for a mammal in need thereof, in combination with a decongestant, with a compound of Formula II, or a respective enantiomer isomer thereof, or a pharmaceutically acceptable salt thereof Treatment of headache or sinus pain.

Wherein R ₂ is straight or branched chain alkyl of 1 to 6 carbon atoms, phenyl or cycloalkyl of 3 to 6 carbon atoms; R ₃ is hydrogen or methyl; R ₄ is hydrogen, methyl or carboxyl.

Preferred compounds of the invention are compounds as (R), (S) or (R, S) isomers wherein R ₄ and R ₃ are hydrogen and R _{2 is-} (CH ₂ ) _0-2 -i C ₄ H ₉ .

More preferred compounds of formula II of the present invention are (S) -3- (aminomethyl) -5-methylhexanoic acid and 3-aminomethyl-5-methyl-hexanoic acid, which are currently common names pregabalin.

The present invention relates to a composition comprising analogs of glutamic acid and gamma-aminobutyric acid (GABA) with decongestants for the treatment of sinus headaches.

The method of the present invention uses any GABA analog. GABA analogs are any compounds derived from or based on gamma-aminobutyric acid. The compounds can be readily used by synthetic methods known commercially or by those skilled in the art of organic chemistry. Preferred GABA analogs to be used in the methods of the invention are cyclic amino acids of formula (I). This is described in US Pat. No. 4,024,175, which is incorporated herein by reference. Another preferred method uses the GABA analog of Formula II, which is described in US Pat. No. 5,563,175, which is incorporated herein by reference.

All that is needed to practice the methods of the present invention is to administer the GABA analogs and decongestants in an effective amount to treat sinus headache or sinus pain. The amount of GABA analog will generally be about 1 to about 300 mg per kg body weight of the subject. Typical dosages will be about 10 to about 5000 mg per day for normal weight adult subjects. Typical dosages that can be administered are expected to be 100 mg 3 to 600 mg 4 times a day. Commercially available capsules of gabapentin 100 mg, 300 mg and 400 mg may be administered. Other forms include liquid and film coated tablets.

If a compound of formula (II), such as pregabalin, is administered, the dosage is 1/6 of gabapentin. The dosage range of pregabalin is about 0.15 mg to about 50 mg per kg body weight of the subject. Typical dosages for pregabalin will be from about 1.6 mg to about 840 mg per day, with each dosage range from about 0.15 mg to about 65 mg per dose.

A therapeutically decongestive effective amount of a sympathetic drug is the amount that produces the desired therapeutic decongestion response upon oral administration and can be readily determined by one skilled in the art using conventional techniques and observing the results obtained under similar circumstances. Many factors to be considered when determining a therapeutically effective amount include the particular compound administered; Bioavailability properties of the pharmaceutical composition administered; Dosing regimen selected; And other associated environments.

The therapeutically decongestive effective amount of the sympathetic neurologic drug will vary from about 1 mg to about 200 mg. Preferred amounts will vary from about 5 mg to about 150 mg.

These sympathomimetic drugs are generally effective when administered orally according to a four-day dosing schedule in unit dosage forms in which the active medication is released as an attribute. For example, for adults, the recommended dose of pseudoephedrine hydrochloride is 60 mg every 6 hours (q.i.d. (4 times per day)). In addition, unit dosage forms containing sympathetic neurologic drugs may be formulated to release the active drug for prolonged periods of time and may be administered with a schedule of less frequent daily effective dose administration. For example, the recommended dosage of pseudoephedrine hydrochloride can be 120 mg twice daily (b.i.d.) for long-release formulations.

In addition to GABA analogs and decongestants, the compositions according to the invention can be administered simultaneously with antihistamines to relieve nasal congestion associated with allergic rhinitis. These antihistamines include chlorpheniramine, brompheniramine, dexchlorpheniramine, dexbropheniramine, tripolydine, diphenhydramine, doxylamine, tripelamineamine, ciproheptadine, carbinoxamine, bromodiphenhydramine, phenaminemin, Pyrylamine, azatadine, terpenadine, astemisol, loratadine, acribastine, cetirizine, aguillastin, evastin, levocarbastine and pharmaceutically acceptable salts thereof.

The composition of the present invention may also comprise a secondary pain relief agent. These pain relief agents include aspirin, acetaminophen, ibuprofen, flurbiprofen, naproxen, mefenamonic acid, ketoprofen, indomethacin, indoprofen, azapropazone, diclofenac, diflusal, fenbufen, phenof Analgesics such as lofen, pyroxhamm, sullindac, suprofen, thiapropenoic acid, tolmetin, doxycamp, meloxycam, tenoxycam, etodolak, oxindadan or mixtures thereof.

Compositions of the present invention may also include antitussives such as, but not limited to, dextromethorphan, codeine, terpine hydrate, and pharmaceutically acceptable salts thereof.

The composition of the present invention may also include an expectorant. Expectant agents useful in the present invention include guipennesine, potassium guaisulfonate, potassium iodide, potassium citrate, glycerol iodide, acetylcysteine, carboxymethylcysteine, ambroxol, sobreol and pharmaceutically acceptable salts thereof This is not restrictive.

The GABA compounds of the present invention may form pharmaceutically acceptable salts with organic and inorganic acids or bases. For example, acid addition salts of basic compounds are prepared by dissolving the free base in an aqueous or aqueous alcohol solution or other suitable solvent containing a suitable acid and isolating the solution to evaporate the salt. Examples of pharmaceutically acceptable salts include salts such as sodium, potassium and magnesium, as well as hydrochloride, hydrobromide, hydrosulfate and the like.

Compounds of formula (II) may contain one or several asymmetric carbon atoms. The present invention includes each diastereomer or enantiomer and mixtures thereof. Each diastereomer or enantiomer can be prepared and separated by methods already known in the art.

Pharmaceutical compositions of a compound of the invention or a salt thereof are prepared by formulating the active compound with a pharmaceutical carrier in unit dosage form. Examples of suitable pharmaceutical carriers comprising a pharmaceutical diluent include gelatin capsules; Sugars such as lactose and sucrose; Starch such as corn starch and potato starch, cellulose derivatives such as sodium carboxymethyl cellulose, ethyl cellulose, methyl cellulose and cellulose acetate phthalate; gelatin; talc; Stearic acid; Magnesium stearate; Vegetable oils such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil and cacao oil; Propylene glycol, glycerin; Sorbitol; Polyethylene glycol; water; Agar; Alginic acid; Isotonic saline, and phosphate buffer solutions, as well as other commercially available materials commonly used in pharmaceutical formulations. The composition of the present invention may also include other ingredients such as colorants, flavors and / or preservatives. If these materials are present they are generally used in relatively small amounts. The composition may also include other therapeutic agents as needed.

The proportion of active ingredient in the composition may vary within wide limits, but for practical purposes it is preferably present at a concentration of at least 10% in the solid composition and at least 2% in the main liquid composition. The most satisfactory composition is the presence of a much higher proportion of active ingredient.

The route of administration of the GABA analog or salt thereof is oral or parenteral. For example, a useful intravenous dose of a GABA analog is 5 to 50 mg and a useful oral dose is 20 to 800 mg. The dosage will fall within the dosage range used in the treatment of pain or will be determined by the needs of the patient as described by the physician.

Advantages of using compounds of formulas (I) and (II), in particular gabapentin and pregabalin, include the relatively nontoxicity of the compound, the ease of manufacture, the fact that the compound is resistant, and the ease of IV administration of the drug. Gabapentin rarely interacts with a major class of drugs because it is not metabolized in the liver and is excreted unchanged from the body. In addition, the drug is not metabolized in the body. Subjects treated by the methods of the invention are mammals, including humans.

Claims (20)

(a) an analgesic effective amount of a GABA analog; And (b) an effective amount of decongestant A method of treating sinus headache or sinus pain, comprising administering a pharmaceutical composition comprising a. The method of claim 1, wherein the GABA analog is a compound of Formula I and a pharmaceutically acceptable salt thereof. <Formula I> In formula, R <_1> is hydrogen or lower alkyl, n is an integer of 4-6. The method of claim 2, wherein the compound of formula I comprises gabapentin. The method of claim 1 wherein the decongestant is selected from the group consisting of pseudoephedrine, ephedrine, phenylephrine, a pharmaceutically acceptable salt thereof and ephedra. The method of claim 2 comprising about 10 mg to about 400 mg of the compound of formula (I). The method of claim 3, comprising about 10 mg to about 400 mg of gabapentin. 4. The method of claim 3 comprising about 10 mg to about 400 mg gabapentin and about 60 mg to about 200 mg decongestant. The method of claim 1, wherein the GABA analog is a compound of Formula II. <Formula II> Wherein R ₂ is straight or branched chain alkyl of 1 to 6 carbon atoms, phenyl or cycloalkyl of 3 to 6 carbon atoms; R ₃ is hydrogen or methyl; R ₄ is hydrogen, methyl or carboxyl. The method of claim 8, wherein the compound of Formula II comprises pregabalin. The method of claim 8, comprising about 0.15 mg to about 65 mg of the compound of Formula II. The method of claim 9, comprising about 0.15 mg to about 65 mg of pregabalin. (a) an analgesic effective amount of a GABA analog; And (b) an effective amount of decongestant Comprising a composition for enhancing analgesic response in a mammal. The composition of claim 12, wherein the GABA analog is a compound of Formula I: and a pharmaceutically acceptable salt thereof. <Formula I> In formula, R <_1> is hydrogen or lower alkyl, n is an integer of 4-6. The composition of claim 13, wherein the compound of formula I comprises gabapentin. The composition of claim 13 comprising from about 10 mg to about 400 mg of a compound of Formula (I). The composition of claim 14, comprising about 10 mg to about 400 mg of gabapentin. The composition of claim 12, wherein the GABA analog is a compound of Formula II: <Formula II> Wherein R ₂ is straight or branched chain alkyl of 1 to 6 carbon atoms, phenyl or cycloalkyl of 3 to 6 carbon atoms; R ₃ is hydrogen or methyl; R ₄ is hydrogen, methyl or carboxyl. The composition of claim 17, wherein the compound of Formula II comprises pregabalin. The composition of claim 17 comprising from about 0.15 mg to about 65 mg of a compound of Formula II. The composition of claim 19 comprising about 0.15 mg to about 65 mg of pregabalin.