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Title:  Composition comprising a tramadol material and an anticonvulsant drug

United States Patent:  6,562,865

Issued:  May 13, 2003

Inventors:  Codd; Ellen E. (Blue Bell, PA); Martinez; Rebecca P. (Abington, PA); Rogers; Kathryn E. (Audubon, PA)

Assignee:  Ortho-McNeil Pharmaceutical, Inc. (Raritan, NJ)

Appl. No.:  634904

Filed:  August 9, 2000

Abstract

This invention relates to a pharmaceutical composition comprising a combination of a tramadol material and an anticonvulsant drug and to the pharmacological use of the composition in treating conditions of pain and neurologic or psychiatric disorders. The composition produces a combination product having improved properties, requiring less of each ingredient and producing a synergistic effect.

DETAILED DESCRIPTION OF THE INVENTION

The tramadol material is any one of (1R,2R or 1S,2S)-2-[(dimethylamino)methyl]-1-(3-methoxyphenyl)-cyclohexanol (tramadol), its N-oxide derivative ("tramadol N-oxide"), and its O-desmethyl derivative ("O-desmethyl tramadol") or mixtures thereof. It also includes the individual stereoisomers, mixtures of stereoisomers, including the racemates, pharmaceutically acceptable salts of the amines, such as the hydrochloride salt, solvates and polymorphs of the tramadol material. Tramadol is commercially available from Grunenthal or may be made by the process described in U.S. Pat. No. 3,652,589, which is herein incorporated by reference.

Tramadol N-oxide is prepared by treating tramadol as a free base with an oxidizing agent, e.g., hydrogen peroxide (30%), in an organic solvent, e.g., methanol or isopropanol, with, but preferably without heating. See, "Reagents For Organic Synthesis", 1, 471, Fieser & Fieser eds., Wiley N.Y.; (1987) and B. Kelentey et al., Arzneim. Forsch., 1957, 7, 594. With heating, the reaction takes about 1 h, whereas without heating the reaction takes about 3 days. Following the oxidation, the mixture is treated with an agent, e.g. PtO2 or preferably Pt/C, for about a day, to destroy the excess hydrogen peroxide. The mixture is filtered, followed by the evaporation of the filtrate and then the residue is recrystallized from an organic solvent mixture, e.g., methylene chloride/ethyl acetate.

O-desmethyl tramadol is prepared by treating tramadol as a free base under O-demethylating reaction conditions, e.g., reacting it with a strong base such as NaOH or KOH, thiophenol and diethylene glycol (DEG) with heating to reflux (Wildes, et al., J. Org. Chem., 1971, 36, 721). The reaction takes about 1 h, followed by cooling and then quenching in water of the reaction mixture. The quenched mixture is acidified, extracted with an organic solvent such as ethyl ether, basified and then extracted with a halogenated organic solvent such as methylene chloride. The extract is then dried and the solvent evaporated to yield the O-desmethyl product, which may then be short-path distilled, converted to its corresponding salt, e.g., treated with an acidified (HCl/ethanol) solution, and recrystallized from an organic solvent mixture, e.g., ethanol/ethyl ether.

Anticonvulsant drugs, according to the scope of the present invention, are effective antiepileptic compounds some of which have been described as useful for the treatment of neuropathic pain and include, without limitation, topiramate, RWJ-333369, gabapentin, lamotrigine, pregabalin, carbamazepine, phenytoin, fosphenytoin, mephenytoin, ethotoin, valproic acid, famotidine, phenobarbital, mephobarbital, metharbital, diphenylhydantoin, primidone, ethosuximide, methsuximide, phensuximide, trimethadione, benzodiazepine, phenacemide, acetazolamide, progabide, clonazepam, divalproex sodium, magnesium sulfate injection, paramethadione, phenytoin sodium, valproate sodium, clobazam, sulthiame, dilantin, diphenylan or L-5-hydroxytrytophan, salts thereof, complexes thereof and mixtures of any of the foregoing.

The anticonvulsant drug topiramate is any one of the 2,3,4,5-bis-O-(1-methylethylidene)-.beta.-D-fructopyranose sulfamates, its derivatives or mixtures thereof. It also includes the individual stereoisomers, mixtures of stereoisomers, including racemates thereof, e.g., the various .alpha. and .beta. attachments, i.e., above and below the plane of the 6-membered ring structure, pharmaceutically acceptable salts, such as the hydrochloride salt, solvates and polymorphs of the topiramate material. Topiramate is commercially available from Ortho Pharmaceutical Corporation or may be made by the process described in U.S. Pat. No. 4,513,006, which is herein incorporated by reference.

RWJ-333369 is disclosed in U.S. Pat. No. 5,698,588 and described as useful in the treatment of central nervous system disorders, especially as anticonvulsants, antiepileptics, neuroprotective agents and centrally acting muscle relaxants. RWJ-333369 is further described by the Chemical Abstracts Service (CAS) Index Name 1,2-ethanediol, 1-(2-chlorophenyl)-, 2-carbamate, (S)- and CAS Registry Number 194085-75-1.

In the pharmaceutical composition of the present invention, the portion of the composition that is an anticonvulsant drug may be either topiramate, gabapentin, lamotrigine, RWJ-333369, another anticonvulsant drug or a combination of topiramate and, without limitation, one or more of another anticonvulsant drug. It is intended that a pharmaceutical composition comprising the combination of a tramadol material and an anticonvulsant drug as the active ingredients in synergistic ratios based on a fraction of their respective ED50 values as well as methods of preparing the instant composition in synergistic ratios are also encompassed within the present invention.

In a pharmaceutical composition of the present invention, a tramadol material and an anticonvulsant drug are present in a ratio based on a fraction of their respective ED50 values which ratio may vary from about 1:1 to about 300:1 or, reversibly, from about 1:1 to about 1:300; preferably, from about 1:1 to about 100:1 or from about 1:1 to about 1:100; and, more preferably, from about 1:1 to about 30:1 or from about 1:1 to about 1:30, depending upon the desired result. An instant composition may comprise, for example, a combination of a tramadol material and the anticonvulsant drug topiramate, wherein the tramadol material and topiramate are present in a ratio based on a fraction of their respective ED50 values, which ratio is from about 1:1 to about 20:1; preferably, from about 1.5:1 to about 10:1; and, more preferably, from about 3:1 to about 5:1. An instant composition may also comprise a combination of a tramadol material and the anticonvulsant drug gabapentin, wherein the tramadol material and gabapentin are present in a ratio based on a fraction of their respective ED50 values, which ratio is from about 2:1 to about 20:1; and, preferably, from about 9:1 to about 15:1. An instant composition may further comprise a combination of a tramadol material and the anticonvulsant drug lamotrigine, wherein the tramadol material and lamotrigine are present in a ratio based on a fraction of their respective ED50 values, which ratio is from about 1:2 to about 1:8; and, preferably, about 1:3. An instant composition may still further comprise a combination of a tramadol material and the anticonvulsant drug RWJ-333369, wherein the tramadol material and RWJ-333369 are present in a ratio based on a fraction of their respective ED50 values, which ratio is from about 1:1 to about 20:1 or from about 1:1 to about 1:20; preferably, from about 1:1 to about 10:1 or from about 1:1 to about 1:10; and, more preferably, from about 1:1 to about 4:1 or from about 1:1 to about 1:4. Compositions comprising a combination of a tramadol material and an anticonvulsant drug within these ratios exhibit synergistic effects. A pharmaceutical composition according to the present invention comprises a therapeutically effective dose of a tramadol material for treating a condition of pain or a neurological or psychiatric disorder in a mammal in need thereof in combination with an anticonvulsant drug. Preferably, the instant composition comprises a combination of tramadol hydrochloride and an anticonvulsant drug selected from topiramate, gabapentin, lamotrigine or RWJ-333369.

Pharmaceutical compositions comprising a combination of a tramadol material and the anticonvulsant drug as the active ingredients in an intimate admixture with a pharmaceutical carrier can be prepared according to conventional pharmaceutical compounding techniques. The carrier may take a wide variety of forms depending on the form of preparation desired for administration, e.g., intravenous, oral or parenteral. The composition may also be administered by means of an aerosol. In preparing the compositions in an oral dosage form, any of the usual pharmaceutical media may be employed. For example, in the case of oral liquid preparations (such as suspensions, elixirs and solution), water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like may be used. In the case of oral solid preparations (such as, for example, powders, capsules and tablets), carriers such as starches, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents and the like, may be used. Because of their ease in administration, tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are obviously employed. If desired, tablets may be sugar-coated or enteric-coated by standard techniques. For parenterals, the carrier will usually comprise sterile water, though other ingredients, for example, to aid solubility or for preservative purposes, may be included. Injectable suspensions may also be prepared, in which case appropriate liquid carriers, suspending agents and the like may be employed. In the case wherein one or more other pharmaceutically active components are added to the composition combining a tramadol material and an anticonvulsant drug, those components may be added in amounts known in the art and may be given at dosages conventional for such components. The pharmaceutical compositions of the present invention will generally be in the form of a dosage unit, e.g., tablet, capsule, powder, injection, teaspoonful and the like, wherein the preferred amount of each of the active ingredient to be contained therein is determined by the aforementioned ratios.

The dosage unit is calculated based on the amount of active ingredient which may be given to a 70 kg human subject in a single dose. An instant pharmaceutical composition may be given at a daily dose of from about 5 mg/day to about 8000 mg/day. However, it will be appreciated that the precise therapeutically effective dose of the active ingredients will vary depending upon the relative amount of each active component being used, upon the particular tramadol material and anticonvulsant drug being used and upon the aforementioned synergistic ratios. A single dose of a formulation of a pharmaceutical composition demonstrating synergistic activity, therefore, may contain a therapeutically effective dose of active ingredient of from about 20 mg to about 400 mg of a combination of a tramadol material and an anticonvulsant drug; preferably, from about 20 mg to about 200 mg; more preferably, from about 20 mg to about 100 mg; and, most preferably, from about 20 mg to about 50 mg. Thus, for example, a 20 mg formulation of a pharmaceutical composition comprising a synergistic combination of a tramadol material and the anticonvulsant drug topiramate, wherein the tramadol material and topiramate are present in a ratio based on a fraction of their respective ED50 values, which ratio is about 3:1 will contain about 15 mg of a tramadol material and about 5 mg of topiramate. Furthermore, the tramadol material and an anticonvulsant drug need not be present in the same formulation to achieve the results described herein. They may be administered individually at about the same time or in a single tablet. Advantageously, a pharmaceutical composition of the present invention may be administered in a single daily dose or the total daily dose may be administered in divided doses of two, three or four times daily. Optimal therapeutically effective doses to be administered may be readily determined by those skilled in the art, will vary with the particular combination of a tramadol material and an anticonvulsant drug used, the amount of active ingredients used in a synergistic ratio based on a fraction of their respective ED50 values, the strength of the preparation, the mode of administration and the advancement of the condition or disorder treated. In addition, factors associated with the particular subject being treated, including subject age, weight, diet and time of administration, will result in the need to adjust the dose to an appropriate therapeutically effective level.

The pharmaceutical compositions of the present invention are useful for treating conditions of pain and certain neurological and psychiatric disorders in mammals by the administration of a composition comprising a combination of a tramadol material and an anticonvulsant drug. Those skilled in the art of treating mammalian pain know that the types of pain experienced by mammals are varied. Examples of conditions of mammalian pain include, but are not limited to, centrally mediated pain, peripherally mediated pain, structural or soft tissue injury related pain, progressive disease related pain and neuropathic pain states, all of which would include acute pain such as caused by acute injury, trauma or surgery; chronic pain such as caused by neuropathic conditions, diabetic peripheral neuropathy, post-herpetic neuralgia, trigeminal neuralgia, post-stroke pain syndromes or cluster or migraine headaches; and inflammatory condition pain such as caused by osteoarthritis, rheumatoid arthritis or as sequela to disease, acute injury or trauma. The composition of the present invention is also useful in the treatment of certain neurological and psychiatric disorders including, but not limited to, bipolar disorder, psychosis, post-traumatic stress disorder, social phobia, obsessive-compulsive disorder; movement disorders such as akathisia, restless leg syndrome, tardive dyskinesia or central tremor; neurodegeneration in diseases such as ischemias (acute, delayed, recovery) or degeneration of nervous system cells due to Alzheimer's disease, Parkinson's disease or surgery; particularly, open-chest surgery; and, more particularly, open-heart or bypass surgery.

Claim 1 of 11 Claims

We claim:

1. A pharmaceutical composition comprising a synergistic combination of a tramadol material and topiramate, wherein the tramadol material and topiramate are present in a ratio based on a fraction of their respective ED50 values, which ratio is from about 1:1 to about 300:1 or from about 1:1 to about 1:300.
 


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