Methods and compositions employing optically pure s(+) vigabatrin

0001METHODS AND COMPOSITIONS EMPLOYING OPTICALLY PURE S(+) VIGABATRIN

1. FIELD OF THE INVENTION

0003The invention relates to methods of prevention, treatment, and/or management of peripheral neuropathy or the symptoms thereof, drug addiction or the symptoms thereof, and symptoms associated with drug withdrawal.

2. BACKGROUND OF THE INVENTION

0005Peripheral neuropathy ("PN") in general is a syndrome that can occur upon the disease or damage of nervous tissue. It is characterized, alone or in combination, by sensory loss, muscle weakness and atrophy, decreased deep tendon reflexes, and vasomotor symptoms. Peripheral neuropathies are classified as those that occur upon disease or damage of a single nerve (mononeuropathy), upon disease or damage of two or more nerves in separate areas (multiple mononeuropathy), and upon disease or damage of many nerves simultaneously (polyneuropathy). Peripheral neuropathies may also be classified by the general type of nerve(s) affected. For example, some neuropathies involve motor fibers, whereas others mainly affect sensory fibers (dorsal root ganglia) or cranial nerves. Some relatively common peripheral neuropathies have also been given specific names: carpal tunnel syndrome is one example; Guillain-Barre syndrome is another.

0006Carpal tunnel syndrome (CTS) is an affliction endured by millions. Occurring most often in women, it is particularly associated with occupations that require repeated forceful wrist flexion, as well as with acromegaly, myxedema, and fluid changes of pregnancy. CTS results from compression of the median nerve in the volar aspect of the wrist between the longitudinal tendons of forearm muscles that flex the hand and the transverse superficial carpal ligament. This compression causes pain, sensory deficit in the palmar aspect of the first three digits, and/or weakness and atrophy in muscles controlling thumb movement. The Merck Manual, 16th ed., 1519 ( 1992). Guillain-Barre syndrome (GBS) is another specific kind of peripheral neuropathy. GBS is an acute, usually rapidly progressive form of inflammatory polyneuropathy characterized by muscular weakness and mild distal sensory loss. It typically occurs between about 5 days to 3 weeks after a banal infectious disorder, surgery, or an immunization, and is thus believed to be caused by an autoimmune reaction of some kind. The most frequently identified cause of GBS is Campylobacter jejuni infection. Hughes, R. A. C, et al, J. Infect. Diseases, 176(Suppl. 2):S92-8 (1997).

0007The diseases and injuries that can lead to peripheral neuropathies generally are numerous and varied. They include, but are 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 HTV; 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).

0008The nature and effectiveness of conventional treatments of peripheral neuropathy vary with the underlying disorder. For example, successful renal transplantation usually diminishes the uremic polyneuropathy that occurs in about half of patients undergoing dialysis. Pirzada, N. A., et al, Postgrad. Med., 102:249-261 (1997). Similarly, immunologically mediated neuropathy may be treated with immunosuppression or immunomodulation therapy. Openshaw, H., Biol. Blood and Marrow Trans., 3:202-209 (1997). Because the etiology of peripheral neuropathy is often difficult to determine, however, its treatment is often slow and ineffective. See, e.g., Hughes, R. A. C, et al., J. Infect. Diseases, 176(Suppl 2):S92-8 (1997). There is thus a need for a safe and effective treatment of peripheral neuropathy. Vigabatrin, chemically named 4-amino-5-hexanoic acid, is an irreversible inhibitor of the gamma-aminobutyric acid-transaminase (GABA-T) enzyme. GABA-T inactivates the inhibitory neurotransmitter 4-aminobutyric acid (GABA), which acts at the brain's GABA/benzodiazepine receptor to increase membrane conductance of chloride ions, stabilizing the membrane potential, and consequently dampening excitatory input.

0009Meldrum, B.S., Brit. J. Clin. Pharm., 27:3S-1 IS (1989). By inhibiting the metabolism of GABA, vigabatrin can increase GABA concentrations in the central nervous system to levels which suppress or diminish the intensity of a variety of seizures. Because vigabatrin is not degraded by the GABA-T enzyme, only new enzyme synthesis can restore GABA-T activity. Thus, even a single dose produces a lasting, dose-dependent inhibition of brain

0010GABA-T in experimental animals, and elevated GABA levels are seen for at least 24 hours. Shields, W. D., and Sankar, R., Sem. Ped. Neur., 4(l):43-50 (1997).

0011Although not yet approved for use in the United States, vigabatrin is currently used in other countries as an anti-epileptic agent. Shields, W. D., and Sankar, R., Sem. Ped. Neur., 4(l):43-50 (1997). It is commonly available as a racemic mixture of the R(-) and S(+) stereoisomers. Further, the S(+) stereoisomer is reported to be active as a GABA-T inhibitor, and in in vivo animal studies of anti-convulsant activity. Gram, L., et al, Brit. J. Clinical Pharmacol, 27:13S-18S, (1989).

0012Thus, it is desired to find a compound with the advantages of vigabatrin for the treatment of a variety of conditions and disorders, particularly in a dosage form that is convenient for administration to a patient, without any of the known disadvantages of vigabatrin.

00133. SUMMARY OF THE INVENTION The use of the optically pure S(+) stereoisomer of vigabatrin in treating peripheral neuropathy, its symptoms, and conditions or disorders related thereto is encompassed by the present invention. Such conditions and disorders include, but are not limited to, carpal tunnel syndrome, Guillain-Barre syndrome, and other peripheral neuropathy disorders such as those resulting from 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. This invention further encompasses a method of treating or preventing peripheral neuropathy which comprises administering to a mammal, preferably a human, in need of such treatment a therapeutically effective amount of S(+) vigabatrin, or a pharmaceutically acceptable salt thereof, substantially free of its R(-) stereoisomer.

0014In another embodiment, the invention encompasses a method of treating or preventing carpal tunnel syndrome which comprises administering to a mammal, preferably a human, in need of such treatment a therapeutically effective amount of S(+) vigabatrin, or a pharmaceutically acceptable salt thereof, substantially free of its R(-) stereoisomer. This invention further encompasses a method of treating or preventing Guillain-Barre syndrome which comprises administering to a mammal, preferably a human, in need of such treatment a therapeutically effective amount of S(+) vigabatrin, or a pharmaceutically acceptable salt thereof substantially free of its R(-) stereoisomer.

0015This invention also encompasses a method of preventing, treating, or managing drug or alcohol addiction, or the symptoms thereof, which comprises administering to a mammal, preferably a human, in need of such treatment a therapeutically effective amount of S(+) vigabatrin, or a pharmaceutically acceptable salt thereof, substantially free of its R(-) stereoisomer.

0016The invention further encompasses a method of alleviating, treating, or managing the pain and other symptoms associated with the termination of drug use (i.e., withdrawal conditions) which comprises administering to a mammal, preferably a human, in need of such treatment a therapeutically effective amount of S(+) vigabatrin, or a pharmaceutically acceptable salt thereof, substantially free of its R(-) stereoisomer.

0017In another embodiment, this invention relates to a composition adapted for the treatment of a mammal, preferably a human, suffering from peripheral neuropathy which comprises an amount of S(+) vigabatrin, or a pharmaceutically acceptable salt or solvate thereof, substantially free of its R(-) stereoisomer, said amount being sufficient to alleviate the symptoms of peripheral neuropathy.

0018This invention further encompasses a pharmaceutical composition employing S(+) vigabatrin, or a pharmaceutically acceptable salt thereof, substantially free of its R(-) stereoisomer, said composition being formulated for controlled-release of the active ingredient(s) therein. Preferably, the composition is adapted for the prevention, treatment, or management of peripheral neuropathy, drug addiction, and alleviation of withdrawal symptoms. This controlled-release formulation is particularly useful within the methods described herein.

0019The invention encompasses single unit dosage forms of optically pure S(+) vigabatrin, or a pharmaceutically acceptable salt thereof, substantially free of its R(-) stereoisomer, which comprises from about 0.01 g to 1 g of active ingredient in a tablet, capsule, or other single unit dosage form suitable for oral administration. The single unit dosage forms of the invention may also be controlled-release forms as described below.

4. DETAILED DESCRIPTION OF THE INVENTION

0021Unexpectedly, substantially optically pure S(+) vigabatrin, or a pharmaceutically acceptable salt thereof, is effective in the prevention, treatment, mitigation, and/or management of peripheral neuropathy ("PN"), alcohol and drug addiction or the symptoms thereof, or conditions associated with alcohol or drug withdrawal. In addition, optically pure S(+) vigabatrin can be used for the treatment, prevention and/or management of these disorders while reducing or avoiding adverse effects, including undesirable side-effects associated with the administration of racemic vigabatrin.

0022Therefore, in one aspect, the present invention relates to a method of treating peripheral neuropathy which comprises administering to a mammal a therapeutically effective amount of S(+) vigabatrin, or a pharmaceutically acceptable salt or solvate thereof, substantially free of its R(-) stereoisomer.

0023In another embodiment, this invention encompasses single unit dosage forms of optically pure S(+) vigabatrin, or a pharmaceutically acceptable salt, solvate, hydrate or clatherate, thereof, substantially free of its R(-) stereoisomer, which comprises from about 0.1 to about 1 g of active ingredient in a compressed tablet. This dosage form is particularly suitable for the treatment of peripheral neuropathies, such as carpal tunnel syndrome and

0024Guillain-Barre syndrome, and addiction and withdrawal symptoms of alcohol and drug use.

0025The methods and compositions of this invention include the benefit of reducing or avoiding adverse effects associated with racemic vigabatrin. The invention also allows the concurrent or sequential use of conventional PN therapies, and drugs such as corticosteroids and antibiotics. The invention further allows the concurrent or sequential use of S(+) vigabatrin and anticonvulsants including, but not limited to, felbamate, gabapentin, lamotrigine, oxcarbazepine, tiagabine, topiramate, zonisamide, carbamazepine, phenobarbital, phenytoin, and valproic acid.

0026The pharmaceutical compositions of the present invention may also be formulated to provide slow or controlled-release of the active ingredient therein using, for example, hydropropylmethyl cellulose in varying proportions to provide the desired release profile, other polymer matrices, gels, permeable membranes, osmotic systems, multilayer coatings, microparticles, liposomes, microspheres, or the like, or a combination thereof. Suitable controlled-release formulations known to those of ordinary skill in the art, including those described herein, may be readily selected for use with the S(+) vigabatrin compositions of the invention. Thus, single unit dosage forms suitable for oral administration, such as tablets, capsules, gelcaps, and the like that are adapted for controlled-release, are encompassed by the present invention. All controlled-release pharmaceutical products have a common goal of improving drug therapy over that achieved by their non-controlled counterparts. Ideally, the use of an optimally designed controlled-release preparation in medical treatment is characterized by a minimum of drug substance being employed to cure or control the condition in a minimum amount of time. Advantages of controlled-release formulations may include: 1) extended activity of the drug; 2) reduced dosage frequency; and 3) increased patient compliance.

0027Most controlled-release formulations are designed to initially release an amount of drug that promptly produces the desired therapeutic effect, and gradual and continual release of other amounts of drug to maintain this level of therapeutic effect over an extended period of time. In order to maintain this constant level of drug in the body, the drug must be released from the dosage form at a rate that will replace the amount of drug being metabolized and excreted from the body.

0028The controlled-release of the active ingredient may be stimulated by various inducers, for example pH, temperature, enzymes, water, or other physiological conditions or compounds. The term "controlled-release component" in the context of the present invention is defined herein as a compound or compounds, including polymers, polymer matrices, gels, permeable membranes, liposomes, microspheres, or the like, or a combination thereof, that facilitates the controlled-release of the active ingredient (e.g., S(+) vigabatrin) in the pharmaceutical composition.

0029The present invention further encompasses the use of S(+) vigabatrin in the prevention and treatment of the symptoms associated with withdrawal from the use of central nervous system ("CNS") stimulants and depressants, such as alcohol and sedatives, and other drugs that act on the CNS which are not considered pure stimulants or depressants, such as barbiturates, psychedelic agents, and marijuana. One embodiment of the present invention relates to the administration of a therapeutically effective amount of S(+) vigabatrin, or a pharmaceutically acceptable salt thereof, substantially free of its R(-) stereoisomer to a mammal for the treatment of such withdrawal symptoms. The invention also encompasses the use of S(+) vigabatrin to prevent, treat, or manage the development of physical dependence on drugs and alcohol. In one embodiment, a therapeutically effective amount of S(+) vigabatrin, or a pharmaceutically acceptable salt thereof, substantially free of its R(-) stereoisomer, is administered to a patient for the treatment of one or more such dependencies.

0030The present invention further encompasses the use of S(+) vigabatrin in combination with standard detoxification methods to prevent or treat drug withdrawal symptoms in a mammal. In an embodiment of this invention, S(+) vigabatrin, or a pharmaceutically acceptable salt thereof, substantially free of its R(-) stereoisomer, is administered before, during, and/or after the detoxification methods. Symptoms of drug withdrawal include, but are not limited to, depression; pain; fever; restlessness; lacrimation; rhinorrhea; uncontrollable yawning; perspiration; piloerection; restless sleep; mydriasis; twitching and muscle spasms; severe aches in the back, abdomen and legs; abdominal and muscle cramps; hot and cold flashes; insomnia; nausea, vomiting, diarrhea; coryza and severe sneezing; and increases in body temperature, blood pressure, respiratory rate, and heart rate (referred to hereinafter, either singly or in combination, as "withdrawal conditions", "withdrawal symptoms", "conditions associated with drug withdrawal", or "withdrawal").

0031The terms "withdrawal conditions", "withdrawal symptoms", "conditions associated with drug withdrawal", and "withdrawal" as used herein, mean the symptoms and disorders, as listed above, that occur during withdrawal from any alcohol or drug addiction.

0032The present invention further encompasses the use of S(+) vigabatrin in combination with standard detoxification methods to prevent or treat alcohol withdrawal symptoms in a mammal. In an embodiment of this invention, S(+) vigabatrin, or a pharmaceutically acceptable salt thereof, substantially free of its R(-) stereoisomer, is administered before, during, and/or after the detoxification methods. Heavy consumers of alcohol acquire a tolerance and a state of dependence to alcohol. Alcohol withdrawal is not as severe as drug withdrawal, but includes many of the same symptoms. Symptoms of alcohol withdrawal include, but are not limited to, drug craving, tremors, irritability, nausea, sleep disturbance, tachycardia, hypertension, sweating, perceptual distortion, and seizures. Moreover, in combination with other health problems, such as malnutrition, infection, or electrolyte imbalance, the syndrome of delirium tremens becomes likely. Delirium tremens is characterized by severe agitation, confusion, visual hallucinations, fever, profuse sweating, tachycardia, nausea, diarrhea, and dilated pupils.

0033The present invention also encompasses the use of S(+) vigabatrin in combination with other pharmacologically active compounds, such as antidepressants, preferably tricyclic antidepressants. Examples of antidepressant compounds include, but are not limited to, tricyclic antidepressants, such as amitriptyline, clomipramine, doxepin, imipramine, trimiprimane, amoxapine, desipramine, maprotiline, nortriptyline, and protryptiline; serotonin-reupake inhibitors, such as fluoxetine, fluvoxamine, paroxetine, sertraline, and venlafaxine; atypical antidepressants, such as bupropion, nefazodone, and trazodone; and other monoamine oxidase inhibitors, such as phenelzine, tranylcypromine, and selgiline, or an isomer of any of the above compounds, either singly or in combination.

0034As used herein, the terms "adverse effects" and "adverse side effects" include, but are not limited to, hyperactivity, agitation, drowsiness, somnolence, fatigue, dizziness, irritability, sedation, weight gain, increased appetite, insomnia, nausea and vomiting, ataxia, decreased appetite, headache, vertigo, and psychosis.

0035The terms "pharmaceutically acceptable salts" or "a pharmaceutically acceptable salt thereof refer to salts prepared from pharmaceutically acceptable nontoxic acids or bases, including inorganic acids and bases; organic acids and bases; solvates; hydrates; and clatherates thereof. Since the compound of the present invention has both acidic and basic moieties, salts may be prepared from pharmaceutically acceptable nontoxic acids or bases. Examples of suitable inorganic bases include metallic salts made from aluminum, calcium, lithium, magnesium, potassium, sodium, and zinc. Appropriate organic bases may be selected, for example, from N,N-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumaine (N-methylglucamine), lysine and procaine. In another embodiment, S(+) vigabatrin is administered as the free acid or free base.

0036The term "racemic", as used herein, means a mixture of the S(+) and R(-) stereoisomers of a compound wherein the S(+) and R(-) stereoisomers are present in approximately a 1 : 1 ratio.

0037The terms "substantially optically pure," "optically pure," and "optically pure stereoisomers", as used herein, mean that the composition contains greater than about 90% of the desired stereoisomer by weight, preferably greater than about 95% of the desired stereoisomer by weight, and most preferably greater than about 99% of the desired stereoisomer by weight, said percent based upon the total weight of vigabatrin. In other words, the term "substantially free" means less than about 10 weight percent, preferably less than about 5 weight percent, and more preferably less than about 1 weight percent of the undesired stereoisomer. The term "peripheral neuropathy", as used herein, is defined as a disorder characterized by sensory loss, muscle weakness and atrophy, decreased deep tendon reflexes, vasomotor symptoms or any combinations thereof resulting from damage or disease of at least one nerve. As used herein, the peripheral neuropathy includes carpal tunnel syndrome, Guillain-Barre syndrome, and related disorders. The phrase "therapeutically effective amount of S(+) vigabatrin", as used herein, means that amount of optically pure S(+) vigabatrin, or a pharmaceutically acceptable salt thereof, substantially free of its R(-) stereoisomer, which provides a therapeutic benefit in the treatment, management, or prevention of a peripheral neuropathy, alcohol addiction, drug addiction, alcohol withdrawal, drug withdrawal, or related disorders. Substantially pure S(+) vigabatrin may be obtained from a racemic mixture of vigabatrin, the chemical synthesis of which can be performed by the methods described in U.S. Patent Nos. 3,960,927 and 5,380,936, the disclosures of which are incorporated herein by express reference thereto. The S(+) stereoisomer of vigabatrin may be obtained from its racemic mixture by chiral separation, such as by gas chromatography, column chromatography, or HPLC. The S(+) stereoisomer of vigabatrin may also be obtained from its racemic mixture by resolution of the stereoisomers using conventional means such as from an optically active resolving acid. See, e.g., Jacques, J., et al, Enantiomers, Racemates and Resolutions, (Wiley-Interscience, New York, 1981); Wilen, S. H., et al, Tetrahedron 33:2725 (1977); Eliel, E. L. Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); Wilen, S. H. Tables of Resolving Agents and Optical Resolutions p. 268 (E.L. Eliel, Ed. Univ. of Notre Dame Press, Notre Dame, IN, 1972). Furthermore, optically pure S(+) vigabatrin can be prepared from the racemic mixture by enzymatic biocatalytic resolution. See, e.g., U.S. Patent No. 5,316,944, the disclosure of which is incorporated herein by express reference thereto.

0038In addition to separation techniques such as those described above, S(+) vigabatrin can be synthesized by stereospecific synthesis using methodology well known to those skilled in the art. Chiral synthesis can result in products of high enantiomeric purity. However, in some cases, the enantiomeric purity of the product is not sufficiently high. The skilled artisan will appreciate that the separation methods described above can be used to further enhance the enantiomeric purity of S(+) vigabatrin obtained by chiral synthesis.

0039The magnitude of a prophylactic or therapeutic dose of S(+) vigabatrin in the acute or chronic management of peripheral neuropathy, drug addiction, alcohol addiction, drug withdrawal, and alcohol withdrawal, as described herein, will vary with the severity of the condition to be treated, and the route of administration. The dose, and perhaps the dose frequency, will also vary according to the age, body weight, and response of the individual patient. Suitable dosing regimens can be readily selected by those skilled in the art with due consideration of such factors. In general, the total daily dose range for S(+) vigabatrin, for the conditions described herein, is from about 0.01 g to about 4.5 g, in single or divided doses. Preferably, a daily dose range should be between about 0.05 g to about 4.0 g, in single or divided doses, while most preferably, a daily dose range should be between about 0.1 g to about 3.0 g, in single or divided doses. The maximum daily dosage for children is preferably about 150 mg/kg. It is preferred that the doses for both adults and children be administered from one to four times daily.

0040In managing an adult patient, the therapy may be initiated at a lower dose, e.g., preferably about 0.1 g to about 1 g per day, and increased by about 0.01 g per day up to the recommended daily dose or higher depending on the patient's global response. When the methods of the present invention are used to treat children, a starting daily dose of no more than about 40 mg/kg is recommended. This may be increased at appropriate intervals up to the daily recommended dose. It is further recommended that patients over 65 years initially receive low doses, and that their dose be titrated based on individual response(s) and blood level(s). It may be necessary to use dosages outside these ranges in some cases as will be apparent to those skilled in the art. Further, it is noted that the clinician or treating physician will know how and when to interrupt, adjust, or terminate therapy in conjunction with individual patient response. Any suitable route of administration may be employed for providing the patient with an effective dosage of S(+) vigabatrin. For example, oral, rectal, nasal, parenteral (subcutaneous, intramuscular, intravenous), sublingual, buccal, mucosal, transdermal, and like forms of administration may be employed. Dosage forms include tablets, troches, lozenges, dispersions, suspensions, suppositories, solutions, capsules, soft elastic gelatin capsules, patches, and the like. In one aspect of the present invention, orally administered compositions of S(+) vigabatrin may be prepared in a controlled-release formulation.

0041The pharmaceutical compositions for use in the present invention comprise optically pure S(+) vigabatrin as the active ingredient, or a pharmaceutically acceptable salt or solvate thereof, and may also contain a pharmaceutically acceptable carrier, and optionally, other therapeutic ingredients.

0042The compositions of the present invention can be prepared in the form of suspensions, solutions and elixirs; aerosols; and can include carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents, and the like, in the case of oral solid preparations (such as powders, capsules, and tablets) with the oral solid preparations being preferred over the oral liquid preparations. A preferred oral solid preparation is capsules. The most preferred oral solid preparation is tablets.

0043Because of their ease of administration, tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are employed. If desired, tablets may be coated by standard aqueous or non-aqueous techniques, and may be formulated for controlled-release using techniques well known in the art. Preferred controlled-release formulations are capsules and tablets.

0044Pharmaceutical compositions of the present invention suitable for oral administration may be presented as discrete pharmaceutical unit dosage forms, such as capsules, cachets, soft elastic gelatin capsules, tablets, or aerosols sprays, each containing a predetermined amount of the active ingredient, as a powder or granules, or as a solution or a suspension in an aqueous liquid, a non-aqueous liquid, an oil-in-water emulsion, or a water- in-oil liquid emulsion. Such compositions may be prepared by any of the methods of pharmacy, but all methods include the step of bringing into association the active ingredient with the carrier which constitutes one or more necessary ingredients. In general, the compositions are prepared by uniformly and intimately admixing the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product into the desired presentation.

0045For example, a tablet may be prepared by compression or molding, optionally, with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as powder or granules, optionally mixed with one or more of a binder, filler, lubricant, inert diluent, or surface active or dispersing agent. Molded tablets may be made by molding, in a suitable machine, a mixture of the powdered compound moistened with an inert liquid diluent and optionally one or more of a binder, filler, lubricant, inert diluent, or surface active or dispersing agent.

0046Optically pure S(+) vigabatrin for use in the present invention may be formulated as a pharmaceutical composition in a soft elastic gelatin capsule unit dosage form by using conventional methods well known in the art. See, e.g., Ebert, Pharm. Tech, l(5):44-50 (1977). Soft elastic gelatin capsules have a soft, globular gelating shell somewhat thicker than that of hard gelatin capsules, wherein a gelatin is plasticized by the addition of plasticizing agent, e.g., glycerin, sorbitol, or a similar polyol. The hardness of the capsule shell may be changed by varying the type of gelatin used and the amounts of plasticizer and water. The soft gelatin shells may contain a preservative, such as methyl- and propylparabens and sorbic acid, to prevent the growth of fungi. The active ingredient may be dissolved or suspended in a liquid vehicle or carrier, such as vegetable or mineral oils, glycols such as polyethylene glycol and propylene glycol, triglycerides, surfactants such as polysorbates, or a combination thereof.

0047Desirably, each unit dosage form, such as a tablet, capsule, cachet, or soft elastic gelatin capsule, contains from about 0.01 g to about 1 g of the active ingredient, and preferably from about 0.025 g to about 0.9 g of the active ingredient, and more preferably about 0.5 g to about 0.8 g of the active ingredient.

0048Optically pure S(+) vigabatrin for use in the present invention may also be formulated for parenteral administration by injection (subcutaneous, intramuscular, or intravenous), and may be dispensed in a unit dosage form, such as a multidose container or an ampule. Compositions of S(+) vigabatrin for parenteral administration may be in the form of suspensions, solutions, emulsions, or the like in aqueous or oily vehicles, and in addition to the active ingredient may contain one or more formulary agents, such as dispersing agents, suspending agents, stabilizing agents, preservatives, and the like. In addition to the common dosage forms set out above, the compounds of the present invention may also be administered by controlled-release means and/or delivery devices such as those described in U.S. Patent Nos.: 3,845,770; 3,916,899; 3,536,809; 3,598,123; 4,008,719; 5,674,533; 5,059,595; 5,591,767; 5,120,548; 5,073,543; 5,639,476; 5,354,556; and 5,733,566 the disclosures of which are incorporated herein by express reference thereto.

0049The controlled-release formulations of the present invention are capable of releasing the S(+) vigabatrin at the required rate to maintain substantially constant pharmacological activity for a period of time sufficient to provide therapeutic benefits. The S(+) vigabatrin may be prepared in a variety of controlled-release formulations, including, but not limited to, controlled-release pharmaceutical compositions in liquid dosage forms (U.S. Patent No. 5,674,533); controlled-release of active agents by the use of a gastro- resistant tablet (U.S. Patent No. 5,059,595); a liquid reservoir transdermal patch (U.S. Patent No. 5,591 ,767); a controlled-release drug delivery device comprised of swellable polymers (U.S. Patent No. 5,120,548); controlled-release formulations containing a trophic factor entrapped by a ganglioside-liposome vehicle (U.S. Patent No. 5,073,543); a stable solid controlled-release formulation having a coating derived from an aqueous dispersion of a hydrophobic acrylic polymer (U.S. Patent No. 5,639,476); a controlled-release powder that contains the active ingredient (U.S. Patent No. 5,354,566); and polymeric microparticles that release antiparasitic compositions (U.S. Patent No. 5,733,566).

0050In one embodiment, the controlled-release component is biodegradable, induced by exposure to the aqueous environment, pH, temperature, or enzymes in the body. In another embodiment, the controlled-release component may swell and form porous openings large enough to release S(+) vigabatrin after administration to a patient.

0051In another embodiment, controlled-release is achieved by the use of coated beads or granules. A solution of S(+) vigabatrin in a non-aqueous solvent, such as a mixture of acetone and alcohol, is coated onto granules, such as small inert seeds or beads, made of a combination of sugar and starch. These granules may be coated with a lipid material, such as beeswax, or a cellulosic material, such as ethylcellulose. The variation in the thickness of the coats and the type of material used in the coating is reflected by the speed the bodily fluids are capable of penetrating the coating and dissolving the S(+) vigabatrin. Preferably, various coating thicknesses of drug granules are present to produce a sustained and controlled-release of S(+) vigabatrin. In another embodiment, a portion of the drug granules is coated only with S(+) vigabatrin, while the remaining portion of the drug granules is coated with S(+) vigabatrin and the lipid material. The drug granules without the lipid material coating provide an initial dose of the drug, while the drug granules coated with the lipid material provide a controlled-release of S(+) vigabatrin.

0052In another embodiment, microencapsulation of S(+) vigabatrin is used in controlled-release applications. Microscopic size particles can form thin coatings of "wall" material around S(+) vigabatrin. Wall-forming materials include, but are not limited to, gelatin and synthetic polymers, such as polyvinyl alcohol, ethylcellulose, polyvinyl chloride, or a mixture thereof. Preferably, an additive, such as acacia, is used for its ability to concentrate wall-forming material into tiny liquid droplets that form a film or coat around the drug or drugs to be encapsulated.

0053In another embodiment, sol-gels may be used, wherein S(+) vigabatrin is incorporated into a sol-gel matrix that is a solid at room temperature. This matrix is implanted into a patient, preferably a mammal, and more preferably a human, having a body temperature high enough to induce gel formation of the sol-gel matrix, thereby releasing S(+) vigabatrin into the patient.

0054In another embodiment, the drug may be embedded in an inert plastic matrix. S(+) vigabatrin is granulated with an inert plastic material, such as polyethylene, polyvinyl acetate, polymethacrylate, or a mixture thereof, and the granulation is compressed into tablets. S(+) vigabatrin is slowly released from the inert plastic matrix by leaching via bodily fluids.

0055In another embodiment, repeat action formulations release two full doses of S(+) vigabatrin sequentially. This method utilizes specialized tablets that release an initial dose of S(+) vigabatrin from the tablet shell, and a second dose is released from an inner core of the tablet, separated from the outer shell by a slowly permeable baffler coating. Moreover, any suitable method known to those of ordinary skill in the art for formulating controlled-release dosage forms may be employed according to the invention.

0056The invention is further defined by reference to the following examples, describing in detail the preparation of the compound and the compositions of the present invention, as well as their utility. It will be apparent to those skilled in the art that many modifications, both to materials and methods, may be practiced without departing from the purpose and interest of this invention.

0057EXAMPLES 5.1 EXAMPLE 1: Potency and Specificity

0058The relative potency and specificity of optically pure S(+)vigabatrin, as compared to R(-)vigabatrin and racemic vigabatrin, as a potent irreversible inhibitor of GABA-T may be determined by pharmacological study. As a consequence of this enzyme's inhibition activity, the compounds will produce proportional increases in concentration of the inhibitory neurotransmitter GABA. The relative specificity of the compounds may be determined against cerebral neuronal and glial cell GABA-T.

0059Because transamination by GABA-T otherwise represents the significant catabolic pathway of cerebral GABA, the irreversible inhibition of GABA-T by S(+) vigabatrin results in an elevation of brain GABA levels throughout the brain. However, glial GABA-T is less sensitive to S(+) vigabatrin, presumably for the lack of an uptake system for the drug into glial cells. Thus the drug may preferentially influence amounts of cerebral neuronal, synaptically-released GABA. Rogawski, M.A., et al, Pharm. Rev., 42(3):223-286 (1990); Jung, M.T, et al, J. Neurochem. 29:797-802 (1977); Abdul-Ghani, A.S., et al, Biochem. Pharm. 30:1203-1209 (1981); Larsson, O.M., et al, Neuropharm. 25:617-625 (1986).

0060The test systems are based on tissue culture techniques with two distinct cerebral cell types: a) cerebral neurons with characteristics of GABAergic neurons derived from cultured cerebral cortex of 15 day mouse embryos, and b) astrocytes obtained by culture of cortical tissue of newborn mice. See Gram, L., et al, Brit. J. Clin. Pharm. 27, (Suppl. 1):13S-18S (1989). Racemic vigabatrin and its stereoisomers may be incubated with the tissue cultures of 10 minutes at 37°C, or alternatively the compounds may be present throughout the full incubation period with the cell cultures. As a function of their molar concentration, S(+)vigabatrin, R(-)vigabatrin and racemic vigabatrin may be compared for their ability to inhibit both preparations of neuronal GABA-T and glial cell GABA-T. The drugs may be compared at the concentrations that inhibit by 50% the enzyme activity of the appropriate GABA-T (IC₅₀). Further, the concentrations of the drugs may be compared for their ability to increase both the cell content, and the neurotransmitter, GABA. (See aforementioned references, and Gram, L., et al, Brit. J. Clin., Pharm. 27, (Suppl. 1):13S-18S (1989)).

00615.2 EXAMPLE 2: Oral Formulation

0062Table 1 : Compressed Tablets

0063<img file="WO0010554A2_D0001.tif" />

0064The active ingredient, S(+) vigabatrin, is sieved through a suitable sieve and blended with the lactose until a uniform blend is formed. Suitable volumes of water are added and the powders are granulated. After drying, the granules are then screened and blended with the remaining excipients. The resulting granules are then compressed into tablets of desired shape. Tablets of other strengths may be prepared by altering the ratio of active ingredient to the excipient(s) or the compression weight.

00655.3 EXAMPLE 3: Controlled-Release Formulation- S.+. Vigabatrin Coated Beads

0066A suspension of S(+) vigabatrin and HPMC (Opadry^®Clear Y-5-7095) may be applied onto 18/20 mesh Nupariel beads in a fluid bed dryer with a Wurster insert at an inlet temperature of 60°C. An Opadry^® Lavender YS-1-4729 HMPC Base filmcoating suspension is then applied after drug loading as a protective coat at a 5% weight gain.

0067After the overcoating process is complete, the S(+) vigabatrin beads are then overcoated with a retardant coating mixture of Eudragit^® RS 30D and Eudragit^® RL 30D at a ratio of 90:10, RS to RL, at a 5% weight gain level. The application of this mixture of

0068Eudragit^® RS 30D and Eudragit^® RL 30D along with talc (included as an antitacking agent) and triethyl citrate (plasticizer) is done at an inlet temperature of 35°C in a Wurster insert. The resulting S(+) vigabatrin beads are given a final overcoat of Opadry^® Lavender YS 1-4729 at a 5% weight gain level, and cured on paper- lined trays in a 45°C dry oven for 2 days. After the curing process is complete, the S(+) vigabatrin beads are filled into gelatin capsules at 0.5 g S(+) vigabatrin strength. All Opadry^® products used in this example and the following examples are available from Colorcon, West Point, PA. All Eudragit^® products used in this example and the following examples are available from Rohm Pharma. The final formula is provided in Table 2 below:

0069Table 2 - Final Formulation of S(+) Vigabatrin Gelatin Capsules

0070<img file="WO0010554A2_D0002.tif" />

00715.4 EXAMPLE 4: Controlled-Release Formulation .S(+) Vigabatrin and Acrylic Polymer Coating

0072S(+) vigabatrin beads are prepared by dissolving S(+) vigabatrin in water, adding Opadry^® Y-5-1442, light pink and mixing for about 1 hour to obtain a 20% w/w suspension. This suspension is sprayed onto Nupareil 18/20 mesh beads using a Wurster insert.

0073The loaded S(+) vigabatrin beads are overcoated to form a protective coating with a 5% w/w gain of Opadry^® Light Pink using a Wurster insert. A retardant coating is then applied to the S(+) vigabatrin beads by coating them with a 5% weight gain of a mixture of Eudragit^® RS 30D and Eudragit^® RL 30D at a ratio of 90:10, RS to RL. The addition of triethyl citrate (plasticizer) and talc (anti-tacking agent) is also included in the Eudragit suspension. A Wurster insert is used to apply the coating suspension.

0074After the retardant coating is applied, the S(+) vigabatrin beads are given a final overcoat of Opadry^® Light Pink to a 5% weight gain using a Wurster insert, and cured in a45°C oven for two days. The cured beads are then filled into gelatin capsules at a 0.05 g S(+) vigabatrin strength. The complete formula is shown in Table 3 below:

0075Table 3 - Final Formulation of S(+) Vigabatrin Gelatin Capsules

0076<img file="WO0010554A2_D0003.tif" />

00775.5 EXAMPLE 5: Preparation of S(+) Vigabatrin Microgranulate

0078A mixture of 80% (w/w) S(+) vigabatrin, 10% (w/w) polyvinylpyrrolidone (PVP K30), and 10% (w/w) 450-mesh lactose may be wetted with 500 mL water and mixed in a mixer-granulator for 10 minutes. A 5% (w/w) solution of polyethylene glycol (PEG 6000) is added as an aqueous solution to the stirred mixture at a rate of 25 mL/min using a 0.8 mm nozzle at a pressure of 2 bars. During the wetting step, the mixer speed is 175 rpm and the speed of the mill is 3000 rpm. After wetting, the kneading and rounding step is done by maintaining mixer and mill speeds at a constant rate for 15 minutes. The resulting microgranulate is dried in an artificial ventilation incubator and sieved through a 225- mesh/cm² screen until a microgranulate with a granule size distribution ranging from 90 μm and a spheroidal shape was obtained. 5.6 EXAMPLE 6: Coating of Microgranulates

0079A. First Film Layer

0080Two kilograms of the microgranulate prepared in accordance with Example 5 are stiπed for 1 minute in a Glatt GPCG3 (Glad, GmbH, Buizen Lorrach, Germany) fluidizer into which air heated to a temperature of 40°C to 45°C was blown at a rate of 40 mVhour. The granulate was sprayed at a pressure of 2 bars and a rate of 10 to 13 g/min with 400 mL of a solution having the following weight percent composition:

0081<img file="WO0010554A2_D0004.tif" />

0082B. Second Film Layer (Waxes)

0083A solution having the following weight percent composition was prepared:

0084<img file="WO0010554A2_D0005.tif" />

00851.15 g of this solution may be applied to 2 kg of the microgranulate previously coated with a first layer as described in Section A of Example 6. The identical operating conditions as in Section A of Example 6 are used in this case. Additional layers may optionally be coated on the beads as described in Section A of Example 6. 5.7 EXAMPLE 7- Oral Liquid Formulation of S.+) Vigabatrin

0086A microgranulate, prepared as described in Example 5 and coated with three successive layers as described in Example 6, may be added to a final proportion of 12.5% (w/w), to a mixture containing 6.2% (w/w) microcrystalline cellulose, 0.8% (w/w) sodium carboxymethylcellulose, 0.5% (w/w) sodium citrate, 0.8% (w/w) citric acid, 0.2 % (w/w) methylparaben. 0.05% (w/w) propylparaben, 2% (w/w) tragacanth, 0.05% (w/w) Span 20 surfactant, 0.2% (w/w) dimethylpolysiloxane, 0.0 1% (w/w) glycamil, 0.25% (w/w) orange- grapefruit flavor, and powdered sugar to 100%. Adding 80 g water to 33 g of this suspension gives a suspension containing 30 mg/mL S(+) vigabatrin. While the present invention has been described with respect to the particular embodiments, it will be apparent to those skilled in the art that various changes and modifications may be made without departing from the spirit and scope of the invention as defined in the claims. Such modifications are also intended to fall within the scope of the appended claims.