Methods and compositions for the treatment of seizure-related disorders

Abstract

Compositions and methods are provided for administering a pharmaceutical composition to a human patient. Compositions are administered to a human patient orally, once daily, at a therapeutically effective dose. The pharmaceutical compositions comprise a drug selected from the group consisting of brivaracetam, divalproex, lacosamide, levetiracetam, oxcarbazepine, vigabatrin, and pharmaceutically acceptable salts of any of the foregoing, and at least one excipient. At least one of said at least one excipients modifies the release of said drug to provide an extended release form. The pharmaceutical composition have pharmacokinetic properties recited in the claims.

1 - 30 . (canceled) 
     
     
         31 : A method of treating seizure disorder in a human patient in need thereof, comprising administering to said human patient orally, once daily, a therapeutically effective dose of a pharmaceutical composition, wherein said pharmaceutical composition comprises one or more pellets or a matrix tablet;
 wherein the pellet comprises   (i) a drug, wherein the drug is lacosamide or a pharmaceutically acceptable salt thereof; and   (ii) one or more extended release excipients selected from the group consisting of plastic matrices, cellulosic polymers, hydroxyalkyl celluloses, cross-linked acrylic acid polymers, polyethylene oxides, waxes, wax-like substances, and acrylic polymers;   wherein the matrix tablet comprises   (iii) a matrix forming material comprising a drug, wherein the drug is lacosamide or a pharmaceutically acceptable salt thereof; and   (iv) wherein the matrix forming material comprises one or more extended release excipients selected from the group consisting of waxes, oils, hardened oil or fats, microcrystalline cellulose, powdered cellulose, ethyl cellulose, hydroxypropyl cellulose, polyvinylpyrrolidone, hydroxypropyl methyl cellulose, and polyethylene glycol; and   
       wherein the pellet or matrix tablet comprises:
 (v) a pH-dependent coating comprising at least one polymer comprising methacrylic acid, an acrylic ester, a methacrylic ester, a cellulose ester, a cellulose ester derivative, or polyvinyl derivative, or combinations thereof; 
 wherein said pharmaceutical composition has a dissolution profile characterized by less than 6% release at two hours, and one or more of the following:
 (a) less than 26% release at 4 hours, 
 (b) less than 42% release at 6 hours, 
 (c) at least 35% release at 9 hours 
 (d) at least 65% release at 12 hours 
 wherein said dissolution is carried out in 900 mL simulated gastric fluid (pH 1.2) at 37±0.5° C. for the first two hours, followed by 900 mL simulated intestinal fluid (pH 6.8) at 37±0.5° C. for the subsequent four hours, followed by 900 mL phosphate buffer (pH 7.5) at 37±0.5° C. for the subsequent 18 hours, wherein all dissolution is performed in a USP Apparatus 1 (Basket), with a rotational speed of 100 rpm; and 
 
 wherein said pharmaceutical composition has a plasma concentration profile for said drug characterized by a T max  of 8 to 20 hours as determined by oral administration of a single dose of said pharmaceutical composition to a fasted human subject. 
 
     
     
         32 : The method of  claim 31 , wherein the pellet further comprises a pore former. 
     
     
         33 : The method of  claim 32 , wherein the pore former is povidone or hydroxypropyl methyl cellulose. 
     
     
         34 : The method of  claim 31 , wherein the pellet one or more extended release excipients comprises a cellulosic polymer, wherein the cellulosic polymer is selected from the group consisting of methyl cellulose, ethyl cellulose, hydroxypropyl cellulose, and sodium carboxymethyl cellulose. 
     
     
         35 : The method of  claim 32 , wherein the pellet one or more extended release excipients comprises a cellulosic polymer, wherein the cellulosic polymer is selected from the group consisting of methyl cellulose, ethyl cellulose, hydroxypropyl cellulose, and sodium carboxymethyl cellulose. 
     
     
         36 : The method of  claim 31 , wherein the pellet comprises an inert core, a drug layer, and an extended release coating comprising the one or more extended release excipients. 
     
     
         37 : The method of  claim 36 , wherein the drug layer further comprises a binder, and wherein the binder is one or more of hydroxypropyl methyl cellulose, copovidone, povidone, hydroxypropyl cellulose, hydroxyethyl cellulose, methyl cellulose, or carboxymethyl cellulose. 
     
     
         38 : The method of  claim 31 , wherein the pellet is an extruded mixture comprising drug and the one or more extended release excipients. 
     
     
         39 : The method of  claim 31 , wherein the extruded mixture further comprises a binder, wherein the binder is one or more of hydroxypropyl methyl cellulose, copovidone, povidone, hydroxypropyl cellulose, hydroxyethyl cellulose, methyl cellulose, or carboxymethyl cellulose. 
     
     
         40 : The method of  claim 31 , wherein the one or more extended release excipients of the matrix forming material comprises a wax, and the wax is carnauba, bees wax, paraffin wax, ceresine, shellac wax, a fatty acid, or a fatty alcohol. 
     
     
         41 : The method of  claim 31 , wherein the one or more extended release excipients of the matrix forming material comprises a hardened oil or fat and the hardened oil or fat is hardened rapeseed oil, castor oil, beef tallow, palm oil, or soya bean oil. 
     
     
         42 : The method of  claim 31 , wherein the pH dependent coating comprises methacrylic acid, acrylic acid, methyl methacrylate, or ethoxyethyl methacrylate, or any combinations thereof. 
     
     
         43 : The method of  claim 31 , wherein said therapeutically effective dose is 100 mg to 700 mg of said drug, and said pharmaceutical composition comprises one, two, three, or four unit dosage forms. 
     
     
         44 : The method of  claim 31 , wherein said pharmaceutical composition has a plasma concentration profile for said drug characterized by a T max  of 12 to 20 hours as determined by oral administration of a single dose of said pharmaceutical composition to a fasted human subject. 
     
     
         45 : The method of  claim 31 , wherein said pharmaceutical composition has a steady state plasma concentration profile for said drug upon once daily oral administration of said pharmaceutical composition characterized by a T max,ss  of 10 to 20 hours, as determined by oral administration of said pharmaceutical composition to a fasted human subject. 
     
     
         46 : The method of  claim 31 , wherein said plasma concentration profile for said drug is further characterized by the AUC 0-inf  providing AUC equivalence to the same daily dose of an immediate release form. 
     
     
         47 : The method of  claim 31 , wherein said pharmaceutical composition is administered 0 to 4 hours before bedtime. 
     
     
         48 : The method of  claim 31 , wherein said pharmaceutical composition is administered between the hours of 8:00 pm and 12:00 am. 
     
     
         49 : The method of  claim 31 , wherein said pharmaceutical composition comprises one, two, or three unit dosage forms, wherein each unit dosage form comprises 200 mg of lacosamide. 
     
     
         50 : The method of  claim 31 , wherein the administration of the pharmaceutical composition results in a reduced frequency or severity of one or more side effects of lacosamide, as compared to the administration of the same daily dose of an immediate release form of lacosamide or a pharmaceutically acceptable salt thereof. 
     
     
         51 : The method of  claim 31 , wherein the administration of a single dose of the pharmaceutical composition results in a reduced frequency or severity of one or more side effects of lacosamide, as compared to the administration of the same dose of an immediate release form of lacosamide or a pharmaceutically acceptable salt thereof. 
     
     
         52 : The method of  claim 50 , wherein the one or more side effects is psychosis, dizziness, cognitive deficits, headache, ataxia, somnolence, tremor, nystagmus, balance disorder, cardiac complications, vertigo, diplopia, blurred vision, nausea, vomiting, diarrhea, fatigue, gait disturbance, asthenia, depression, pruritus, neutropenia, anemia, tinnitus, constipation, dehydration, dry mouth, irritability, pyrexia, increased incidence of falls, muscle spasms, paresthesia, cognitive disorder, hypoaesthesia, dysarthria, disturbance in attention, cerebellar syndrome, confusion, or mood disorders, or any combinations thereof. 
     
     
         53 : The method of  claim 51 , wherein the one or more side effects is dizziness, headache, somnolence, tremor, nystagmus, cardiac complications, diplopia, blurred vision, nausea, vomiting, diarrhea, fatigue, asthenia, pruritus, tinnitus, constipation, dehydration, dry mouth, irritability, pyrexia, muscle spasms, paresthesia, hypoaesthesia, or confusion, or any combinations thereof. 
     
     
         54 : The method of  claim 31 , wherein the fasted human subject in which the T max  is determined is a subject of a fasted, single dose, human pharmacokinetic study. 
     
     
         55 : The method of  claim 44 , wherein the fasted human subject in which the T max  is determined is a subject of a fasted, single dose, human pharmacokinetic study. 
     
     
         56 : The method of  claim 45 , wherein the fasted human subject in which the T max,ss  is determined is a subject of a fasted human pharmacokinetic study. 
     
     
         57 : The method of  claim 31 , wherein the seizure disorder is characterized by partial onset seizures. 
     
     
         58 : A method of treating a seizure disorder in a human patient in need thereof, comprising administering to said human patient orally, once daily, a therapeutically effective dose of a pharmaceutical composition, wherein said pharmaceutical composition comprises one or more pellets or a matrix tablet:
 wherein the pellet comprises   (i) a drug, wherein the drug is lacosamide or a pharmaceutically acceptable salt thereof; and   (ii) one or more extended release excipients selected from the group consisting of plastic matrices, cellulosic polymers, hydroxyalkyl celluloses, cross-linked acrylic acid polymers, polyethylene oxides, waxes, wax-like substances, and acrylic polymers;   wherein the matrix tablet comprises   (iii) a matrix forming material comprising a drug, wherein the drug is lacosamide or a pharmaceutically acceptable salt thereof; and   (iv) wherein the matrix forming material comprises one or more extended release excipients selected from the group consisting of waxes, oils, hardened oil or fats, microcrystalline cellulose, powdered cellulose, ethyl cellulose, hydroxypropyl cellulose, polyvinylpyrrolidone, hydroxypropyl methyl cellulose, and polyethylene glycol; and   
       wherein the pellet or matrix tablet comprises:
 (v) a pH-dependent coating comprising at least one polymer comprising methacrylic acid, an acrylic ester, a methacrylic ester, a cellulose ester, a cellulose ester derivative, or polyvinyl derivative, or combinations thereof; 
 wherein said pharmaceutical composition has a dissolution profile characterized by less than 6% release at two hours, and one or more of the following:
 (a) less than 26% release at 4 hours, 
 (b) less than 42% release at 6 hours, 
 (c) at least 35% release at 9 hours 
 (d) at least 65% release at 12 hours 
 wherein said dissolution is carried out in 900 mL simulated gastric fluid (pH 1.2) at 37±0.5° C. for the first two hours, followed by 900 mL simulated intestinal fluid (pH 6.8) at 37±0.5° C. for the subsequent four hours, followed by 900 mL phosphate buffer (pH 7.5) at 37±0.5° C. for the subsequent 18 hours, wherein all dissolution is performed in a USP Apparatus 1 (Basket), with a rotational speed of 100 rpm; and 
 
 wherein said pharmaceutical composition has a plasma concentration profile for said drug characterized by a median T max  of 8 to 20 hours as determined by oral administration of said pharmaceutical composition to human subjects of a fasted, single dose, human pharmacokinetic study. 
 
     
     
         59 : The method of  claim 58 , wherein the pellet comprises an inert core, a drug layer, and an extended release coating comprising the one or more extended release excipient. 
     
     
         60 : The method of  claim 59 , wherein the pellet is an extruded mixture comprising drug and the one or more extended release excipients. 
     
     
         61 : The method of  claim 58 , wherein the seizure disorder is characterized by partial onset seizures.