Compositions and methods for treating epilepsy, seizures and other conditions

Abstract

Compositions are provided for the liquid oral administration of topiramate and its salts. The invention further provides methods for treating diseases and disorders using the compositions.

1 . A liquid pharmaceutical composition comprising:
 i. topiramate, or a pharmaceutically acceptable addition salt thereof, in an amount of from about 1.2% w/v (i.e., 12 mg/ml) to about 10% w/v (i.e., 100 mg/ml); and   ii. a solvent component comprising one or more organic solvents in an amount of from about 80% to about 120% w/v;   iii. wherein the pharmaceutical composition is substantially anhydrous.   
     
     
         2 . The liquid pharmaceutical composition of  claim 1 , wherein;
 the total amount of water present in the composition is 0.35% w/w or less; and   the pharmaceutical composition is a liquid for oral administration and is ready to use.   
     
     
         3 - 4 . (canceled) 
     
     
         5 . The liquid pharmaceutical composition of  claim 1  wherein the composition is stable for either at least 24 months at 20-25° C. or for at least 24 months at controlled room temperature. 
     
     
         6 . (canceled) 
     
     
         7 . The liquid pharmaceutical composition of  claim 1 , wherein the topiramate is in the form of a free acid, and is present in an amount of from about 2.0% to about 3.0% w/v. 
     
     
         8 - 9 . (canceled) 
     
     
         10 . The liquid pharmaceutical composition of  claim 1 , wherein the organic solvents are selected from polyethers, lower polyhydroxy alcohols, ethanol, propylene glycol, isosorbide dimethyl ether, di(ethylene glycol) ethyl ether, mineral oil; light mineral oil; glycols, such as glycerol behenate and polyethylene glycols (PEGs), hydrogenated vegetable oil, including cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, soybean oil, and mixtures thereof, for example glycerin and polyethylene glycols of molecular weight 300 to about 1000, for example glycerin and polyethylene glycols of molecular weight about 400. 
     
     
         11 - 13 . (canceled) 
     
     
         14 . The liquid pharmaceutical composition of  claim 10 , wherein the organic solvents comprise glycerin which is present in the composition in an amount of about 60% to about 70%, or about 60% to about 65%, or about 63%, and the polyethylene glycol of molecular weight about 400 which is present in the composition in an amount of about 40% to about 60%, or about 45% to about 55%, or about 50%; wherein the composition optionally further comprises one or more preservatives selected from parabens, benzyl alcohol, benzoic acid, sorbic acid, sodium benzoate, and antibacterial agents selected from halogenated diphenyl ether (e.g. triclosan), herbal extracts and essential oils (e.g., rosemary extract, tea extract,  magnolia  extract, thymol, menthol, eucalyptol, geraniol, carvacrol, citral, hinokitol, catechol, methyl salicylate, epigallocatechin gallate, epigallocatechin, gallic acid, miswak extract, sea-buckthorn extract), bisguanide antiseptics (e.g., chlorhexidine, alexidine or octenidine), quaternary ammonium compounds (e.g., cetylpyridinium chloride (CPC), benzalkonium chloride, tetradecylpyridinium chloride (TPC), N-tetradecyl-4-ethylpyridinium chloride (TDEPC)), phenolic antiseptics, hexetidine, octenidine, sanguinarine, povidone iodine, delmopinol, salifluor, phthalic acid, monoperthalic acid and its esters, ascorbyl stearate, oleoyl sarcosine, alkyl sulfate, dioctyl sulfosuccinate, salicylanilide, domiphen bromide, delmopinol, octapinol and other piperidino derivatives, nicin preparations, and mixtures of any of the foregoing. 
     
     
         15 - 20 . (canceled) 
     
     
         21 . The liquid pharmaceutical composition of  claim 1 , comprising the following components:
 b. polyethylene glycol 400 in an amount of about 50% w/v;   c. a paraben component comprising one or more parabens, the paraben component being in an amount of about 2.4% w/v;   d. glycerin in an amount of about 40% w/v to about 70% w/v for example from about 60% to about 65%, or about 63%;   e. topiramate, or a pharmaceutically acceptable addition salt thereof, in an amount of about 2.5% w/v;   f. one or more sweeteners in an amount of about 1% w/v; and   g. a flavor component comprising one or more flavor compounds, the flavor component being in an amount of about 0.2% w/v;   
       wherein the composition has one or more of the following features:
 h. a refractive index of from about 1.3 to about 1.38; 
 i. a viscosity of 300-600 cps, for example 450 cps; or 
 j. a density of 1.1-1.3, for example about 1.2 g/ml. 
 
     
     
         22 - 26 . (canceled) 
     
     
         27 . A dosage dispensing unit comprising the composition of  claim 1 . 
     
     
         28 - 31 . (canceled) 
     
     
         32 . A direct dosing device comprising a composition according to  claim 1 , for example: a syringe, for example an oral syringe, a cup for example a dosing cup, an ampoule, a vial, a spoon for example a dosage spoon, teaspoon or tablespoon, a dropper or dropper assembly, a pipette, or a measuring device with graduations. 
     
     
         33 - 37 . (canceled) 
     
     
         38 . The direct dosing device of  claim 32 , wherein the direct dosing device contains from 25 mg to 400 mg of topiramate or a pharmaceutically acceptable addition salt thereof. 
     
     
         39 - 111 . (canceled) 
     
     
         112 . A liquid oral pharmaceutical composition according to  claim 1 ,
 wherein a composition having topiramate in an amount of 2.5% w/v (i.e., 25 mg/ml) is bioequivalent to a 25 mg topiramate capsule formulation, wherein the capsule formulation comprises topiramate-coated beads in a hard gelatin capsule, wherein the amount of topiramate in the capsule formulation is 25 mg, and the inactive ingredients of the capsule formulation comprise cellulose acetate, gelatin, povidone, sodium lauryl sulfate, sorbitan monolaurate, sugar spheres comprising sucrose and starch; for example wherein the capsule formulation further comprises pharmaceutically acceptable dyes or pigments, e.g., black pharmaceutical ink and/or titanium dioxide.   
     
     
         113 . (canceled) 
     
     
         114 . The liquid oral pharmaceutical composition of claim  112 , wherein:
 the topiramate, or pharmaceutically acceptable addition salt thereof, is present in an amount of about 2.5% w/v (i.e., 25 mg/ml); and   the composition exhibits a total amount of topiramate absorbed that is bioequivalent to a 25 mg topiramate capsule formulation, wherein the capsule formulation comprises topiramate-coated beads in a hard gelatin capsule, wherein the amount of topiramate in the capsule formulation is 25 mg, and the inactive ingredients of the capsule formulation comprise cellulose acetate, gelatin, povidone, sodium lauryl sulfate, sorbitan monolaurate, sugar spheres comprising sucrose and starch; for example wherein the capsule formulation further comprises pharmaceutically acceptable dyes or pigments, e.g., black pharmaceutical ink and/or titanium dioxide upon administration to a human subject, wherein the bioequivalence of the total amount of topiramate absorbed is established by a 90% confidence interval for AUC 0-∞  and AUC 0-t  which is between 80% and 125% upon administration with or without food.   
     
     
         115 . (canceled) 
     
     
         116 . (canceled) 
     
     
         117 . A liquid oral pharmaceutical composition comprising topiramate, or a pharmaceutically acceptable addition salt thereof, that is bioequivalent to a 25 mg topiramate capsule formulation, wherein the capsule formulation comprises topiramate-coated beads in a hard gelatin capsule, wherein the amount of topiramate in the capsule formulation is 25 mg, and the inactive ingredients of the capsule formulation comprise cellulose acetate, gelatin, povidone, sodium lauryl sulfate, sorbitan monolaurate, sugar spheres comprising sucrose and starch; for example wherein the capsule formulation further comprises pharmaceutically acceptable dyes or pigments, e.g., black pharmaceutical ink and/or titanium dioxide. 
     
     
         118 . The liquid oral pharmaceutical composition of  claim 114 , wherein:
 when the topiramate, or pharmaceutically acceptable addition salt thereof, is present in an amount of about 2.5% w/v (i.e., 25 mg/ml), the composition exhibits:   a fasting median Tmax (in hours) of from about 0.3 to about 1.25, or from about 0.3 to about 1.0, or from about 0.3 to about 0.7, or about 0.5; and/or   a fed median Tmax (in hours) of from about 3 to about 8, or from about 4 to about 7, or from about 5 to about 6, or about 5.5.   
     
     
         119 - 120 . (canceled) 
     
     
         121 . The liquid pharmaceutical composition of  claim 1 , comprising the following components:
 a. polyethylene glycol 400 in an amount of about 45% to about 55% w/v;   b. glycerin in an amount of about 60% to about 65%; and   c. topiramate, or a pharmaceutically acceptable addition salt thereof, in an amount of about 2.5% w/v.   
     
     
         122 . The liquid pharmaceutical composition of  claim 121 , further comprising one or more of the following components:
 d. a paraben component comprising one or more parabens;   e. one or more sweeteners; and   f. a flavor component comprising one or more flavor compounds.   
     
     
         123 . The liquid pharmaceutical composition of  claim 1 , comprising the following components:
 a. polyethylene glycol 400 in an amount of about 50% w/v;   b. glycerin in an amount of about 63%; and   c. topiramate, or a pharmaceutically acceptable addition salt thereof, in an amount of about 2.5% w/v.   
     
     
         124 . The liquid pharmaceutical composition of  claim 123 , further comprising one or more of the following components:
 d. a paraben component comprising one or more parabens;   e. one or more sweeteners; and   f. a flavor component comprising one or more flavor compounds.   
     
     
         125 . A dosage dispensing unit comprising the liquid pharmaceutical composition of  claim 121 . 
     
     
         126 . A direct dosing device comprising the liquid pharmaceutical composition of  claim 121 .