Topiramate Compositions and Methods of Making and Using the Same

Abstract

The present invention is directed to compositions comprising topiramate and a sulfoalkyl ether cyclodextrin, and methods of making and using the same.

1 . A composition comprising topiramate, or a salt thereof, and compound of Formula I: 
     
       
         
         
             
             
         
       
     
     wherein: n is 4, 5 or 6; R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8  and R 9  are each, independently, —O— or a —O—(C 2 -C 6  alkylene)-SO 3   −  group, wherein at least one of R 1  and R 2  is independently a —O—(C 2 -C 6  alkylene)-SO 3   −  group; and S 1 , S 2 , S 3 , S 4 , S 5 , S 6 , S 7 , S 8  and S 9  are each, independently, H or a pharmaceutically acceptable cation. 
   
   
       2 . The composition of  claim 1 , wherein at least one of R 1  and R 2  is independently a —O—(C 2 -C 6  alkylene)-SO 3   −  group that is a —O—(CH 2 ) m SO 3   −  group, wherein m is 2 to 6, and the pharmaceutically acceptable cation is H, an alkali metal, an alkaline earth metal, an ammonium ion, or an amine cation. 
   
   
       3 . The composition of  claim 1 , wherein the compound of Formula I is a compound of Formula III: 
     
       
         
         
             
             
         
       
     
     wherein R═(H) 21 —, or (—(CH 2 ) 4 —SO 3 Na) x . 
   
   
       4 . The composition of  claim 3 , wherein x=6.0-7.1. 
   
   
       5 . The composition of  claim 1 , wherein the topiramate is present in the composition at a concentration of about 5 mg/mL to about 100 mg/mL. 
   
   
       6 . The composition of  claim 1 , wherein the topiramate is present in the composition at a concentration of about 5 mg/mL to about 50 mg/mL. 
   
   
       7 . The composition of  claim 1 , wherein the topiramate is present in the composition at a concentration of about 10 mg/mL to about 20 mg/mL. 
   
   
       8 . The composition of  claim 1 , wherein the compound of Formula I is present in the composition at a concentration of about 1 mg/mL to about 700 mg/mL. 
   
   
       9 . The composition of  claim 1 , wherein the compound of Formula I and topiramate are present in a ratio of about 1.4:1. 
   
   
       10 . The composition of  claim 1 , wherein the compound of Formula I and topiramate are present in a ratio of about 1.4:1 or greater. 
   
   
       11 . The composition of  claim 1 , wherein the compound of Formula I and topiramate are present in a ratio of about 1.4:1 to about 5:1. 
   
   
       12 . The composition of  claim 1 , further comprising a pharmaceutically acceptable carrier. 
   
   
       13 . The composition of  claim 1 , wherein the composition is an aqueous solution that is stable at 25° C. for a period of at least 12 weeks. 
   
   
       14 . The composition of  claim 1 , wherein the composition is an aqueous solution that is stable at 40° C. for a period of at least 12 weeks. 
   
   
       15 . The composition of  claim 1 , wherein the composition provides a similar bioavailability of topiramate upon either intravenous administration or oral administration to a subject. 
   
   
       16 . A method for treating a patient who has or is at risk for developing a condition amenable to treatment with topiramate, the method comprising parenterally administering an effective amount of the composition of  claim 1  to the patient so as to treat the condition. 
   
   
       17 . The method of  claim 16 , wherein the condition is selected from epilepsy, seizures, anoxia, stroke, status epilepticus, refractory status epilepticus, gambling addiction, migraines, substance dependence, alcoholism, cocaine dependence, nicotine dependence, metabolic syndrome X, diabetes mellitus, type 2, vomiting, obsessive-compulsive disorder, refractory generalized social phobia, Tourette syndrome, levodopa-induced dyskinesia in Parkinson's Disease, refractory POS, Prader-Willi syndrome, multiple sclerosis, Lennox-Gastaut syndrome, Dravet's syndrome, bipolar disorder, obesity, post traumatic stress disorder, cluster headaches, severe headaches, and conditions caused by exposure to a chemical warfare nerve agent. 
   
   
       18 . A method for providing neuroprotection in a patient, comprising administering an effective amount of the composition of  claim 1  intravenously to the patient. 
   
   
       19 . The method of  claim 18 , wherein the patient is a neonatal patient. 
   
   
       20 . The method of  claim 19 , wherein the neonatal patient suffers from hypoxic-ischemic encephalopathy, subdural hematoma, or infection. 
   
   
       21 . The method of  claim 18 , wherein the neuroprotection is needed during surgery. 
   
   
       22 . The method of  claim 16 , wherein oral topiramate therapy for the patient has been interrupted. 
   
   
       23 . The method of  claim 16 , wherein the patient is a neonatal patient. 
   
   
       24 . The method of  claim 23 , wherein the neonatal patient suffers from hypoxic-ischemic encephalopathy, subdural hematoma, or infection. 
   
   
       25 . The method of  claim 16 , wherein the patient is a pediatric patient, an adult patient, or a geriatric patient. 
   
   
       26 . The method of  claim 16 , wherein the composition of  claim 1  is administered once or twice daily. 
   
   
       27 . The method of  claim 16 , wherein the effective amount comprises about 0.2 mg/kg/day to about 50 mg/kg/day topiramate. 
   
   
       28 . The method of  claim 16 , wherein the effective amount comprises about 0.5 mg/kg/day to about 15 mg/kg/day topiramate. 
   
   
       29 . The method of  claim 16 , wherein the effective amount comprises about 1 mg/kg/day to about 10 mg/kg/day topiramate. 
   
   
       30 . The method of  claim 16 , wherein the effective amount comprises about 1 mg/kg/day to about 5 mg/kg/day topiramate. 
   
   
       31 . The method of  claim 16 , wherein the composition is administered intravenously and has a similar effectiveness as a similar dose of topiramate that is orally administered. 
   
   
       32 . A method for loading a patient to attain an effective topiramate concentration, the method comprising parenterally administering to the patient an amount of the composition of  claim 1  comprising a topiramate loading dose. 
   
   
       33 . The method of  claim 32 , wherein the topiramate loading dose, LD(mg), is an amount of topiramate given by:
     LD (mg)=[ TPM (mg/L)]×(0.7 L/kg)×( P (kg))   
     where [TPM(mg/L)] is a target change in the in vivo topiramate concentration of the patient, and P(kg) is the mass of the patient in kilograms.