Synergistic compositions comprising (R)-dimiracetam (1) and (S)-dimiracetam (2) in a non-racemic ratio

Abstract

The present invention relates to a composition of enantiomers of 3,6,7,7a-tetrahydro-1H-pyrrolo[1,5-a]imidazole-2,5-dione and pharmaceutically acceptable solvates or co-crystals thereof in a certain ratio, a pharmaceutical composition comprising said composition, its use as a medicament and the use of the inventive compositions or pharmaceutical compositions in the treatment and/or prevention of a disease or disorder typically and preferably selected from peripheral sensory neuropathy, preferably peripheral neuropathic pain; seizure; depression; or cognitive impairment.

What is claimed is: 
     
         1 . A method of treating a sensory symptom of peripheral nerve damage in a subject, comprising:
 administering to the subject a composition comprising (R)-3,6,7,7a-tetrahydro-H-pyrrolo[1,5-a]imidazole-2,5-dione ((R)-dimiracetam (1)) and (S)-3,6,7,7a-tetrahydro-H-pyrrolo[1,5-a]imidazole-2,5-dione ((S)-dimiracetam (2)),   
       
         
           
           
               
               
           
         
       
       and/or pharmaceutically acceptable solvates or co-crystals thereof,
 wherein an enantiomeric excess (ee) of the (R)-dimiracetam (1) is equal to or higher than 33% and lower than or equal to 54%. 
 
     
     
         2 . The method of  claim 1 , wherein the sensory symptom of peripheral nerve damage comprises cold-sensitivity, tingling, burning, or aching. 
     
     
         3 . The method of  claim 1 , wherein the sensory symptom of peripheral nerve damage is an allodynia. 
     
     
         4 . The method of  claim 3 , wherein the allodynia is primary allodynia or secondary allodynia. 
     
     
         5 . The method of  claim 1 , wherein the sensory symptom of peripheral nerve damage is hyperalgesia. 
     
     
         6 . The method of  claim 5 , wherein the hyperalgesia is oxaliplatin-induced hyperalgesia. 
     
     
         7 . The method of  claim 1 , further comprising administering an antitumor drug. 
     
     
         8 . The method of  claim 7 , wherein the antitumor drug is selected from the group consisting of a kinase inhibitor, a proteasome inhibitor, a taxane, a vinca alkaloid, and a platinum salt. 
     
     
         9 . The method of  claim 8 , wherein the antitumor drug is selected from the group consisting of sorafenib, sunitinib, afatinib, axitinib, vandetanib, vemurafenib, ixazomib, bortezomib, paclitaxel, docetaxel, cabazitaxel, vincristine, vinblastine, vindesine, vinorelbine, nedaplatin, lobaplatin, picoplatin, satraplain, cisplatin, carboplatin, and oxaliplatin. 
     
     
         10 . The method of  claim 1 , further comprising administering an antiviral drug. 
     
     
         11 . The method of  claim 10 , wherein the antiviral drug is a nucleoside or a nucleotide. 
     
     
         12 . The method of  claim 11 , wherein the antiviral drug is of zalcitabine, didanosine, stavudine, or zidovudine. 
     
     
         13 . The method of  claim 1 , wherein the composition is administered orally, intramuscularly, subcutaneously, topically, transdermally, intranasally, intravenously, sublingually, or intrarectally. 
     
     
         14 . The method of  claim 1 , wherein the composition is administered in a dose of between 10 mg and 3000 mg per administration. 
     
     
         15 . The method of  claim 1 , wherein the subject is a human subject or a veterinary subject. 
     
     
         16 . A method of inhibiting glutamate-induced glutamate release in a subject, comprising:
 administering to the subject a composition comprising (R)-3,6,7,7a-tetrahydro-1H-pyrrolo[1,5-a]imidazole-2,5-dione ((R)-dimiracetam (1)) and (S)-3,6,7,7a-tetrahydro-H-pyrrolo[1,5-a]imidazole-2,5-dione ((S)-dimiracetam (2)),   
       
         
           
           
               
               
           
         
       
       and/or pharmaceutically acceptable solvates or co-crystals thereof,
 wherein an enantiomeric excess (ee) of the (R)-dimiracetam (1) is equal to or higher than 33% and lower than or equal to 54%. 
 
     
     
         17 . The method of  claim 16 , wherein the glutamate-induced glutamate release results from a damaged peripheral nerve. 
     
     
         18 . A pharmaceutical composition in a dosage form for oral administration, comprising:
 a composition comprising (R)-3,6,7,7a-tetrahydro-1H-pyrrolo[1,5-a]imidazole-2,5-dione ((R)-dimiracetam (1)) and (S)-3,6,7,7a-tetrahydro-1H-pyrrolo[1,5-a]imidazole-2,5-dione ((S)-dimiracetam (2)),   
       
         
           
           
               
               
           
         
       
       and/or pharmaceutically acceptable solvates or co-crystals thereof, wherein an enantiomeric excess (ee) of the (R)-dimiracetam (1) is equal to or higher than 33% and lower than or equal to 54%; and
 a pharmaceutically acceptable carrier, 
 wherein the composition is present in the dosage form in an amount between 10 mg and 3000 mg. 
 
     
     
         19 . The pharmaceutical composition of  claim 18 , wherein the dosage form is a tablet, a capsule, a sachet, a powder, a granule, or an oral solution. 
     
     
         20 . The pharmaceutical composition of  claim 18 , wherein the pharmaceutically acceptable carrier comprises a pharmaceutically acceptable excipient, a pharmaceutically acceptable vehicle, a pharmaceutically acceptable adjuvant, a pharmaceutically acceptable additive, a pharmaceutically acceptable surfactant, a pharmaceutically acceptable desiccant, or a pharmaceutically acceptable diluent. 
     
     
         21 . The pharmaceutical composition of  claim 18 , wherein the dosage form is a single dosage unit.