Stabilized oral pharmaceutical composition

Abstract

An orally deliverable pharmaceutical composition is provided comprising an aminosulfonyl-comprising drug, for example a selective cyclooxygenase-2 inhibitory drug such as celecoxib, and a solvent liquid comprising a polyethylene glycol and one or more free radical-scavenging antioxidants. At least a substantial part of the drug is in dissolved form in the solvent liquid. The composition has rapid-onset properties and is useful in treatment of cyclooxygenase-2 mediated conditions and disorders.

1 . An orally deliverable pharmaceutical composition comprising (a) a drug of low water solubility in a therapeutically and/or prophylactically effective amount and (b) a solvent liquid that comprises at least one pharmaceutically acceptable polyethylene glycol and at least one pharmaceutically acceptable free radical-scavenging antioxidant, wherein a substantial portion of the drug is in dissolved or solubilized form in the solvent liquid, and wherein the drug is a selective cyclooxygenase-2 inhibitory drug having the formula:  
       
         
           
           
               
               
           
         
       
       where R 4  is hydrogen or a C 1-4  alkyl or alkoxy group, X is N or CR 5  where R 5  is hydrogen or halogen, and Y and Z are independently carbon or nitrogen atoms defining adjacent atoms of a five- to six-membered ring that is unsubstituted or substituted at one or more positions with oxo, halo, methyl or halomethyl groups.  
     
     
         2 - 3 . (canceled)  
     
     
         4 . The composition of  claim 1  wherein the five- to six-membered ring is selected from the group consisting of cyclopentenone, furanone, methylpyrazole, isoxazole and pyridine rings substituted at no more than one position.  
     
     
         5 . The composition of  claim 1  wherein the drug is selected from the group consisting of celecoxib, deracoxib, valdecoxib and JTE-522.  
     
     
         6 . The composition of  claim 1  wherein the drug is celecoxib.  
     
     
         7 . The composition of  claim 1  wherein the drug is valdecoxib.  
     
     
         8 . The composition of  claim 1  that further comprises a vasomodulator, wherein the selective cyclooxygenase-2 inhibitory drug and the vasomodulator are present in total and relative amounts effective to relieve pain in headache or migraine.  
     
     
         9 . The composition of  claim 1  that further comprises an alkylxanthine compound, wherein the selective cyclooxygenase-2 inhibitory drug and the alkylxanthine compound are present in total and relative amounts effective to relieve pain in headache or migraine.  
     
     
         10 . The composition of  claim 9  wherein the alkylxanthine compound is caffeine.  
     
     
         11 . The composition of  claim 1  wherein the polyethylene glycol has an average molecular weight of about 100 to about 10,000.  
     
     
         12 . The composition of  claim 1  wherein the polyethylene glycol is of liquid grade.  
     
     
         13 . The composition of  claim 1  wherein the at least one free radical-scavenging antioxidant is present in the solvent liquid in a total amount of about 0.01% to about 5% by weight of the composition.  
     
     
         14 . The composition of  claim 1  wherein the at least one free radical-scavenging antioxidant is present in the solvent liquid in a total amount of about 0.01% to about 1% by weight of the composition.  
     
     
         15 . The composition of  claim 1  wherein the at least one free radical-scavenging antioxidant is selected from the group consisting of vitamin E, ascorbic acid and salts thereof, butylated hydroxyanisole, butylated hydroxytoluene, fumaric acid and salts thereof, hypophosphorous acid, malic acid, alkyl gallates, sodium thiosulfate, sodium sulfite, sodium bisulfite and sodium metabisulfite.  
     
     
         16 . The composition of  claim 1  wherein the at least one free radical-scavenging antioxidant is propyl gallate.  
     
     
         17 . The composition of  claim 1  wherein the at least one free radical-scavenging antioxidant is vitamin E.  
     
     
         18 . The composition of  claim 1  wherein substantially all of the drug present in the composition is in dissolved or solubilized form.  
     
     
         19 . The composition of  claim 1  wherein the solvent liquid further comprises a turbidity-decreasing polymer.  
     
     
         20 . The composition of  claim 19  wherein the at least one turbidity-decreasing polymer is hydroxypropylmethylcellulose.  
     
     
         21 . The composition of  claim 1  wherein the solvent liquid further comprises at least one pharmaceutically acceptable fatty acid and at least one pharmaceutically acceptable organic amine.  
     
     
         22 . The composition of  claim 21  wherein the at least one fatty acid is oleic acid.  
     
     
         23 . The composition of  claim 21  wherein the at least one organic amine is a tertiary amine selected from the group consisting of triethanolamine and dimethylaminoethanol.  
     
     
         24 . The composition of  claim 1  that comprises one or more discrete dose units, wherein a therapeutically and/or prophylactically effective amount of the drug is contained in one to a small plurality of said dose units.  
     
     
         25 . The composition of  claim 24  wherein each dose unit is a liquid-filled capsule having a capsule wall.  
     
     
         26 . The composition of  claim 25  wherein the capsule wall comprises a turbidity-decreasing polymer.  
     
     
         27 . The composition of  claim 26  wherein the turbidity-decreasing polymer is hydroxypropylmethylcellulose.  
     
     
         28 . A method of treating a medical condition or disorder in a subject where treatment with a cyclooxygenase-2 inhibitor is indicated, comprising orally administering to the subject a composition of  claim 1 .  
     
     
         29 . A method of analgesia comprising orally administering an effective pain-relieving amount of a composition of  claim 1  to a subject in need of analgesia.  
     
     
         30 . The method of  claim 29  wherein the subject suffers from headache or migraine and wherein there is further orally administered to the subject a vasomodulator, the selective cyclooxygenase-2 inhibitory drug and the vasomodulator being administered in total and relative amounts effective to relieve pain in the headache or migraine.  
     
     
         31 . The method of  claim 29  wherein the subject suffers from headache or migraine and wherein there is further orally administered to the subject an alkylxanthine compound, the selective cyclooxygenase-2 inhibitory drug and the alkylxanthine compound being administered in total and relative amounts effective to relieve pain in the headache or migraine.  
     
     
         32 . (canceled).