Cyclooxygenase-2 inhibitor compositions having rapid onset of therapeutic effect

Abstract

Pharmaceutical compositions are provided comprising one or more orally deliverable dose units, each comprising a selective cyclooxygenase-2 inhibitory drug of low water solubility in a therapeutically effective amount, wherein the drug is present in the form of solid particles, about 25% to 100% by weight of which are smaller than 1 μm. The compositions are useful in treatment or prophylaxis of cyclooxygenase-2 mediated conditions and disorders and have particular advantages where rapid onset of therapeutic effect is desired.

What is claimed is:  
     
         1 . A pharmaceutical composition comprising one or more orally deliverable dose units, each comprising (a) a selective cyclooxygenase-2 inhibitory drug of low water solubility wherein the drug is present in solid particles having a D 90  particle size of about 0.01 μm to about 200 μm, a sufficient portion by weight of the particles being smaller than 1 μm to provide a substantially higher C max  and/or a substantially shorter T max  and/or a substantially shorter time to reach a threshold blood serum concentration for therapeutic effect, by comparison with an otherwise similar composition wherein substantially all of the particles are larger than 1 μm, and (b) a second drug selected from vasomodulators and alkylxanthine compounds; wherein the selective cyclooxygenase-2 inhibitory drug and the second drug are present in total and relative amounts effective to relieve pain.  
     
     
         2 . The composition of  claim 1  wherein the second drug is an alkylxanthine compound.  
     
     
         3 . The composition of  claim 2  wherein the alkylxanthine compound is selected from caffeine, theophylline and theobromine.  
     
     
         4 . The composition of  claim 2  wherein the alkylxanthine compound is caffeine.  
     
     
         5 . The composition of  claim 1  having total bioavailability of said selective cyclooxygenase-2 inhibitory drug that is greater than that of an otherwise similar composition wherein substantially all of said selective cyclooxygenase-2 inhibitory drug particles are larger than 1 μm.  
     
     
         6 . The composition of  claim 1  exhibiting a substantially shorter time to reach a therapeutically effective threshold blood serum concentration of said selective cyclooxygenase-2 inhibitory drug, by comparison with an otherwise similar composition wherein substantially all of the selective cyclooxygenase-2 inhibitory drug particles are larger than 1 μm.  
     
     
         7 . The composition of  claim 1  wherein substantially all of said selective cyclooxygenase-2 inhibitory drug particles are smaller than 1 μm.  
     
     
         8 . The composition of  claim 1  wherein the dose units are in the form of discrete solid articles.  
     
     
         9 . The composition of  claim 8  wherein the solid articles are tablets or capsules.  
     
     
         10 . The composition of  claim 1  that is in the form of a substantially homogeneous flowable mass from which single dose units are measurably removable.  
     
     
         11 . The composition of  claim 10  wherein the substantially homogeneous flowable mass is a liquid suspension.  
     
     
         12 . The composition of  claim 1  wherein said solid selective cyclooxygenase-2 inhibitory drug particles have a D 25  particle size of about 450 nm to about 1000 nm.  
     
     
         13 . The composition of  claim 1  wherein about 25% to 100% by weight of said solid selective cyclooxygenase-2 inhibitory drug particles have a particle size of about 450 nm to about 1000 nm.  
     
     
         14 . The composition of  claim 1  wherein said solid selective cyclooxygenase-2 inhibitory drug particles have a weight average particle size of about 450 nm to about 1000 nm.  
     
     
         15 . The composition of  claim 1  wherein the selective cyclooxygenase-2 inhibitory drug is a compound of formula  
       
         
           
           
               
               
           
         
       
       where R 3  is a methyl or amino group, 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.  
     
     
         16 . The composition of  claim 15  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.  
     
     
         17 . The composition of  claim 1  wherein the selective cyclooxygenase-2 inhibitory drug is selected from the group consisting of celecoxib, deracoxib, valdecoxib, rofecoxib, 5-chloro-3-(4-methylsulfonyl)phenyl-2-(2-methyl-5-pyridinyl)pyridine, 2-(3,5-difluorophenyl)-3-[4-(methylsulfonyl)phenyl]-2-cyclopenten-1-one and (S)-6,8-dichloro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid.  
     
     
         18 . The composition of  claim 17  wherein the selective cyclooxygenase-2 inhibitory drug is celecoxib.  
     
     
         19 . The composition of  claim 18  comprising about 10 mg to about 1000 mg celecoxib in each dose unit.  
     
     
         20 . A method of analgesia comprising orally administering, to a subject in need of analgesia, (a) a first pharmaceutical composition comprising one or more orally deliverable dose units, each comprising a selective cyclooxygenase-2 inhibitory drug of low water solubility in a therapeutically effective amount, wherein the drug is present in solid particles having a D 90  particle size of about 0.01 μm to about 200 μm, a sufficient portion by weight of the particles being smaller than 1 μm to provide a substantially higher C max  and/or a substantially shorter T max  and/or a substantially shorter time to reach a threshold blood serum concentration for therapeutic effect, by comparison with an otherwise similar composition wherein substantially all of the particles are larger than 1 μm, and (b) a second pharmaceutical composition comprising a vasomodulator and/or an alkylxanthine compound; wherein the first and second compositions are administered in total and relative amounts effective to relieve pain.  
     
     
         21 . The method of  claim 20  wherein the second composition comprises an alkylxanthine compound.  
     
     
         22 . The method of  claim 21  wherein the alkylxanthine compound is selected from caffeine, theophylline and theobromine.  
     
     
         23 . The method of  claim 21  wherein the alkylxanthine compound is caffeine.  
     
     
         24 . The method of  claim 20  wherein the subject suffers from headache or migraine and wherein the first and second compositions are administered in total and relative amounts effective to relieve pain in the headache or migraine.  
     
     
         25 . The method of  claim 20  wherein the first and second compositions are administered at substantially the same time.  
     
     
         26 . The method of  claim 20  wherein the first and second compositions are administered at substantially different times.  
     
     
         27 . A method of analgesia comprising orally administering, to a subject in need of analgesia, an effective pain-relieving amount of a composition of  claim 1 .  
     
     
         28 . The method of  claim 27  wherein the subject suffers from headache or migraine and wherein said composition is administered in an amount effective to relieve pain in the headache or migraine.  
     
     
         29 . A pharmaceutical composition comprising one or more orally deliverable dose units, each comprising (a) a selective cyclooxygenase-2 inhibitory drug of low water solubility, wherein the drug is present in solid particles having a D 90  particle size of about 0.01 μm to about 200 μm, and wherein about 25% to 100% by weight of the particles are smaller than 1 μm, and (b) a second drug selected from vasomodulators and alkylxanthine compounds; wherein the selective cyclooxygenase-2 inhibitory drug and the second drug are present in total and relative amounts effective to relieve pain.  
     
     
         30 . The composition of  claim 29  wherein the second drug is an alkylxanthine compound.  
     
     
         31 . The composition of  claim 30  wherein the alkylxanthine compound is selected from caffeine, theophylline and theobromine.  
     
     
         32 . The composition of  claim 30  wherein the alkylxanthine compound is caffeine.  
     
     
         33 . The composition of  claim 29  wherein substantially all of said solid selective cyclooxygenase-2 inhibitory drug particles are smaller than 1 μm.  
     
     
         34 . The composition of  claim 29  wherein the dose units are in the form of discrete solid articles.  
     
     
         35 . The composition of  claim 34  wherein the solid articles are tablets or capsules.  
     
     
         36 . The composition of  claim 29  that is in the form of a substantially homogeneous flowable mass from which single dose units are measurably removable.  
     
     
         37 . The composition of  claim 36  wherein the substantially homogeneous flowable mass is a liquid suspension.  
     
     
         38 . The composition of  claim 29  wherein said solid selective cyclooxygenase-2 inhibitory drug particles have a D 25  particle size of about 450 nm to about 1000 nm.  
     
     
         39 . The composition of  claim 29  wherein about 25% to 100% by weight of said solid selective cyclooxygenase-2 inhibitory drug particles have a particle size of about 450 nm to about 1000 nm.  
     
     
         40 . The composition of  claim 29  wherein said solid selective cyclooxygenase-2 inhibitory drug particles have a weight average particle size of about 450 nm to about 1000 nm.  
     
     
         41 . The composition of  claim 29  wherein the selective cyclooxygenase-2 inhibitory drug is a compound of formula  
       
         
           
           
               
               
           
         
       
       where R 3  is a methyl or amino group, 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.  
     
     
         42 . The composition of  claim 41  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.  
     
     
         43 . The composition of  claim 29  wherein the selective cyclooxygenase-2 inhibitory drug is selected from the group consisting of celecoxib, deracoxib, valdecoxib, rofecoxib, 5-chloro-3-(4-methylsulfonyl)phenyl-2-(2-methyl-5-pyridinyl)pyridine, 2-(3,5-difluorophenyl)-3-[4-(methylsulfonyl)phenyl]-2-cyclopenten-1-one and (S)-6,8-dichloro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid.  
     
     
         44 . The composition of  claim 43  wherein the selective cyclooxygenase-2 inhibitory drug is celecoxib.  
     
     
         45 . The composition of  claim 44  comprising about 10 mg to about 1000 mg celecoxib in each dose unit.  
     
     
         46 . A method of analgesia comprising orally administering, to a subject in need of analgesia, (a) a first pharmaceutical composition comprising one or more orally deliverable dose units, each comprising a selective cyclooxygenase-2 inhibitory drug of low water solubility in a therapeutically effective amount, wherein the drug is present in solid particles having a D 90  particle size of about 0.01 μm to about 200 μm, wherein about 25% to 100% by weight of the particles are smaller than 1 μm, and (b) a second pharmaceutical composition comprising a vasomodulator and/or an alkylxanthine compound; wherein the first and second compositions are administered in total and relative amounts effective to relieve pain.  
     
     
         47 . The method of  claim 46  wherein the second composition comprises an alkylxanthine compound.  
     
     
         48 . The method of  claim 47  wherein the alkylxanthine compound is selected from caffeine, theophylline and theobromine.  
     
     
         49 . The method of  claim 47  wherein the alkylxanthine compound is caffeine.  
     
     
         50 . The method of  claim 46  wherein the subject suffers from headache or migraine and wherein the first and second compositions are administered in total and relative amounts effective to relieve pain in the headache or migraine.  
     
     
         51 . The method of  claim 46  wherein the first and second compositions are administered at substantially the same time.  
     
     
         52 . The method of  claim 46  wherein the first and second compositions are administered at substantially different times.  
     
     
         53 . A method of analgesia comprising orally administering, to a subject in need of analgesia, an effective pain-relieving amount of a composition of  claim 29 .  
     
     
         54 . The method of  claim 53  wherein the subject suffers from headache or migraine and wherein said composition is administered in an amount effective to relieve pain in the headache or migraine.  
     
     
         55 . A pharmaceutical composition comprising one or more orally deliverable dose units, each comprising (a) a selective cyclooxygenase-2 inhibitory drug of low water solubility wherein the drug is present in solid particles having a D 90  particle size of about 0.01 μm to about 200 μm, a sufficient portion by weight of the particles being smaller than 1 μm to provide a substantially higher C max  and/or a substantially shorter T max  and/or a substantially shorter time to reach a threshold blood serum concentration for therapeutic effect, by comparison with an otherwise similar composition in which at least 80% of the drug by weight is in the form of particles larger than 1 μm and smaller than 10 μm, and (b) a second drug selected from vasomodulators and alkylxanthine compounds; wherein the selective cyclooxygenase-2 inhibitory drug and the second drug are present in total and relative amounts effective to relieve pain.  
     
     
         56 . A pharmaceutical composition comprising one or more orally deliverable dose units, each comprising (a) nanoparticles of a selective cyclooxygenase-2 inhibitory drug of low water solubility wherein the drug is present in nanoparticle form in an amount to provide a substantially higher C max  and/or a substantially shorter T max  and/or a substantially shorter time to reach a threshold blood serum concentration for therapeutic effect, by comparison with an otherwise similar composition containing the same amount of drug as is present in the nanoparticles wherein at least 80% of the drug by weight in the otherwise similar composition is in the form of particles larger than 1 μm and smaller than 10 μm, and (b) a second drug selected from vasomodulators and alkylxanthine compounds; wherein the selective cyclooxygenase-2 inhibitory drug and the second drug are present in total and relative amounts effective to relieve pain.  
     
     
         57 . A method of analgesia comprising orally administering, to a subject in need of analgesia, (a) a first pharmaceutical composition comprising one or more orally deliverable dose units, each comprising a selective cyclooxygenase-2 inhibitory drug of low water solubility in a therapeutically effective amount, wherein the drug is present in solid particles having a D 90  particle size of about 0.01 μm to about 200 μm, a sufficient portion by weight of the particles being smaller than 1 μm to provide a substantially higher C max  and/or a substantially shorter T max  and/or a substantially shorter time to reach a threshold blood serum concentration for therapeutic effect, by comparison with an otherwise similar composition in which at least 80% of the drug by weight is in the form of particles larger than 1 μm and smaller than 10 μm, and (b) a second pharmaceutical composition comprising a vasomodulator and/or an alkylxanthine compound; wherein the first and second compositions are administered in total and relative amounts effective to relieve pain.  
     
     
         58 . A method of analgesia comprising orally administering, to a subject in need of analgesia, (a) a first pharmaceutical composition comprising one or more orally deliverable dose units, each comprising nanoparticles of a selective cyclooxygenase-2 inhibitory drug of low water solubility wherein the drug is present in nanoparticle form in an amount to provide a substantially higher C max  and/or a substantially shorter T max  and/or a substantially shorter time to reach a threshold blood serum concentration for therapeutic effect, by comparison with an otherwise similar composition containing the same amount of drug as is present in the nanoparticles wherein at least 80% of the drug by weight in the otherwise similar composition is in the form of particles larger than 1 μm and smaller than 10 μm, and (b) a second pharmaceutical composition comprising a vasomodulator and/or an alkylxanthine compound; wherein the first and second compositions are administered in total and relative amounts effective to relieve pain.