Pharmaceutical Compositions For The Coordinated Delivery Of NSAIDs

Abstract

The present invention is directed to drug dosage forms that release an agent that raises the pH of a patient's gastrointestinal tract, followed by a non-steroidal anti-inflammatory drug. The dosage form is designed so that the NSAID is not released until the intragastric pH has been raised to a safe level. The invention also encompasses methods of treating patients by administering this coordinated release, gastroprotective, antiarthritic/analgesic combination unit dosage form to achieve pain and symptom relief with a reduced risk of developing gastrointestinal damage such as ulcers, erosions and hemorrhages.

What is claimed is: 
     
         1 . A pharmaceutical composition in unit dose form suitable for oral administration to a patient, comprising:
 (a) an acid inhibitor present in an amount effective to raise the gastric pH of said patient to at least 3.5 upon the administration of one or more of said unit dosage forms;   (b) a non-steroidal anti-inflammatory drug (NSAID) present in an amount effective to reduce or eliminate pain or inflammation in said patient upon administration of one or more of said unit dosage forms;   and wherein:
 i) said unit dosage form is a tablet in which said NSAID is present in a core; 
 ii) said tablet comprises a coating, wherein said coating surrounds said core and does not release said NSAID until the pH of the surrounding medium is 3.5 or higher; and 
 iii) said acid inhibitor is in one or more layers outside said core, wherein said one or more layers:
 A) do not include an NSAID; 
 B) are not surrounded by an enteric coating; and 
 C) upon ingestion of said tablet by a patient, release said acid inhibitor into said patient's stomach. 
 
   
     
     
         2 . The pharmaceutical composition of  claim 1 , wherein there is a single core comprising said NSAID and said acid inhibitor is an H2 blocker. 
     
     
         3 . The pharmaceutical composition of  claim 1 , wherein there is a single core comprising said NSAID and said acid inhibitor is selected from the group consisting of: cimetidine; ranitidine; ebrotidine; pabutidine; lafutidine; loxtidine and famotidine. 
     
     
         4 . The pharmaceutical composition of  claim 3 , wherein said acid inhibitor is famotidine, present in said unit dosage form in an amount of between 5 mg and 100 mg. 
     
     
         5 . The pharmaceutical composition of  claim 2  wherein said NSAID is selected from the group consisting of: aspirin; acetaminophen; ibuprofen; flurbiprofen; ketoprofen; lornoxicam; naproxen; oxaprozin; etodolac; indomethacin; ketorolac; nabumetone; diclofenac; ketorolac; mefenamic acid; diflunisal; sulindac; tolmetin, fenoprofen; suprofen; benoxaprofen; aceclofenac; tolfenamic acid; oxyphenbutazone; azapropazone; phenylbutazone; celecoxib; rofecoxib; meloxicam; piroxicam; droxicam; tenoxicam; valdecoxib; parecoxib; etoricoxib; lumiracoxib; CS-502; JTE-522; L-745,337; and NS398. 
     
     
         6 . The pharmaceutical composition of  claim 1 , wherein there is a single core comprising NSAID and said acid inhibitor is a proton pump inhibitor. 
     
     
         7 . The pharmaceutical composition of  claim 1 , wherein there is a single core comprising NSAID and said acid inhibitor is selected from the group consisting of: omeprazole, esomeprazole, lansoprazole, pantoprazole, rabeprazole, pariprazole and leminoprazole. 
     
     
         8 . The pharmaceutical composition of  claim 7 , wherein said acid inhibitor is omeprazole, present in said unit dosage form in an amount of between 5 mg and 50 mg. 
     
     
         9 . The pharmaceutical composition of  claim 7 , wherein said acid inhibitor is lansoprazole, present in said unit dosage form in an amount of between 5 mg and 150 mg. 
     
     
         10 . The pharmaceutical composition of  claim 9 , wherein said lansoprazole is present in said unit dosage form in an amount of between 5 mg and 30 mg. 
     
     
         11 . The pharmaceutical composition of  claim 7 , wherein said acid inhibitor is pantoprazole, present in said unit dosage form in an amount of between 10 mg and 200 mg. 
     
     
         12 . The pharmaceutical composition of  claim 1 , wherein there is a single core comprising NSAID and said acid inhibitor is selected from the group consisting of: AZD-0865, AR-H047108, CS-526, pumaprazole, revaprazan and soraprazan. 
     
     
         13 . The pharmaceutical composition of  claim 12 , wherein said acid inhibitor is selected from the group consisting of: pumaprazole, revaprazan and soraprazan. 
     
     
         14 . The pharmaceutical composition of  claim 7 , wherein said NSAID is selected from the group consisting of: aspirin; acetaminophen; ibuprofen; flurbiprofen; ketoprofen; lornoxicam; naproxen; oxaprozin; etodolac; indomethacin; ketorolac; nabumetone; diclofenac; ketorolac; mefenamic acid; diflunisal; sulindac; tolmetin, fenoprofen; suprofen; benoxaprofen; aceclofenac; tolfenamic acid; oxyphenbutazone; azapropazone; phenylbutazone; celecoxib; rofecoxib; meloxicam; piroxicam; droxicam; tenoxicam; valdecoxib; parecoxib; etoricoxib; lumiracoxib; CS-502; JTE-522; L-745,337; and NS398. 
     
     
         15 . The pharmaceutical composition of  claim 1 , wherein:
 a) said acid inhibitor is selected from the group consisting of: omeprazole, esomeprazole, lansoprazole, pantoprazole and rabeprazole; pariprazole, leminoprazole, pumaprazole, revaprazan and soraprazan;   b) there is a single core comprising said NAID and said NSAID is selected from the group consisting of celecoxib; rofecoxib; meloxicam; piroxicam; droxicam; tenoxicam; valdecoxib, parecoxib, etoricoxib, flurbiprofen; ketoprofen; lornoxicam; naproxen; oxaprozin; etodolac; indomethacin; ketorolac; nabumetone; diclofenac; ketorolac; mefenamic acid; diflunisal; sulindac; tolmetin; fenoprofen; suprofen; benoxaprofen; aceclofenac; tolfenamic acid; oxyphenbutazone; azapropazone; and phenylbutazone.   
     
     
         16 . A method of treating a patient for pain or inflammation, comprising administering to said patient a therapeutically effective amount of the pharmaceutical composition of  claim 1 . 
     
     
         17 . The method of  claim 16 , wherein said pain or inflammation is due to either osteoarthritis or rheumatoid arthritis. 
     
     
         18 . A pharmaceutical composition in unit dose form suitable for oral administration to a patient, comprising:
 (a) an acid inhibitor present in an amount effective to raise the gastric pH of said patient to at least 3.5 upon the administration of one or more of said unit dosage forms;   (b) a non-steroidal anti-inflammatory drug (NSAID) present in an amount effective to reduce or eliminate pain or inflammation in said patient upon administration of one or more of said unit dosage forms;   and wherein:
 i) said unit dosage form is a capsule in which said NSAID is present in a core; 
 ii) said capsule comprises a coating, wherein said coating surrounds said core containing said NSAID and does not release said NSAID until the pH of the surrounding medium is 3.5 or higher; and 
 iii) said acid inhibitor is in one or more layers outside said core, wherein said one or more layers:
 A) do not include an NSAID; 
 B) are not surrounded by an enteric coating; and 
 C) upon ingestion of said capsule by a patient, release said acid inhibitor into said patient's stomach. 
 
   
     
     
         19 . The pharmaceutical composition of  claim 18 , wherein there are multiple particles of said NSAID each constituting a core surrounded by said coating that does not release said NSAID until the pH of the surrounding medium is 3.5 or higher. 
     
     
         20 . The pharmaceutical composition of  claim 18 , wherein said acid inhibitor is an H2 blocker. 
     
     
         21 . The pharmaceutical composition of  claim 18 , wherein said acid inhibitor is selected from the group consisting of: cimetidine; ranitidine; ebrotidine; pabutidine; lafutidine; loxtidine and famotidine. 
     
     
         22 . The pharmaceutical composition of  claim 21 , wherein said acid inhibitor is famotidine, present in said unit dosage form in an amount of between 5 mg and 100 mg. 
     
     
         23 . The pharmaceutical composition of  claim 20 , wherein said NSAID is selected from the group consisting of aspirin; acetaminophen; ibuprofen; flurbiprofen; ketoprofen; lornoxicam; naproxen; oxaprozin; etodolac; indomethacin; ketorolac; nabumetone; diclofenac; ketorolac; mefenamic acid; diflunisal; sulindac; tolmetin, fenoprofen; suprofen; benoxaprofen; aceclofenac; tolfenamic acid; oxyphenbutazone; azapropazone; phenylbutazone; celecoxib; rofecoxib; meloxicam; piroxicam; droxicam; tenoxicam; valdecoxib; parecoxib; etoricoxib; lumiracoxib; CS-502; JTE-522; L-745,337; and NS398. 
     
     
         24 . The pharmaceutical composition of  claim 18 , wherein said acid inhibitor is a proton pump inhibitor. 
     
     
         25 . The pharmaceutical composition of  claim 18 , wherein acid inhibitor is selected from the group consisting of: omeprazole, esomeprazole, lansoprazole, pantoprazole, rabeprazole, pariprazole and leminoprazole. 
     
     
         26 . The pharmaceutical composition of  claim 25  wherein said acid inhibitor is omeprazole, present in said unit dosage form in an amount of between 5 mg and 50 mg. 
     
     
         27 . The pharmaceutical composition of  claim 25 , wherein said acid inhibitor is lansoprazole, present in said unit dosage form in an amount of between 5 mg and 150 mg. 
     
     
         28 . The pharmaceutical composition of  claim 27 , wherein said lansoprazole is present in said unit dosage form in an amount of between 5 mg and 30 mg. 
     
     
         29 . The pharmaceutical composition of  claim 25 , wherein said acid inhibitor is pantoprazole, present in said unit dosage form in an amount of between 10 mg and 200 mg. 
     
     
         30 . The pharmaceutical composition of  claim 18 , wherein said acid inhibitor is selected from the group consisting of: AZD-0865, AR-H047108, CS-526, pumaprazole, revaprazan and soraprazan. 
     
     
         31 . The pharmaceutical composition of  claim 30 , wherein said acid inhibitor is selected from the group consisting of pumaprazole, revaprazan and soraprazan. 
     
     
         32 . The pharmaceutical composition of  claim 24 , wherein said NSAID is selected from the group consisting of: aspirin; acetaminophen; ibuprofen; flurbiprofen; ketoprofen; lornoxicam; naproxen; oxaprozin; etodolac; indomethacin; ketorolac; nabumetone; diclofenac; ketorolac; mefenamic acid; diflunisal; sulindac; tolmetin, fenoprofen; suprofen; benoxaprofen; aceclofenac; tolfenamic acid; oxyphenbutazone; azapropazone; phenylbutazone; celecoxib; rofecoxib; meloxicam; piroxicam; droxicam; tenoxicam; valdecoxib; parecoxib; etoricoxib; lumiracoxib; CS-502; JTE-522; L-745,337; and NS398. 
     
     
         33 . A method of treating a patient for pain or inflammation, comprising administering to said patient a therapeutically effective amount of the pharmaceutical composition of  claim 18 . 
     
     
         34 . The method of  claim 33 , wherein said pain or inflammation is due to either osteoarthritis or rheumatoid arthritis. 
     
     
         35 . A pharmaceutical composition in unit dose form suitable for oral administration to a patient, comprising:
 (a) an acid inhibitor present in an amount effective to raise the gastric pH of said patient to at least 3.5 upon the administration of one or more of said unit dosage forms;   (b) aspirin present in an amount effective, upon the administration of one or more of said unit dosage forms, to treat said patient for a condition that responds to NSAID treatment;   and wherein:
 i) said unit dosage form is a tablet in which said aspirin is present in a core; 
 ii) said tablet comprises a coating, wherein said coating surrounds said core and does not release said aspirin until the pH of the surrounding medium is 3.5 or higher; and 
 iii) said acid inhibitor is in one or more layers outside said core, wherein said one or more layers:
 A) do not include an NSAID; 
 B) are not surrounded by an enteric coating; and 
 C) upon ingestion of said tablet by a patient, release said acid inhibitor into said patient's stomach. 
 
   
     
     
         36 . The pharmaceutical composition of  claim 35 , wherein said aspirin is present at 20-200 mg. 
     
     
         37 . The pharmaceutical composition of  claim 35 , wherein there is a single core comprising said aspirin and said acid inhibitor is an H2 blocker. 
     
     
         38 . The pharmaceutical composition of  claim 35 , wherein there is a single core comprising said aspirin and said acid inhibitor is selected from the group consisting of: cimetidine; ranitidine; ebrotidine; pabutidine; lafutidine; loxtidine and famotidine. 
     
     
         39 . The pharmaceutical composition of  claim 37 , wherein said aspirin is present at 20-200 mg. 
     
     
         40 . The pharmaceutical composition of  claim 35 , wherein there is a single core comprising said aspirin and said acid inhibitor is a proton pump inhibitor. 
     
     
         41 . The pharmaceutical composition of  claim 35 , wherein there is a single core comprising NSAID and said acid inhibitor is selected from the group consisting of omeprazole, esomeprazole, lansoprazole, pantoprazole, rabeprazole, pariprazole and leminoprazole. 
     
     
         42 . The pharmaceutical composition of  claim 35 , wherein there is a single core comprising NSAID and said acid inhibitor is selected from the group consisting of: AZD-0865, AR-H047108, CS-526, pumaprazole, revaprazan and soraprazan. 
     
     
         43 . The pharmaceutical composition of  claim 40 , wherein said aspirin is present at 20-200 mg. 
     
     
         44 . A method of treating a patient for a condition in which an NSAID is effective comprising administering to said patient an effective amount of the pharmaceutical composition of  claim 35 . 
     
     
         45 . A method of providing low dose aspirin therapy to a patient comprising administering to said patient an effective amount of the pharmaceutical composition of  claim 36 . 
     
     
         46 . A pharmaceutical composition in unit dose form suitable for oral administration to a patient, comprising:
 (a) an acid inhibitor present in an amount effective to raise the gastric pH of said patient to at least 3.5 upon the administration of one or more of said unit dosage forms;   (b) aspirin present in an amount effective, upon the administration of one or more of said unit dosage forms, to treat said patient for a condition that responds to aspirin treatment;   and wherein:
 i) said unit dosage form is a capsule in which said aspirin is present in a core; 
 ii) said capsule comprises a coating, wherein said coating surrounds said core containing said aspirin and does not release said aspirin until the pH of the surrounding medium is 3.5 or higher; and 
 iii) said acid inhibitor is in one or more layers or particles outside said core, wherein said one or more layers or particles:
 A) do not include an NSAID; 
 B) are not surrounded by an enteric coating; and 
 C) upon ingestion of said capsule by a patient, release said acid inhibitor into said patient's stomach. 
 
   
     
     
         47 . The pharmaceutical composition of  claim 46 , wherein said aspirin is present at 20-200 mg. 
     
     
         48 . The pharmaceutical composition of  claim 46 , wherein there are multiple particles of said aspirin each constituting a core surrounded by said coating that does not release said aspirin until the pH of the surrounding medium is 3.5 or higher. 
     
     
         49 . The pharmaceutical composition of  claim 46 , wherein said acid inhibitor is an H2 blocker. 
     
     
         50 . The pharmaceutical composition of  claim 46 , wherein said acid inhibitor is selected from the group consisting of: cimetidine; ranitidine; ebrotidine; pabutidine; lafutidine; loxtidine and famotidine. 
     
     
         51 . The pharmaceutical composition of  claim 46 , wherein said aspirin is present at 20-200 mg. 
     
     
         52 . The pharmaceutical composition of  claim 46 , wherein said acid inhibitor is a proton pump inhibitor. 
     
     
         53 . The pharmaceutical composition of  claim 46 , wherein acid inhibitor is selected from the group consisting of: omeprazole, esomeprazole, lansoprazole, pantoprazole, rabeprazole, pariprazole and leminoprazole. 
     
     
         54 . The pharmaceutical composition of  claim 46 , wherein said acid inhibitor is selected from the group consisting of: AZD-0865, AR-H047108, CS-526, pumaprazole, revaprazan and soraprazan. 
     
     
         55 . A method of treating a patient for a condition for which aspirin is effective, comprising administering to said patient an effective amount of the pharmaceutical composition of  claim 46 . 
     
     
         56 . A method of providing low dose aspirin therapy to a patient comprising administering to said patient an effective amount of the pharmaceutical composition of  claim 47 .