Pharmaceutical Compositions for the Coordinated Delivery of NSAIDs

• US 20120064156A1
• Filed: 08/23/2011
• Published: 03/15/2012
• Est. Priority Date: 06/01/2001
• Status: Active Grant

• Current Assignee: Nuvo Pharmaceuticals (Ireland) Designated Activity Company
• Original Assignee: John R. Plachetka
• Inventors: Plachetka, John R.
• Granted Patent: US 8,557,285 B2
• Time in Patent Office: Days
• US Class Current: 424/463
• CPC Class Codes: A61K 31/192 having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid cannabinoids A61K31/658
• CPC Class Codes: A61K 31/426 1,3-Thiazoles
• CPC Class Codes: A61K 31/4439 containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole nicotine A61K31/465
• CPC Class Codes: A61K 31/495 having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazinesA61K31/48 takes precedence ; with three nitrogen atoms A61K31/53
• CPC Class Codes: A61K 31/60 Salicylic acid; Derivatives thereof
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 9/0053 Mouth and digestive tract, i.e. intraoral and peroral administration rectal administration A61K9/0031
• CPC Class Codes: A61K 9/1611 Inorganic compounds
• CPC Class Codes: A61K 9/209 containing drug in at least two layers or in the core and in at least one outer layer
• CPC Class Codes: A61K 9/2095 Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing mechanical aspects A61J3/00
• CPC Class Codes: A61K 9/28 Dragees; Coated pills or tablets , e.g. with film or compression coating A61K9/2072 takes precedence, e.g. partially coated tablets A61K9/2072, coated multilayer tablets A61K9/2086, tablets with drug-coated core A61K9/209
• CPC Class Codes: A61K 9/2846 Poly(meth)acrylates
• CPC Class Codes: A61K 9/2866 Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
• CPC Class Codes: A61K 9/2886 having two or more different drug-free coatings; Tablets of the type inert core-drug layer-inactive layer of the type active core-drug layer-inactive layer A61K9/209
• CPC Class Codes: A61K 9/4891 Coated capsules; Multilayered drug free capsule shells with drug coating for immediate release A61K9/4808; osmotic devices A61K9/0004
• CPC Class Codes: A61K 9/5026 obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
• CPC Class Codes: A61K 9/5073 having two or more different coatings optionally including drug-containing subcoatings
• CPC Class Codes: A61K 9/5084 Mixtures of one or more drugs in different galenical forms, at least one of which being granules, microcapsules or (coated) microparticles according to A61K9/16 or A61K9/50, e.g. for obtaining a specific release pattern or for combining different drugs tablets containing such a mixture A61K9/2077
• CPC Class Codes: A61K 9/5089 Processes
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 29/00 : Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

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.

Claims

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 112 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.