Substituted benzimidazole dosage forms and methods of using same

• US 6,699,885 B2
• Filed: 01/19/2002
• Issued: 03/02/2004
• Est. Priority Date: 01/04/1996
• Status: Expired due to Term

• Current Assignee: Curators of the University of Missouri (University of Missouri)
• Original Assignee: Curators of the University of Missouri (University of Missouri)
• Inventors: Phillips, Jeffrey O.
• Primary Examiner(s): FAN, JANE T
• Application Number:
  US10/054,350
• Publication Number:
  US 20030191159A1
• Time in Patent Office: 773 Days
• Field of Search: 514/338, 514/395
• US Class Current: 514/338
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/00 Medicinal preparations containing organic active ingredients
• 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 33/00 Medicinal preparations containing inorganic active ingredients
• CPC Class Codes: A61K 36/185 Magnoliopsida (dicotyledons)
• CPC Class Codes: A61K 36/42 Cucurbitaceae (Cucumber family)
• CPC Class Codes: A61K 36/48 Fabaceae or Leguminosae (Pea or Legume family); Caesalpiniaceae; Mimosaceae; Papilionaceae
• CPC Class Codes: A61K 36/534 Mentha (mint)
• CPC Class Codes: A61K 36/898 Orchidaceae (Orchid family)
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 47/02 Inorganic compounds
• CPC Class Codes: A61K 9/0007 Effervescent A61K9/0065 takes precedence
• CPC Class Codes: A61K 9/0056 Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
• CPC Class Codes: A61K 9/0095 Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches A61K9/0007 takes precedence; eatable gels or foams A61K9/0056; oral mucosa adhesive forms A61K9/006
• CPC Class Codes: A61K 9/2009 Inorganic compounds
• CPC Class Codes: A61K 9/2013 Organic compounds, e.g. phospholipids, fats
• CPC Class Codes: A61K 9/2054 Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
• CPC Class Codes: A61K 9/2081 with microcapsules or coated microparticles according to A61K9/50
• CPC Class Codes: A61K 9/2086 Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat active cores with a complete drug-free outer coat A61K9/28
• 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 9/2813 : Inorganic compounds
• CPC Class Codes: A61P 1/00 : Drugs for disorders of the alimentary tract or the digestive system
• 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 1/06 : Anti-spasmodics, e.g. drugs for colics, esophagic dyskinesia
• CPC Class Codes: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Abstract

Disclosed herein are methods, kits, combinations, and compositions for treating gastric acid disorders employing pharmaceutical compositions comprising a proton pump inhibiting agent (PPI) and a buffering agent in a pharmaceutically acceptable carrier.

Claims

1. A method of treating a gastric acid related disorder in a subject in need thereof, comprising:

providing a solid pharmaceutical composition for oral administration to the subject, the composition consisting essentially of;

(a) a therapeutically effective amount of at least one acid labile, substituted benzimidazole H⁺, K⁺-ATPase proton pump inhibitor;

(b) at least one buffering agent in an amount of about 0.1 mEq to about 2.5 mEq per mg proton pump inhibitor; and

(c) one or more optional pharmaceutically acceptable excipients; and

orally administering the pharmaceutical composition to the subject,

wherein upon oral administration of the pharmaceutical composition to the subject, an initial serum concentration of the proton pump inhibitor greater than about 0.1 μ

g/ml is obtained at any time within about 30 minutes after administration of the composition.

2. The method of claim 1, wherein the composition is administered in an amount to achieve an initial serum concentration of the proton pump inhibitor greater than about 0.15 μ

g/ml at any time within about 30 minutes after administration of the composition.

3. The method of claim 1, wherein the pharmaceutical composition is in a form selected from the group consisting of a tablet, capsule, powder, suspension tablet, effervescent tablet or capsule, chewable tablet, granules, pellets, and a liquid created by mixing any of the foregoing with an aqueous medium.

4. The method of claim 1, wherein the amount of the proton pump inhibitor absorbed into the serum is therapeutically effective in treating the gastric acid related disorder selected from the group consisting of duodenal ulcer disease, gastric ulcer disease, gastroesophageal reflux disease, erosive esophagitis, poorly responsive symptomatic gastroesophageal reflux disease, pathological gastrointestinal hypersecretory disease, Zollinger Ellison Syndrome, heartburn, esophageal disorder, and acid dyspepsia.

5. The method of claim 1, wherein the proton pump inhibitor is selected from the group consisting of omeprazole, lansoprazole, rabeprazole, esomeprazole, pantoprazole, pariprazole, and leminoprazole, or an enantiomer, isomer, tautomer, ester, amide, derivative, prodrug, free base, or salt thereof.

6. The method of claim 1, wherein the amount of the proton pump inhibitor is about 2 mg to about 300 mg.

7. The method of claim 1, wherein the amount of the proton pump inhibitor is about 10 mg to about 120 mg.

8. The method of claim 1, wherein the amount of the proton pump inhibitor is about 2 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, a 115 mg, or about 120 mg.

9. The method of claim 1, wherein the amount of the buffering agent is about 10 mEq to about 70 mEq.

10. The method of claim 1, wherein the amount of the buffering agent is at least 10 mEq.

11. The method of claim 1, wherein the amount of the buffering agent is about 15 mEq to about 55 mEq.

12. The method of claim 1, wherein the buffering agent comprises a combination of calcium carbonate and sodium bicarbonate.

13. The method of claim 1, wherein the buffering agent comprises a bicarbonate salt of a Group IA metal.

14. The method of claim 1, wherein the buffering agent is selected from the group consisting of a bicarbonate salt of a Group IA metal, an alkali earth metal buffering agent, a calcium buffering agent, a magnesium buffering agent, an aluminum buffering agent, sodium bicarbonate, potassium bicarbonate, magnesium hydroxide, magnesium lactate, magnesium gluconate, magnesium oxide, magnesium aluminate, magnesium carbonate, magnesium silicate, magnesium citrate, aluminum hydroxide, aluminum phosphate, aluminum hydroxide/magnesium carbonate, potassium carbonate, potassium citrate, aluminum hydroxide/sodium bicarbonate coprecipitate, aluminum glycinate, aluminum magnesium hydroxide, sodium citrate, sodium tartrate, sodium acetate, sodium carbonate, sodium polyphosphate, potassium polyphosphate, sodium pyrophosphate, sodium dihydrogen phosphate, potassium pyrophosphate, disodium hydrogenphosphate, dipotassium hydrogenphosphate, trisodium phosphate, tripotassium phosphate, potassium metaphosphate, calcium acetate, calcium glycerophosphate, calcium chloride, calcium hydroxide, calcium lactate, calcium carbonate, calcium gluconate, calcium bicarbonate, calcium citrate, calcium phosphate magnesium phosphate, potassium phosphate, sodium phosphate, trihydroxymethylaminomethane, an amino acid, an acid salt of an amino acid, an alkali salt of an amino acid, and combinations of any of the foregoing.

15. The method of claim 1, wherein the buffering agent comprises sodium bicarbonate.

16. The method of claim 15, wherein the sodium bicarbonate is in an amount from about 250 mg to about 4000 mg.

17. The method of claim 15, wherein the sodium bicarbonate is in an amount from about 1000 mg to about 2000 mg.

18. The method of claim 15, wherein the sodium bicarbonate is in an amount of at least about 400 mg.

19. The method of claim 1, wherein the buffering agent comprises calcium carbonate.

20. The method of claim 19, wherein the calcium carbonate is in an amount from about 250 mg to about 4000 mg.

21. The method of claim 19, wherein the calcium carbonate is in an amount from about 1000 mg to about 2000 mg.

22. The method of claim 19, wherein the calcium carbonate is in an amount of at least about 400 mg.

23. The method of claim 1, wherein the excipient is selected from the group consisting of a pharmaceutically compatible carrier, a binder, a suspending agent, a flavoring agent, a sweetening agent, a disintegrant, a flow aid, a lubricant, an adjuvant, a colorant, a diluent, a moistening agent, a preservative, a parietal cell activator, an anti-foaming agent, an antioxidant, a chelating agent, an antifungal agent, an antibacterial agent, e* an isotonic agent, and combinations of any of the foregoing.

24. The method of claim 1, wherein the excipient is one or more flavoring agents selected from the group consisting of aspartame, thaumatin, sucrose, dextrose, or a chocolate, a cocoa, a cola, a peppermint, a spearmint, a watermelon, an apple, a caramel, a meat, a root beer, a maple, a cherry, a coffee, a mint, a licorice, a nut, a butter, a butterscotch, a butter pecan, or a peanut butter flavoring, and combinations of any of the foregoing.

25. The method of claim 1, wherein the composition is administered once or twice a day.

26. A method of treating a gastric acid related disorder in a subject in need thereof, comprising:

orally administering to the subject a single dose of a solution or suspension of a pharmaceutical composition, the composition consisting essentially of;

(a) a therapeutically effective amount of at least one acid labile, substituted benzimidazole H⁺, K⁺-ATPase proton pump inhibitor;

(b) at least one buffering agent in an amount of about 0.1 mEq to about 2.5 mEq per mg proton pump inhibitor; and

(c) one or more optional pharmaceutically acceptable excipients wherein an initial serum concentration of the proton pump inhibitor greater than about 0.1 μ

g/ml is obtained at any time within about 30 minutes after administration of the composition, and wherein the administering step does not require further administration of the buffering agent(s) beyond that administered in the single dose.

27. The method of claim 26, wherein the composition is administered in an amount to achieve an initial serum concentration of the proton pump inhibitor greater than about 0.15 μ

g/ml at any time within about 30 minutes after administration of the composition.

28. The method of claim 26, wherein the subject is fasting.

29. The method of claim 26, wherein the proton pump inhibitor is selected from the group consisting of omeprazole, lansoprazole, rabeprazole, esomeprazole, pantoprazole, pariprazole, and leminoprazole, or an enantiomer, isomer, tautomer, ester, amide, derivative, prodrug, free base, or salt thereof.

30. The method of claim 26, wherein the amount of the proton pump inhibitor is about 2 mg to about 300 mg.

31. The method of claim 26, wherein the amount of the proton pump inhibitor is about 10 mg to about 120 mg.

32. The method of claim 26, wherein the amount of the proton pump inhibitor is about 2 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 rug, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 rug, about 100 mg, about 105 mg, about 110 mg, about 15 mg, or about 120 mg.

33. The method of claim 26, wherein the amount of the buffering agent is about 10 mEq to about 70 mEq.

34. The method of claim 26, wherein the amount of the buffering agent is at least 10 mEq.

35. The method of claim 26, wherein the amount of the buffering agent is about 15 mEq to about 55 mEq.

36. The method of claim 26, wherein the buffering agent comprises a combination of calcium carbonate and sodium bicarbonate.

37. The method of claim 26, wherein the buffering agent comprises a bicarbonate salt of a Group IA metal.

38. The method of claim 26, wherein the buffering agent is selected from the group consisting of a bicarbonate salt of a Group IA metal, an alkali earth metal buffering agent, a calcium buffering agent, a magnesium buffering agent, an aluminum buffering agent, sodium bicarbonate, potassium bicarbonate, magnesium hydroxide, magnesium lactate, magnesium gluconate, magnesium oxide, magnesium aluminate, magnesium carbonate, magnesium silicate, magnesium citrate, aluminum hydroxide, aluminum phosphate, aluminum hydroxide/magnesium carbonate, potassium carbonate, potassium citrate, aluminum hydroxide/sodium bicarbonate coprecipitate, aluminum glycinate, aluminum magnesium hydroxide, sodium citrate, sodium tartrate, sodium acetate, sodium carbonate, sodium (polyphosphate, sodium dihydrogen phosphate, potassium polyphosphate, sodium pyrophosphate, potassium pyrophosphate, disodium hydrogenphosphate, dipotassium hydrogenphosphate, trisodium phosphate, tripotassium phosphate, potassium metaphosphate, calcium acetate, calcium glycerophosphate, calcium chloride, calcium hydroxide, calcium lactate, calcium carbonate, calcium gluconate, calcium bicarbonate, calcium citrate, calcium phosphate magnesium phosphate, potassium phosphate, sodium phosphate, trihydroxymethylaminomethane, ail amino acid, an acid salt of an amino acid, an alkali salt of an amino acid, and combinations of any of the foregoing.

39. The method of claim 26, wherein the buffering agent comprises sodium bicarbonate.

40.The method of claim 39, wherein the sodium bicarbonate is in an amount from about 250 mg to about 4000 mg.

40. The method of claim 39, wherein the sodium bicarbonate is in an amount from about 1000 mg to about 2000 mg.

41. The method of claim 39, wherein the sodium bicarbonate is in an amount of at least about 400 mg.

42. The method of claim 39, wherein the buffering agent comprises calcium carbonate.

46. The method of claim 26, wherein the excipient is selected from the group consisting of a pharmaceutically compatible carrier, a binder, a suspending agent, a flavoring agent, a sweetening agent, a disintegrant, a flow aid, a lubricant, an adjuvant, a colorant, a diluent, a moistening agent, a preservative, a parietal cell activator, an anti-foaming agent, an antioxidant, a chelating agent, an antifungal agent, an antibacterial agent, or an isotonic agent, and combinations of any of the foregoing.

47. The method of claim 26, wherein the subject is an adult human.

48. The method of claim 26, wherein the disorder is selected from the group consisting of duodenal ulcer disease, gastric ulcer disease, gastroesophageal reflux disease, erosive esophagitis, poorly responsive symptomatic gastroesophageal reflux disease, pathological gastrointestinal hypersecretory disease, Zollinger Ellison Syndrome, heartburn, esophageal disorder, and acid dyspepsia.

49. The method of claim 26, wherein the excipient is one or more flavoring agents selected from the group consisting of aspartame, thaumatin, sucrose, dextrose, or a chocolate, a cocoa, a cola, a peppermint, a spearmint, a watermelon, an apple, a caramel, a meat, a root beer, a maple, a cherry, a coffee, a mint, a licorice, a nut, a butter, a butterscotch, a butter pecan, or a peanut butter flavoring, and combinations of any of the foregoing.

50. The method of claim 26, wherein the composition is administered once or twice a day.

43. The method of claim 43, wherein the calcium carbonate is in an amount from about 250 mg to about 4000 mg.

44. The method of claim 43, wherein the calcium carbonate is in an amount from about 1000 mg to about 2000 mg.

45. The method of claim 43, wherein the calcium carbonate is in an amount of at least about 400 mg.