Composition for the treatment and prevention of ischemic events

• US 20020051814A1
• Filed: 09/13/2001
• Published: 05/02/2002
• Est. Priority Date: 09/11/2000
• Status: Active Grant

• Current Assignee: Andrx Pharmaceuticals LLC (Abbvie Incorporated)
• Original Assignee: Andrx Pharmaceuticals LLC (Abbvie Incorporated)
• Inventors: Chen, Chih-Ming
• Granted Patent: US 7,029,701 B2
• Time in Patent Office: Days
• US Class Current: 424/451
• 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 31/4439 containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole nicotine A61K31/465
• CPC Class Codes: A61K 31/616 by carboxylic acids, e.g. acetylsalicylic acid
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 9/5078 with drug-free core

Abstract

The invention relates to pharmaceutical compositions comprising omeprazole and aspirin wherein the combination is useful for the treatment and prevention of cardiovascular events including heart attacks and platelet aggregation leading to a potential cardiac event. A variety of drug delivery systems may be utilized to deliver the combination of active ingredients. The preferred delivery system utilizes a tablet or capsule containing an inert sugar core particle that is coated with subparticles of a coated omeprazole wherein the coating contains omeprazole, a binder, a surface active agent and a basifying agent along with a filler. The aspirin may be combined with this formulation to coat the sugar sphere or it may be part of a separate coating composition that forms a multilayer system that is ultimately coated with an enteric coating and then formed into the tablet or capsule by conventional means.

Claims

1. A pharmaceutical composition comprising a single unit dose containing aspirin and omeprazole and a pharmaceutically acceptable excipient.

2. The composition according to claim 1 wherein the single unit dose comprises a sustained release formulation.

3. The composition according to claim 1 wherein the single unit dose contains between 5 to 40 mgs of omeprazole and 30 to 250 mgs of aspirin.

4. A sustained release formulation comprising:

(a) a coated particle of omeprazole wherein the particle is coated with a composition comprising omeprazole, a surfactant, a binder, an alkaline material and a filler; and

(b) aspirin; and

(c) an enteric coating surrounding the aspirin and coated particle of omeprazole.

5. The formulation according to claim 4 in the form of a tablet.

6. The formulation according to claim 4 in the form of a capsule.

29. A capsule according to claim 4 that further comprises a separating layer between the active layer and the enteric coating layer.

30. A capsule according to claim 4 that excludes a separating layer between the active layer and the enteric coating layer.

7. A stable pharmaceutical composition of omeprazole and aspirin for oral administration which consists essentially of:

(a) a pellet comprising an inert core component, a therapeutically effective amount of omeprazole, aspirin, a surface active agent, a filler, a pharmaceutically acceptable alkaline agent and a binder; and

(b) a layer of coating on said pellet which comprises a layer of an enteric coating agent.

8. A pharmaceutical composition of omeprazole as defined in claim 7 wherein the alkaline material is selected from the group consisting of the sodium, potassium, calcium, magnesium and aluminum salts of phosphoric acid, carbonic acid and citric acid.

9. A pharmaceutical composition of omeprazole as defined in claim 7 wherein the alkaline material is selected from the group consisting of aluminum hydroxides, calcium hydroxides, magnesium hydroxides and magnesium oxide.

10. A pharmaceutical composition of omeprazole as defined in claim 7 wherein the acid resistant component is selected from the group consisting of cellulose acetate phthalate, hydroxypropylmethyl cellulose phthalate, polyvinyl acetate phthalate, carboxymethylethylcellulose, co-polymerized methacrylic acid/methacrylic acid methyl esters.

11. A pharmaceutical composition of omeprazole as defined in claim 7 wherein the enteric coating agent also includes an inert processing aid.

12. A pharmaceutical composition of omeprazole as defined in claim 7 wherein the enteric coating agent around the core includes from 10 to 80 wt % of and inert processing aid.

13. A pharmaceutical composition of omeprazole as defined in claim 7 which includes a sodium lauryl sulfate as the surface active agent.

14. A pharmaceutical composition as defined in claim 7 wherein the core contains a non-pareil sugar seed.

16. A pelleted pharmaceutical dosage formulation as defined in claim 15 wherein the alkaline agent is disodium phosphate.

15. A pelleted pharmaceutical dosage formulation which consists essentially of:

(a) a core comprising a non-pareil sugar seed coated with drug layer composition comprising omeprazole, a binder, an alkaline agent, a filler and a surface active agent; and

(b) an enteric coating agent around said core, said enteric coating comprising hydroxypropylmethyl cellulose phthalate and talc.

17. A controlled release dosage form which comprises:

(a) a homogeneous compressed core that comprises a compressed granulation of;

(i) particles of aspirin coated with an enteric polymer that are dispersed onto a solid pharmaceutical filler and

(ii) particles of omeprazole that are uncoated or coated with an enteric polymer that are dispersed onto a solid pharmaceutical filler; and

(b) a continuous compressed outer layer around said homogeneous compressed core that comprises a compressed granulation of one or more pharmaceutically acceptable polymers that form a hydrogel and that may additionally comprise aspirin and omeprazole.

18. A controlled release dosage form which comprises:

(a) a compressed tablet core which contains a coated aspirin and omeprazole, a pharmaceutically acceptable, water swellable polymer and an osmotic agent; and

(b) an outer coating layer which completely covers the osmotic core and comprises a pH sensitive coating agent and a water insoluble polymer.

Optional coatings or seal coatings may additionally be applied.

19. A once a day controlled release medicament which comprises:

(a) a homogeneous compressed core of granules produced in a fluidized bed, said core comprising;

(i) a medicament selected from a coated aspirin along with omeprazole;

(ii) a water soluble osmotic compound;

(iii) one or more osmotic polymers wherein one of the osmotic polymers is a water swellable osmotic polymer; and

(b) a membrane coating around said homogeneous compressed core.

20. A once-a-day aspirin/omeprazole delivery system for the treatment and prevention of heart attacks that comprises:

(a) from 20 to 50 wt. % of enteric polymeric membrane coated pellets comprising a polymer membrane coated core which comprises a biologically inert core which is coated with a first layer that comprises aspirin and a polymeric binder; and

a second layer that comprises a membrane comprising a polymeric enteric coating material; and

(b) from 50 to 80 wt. % of delayed pulse polymer membrane coated pellets comprising a polymeric membrane coated core which comprises a biologically inert core which is coated with a combined first layer which comprises omeprazole and a polymeric binder polymer and a second layer which comprises a polymeric membrane that is permeable to omeprazole; and

(c) a unit dose containment system.

21. A controlled release formulation which comprises:

(a) a core element comprising a compressed tablet which comprises a therapeutic dose of a combination of coated aspirin and omeprazole and an optional amount of a solubility modulating substance that is sufficient to control the release of said aspirin/omeprazole to provide a therapeutic level over a period of about 24 hours and;

(b) a sufficient amount of a substantially uniform enteric coating.

22. A controlled release pharmaceutical tablet comprising:

(a) a compressed core which comprises;

(i) a medicament selected from the combination of a anti-thrombotically effective amount of aspirin and omeprazole;

(ii) at least 23% to 55% by weight, based on the total weight of the core, of a water soluble osmotic agent;

(iii) a water soluble pharmaceutically acceptable polymeric binder;

(iv) a water-swellable pharmaceutically acceptable polymer;

(v) a conventional pharmaceutical excipient; and

(b) a membrane coating comprising;

(i) a modified water insoluble pharmaceutically acceptable polymer; and

(ii) a pharmaceutically acceptable water soluble polymer.

28. The method according to claim 27 wherein the patient is at risk of a heart attack or the patient has cardiovascular disease that potentially could lead to a heart attack.

23. A controlled release pharmaceutical unit dose composition for oral administration comprising:

(a) an internal phase which comprises a coated aspirin in combination with a pharmaceutically effective amount of omeprazole in admixture with a hydrogel forming agent; and

(b) an external phase which comprises a coating which resists dissolution in the stomach.

24. A controlled release pharmaceutical tablet having at least one passageway, said tablet comprising:

(a) a compressed core that comprises;

(i) a combination of a therapeutically effective amount of coated aspirin and omeprazole;

(ii) an amount of a water soluble osmotic agent which is effective to cause the combination to be delivered from said passageway in the presence of aqueous media;

(iii) a water-swellable pharmaceutically acceptable polymer; and

(b) a membrane coating comprising a water insoluble pharmaceutically acceptable polymer.

25. A pharmaceutical dosage form which comprises:

(a) a compressed core which comprises;

(i) a combination of coated aspirin and omeprazole or aspirin as the active in the core or omeprazole as the active in the core;

(ii) from 5 to 20 wt. % of a water soluble osmotic agent based upon the total weight of the core;

(iii) a water soluble pharmaceutically acceptable polymeric binder;

(iv) a conventional pharmaceutical excipient; and

(b) a dual layer membrane coating around said core which comprises;

(i) a first inner coating layer for sustained release of the medicaments, said inner coating layer comprising a plasticized water insoluble pharmaceutically acceptable polymer and a pharmaceutically acceptable water soluble polymer, and;

(ii) a second outer coating layer for immediate release of a medicament, said outer coating layer optionally comprising an effective amount of aspirin or omeprazole and having a water soluble polymer.

26. A controlled release dosage pharmaceutical tablet which comprises:

(a) an osmotic core which comprises a coated aspirin and omeprazole and a water swellable component selected from the group consisting of hydroxypropylmethyl cellulose and a polyethylene oxide in admixture with the coated aspirin and omeprazole;

(b) a coating which comprises a water resistant polymer and a minor amount of a non-toxic, water soluble, pharmaceutically acceptable compound in an amount which is sufficient to dissolve in gastrointestinal fluid and form a plurality of micropores in the outside of said table, said water resistant polymer which are microporous to the passage of gastrointestinal fluid.

27. A method of treating a patient in need of a prophylatic or therapeutic effective amount of aspirin in combination with omeprazole comprising administering to said patient a composition comprising aspirin and omeprazole in a single unit dosage form.