Gastric retention dosage form having multiple layers

• US 6,797,283 B1
• Filed: 12/22/1999
• Issued: 09/28/2004
• Est. Priority Date: 12/23/1998
• Status: Expired due to Fees

• Current Assignee: Encinal Pharmaceutical Investments, LLC
• Original Assignee: ALZA Corporation (Johnson & Johnson)
• Inventors: Edgren, David E., Jao, Francisco, Wong, Patrick S. -L.
• Primary Examiner(s): Page, Thurman K.
• Assistant Examiner(s): CHOI, FRANK I
• Application Number:
  US09/469,399
• Time in Patent Office: 1,742 Days
• Field of Search: 424/457, 424/465, 424/468, 424/469, 424/470, 424/472, 424/473, 424/484, 424/485, 424/487, 424/488, 424/DIG.6, 514/152, 514/263.38, 514/315, 514/365, 514/369, 514/370, 514/371, 514/400, 514/401, 514/423, 514/428, 514/431, 514/449, 514/471, 514/634, 514/635, 514/646, 514/676, 514/688, 514/769, 514/770, 514/772, 514/772.3, 514/772.4, 514/772.5, 514/772.6, 514/772.7, 514/777, 514/778, 514/779, 514/781, 514/782, 514/784, 514/785, 514/786, 514/836, 514/866, 514/884, 514/909, 514/960, 514/961, 514/965, D24/100, D24/101, D24/102
• US Class Current: 424/472
• CPC Class Codes: A61K 9/0065 Forms with gastric retention, e.g. floating on gastric juice, adhering to gastric mucosa, expanding to prevent passage through the pylorus
• CPC Class Codes: Y10S 424/06 Chelate

Abstract

The present invention is directed to a multilayered dosage form which is adapted for retention in the stomach and useful for the prolonged delivery of an active agent to a fluid environment of use. The active agent dosage form is a multilayer core, often bilayer, formed of polymer matrices that swell upon contact with the fluids of the stomach. At least one layer of the multilayered dosage form includes an active agent. A portion of the polymer matrices are surrounded by a band of insoluble material that prevents the covered portion of the polymer matrices from swelling and provides a segment of the dosage form that is of sufficient rigidity to withstand the contractions of the stomach and delay expulsion of the dosage form from the stomach until substantially all of the active agent has been dispensed.

Claims

1. An active agent dosage form comprising:

a first layer comprising an amount of swellable polymer, said amount being sufficient to swell said first layer such that the active agent dosage form is retained within a stomach of a subject;

a second layer laminated with the first layer at a common surface, said second layer comprising a therapeutic amount of an active agent and being formulated to swell to a lesser extent than the first layer; and

at least one band of insoluble material circumscribing only a portion of said first layer and said second layer, said at least one band of insoluble material binding together the first layer and the second layer.

2. The active agent dosage form of claim 1, wherein the number average molecular weight of the swellable polymer is between about 100,000 and 20,000,000 grams per mole.

3. The active agent dosage forn of claim 2, wherein the swellable polymer is polyethylene oxidc, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cclulose, sodium carboxy methylcellulose, calcium carboxymethyl cellulose, methyl cellulose, polyacrylic acid, maltodextrin, pre-gelatinized starch, guar gum, sodium alginate, or polyvinyl alcohol.

4. The active agent dosage form of claim 1, wherein the second layer comprises a hydroattractant selected from low-substituted hydroxypropyl cellulose, microcrystalline cellulose, cross-linked sodium or calcium carboxymethyl cellulose, cellulose fiber, cross-linked polyvinyl pyrrolidone, cross-linked polyacrylic acid, a cross-linked ion exchange resin, alginates, colloidal magnesium-aluninum silicate, corn starch granules, rice starch granules, potato starch granules, sodium carboxymethyl starch, sugars, and sodium chloride, and the first layer optionally comprises a hydroattractant selected from low-substituted hydroxypropyl cellulose, microcrystalline cellulose, cross-linked sodium or calcium carboxymethyl cellulose, cellulose fiber, ctoss-linked polyvinyl pyrrolidone, cross-linked polyacrylic acid, cross-linked ion exchange resin, alginates, colloidal magnesium-aluminum silicate, corn starch granules, rice starch granules, potato starch granules, sodium carboxym ethyl starch, sugars and sodium chloride.

5. The active agent dosage form of claim 1, wherein the first layer swells more rapidly than does the second layer.

6. The active agent dosage form of claim 1, wherein the active agent is an antiviral, antimicrobial antidiabetic, antihyperglycemic, hypoglycemic, antidepressant, antiobesity or antifugal active agent.

7. The active agent dosage form of claim 1, wherein the second layer includes 5 to 99.99 weight percent of a swellable polymer and further includes up to 60 weight percent, inclusive, of a hydroattractant.

8. The active agent dosage form of claim 1, wherein the first layer is formulated such that the active agent dosage form is retained within the stomach for a prolonged period of time.

9. The active agent dosage form of claim 8, wherein the prolonged period of time is at least 3 hours.

10. The active agent dosage form of claim 1, wherein the first layer is formulated such that the active agent dosage form is retained within the stomach for between about 6 to 12 hours.

11. The active agent dosage form of claim 1, wherein the first layer comprises polyethylene oxide having a number average molecular weight of at least 100,000 grams per mole.

12. The active agent dosage form of claim 11, wherein the active agent is an antiviral, antimicrobial, antidiabetic, antihyperglycemic, hypoglycemic, antidepressant, antiobesity or antifungal active agent.

13. The active agent dosage form of claim 12, wherein the active agent is acyclovir, ganciclovir, ritonavir, minocycline, cimetidine, ranitidine, captopril, methyldopa, selegiline, minocycline, fexofenadine, metformin, bupropion, orlistat or a pharmaceutically acceptable salt thereof.

14. The active agent dosage form of claim 11, wherein the active agent is metformin or a pharmaceutically acceptable salt thereof.

15. The active agent dosage form of claim 1, wherein the second layer comprises an active agent selected from the group consisting of acyclovir, ganciclovir, ritonavir, metformin, bupropion, orlistat and minocycline, and the second layer comprises a bioerodible polymer, wherein the dosage form is formulated to release a therapeutically-effective amount of the active agent to the stomach of a subject over at least a 3 hour period.

19. The active agent dosage form of claim 1, further comprising a gastric-emptying delaying agent.

20. The active agent dosage form of claim 19, wherein the gastric-emptying delaying agent is selected from anticholinergic agents, methylcellulose, guar gum, fats and fatty acids of 10-15 carbon atoms.

21. The active agent dosage form of claim 1, wherein the active agent comprises a liquid active agent formulation.

22. The active agent dosage form of claim 21, wherein the liquid active agent formulation is sorbed into porous particles.

23. The active agent dosage form of claim 22, wherein the porous particles are calcium hydrogen phosphate or magnesium aluminometasilicate.

24. The active agent dosage form of claim 1, wherein the dosage form comprises a pH regulating agent.

25. The active agent dosage form of claim 22, wherein the liquid active agent formulation comprises a pH regulating agent selected from organic and inorganic acids and bases.

26. The active agent dosage form of claim 22, wherein the liquid active agent formulation comprises a chelating agent.

16. A method for treating a subject in need thereof with an active agent, the method comprising:

administering to the subject a multilayered dosage form which is retained in a stomach of the subject over a prolonged period of time, the dosage form comprising;

a first layer comprising an amount of swellable polymer, said amount being sufficient to swell said first layer such that said active agent dosage form is retained within the stomach of a subject;

a second layer laminated with the first layer at a common surface, said second layer comprising a therapeutic amount of an active agent and being formulated to swell to a lesser extent than the first layer; and

at least one band of insoluble material circumscribing only a portion of said first layer and said second layer, said at least one band of insoluble material binding together the first layer and the second layer.

17. The method of claim 16, which comprises administering one or more of the multilayered dosage forms to the subject in the fed state at the start of each dosing period.

18. The method of claim 17, wherein the administration of one or more of the multi-layered dosage forms occurs within one hour of the subject consuming food.