Modified release formulations and methods of treating inflammatory bowel disease
View Patent ↗Methods and formulations for treating inflammatory bowel disease are disclosed. The methods and formulations include, but are not limited to, methods and formulations for delivering effective concentrations of 4-aminosalicylic acid and/or 5-aminosalicylic acid, and pharmaceutically acceptable salts and pro-drugs thereof, to affected areas of the intestine, i.e., distal gut. The methods and formulations comprise modified-release elements, providing for drug delivery to the affected or desired area. Diseases and conditions treatable with the present invention include Crohn's disease and ulcerative colitis.
1. A pharmaceutical composition for administration to a subject in need thereof comprising a dose of an aminosalicylate active agent chosen from 4-amino salicylic acid, 5-amino salicylic acid, and pharmaceutically acceptable salts, esters and pro-drugs thereof; at least one polymer chosen from water-soluble cellulosic polymers, polyvinyl alcohol, polyvinylpyrrolidone, polyethylene glycol, water-insoluble acrylate polymers, water-insoluble cellulosic polymers, and mixtures thereof; and at least one pharmaceutically acceptable excipient chosen from carriers, fillers, extenders, binders, absorbents, lubricants, and stabilizers; wherein the composition exhibits:
(a) a drug-release profile that is independent of surrounding pH; and
(b) a dissolution profile, when tested in a U.S.P. Type II apparatus (paddles) at 37° C and 50 rpm, in pH 6.8 buffer for the test:
1 hour: less than or equal to about 20% drug released;
2 hours: less than or equal to about 35% drug released;
3 hours: less than or equal to about 50% drug released;
4 hours: less than or equal to about 60% drug released;
6 hours: less than or equal to about 75% drug released; and
12 hours: from about 25% to about 100% drug released; and wherein upon administration, the composition exhibits:
(c) at least one ratio chosen from a total urine recovery or total plasma (AUC) ratio of metabolite of the active agent to the active agent greater than or equal to 10:1, and a Cmax ratio of metabolite of the active agent to the active agent greater than or equal to 5:1; and
(d) from greater than 30% to about 100% of the dose of the active agent excreted in the urine as metabolite of the active agent and the active agent,
wherein the composition comprises a modified-release matrix core.
2. The composition according to claim 1 , wherein the dissolution profile, when tested in a U.S.P. Type II apparatus (paddles) at 37° C. and 50 rpm, in pH 6.8 buffer for the test:
1 hour: less than or equal to about 10% drug released;
2 hours: less than or equal to about 20% drug released;
3 hours: less than or equal to about 30% drug released;
4 hours: less than or equal to about 40% drug released;
6 hours: less than or equal to about 50% drug released; and
12 hours: from about 25% to about 100% drug released.
3. The composition according to claim 1 , wherein the dissolution profile, when tested in a U.S.P. Type II apparatus (paddles) at 37° C. and 50 rpm, in pH 6.8 buffer for the test:
1 hour: less than or equal to about 5% drug released;
2 hours: less than or equal to about 10% drug released;
3 hours: from about 5% to about 30% drug released;
4 hours: from about 10% to about 40% drug released;
6 hours: from about 20% to about 50% drug released; and
12 hours: from about 40% to about 100% drug released.
4. The composition according to claim 1 , wherein the composition comprises a semi-permeable membrane.
5. The composition according to claim 1 , wherein the aminosalicylate and/or salicylic acid is 4-aminosalicylic acid or pharmaceutical salt thereof.
6. The composition according to claim 5 , wherein 4-aminosalicylic acid is sodium 4-aminosalicylate.
7. The composition according to claim 1 , wherein the aminosalicylate active agent is chosen from olsalazine (5,5′-azo-bis salicylic acid), balsalazide, 4,5′-azo-bis salicylic acid, 4,4′-azo-bis salicylic acid, and pharmaceutically acceptable salts thereof.
8. The composition according to claim 1 , wherein the at least one pharmaceutically acceptable excipient is chosen from carriers, fillers, extenders, binders, humectants, disintegrating agents, solution-retarding agents, absorption accelerators, wetting agents, absorbents, lubricants, stabilizers, coloring agents, buffering agents, dispersing agents, preservatives, organic acids, and organic bases.
9. The composition according to claim 1 , wherein the total urine recovery ratio of the metabolite of the active agent to the active agent is greater than 20:1.
10. The composition according to claim 9 , wherein the total urine recovery ratio of the metabolite of the active agent to the active agent is greater than 100:1.
11. The composition according to claim 1 , wherein the Cmax ratio of the metabolite of the active agent to the active agent is greater than or equal to 10:1.
12. The composition according to claim 1 , wherein the dose of the aminosalicylate active agent ranges from 100 mg to 8000 mg.
13. The composition according to claim 1 , wherein the dose is chosen from single and divided dosages.
14. A method of treating inflammatory bowel disease comprising administering to a subject in need thereof an effective amount of a pharmaceutical composition comprising a dose of an aminosalicylate active agent chosen from 4-amino salicylic acid, 5-amino salicylic acid, and pharmaceutically acceptable salts, esters and prodrugs thereof; at least one polymer chosen from water-soluble cellulosic polymers, polyvinyl alcohol, polyvinylpyrrolidone, polyethylene glycol, water-insoluble acrylate polymers, water-insoluble cellulosic polymers, and mixtures thereof; and at least one pharmaceutically acceptable excipient chosen from carriers, fillers, extenders, absorbents, lubricants, and stabilizers; wherein the composition exhibits:
(a) a drug-release profile that is independent of surrounding pH; and
(b) a dissolution profile, when tested in a U.S.P. Type II apparatus (paddles) at 37° G and 50 rpm, in pH 6.8 buffer for the test:
1 hour: less than or equal to about 20% drug released;
2 hours: less than or equal to about 35% drug released;
3 hours: less than or equal to about 50% drug released;
4 hours: less than or equal to about 60% drug released;
6 hours: less than or equal to about 75% drug released; and
12 hours: from about 25% to about 100% drug released; and wherein upon administration, the composition exhibits:
(c) at least one ratio chosen from a total urine recovery or total plasma (AUG) ratio of metabolite of the active agent to the active agent greater than or equal to 10:1, and a Gmax ratio of metabolite of the active agent to the active agent greater than or equal to 5:1; and
(d) from greater than 30% to about 100% of the dose of the active agent excreted in the urine as metabolite of the active agent and the active agent,
wherein the composition comprises a modified-release matrix core.
15. The method according to claim 14 , wherein the pharmaceutical composition is administered in a modified-release formulation.
16. The method according to claim 15 , wherein the modified-release formulation exhibits a release profile with properties chosen from delayed-release and extended-release.
17. The method according to claim 14 , wherein the dose of the aminosalicylate active agent ranges from 100 mg to 8000 mg.
18. The method according to claim 14 , wherein the dose is chosen from single and divided dosages.
19. The composition according to claim 1 , wherein the water-soluble cellulosic polymer is hydroxypropyl methylcellulose.
20. The composition according to claim 1 , wherein the water-insoluble cellulosic polymer is ethylcellulose.