SOLID COMPOSITION FOR CONTROLLED RELEASE OF IONIZABLE ACTIVE AGENTS WITH POOR AQUEOUS SOLUBILITY AT LOW PH AND METHODS OF USE THEREOF

1 . A solid pharmaceutical composition for the controlled release of an active agent in the gastrointestinal tract, comprising:

(a) at least one acid active agent with a solubility of less than about 0.3 mg/ml in an aqueous solution at a pH of at most about the pKa of the acid active agent at a temperature of about 37° C., or a pharmaceutically acceptable salt thereof;

(b) at least one hydrophilic polymer; and

(c) at least one alkalizer;

wherein the composition reduces evacuation from the stomach; and

provides at least about 70% release of the active agent for a period of time from about between about 7 to about 12 hours following oral administration

2 . The solid composition of claim 1 , wherein the solubility of said active agent or a pharmaceutically acceptable salt thereof is less than about 0.2 mg/ml in an aqueous solution at a pH of at most about the pKa of the acid active agent at a temperature of about 37° C.

3 . The solid composition of claim 1 , wherein the solubility of said active agent or a pharmaceutically acceptable salt thereof is less than about 0.1 mg/ml in an aqueous solution at a pH of at most about the pKa of the acid active agent at a temperature of about 37° C.

4 . The solid composition of claim 1 , wherein the composition provides near zero order release profile independent of a pH range of about 1 to about 7.4.

5 . The solid composition of claim 1 , wherein the active agent has a solubility of less than about 0.1 mg/ml in an aqueous solution at a pH of about 1 to about 6.8.

6 . The solid composition of claim 1 , wherein the active agent has the formula (I):

wherein:

R 1 is selected from the group consisting of H, halogen, —OH, —C 1-10 -alkyl and C 1-6 -alkylamino; and

X is selected from the group consisting of: F and I.

7 . The solid composition of claim 1 , wherein the active agent is [4-(6-fluoro-7-methylamino-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-phenyl]-5-chloro-thiophen-2-yl-sulfonylurea potassium salt.

8 . The solid composition of claim 1 , wherein the amount of active agent is about 50 mg.

9 . The solid composition of claim 1 , wherein the amount of hydrophilic polymer is less than about 27.8% w/w of the composition.

10 . The solid composition of claim 1 , wherein the amount of hydrophilic polymer is between about 27.8% w/w to about 15 w/w % of the total composition.

11 . The solid composition of claim 1 , wherein the hydrophilic polymer has an average molecular weight of between about 0.82 and about 9×10 5 Daltons.

12 . The solid composition of claim 11 , wherein the at least one hydrophilic polymer is a combination of hydrophilic polymers.

13 . The solid composition of claim 1 , wherein the hydrophilic polymer is selected from the group consisting of a cellulose ether, polyethylene oxide, acrylic acid, and combinations thereof.

14 . The solid composition of claim 1 , wherein the cellulose ether is METHOCEL™ K4M or K100M.

15 . The solid composition of claim 1 , wherein the polyethylene oxide is POLYOX™ WSR 1105.

16 . The solid composition of claim 1 , wherein the alkalizer selected from the group consisting of calcium carbonate, magnesium oxide, sodium bicarbonate and arginine and pharmaceutically acceptable salts thereof.

17 . The solid composition of claim 1 , wherein the total amount of alkalizer is from about 5 weight percent to about 50 weight percent of the total composition.

18 . The solid composition of claim 1 , wherein the total amount of alkalizer is from about 15 weight percent to about 30 weight percent of the total composition.

19 . The solid composition of claim 18 , wherein the combined weight percent of the alkalizer is greater than or equal to the weight percent of the active agent.

20 . The solid composition of claim 1 , wherein the weight ratio of said alkalizer to said hydrophilic polymer is from about 0.9 to about 0.69.

21 . The solid composition of claim 1 , wherein said composition comprises from about 7.6% w/w to about 8.9% w/w active agent; from about 27.8% w/w to about 15% w/w hydrophilic polymer; and from about 15% w/w to about 30% w/w alkalizer of the total composition.

22 . The solid composition of claim 1 , wherein the composition provides at least about 70% release of the active agent between about 7 to about 9 hours following oral administration.

23 . The solid composition of claim 1 , wherein the composition provides at least about 70% release of the active agent between about 10 to about 12 hours following oral administration.

24 . The solid composition of claim 1 , wherein the composition is a non-disintegrating matrix tablet.

25 . The solid composition of claim 1 , wherein the composition is a slow-disintegrating matrix tablet.

26 . The solid composition of claim 1 , further comprising a buffering system selected from at least one or combination of alkalizers and citric acid.

27 . The solid composition of claim 1 , wherein the composition is a floatation tablet.

28 . A method for treating a cardiovascular disorder in a subject in need thereof, said method comprising:

administering to said subject a composition of claim 1 .

29 . The method of claim 28 , wherein the cardiovascular disorder is thrombosis.

30 . A method for producing a tablet, comprising:

(1) producing a mixture comprising:

(a) at least one weak acid active agent with a solubility of less than about 0.1 mg/ml in an aqueous solution at a pH of at most about the pKa of the active acid agent at a temperature of about 37° C., or a pharmaceutically acceptable salt thereof;

(b) at least one hydrophilic polymer which is not instantly soluble in gastric fluids; and

(c) an alkalizer;

wherein the composition reduces evacuation from the stomach; and

provides at least about 70% release of the active agent for a period of time from about between about 7 to about 12 hours following oral administration; and

(2) compressing the mixture to produce the tablet.