Controlled-release formulations, method of manufacture, and use thereof

1. A controlled-release composition, comprising:

a non-gelling matrix consisting of

a pharmaceutically effective amount of an active agent or a pharmaceutically acceptable salt, solvate, ester, and/or prodrug thereof,

an ionic non-gelling matrix polymer that is practically insoluble and unswellable at a first aqueous fluid pH and is soluble at a second aqueous fluid pH,

a pH modifier which is present in an amount from about 2 to about 50 wt % based on the total weight of the composition; and

a soluble, non-gelling pharmaceutically acceptable excipient; and

the composition is substantially free of a gelling or swelling excipient and does not contain a functional coating.

2. The controlled-release composition of claim 1 , wherein the ionic non-gelling matrix polymer is selected from the group consisting of cellulose acetate phthalate, cellulose acetate succinate, hypromellose phthalate, hypromellose acetate succinate, a methacrylic acid-methyl methacrylate co-polymer, polyvinylacetate phthalate, hydroxyethyl cellulose phthalate, cellulose acetate maleate, cellulose acetate trimellitate, cellulose acetate butyrate, cellulose acetate propionate, a methacrylic acid-methyl methacrylate co-polymer, a methacrylic acid-ethyl acrylate co-polymer, a methacrylic acid-methyl acrylate-methyl methacrylate, and a combination thereof.

3. The controlled-release composition of claim 1 , wherein the ionic non-gelling matrix polymer is selected from the group consisting of a methacrylic acid-methyl methacrylate co-polymer, a methacrylic acid-ethyl acrylate co-polymer, methacrylic acid-methyl acrylate-methyl methacrylate, and a combination thereof.

4. The controlled-release composition of claim 1 , wherein the ionic non-gelling matrix polymer is present in an amount from about 5 to about 85 wt % based on the total weight of the composition.

5. The controlled-release composition of claim 1 , wherein the active agent is selected from the group consisting of an antihypertensive agent, an antidepressant agent, an antianxiety agent, an anticlotting agent, an anticonvulsant agent, a blood glucose-lowering agent, a decongestant agent, an antihistamine agent, an antitussive agent, an anti-inflammatory agent, an antipsychotic agent, a cognitive enhancer, a cholesterol-reducing agent, an antiobesity agent, an autoimmune disorder agent, an anti-impotence agent, an antibacterial agent, an antifungal agent, a hypnotic agent, an anti-Parkinsonism agent, an antiviral agent, an anti-neoplastic agent, a barbituate agent, a sedative agent, a nutritional agent, a beta blocker, an emetic agent, an anti-emetic agent, a diuretic agent, an anticoagulant agent, a cardiotonic agent, an androgen agent, a corticoid, an anabolic agent, a growth hormone secretagogue, an anti-infective agent, a coronary vasodilator, a carbonic anhydrase inhibitor, an antiprotozoal agent, a gastrointestinal agent, a serotonin antagonist, an anesthetic agent, a hypoglycemic agent, a dopaminergic agent, an anti-Alzheimer's Disease agent, an anti-ulcer agent, a platelet inhibitor, a glycogen phosphorylase inhibitor, a muscle relaxant, and a pharmaceutically acceptable combination thereof.

6. The controlled-release composition of claim 5 , wherein the active agent has a solubility of greater than or equal to about 2.0 mg/ml in an aqueous medium at room temperature.

7. The controlled-release composition of claim 5 , wherein the active agent is quetiapine, or a salt, solvate, ester, and/or prodrug thereof.

8. The controlled-release composition of claim 1 , wherein the pH modifier is a pharmaceutically acceptable organic acid, or an alkali metal or alkaline earth metal salt thereof.

9. The controlled-release composition of claim 7 , wherein the pH modifier is sodium citrate.

10. The controlled-release composition of claim 1 , wherein the soluble, non-gelling pharmaceutically acceptable excipient is a sugar polyol, a monosaccharide, a disaccharide, a polysaccharide, or a combination thereof.

11. The controlled-release composition of claim 1 , wherein the soluble, non-gelling pharmaceutically acceptable excipient is lactose, sucrose, dextrose, fructose, glucose, maltose, polydexotrose, sorbitol, xylitol, mannitol, galactitol, maltitol, lactitol, erythritol, maltose, dextrin, maltodextrin, xylose, galactose, trehalose, tagatose, or a combination thereof.

12. The controlled-release composition of claim 1 , wherein the soluble, non-gelling pharmaceutically acceptable excipient is present in an amount from about 1 to about 70 wt % based on the total weight of the composition.

13. The controlled-release composition of claim 1 , wherein the first aqueous fluid has a pH equal to or less than about 4.5, and the second aqueous fluid has a pH greater than about 4.5.

14. The controlled-release composition of claim 12 , wherein the first aqueous fluid is human gastric fluid, and the second aqueous fluid is human intestinal fluid.

15. The controlled-release composition of claim 1 , wherein the composition is a tablet, a capsule, a granule, a mini-tablet, or a pellet.

16. The controlled-release composition of claim 1 , wherein the controlled-release composition is in a once a day dosage form or a twice a day dosage form.

17. The controlled-release composition of claim 1 ,

wherein the composition exhibits a dissolution profile after combining the composition with 900 ml of pH 6.8 buffer at 37° C.±0.5° C. according to USP 28 <711> test method 1 (basket) at a speed of 100 rpm,

wherein from about 1 to about 30 wt % of the total amount of the active agent is released at 3 hours.

18. The controlled-release composition of claim 1 ,

wherein the composition exhibits a dissolution profile after combining the composition with 900 ml of pH 6.8 buffer at 37° C.±0.5° C. according to USP 28 <711> test method 1 (basket) at a speed of 100 rpm,

wherein from about 1 to about 40 wt % of the total amount of the active agent is released at 4 hours.

19. The controlled-release composition of claim 1 wherein the composition exhibits a dissolution profile after combining the composition with 900 ml of pH 6.8 buffer at 37° C.±0.5° C. according to USP 28 <711> test method 1 (paddle) at a speed of 100 rpm,

wherein from about 1 to about 45 wt % of the total amount of the active agent is released at 6 hours.

20. The controlled-release composition of claim 1 wherein the composition exhibits a dissolution profile after combining the composition with 900 ml of pH 6.8 buffer at 37° C.±0.5° C. according to USP 28 <711> test method 1 (paddle) at a speed of 100 rpm,

wherein from about 15 to about 70 wt % of the total amount of the active agent is released at 8 hours.

21. The controlled-release composition of claim 1 wherein the composition exhibits a dissolution profile after combining the composition with 900 ml of pH 6.8 buffer at 37° C.±0.5° C. according to USP 28 <711> test method 1 (paddle) at a speed of 100 rpm,

wherein from about 18 to about 80 wt % of the total amount of the active agent is released at 10 hours.

22. The controlled-release composition of claim 1 wherein the composition exhibits a dissolution profile after combining the composition with 900 ml of pH 6.8 buffer at 37° C.±0.5° C. according to USP 28 <711> test method 1 (paddle) at a speed of 100 rpm,

wherein from about 25 to about 85 wt % of the total amount of the active agent is released at 12 hours.

23. The controlled-release composition of claim 1 wherein the composition exhibits a dissolution profile after combining the composition with 900 ml of pH 6.8 buffer at 37° C.±0.5° C. according to USP 28 <711> test method 1 (paddle) at a speed of 100 rpm,

wherein from about 25 to about 90 wt % of the total amount of the active agent is released at 14 hours.

24. The controlled-release composition of claim 1 wherein the composition exhibits a dissolution profile after combining the composition with 900 ml of pH 6.8 buffer at 37° C.±0.5° C. according to USP 28 <711> test method 1 (paddle) at a speed of 100 rpm,

wherein from about 25 to about 95 wt % of the total amount of the active agent is released at 18 hours.

25. The controlled-release composition of claim 1 , wherein a dissolution profile of the composition is substantially the same as a dissolution profile of an equivalent strength of a reference drug product when the dissolution profile is determined by using the conditions according to USP 28 <711> test method 2 (paddle), using of 900 ml of a dissolution medium at 37° C.±0.5° C., and 50 rpm paddle speed, wherein the dissolution medium is purified water, 0.1N HCl, 0.1N NaOH, 7.5 pH buffer, 6.8 pH buffer, or 0.5M sodium dodecyl sulfate.

26. The controlled-release composition of claim 1 , wherein the composition is bioequivalent to an equivalent strength of a reference drug product.

27. The controlled-release composition of claim 26 , wherein the 90% confidence limits of a ratio of a geometric mean of logarithmic transformed AUC 0-∞ of the composition to a geometric mean of logarithmic transformed AUC 0-∞ of the reference drug is about 0.80 to about 1.25.

28. The controlled-release composition of claim 26 , wherein the 90% confidence limits of a ratio of a geometric mean of logarithmic transformed AUC 0-t of the composition to a geometric mean of logarithmic transformed AUC 0-t of the reference drug is about 0.80 to about 1.25.

29. The controlled-release composition of claim 26 , wherein the 90% confidence limits of a ratio of a geometric mean of logarithmic transformed C max of the composition to a geometric mean of logarithmic transformed C max of the reference drug is about 0.7 to about 1.43.

30. The controlled-release composition of claim 26 , wherein the 90% confidence limits of a ratio of a geometric mean of logarithmic transformed C max of the composition to a geometric mean of logarithmic transformed C max of the reference drug is about 0.8 to about 1.25.

31. A method of treating a patient in need of an active agent therapy, comprising administering the controlled-release composition of claim 1 to the patient.