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Details for Patent: 5,773,025

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Details for Patent: 5,773,025

Title: Sustained release heterodisperse hydrogel systems--amorphous drugs
Abstract:Sustained release oral solid dosage forms comprising agglomerated particles of a therapeutically active medicament in amorphous form, a gelling agent, an ionizable gel strength enhancing agent and an inert diluent, as well as processes for preparing and using the same are disclosed. The sustained release oral solid dosage forms are useful in the treatment of hypertension in human patients.
Inventor(s): Baichwal; Anand (Wappingers Falls, NY)
Assignee: Edward Mendell Co., Inc. (Patterson, NY)
Filing Date:Apr 18, 1996
Application Number:08/634,295
Claims:1. A bioavailable sustained release oral solid dosage form comprising agglomerated particles of a therapeutically active medicament in amorphous form having an aqueous solubility of less than about 10 g/l, a gelling agent comprising xanthan gum and locust bean gum in a ratio from about 1:3 to about 3:1, an ionizable gel strength enhancing agent selected from the group consisting of monovalent organic salts, monovalent inorganic salts, divalent organic salts, divalent inorganic salts, multivalent organic salts, multivalent inorganic salts and mixtures thereof and an inert diluent, wherein the ratio of said inert diluent to said gelling agent is from about 1:8 to about 8:1, and wherein said ionizable gel strength enhancing agent increases the gel strength of said gelling agent when said dosage form is exposed to gastrointestinal fluid, and wherein the amorphous form of said medicament affects the bioavailability of said oral dosage form.

2. The sustained release oral solid dosage form of claim 1 wherein said amorphous form of medicament is selected from the group consisting of a solid solution, a solid dispersion and mixtures of the foregoing.

3. The sustained release oral solid dosage form of claim 1 wherein said medicament is suspended or dissolved in polyethylene glycol prior to incorporation of the remaining ingredients of said solid dosage form, said polyethylene glycol being solid at room temperature.

4. The sustained release oral solid dosage form of claim 3 wherein said polyethylene glycol comprises a polyethylene glycol-water slurry.

5. The sustained release oral solid dosage form of claim 1 wherein said agglomerated particles further comprise a pharmaceutically acceptable hydrophobic material selected from the group consisting of an alkylcellulose, acrylic polymer, zein, methacrylic acid ester, waxes, shellac, hydrogenated vegetable oils and mixtures thereof.

6. The sustained release oral solid dosage form of claim 1 wherein said gelling agent further comprises at least one agent selected from the group consisting of an alginate, pectin, guar gum, modified starch, cellulose and mixtures of any of the foregoing.

7. The sustained release oral solid dosage form of claim 6 wherein said cellulose is selected from the group consisting of hydroxypropylmethylcellulose, methylcellulose, sodium carboxymethylcellulose and hydroxypropyl cellulose and mixtures of any of the foregoing.

8. The sustained release solid dosage form of claim 1 further comprising a coating comprising a hydrophobic material, said coating comprising from about 1% to about 20% of the total weight of said tablet, said tablet coating covering at least part of the surface of said tablet.

9. The sustained release solid dosage form of claim 1 wherein said ionizable gel strength enhancing agent comprises an alkali metal or an alkaline earth metal sulfate, chloride, borate, bromide, citrate, acetate or lactate.

10. The sustained release solid dosage form of claim 1, wherein said medicament is selected from the group consisting of nifedipine, nimodipine, nivadipine, nitrendipine, nisolidipine, niludipine, nicardipine and felodipine.

11. The sustained release solid dosage form of claim 10, wherein said medicament is nifedipine.

12. The sustained release solid dosage form of claim 1, comprising a gelatin capsule containing a sufficient amount of said agglomerated particles to provide an effective dose of said therapeutically active medicament.

13. The sustained release solid dosage form of claim 1 wherein said dosage form is a compressed tablet.

14. The sustained release solid dosage form of claim 13, wherein said tablet is coated with an enteric or hydrophobic polymer.

15. The sustained release solid dosage form of claim 13, wherein at least a portion of a surface of said tablet is coated with a hydrophobic polymer to a weight gain from about 1 to about 20 percent, by weight.

16. The sustained release solid dosage form of claim 1, wherein said agglomerated particles is coated with a hydrophobic polymer to a weight gain from about 1 to about 20 percent, by weight.

17. The sustained release solid dosage form of claim 1 wherein said agglomerated particles further comprise an amount of a pharmaceutically acceptable hydrophobic material effective to slow the hydration of said gelling agent when said formulation is exposed to gastrointestinal fluid.

18. A bioavailable sustained release oral solid dosage form comprising compressed agglomerated particles comprising a therapeutically active medicament in amorphous form having an aqueous solubility of less than about 10 g/l, a gelling agent, a hydrophobic material in an effective amount to slow the hydration of the gelling agent when said dosage form is exposed to gastrointestinal fluid and an inert diluent, the ratio of inert diluent to gelling agent being from about 1:8 to about 8:1, wherein said medicament is suspended or dissolved in a pharmaceutically acceptable wetting agent prior to incorporation with the remaining ingredients of said dosage form, and wherein the amorphous form of said medicament affects the bioavailability of said oral dosage form.

19. A process for the preparation of a bioavailable sustained release solid dosage form for administration of a medicament comprising combining a medicament in amorphous form having an aqueous solubility of less than about 10 g/l with a wetting agent in such a manner as to create a solid dispersion or solution, mixing the resulting solid solution or dispersion with a gelling agent comprising xanthan gum and locust bean gum, an ionizable gel strength enhancing agent selected from the group consisting of monovalent organic salts, monovalent inorganic salts, divalent organic salts, divalent inorganic salts, multivalent organic salts, multivalent inorganic salts and mixtures thereof, and an inert diluent, to form agglomerated particles, and compressing said agglomerated particles into tablets containing a therapeutically effective amount of said medicament; wherein the amorphous form of said medicament affects the bioavailability of said oral dosage form.

20. The process according to claim 19 wherein said medicament, gelling agent, ionizable gel enhancing agent and inert diluent are combine by dry blending.

21. The process of claim 19, wherein the wetting agent is a polyethylene glycol that is solid at room temperature.

22. The process according to claim 21 further comprising premixing said polyethylene glycol with water to form a polyethylene glycol-water slurry and admixing said slurry with a mixture of said medicament, said gelling agent, said ionizable gel enhancing agent and said inert diluent; and thereafter drying and milling the resultant mixture.

23. The process according to claim 20 further comprising wet-granulating said mixture of medicament, gelling agent, ionizable gel enhancing agent and inert diluent as a sustained release excipient prior to mixing with said solid dispersion or solution of said medicament.

24. The process according to claim 23 further comprising adding ethylcellulose to said slurry before the addition of said medicament, gelling agent, ionizable gel enhancing agent and inert diluent.

25. The process according to claim 24 further comprising dissolving the medicament in polyethylene glycol and thereafter adding said gelling agent, said ionizable gel enhancing agent, said inert diluent and said ethylcellulose to the resulting combination.

26. The process according to claim 24 further comprising preparing said polyethylene glycol-water slurry by mixing polyethylene glycol with heated water.

27. The process according to claim 19 wherein the gelling agent comprises at least one naturally occurring gum suitable for forming a sustained release gel upon contact with environmental fluid.

28. The process according to claim 19 wherein said gelling agent further comprises an agent selected from the group consisting of alginates, carrageenan, pectin, guar gum, xanthan gum, locust bean gum, modified starch, cellulose and mixtures of any of the foregoing.

29. The process according to claim 24 wherein said cellulose is selected from the group consisting of hydroxypropylmethylcellulose, methylcellulose, sodium carboxymethylcellulose and hydroxypropyl cellulose and mixtures of any of the foregoing.

30. The process according to claim 19 wherein said ionizable gel strength enhancing agent comprises an alkali metal or an alkaline earth metal sulfate, chloride, borate, bromide, citrate, acetate or lactate.

31. The process of claim 19, wherein said composition further comprises an amount of a pharmaceutically acceptable hydrophobic material effective to slow the hydration of the gelling agent when said solid dosage form is exposed to gastrointestinal fluid.

32. A method of treating a patient comprising administering a dosage form of claim 11 to a patient in need of antihypertensive treatment.

33. A method of preparing a bioavailable sustained release oral dosage form comprising combining a sustained release excipient with a medicament in amorphous form having an aqueous solubility of less than 10 g/liter and with polyethylene glycol and then drying and milling the resulting combined composition and

said sustained release excipient comprises a gelling agent, an ionizable gel enhancing agent and an inert diluent, the ratio of inert diluent to gelling agent being from about 1:8 to about 8:1, said ionizable gel strength enhancing agent increasing the gel strength of a gel formed when said solid dosage form is exposed to environmental fluid, and said gelling agent comprises xanthan gum and locust bean gum and said locust bean gum being from about 1:3 to about 3:1; wherein the amorphous form of said medicament affects the bioavailability of said oral dosage form.

34. The method of claim 33, wherein the polyethylene glycol is mixed with water to form a polyethylene glycol-water slurry prior to the combination of the medicament with the excipient.

35. A bioavailable sustained release oral solid dosage form comprising agglomerated particles of a therapeutically active medicament in amorphous form having an aqueous solubility of less than about 10 g/l, a gelling agent comprising a heteropolysaccharide gum and a homopolysaccharide gum in a ratio from about 1:3 to about 3:1, an ionizable gel strength enhancing agent selected from the group consisting of monovalent organic salts, monovalent inorganic salts, divalent organic salts, divalent inorganic salts, multivalent organic salts, multivalent inorganic salts and mixtures thereof, and an inert diluent, wherein the ratio of said inert diluent to said gelling agent is from about 1:8 to about 8:1, and wherein said ionizable gel strength enhancing agent increases the gel strength of said gelling agent when said dosage form is exposed to gastrointestinal fluid, and wherein the amorphous form of said medicament affects the bioavailability of said oral dosage form.
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