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Claims for Patent: 7,108,866

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Claims for Patent: 7,108,866

Title:Chronotherapeutic diltiazem formulations and the administration thereof
Abstract:A controlled-release Galenical preparation of pharmaceutically acceptable Diltiazem including the pharmaceutically acceptable salts thereof, suitable for evening dosing every 24 hours containing from about 120 mg to about 540 mg or more (as desired) of the form of Diltiazem associated with excipients to provide controlled (sustained) release of the form of Diltiazem for providing a C.sub.max of Diltiazem in the blood at between about 10 hours and about 15 hours after administration, the preparation comprising the form of Diltiazem in oral sustained-release dosage form in which the Diltiazem is adapted to be released after administration over a prolonged period of time and exhibits when given to humans(i) a higher bioavailability when given at night compared to when given in the morning without food according to FDA guidelines or criteria and(ii) bioequivalence when given in the morning with and without food according to the same FDA guidelines or criteria.
Inventor(s): Albert; Kenneth Stephen (Mt. Kisco, NY), Maes; Paul Jose (Oakville, CA)
Assignee: Biovall Laboratories International SRL (St. Michael, BB)
Application Number:09/567,451
Patent Claims: 1. An orally administrable controlled-release composition comprising a pharmaceutically acceptable form of diltiazem selected from the group consisting of diltiazem and the pharmaceutically acceptable salts thereof, suitable for evening dosing every 24 hours, the dosage comprising at least one bead comprising a core and at least one coating, the at least one bead being formulated in an oral dosage form containing from about 120 mg to about 540 mg of the form of diltiazem, the diltiazem in the core of each bead associated with excipients, the at least one coating covering the core comprising an amount of a water swellable and diffusible coating which permits hydration of the core by gastrointestinal fluids, the water swellable and diffusible coating comprising the following constituents: (i) an amount of at least one hydrophilic polymer which is selected from the group consisting of hydroxypropylmethylcellulose, hydroxyethylcellulose, and hydroxypropylcellulose, and/or an amount of at least one lubricant which is selected from the group consisting of talc, and magnesium stearate; and (ii) an amount at least one water-, acid- or base-insoluble neutral acrylic polymer, wherein said constituents (i) and (ii) which comprise said coating, the ratios thereof, and the amount of said coating are formulated such that said orally administrable composition: A) in vitro exhibits the following in vitro release characteristics; (i) releases the diltiazem or a pharmaceutically acceptable salt thereof into an aqueous medium at the following rates when measured using the method of United States Pharmacopoeia No. XXIII at 100 rpm in 900 ml of water: (a) between about 1% and about 15% after about 2 hours; (b) between about 7% and about 35% after about 4 hours; (c) between about 30% and about 58% after about 8 hours; (d) between about 55% and about 80% after about 14 hours; (e) in excess of about 75% after about 24 hours; and/or (ii) releases the diltiazem or pharmaceutically acceptable salt thereof into a buffered medium having a pH between about 5.5 and about 6.5, at the following rates measured using the method of United States Pharmacopoeia No. XXIII at 100 rpm in 900 ml of the buffered medium: (a) between about 1% and about 25% after about 2 hours; (b) between about 7% and about 45% after about 4 hours; (c) between about 30% and about 68% after about 8 hours; (d) in excess of about 75% after about 24 hours; and further wherein said orally administrable composition having said in vitro release characteristics results in a composition that: B) when orally given to humans exhibit the following properties: (i) a higher bioavailability when given at night compared to when given in the morning without food according to FDA guidelines or criteria and (ii) bioequivalence when given in the morning with or without food according to the same FDA guidelines or criteria; and (iii) provides a Cmax of diltiazem in the blood at between about 10 hours and 15 hours after administration.

2. The controlled release preparation of claim 1 wherein said neutral acrylic polymer is a neutral copolymer of acrylic acid ethyl ester and acrylic acid methyl ester.

3. The controlled-release preparation of claim 1 in which the form of diltiazem is adapted to be control released after administration of the preparation over a period of time and is more preferably adapted to release the diltiazem (i) into an aqueous medium at the following rates measured using the method of United States Pharmacopoeia No. XXIII at 100 rpm in 900 ml of water: (a) between about 4% and about 8% after about 2 hours; (b) between about 16% and about 21% after about 4 hours; (c) between about 44% and about 52% after about 8 hours; (d) between about 69% and about 76% after about 14 hours; and (e) and in excess of about 85% after about 24 hours; and/or (ii) into a buffered medium having a pH about 5.8 at the following rates measured using the method of United States Pharmacopoeia No. XXIII at 100 rpm in 900 ml of the buffered medium: (a) between about 4% and about 15% after about 2 hours; (b) between about 16% and about 30% after about 4 hours; (c) between about 44% and about 62% after about 8 hours; (d) in excess of about 80% after about 24 hours.

4. The preparation of claim 1 wherein the Cmax of diltiazem in the blood is obtained between about 11 about 13 hours after administration of the preparation.

5. The preparation of claim 1, 2, 3 or 4 wherein the form of diltiazem is Diltiazem HCl.

6. The preparation of claim 4 wherein the preparation is a diffusion controlled preparation.

7. The preparation of claim 3 wherein the preparation releases the diltiazem at a rate of less than about 15% of the total amount of active per hour during dissolution.

8. The preparation of claim 7 in capsule form.

9. The preparation of claim 7 in tablet form.

10. The preparation of claim 7 wherein the preparation comprises a plurality of microgranules, each microgranule comprising a central core containing the form of diltiazem coated with a microporous membrane and the central core comprises diltiazem or pharmaceutically acceptable salt thereof associated with a wetting agent.

11. The preparation of claim 10 wherein the diltiazem is mixed (in whole or in part) with the wetting agent.

12. The preparation of claim 11 wherein the wetting agent assists to maintain the solubility of the diltiazem in each microgranule, ensuring that the solubility of the diltiazem is unaffected by the pH of the gastrointestinal tract or other adverse conditions which the composition will meet therein.

13. The preparation of claim 12 wherein the membrane comprises a water-dispersible or water-soluble polymer and a water-, acid- and base-insoluble polymer of a neutral acrylic polymer of acrylic acid ethyl ester and acrylic acid methyl ester which hydrates the preparation.

14. The preparation of claim 10 wherein the preparation comprises a mixture of the diltiazem and/or pharmaceutically acceptable salt with the wetting agent and the membrane comprises a water-dispersible or water-soluble polymer and a water-, acid- and base-insoluble polymer of a neutral acrylic polymer of acrylic acid ethyl ester and acrylic acid methyl ester which hydrates the preparation.

15. The preparation of claim 14 wherein the membrane comprises a neutral acrylic polymer of acrylic acid ethyl ester and acrylic acid methyl ester and hydroxypropylmethylcellulose.

16. The preparation of claim 15 wherein the membrane hydrates the core within a membrane which when put in gastrointestinal fluid causes the membrane to swell while fluid penetrates and hydrates the microgranule, and dissolves the diltiazem and wetting agent and benefits from a concentration gradient through the membrane (high concentration inside and low concentration outside).

17. The preparation of claim 11 wherein the diltiazem is mixed with the wetting agent and the membrane comprises an acrylic membrane and plasticizer combined to form the membrane thereby providing a mechanism of release from this membrane which "washes" the diltiazem through pores created when the plasticizer incorporated in the membrane, is released in gastrointestinal fluid.

18. The preparation of claim 7 wherein the preparation comprises a plurality of microgranules comprising a central core containing the form of diltiazem coated with a microporous membrane and the central core comprises diltiazem or a pharmaceutically acceptable salt thereof associated with any suitable dissolution agent (other than a wetting agent) to assist in the release of the diltiazem from the preparation.

19. The preparation of claim 18 wherein the dissolution agent is an organic acid comprising adipic acid, ascorbic acid, citric acid, fumaric acid, malic acid, succinic acid or tartaric acid which permits the diltiazem to dissolve in gastrointestinal fluids even when the microgranules pass into the regions of the gastrointestinal tract of the intestine at which pH diltiazem is much less soluble.

20. A method of treatment of a patient's hypertension and/or angina comprising the administration of the preparation of diltiazem of claim 1 to the patient in the evening for effective treatment of the patient's hypertension and/or angina the next morning, the method comprising administering to a patient in need thereof the preparation in the evening.

21. A method of treatment of a patient's hypertension and/or angina comprising the administration of the preparation of diltiazem of claim 2 to the patient in the evening for effective treatment of the patient's hypertension and/or angina the next morning.

22. A method of treatment of a patient's hypertension and/or angina comprising the administration of the preparation of diltiazem of claim 3 to the patient in the evening for effective treatment of the patient's hypertension and/or angina the next morning.

23. A method of treatment of a patient's hypertension and/or angina comprising the administration of the preparation of diltiazem of claim 4 to the patient in the evening for effective treatment of the patient's hypertension and/or angina the next morning.

24. A method of treatment of a patient's hypertension and/or angina comprising the administration of the preparation of diltiazem of claim 5 to the patient in the evening for effective treatment of the patient's hypertension and/or angina the next morning.

25. A method of treatment of a patient's hypertension and/or angina comprising the administration of the preparation of diltiazem of claim 6 to the patient in the evening for effective treatment of the patient's hypertension and/or angina the next morning.

26. A method of treatment of a patient's hypertension and/or angina comprising the administration of the preparation of diltiazem of claim 7 to the patient in the evening for effective treatment of the patient's hypertension and/or angina the next morning.

27. A method of treatment of a patient's hypertension and/or angina comprising the administration of the preparation of diltiazem of claim 8 to the patient in the evening for effective treatment of the patient's hypertension and/or angina the next morning.

28. A method of treatment of a patient's hypertension and/or angina comprising the administration of the preparation of diltiazem of claim 9 to the patient in the evening for effective treatment of the patient's hypertension and/or angina the next morning.

29. A method of treatment of a patient's hypertension and/or angina comprising the administration of the preparation of diltiazem of claim 10 to the patient in the evening for effective treatment of the patient's hypertension and/or angina the next morning.

30. A method of treatment of a patient's hypertension and/or angina comprising the administration of the preparation of diltiazem of claim 11 to the patient in the evening for effective treatment of the patient's hypertension and/or angina the next morning.

31. A method of treatment of a patient's hypertension and/or angina comprising the administration of the preparation of diltiazem of claim 12 to the patient in the evening for effective treatment of the patient's hypertension and/or angina the next morning.

32. A method of treatment of a patient's hypertension and/or angina comprising the administration of the preparation of diltiazem of claim 13 to the patient in the evening for effective treatment of the patient's hypertension and/or angina the next morning.

33. A method of treatment of a patient's hypertension and/or angina comprising the administration of the preparation of diltiazem of claim 14 to the patient in the evening for effective treatment of the patient's hypertension and/or angina the next morning.

34. A method of treatment of a patient's hypertension and/or angina comprising the administration of the preparation of diltiazem of claim 15 to the patient in the evening for effective treatment of the patient's hypertension and/or angina the next morning.

35. A method of treatment of a patient's hypertension and/or angina comprising the administration of the preparation of diltiazem of claim 16 to the patient in the evening for effective treatment of the patient's hypertension and/or angina the next morning.

36. A method of treatment of a patient's hypertension and/or angina comprising the administration of the preparation of diltiazem of claim 17 to the patient in the evening for effective treatment of the patient's hypertension and/or angina the next morning.

37. A method of treatment of a patient's hypertension and/or angina comprising the administration of the preparation of diltiazem of claim 18 to the patient in the evening for effective treatment of the patient's hypertension and/or angina the next morning.

38. A method of treatment of a patient's hypertension and/or angina comprising the administration of the preparation of diltiazem of claim 19 to the patient in the evening for effective treatment of the patient's hypertension and/or angina the next morning.

39. The preparation of claim 1 wherein the preparation contains 120 mg of diltiazem.

40. The preparation of claim 1 wherein the preparation contains 180 mg of diltiazem.

41. The preparation of claim 1 wherein the preparation contains 240 mg of diltiazem.

42. The preparation of claim 1 wherein the preparation contains 300 mg of diltiazem.

43. The preparation of claim 1 wherein the preparation contains 360 mg of diltiazem.

44. The preparation of claim 1 wherein the preparation contains 420 mg of diltiazem.

45. A method of treatment of a patient's hypertension and/or angina comprising the administration of the preparation of diltiazem of claim 39, 40, 41, 42, 43 or 44 to the patient in the evening for effective treatment of the patient's hypertension and/or angina the next morning.

46. The preparation of claim 15 wherein the wetting agent is selected from: sugars; saccharose, mannitol, sorbitol; lecithins; C.sub.12 to C.sub.20 fatty acid esters of saccarose; xylose esters or xylites; polyoxyethylenic glycerrides; esters of fatty acids and polyoxyethylene; sorbitan fatty acid ester; polyglycides-glycerides and polyglycides-alcohols ester; and metal salts.

47. The preparation of claim 10 wherein the wetting agent is in association with the diltiazem in the microgranule and not mixed therewith, the membrane comprises a water-soluble or water dispersible polymer or copolymer selected from the group consisting of hydroxypropylmethylcellulose and a water-, acid- and base-insoluble polymer which is a neutral copolymer of acrylic acid ethyl ester and acrylic acid methyl ester which enables the bead to be hydrated by the introduction of gastrointestinal fluids into the core hydrating the core and therefore mixing the diltiazem and the wetting agent.

48. A method of treatment of a patient's hypertension and/or angina comprising the administration of the preparation of diltiazem of claim 46 to the patient in the evening for effective treatment of the patient's hypertension and/or angina the next morning.

49. A method of treatment of a patient's hypertension and/or angina comprising the administration of the preparation of diltiazem of claim 47 to the patient in the evening for effective treatment of the patient's hypertension and/or angina the next morning.

50. A controlled-release preparation of pharmaceutically acceptable form of diltiazem according to claim 1 which comprises the following constituents: TABLE-US-00017 % W/W (i) in the core: (a) Diltiazem hydrochloride 69 73 (b) Microcrystalline cellulose 8 9.5 (c) (Polyvinyl Pyrrolidone) 1 2 (d) Sucrose stearate 7 8 (ii) in the membrane: (e) Magnesium stearate NF 0.5 2.5 (f) Talc USP 0.5 5.0 (g) Titanium dioxide. (USP) 0.15 0.3 (h) Hydroxypropylmethylcellulose 2910 0.3 0.6 (i) (Polyoxyethylene Sorbitan Monooleate) 0.01 0.025 (j) Simethicone C emulsion USP. (dry of 30%) 0.01 0.015 (k) a neutral acrylic polymer of acrylic acid 7 11 ethyl ester and acrylic acid methyl ester (dry of 30%) Purified water USP 0 (used for mixing).

51. A method of treatment of a patient's hypertension and/or angina comprising the administration of the preparation of diltiazem of claim 50 to the patient in the evening for effective treatment of the patient's hypertension and/or angina the next morning.

52. The preparation of claim 10 in which the core and membrane comprise: (i) in the core, (a) between about 50% and about 85% (% w/w of the total preparation) of diltiazem or pharmaceutically acceptable salt thereof; and (b) between about 2% and about 25% wetting agent (% w/w of the total preparation); together with suitable adjuvants; and (ii) in the membrane, (c) between about 0.1% and about 50% of the total preparation of lubricant selected from the group consisting of talc, and magnesium stearate; (d) between about 0.1% and about 2% of the total preparation of water-soluble and/or water-dispersible polymer selected from the group consisting of hydroxypropylmethylcellulose, hydroxyethyl-cellulose, hydroxypropylcellulose, and any combination thereof; and (e) between about 5% and about 20% (% w/w of the preparation) of a neutral copolymer of acrylic acid ethyl ester and acrylic acid methyl ester, together with suitable adjuvants.

53. A method of treatment of a patient's hypertension and/or angina comprising the administration of the preparation of diltiazem of claim 52 to the patient in the evening for effective treatment of the patient's hypertension and/or angina the next morning.

54. The preparation of claim 10 in which the core and membrane comprise: (i) in the core, (a) between about 69% and about 73% (% w/w of the total preparation) of diltiazem or pharmaceutically acceptable salt thereof; and (b) between about 7% and about 8% wetting agent (% w/w of the total preparation); together with suitable adjuvants; and (ii) in the membrane, (c) between about 0.1% and about 50% of the total preparation of lubricant selected from the group consisting of talc, and magnesium stearate; (d) between about 0.3% and about 0.6% of the total preparation of water-soluble and/or water-dispersible polymer selected from the group consisting of hydroxypropylmethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, and any combination thereof; and (e) between about 7% and about 11% (% w/w of the preparation) of a neutral copolymer of acrylic acid ethyl ester and acrylic acid methyl ester, together with suitable adjuvants.

55. A method of treatment of a patient's hypertension and/or angina comprising the administration of the preparation of diltiazem of claim 54 to the patient in the evening for effective treatment of the patient's hypertension and/or angina the next morning.

56. The preparation of claim 10 wherein the preparation is a tablet and the tablet comprises microgranules in association with wax placebo beads which wax placebo beads serve to absorb the shock placed on the microgranules of diltiazem during the tablet process, together with suitable excipients and adjuvants.

57. A method of treatment of a patient's hypertension and/or angina comprising the administration of the preparation of diltiazem of claim 56 to the patient in the evening for effective treatment of the patient's hypertension and/or angina the next morning.

58. The controlled-release preparation of claim 2 in which the diltiazem is adapted to be control released after administration of the preparation over a period of time wherein the preparation comprises a plurality of microgranules, each microgranule comprising a central core containing the form of diltiazem coated with a microporous membrane and the central core comprises diltiazem or pharmaceutically acceptable salt thereof associated with a wetting agent in which the core and membrane comprise: (i) in the core, (a) between about 50% and about 85% (% w/w of the total preparation) of diltiazem or pharmaceutically acceptable salt thereof; and (b) between about 2% and about 25% wetting agent (% w/w of the total preparation); together with suitable adjuvants; and (ii) in the membrane, (c) between 0.1% and about 50% of the total preparation of lubricant selected from the group consisting of talc, and magnesium stearate; (d) between about 0.1% and about 2% of the total preparation of water-soluble and/or water-dispersible polymer selected from the group consisting of hydroxypropylmethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, and any combination thereof; and (e) between about 5% and about 20% (% w/w of the preparation) of a neutral copolymer of acrylic acid ethyl ester and acrylic acid methyl ester, together with suitable adjuvants.

59. The preparation of claim 58 wherein the microgranules are in capsule form.

60. The preparation of claim 58 wherein the microgranules are in tablet form.

61. The preparation of claim 58 wherein the core and membrane comprise: (i) in the core, (a) between about 69% and about 73% (% w/w of the total preparation) of diltiazem or pharmaceutically acceptable salt thereof; and (b) between about 7% and about 8% wetting agent (% w/w of the total preparation); together with suitable adjuvants; and (ii) in the membrane, (c) between about 0.1% and about 50% of the total preparation of lubricant selected from the group consisting of talc, and magnesium stearate; (d) between about 0.3% and about 0.6% of the total preparation of water-soluble and/or water-dispersible polymer selected from the group consisting of hydroxypropylmethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, and any combination thereof; and (e) between about 7% and about 11% (% w/w of the preparation) of a neutral copolymer of acrylic acid ethyl ester and acrylic acid methyl ester, together with suitable adjuvants.

62. A controlled-release preparation of pharmaceutically acceptable form of diltiazem according to claim 1, which preparation comprises a plurality of microgranules, each microgranule comprising a central core containing the form of diltiazem coated with a microporous membrane and the central core comprises diltiazem or pharmaceutically acceptable salt thereof associated with a wetting agent in which the core and membrane comprise: TABLE-US-00018 % W/W (i) in the core: (a) Diltiazem hydrochloride 69 73 (b) Microcrystalline cellulose 8 9.5 (c) (Polyvinyl Pyrrolidone) 1 2 (d) Sucrose stearate 7 8 (ii) in the membrane: (e) Magnesium stearate NF 0.5 2.5 (f) Talc USP 0.5 5.0 (g) Titanium dioxide. (USP) 0.15 0.3 (h) Hydroxypropylmethylcellulose 2910 0.3 0.6 (i) (Polyoxyethylene Sorbitan Monooleate) 0.01 0.025 (j) Simethicone C emulsion USP. (dry of 30%) 0.01 0.015 (k) a neutral acrylic polymer of acrylic acid 7 11 ethyl ester and acrylic acid methyl ester (dry of 30%) Purified water USP 0 (used for mixing).

63. The preparation of claim 58 wherein the preparation is a tablet and the tablet comprises microgranules in association with wax placebo beads which wax placebo beads serve to absorb the shock placed on the microgranules of diltiazem during the tablet process, together with suitable excipients and adjuvants.

64. A method of treatment of a patient's hypertension and/or angina comprising the administration of the preparation of diltiazem of claim 58 to the patient in the evening for effective treatment of the patient's hypertension and/or angina the next morning.

65. A controlled-release preparation of pharmaceutically acceptable form of diltiazem according to claim 1, wherein the preparation comprises a plurality of microgranules, each microgranule comprising a central core containing the form of diltiazem coated with a microporous membrane and the central core comprises diltiazem or pharmaceutically acceptable salt thereof associated with a wetting agent, wherein the wetting agent is selected from: sugars; saccharose, mannitol, sorbitol; lecithins; C.sub.12 to C.sub.20 fatty acid esters of saccarose; xylose esters or xylites; polyoxyethylenic glycerrides; esters of fatty acids and polyoxyethylene; sorbitan fatty acid esters; polyglycides-glycerides and polyglycides-alcohols ester; and metal salts.

66. A method of treatment of a patient's hypertension and/or angina comprising the administration of the preparation of diltiazem of claim 65 to the patient in the evening for effective treatment of the patient's hypertension and/or angina the next morning.

67. A method of treatment of a patient's hypertension and/or angina comprising the administration of the preparation of diltiazem of claim 63 to the patient in the evening for effective treatment of the patient's hypertension and/or angina the next morning.

68. A controlled-release preparation of pharmaceutically acceptable form of diltiazem according to claim 1 wherein the preparation comprises a plurality of microgranules, each microgranule comprising a central core containing the form of diltiazem coated with a microporous membrane and the central core comprises diltiazem or pharmaceutically acceptable salt thereof associated with a wetting agent, in which the core and membrane comprise: TABLE-US-00019 % W/W (i) in the core: (a) Diltiazem hydrochloride 69 73 (b) Microcrystalline cellulose 8 9.5 (c) (Polyvinyl Pyrrolidone) 1 2 (d) Sucrose stearate 7 8 (ii) in the membrane: (e) Magnesium stearate NF 0.5 2.5 (f) Talc USP 0.5 5.0 (g) Titanium dioxide. (USP) 0.15 0.3 (h) Hydroxypropylmethylcellulose 2910 0.3 0.6 (i) (Polyoxyethylene Sorbitan Monooleate) 0.01 0.025 (l) Simethicone C emulsion USP. (dry of 30%) 0.01 0.015 (k) neutral acrylic polymer of acrylic acid ethyl 7 11 ester and acrylic acid methyl ester (dry of 30%) Purified water USP 0 (used for mixing).

69. A method of treatment of a patient's hypertension and/or angina comprising the administration of the preparation of diltiazem of claim 66 to the patient in the evening for effective treatment of the patient's hypertension and/or angina the next morning.

70. A controlled-release preparation of pharmaceutically acceptable form of diltiazem according to claim 3, wherein the preparation comprises a plurality of microgranules, each microgranule comprising a central core containing the form of diltiazem coated with a microporous membrane and the central core comprises diltiazem or pharmaceutically acceptable salt thereof associated with a wetting agent, in which the core and membrane comprise: (i) in the core, (a) between about 50% and about 85% (% w/w of the total preparation) of diltiazem or pharmaceutically acceptable salt thereof; and (b) between about 2% and about 25% wetting agent (% w/w of the total preparation); together with suitable adjuvants; and (ii) in the membrane, (c) between about 0.1% and about 50% of the total preparation of lubricant selected from the group consisting of talc, and magnesium stearate; (d) between about 0.1% and about 2% of the total preparation of water-soluble and/or water-dispersible polymer selected from the group consisting of hydroxypropylmethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, and any combination thereof; and (e) between about 5% and about 20% (% w/w of the preparation) of a neutral copolymer of acrylic acid ethyl ester and acrylic acid methyl ester, together with suitable adjuvants which permits hydration of the core by gastrointestinal fluids.

71. A method of treatment of a patient's hypertension and/or angina comprising the administration of the preparation of diltiazem of claim 70 to the patient in the evening for effective treatment of the patient's hypertension and/or angina the next morning.

72. A controlled-release preparation of pharmaceutically acceptable form of diltiazem according to claim 3, wherein the preparation comprises a plurality of microgranules, each microgranule comprising a central core containing the form of diltiazem coated with a microporous membrane and the central core comprises diltiazem or pharmaceutically acceptable salt thereof associated with a wetting agent, in which the core and membrane comprise: (i) in the core, (a) between about 69% and about 73% (% w/w of the total preparation) of diltiazem or pharmaceutically acceptable salt thereof; and (b) between about 7% and about 8% wetting agent (% w/w of the total preparation); together with suitable adjuvants; and (ii) in the membrane, (c) between about 0.1% and about 50% of the total preparation of lubricant selected from the group consisting of talc, and magnesium stearate; (d) between about 0.3% and about 0.6% of the total preparation of water-soluble and/or water-dispersible polymer selected from the group consisting of hydroxypropylmethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, and any combination thereof; and (e) between about 7% and about 11% (% w/w of the preparation) of a neutral copolymer of acrylic acid ethyl ester and acrylic acid methyl ester, together with suitable adjuvants which permits hydration of the core by gastrointestinal fluids.

73. A method of treatment of a patient's hypertension and/or angina comprising the administration of the preparation of diltiazem of claim 72 to the patient in the evening for effective treatment of the patient's hypertension and/or angina the next morning.

74. A controlled-release preparation of pharmaceutically acceptable form of diltiazem according to claim 1 wherein the preparation comprises a plurality of microgranules, each microgranule comprising a central core containing the form of diltiazem coated with a microporous membrane and the central core comprises diltiazem or pharmaceutically acceptable salt thereof associated with a wetting agent in which the core and membrane comprise: (i) in the core, (a) between about 50% and about 85% (% w/w of the total preparation) of diltiazem or pharmaceutically acceptable salt thereof; and (b) between about 2% and about 25% wetting agent (% w/w of the total preparation); together with suitable adjuvants; and (ii) in the membrane, (c) between about 0.1% and about 50% of the total preparation of lubricant selected from the group consisting of talc, and magnesium stearate; (d) between about 0.1% and about 2% of the total preparation of water-soluble and/or water-dispersible polymer selected from the group consisting of hydroxypropylmethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, and any combination thereof; and (e) between about 5% and about 20% (% w/w of the preparation) of a neutral copolymer of acrylic acid ethyl ester and acrylic acid methyl ester, together with suitable adjuvants which permits hydration of the core by gastrointestinal fluids.

75. The preparation of claim 74 wherein the microgranules are in capsule form.

76. The preparation of claim 74 wherein the microgranules are in tablet form.

77. The preparation of claim 74, 75 or 76 wherein the core and membrane comprise: (i) in the core, (a) between about 69% and about 73% (% w/w of the total preparation) of diltiazem or pharmaceutically acceptable salt thereof; and (b) between about 7% and about 8% wetting agent (% w/w of the total preparation); together with suitable adjuvants; and (ii) in the membrane, (c) between about 0.1% and about 50% of the total preparation of lubricant selected from the group consisting of talc, and magnesium stearate; (d) between about 0.3% and about 0.6% of the total preparation of water-soluble and/or water-dispersible polymer selected from the group consisting of hydroxypropylmethylcellulose, hydroxyethyl-cellulose, hydroxypropylcellulose, and any combination thereof; and (e) between about 7% and about 11% (% w/w of the preparation) of a neutral copolymer of acrylic acid ethyl ester and acrylic acid methyl ester, together with suitable adjuvants.

78. The preparation of claim 74, 75 or 76 wherein the core and membrane comprise: TABLE-US-00020 % W/W (i) in the core: (a) Diltiazem hydrochloride 69 73 (b) Microcrystalline cellulose 8 9.5 (c) (Polyvinyl Pyrrolidone) 1 2 (d) Sucrose stearate 7 8 (ii) in the membrane: (e) Magnesium stearate NF 0.5 2.5 (f) Talc USP 0.5 5.0 (g) Titanium dioxide. (USP) 0.15 0.3 (h) Hydroxypropylmethylcellulose 2910 0.3 0.6 (i) (Polyoxyethylene Sorbitan Monooleate) 0.01 0.025 (j) Simethicone C emulsion USP. (dry of 30%) 0.01 0.015 (k) a neutral acrylic 7 11 polymer of acrylic acid ethyl ester and acrylic acid methyl ester. (dry of 30%) Purified water USP 0 (used for mixing).

79. The preparation of claim 74 or 76 wherein the preparation is a tablet and the tablet comprises microgranules in association with wax placebo beads which wax placebo beads serve to absorb the shock placed on the microgranules of diltiazem during the tablet process, together with suitable excipients and adjuvants.

80. A method of treatment of a patient's hypertension and/or angina comprising the administration of the preparation of diltiazem of claim 74, 75 or 76 to the patient in the evening for effective treatment of the patient's hypertension and/or angina the next morning.

81. The controlled release preparation of claim 1 wherein said neutral acrylic polymer is a neutral copolymer of acrylic acid ethyl ester and acrylic acid methyl ester.

82. The preparation of claim 70, 72 and 74 wherein the lubricant is selected from the group consisting of talc, and magnesium stearate.

83. A method of treatment of a patient's hypertension and/or angina comprising the administration of the preparation of diltiazem of claim 81 to the patient in the evening for effective treatment of the patient's hypertension and/or angina the next morning.

84. A method of treatment of a patient's hypertension and/or angina comprising the administration of the preparation of diltiazem of claim 82 to the patient in the evening for effective treatment of the patient's hypertension and/or angina the next morning.

85. The preparation of claim 1 in capsule form.

86. The preparation of claim 1 in tablet form.

87. The preparation of claim 2 in capsule form.

88. The preparation of claim 2 in tablet form.
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