Three-phase pharmaceutical form with constant and controlled release of amorphous active ingredient for single daily application

• US 6,042,847 A
• Filed: 11/12/1997
• Issued: 03/28/2000
• Est. Priority Date: 05/19/1995
• Status: Expired due to Fees

• Current Assignee: LEK, tovarna farmacevtskih in kemicnih izdelkov DD
• Original Assignee: LEK, tovarna farmacevtskih in kemicnih izdelkov DD
• Inventors: Kerc, Janez, Kofler, Bojan, Rebic, Ljubomira Barbara
• Primary Examiner(s): Williamson, Michael A.
• Application Number:
  US08/945,984
• Time in Patent Office: 867 Days
• Field of Search: 424/472
• US Class Current: 424/472
• CPC Class Codes: A61K 9/2077 Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
• CPC Class Codes: A61K 9/2846 Poly(meth)acrylates
• CPC Class Codes: A61K 9/2866 Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
• CPC Class Codes: A61K 9/2886 having two or more different drug-free coatings; Tablets of the type inert core-drug layer-inactive layer of the type active core-drug layer-inactive layer A61K9/209
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system

Abstract

Described is a novel three-phase pharmaceutical form with constant and controlled release of an amorphous active ingredient stabilized with polymers for a single daily peroral application, which is especially suitable for active ingredients existing in amorphous form or in one or more polymorphous forms, which exhibit poor solubility in crystal form depending on the polymorphous form, particle size and the specific surface area of the active ingredient. The active ingredient can be used in its amorphous or any polymorphous form, which in the process of the preparation of the three-phase pharmaceutical form according to the invention is converted into the amorphous form. The three-phase pharmaceutical form with constant and controlled release of an amorphous active ingredient for a single daily peroral application contains a core consisting of a first and a second phase and a coating representing the third phase. In the first phase the three-phase pharmaceutical form contains an amorphous active ingredient, the water-soluble polymer polyvinylpyrrolidone and a cellulose ether as carriers of the amorphous active ingredient and simultaneously as inhibitors of its crystallization, a surfactant that improves the solubility of the active ingredient and promotes the absorption of the amorphous active ingredient from gastrointestinal tract, in the second phase it contains a cellulose ether and a mixture of mono-, di- and triglycerides as sustained release agents and the third phase is represented by a poorly soluble or gastro-resistant film coating, which in the first few hours after the application controls the release of the active ingredient and can consist of an ester of hydroxypropylmethylcellulose with phthalic anhydride or of a copolymerizate based on methacrylic acid and ethyl acrylate. Described is also a process for the preparation of this pharmaceutical form.

Claims

1. A three-phase pharmaceutical form with constant and controlled release of amorphous active ingredient for a single daily peroral application characterized in that it contains a core consisting of a first and a second phase wherein

the first phase contains a mixture of an amorphous active ingredient in an amount from 0.05 mg to 300 mg, a water-soluble polymer polyvinylpyrrolidone in the range from 1 to 40 wt. % with respect to the total weight of the pharmaceutical form a surfactant in the ran(c from 0.1 to 20 wt % with respect to the total weight of the pharmaceutical form and a cellulose ether in the range from 10 to 70 wt % with respect to the total weight of the pharmaceutical form, said first phase being homogeneously mixed with

the second phase containing a cellulose ether in the range from 5 to 40 wt % with respect to the total weight of the pharmaceutical form, a mixture of mono-, di- and triglycerides in the range flow 0 to 10 wt % with respect to the total weight of the pharmaceutical form and usual adjuvants;

wherein the weight ratio between the water soluble polymer polyvinylpyrrolidone and the cellulose ether in the first phase is in the range from 1;

10 to 10;

1, the weight ratio between the amor-phous active ingredient, the water soluble polymer polyvinylpyrrolidone and the cellulose ether in the first phase is in the range from 1;

20;

30 to 10;

2;

1, and the weight ratio between the cellulose ether of the first phase having an average molecular weight in the range of 5000 g/mol to 50000 g/mol and the cellulose ether of the second phase having an average molecular weight in the range of 50000 g/mol to 300000 g/mol is in the range of 5;

1 to 1;

5;

and a third phase surrounding the core and represented by a coating, said third phase being at film coating consisting of an ester of hydroxypropylmethylcellulose with phthalic anhydride in the weight ratio of the coating with respect to the core ranging from 2 to 10 wt % or of a copolymerizate of methacrylic acid and ethyl acrylate in the weight ratio of the coating with respect to the core in the range from 2 to 15 wt % and usual adjuvants.

2. A three-phase pharmaceutical form according to claim 1, characterized in that the active ingredient is selected from the group consisting of active ingredients acting as analgesics, anticonvulsants, antiparkinsonian drugs, anesthetics, antibiotics, antimalarials, antihypertensives, antihistaminics, antipyretics, alpha-blockers, alpha-adrenergic agonists, bactericides, bronchodilators, beta-adrenergic stimulants, beta-adrenergic blockers, contraceptives, cardiovascular active ingredients, calcium channel inhibitors, diuretics, hypnotics, hormones, hyperglycemics, hypoglycemics, muscle relaxants and contractors, parasympathomimetics, sedatives, sympathomimetics, tranquilizers, antimigraine drugs, and vitamins.

3. A three-phase pharmaceutical form according to claim 1, characterized in that the active ingredient is nifedipine.

4. A three-phase pharmaceutical form according to claim 1, characterized in that the active ingredient is felodipine.

5. A three-phase pharmaceutical form according to claim 1, characterized in that the active ingredient is nicardipine hydrochloride.

6. A three-phase pharmaceutical form according to claim 1, characterized in that the active ingredient is amlodipine benzenesulfonate.

7. A three-phase pharmaceutical form according to claim 1, characterized in that the active ingredient is fenofibrate.

8. A three-phase pharmaceutical form according to claim 1, characterized in that the first phase of the pharmaceutical form contains the water-soluble polymer polyvinylpyrrolidone with an average molecular weight in the range from 2000 g/mol to 1100000 g/mol.

9. A three-phase pharmaceutical form according to claim 1, characterized in that the first phase of the pharmaceutical form contains the water-soluble polymer polyvinylpyrrolidone with a K-value in the range from 10 to 95.

10. A three-phase pharmaceutical form according to claim 1, characterized in that the first phase of the pharmaceutical form contains a surfactant selected from the group consisting of sodium lauryl sulfate, various types of poloxamers, natural or synthetic lecithins and esters of sorbitan with various fatty acids, esters of polyethylene sorbitan with various fatty acids, derivatives of polyoxyethylated castor oil, derivatives of polyoxyethylated hydrogenated castor oil, and esters of polyoxyethylene with various fatty acids.

11. A three-phase pharmaceutical form according to claim 1, characterized in that the first phase of the pharmaceutical form contains a cellulose ether selected from the group consisting of methylcellulose, ethylcellulose, hydroxyethylcellulose, propylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, and carboxymethylcellulose.

12. A three-phase pharmaceutical form according to claim 1, characterized in that the first phase of the pharmaceutical form contains a cellulose ether which is a hydroxypropylmethylcellulose with a content of methoxy groups ranging from 19 to 30% and with a content of hydroxypropoxy groups ranging from 4 to 12%.

13. A three-phase pharmaceutical form according to claim 1, characterized in that the second phase of the pharmaceutical form contains a cellulose ether selected from the group consisting of methylcellulose, ethylcellulose, hydroxyethylcellulose, propylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose and, carboxymethylcellulose.

14. A three-phase pharmaceutical form according to claim 1, characterized in that the second phase of the pharmaceutical form contains a cellulose ether which is hydroxypropylmethylcellulose with a content of methoxy groups ranging from 19 to 30% and with content of hydroxypropoxy groups ranging from 4 to 12%.

15. A three-phase pharmaceutical form according to claim 1, characterized in that the second phase of the pharmaceutical form contains a mixture of mono-, di- and triglycerides comprising from 20 to 60 wt. % of triglyceride, from 25 to 65 wt. % of diglyceride, from 10 to 20 wt. % of monoglyceride and from 0 to 5 wt. % of glycerol.

16. A three-phase pharmaceutical form according to claim 1, characterized in that the mixture of mono-, di- and triglycerides is selected from the group consisting of a mixture of glycerol mono-, di- and tristearate, a mixture of glycerol mono-, di- and tripalmitate, a mixture of glycerol mono-, di- and trioleate, and a mixture of glycerol mono-, di- and tripalmitostearate.

17. A three-phase pharmaceutical form according to claim 1, characterized in that the second phase of the pharmaceutical form contains adjuvants selected from the group consisting of lactose, starch, saccharose, gelatin, carboxymethylcellulose, sodium cross-linked carboxymethylcellulose, polyvinylpyrrolidone, cross-linked polyvinylpyrrolidone, magnesium stearate, calcium stearate, aluminum silicate, palmitic acid, stearic acid, and siliconized talc.

18. A three-phase pharmaceutical form according to claim 1, characterized in that the third phase of the pharmaceutical form contains a film coating consisting of an ester of hydroxypropyl methylcellulose with phthalic anhydride with a content of methoxy groups ranging from 18 to 25%, a content of hydroxypropoxy groups ranging from 4 to 10% and content of carboxybenzoyl groups ranging from 20 to 35%.

19. A three-phase pharmaceutical form according to claim 1, characterized in that the third phase of the pharmaceutical form contains a film coating consisting of an ester of hydroxypropyl methylcellulose with phthalic anhydride with an average molecular weight from 2000 g/mol to 100000 g/mol.

20. A three-phase pharmaceutical form according to claim 1, characterized in that the third phase of the pharmaceutical form contains a film coating consisting of a copolymerizate of methacrylic acid and ethyl acrylate with a content of methacrylic groups ranging from 40 to 50%.

21. A three-phase pharmaceutical form according to claim 1, characterized in that the third phase of the pharmaceutical form contains a film coating consisting of a copolymerizate of methacrylic acid and ethyl acrylate with an average molecular weight in the range from 100000 g/mol to 300000 g/mol.

22. A three-phase pharmaceutical form according to claim 1, characterized in that the third phase of the pharmaceutical form contains adjuvants selected from the group consisting of polyethylene glycols of various molecular weights, triacetine, dibutyl sebacate, triethylcitrate, cellulose ethers, additives and pigments.

23. A three-phase pharmaceutical form according to claim 1, characterized in that the weight ratio between the water-soluble polymer polyvinylpyrrolidone and the cellulose ether in the first phase of the three-phase pharmaceutical form is in the range from 1:

3 to 3;

1.

24. A three-phase pharmaceutical form according to claim 1, characterized in that the weight ratio between the surfactant and the active ingredient is in the range from 0.1:

100 to 10;

1.

25. A three-phase pharmaceutical form according to claim 1, characterized in that the weight ratio between the surfactant and the active ingredient is in the range from 0.5:

100 to 3;

1.

26. A three-phase pharmaceutical form according to claim 1, characterized in that the weight ratio between the amorphous active ingredient, the water soluble polymer polyvinylpyrrolidone and the cellulose ether in the first phase of the three-phase pharmaceutical form is in the range from 1:

2;

3 to 3;

2;

1.

27. A three-phase pharmaceutical form according to claim 1, characterized in that the weight ratio between the cellulose ether in the first phase and the cellulose ether in the second phase of the three-phase pharmaceutical form is in the range from 3:

1 to 1;

3.

28. A three-phase pharmaceutical form according to claim 1, characterized in that it is in the form of tablets or capsules.

29. A three-phase pharmaceutical form according to claim 1, wherein the active ingredient is nifedipine in an amount from 30 mg to 90 mg.

30. A three-phase pharmaceutical form according to claim 1, wherein the active ingredient is nifedipine in an amount of 30 mg.

31. A three-phase pharmaceutical form according to claim 1, wherein the active ingredient is nifedipine in an amount of 60 mg.

32. A three-phase pharmaceutical form according to claim 1, wherein the active ingredient is nifedipine in all amount of 90 mg.

43. A process for the preparation of a three-phase pharmaceutical form according to claim 32, characterized in that the first phase of the pharmaceutical form contains the water-soluble polymer polyvinylpyrrolidone with a K-value ranging from 10 to 95.

33. A process for the preparation of a three-phase pharmaceutical from with constant and controlled release of amorphous active ingredient for a single daily peroral application, containing a core consisting of a first and second phase wherein

the first phase contains a mixture of an amorphous active ingredient in an amount from 0.05 mg to 300 mg, the water-soluble polymer polyvinylpyrrolidone in the range from 1 to 40 wt. % with respect to the total weight of the pharmaceutical form, a surfactant in the range from 0.1 to 20 wt % with respect to the total weight of the pharmaceutical form and a cellulose ether in the range from 10 to 70 wt % with respect to the total weight of the pharmaceutical form, said first phase being homogeneously mixed with

the second phase containing a cellulose ether in the range from 5 to 40 wt % with respect to the total weight of the pharmaceutical form, a mixture of mono- di- and triglycerides in the range form 0 to 10 wt % with respect to the total weight of the pharmaceutical form and usual adjuvants;

wherein the weight ratio between the water soluble polymer polyvinylpyrrolidone and the cellulose ether in the first phase is in the range from 1;

10 to 10;

1, the weight ratio between the amorphous active ingredient, the water soluble polymer polyvinylpyrrolidone and the cellulose ether in the first phase is in the range from 1;

20;

30 to 10;

2;

1, and the weight ratio between the cellulose ether of the first phase having an average molecular weight in the range of 5000 g/mol to 50000 g/mol and the cellulose ether of the second phase having an average molecular weight in the range of 50000 g/mol to 300000 g/mol is in the range off 5;

1 to 1;

5

and at third phase surrounding, the core and represented by a coating, said third phase being a film coating consisting of an ester of hydroxypropylmethylcellulose with phthalic anhydride in the weight ratio of the coating with respect to the core ranging from 2 to 10 wt % or of a copolymerizate of methacrylic acid and ethyl acrylate in the weight ratio of the coating with respect to the core in the range from 2 to 15 wt % and usual adjuvants,

wherein an active ingredient, a surfactant and the water-soluble polymer polyvinylpyrrolidone are dissolved in an organic solvent at a temperature from 30°

C. to 70°

C. in a fluid bed granulator the resulting solution is sprayed onto cellulose ether in the fluid bed, the obtained granulate is homogeneously mixed with a cellulose ether and other usual adjuvants at room temperature and the granulate is compressed into tablets, which are coated with at film coating.

34. A process for the preparation of a three-phase pharmaceutical form according to claim 33, characterized in that as the organic solvent the are selected solvents from the group consisting of alcohols, ketones, esters, ethers, aliphatic hydrocarbons, halogenated hydrocarbons, cycloaliphatic, aromatic, heterocyclic solvents and mixtures thereof.

35. A process for the preparation of a three-phase pharmaceutical form according to claim 33, characterized in that as the organic solvent are solvents selected from the group consisting of ethanol, methanol, isopropyl alcohol, n-butyl alcohol, acetone, diethyl ether, ethyl acetate, isopropyl acetate, methyl acetate, dichloromethane, chloroform, and mixtures thereof.

36. A process for the preparation of a three-phase pharmaceutical form according to claim 33, characterized in that the active ingredient is selected from the group consisting of active ingredients acting as analgesics, anticonvulsants, antiparkinsonian drugs, anesthetics, antibiotics, antimalarials, antihypertensives, antihistaminics, antipyretics, alpha-blockers, alpha-adrenergic agonists, bactericides, bronchodilators, beta-adrenergic stimulants, beta-adrenergic blockers, contraceptives, cardiovascular agents, calcium channel inhibitors, diuretics, hypnotics, hormones, hyperglycemics, hypoglycemics, muscle relaxants and contractors, parasympathomimetics, sedatives, sympathomimetics, tranquilizers, antimigraine drugs, and vitamins.

37. A process for the preparation of a three-phase pharmaceutical form according to claim 33, characterized in that the active ingredient is nifedipine.

38. A process for the preparation of a three-phase pharmaceutical form according to claim 33, characterized in that the active ingredient is felodipine.

39. A process for the preparation of a three-phase pharmaceutical form according to claim 33, characterized in that the active ingredient is nicardipine hydrochloride.

40. A process for the preparation of a three-phase pharmaceutical form according to claim 33, characterized in that the active ingredient is amlodipine benzene sulfonate.

41. A process for the preparation of a three-phase pharmaceutical form according to claim 33, characterized in that the active ingredient is fenofibrate.

42. A process for the preparation of a three-phase pharmaceutical form according to claim 33, characterized in that the first phase of the pharmaceutical form contains the water-soluble polymer polyvinylpyrrolidone with an average molecular weight in the range from 2000 g/mol to 1100000 g/mol.

44. A process for the preparation of a three-phase pharmaceutical form according to claim 33, characterized in that the first phase of the pharmaceutical form contains a surfactant selected from the group consisting of sodium lauryl sulfate, various types of poloxamers, natural and synthesized lecithins and esters of sorbitan with various fatty acids, esters of polyoxyethylene sorbitan with various fatty acids, derivatives of polyoxyethylated castor oil, derivatives of polyoxyethylated hydrogenated castor oil, and esters of polyoxyethylene with various fatty acids.

45. A process for the preparation of a three-phase pharmaceutical form according to claim 33, characterized in that the first phase of the pharmaceutical form contains the cellulose ether selected from a group consisting of methylcellulose, ethylcellulose, hydroxyethylcellulose, propylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, and carboxymethylcellulose.

46. A process for the preparation of a three-phase pharmaceutical form according to claim 33, characterized in that the first phase of the pharmaceutical form contains a cellulose ether which is hydroxypropylmethylcellulose with a content of methoxy groups ranging from 19 to 30% and with a content of hydroxypropoxy groups ranging from 4 to 12%.

47. A process for the preparation of a three-phase pharmaceutical form according to claim 33, characterized in that the second phase of the pharmaceutical form contains the cellulose ether selected from a group consisting of methylcellulose, ethylcellulose, hydroxyethylcellulose, propylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, and carboxymethylcellulose.

48. A process for the preparation of a three-phase pharmaceutical form according to claim 33, characterized in that the second phase of the pharmaceutical form contains a cellulose ether with an average molecular weight ranging from 50000 g/mol to 300000 g/mol.

49. A process for the preparation of a three-phase pharmaceutical form according to claim 33, characterized in that the second phase of the pharmaceutical form contains a cellulose ether, which is a hydroxypropylmethylcellulose with a content of methoxy groups ranging from 19 to 30% and with a content of hydroxypropoxy groups ranging from 4 to 12%.

50. A process for the preparation of a three-phase pharmaceutical form according to claim 33, characterized in that the second phase of the pharmaceutical form contains a mixture of mono-, di- and triglycerides comprising from 20 to 60 wt. % of triglyceride, from 25 to 65 wt. % of diglyceride, from 10 to 20 wt. % of monoglyceride and from 0 to 5 wt. % of glycerol.

51. A process for the preparation of a three-phase pharmaceutical form according to claim 33, characterized in that the mixture of mono-, di- and triglycerides is selected from the group consisting of a mixture of glycerol mono-, di- and tristearate, a mixture of glycerol mono-, di- and tripalmitate, a mixture of glycerol mono-, di- and trioleate, and a mixture of glycerol mono-, di- and tripalmitostearate.

52. A process for the preparation of a three-phase pharmaceutical form according to claim 33, characterized in that the second phase of the pharmaceutical form contains adjuvants selected from the group consisting of lactose, starch, saccharose, gelatin, carboxymethylcellulose, sodium cross-linked carboxymethylcellulose, polyvinylpyrrolidone, cross-linked polyvinylpyrrolidone, magnesium stearate, calcium stearate, aluminum silicate, palmitic acid, stearic acid, and siliconized talc.

53. A process for the preparation of a three-phase pharmaceutical form according to claim 33, characterized in that the third phase of the pharmaceutical form contains a film coating consisting of an ester of hydroxypropyl methylcellulose with phthalic acid anhydride with a content of methoxy groups ranging from 18 to 25%, with a content of hydroxypropoxy groups ranging from 4 to 10% and with a content of carboxybenzoyl groups ranging from 20 to 35%.

54. A process for the preparation of a three-phase pharmaceutical form according to claim 33, characterized in that the third phase of the pharmaceutical form contains a film coating consisting of an ester of hydroxypropyl methylcellulose with phthalic anhydride with an average molecular weight from 2000 g/mol to 100000 g/mol.

55. A process for the preparation of a three-phase pharmaceutical form according to claim 33, characterized in that the third phase of the pharmaceutical form contains a film coating consisting of a copolymerizate of methacrylic acid and ethyl acrylate with a content of methacrylic groups ranging from 40 to 50%.

56. A process for the preparation of a three-phase pharmaceutical form according to claim 33, characterized in that the third phase of the pharmaceutical form contains a film coating consisting of a copolymerizate of methacrylic acid and ethyl acrylate with an average molecular weight ranging from 100000 g/mol to 300000 g/mol.

57. A process for the preparation of a three-phase pharmaceutical form according to claim 33, characterized in that the third phase of the pharmaceutical form contains adjuvants selected from the group consisting of polyethylene glycols of various molecular weights, triacetine, dibutyl sebacate triethylcitrate, cellulose ethers, additives, and pigments.

58. A process for the preparation of a three-phase pharmaceutical form according to claim 33, characterized in that the weight ratio between the water-soluble polymer polyvinylpyrrolidone and the cellulose ether in the first phase of the three-phase pharmaceutical form is in the range from 1:

3 to 3;

1.

59. A process for the preparation of a three-phase pharmaceutical form according to claim 33, characterized in that the weight ratio between the surfactant and the active ingredient is in the range from 0.1:

100 to 10;

1.

60. A process for the preparation of a three-phase pharmaceutical form according to claim 33, characterized in that the weight ratio between the surfactant and the active ingredient is in the range from 0.5:

100 to 3;

1.

61. A process for the preparation of a three-phase pharmaceutical form according to claim 33, characterized in that the weight ratio between the amorphous active ingredient, the water-soluble polymer polyvinylpyrrolidone and the cellulose ether in the first phase of the three-phase pharmaceutical form is in the range from 1:

2;

3 to 3;

2;

1.

62. A process for the preparation of a three-phase pharmaceutical form according to claim 33, characterized in that the weight ratio between the cellulose ether in the first phase and the cellulose ether in the second phase of the three-phase pharmaceutical form is in the range from 3:

1 to 1;

3.

63. A process for the preparation of a three-phase pharmaceutical form according to claim 33, characterized in that the three-phase pharmaceutical form is in the form of tablets or capsules.