Pharmaceutical formulation

• US 20030068369A1
• Filed: 01/30/2002
• Published: 04/10/2003
• Est. Priority Date: 01/30/2001
• Status: Active Grant

• Current Assignee: Capsugel Belgium NV (Lonza Group AG)
• Original Assignee: Capsugel Belgium NV (Lonza Group AG)
• Inventors: Brown, Adrian, Raby, Ronald K. Jr., Matthews, Wayne, McAllister, Stephen Mark, Margetson, Daniel N., Clarke, Allan J.
• Granted Patent: US 8,367,101 B2
• Time in Patent Office: Days
• US Class Current: 424/465
• CPC Class Codes: A61K 9/4808 characterised by the form of the capsule or the structure of the filling; Capsules containing small tablets; Capsules with outer layer for immediate drug release capsules filled with granules or microparticles A61K9/16; filled with microcapsules or coated microparticles A61K9/50; with mixture of different granules, microcapsules, (coated) microparticles A61K9/5084
• CPC Class Codes: A61K 9/4816 Wall or shell material
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: Y02A 50/30 Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

The present invention is directed to pharmaceutically acceptable polymeric compositions suitable for injection molding of single or multi-component pharmaceutical dosage forms comprising a plurality of drug substance containing sub-units, being capsule compartments and/or solid sub-units comprising a solid matrix of a polymer which contains a drug substance, the sub-units being connected together in the assembled dosage form by a weld between parts of the assembled dosage form.

Claims

1. A pharmaceutical composition for moulded capsules comprising Eudragit 4135F present in an amount of about 20 to 90% w/w;

a lubricant present in an amount of 0 to about 30% w/w;

a dissolution modifying excipient present in an amount of about 2.5 to about 70% w/w, and optionally a surfactant present in an amount of 0 to 10%, a plasticizer present in an amount of 0 to 10% w/w and/or a processing agent present in an amount of 0 to about 10% w/w.

2. The composition according to claim 1 wherein the Eudragit 4135F is present in an amount of about 50 to 90% w/w.

3. The composition according to claim 1 which comprises a surfactant which is present in an amount of less than 5% w/w.

4. The composition according to claim 3 wherein the surfactant is sodium dodecyl sulphate or is a block copolymer of ethylene oxide and propylene oxide.

5. The composition according to claim 4 wherein the surfactant is sodium dodecyl sulphate is present in an amount of less than 2% w/w.

6. The composition according to claim 4 wherein the surfactant is a block copolymer of ethylene oxide and propylene oxide.

7. The composition according to claim 1 wherein the lubricant is present in an amount of about 10 to 30% w/w.

8. The composition according to claim 1 wherein the lubricant is stearyl alcohol, glycerol monosterate (GMS), talc, magnesium stearate, silicon dioxide, amorphous silicic acid, or fumed silica;

and combinations or mixtures thereof.

9. The composition according to claim 8 wherein the lubricant is stearyl alcohol.

10. The composition according to claim 9 wherein the stearyl alcohol is present from about 10 to about 15% w/w.

11. The composition according to claim 1 wherein the dissolution modifying excipient is a swellable solid which is ethyl cellulose, cellulose acetate phthalate;

hydroxypropyl cellulose, hydroxypropylmethyl cellulose, hydroxypropylmethyl cellulose phthalate, or other hydroxyalkylcellulose derivative; and

combinations or mixtures thereof.

12. The composition according to claim 11 wherein the dissolution modifying excipient is hydroxypropylmethyl cellulose, hydroxypropylmethyl cellulose phthalate, or hydroxypropyl cellulose.

13. The composition according to claim 12 wherein the swellable solid is present in an amount of 10 to 50% w/w.

14. The composition according to claim 1 wherein the dissolution modifying excipient is xylitol, mannitol, lactose, Starch 1500, sodium chloride, sodium starch glycollate, croscarmellose sodium, crospovidone (cross-linked polyvinyl pyrrolidone), copovidone, polyvinyl pyrrolidone copovidone;

and combinations or mixtures thereof.

15. The composition according to claim 14 wherein the dissolution modifying excipient is present in an amount of 40 to 70% w/w.

16. The composition according to claim 11 wherein the dissolution modifying excipient is a combination of a swellable solid and lactose, sodium starch glycollate, croscarmellose sodium, copovidone, crospovidone (cross-linked polyvinyl pyrrolidone), or polyvinyl pyrrolidone copovidone.

17. The composition according to claim 16 wherein the dissolution modifying excipient is hydroxypropylcellulose and lactose.

18. The composition according to claim 1 wherein the surfactant is a block copolymer of ethylene oxide and propylene oxide, lecithin, sodium dioctyl sulfosuccinate, sodium dodecyl sulphate, Polyoxyl 40 hydrogenated castor oil, polyoxyethylene sorbitan fatty acid esters, the sorbitan fatty acid esters, polyethylene glycol, Vitamin E-TPGS®

(d-alpha-tocopheryl polyethylene glycol 1000 succinate), sucrose fatty acid ester; and

combinations and mixtures thereof.

19. The composition according claim 18 wherein the dissolution modifying excipient is a combination of a swellable solid and lactose, sodium starch glycollate, croscarmellose sodium, copovidone, crospovidone (cross-linked polyvinyl pyrrolidone), or polyvinyl pyrrolidone copovidone.

20. The composition according to claim 1 wherein the plasticizer is triethyl citrate (TEC), tributyl citrate, acetyl triethyl citrate (ATEC), acetyl tributyl citrate (ATBC), dibutyl phthalate, dibutyl sebacate (DBS), diethyl phthalate, vinyl pyrrolidone glycol triacetate, polyethylene glycol, polyoxyethylene sorbitan monolaurate, propylene glycol, or castor oil;

and combinations or mixtures thereof.

21. The composition according to claim 1 wherein the processing agent is talc.

22. The composition according to claim 21 wherein the processing agent is present in an amount of about 1 to about 5% w/w.

23. The composition according to claim 1 which further comprises an absorption enhancer.

24. The composition according to claim 23 wherein the absorption enhancer is chitosan, lecithin, lectin, a sucrose fatty acid ester, Vitamin E-TPGS;

and combinations or mixtures thereof.

31. The pharmaceutical composition according to claim 1 which is:

36. The composition according to claim 1 wherein

37. The composition according to claim 1 which is

38. The composition according to claim 1 wherein the lubricant is stearyl alcohol present in an amount of 10 to 15% w/w, the lubricant is SDS or a present in an amount of a block copolymer of ethylene oxide and propylene oxide at less than 5% w/w;

a dissolution modifying excipient is HPC, HPMC, sodium starch glycollate, croscarmellose sodium, copovidone, or lactose, and combinations or mixtures thereof, present in an amount of about 2.5 to about 70% w/w.

39. An injection molded capsule shell, linker or spacer having a composition according to claim 1.

40. A multicomponent injection molded capsule shell, linker or spacer having a composition according to claim 1.

41. A welded multicomponent injection molded capsule shell, linker or spacer having a composition according to claim 1.

25. The composition according to claim I wherein the Eudragit 4135F is present in an amount of about 50 to 90% w/w, the lubricant is stearyl alcohol, and the dissolution modifying excipient is hydroxypropylmethylcellulose, hydroxypropylcellulose, or a hydroxylalkyl cellulose derivative or salt thereof.

26. The composition according to claim 25 wherein the dissolution modifying excipient also includes a disintegrant.

27. The composition according to claim 26 wherein the disintegrant is sodium starch glycollate, croscarmellose sodium, copovidone, crospovidone (cross-linked polyvinyl pyrrolidone), or polyvinyl pyrrolidone copovidone, or a combination or mixture thereof.

28. The composition according to claim 25 wherein the dissolution modifying excipient also includes a wicking agent.

29. The composition according to claim 28 wherein the wicking agent is lactose.

30. The composition according to claim 25 wherein the processing aid is talc.

32. A pharmaceutical composition for molded capsule shells comprising:

33. A pharmaceutical composition for molded capsule shells comprising:

34. A pharmaceutical composition for molded capsule shells comprising:

35. A pharmaceutical composition for molded capsule shells comprising:

42. A multi-component pharmaceutical dosage form which comprises a plurality of sub-units, each sub-unit being selected from

a) a drug substance-containing capsule compartment which is soluble or disintegrable in a patient'"'"'s gastro-intestinal environment for release of the drug substance contained in the capsule compartment, and

b) a solid matrix comprising a polymer and containing a drug substance, the polymer being soluble, dispersible or disintegrable in a patient'"'"'s gastro-intestinal environment for release of the drug substance contained in the solid matrix, and in which, at least prior to administration to a patient, the sub-units are welded together in an assembled dosage form.

43. A multi-component pharmaceutical dosage form according to claim 42, in which at least one of the sub-units is a solid matrix comprising Eudragit 4135F present in an amount of about 20 to 90% w/w, and a dissolution-modifying excipient present in an amount of about 2.5 to about 30% w/w.

44. A multi-component pharmaceutical dosage form according to claim 43, in which the solid matrix also comprises a lubricant present in an amount up to about 30% w/w.

45. A multi-component pharmaceutical dosage form according to claim 43, in which the solid matrix also comprises a plasticizer present in an amount up to about 10% w/w.

46. A multi-component pharmaceutical dosage form according to claim 43 in which the solid matrix also comprises a processing agent present in an amount up to about 10% w/w.

47. A dosage form according to claim 42, comprising plurality of drug substance-containing capsule compartments, each compartment being physically separated from at least one adjacent compartment by a wall made of a pharmaceutically acceptable polymer material.

48. A multi-component pharmaceutical dosage form according to claim 47, in which the wall comprises Eudragit 4135F present in an amount of about 20 to 90% w/w, and a dissolution-modifying excipient present in an amount of about 2.5 to about 30% w/w.

49. A multi-component pharmaceutical dosage form according to claim 47, in which the wall also comprises a lubricant present in an amount up to about 30% w/w.

50. A multi-component pharmaceutical dosage form according to claim 47, in which the wall also comprises a plasticizer present in an amount up to about 10% w/w.

51. A multi-component pharmaceutical dosage form according to claim 47, in which the wall also comprises a processing agent present in an amount up to about 10% w/w.

52. A dosage form according to claim 47, in which at least one of the sub-units is a drug substance-containing capsule compartments having a wall with a thickness in the range of about 0.3-0.8 mm.

53. A dosage form according to claim 42, in which at least one of the sub-units is a substantially immediate release sub-unit.

54. A dosage form according to claim 42 which at least one of the sub-units is a sustained release or pulsed release sub-unit.

55. A set of multi-component dosage forms, each comprising a plurality of sub-units each sub-unit being selected from:

a) a drug substance-containing capsule compartment which is soluble or disintegrable in a patient'"'"'s gastrointestinal environment for release of the drug substance contained in the capsule compartment, and

b) a solid matrix comprising a polymer and containing a drug substance, the polymer being soluble, dispersible or disintegrable in a patient'"'"'s gastro-intestinal environment for release of the drug substance contained in the solid matrix, in which at least one of the dosage forms of the set comprises at least one said drug substance-containing capsule compartment and at least one other dosage form of the set comprises at least one said solid matrix, and

in which the drug substance-containing capsule compartment of said at least one of the dosage forms is interchangeable with said solid matrix of said at least one other dosage form, and

in which at least prior to administration to a patient, the sub-units of each dosage form are welded together to provide an assembled dosage form.

56. A process for making a pharmaceutical dosage form comprising the steps of:

a) introducing Eudragit 4135F and an excipient composition simultaneously, and at substantially the same location, into an elongated hot melt extruder;

b) mixing said Eudragit 4135F and said excipient composition in the hot melt extruder to form a homogeneous composition therein and ejecting the homogeneous composition in the form of a strand from the hot melt extruder though a die at a location remote from said same location at which the Eudragit 4135F and said excipient composition are introduced;

c) cutting the strand into pellets;

d) introducing said pellets into an injection molder and forming thin-walled capsule compartments from said pellets by injection molding.

57. The process according to claim 56, in which the excipient composition comprises a dissolution modifying excipient.

58. The process according to claim 56, in which the excipient composition comprises a surfactant.

59. The process according to claim 56, in which the excipient composition comprises a lubricant.

60. The process according to claim 56, in which the hot melt extruder is maintained at a temperature not exceeding approximately 135°

C.

61. The process according to claim 56, in which the hot melt extruder is maintained at a temperature not lower than the Eudragit 4135F and said excipient composition melting points.

62. The process according to claim 56, in which the temperature in the hot melt extruder gradually increases along the length of the hot melt extruder, from said same location at which the Eudragit 4135F and an excipient composition are introduced, to the die, the maximum temperature not exceeding approximately 135°

C.

63. The process according to claim 56, in which the hot melt extruder comprises an elongated barrel having first and second opposite ends, and twin screws within the barrel for propelling Eudragit 4135F and said excipient composition along the length of the interior of the barrel, said substantially same location at which the Eudragit 4135F and said excipient composition are introduced is located adjacent the first end of the barrel, and said die is located adjacent the second end of the barrel.

64. The process according to claim 56, in which the injection molding of the thin-walled capsule compartments is carried using an injection molder having a barrel and a nozzle, while maintaining the injection molder barrel at a temperature in the range of about 120°

C. to 140°

C.

65. The process according to claim 56, in which the injection molding of the thin-walled capsule compartments is carried using an injection molder having a barrel and a nozzle, while maintaining the injection molder nozzle at a temperature in the range of about 140°

C. to 190°

C.

66. The process according to claim 56, in which the injection molding of the thin-walled capsule compartments is carried using an injection molder having a barrel and a nozzle, while maintaining the injection molder nozzle at a temperature of about 165 to 170°

C.

67. The process according to claim 56, in which the injection molding of the thin-walled capsule compartments is carried using an injection molder having a barrel and a nozzle, while maintaining the injection molder barrel at a temperature in the range of about 120°

C. to 140°

C. and maintaining the injection molder nozzle at a temperature in the range of about 140°

C. to 190°

C.

68. The process according to claim 56 wherein the pharmaceutical dosage forms are assembled using said capsule compartments as components of said dosage forms.

69. The process according to claim 68 wherein the said capsule compartments of the assembled dosage form are connected together by at least one weld where adjacent parts of said components are in contact.

70. The process according to claim 69 wherein the weld is produced by a thermal weld, an ultrasonic weld, an inductive weld, or an adhesive weld.