Pharmaceutical formulations

• US 20070178156A1
• Filed: 03/11/2005
• Published: 08/02/2007
• Est. Priority Date: 03/12/2004
• Status: Abandoned Application

• Current Assignee: Capsugel Belgium NV (Lonza Group AG)
• Original Assignee: Capsugel Belgium NV (Lonza Group AG)
• Inventors: Brown, Adrian, Raby, Ronald, Matthews, Wayne, McAllister, Stephen, Margetson, Daniel
• Application Number:
  US10/598,810
• Publication Number:
  US 20070178156A1
• Time in Patent Office: Days
• US Class Current: 424/472
• CPC Class Codes: A61K 47/32 Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers , poly(meth)acrylates, or polyvinyl pyrrolidone
• CPC Class Codes: A61K 9/1617 Organic compounds, e.g. phospholipids, fats
• CPC Class Codes: A61K 9/1623 Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules
• CPC Class Codes: A61K 9/1647 Polyesters, e.g. poly(lactide-co-glycolide)
• CPC Class Codes: A61K 9/1652 Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin homeopathic globules A61K9/1623
• CPC Class Codes: A61K 9/4816 Wall or shell material
• CPC Class Codes: A61K 9/5026 obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
• CPC Class Codes: A61K 9/5047 Cellulose ethers containing no ester groups, e.g. hydroxypropyl methylcellulose

Abstract

The present invention is directed to novel pharmaceutically acceptable polymeric compositions suitable for melt extrusion and 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.

Claims

1. A capsule having a shell wall, a linker, or a capsule subunit, composed of a pharmaceutically acceptable composition comprising a copolymer of Ammonio methacrylate Copolymer Type A (Eudragit RL) or Ammonio methacrylate Copolymer Type B (Eudragit RS) present in an amount of about 10 to about 80% w/w;

at least one dissolution modifying excipient, present in a total amount of about 20% to about 70% w/w;

a lubricant present in an amount of about 5% to about 25% w/w; and

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

2. The shell wall, linker, or subunit according to claim 1 wherein the copolymer is Ammonio methacrylate Copolymer Type A.

3. The shell wall, linker, or subunit according to claim 2 wherein the copolymer Type A is present in an amount of about 15 to about 50% w/w.

4. The shell wall, linker, or subunit according to claim 2 wherein the copolymer Type A is present in an amount of about 20 to about 40% w/w.

5. The shell wall, linker, or subunit according to claim 1 wherein the surfactant is present in an amount of less than 2% w/w.

6. The shell wall, linker, or subunit according to claim 5 wherein the surfactant is sodium dodecyl sulphate or is a block copolymer of ethylene oxide and propylene oxide.

7. The shell wall, linker, or subunit according to claim 1 wherein the lubricant is stearyl alcohol, glycerol monostearate (GMS), talc, magnesium stearate, silicon dioxide, amorphous silicic acid, or fumed silica;

and combinations or mixtures thereof.

8. The shell wall, linker, or subunit according to claim 7 wherein the lubricant is present in an amount of about 10 to 30% w/w.

9. The shell wall, linker, or subunit according to claim 8 wherein the lubricant is stearyl alcohol.

10. The shell wall, linker, or subunit according to claim 9 wherein the stearyl alcohol is present from about 10 to about 15% w/w.

11. The shell wall, linker, or subunit according to claim 1 wherein the lubricant is stearyl alcohol.

12. The shell wall, linker, or subunit according to claim 11 wherein the stearyl alcohol is present from about 10 to about 15% w/w.

13. The shell wall, linker, or subunit according to claim 1 wherein the dissolution modifying excipient is a swellable solid.

14. The shell wall, linker, or subunit according to claim 13 wherein the swellable solid is a cellulosic derivatives of ethyl cellulose, cellulose acetate phthalate;

hydroxypropyl cellulose, hydroxypropylmethyl cellulose, hydroxypropylmethyl cellulose phthalate, or other hydroxyalkylcellulose derivative, and combinations or mixtures thereof.

15. The shell wall, linker, or subunit according to claim 13 wherein the swellable solid is at least one of a hydroxypropyl cellulose, or hydroxypropylmethyl cellulose, and a combination or mixture thereof.

16. The shell wall, linker, or subunit according to claim 1 wherein the dissolution modifying excipient is composed of a blend of hydroxypropyl cellulose polymers, each having a differing molecular weight, present in a total amount of about 30% to about 80% w/w.

17. The shell wall, linker, or subunit according to claim 1 wherein the blend of hydroxypropyl cellulose polymers is composed of polymers having a molecular weight averaged of 80,000 and 140,000 (Klucel EF and Klucel JF), or 80,000, 140,000 and 370,000 (Klucel EF, JF and GF), or 140,000 and 370,000 (Klucel JF and GF).

18. The shell wall, linker, or subunit according to claim 1 wherein the dissolution modifying excipient is a non-reducing sugar, a low molecular solute, or a water soluble filler.

19. The shell wall, linker, or subunit according to claim 18 wherein the low molecular weight solutes or sugars are xylitol, mannitol, lactose, starch, or sodium chloride, or combinations or mixtures thereof.

20. The shell wall, linker, or subunit according to claim 1 wherein the dissolution modifying excipient is a disintegrant.

21. The shell wall, linker, or subunit according to claim 20 wherein the disintegrant is sodium starch glycollate, croscarmellose sodium, crospovidone (cross-linked polyvinyl pyrrolidone), copovidone, polyvinyl pyrrolidone;

and combinations or mixtures thereof.

22. The shell wall, linker, or subunit 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.

23. The shell wall, linker, or subunit according to claim 1 wherein the processing agent is talc.

24. The shell wall, linker, or subunit according to claim 23 wherein the processing agent is present in an amount of about 1 to about 5% w/w.

25. The shell wall, linker, or subunit according to claim 1 which further comprises an absorption enhancer.

26. The shell wall, linker, or subunit according to claim 25 wherein the absorption enhancer is chitosan, lecithin, lectin, a sucrose fatty acid ester, Vitamin E-TPGS;

and combinations or mixtures thereof.

30. The composition according to claim 1 wherein the blend of hydroxypropyl cellulose is composed of polymers having a molecular weight averaged of 140,000 and 370,000 (Klucel JF and GF).

31. The composition according to claim 1 wherein the blend of hydroxypropyl cellulose is composed of polymers having a molecular weight averaged of 80,000 and 370,000 (Klucel EF and Klucel GF).

39. An injection molded capsule shell, linker or spacer having a composition as defined in claim 1.

40. A multicomponent injection molded capsule shell, linker or spacer having a composition as defined in claim 1.

41. A welded, or mechanically joined, multicomponent injection molded capsule shell, linker or spacer having a composition as defined in claim 1.

27. A capsule having a shell wall, a linker, or other capsule subunit composed of a pharmaceutically acceptable composition comprising a copolymer of Ammonio methacrylate Copolymer Type A (Eudragit RL) present in an amount of about 15 to 50% w/w, a lubricant which is stearyl alcohol, and at least one dissolution modifying excipient which is a hydroxypropylcellulose derivative, wherein the shell wall, the linker or subunit all being comprised of the pharmaceutical composition.

28. The composition according to claim 27 wherein the hydroxypropyl cellulose is a blend of hydroxypropyl cellulose'"'"'s having differing molecular weight.

29. The composition according to claim 28 wherein the blend of hydroxypropyl cellulose is composed of polymers having a molecular weight averaged of 80,000 and 140,000 (Klucel EF and Klucel JF).

32. The composition according to claim 28 wherein the blend of hydroxypropyl cellulose is of equal % w/w.

33. The composition according to claim 28 wherein the blend of hydroxypropyl cellulose is about 32% w/w.

34. The composition according to claim 27 wherein the hydroxypropyl cellulose is present in an amount of about 50% w/w.

35. The composition according to claim 27 which further comprises a wicking agent.

36. The composition according to claim 35 wherein the wicking agent is lactose.

37. The composition according to claim 36 wherein the lactose is present in an amount of about 13% w/w.

38. (canceled)

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, a capsule subunit, or linker being comprised of a pharmaceutical composition comprising a copolymer of Ammonio methacrylate Copolymer Type A or Ammonio methacrylate Copolymer Type B present in an amount of about 15 to 80% w/w, at least one hydroxypropyl cellulose present in an amount of about 30% to about 70% w/w 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, and in which, at least prior to administration to a patient, the sub-units are welded together or mechanically joined in an assembled dosage form.

43. A multi-component pharmaceutical dosage form according to claim 42, in which the solid matrix also comprises a lubricant present in an amount of about 10 to about 25% w/w.

44. A dosage form according to claim 42, 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 0.1-0.8 mm.

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

46. A capsule having a shell wall, a linker, or a capsule subunit, comprising a pharmaceutically acceptable of:

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

a) introducing a copolymer of Ammonio methacrylate Copolymer Type A (Eudragit RL) or Ammonio methacrylate Copolymer Type B (Eudragit RS) present in an amount of about 10 to about 80% w/w;

at least one dissolution modifying excipient, present in a total amount of about 20% to about 70% w/w;

a lubricant present in an amount of about 5% to about 25% w/w; and

optionally a surfactant present in an amount of 0 to about 10%, a plasticizer present in an amount of 0 to about 10% w/w and/or a processing agent present in an amount of 0 to about 10% w/w;

simultaneously, and at substantially the same location, into an elongated hot melt extruder;

b) mixing said copolymer 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 copolymer and said excipient composition are introduced;

c) cutting the strand into pellets;

d) introducing said pellets into an injection molder and forming subunits of a thin-walled capsule compartment, a solid matrix subunit or a linker, from said pellets by injection molding.

48. The process according to claim 47, in which the hot melt extruder is maintained at a temperature not lower than the copolymer and said excipient composition melting points.

51. The process according to claim 47 wherein the pharmaceutical dosage forms are assembled using said capsule compartments as components of said dosage forms.

52. The process according to claim 51 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, or are mechanically joined in an assembled dosage form.

49. The process according to claim 49, 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 copolymer and an excipient composition are introduced, to the die.

50. The process according to claim 49, in which the hot melt extruder comprises an elongated barrel having first and second opposite ends, and twin screws within the barrel for propelling copolymer and said excipient composition along the length of the interior of the barrel, said substantially same location at which the copolymer 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.