Methotrexate Dosage Form

Abstract

The present invention relates to a pharmaceutical dosage form comprising an active ingredient such as methotrexate or a pharmaceutically acceptable salt thereof, in particular in the form of pellets, such as multiparticulates, mini-tablets or granulate. It further relates to oral dosage forms for which saturation kinetics limits the oral use of higher dosages of active ingredients.

Claims

1. A pharmaceutical composition comprising a plurality of pellets, wherein each pellet has a smallest diameter ≤5 mm, preferably ≤3 mm, and wherein each pellet comprises methotrexate or a pharmaceutically acceptable salt thereof.

2. A pharmaceutical composition for oral administration comprising methotrexate or a pharmaceutically acceptable salt thereof, comprising a plurality of pellets, wherein each pellet has a smallest diameter 5 mm, preferably 3 mm, and wherein at least 80% of the total amount of methotrexate of said pharmaceutical composition have been released within 4 hours of administration and/or as measured in an USP Dissolution Apparatus 2 in 500 ml 0.1 N HCl at 37° C.±0.5° C.

3. The pharmaceutical composition according to any of the preceding claims, comprising at least 10 mg methotrexate or a pharmaceutically acceptable salt thereof, wherein at least one of the pellets provides immediate release of said methotrexate; and at least one of the pellets provides delayed release and/or a predetermined lag time prior to release of methotrexate.

4. The pharmaceutical composition according to any of the preceding claims, comprising at least 15 mg methotrexate or a pharmaceutically acceptable salt thereof comprising: a. At least one pellet A providing immediate release of methotrexate. b. at least one pellet B providing delayed release of methotrexate, and c. at least one pellet C providing delayed release of methotrexate wherein said pellet C provides slower release than said pellet B.

5. The pharmaceutical composition according to any of the preceding claims, wherein said at least one pellet providing immediate release of methotrexate, allows release of at least 90% of the active ingredient of said pellet in in 500 ml 0.1 N HCl, measured in a USP Dissolution Apparatus 2, Paddle, (37° C.±0.5° C.), within 5 minutes, 10 minutes, 15 minutes, 20 minutes, 25 minute or within 30 minutes.

6. A pharmaceutical composition comprising a plurality of pellets, wherein each pellet comprises methotrexate or a pharmaceutically acceptable salt thereof, and preferably wherein at least one of the pellets provides immediate release of said methotrexate; and preferably wherein at least one of the pellets provides delayed release and/or a predetermined lag time prior to release of methotrexate; and wherein at least 80% of the total amount of methotrexate of said pharmaceutical composition have been released within 4 hours of administration and/or as measured in an USP Dissolution Apparatus 2 in 500 ml 0.1 N HCl at 37° C.±0.5° C.

7. A pharmaceutical composition comprising i. At least one pellet providing immediate release of methotrexate or a pharmaceutically acceptable salt thereof, and ii. If the pharmaceutical composition comprises more than 10 mg methotrexate further at least one pellet providing delayed release of methotrexate; wherein said pharmaceutical composition allows release of at least 80% of the total amount of methotrexate within 4 hours of administration.

8. A pharmaceutical composition comprising a plurality of pellets, said composition comprising a total dosage of 1-30 mg methotrexate or a pharmaceutically acceptable salt thereof, and wherein said composition comprises: a. At least one pellet A providing immediate release of methotrexate. b. For the composition comprising more than 10 mg, such as at least 12.5 mg, more preferred 15 mg, preferably 17.5 mg, more preferred 20 mg methotrexate, further at least one pellet B providing delayed release of methotrexate, and preferably c. For the composition comprising at least 15 mg, preferably 17.5 mg, more preferred 20 mg methotrexate, further at least one pellet C providing delayed release of methotrexate wherein said pellet C provides slower release than said pellet B.

9. A pharmaceutical composition comprising a plurality of at least two, preferably at least three, pellets, providing a total dosage of methotrexate or a pharmaceutically acceptable salt thereof of 1-30 mg, wherein said composition comprises pellets providing immediate release of methotrexate; and for dosages of 12.5-30 mg further comprises pellets providing delayed release of methotrexate; and for dosages of 20-30 mg comprises pellets providing an additional delayed release of methotrexate.

10. A pharmaceutical composition comprising a total amount of methotrexate, or a pharmaceutically acceptable salt thereof, of 15-50 mg, preferably 20-30 mg, wherein said pharmaceutical composition releases at least 80% of the total amount of methotrexate within 4 hours; and wherein said pharmaceutical composition comprises i) at least one immediate release pharmaceutical composition comprising 10-15 mg methotrexate and providing release of at least 8-10 mg of methotrexate within 1 hour; and ii) at least one delayed release pharmaceutical composition comprising a content of methotrexate of at least 2.5 mg, more preferred at least 5 mg methotrexate, wherein said delayed release pharmaceutical composition releases less than 50% of said content of methotrexate within 1 hour; preferably each composition comprises one or more pellets, such as one or more tablets.

11. A delayed release pharmaceutical composition comprising a content of methotrexate, or a pharmaceutically acceptable salt thereof, of at least 2.5 mg, more preferred at least 5 mg methotrexate, wherein said delayed release pharmaceutical composition releases less than 50% of said content of methotrexate within 1 hour; for use in a treatment comprising oral administration of a total amount of methotrexate, or a pharmaceutically acceptable salt thereof, of 15-50 mg, preferably 20-30 mg; wherein said treatment further comprises administration of at least one immediate release pharmaceutical composition comprising 10-15 mg methotrexate and providing release of at least 8-10 mg of methotrexate within 1 hour, subject to the proviso than said delayed release pharmaceutical dosage forms and said immediate release pharmaceutical composition releases at least 80% of the total amount of methotrexate within 4 hours; preferably each composition comprises one or more pellets, such as one or more tablets.

12. An immediate release pharmaceutical composition comprising 10-15 mg methotrexate, or a pharmaceutically acceptable salt thereof, and providing release of at least 8-10 mg of methotrexate within 1 hour, for use in a treatment comprising oral administration of a total amount of methotrexate, or a pharmaceutically acceptable salt thereof, of 15-50, preferably 20-30 mg; wherein said treatment further comprises administration of at least one delayed release pharmaceutical composition comprising a content of methotrexate, or a pharmaceutically acceptable salt thereof, of at least 2.5 mg, more preferred at least 5 mg methotrexate, wherein said delayed release pharmaceutical composition releases less than 50% of said content of methotrexate within 1 hour; subject to the proviso that said delayed release pharmaceutical dosage forms and said immediate release pharmaceutical composition releases at least 80% of the total amount of methotrexate within 4 hours; preferably each composition comprises one or more pellets, such as one or more tablets.

13. The pharmaceutical composition according to any of the preceding claims, wherein each pellet has a size of less than 5.00 mm, 4.75 mm, 4.50 mm, 4.25 mm, 4.00 mm, 3.75 mm, 3.50 mm, 3.25 mm, 3.00 mm, 2.75 mm, 2.50 mm, 2.25 mm, 2.00 mm, 1.75 mm, 1.50 mm, 1.25 mm, 1.00 mm, 0.75 mm, 0.50 mm or less than 0.25 mm.

14. The pharmaceutical composition according to any of the preceding claims, wherein said pellets have a size selected among 0.01-5 mm, 0.1-4.5 mm, 0.2-4 mm, 0.3-3.5 mm, 0.4-3 mm, 0.5-2.5 mm, 0.6-2 mm, 0.75-1.5 mm, and about 1 mm.

15. The pharmaceutical composition according to any of the preceding claims, wherein at least one of said pellets provides immediate release of methotrexate.

16. The pharmaceutical composition according to any of the preceding claims comprising at least 10 mg, preferably at least 12.5 mg, more preferred at least 15 mg methotrexate, wherein at least one of said pellets provides a predetermined delay of release of methotrexate.

17. The pharmaceutical composition according to any of the preceding claims, wherein 20-90%, more preferred 30-80%, preferably 40-70%, more preferred at least 50% of the total amount of methotrexate has been released after 1 hour.

18. The pharmaceutical composition according to any of the preceding claims, wherein 50-100%, more preferred 60-95%, preferably 65-90%, more preferred at least 70% of the total amount of methotrexate has been released after 2 hours.

19. The pharmaceutical composition according to any of the preceding claims, wherein 60-100%, more preferred 70-99%, preferably 80-98%, more preferred more than 85% of the total amount of methotrexate has been released after 3 hours.

20. The pharmaceutical composition according to any of the preceding claims, wherein 80-100%, more preferred 85-99%, preferably 90-98%, more preferred 93-97.5% of the total amount of methotrexate has been released after 4 hours.

21. The pharmaceutical composition according to any of claims 17-20, comprising an amount of methotrexate selected among at least 10, 12.5, 15, 20, 25 and 30 mg.

22. The pharmaceutical composition according to any of the preceding claims, wherein at least 80% of the total amount of methotrexate has been released within 4 hours, preferably 3 hours, of administration.

23. The pharmaceutical composition according to any of the preceding claims, wherein said at least one pellet providing immediate release of methotrexate, allows release of at least 80% of the active ingredient of said pellet in in 500 ml 0.1 N HCl, measured in a USP Dissolution Apparatus 2, Paddle, (37° C.±0.5° C.), within 5 minutes, 10 minutes, 15 minutes, 20 minutes, 25 minutes, 30 minutes, 35 minutes, 40 minutes, 45 minutes, 50 minutes, 55 minutes, or within 60 minutes.

24. The pharmaceutical composition according to any of the preceding claims, wherein said at least one pellet providing delayed release and/or a predetermined lag time prior to release of methotrexate, allows release of at least 80% of the active ingredient of said pellet in in 500 ml 0.1 N HCl, measured in an USP Dissolution Apparatus 2, Paddle, (37° C.±0.5° C.), within 5 minutes, 10 minutes, 15 minutes, 20 minutes, 25 minutes, 30 minutes, 35 minutes, 40 minutes, 45 minutes, 50 minutes, 55 minutes, 60 minutes, 65 minutes, 70 minutes, 75 minutes, 80 minutes, 85 minutes, 90 minutes, 95 minutes, 100 minutes, 105 minutes, 110 minutes, 115 minutes, 120 minutes, 125 minutes, 130 minutes, 135 minutes, 140 minutes, 145 minutes, 150 minutes, 155 minutes, 160 minutes, 165 minutes, 170 minutes, 175 minutes, 180 minutes, 185 minutes, 190 minutes, 195 minutes, 200 minutes, 205 minutes, 210 minutes, 215 minutes, 220 minutes, 225 minutes, 230 minutes, 235 minutes or within 240 minutes.

25. The pharmaceutical composition according to any of the preceding claims, wherein said at least one pellet providing delayed release and/or a predetermined lag time prior to release of methotrexate, provides release of at least 80% of the active ingredient of said pellet in in 500 ml phosphate buffer pH 6.8, measured in an USP Dissolution Apparatus 2, Paddle, (37° C.±0.5° C.), within 5 minutes, 10 minutes, 15 minutes, 20 minutes, 25 minutes, 30 minutes, 35 minutes, 40 minutes, 45 minutes, 50 minutes, 55 minutes, 60 minutes, 65 minutes, 70 minutes, 75 minutes, 80 minutes, 85 minutes, 90 minutes, 95 minutes, 100 minutes, 105 minutes, 110 minutes, 115 minutes, 120 minutes, 125 minutes, 130 minutes, 135 minutes, 140 minutes, 145 minutes, 150 minutes, 155 minutes, 160 minutes, 165 minutes, 170 minutes, 175 minutes, 180 minutes, 185 minutes, 190 minutes, 195 minutes, 200 minutes, 205 minutes, 210 minutes, 215 minutes, 220 minutes, 225 minutes, 230 minutes, 235 minutes or within 240 minutes.

26. The pharmaceutical composition according to any of the preceding claims, wherein said at least one pellet providing delayed release and/or a predetermined lag time prior to release of methotrexate, provides release of at least 80% of the active ingredient in 0.9% saline, measured in an USP Dissolution Apparatus 2, Paddle, (37′C ±0.5° C.), within 5 minutes, 10 minutes, 15 minutes, 20 minutes, 25 minutes, 30 minutes, 35 minutes, 40 minutes, 45 minutes, 50 minutes, 55 minutes, 60 minutes, 65 minutes, 70 minutes, 75 minutes, 80 minutes, 85 minutes, 90 minutes, 95 minutes, 100 minutes, 105 minutes, 110 minutes, 115 minutes, 120 minutes, 125 minutes, 130 minutes, 135 minutes, 140 minutes, 145 minutes, 150 minutes, 155 minutes, 160 minutes, 165 minutes, 170 minutes, 175 minutes, 180 minutes, 185 minutes, 190 minutes, 195 minutes, 200 minutes, 205 minutes, 210 minutes, 215 minutes, 220 minutes, 225 minutes, 230 minutes, 235 minutes or within 240 minutes.

27. The pharmaceutical composition according to any of the preceding claims, wherein said composition allows release of at least 80% of the active ingredient in in 500 ml 0.1 N HCl, measured in an USP Dissolution Apparatus 2, Paddle, (37° C.±0.5° C.), within 5 minutes, 10 minutes, 15 minutes, 20 minutes, 25 minutes, 30 minutes, 35 minutes, 40 minutes, 45 minutes, 50 minutes, 55 minutes, 60 minutes, 65 minutes, 70 minutes, 75 minutes, 80 minutes, 85 minutes, 90 minutes, 95 minutes, 100 minutes, 105 minutes, 110 minutes, 115 minutes, 120 minutes, 125 minutes, 130 minutes, 135 minutes, 140 minutes, 145 minutes, 150 minutes, 155 minutes, 160 minutes, 165 minutes, 170 minutes, 175 minutes, 180 minutes, 185 minutes, 190 minutes, 195 minutes, 200 minutes, 205 minutes, 210 minutes, 215 minutes, 220 minutes, 225 minutes, 230 minutes, 235 minutes or within 240 minutes.

28. The pharmaceutical composition according to any of the preceding claims, wherein said composition allows release of at least 80% of the active ingredient in 500 ml phosphate buffer pH 6.8, measured in an USP Dissolution Apparatus 2, Paddle, (37° C.±0.5° C.), within 5 minutes, 10 minutes, 15 minutes, 20 minutes, 25 minutes, 30 minutes, 35 minutes, 40 minutes, 45 minutes, 50 minutes, 55 minutes, 60 minutes, 65 minutes, 70 minutes, 75 minutes, 80 minutes, 85 minutes, 90 minutes, 95 minutes, 100 minutes, 105 minutes, 110 minutes, 115 minutes, 120 minutes, 125 minutes, 130 minutes, 135 minutes, 140 minutes, 145 minutes, 150 minutes, 155 minutes, 160 minutes, 165 minutes, 170 minutes, 175 minutes, 180 minutes, 185 minutes, 190 minutes, 195 minutes, 200 minutes, 205 minutes, 210 minutes, 215 minutes, 220 minutes, 225 minutes, 230 minutes, 235 minutes or within 240 minutes.

29. The pharmaceutical composition according to any of the preceding claims, wherein said composition allows release of at least 80% of the active ingredient in 0.9% saline, measured in an USP Dissolution Apparatus 2, Paddle, (37° C.±0.5° C.), within 5 minutes, 10 minutes, 15 minutes, 20 minutes, 25 minutes, 30 minutes, 35 minutes, 40 minutes, 45 minutes, 50 minutes, 55 minutes, 60 minutes, 65 minutes, 70 minutes, 75 minutes, 80 minutes, 85 minutes, 90 minutes, 95 minutes, 100 minutes, 105 minutes, 110 minutes, 115 minutes, 120 minutes, 125 minutes, 130 minutes, 135 minutes, 140 minutes, 145 minutes, 150 minutes, 155 minutes, 160 minutes, 165 minutes, 170 minutes, 175 minutes, 180 minutes, 185 minutes, 190 minutes, 195 minutes, 200 minutes, 205 minutes, 210 minutes, 215 minutes, 220 minutes, 225 minutes, 230 minutes, 235 minutes or within 240 minutes.

30. The pharmaceutical composition according to any of the preceding claims, wherein at least one of the pellets comprises at least one excipient and/or coating controlling the release of methotrexate.

31. The pharmaceutical composition according to any of the preceding claims, wherein at least one of the pellets comprises a coating controlling the release of methotrexate, wherein said coating comprises at least two excipients: a. A first coating excipient; and b. A second coating excipient, wherein said second coating excipient preferably has higher solubility than said first coating excipient; preferably said solubility is measured in an aqueous solvent, such as selected among water, 0.1 N HCl, phosphate buffer pH 6.8, and 0.9% saline.

32. The pharmaceutical composition according to claim 30 or 31, wherein said first coating excipient is selected among ethyl cellulose, shellac, cellulose acetate, Eudragit RL (acrylic polymer), Eudragit RS, Eudragit NE (acrylcopolymer), Kollicoat SR 30 D (poly vinyl acetate), and a mixture of any of these.

33. The pharmaceutical composition according to any of claims 30-32, wherein said second coating excipient is selected among hypromellose, methylcellulose, Polyethylene glycol (6000), Eudragit L, hypromellose acetate succinate, polyvinyl alcohol, and a mixture of any of these.

34. The pharmaceutical composition according to any of the claims 30-33, wherein said first coating excipient comprises ethyl cellulose and/or said second coating excipient comprises hypromellose.

35. The pharmaceutical composition according to any of the preceding claims, wherein said coating comprises at least 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4.5%, 4%, 3.5%, 3%, 2.9%, 2.8%, 2.7%, 2.6%, 2.5%, 2.4%, 2.3%, 2.2%, 2.1%, 2%, 1.9%, 1.8%, 1.7%, 1.6%, 1.5%, 1.4%, 1.3%, 1.2%, 1.1%, 1%, 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2% or at least 0.1% w/w of said first coating excipient and/or said second coating excipient.

36. The pharmaceutical composition according to any of the preceding claims, wherein said coating comprises more than 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4.5%, 4%, 3.5%, 3%, 2.9%, 2.8%, 2.7%, 2.6%, 2.5%, 2.4%, 2.3%, 2.2%, 2.1%, 2%, 1.9%, 1.8%, 1.7%, 1.6%, 1.5%, 1.4%, 1.3%, 1.2%, 1.1%, 1%, 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2% or at least 0.1% w/w of said first coating excipient and/or said second coating excipient.

37. The pharmaceutical composition according to any of the preceding claims, wherein said first plurality of pellets comprises an amount selected among 2-20, 4-15, 6-10, and about 8% w/w of said first coating excipient and/or said second coating excipient.

38. The pharmaceutical composition according to any of the preceding claims, wherein said second plurality of pellets comprises an amount selected among 0.1-15, 0.25-10, 0.5-5, 1-4, 1.5-3, and about 2% w/w of said first coating excipient and/or said second coating excipient.

39. The pharmaceutical composition according to any of the preceding claims, wherein said third plurality of pellets comprises about an amount selected among 0.1-15, 0.25-10, 0.5-5, 1-4, 1.5-3, and about 1.8% w/w of said first coating excipient and/or said second coating excipient.

40. The pharmaceutical composition according to any of the preceding claims, wherein at least one of the pellets comprises a core, such as a tablet, wherein said core comprises: i. methotrexate or a pharmaceutically acceptable salt thereof; ii. at least one binder and/or filler; iii. at least one disintegrant and/or dissolution excipient; and iv. preferably at least one lubricant glidant.

41. The pharmaceutical composition according to claim 40, wherein said at least one binder and/or filler is selected among the group consisting of saccharides and their derivatives, such as disaccharides (sucrose, lactose); polysaccharides and their derivatives, such as starches, cellulose or modified cellulose, such as microcrystalline cellulose, and cellulose ethers, such as hydroxypropyl cellulose (HPC); sugar alcohols such as xylitol, sorbitol or mannitol; protein such as gelatin; synthetic polymers, such as polyvinylpyrrolidone (PVP) and polyethylene glycol (PEG); and a mixture of any of these.

42. The pharmaceutical composition according to claim 40 or 41, wherein said at least one binder and/or filler is selected among the group consisting of microcrystalline cellulose, lactose monohydrate, and a mixture of these.

43. The pharmaceutical composition according to any of the claims 40-42, wherein said at least one disintegrant and/or dissolution excipient is selected among the group consisting of sodium starch glycolate, crosslinked polymers, such as crosslinked polyvinylpyrrolidone (crospovidone) or crosslinked sodium carboxymethyl cellulose (croscarmellose sodium), and a mixture of any of these.

44. The pharmaceutical composition according to any of the claims 40-43, wherein said at least one disintegrant and/or dissolution excipient is sodium starch glycolate.

45. The pharmaceutical composition according to any of the claims 40-44, wherein said at least one lubricant is selected among the group consisting of talc, silica, and fats, such as vegetable stearin, magnesium stearate or stearic acid, and a mixture of any of these.

46. The pharmaceutical composition according to any of the claims 40-45, wherein said at least one lubricant is magnesium stearate.

47. The pharmaceutical composition according to any of the claims 40-46, wherein the total amount of binder and filler is selected among 10-90, 20-80, 30-70, 40-60, 50-55, and about 52% w/w.

48. The pharmaceutical composition according to any of the claims 40-47, wherein the total amount of disintegrant and dissolution excipient is selected among 5-95, 10-90, 15-80, 20-70, 25-60, 30-50, 35-45 and about 40% w/w.

49. The pharmaceutical composition according to any of the claims 40-48, wherein the total amount of lubricant is selected among 0.1- 5, 0.2-3, 0.3-2, 0.5-1.5 and about 1% w/w.

50. The pharmaceutical composition according to any of the preceding claims, wherein said pharmaceutical composition is for oral administration.

51. The pharmaceutical composition according to any of the preceding claims, wherein at least 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or at least 100% of the total methotrexate have been released within 4 hours.

52. The pharmaceutical composition according to any of the preceding claims, wherein said pellet comprises 0.1 mg-5 mg methotrexate, 0.15 mg-2 mg, 0.2 mg-1.5 mg, 0.25 mg-1 mg, 0.3 mg-0.8 mg, 0.35 mg-0.6 mg, 0.4 mg-0.5 mg, 0.45 mg-0.5 mg or about 0.45 mg methotrexate.

53. The pharmaceutical composition according to any of the preceding claims, wherein said composition comprises at least 2.5 mg, 5 mg, 7.5 mg, 10 mg, 12.5 mg, 15 mg, 17.5 mg, 20 mg, 22.5 mg, 25 mg, 27.5 mg or at least 30 mg methotrexate.

54. The pharmaceutical composition according to any of the preceding claims, wherein said composition comprises between 1 mg-50 mg methotrexate, between 2 mg-49 mg, 3 mg-48 mg, 4 mg-47 mg, 5 mg-46 mg, 6 mg-45 mg, 7 mg-44 mg, 8 mg—43 mg, 9 mg-42 mg, 10 mg-41 mg, 11 mg-40 mg, 12 mg-39 mg, 13 mg-38 mg, 14 mg-37 mg, 15 mg-36 mg, 16 mg-35 mg, 17 mg-34 mg, 18 mg-33 mg, 19 mg-32 mg, 20 mg-31 mg, 21 mg-30 mg, 22 mg-29 mg, 23 mg-28 mg, 24-27 mg, 25-26 mg or about 25 mg methotrexate.

55. The pharmaceutical composition according to any of the preceding claims, wherein the plurality of pellets providing immediate release comprises a total of no more than 2.5 mg, 5 mg, 7.5 mg, 10 mg, 12.5 mg, 15 mg methotrexate.

56. The pharmaceutical composition according to any of the preceding claims, wherein said composition is for use in a method of treatment of a disease and/or for use in a prophylaxis of a disease and/or for alleviating the symptoms of a disease.

57. The pharmaceutical composition according to any of the preceding claims, wherein said disease is an arthritis.

58. The pharmaceutical composition according to any of the preceding claims, wherein said arthritis is selected among Rheumatoid arthritis, polyarticular juvenile idiopathic arthritis and or psoriasis arthritis.

59. The pharmaceutical composition according to any of the preceding claims, wherein said disease is selected among psoriasis, Crohn's disease and or a cancer.

60. The pharmaceutical composition according to any of the preceding claims, wherein said cancer is selected among a breast cancer, a cancer vesicae urinariae, choriocarcinoma, a head and neck cancer, a lymphoma and a leukemia.

61. The pharmaceutical composition according to any of the preceding claims, for use in a treatment, wherein the subject is a child or less than 18 years old.

62. The pharmaceutical composition according to any of the preceding claims, wherein the pellets have colours depending on their release characteristics.

63. The pharmaceutical composition according to any of the preceding claims, wherein each of said pellets is a tablet.

64. The pharmaceutical composition according to any of the preceding claims, wherein a plurality of said pellets are compressed to form a tablet.

65. The pharmaceutical composition according to claim 63 or 64, wherein said tablet is adapted to disintegrate in the stomach of a subject.

66. The pharmaceutical composition according to any of the preceding claims, wherein said pellets are in a capsule or a sachet.

67. The pharmaceutical composition according to any of the preceding claims, wherein said composition comprises or is obtainable by combining a number of pellets selected among 1-200, 1-150, 1-120, 1-100, 1-90, 1-80, 1-70, 1-66, 1-60, 2-50, 3-40, 4-30, 5-25, 6-20, 7-18, 8-16, 9-14, 10-12, and 11 pellets.

68. The pharmaceutical composition according to any of the preceding claims, for use in a treatment wherein said composition is administered once a week or twice within 12, preferably 8 hours once a week.

69. A method for the manufacture of a pharmaceutical composition according to any of the preceding claims.

70. A method for the manufacture of a pharmaceutical composition comprising more than 10 mg methotrexate according to any of the preceding claims comprising: i. Manufacturing at least two different types of pellets, wherein each type of pellet has specific release characteristics, and ii. Mixing the pellets according to the desired final release characteristics and total amount of methotrexate.

71. The method or pharmaceutical formulation according to any of the preceding claims, wherein methotrexate is replaced or accompanied with one or more active ingredients, preferably wherein at least one active ingredient is a chemotherapeutic agent.

72. The method or pharmaceutical formulation according to any of the preceding claims, wherein the composition further comprising one or more active ingredients in addition to methotrexate of a pharmaceutical acceptable salt thereof, preferably selected among chemotherapeutic agents.

73. The method or pharmaceutical formulation according to any of the preceding claims, wherein the composition comprises 1-15 mg methotrexate or a pharmaceutically acceptable salt thereof and wherein the composition only comprises pellets providing immediate release of methotrexate.

74. The method or pharmaceutical formulation according to any of the preceding claims, wherein the composition comprises 10-30 mg methotrexate or a pharmaceutically acceptable salt thereof and wherein the composition comprises pellets providing immediate release of methotrexate and pellets providing delayed release or a predetermined lag time before release of methotrexate.

75. The method or pharmaceutical formulation according to any of the preceding claims, wherein the composition comprises 15-50 mg methotrexate or a pharmaceutically acceptable salt thereof, and wherein the composition comprises first pellets providing immediate release of methotrexate, second and one or more further pellets providing delayed release or a predetermined lag time before release of methotrexate and wherein the release of the one or more further pellets are slower than the release of methotrexate of the second pellets.

76. Use of the pharmaceutical composition according to any of the preceding claims in the manufacturing of a medicament for the treatment of a disease, wherein said disease is a disease according to any of the preceding claims.

77. A method of treating the disease according to any of the preceding claims, comprising administering a therapeutically effective amount of the composition of any of the preceding claims.

78. Method of oral administration of a dosage form comprising a total amount of methotrexate, or a pharmaceutically acceptable salt thereof, of 15-50, preferably 20-30 mg, wherein said dosage form comprises i) at least one immediate release pharmaceutical composition comprising 10-15 mg methotrexate and providing release of at least 8-10 mg of methotrexate within 1 hour; and ii) at least one delayed release pharmaceutical composition comprising a content of methotrexate of at least 2.5 mg, more preferred at least 5 mg methotrexate, wherein said delayed release pharmaceutical composition releases less than 50% of said content of methotrexate within 1 hour; subject to the proviso that said dosage form releases at least 80% of the total amount of methotrexate within 4 hours; preferably each composition comprises one or more pellets, such as one or more tablets.

79. A pharmaceutical composition comprising a plurality of pellets, wherein each pellet comprises methotrexate or a pharmaceutically acceptable salt thereof, and wherein at least one of the pellets provides immediate release of said methotrexate; and preferably wherein at least one of the pellets provides delayed release and/or a predetermined lag time prior to release of methotrexate; and wherein at least 80% of the total amount of methotrexate of said pharmaceutical composition have been released within 4 hours of administration and/or as measured in an USP Dissolution Apparatus 2 in 500 ml 0.1 N HCl at 37° C.±0.5° C.

80. The pharmaceutical composition according to any of the preceding claims, wherein at least 50% of the total amount of methotrexate has been released after 1 hour.

81. The pharmaceutical composition according to any of the preceding claims, wherein 60-100% of the total amount of methotrexate has been released after 2 hours.

82. The pharmaceutical composition according to any of the preceding claims, wherein 80-100% of the total amount of methotrexate has been released after 3 hours.

83. The pharmaceutical composition according to any of the preceding claims, wherein 80-100% of the total amount of methotrexate has been released after 4 hours.

84. The pharmaceutical composition according to any of the preceding claims, comprising an amount of methotrexate selected among at least 10, 12.5, 15, 20, 25 and 30 mg.

85. The pharmaceutical composition according to any of the preceding claims, wherein said disease is an inflammatory disease or a cancer.

86. The pharmaceutical composition according to any of the preceding claims, wherein said inflammatory disease is selected among Rheumatoid arthritis, juvenile idiopathic arthritis, psoriasis and or psoriasis arthritis and said cancer is selected among Acute Lymphocytic Leukemia or Chronic Lymphocytic Leukemia.

87. The pharmaceutical composition according to any of the preceding claims, wherein said pellets are in a capsule or a sachet.

88. The pharmaceutical composition according to any of the preceding claims, for use in a treatment wherein said composition is administered once a week or twice within 12, preferably 8 hours once a week.

89. The pharmaceutical composition according to any of the preceding claims, comprising methotrexate, or a pharmaceutically acceptable salt thereof, as the sole active ingredient.

90. The pharmaceutical composition according to any of the preceding claims for oral administration.

91. The pharmaceutical composition according to any of the preceding claims, wherein said pharmaceutical composition is or comprises a solid dosage form.

92. The pharmaceutical composition according to any of the preceding claims, wherein the composition is formulated as a single dose formulation, such as a tablet, capsule or sachet.

93. The pharmaceutical composition according to any of the preceding claims, wherein at least 80% of the total amount of methotrexate have been released within 4 hours of administration and/or as measured in an USP dissolution apparatus 2 in 500 mL 0.1 N HCl at 37° C.±0.5° C. after storage of said pharmaceutical composition at room temperature for 3 months.

94. The pharmaceutical composition according to any of the preceding claims, wherein at least 85% of the total amount of methotrexate have been released within 4 hours of administration and/or as measured in an USP dissolution apparatus 2 in 500 mL 0.1 N HCl at 37° C.±0.5° C. after storage of said pharmaceutical composition at room temperature for 3 months.

95. The pharmaceutical composition according to any of the preceding claims, wherein at least 90% of the total amount of methotrexate have been released within 4 hours of administration and/or as measured in an USP dissolution apparatus 2 in 500 mL 0.1 N HCl at 37° C.±0.5° C. after storage of said pharmaceutical composition at room temperature for 3 months.

96. The pharmaceutical composition according to any of the preceding claims, wherein at least 80% of the total amount of methotrexate have been released within 4 hours of administration and/or as measured in an USP dissolution apparatus 2 in 500 mL 0.1 N HCl at 37° C.±0.5° C. after storage of said pharmaceutical composition at room temperature for 6 months.

97. The pharmaceutical composition according to any of the preceding claims, wherein at least 85% of the total amount of methotrexate have been released within 4 hours of administration and/or as measured in an USP dissolution apparatus 2 in 500 mL 0.1 N HCl at 37° C.±0.5° C. after storage of said pharmaceutical composition at room temperature for 6 months.

98. The pharmaceutical composition according to any of the preceding claims, wherein at least 90% of the total amount of methotrexate have been released within 4 hours of administration and/or as measured in an USP dissolution apparatus 2 in 500 mL 0.1 N HCl at 37° C.±0.5° C. after storage of said pharmaceutical composition at room temperature for 6 months.

Description

FIGURES

[0250] FIG. 1 shows concentration-time profiles of MTX following PO (Peroral) administration of 15 mg MTX and concentration-time profiles of MTX following SC (subcutaneous) administration of 15 mg MTX.

[0251] FIG. 2 shows release profiles from IR (immediate release) mini-tablets in 0.1 N HCL.

[0252] FIG. 3 shows release profiles from IR (immediate release) mini-tablets in phosphate buffer pH 6.8.

[0253] FIG. 4 shows release from minitablets coated with 25% HPMC film.

[0254] FIG. 5 shows release from minitablets coated with 22.5% HPMC film.

[0255] FIG. 6 shows simulation of pharmacokinetic profiles of oral immediate release dosing 5-25 mg (ng/ml*min).

[0256] FIG. 7 shows the pharmacokinetic profile of calculated result of two doses of MTX given two hours apart. 10 mg fast release and 5 mg slow release: Ka for first dose is 1.48 (immediate release) and Ka for the second dose is 0.7. AUC (0-24h)=1711 ng/mL*hr.

[0257] FIG. 8 shows the pharmacokinetic profile of calculated result of two doses given two hours apart: 10 mg fast release and 10 mg slow release: Ka for first dose is 1.48 (immediate release) and Ka for the second dose is 0.22. F=80% for the second dose. AUC(0-24h)=2000 ng/mL*hr.

[0258] FIG. 9 shows the pharmacokinetic profile of calculated result of two doses given two hours apart: 12.5 mg fast release and 12.5 mg slow release: Ka for first dose is 1.48 (immediate release) and Ka for the second dose is 0.22. AUC(0-24h)=2657 ng/mL*hr. Cmax is at the point of “saturation level”.

[0259] FIG. 10 shows dissolution profile of delayed release minitablets (80% released within 120 minutes).

[0260] FIG. 11 shows dissolution profiles of delayed release minitablets (80% released within 180 minutes).

[0261] FIG. 12 shows dissolution profiles of delayed release minitablets (80% released within 240 minutes).

[0262] FIG. 13 shows simulations of dissolution profiles of preferred embodiments of the invention.

[0263] The straight line shows what the profile would look like if the release was linear.

[0264] All cited references are incorporated by reference.

[0265] The accompanying Figures and Examples are provided to explain rather than limit the present invention. It will be clear to the person skilled in the art that aspects, embodiments, claims and any items of the present invention may be combined.

[0266] Unless otherwise mentioned, all percentages are in weight/weight. Unless otherwise mentioned, all measurements are conducted under standard conditions (ambient temperature and pressure). Unless otherwise mentioned, test conditions are according to European Pharmacopoeia 8.0.

EXAMPLES

Example 1

[0267] Development of Methotrexate Mini Tablets

[0268] Mini-tablet (or pellet) formulations are developed with immediate release and with lag time/burst release to deliver the dose in the intestine within maximum 4 hours from dosing. These different formulations can then be combined in a capsule and may increase bioavailability compared to conventional tablets. Different formulations may provide the desired amount of methotrexate and desired release profile(s).

[0269] Substances: Methotrexate disodium, Microcrystalline cellulose, Lactose monohydrate, Lactose Monohydrate (spraydried), Sodium starch glycolate, Magnesium stearate, Ethycellulose 7 cps, Hypromellose 3 cps, Ethanol 96%, Purified water.

[0270] Methotrexate exists as either the acid (molecular weight: 454.4) or the di-sodium salt (molecular weight: 498.40). In pharmaceutical products, Methotrexate is declared as the acid, but often added as the di-sodium salt (conversion factor 1.096), as this is freely soluble in water; the acid is practically insoluble in water.

[0271] Methotrexate di-sodium salt was sourced from Fermion, Finland.

[0272] Placebo mini-tablets for initial film coating experiments were produced in-house and were composed by Lactose monohydrate (67%), Microcrystalline cellulose (27%), Croscarmellose sodium (5%) and Magnesium stearate (1%) and compressed at a tooling similar to the size used for the Methotrexate mini-tablets.

[0273] Major Equipment Used is Listed in Table 1

TABLE-US-00001 TABLE 1 equipment Process Equipment Type and size Mixing Blender Turbula blender Compression Tablet press Diaf TM20 single punch tablet press with 2.0 mm round tooling Film coating Fliud-bed with wurster Aeromatic-Fielder STREA-1

[0274] Methods

[0275] The aim is a dose of 15 mg Methotrexate given with two or three release profiles, the first profile being immediate release (IR). Later profiles must deliver the dose within three-four hours post dosing.

[0276] With up to three release profiles, each profile can hold 5 mg dose. This was formulated in 11 mini-tablets each with tablet weight of 7.0 mg to be contained in a small capsule size (3*11 mini-tablets).

[0277] Excipients were chosen from those used in marketed products (e.g. Emthexate (TEVA) containing Microcrystalline cellulose, starch, magnesium stearate, silicon dioxide and lactose monohydrate).

[0278] Methotrexate Dissolution

[0279] Methotrexate dissolution was tested using the following parameters:

[0280] USP dissolution <711>, apparatus 2

[0281] Dissolution medium: 0.1 N HCl

[0282] 500 mL dissolution medium, 75 RPM

[0283] Sample times: every half hour up to 6 hours.

[0284] Samples were quantified using HPLC or UV absorption at 303 nm.

[0285] Results and Discussion

[0286] Laboratory Experiments

[0287] First mixing experiments were a test of whether direct compression was possible or a granulation had to be introduced. Formulations were based on earlier experience with similar formulation principle (Table 2). In the second formulation Microcrystalline cellulose had been exchanged with Lactose monohydrate, otherwise formulations were identical.

[0288] The ingredients except magnesium stearate were mixed in the Turbula mixer at 22 rpm for 5 minutes in a 350 mL container. Magnesium stearate was added and mixed in for 1 minute.

TABLE-US-00002 TABLE 2 Composition of core tablets Batch no RD1907-1-T1 RD1907-2-T1 Methotrexate 2.847 g  7.117% 1.423 g  7.117% disodium Microcrystalline 8.000 g 20.0%  — — cellulose Lactose 12.753 g 31.833% — — monohydrate Lactose — — 10.377 g 51.883% Monohydrate spray dried Sodium starch 16.000 g 40.0%  8.000 g 40.000% glycolate Type A Magnesium stearate 0.400 g 1.00% 0.200 g  1.000% Total 40.0 g — 20.0 g —

[0289] Mini-tablets were compressed on the Diaf single punch tablet press using 2 mm tooling. In-process control was tablet weight (40 mini-tablets) and tablet thickness and friability (1 g product tested for 5 minutes at 45 rpm in Turbula mixer). The mix's compressed well; data are presented in Table 3.

[0290] A third batch, RD1907-3-T1, was compressed with same composition as RD1907-1-T1 to have enough mini-tablets for coating experiments.

TABLE-US-00003 TABLE 3 In-process data from compression Batch no RD1907-1-T1 RD1907-2-T1 RD1907-3-T1 Strength 5 mg/11 mini-tablets Compression 3⅙ setting Compression Approx. 65 stroke/min 55 stroke/min speed Tablet 7.011 mg/1.95% 7.537 mg/0.70% 6.971 mg/0.96% weight/RSD Tablet 1.84 mm 1.87 mm 1.81 mm thickness Friability 0.46% 1.00% 0.77%

[0291] Active mini-tablets were mixed with placebo mini-tablets to allow film coating in the STREA fluid-bed. As the active tablets were yellow from the API, mini-tablets could easily be sorted after coating. Typically, 10 g active mini-tablets were used; coating batch size was 300 g.

[0292] To achieve an IR formulation, mini-tablets were coated with a HPMC film (Table 4). Different barrier films based on ethylcellulose added hypromellose to form pores in the film, were produced and coated onto mini-tablets to achieve delayed burst release. By decreasing the content of hypromellose in the film, the film improved in delaying release.

TABLE-US-00004 TABLE 4 Composition of film coating Film HPMC film 20% HPMC 22.5% HPMC 25% HPMC Ethocel 7 cps — — 44.8 g 6.4% 55.8 g 6.2% 42.0 g 6.0% Ethanol 96% 448.5 g 69.0% 483.0 g 69.0% 621.0 g 69.0% 483.0 g 69.0% Hypromellose 3 52.0 g  8.0% 11.2 g 1.6% 16.2 g 1.8% 14.0 g 2.0% Purified water 149.5 g 23.0% 161.0 g 23.0% 207.0 g 23.0% 161.0 g 23.0% Total 650 g — 700 g — 900 g — 700 g —

[0293] Table 5 gives standard process parameters for film coating in STREA fluid-bed. At specified weight gains, the fluid-bed was stopped and samples drawn to be tested for dissolution.

TABLE-US-00005 TABLE 5 Process parameters for film coating Batch size (tablets) 300 g Atomizer air (bar) 0.75-1.0  Inlet air temperature (° C.) Approx. 32 Outlet air temperature (° C.) 26-28 PV flow rate (g/min) Approx. 4.0

[0294] IR Product

[0295] Batch RD1907-1-T1 was coated with the HPMC film as batch RD1907-1-T1-C1. The coating process was stopped at 15% weight gain, and the mini-tablets were tested in dissolution in three media: 0.1 N HCl, phosphate buffer pH 6.8 and 0.9% saline. 11 mini-tablets corresponding to 5 mg methotrexate were tested in 500 mL media at 75 rpm. Results are presented in FIG. 2 and FIG. 3, which demonstrate that Methotrexate were release within 15 minutes independent on media used.

[0296] Delayed Release Products

[0297] Batch RD1907-1-T1 and RD1907-2-T1 were coated with the 20% HPMC film as batch RD1907-1-T1-C2 and RD1907-2-T1-C1 respectively, with sampling after 15%, 17.5% and 20% weight gain (FIG. 5). The release rate was found to be too slow when release was achieved without achieving a delay before release was started, and none of the batches released fully (>80%) within 4 hours. Further the batch RD1907-2-T1-C1 released slower and more incomplete compared to batch RD1907-1-T1-C2 which must be caused by the core tablet holding different filler. This core composition may not be optimal for this formulation.

[0298] To achieve steeper release and a lag time, Batch RD1907-1-T1 and RD1907-3-T1 were coated with first 25% HPMC film (FIG. 4) and next 22.5% HPMC film (FIG. 5).

[0299] With the 25% HPMC film, a lag time with no release was achieved with 15% weight gain or more. The release when first started was faster than for the 20% HPMC film but decreased with thickness of the film/weight gain.

[0300] With 20% weight gain, a lag time of 1-1½ hour was achieved and 80% of the dose was released after 3 hours. However, release rate from 2 hours onwards was low (10% every 30 min).

[0301] Very similar results were achieved with the 22.5% HPMC film but with lower weight gain. 15% weight gain with this film gave same result as 20% weight gain with the 25% HPMC film. With the 22.5% HPMC film it was possible to achieve longer lag-time and still have a acceptable release rate.

CONCLUSION

[0302] Mini-tablets with different release profiles all releasing the Methotrexate between 15 minutes and 4 hours have been developed. From these formulations, two or three release profiles can be selected to deliver the dose at intervals over the stomach and intestine.

[0303] A combination of two equal doses of immediate release MTX (ka=1,48) and slow release MTX (simulated to be released (ka=0.22) at two hours after first dose) seems to give high exposure of MTX. The second dose is expected to have a lower bioavailability of 80% in comparison to the first dose, due to less effective absorption from the lower part of the small intestine. A release that gives rise to a plasma concentration lower than approximately 200 ng/ml is believed to be in the linear range of absorption from the gut of MTX. A combination of mini-tablets with different in-vitro release profiles may result in better bioavailability mimicking the pharmacokinetic profiles of subcutaneous dosing of MTX.

[0304] The experiments and calculations indicate an immediate release profile in combination with RD1907-3-T1-C1 20% as well as RD1907-3-T1-C2 17.5% WG is believed to offer the best combination of mini-tablets.

TABLE-US-00006 TABLE 6 Release data Time (min)/% released 0 15 30 45 60 90 120 RD1907-1-T1-C1 0.00 103.5 103.9 103.7 103.8 104.0 103.9 in 0.1N HCL RD1907-1-T1-C1 0.00 106.3 106.4 106.2 106.5 106.9 106.9 in ph. 6.8 RD1907-1-T1-C1 0.00 105.2 105.7 105.7 105.7 105.8 106.1 in 0.9% saline

TABLE-US-00007 TABLE 7a Release data Time (min)/% released 0 30 60 90 120 150 180 RD1907-1-T1-C2 17.5% wg 0.0 0.4 8.3 24.2 30.7 45.8 60.5 RD1907-1-T1-C2 20% wg 0.0 0.4 0.4 10.3 17.8 29.3 44.0 RD1907-2-T1-C1 15% wg 0.0 0.6 0.6 1.4 3.0 9.0 19.3 RD1907-2-T1-C1 17.5% wg 0.0 3.7 4.9 4.0 1.8 3.6 7.7 RD1907-2-T1-C1 20% wg 0.0 0.5 0.1 0.2 2.3 2.1 10.1 RD1907-3-T1-C2 20% wg 0.0 0.0 0.3 0.1 9.4 39.8 57.5 Immediate release 0.0 100 100 100 100 100 100 RD1907-1-T1-C3 10% wg 0.0 70.4 82.2 84.6 90.2 92.6 94.4 RD1907-1-T1-C3 12.5% wg 0.0 23.4 71.7 79.3 84.1 87.7 90.6 RD1907-3-T1-C1 15% wg 0.0 0.0 43.8 73.8 82.6 88.3 92.8 RD1907-3-T1-C2 12.5% wg 0.0 0.0 20.1 68.1 79.0 85.3 89.6 RD1907-3-T1-C1 20% wg 0.0 0.0 1.3 22.6 65.6 74.9 81.8 RD1907-1-T1-C3 15% wg 0.0 0.1 59.3 72.3 79.6 85.0 89.1 RD1907-3-T1-C2 15% wg 0.0 0.0 6.2 25.6 59.4 72.2 79.5 RD1907-3-T1-C1 25% wg 0.0 1.0 3.3 11.1 30.2 56.1 67.5 RD1907-1-T1-C2 15% wg 0.0 12.4 29.9 46.2 63.0 69.7 74.0 RD1907-3-T1-C2 17.5% wg 0.0 0.0 0.0 4.4 37.0 62.1 71.4

TABLE-US-00008 TABLE 7b Release data Time (min)/% released 210 240 270 300 330 360 number RD1907-1-T1-C2 17.5% wg 66.6 70.9 74.6 78.1 — — RD1907-1-T1-C2 20% wg 53.8 61.2 66.4 70.7 — — RD1907-2-T1-C1 15% wg 33.7 44.1 53.0 63.5 — — RD1907-2-T1-C1 17.5% wg 19.0 31.4 43.2 51.4 — — RD1907-2-T1-C1 20% wg 13.3 23.1 36.5 46.7 — — RD1907-3-T1-C2 20% wg 67.0 74.2 80.3 85.1 89.7 92.3 Immediate release 100 100 100 100 1 RD1907-1-T1-C3 10% wg 95.0 95.0 96.8 97.4 — — 2 RD1907-1-T1-C3 12.5% wg 92.1 92.9 95.3 96.4 — — 3 RD1907-3-T1-C1 15% wg 95.9 98.4 100.4 102.0 103.2 104.0 4 RD1907-3-T1-C2 12.5% wg 93.5 96.1 98.1 99.9 101.7 102.8 5 RD1907-3-T1-C1 20% wg 87.2 91.5 94.8 97.5 100.1 101.6 6 RD1907-1-T1-C3 15% wg 91.2 92.6 95.4 96.7 — —  .sup. 6B RD1907-3-T1-C2 15% wg 84.7 89.3 92.7 95.6 98.2 100.0 7 RD1907-3-T1-C1 25% wg 75.7 81.9 86.4 90.2 93.8 96.0 8 RD1907-1-T1-C2 15% wg 77.5 80.1 82.2 84.9 — — 9 RD1907-3-T1-C2 17.5% wg 78.0 83.2 87.5 90.8 94.2 96.3 10 

TABLE-US-00009 TABLE 8a In-vitro dissolution mini-tablet profile number 2 3 4 5 1 RD1907- RD1907- RD1907- RD1907- IR 1-T1-C3 1-T1-C3 3-T1-C1 3-T1-C2 product 10% wg 12.5% wg 15% wg 12.5% wg 0 0 0 0 0 0 30 100 70.4 23.4 0 0 60 100 82.2 71.7 43.8 20.1 90 100 84.6 79.3 73.8 68.1 120 100 90.2 84.1 82.6 79 150 100 92.6 87.7 88.3 85.3 180 100 94.4 90.6 92.8 89.6 210 100 95 92.1 95.9 93.5 240 100 95 92.9 98.4 96.1 % At least At least At least At least At least dissolved 80% within 80% within 80% within 80% within 80% within one hour one hour two hours two hours three hours

TABLE-US-00010 TABLE 8b In-vitro dissolution mini-tablet profile number 6 6B 7 8 9 10 RD1907- RD1907- RD1907- RD1907- RD1907- RD1907- 3-T1-C1 1-T1-C3 3-T1-C2 3-T1-C1 1-T1-C2 3-T1-C2 20% wg 15% wg 15% wg 25% wg 15% wg 17.5% wg 0 0 0 0 0 0 0 30 0 0.1 0 1 12.4 0 60 1.3 59.3 6.2 3.3 29.9 0 90 22.6 72.3 25.6 11.1 46.2 4.4 120 65.6 79.6 59.4 30.2 63 37.0 150 74.9 85.0 72.2 56.1 69.7 62.1 180 81.8 89.1 79.5 67.5 74 71.4 210 87.2 91.2 84.7 75.7 77.5 78.0 240 91.5 92.6 89.3 81.9 80.1 83.2 % At least At least At least At least At least At least dissolved 80% within 80% within 80% within 80% within 80% within 80% within three hours 3 hours four hours four hours four hours four hours

TABLE-US-00011 TABLE 9 Capsules with minitablets: Example of Proposed Profile Combinations Profile 1 6 10 5 mg capsule 5 mg 7.5 mg capsule 7.5 mg 10 mg capsule 10 mg 12.5 mg capsule 12.5 mg 12.5 mg capsule 10 mg 2.5 mg 12.5 mg capsule 7.5 mg 5 mg 15 mg capsule 12.5 mg 2.5 mg 15 mg capsule 10 mg 5 mg 15 mg capsule 7.5 mg 7.5 mg 17.5 mg capsule 12.5 mg 5 mg 17.5 mg capsule 10 mg 7.5 mg 20 mg capsule 12.5 mg 7.5 mg 20 mg capsule 10 mg 10 mg 22.5 mg capsule 12.5 mg 10 mg 22.5 mg capsules 12.5 mg 5 mg 5 mg 22.5 mg capsule 10 mg 10 mg 2.5 mg 22.5 mg capsule 10 mg 7.5 mg 5 mg 22.5 mg capsule 10 mg 5 mg 7.5 mg 25 mg capsule 12.5 mg 12.5 mg 25 mg capsule 12.5 mg 7.5 mg 5 mg 25 mg capsules 12.5 mg 5 mg 7.5 mg 25 mg capsule 10 mg 10 mg 5 mg 25 mg capsule 10 mg 7.5 mg 7.5 mg 25 mg capsule 10 mg 5 mg 10 mg 27.5 mg capsule 12.5 mg 10 mg 5 mg 27.5 mg capsule 12.5 mg 7.5 mg 7.5 mg 27.5 mg capsules 12.5 mg 5 mg 10 mg 27.5 mg capsule 10 mg 10 mg 7.5 mg 27.5 mg capsule 10 mg 7.5 mg 10 mg 30 mg capsule 12.5 mg 12.5 mg 5 mg 30 mg capsule 12.5 mg 10 mg 7.5 mg 30 mg capsule 12.5 mg 7.5 mg 10 mg 30 mg capsule 10 mg 10 mg 10 mg

[0305] Profile 1 may be substituted with profile 2, profile 6 may be substituted with profile 3, 4, 5 or 6B and profile 10 may be substituted with profile 7, 8 or 9.

TABLE-US-00012 TABLE 10 Proposed combination of minitablets profiles for future manufacturing Mini-tablet profile Mini-tablet Amount (Delayed Amount n Dose profile MTX release) MTX profiles 5 mg Immediate 5 mg 1 release 7.5 mg Immediate 7.5 mg 1 release 10 mg Immediate 10 mg 1 release 12.5 mg Immediate 12.5 mg 1 release 15 mg Immediate 10 mg RD-1907-3-T1- 5 mg 2 release C1 20% WG 17.5 mg Immediate 10 mg RD-1907-3-T1- 7.5 mg 2 release C1 20% WG 20 mg Immediate 10 mg RD-1907-3-T1- 5 mg 3 release C1 20% WG RD1907-3-T1- 5 mg C2 17.5% WG 22.5 mg Immediate 12.5 mg RD-1907-3-T1- 5 mg 3 release C1 20% WG RD1907-3-T1- 5 mg C2 17.5% WG 25 mg Immediate 12.5 mg RD-1907-3-T1- 5 mg 3 release C1 20% WG RD1907-3-T1- 7.5 mg C2 17.5% WG 30 mg Immediate 15 mg RD-1907-3-T1- 7.5 mg 3 release C1 20% WG RD1907-3-T1- 7.5 mg C2 17.5% WG

[0306] The simulated and proposed combinations have been based on the following data and results:

TABLE-US-00013 3 mini-tablet dissolution profiles Time (min)/% released 0 30 60 90 120 150 180 210 240 immediate 0 100 100 100 100 100 100 100 100 release RD1907- 0 0 1.3 22.6 65.6 74.9 81.8 87.2 91.5 3-T1-C1 20% wg RD1907- 0 0 0 4.4 37 62.1 71.4 78 83.2 3-T1-C2 17.5% wg

TABLE-US-00014 TABLE 11 Combination of mini-tables: constructed dissolution profiles Combination of mini-tablets: Constructed dissolution profiles 0 30 60 90 120 150 180 210 240 15 mg composition   10 mg 0 66.7 66.7 66.7 66.7 66.7 66.7 66.7 66.7   5 mg 0 0.0 0.4 7.5 21.9 25.0 27.3 29.1 30.5 Total 0 66.7 67.1 74.2 88.5 91.6 93.9 95.7 97.2 17.5 mg composition   10 mg 0 57.1 57.1 57.1 57.1 57.1 57.1 57.1 57.1  7.5 mg 0 0.0 0.6 9.7 28.1 32.1 35.1 37.4 39.2 Total 0 57.1 57.7 66.8 85.3 89.2 92.2 94.5 96.4 20 mg composition   10 mg 0 50.0 50.0 50.0 50.0 50.0 50.0 50.0 50.0   10 mg 0 0.0 0.7 11.3 32.8 37.5 40.9 43.6 45.8 Total 0 50.0 50.7 61.3 82.8 87.5 90.9 93.6 95.8 22.5 mg composition 12.5 mg 0 55.6 55.6 55.6 55.6 55.6 55.6 55.6 55.6   5 mg 0 0.0 0.3 5.0 14.6 16.6 18.2 19.4 20.3   5 mg 0 0.0 0.0 1.0 8.2 13.8 15.9 17.3 18.5 Total 0 55.6 55.8 61.6 78.4 86.0 89.6 92.3 94.4 25 mg composition 12.5 mg 0 50.0 50.0 50.0 50.0 50.0 50.0 50.0 50.0   5 mg 0 0.0 0.3 4.5 13.1 15.0 16.4 17.4 18.3  7.5 mg 0 0.0 0.0 1.3 11.1 18.6 21.4 23.4 25.0 Total 0 50.0 50.3 55.8 74.2 83.6 87.8 90.8 93.3 30 mg composition   15 mg 0 50.0 50.0 50.0 50.0 50.0 50.0 50.0 50.0  7.5 mg 0 0.0 0.3 5.7 16.4 18.7 20.5 21.8 22.9  7.5 mg 0 0.0 0.0 1.1 9.3 15.5 17.9 19.5 20.8 Total 0 50.0 50.3 56.8 75.7 84.3 88.3 91.3 93.7

TABLE-US-00015 TABLE 12 Bioequivalence analysis of SC injection and Oral MTX BE analysis comparing Otrexup (administered intramuscular or subcutaneous) to oral methotrexate at the 4 doses tested Methotrexate Injection - SC Injection (Thigh) Oral MTX Ratio of Intra- Dose Level Geometric Geometric Geometric 90% CI for Subject PK Parameter LS Mean LS Mean LS Mean(%) Ratio (%) CV (%) Methotrexate 10 mg n 12 12 AUC.sub.(0-24) 1441.5 1223.7 117.80 (110.5, 125.6) 8.9 (ng .Math. hr/mL) AUC.sub.(0-inf) 1470.3 1246.9 117.91 (110.7, 125.6) 8.9 (ng .Math. hr/mL) C.sub.max 178.4 247.2 72.17 (62.6, 83.2) 20 (ng/mL) Methotrexate 15 mg n 12 12 AUC.sub.(0-24) 1992.7 1752.0 113.74 (106.1, 122.0) 10.0 (ng .Math. hr/mL) AUC.sub.(0-inf) 2040.6 1786.6 114.22 (106.3, 122.7) 10.2 (ng .Math. hr/mL) C.sub.max 259.9 349.4 74.38 (68.2, 81.1) 12.4 (ng/mL) Methotrexate 20 mg n 12 12 AUC.sub.(0-24) 2542.1 1927.2 131.90 (120.3, 144.6) 13.1 (ng .Math. hr/mL) AUC.sub.(0-inf) 2581.8 1949.7 132.42  120.7, 145.3) 13.2 (ng .Math. hr/mL) C.sub.max 385.7 440.4 87.57  (74.0, 103.6) 24.5 (ng/mL) Methotrexate 25 mg n 11 11 AUC.sub.(0-24) 2708.6 1987.8 136.26 (122.2, 152.0) 14.4 (ng .Math. hr/mL) AUC.sub.(0-inf) 2745.3 2012.4 136.42 (122.4, 152.0) 14.3 (ng .Math. hr/mL) C.sub.max 395.9 423.5 93.47 (79.06, 110.5) 22.3 (ng/mL)

Example 2

[0307] In this example minitablets were prepared using methods essentially as described in example 1.

[0308] A mixture of the following ingredients was prepared:

TABLE-US-00016 Microcrystalline cellulose 260 g Sodium starch glycolate 520 g Lactose 404.82 g Magnesium stearate 13 g Methotrexate 102.18 g

[0309] The mixture was obtained by mixing all ingredients except magnesium stearate for 5 minutes in a Turbala mixer for 5 minutes, whereafter magnesium stearate was added and mixing continued for another 60 s.

[0310] The mixture was compressed into minitablets using the Diaf single punch tablet press using 2 mm tooling.

[0311] The formed mini-tablets each comprised 0.417 mg methotrexate (corresponding to that 12 mini-tablets in total comprise 5 mg methotrexate). The minitablets were coated and colored according to the release profile. The following mini-tablets were prepared:

TABLE-US-00017 Immediate release red ER minitablet A Yellow ER minitablet B White.

[0312] The ER minitablets provided delayed release of methotrexate and the release of methotrexate were slower for ER minitablets B in comparison with ER minitablets A.

[0313] Subsequent pharmaceutical compositions, in form of capsules, were prepared using combinations of these mini-tablets:

TABLE-US-00018 no mini- tablet in Mini-tablet Amount each Dose profile MTX capsule Color 10 mg Immediate release 10 mg 24 Red 20 mg Immediate release 10 mg 24 Red ER minitablet A 5 mg 12 Yellow ER minitablet B 5 mg 12 White 25 mg Immediate release 12.5 mg 30 Red ER minitablet A 5 mg 12 Yellow ER minitablet B 7.5 mg 18 White

Example 3

[0314] Capsules comprising 5 mg or 10 mg metothrexate, comprising only immediate release pellets and capsules comprising 15 mg, 20 mg or 25 mg, comprising both immediate release pellets and delayed release pellets were provided as described in Example 1.

[0315] Capsules were placed in closed containers at room temperature (25° C.) and 60% relative humidity, and stored for 3 months.

[0316] The dissolution profiles were determined for the capsules in the beginning (T=0) and after 3 months storage.

[0317] Dissolution profiles at time 0:

TABLE-US-00019 15 30 60 90 150 180 210 240 5-10 mg 81.9 92.1 97.4 97.6 98.1 98 98.2 98.1 15 mg 56.4 62.4 64.2 67.4 85.5 88.3 89.2 91.2 20 mg 36.6 44.2 47.9 50.3 79 85.2 88.5 90.6 25 mg 31.9 40.7 47.7 51 81.4 87.5 90.9 93

[0318] Dissolution profile after 3 months storage at 25° C. and 60% relative humidity:

TABLE-US-00020 15 30 60 90 150 180 210 240 5-10 mg 75.8 89.6 96 96.1 96 96.2 96 96 15 mg 49.1 61.9 65.7 66.9 82.4 86.7 89.5 91.5 20 mg 36.8 44 47.2 48.4 71.9 80 84.8 87.9 25 mg 31.7 42.1 46.3 48.3 67.7 76 80.7 84.1

[0319] The results show that the pharmaceutical composition have the desired release profiles, more than 80% release after 4 hours, and maintain the desired release profiles after 3 months storage under the selected conditions (25° C., 60% relative humidity).