PHARMACEUTICAL COMPOSITIONS COMPRISING EVEROLIMUS

• US 20180161280A1
• Filed: 02/12/2018
• Published: 06/14/2018
• Est. Priority Date: 03/19/2013
• Status: Abandoned Application

• Current Assignee: Novartis Ag
• Original Assignee: Novartis Ag
• Inventors: DIEDERICH, Anke, KUNZLER, Hans-Ulrich, GRANER, Oliver
• Application Number:
  US15/894,683
• Publication Number:
  US 20180161280A1
• Time in Patent Office: Days
• CPC Class Codes: A61J 1/035 Blister-type containers blisters in general B65D75/36
• CPC Class Codes: A61K 31/436 the heterocyclic ring system containing a six-membered ring having oxygen as a ring hetero atom, e.g. rapamycin
• CPC Class Codes: A61K 9/1635 obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
• CPC Class Codes: A61K 9/167 with an outer layer or coating comprising drug; with chemically bound drugs or non-active substances on their surface with further drug-free outer coating A61K9/5073
• CPC Class Codes: A61K 9/1682 Processes
• CPC Class Codes: A61K 9/2054 Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
• 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 9/2893 Tablet coating processes mechanical aspects A61J3/06
• CPC Class Codes: A61K 9/501 Inorganic compounds
• 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
• CPC Class Codes: A61K 9/5089 Processes
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 37/06 Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: B65D 2565/387 Materials used as gas barriers
• CPC Class Codes: B65D 65/38 Packaging materials of special type or form
• CPC Class Codes: B65D 75/36 one sheet or blank being recessed and the other formed of relatively stiff flat sheet material, e.g. blister packages , the recess or recesses being preformed B65D73/0057, B65D73/0092 take precedence

Abstract

The invention relates to a pharmaceutical formulation comprising 40-O-(2-hydroxy)ethyl-rapamycin in a high drug load part and an immediate release part. In addition, the invention relates to a formulation comprising 40-O-(2-hydroxy)ethyl-rapamycin in a first layer and a surfactant in a layer beneath the first layer. The pharmaceutical composition is particularly suitable for use as a medicament.

Claims

1. A pharmaceutical formulation comprising a first part and a second part, wherein the first part comprises a layer with more than 40 wt % of 40-O-(2-hydroxy)ethyl-rapamycin and the second part releases more than 85 wt % of 40-O-(2-hydroxy)ethyl-rapamycin of the second part in less than 60 minutes.

2. A pharmaceutical formulation according to claim 1, wherein the first part comprises a layer with more than 45 wt %, 50 wt %, 60 wt %, 70 wt %, 80 wt %, or 90 wt % of 40-O-(2-hydroxy)ethyl-rapamycin.

3. A pharmaceutical formulation according to claim 1 or 2, wherein the first part comprises a layer with between 50 to 80 wt % of 40-O-(2-hydroxy)ethyl-rapamycin.

4. A pharmaceutical formulation according to any one of claim 1 or 3, wherein the first part comprises a layer with between 55 to 70 wt % of 40-O-(2-hydroxy)ethyl-rapamycin.

5. A pharmaceutical formulation according to any one of claim 1 or 4, wherein the first part comprises a layer with between 60 to 70 wt % of 40-O-(2-hydroxy)ethyl-rapamycin.

6. A pharmaceutical formulation according to claim 1 or 5, wherein the second part releases more than 80% or 90% of 40-O-(2-hydroxy)ethyl-rapamycin of the second part in less than 30 minutes.

7. A pharmaceutical formulation according to any one of claims 1 to 6, wherein the weight ratio of 40-O-(2-hydroxy)ethyl-rapamycin in the first and the second part is from 2:

5 to 20;

1.

8. A pharmaceutical formulation according to any one of the previous claims, wherein the first part and/or the second part is in a form of a minitablet, pellet, microparticle, microcapsule, granule, bead, tablet, a coating layer of a coated minitablet, pellet, microparticle, microcapsule, granule, bead, tablet, or a layer of a double or multilayer tablet.

9. A pharmaceutical formulation according to any one of the previous claims, wherein the first part is in a form of a coating and the second part is in a form of a coating.

10. A pharmaceutical formulation according to claim 9, wherein the first and the second part are in the form of a coating of a coated bead or pellet.

11. A pharmaceutical formulation according to claim 8, wherein the first part is in the form of a pellet or a microcapsule, and the second part is in the form of a minitablet or tablet.

12. A pharmaceutical formulation according to any one of the previous claims, wherein the second part comprises a layer with less than 40 wt % of 40-O-(2-hydroxy)ethyl-rapamycin, preferably less than 20 wt % of 40-O-(2-hydroxy)ethyl-rapamycin.

13. A pharmaceutical formulation according to any one of the previous claims, wherein the formulation further comprises a surfactant.

14. A pharmaceutical formulation according to claim 13, wherein the surfactant is in a coating, wherein the coating with the surfactant is enclosed at least by the layer with more than 40 wt % of 40-O-(2-hydroxy)ethyl-rapamycin.

19. A pharmaceutical formulation according to any one of the previous claims, wherein the formulation comprises a further coating.

20. A pharmaceutical formulation according to claim 19, wherein the coating is extended release coating or a protection coating.

21. A pharmaceutical formulation according to claim 20, wherein the extended release coating comprises polymer with pH independent water solubility.

22. A pharmaceutical formulation according to claim 21, wherein the polymer is cellulose ether, polymethacrylate, polyvinylacetate or a combination thereof.

23. A pharmaceutical formulation according to claim 21 or 22, wherein the polymer is ethyl cellulose.

24. A pharmaceutical formulation according to any one of claims 10 to 20, wherein the coating further comprises a water soluble polymer.

25. A pharmaceutical formulation according to claim 20, wherein the protection coating is encaging the layer comprising 40-O-(2-hydroxy)ethyl-rapamycin or is separating the layer comprising 40-O-(2-hydroxy)ethyl-rapamycin from adjacent layer.

28. A pharmaceutical formulation according to claim 20 or 27, wherein the protection coating comprises talc and/or hypromellose.

29. A pharmaceutical formulation according to any one of claims 13 to 27, wherein the surfactant is polyoxyethylene-polyoxypropylene co-polymer or block co-polymer, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene fatty acid ester, poly-oxyethylene alkyl ether, sodium alkyl sulfate or sulfonate, sodium alkyl aryl sulfonate, water soluble tocopheryl polyethylene glycol succinic acid ester, polyglycerol fatty acid ester, alkylene polyol ether or ester, polyethylene glycol glyceryl fatty acid ester, sterol, transesterified and polyoxyethylated caprylic-capric acid glyceride, sugar fatty acid ester, PEG sterol ether, phospholipids, salts of a fatty acid, fatty acid sulfate or sulfonate, salt of fatty acid, fatty acid sulfate or sulfonate, medium or long-chain alkyl ammonium salt, bile acid or salt thereof, glycolic acid or a salt, polyoxyethylene mono ester of a saturated C10 to C22 fatty acid, or a combination thereof.

30. A pharmaceutical formulation according to any one of claims 13 to 29, wherein the surfactant is polyoxyethylene-polyoxypropylene co-polymer or block co-polymer or a water soluble tocopheryl polyethylene glycol succinic acid ester.

31. A pharmaceutical formulation according to any one of claims 13 to 30, wherein the surfactant is a water soluble tocopheryl polyethylene glycol succinic acid ester.

32. A pharmaceutical formulation according to any one of claims 13 to 30, wherein the surfactant is polyoxyethylene-polyoxypropylene co-polymer.

33. A pharmaceutical formulation according to any one of claims 13 to 30, wherein the surfactant is sodium alkyl sulfate.

34. A pharmaceutical formulation according to any one of claims 13 to 33, wherein the weight ratio of the surfactant to 40-O-(2-hydroxy)ethyl-rapamycin is from 10:

1 to 1;

200 by weight.

35. A pharmaceutical formulation according to any one of claims 1 to 34, wherein the formulation further comprises crospovidone, croscarmellose sodium or sodium starch glycolate.

36. A pharmaceutical formulation according to any one of claims 1 to 35, wherein the formulation comprises crospovidone.

37. A pharmaceutical formulation according to any one of claims 13 to 36, wherein the surfactant is vitamin E polyethylene glycol 1000 succinate, poloxamer 188, sodium lauryl sulfate, or combinations thereof.

38. A pharmaceutical formulation according to any one of claims 13 to 37, wherein the formulation comprises a layer separating the surfactant from the 40-O-(2-hydroxy)ethyl-rapamycin.

39. A pharmaceutical formulation according to any one of claims 1 to 38, further comprising a desiccant.

40. A pharmaceutical formulation according to any one of claims 1 to 39, wherein the pharmaceutical formulation is in a form of a pellet comprising a starter core with a diameter of between 100 μ

m and 1 mm.

41. A package comprising at least one pharmaceutical formulation as defined in any one of claims 1 to 40, wherein said at least one pharmaceutical formulation is packed in a package sealed against vapor and moisture permeation.

42. A package comprising at least one pharmaceutical formulation as defined in any one of claims 1 to 40 according to claim 41, wherein the pharmaceutical formulation is further protected against light.

43. A package according to claim 41 or 42, which is a blister pack.

44. A package according to claim 41 or 42, which is a bottle made mainly or completely of HDPE (high density polyethylene).

45. A package according to any one of claims 41 to 43, wherein the formulation is sealed against vapor permeation by forming a foil/foil blister, preferably an aluminium/aluminium blister, or by forming a pack comprising a blister base part and a cover film consisting of aluminium or an aluminium/plastics material composite, and a lower sealing tray, which is formed from an aluminium/plastics material laminate, being sealed against the rear of the blister base part.

46. A package according to any one of claims 41 to 45 meeting the USP 671-requirements of highest class.

47. A process for preparing a pharmaceutical formulation according to any one of claims 1 to 40, wherein 40-O-(2-hydroxy)ethyl-rapamycin is mixed with pharmaceutically acceptable excipient and formulated in the pharmaceutical formulation.

48. A process for preparing a pharmaceutical formulation as defined in any one of claims 1 to 13 or 15 to 40, wherein at least a layer comprising more than 40 wt % of 40-O-(2-hydroxy)ethyl-rapamycin for the first part is provided by mixing a pharmaceutically acceptable excipient and 40-O-(2-hydroxy)ethyl-rapamycin, and the second part is prepared by mixing 40-O-(2-hydroxy)ethyl-rapamycin and pharmaceutically acceptable excipients.

49. A process for preparing a pharmaceutical formulation as defined in any one of claims 1 to 13 or 15 to 40, wherein the layer comprising more than 40 wt % of 40-O-(2-hydroxy)ethyl-rapamycin of the first part is deposited in a form of a coating on a core and the second part is deposited as a second coating comprising less than 40 wt % of 40-O-(2-hydroxy)ethyl-rapamycin on the first coating, optionally with an additional sub—

or top coating.

51. A process for preparing a pharmaceutical formulation according to any one of claims 47 to 50, wherein coatings are deposited on a starter core with a diameter of between 100 μ

m and 1 mm.

52. A pharmaceutical formulation according to any one of claims 1 to 40 for use as a medicament.

53. A pharmaceutical formulation according to claim 52 for use in the treatment of a tumor disease or in the prophylaxis of organ rejection.

54. A pharmaceutical formulation according to any one of claims 1 to 40, wherein the formulation if free of Eudragit L.

15. A pharmaceutical formulation comprising 40-O-(2-hydroxy)ethyl-rapamycin in a first layer and a surfactant in a second layer, wherein the second layer is beneath the first layer.

16. A pharmaceutical formulation comprising 40-O-(2-hydroxy)ethyl-rapamycin in a first layer and a surfactant in a second layer according to claim 15, wherein the first and the second layer are coatings.

17. A pharmaceutical formulation comprising 40-O-(2-hydroxy)ethyl-rapamycin in a first layer and a surfactant in a second layer according to claim 15 or 16, wherein the second layer with the surfactant is enclosed at least by the first layer.

18. A pharmaceutical formulation comprising 40-O-(2-hydroxy)ethyl-rapamycin in a first layer and a surfactant in a second layer according to any one of claims 15 to 17, wherein 40-O-(2-hydroxy)ethyl-rapamycin in the first layer is in a solid dispersion and the solid dispersion comprises 18 to 50 wt % of 40-O-(2-hydroxy)ethyl-rapamycin.

26. A pharmaceutical formulation comprising 40-O-(2-hydroxy)ethyl-rapamycin in a first layer and a surfactant in a second layer according to any one of claims 15 to 25, wherein the pharmaceutical formulation is in a form of a pellet.

27. A pharmaceutical formulation comprising 40-O-(2-hydroxy)ethyl-rapamycin in a first layer and a surfactant in a second layer according to 26, wherein the 40-O-(2-hydroxy)ethyl-rapamycin load is between 1.4 to 15 wt %.

50. A process for preparing a pharmaceutical formulation as defined in any one of claims 15 to 40, wherein a second layer comprising a surfactant is provided and above the second layer, a first layer comprising 40-O-(2-hydroxy)ethyl-rapamycin is deposited, optionally with a layer separating the a first and the second layer.

57. A pharmaceutical formulation comprising 40-O-(2-hydroxy)ethyl-rapamycin according to claim 55, further defined according to any one of the claims 15 to 40, respectively, either alone or in combination.

58. A pharmaceutical composition according to any one of claims 15 to 40, wherein the formulation further comprises a part releasing at least 85 wt % 40-O-(2-hydroxy)ethyl-rapamycin of that part in less than 60 minutes, preferably less than 30 minutes.

55. A pharmaceutical formulation comprising 40-O-(2-hydroxy)ethyl-rapamycin in a first layer and a surfactant in a second layer, wherein the second layer is above the first layer and the surfactant is not poloxamer 188 and TPGS.

56. A pharmaceutical formulation comprising 40-O-(2-hydroxy)ethyl-rapamycin in a first layer and a surfactant in a second layer according to claim 55, wherein the first and the second layers are coatings and the second layer is enclosing the first layer.