PHARMACEUTICAL COMPOSITIONS COMPRISING 40 - O - ( 2 - HYDROXY) ETHYL - RAPAMYCIN

• US 20140242162A1
• Filed: 10/03/2012
• Published: 08/28/2014
• Est. Priority Date: 10/06/2011
• Status: Abandoned Application

• Current Assignee: Novartis Ag
• Original Assignee: Novartis Ag
• Inventors: Diederich, Anke, Liechti, Kurt, Kuehl, Peter, Cheung, Wing
• Application Number:
  US14/349,166
• Publication Number:
  US 20140242162A1
• Time in Patent Office: Days
• US Class Current: 424/461
• 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 9/0053 Mouth and digestive tract, i.e. intraoral and peroral administration rectal administration A61K9/0031
• CPC Class Codes: A61K 9/145 with organic compounds
• CPC Class Codes: A61K 9/146 with organic macromolecular compounds
• CPC Class Codes: A61K 9/2013 Organic compounds, e.g. phospholipids, fats
• CPC Class Codes: A61K 9/2072 characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms A61K9/0004, A61K9/0056, A61K9/0065 take precedence
• CPC Class Codes: A61K 9/2813 Inorganic compounds
• CPC Class Codes: A61K 9/2846 Poly(meth)acrylates
• CPC Class Codes: A61K 9/2866 Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
• CPC Class Codes: A61K 9/2886 having two or more different drug-free coatings; Tablets of the type inert core-drug layer-inactive layer of the type active core-drug layer-inactive layer A61K9/209
• CPC Class Codes: A61K 9/2893 Tablet coating processes mechanical aspects A61J3/06
• 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: A61K 9/4833 Encapsulating processes; Filling of capsules mechanical aspects A61J3/07
• CPC Class Codes: A61K 9/485 Inorganic compounds
• CPC Class Codes: A61K 9/4858 Organic compounds
• CPC Class Codes: A61K 9/4866 Organic macromolecular compounds
• CPC Class Codes: A61K 9/4891 Coated capsules; Multilayered drug free capsule shells with drug coating for immediate release A61K9/4808; osmotic devices A61K9/0004
• CPC Class Codes: A61K 9/5073 having two or more different coatings optionally including drug-containing subcoatings
• CPC Class Codes: A61K 9/5078 with drug-free core
• CPC Class Codes: A61K 9/5089 : Processes
• CPC Class Codes: A61K 9/7007 : Drug-containing films, membranes or sheets A61K9/0041, A61K9/0043, A61K9/006, A61K9/0063 take precedence
• CPC Class Codes: A61P 35/00 : Antineoplastic agents
• CPC Class Codes: A61P 37/02 : Immunomodulators
• CPC Class Codes: A61P 37/06 : Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Abstract

The invention relates to extended release pharmaceutical formulations in form of multiparticulates comprising 40-O-(2-hydroxy)ethyl-rapamycin, to dosage forms which comprise said pharmaceutical formulations, to methods of preparing said pharmaceutical formulations and said dosage forms, to uses of said pharmaceutical formulations and said dosage for the manufacture of a medicament for the treatment or prevention of diseases or conditions responsive to inhibition of mTOR signaling pathway, such as for instance proliferative diseases or immunosuppression.

Claims

1. An extended release pharmaceutical formulation for oral administration in form of a multiparticulate comprising a) 40-O-(2-hydroxy)ethyl-rapamycin and b) at least one extended release coating which comprises i) a water insoluble coating forming polymer and ii) optionally a pore former.

2. An extended release pharmaceutical formulation according to claim 1 wherein the pore former is a water soluble cellulose ether such as e.g. hydroxypropylcellulose (HPC (Klucel™

EF, EXF, LF) or hydroxypropyl methylcellulose (HPMC, MethoceP™

E3/E5, Pharmacoat 603™

), polyethylen glycol (Macrogol 1500, 3500, 4000,

     6000), poloxamer 188 (Pluronic F68™

) or povidone (PVP, Kollidon K25/K30)M or combinations thereof.

3. An extended release pharmaceutical formulation according to claim 1 or 2 wherein the pore former is hydroxypropylcellulose 300-600 cp (HPC), HPMC 2910 3 cP, or polyethylen glycol or povidone.

4. An extended release pharmaceutical formulation according to any of the previous claims wherein the coating forming polymer is a water insoluble cellulose ether e.g. ethylcellulose or cellulose acetate, or polymethacrylates, e.g. ammonio methacrylate copolymers (Eudragit RS/RL), polyvinylacetate or combinations thereof.

5. An extended release pharmaceutical formulation according to any of the previous claims wherein the coating forming polymer is Eudragit RS or Eudragit RL or a mixture thereof.

6. An extended release pharmaceutical formulation according to any of the previous claims wherein the pore former is water soluble cellulose ether and the coating forming polymer is water insoluble cellulose ether.

7. An extended release pharmaceutical formulation according to any of the previous claims wherein the coating further comprises a plasticizer.

8. An extended release pharmaceutical formulation according to any of the previous claims wherein said formulation comprises the 40-O-(2-hydroxy)ethyl-rapamycin in an inner layer with a fast dissolving or disintegrating matrix layer.

9. An extended release pharmaceutical formulation according to claim 8 wherein the fast dissolving or disintegrating matrix layer is placed on a starter core.

10. An extended release pharmaceutical formulation according to any of the previous claims wherein said formulation further comprises a protection layer.

11. An extended release pharmaceutical formulation according to claim 10 wherein the protection layer separates the layer comprising the 40-O-(2-hydroxy)ethyl-rapamycin from an adjacent layer.

12. An extended release pharmaceutical formulation according to claim 11 wherein the adjacent layer is the extended release coating.

13. An extended release pharmaceutical formulation according to claim 12 wherein the extended release coating is the top coating.

14. An extended release pharmaceutical formulation according to claim 13 wherein the protection layer comprises a matrix former antitacking agent and optionally an inorganic pigment.

15. A pharmaceutical composition according to claim 14 wherein the protection layer comprises Talc and Hypromellose 2910 3 cP.

24. A solid dosage form comprising an extended release pharmaceutical formulation according to claims 1 to 23 in the form a minitablet, pellets, microparticles, granules or beads.

25. A solid dosage form according to claim 24 which is a hard capsule, tablet, sachet or stickpack.

26. A solid dosage form according to claim 25 wherein the hard HPMC capsule comprises additional desiccant, e.g. crospovidone, croscarmellose sodium or sodium starch glycolate.

27. A process for the manufacture of an extended release pharmaceutical formulation according to claims 1 to 23 comprising

(i) preparing an organic spray fluid mixture in which the polymer in colloidal manner and 40-O-(2-hydroxy)ethyl-rapamycin are dispersed or dissolved

(ii) coalescing on the surface of core particle and fusing together as uniform, smooth layer of solid dispersion upon removal of the solvent,

(iii) coating the obtained particles optionally with additional functional layers and a modified release coating.

28. A process for the manufacture of an extended release pharmaceutical formulation according to claims 1 to 23 comprising

(iv) adding a matrix layer comprising the active ingredient on a starter core particles,

(v) optionally adding a protective layer on the matrix layer comprising the active ingredient,

(vi) coating the particles with an extended release coat.

29. A method of treating an mTOR pathway driven disease wherein everolimus is administered with an extended release pharmaceutical formulation or a solid dosage form according to claims 1 to 26.

30. An extended release pharmaceutical formulation according to any one of claims 1 to 23 or a solid dosage form according to any one of claims 24 to 26 for use as a medicine.

31. Use of an extended release pharmaceutical formulation according to any one of claims 1 to 23 or a solid dosage form according to claims 24 to 26 for the manufacture of a medicament for the treatment of an mTOR pathway driven disease.

32. A method for the treatment of mTOR pathway driven disease using an extended release pharmaceutical formulation or a sold dosage form according to claims 1 to 26 wherein 40-O-(2-hydroxy)ethyl-rapamycin is administered in a dose of 1 mg to 40 mg once per day or 20 mg to 80 mg every second day or 40 mg to 150 mg once per week.

16. An extended release pharmaceutical formulation for oral administration in form of a multiparticulate comprising 40-O-(2-hydroxy)ethyl-rapamycin in a carrier matrix comprising hydrophilic matrix formers enabling diffusion controlled release of 40-O-(2-hydroxy)ethyl-rapamycin or lipophilic matrix formers enabling erosion controlled release of 40-O-(2-hydroxy)ethyl-rapamycin and optionally further functional layers and/or coatings.

17. An extended release pharmaceutical formulation according to claim 16 wherein the matrix formers are sodium alginate, carboxymethylcellulose sodium, (or “

CMC sodium”

), methylcellulose, ethylcellulose and cellulose acetate or polymethacrylates, e.g. ammonio methacrylate copolymers (Eudragit RS/RL), hydroxypropyl methylcellulose (“

HPMC”

), e.g. Methocel™

CR grades, hydroxypropyl cellulose, e.g. KluceP™

HF/MF, polyoxyethylene, e.g. Polyox™

or polyvinylpyrrolidone (“

PVP”

), e.g. PVP K60, K90, carrageenan, such as Viscarin™

GP-2091/GP-379 or combinations thereof.

18. An extended release pharmaceutical formulation according to claim 16 wherein the matrix formers are glyceryl monostearate, e.g. Cutina GMS, glyceryl behenate, e.g. Compritol 888 ATO, stearyl alcohol, hart fat, e.g. Gelucire™

, or Vitamin E polyethylen glycol succinate, e.g. Speziol TPGS or combinations thereof.

19. An extended release pharmaceutical formulation for oral administration in form of a multiparticulate comprising 40-O-(2-hydroxy)ethyl-rapamycin, wherein less than 45% of the active ingredient is released from said pharmaceutical composition after 30 min as determined by a dissolution assay in 900 mL phosphate buffer pH 6.8 containing sodium dodecyl sulfate 0.2% at 37°

C. and the dissolution is performed using a paddle method at 75 rpm according to Ph.Eur. monograph 2.9.3.

20. An extended release pharmaceutical formulation according to claim 19 the pharmaceutical formulation shows an in-vitro dissolution of component a) of <

45% at 0.5 h, 20-80% at 1 h, >

50% at 2 h and >

65% at 3 h.

21. An extended release pharmaceutical formulation according to claim 20 comprising a) 40-O-(2-hydroxy)ethyl-rapamycin and b) at least one diffusion controlled extended release coating or c) carrier matrix comprising hydrophilic matrix formers enabling diffusion or a lipophilic matrix enabling erosion controlled release, wherein less than 45% of the active ingredient is released from said pharmaceutical composition after 30 min as determined by a dissolution assay in 900 mL phosphate buffer pH 6.8 containing sodium dodecyl sulfate 0.2% at 37°

C. and the dissolution is performed using a paddle method at 75 rpm according to Ph.Eur. monograph 2.9.3.

22. An extended release pharmaceutical formulation according of the previous claims further comprising one or more excipients selected from a binder, a filler, a disintegrant, a lubricant or a desiccant.

23. An extended release pharmaceutical formulation according to claim 20 comprising crospovidone, croscarmellose sodium or sodium starch glycolate as internal desiccant.

33. A method of reducing everolimus C_max to C_min ratio in a patient comprising administering an extended release pharmaceutical formulation for oral administration in form of a multiparticulates comprising a) 40-O-(2-hydroxy)ethyl-rapamycin and b) at least one extended release coating which comprises i) a water insoluble coating forming polymer and optionally a pore former or c) carrier matrix comprising hydrophilic matrix formers enabling diffusion or a lipophilic matrix enabling erosion controlled release.

34. An extended release pharmaceutical formulation for oral administration in form of a multiparticulate comprising a) 40-O-(2-hydroxy)ethyl-rapamycin and b) at least one diffusion controlled extended release coating and/or c) carrier matrix comprising hydrophilic matrix formers enabling diffusion or erosion controlled release wherein C_max to C_min ratio of the formulation is <

5 at steady state.