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

• US 20170049754A1
• Filed: 11/07/2016
• Published: 02/23/2017
• 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:
  US15/345,498
• Publication Number:
  US 20170049754A1
• Time in Patent Office: Days
• US Class Current: 1/1
• 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 multi particulate comprising a) 40-O-(2-hydroxy)ethyl-rapamycin, b) at least one extended release coating which comprises a water insoluble coat forming polymer and c) a protection layer, wherein the protection layer separates a layer comprising the 40-O-(2-hydroxy)ethyl-rapamycin from the extended release coating.

2. An extended release pharmaceutical formulation for oral administration in form of a multiparticulate according to claim 1, wherein the extended release coating further comprises a pore former.

3. An extended release pharmaceutical formulation according to claim 2, wherein the pore former is a water soluble cellulose ether, polyethylene glycol, poloxamer 188, povidone, or a combination thereof.

4. An extended release pharmaceutical formulation according to claim 2, wherein the pore former is hydroxypropylcellulose 300-600 cp, hydroxypropylmethylcellulose 2910 3 cp, or polyethylene glycol or povidone.

5. An extended release pharmaceutical formulation according to claim 1, wherein the coating forming polymer is a water insoluble cellulose ether or cellulose acetate, or polymethacrylate, polyvinylacetate or a combination thereof.

6. An extended release pharmaceutical formulation according to claim 1, wherein the coating forming polymer is Eudragit RS or Eudragit RL or a mixture thereof.

7. An extended release pharmaceutical formulation according to claim 2, wherein the pore former is water soluble cellulose ether and the coating forming polymer is water insoluble cellulose ether.

8. An extended release pharmaceutical formulation according to claim 1, wherein the coating further comprises a plasticizer.

9. An extended release pharmaceutical formulation according to claim 1, wherein said formulation comprises the 40-O-(2-hydroxy)ethyl-rapamycin in an inner layer with a fast dissolving or disintegrating matrix layer.

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

11. An extended release pharmaceutical formulation according to claim 1, wherein the extended release coating is the top coating.

12. A pharmaceutical composition according to claim 11, wherein the protection layer comprises Talc and Hypromellose 2910 3 cp.

13. An extended release pharmaceutical formulation for oral administration in form of a multiparticulate comprising 40-O-(2-hydroxy)ethyl-rapamycin according to claim 1, 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.

14. An extended release pharmaceutical formulation according to claim 13, wherein 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.

15. An extended release pharmaceutical formulation according to claim 14 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.

16. An extended release pharmaceutical formulation according to claim 1 further comprising one or more excipients selected from a binder, a filler, a disintegrant, a lubricant or a desiccant.

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

18. A solid dosage form according to claim 17 which is a hard capsule, tablet, sachet or stickpack.

19. A solid dosage form according to claim 17 wherein the hard hydroxypropylmethylcellulose capsule comprises additional desiccant.

20. A process for the manufacture of an extended release pharmaceutical formulation according to claim 1 comprising

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

(ii) coalescing on the surface of a 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.

21. A process for the manufacture of an extended release pharmaceutical formulation according to claim 1 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.

22. 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 claim 1.

23. An extended release pharmaceutical formulation for oral administration in form of a multiparticulate comprising:

a. a layer or core comprising 40-O-(2-hydroxy)ethyl-rapamycin;

b. at least one extended release coating which comprises;

i. a water insoluble coat forming polymer that is a water insoluble cellulose ether or cellulose acetate, or polymethacrylate, polyvinylacetate or a combination thereof

ii. and a pore former that is water soluble cellulose ether, polyethylene glycol, poloxamer 188, povidone, or a combination thereof; and

c. a protection layer, wherein the protection layer separates the layer or core comprising the 40-O-(2-hydroxy)ethyl-rapamycin from the extended release coating.