COMPOSITIONS FOR ILEO-JEJUNAL DRUG DELIVERY

• US 20180193274A1
• Filed: 12/23/2015
• Published: 07/12/2018
• Est. Priority Date: 12/24/2014
• Status: Abandoned Application

• Current Assignee: Principia Biopharma Inc. (Sanofi )
• Original Assignee: Principia Biopharma Inc. (Sanofi )
• Inventors: NUNN, Philip A., BERNER, Bret, MASJEDIZADEH, Mohammad Reza
• Application Number:
  US15/539,100
• Publication Number:
  US 20180193274A1
• Time in Patent Office: Days
• CPC Class Codes: A61K 31/519 ortho- or peri-condensed with heterocyclic rings
• CPC Class Codes: A61K 47/12 Carboxylic acids; Salts or anhydrides thereof
• CPC Class Codes: A61K 47/26 Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
• CPC Class Codes: A61K 47/32 Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers , poly(meth)acrylates, or polyvinyl pyrrolidone
• CPC Class Codes: A61K 47/38 Cellulose; Derivatives thereof
• CPC Class Codes: A61K 9/0004 Osmotic delivery systems; Sustained release driven by osmosis, thermal energy or gas
• CPC Class Codes: A61K 9/2813 Inorganic compounds
• CPC Class Codes: A61K 9/282 Organic compounds, e.g. fats
• CPC Class Codes: A61K 9/2846 Poly(meth)acrylates
• CPC Class Codes: A61K 9/2853 obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers, poly(lactide-co-glycolide)
• 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 9/5026 obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
• CPC Class Codes: A61K 9/5073 having two or more different coatings optionally including drug-containing subcoatings
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia

Abstract

The current invention affords new formulations which deliver reversible and irreversible covalent kinase inhibitors, in particular BTK inhibitors, into the small intestine and specifically into the ileum and jejunum of the small intestine.

Claims

1. A solid oral dosage form comprising

(a) a compound according to formula Ia or Ib, and/or a pharmaceutically acceptable salt thereof:

2. A solid oral dosage form comprising:

(a) a core comprising a compound according to Ia or Ib as described in claim 1, and/or a pharmaceutically acceptable salt thereof, and

(b) an enteric coating covering the core;

wherein the solid oral dosage form releases less than about 10% by weight of said compound and/or said pharmaceutically acceptable salt thereof, in about 1.5 hours in a dissolution vessel comprising an aqueous solution at a pH of less than about 3;

less than about 10% by weight of said compound and/or said pharmaceutically acceptable salt thereof, in about 1.5 hours in a dissolution vessel comprising an aqueous solution at a pH of from about 4.5 to about 5.5; and

, the solid oral dosage form releases not less than about 80% by weight of said compound and/or said pharmaceutically acceptable salt thereof, from about twenty minutes to about two hours in a dissolution vessel comprising an aqueous solution at a pH of from about 6.4 to about 7.4.

5. The solid oral dosage form according to claim 2 or 4 wherein the solid oral dosage form releases less than about 10% by weight of said compound and/or said pharmaceutically acceptable salt thereof, in about 1.5 hours in a dissolution vessel comprising an aqueous solution at a pH of from about 5.1 to about 5.5.

6. The solid oral dosage form according to any one of claim 2, 4, or 5 wherein the solid oral dosage releases less than about 25% of said compound and/or said pharmaceutically acceptable salt thereof, in about 15 minutes in a dissolution vessel comprising an aqueous solution at a pH of from about 6.4 to about 7.4.

7. The solid oral dosage form according to any one of claim 2, 4, or 5 wherein the solid oral dosage releases less than about 80% of said compound and/or said pharmaceutically acceptable salt thereof, in about 30 minutes in a dissolution vessel comprising an aqueous media at a pH of from about 6.4 to about 7.4.

8. The solid oral dosage form according to any one of claim 2, 4, or 5 wherein the solid oral dosage form releases less than about 80% of said compound and/or said pharmaceutically acceptable salt thereof, in about 45 minutes in a dissolution vessel comprising an aqueous solution at a pH of from about 6.4 to about 7.4.

9. The solid oral dosage form according to any one of claim 2, 4, or 5 wherein the solid oral dosage form releases less than about 80% of said compound and/or said pharmaceutically acceptable salt thereof, in about 60 minutes in a dissolution vessel comprising an aqueous solution at a pH of from about 6.4 to about 7.4.

10. The solid oral dosage form according to any one of claim 2, 4, or 5 wherein the solid oral dosage releases at least about 80% of said compound and/or said pharmaceutically acceptable salt thereof, in about 120 minutes in a dissolution vessel comprising an aqueous solution at a pH of from about 6.4 to about 7.4.

11. The solid oral dosage form according to any one of claims 6 to 10 wherein the aqueous solution is a simulated intestinal fluid at a pH of from about 6.4 to 7.4.

12. The solid oral dosage form according to any of claims 2, 4-11 wherein the solid oral dosage form comprises a pharmaceutically acceptable acid salt of the compound.

13. The solid oral dosage form according to any of claims 2, 4-12 wherein the core further comprises a pharmaceutically acceptable acid within the core sufficient to enhance dissolution of the said compound and/or said pharmaceutically acceptable salt thereof.

14. The solid oral dosage form according to any of claims 2, 4-13 wherein the core further comprises a pharmaceutically acceptable acid in a quantity sufficient to produce an acidic aqueous solution within the solid oral dosage form prior to the release of the compound and/or the pharmaceutically acceptable salt thereof, from the solid oral dosage form.

15. The solid oral dosage form according to any of claims 2, 4-12 wherein the core further comprises a surfactant which is present at a concentration above its critical micelle concentration upon disintegration in about 50 mL of aqueous media.

16. The solid oral dosage form according to any of claims 2, 4-12 wherein the core further comprises a surfactant which is present at a concentration above its critical micelle concentration upon disintegration in about 20 mL of aqueous media.

17. The solid oral dosage form according to any of claims 2, 4-16 wherein the mean particle size of the compound and/or the pharmaceutically acceptable salt thereof, is from about 0.3 micron to about 100 microns.

18. The solid oral dosage form according to claim 17 wherein the mean particle size of the compound and/or the pharmaceutically acceptable salt thereof, is from about 1 micron to about 50 microns.

19. The solid oral dosage form according to claim 17 wherein the mean particle size of the compound and/or the pharmaceutically acceptable salt thereof, is less than or equal to about 15 micron.

20. The solid oral dosage form according to any one of claims 2, 4-19 wherein the enteric coating is from about 10% to about 150% of the weight of the core.

21. The solid oral dosage form according to any one of claims 2, 4-19 wherein the enteric coating is from about 20 to about 100% of the weight of the core.

22. The solid oral dosage form according to any one of claims 2, 4-19 wherein the enteric coating is from about 30 to about 60% of the weight of core.

23. The solid oral dosage form according to any one of claims 2, 4-22 wherein the enteric coating is from about 5 to about 500 microns thick.

24. The solid oral dosage form according to any one of claims 2, 4-23 wherein the enteric coating is 8 to 150 microns thick.

25. The solid oral dosage form according to any one of claims 2, 4-24 wherein the enteric coating is 50 to 100 microns thick.

26. The solid oral dosage form according to any one of claims 2, 4-25 wherein the enteric coating is selected from polymerized gelatin, shellac, methacrylic acid copolymer type CNF, cellulose butyrate phthalate, cellulose hydrogen phthalate, cellulose proprionate phthalate, polyvinyl acetate phthalate (PVAP), cellulose acetate phthalate (CAP), cellulose acetate trimellitate (CAT), hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate, dioxypropyl methylcellulose succinate, carboxymethyl ethylcellulose (CMEC), hydroxypropyl methylcellulose acetate succinate (HPMCAS), and (meth)acrylic acid polymers and copolymers which polymers are made from one, and which copolymers are made from two or more monomers, selected from methyl acrylate, ethyl acrylate, methyl methacrylate, and ethyl methacrylate.

27. The solid oral dosage form according to claim 26 wherein the enteric coating comprises a poly(meth)acrylate polymer.

28. The solid oral dosage form according to claim 27 wherein the enteric coating is a Eudragit®

L or S series.

29. The solid oral dosage form according to claim 28 wherein the enteric coating is a Eudragit®

L100, L12.5, S100, S12.5, or FS 30D.

30. The solid oral dosage form according to any one of claims 2, 4-25 wherein the enteric coating comprises a cellulose derivative.

31. The solid oral dosage form according to claim 30 wherein the cellulose derivative is selected from methylcellulose, cellulose acetate phthalate, hydroxymethyl cellulose phthalate (HPMCP), hydroxypropyl methyl cellulose succinate (HPMCS), and hydroxymethyl cellulose acetate succinate (HPMCAS).

32. The solid oral dosage form according to any one of claims 2, 4-25 wherein the enteric coating comprises a polyvinyl acetate phthalate (PVAP) polymer.

33. The solid oral dose form according to any one of claims 2, 4-32 wherein the core further comprises a subcoat between the enteric coating and the core.

34. The solid oral dosage form according to claim 33 wherein the subcoat is a water soluble or hydrophilic erodible polymer.

35. The solid oral dosage form according to claim 34 wherein the subcoat is a low molecular weight polymer selected from hydroxymethyl cellulose (HPMC), hydroxyethyl cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, microcrystalline cellulose, polyvinylpyrrolidiones, polysaccharides (or a polysaccharide derivative), polyvinyl alcohols, polyethylene glycol (PEG), polypropylene glycol (PPG), and PEG-PPG block copolymers.

36. The solid oral dosage form according to claim 33 wherein the subcoat is a water insoluble composition and comprises (i) particles of a water soluble compound capable of forming channels in the water insoluble composition or (ii) water insoluble hydrophilic particles which causes swelling of the subcoat when in contact with an aqueous media.

37. The solid oral dosage form according to claim 36 wherein the subcoat comprises particles of a water soluble compound.

38. The solid oral dosage form according to claim 36 wherein the subcoat comprises water insoluble hydrophilic particles which causes swelling of the subcoat when in contact with an aqueous media.

39. The solid oral dosage form according to claim 36 wherein the subcoat is water insoluble composition and comprises particles of a water soluble compound which forms channels allowing influx of water into the solid oral dosage form and diffusion of the compound and/or the pharmaceutically acceptable salt thereofinto the intestine.

40. The solid oral dosage form according to claim 36 wherein the subcoat is a water insoluble composition comprising particles of a water soluble compound capable of forming channels that are impermeable to the compound and/or the pharmaceutically acceptable salt thereof, but allows entry of water and swelling and rupturing of the subcoat and causing release of the compound and/or the pharmaceutically acceptable salt thereof.

41. The solid oral dosage form according to any one of claims 1 to 40 wherein the solid oral dosage is a tablet or a capsule.

42. The solid oral dosage form according to any one of claims 1 to 41 wherein the pharmaceutically acceptable excipient is independently selected from binders, surfactants, diluents, buffers, antiadherents, glidants, disintegrants, antioxidants, antifoaming agents, fillers, flavors, colors, lubricants, sorbents, preservatives, plasticizers, and sweeteners.

43. The solid oral dosage form according to any one of claims 1 to 42, wherein the AUC resulting from administration of the solid oral dosage is at least about 50% greater than the AUC resulting from administration of an immediate release dosage form having an equivalent amount of the compound and/or the pharmaceutically acceptable salt thereof.

44. The solid oral dosage form according to claim 43 comprising the compound and/or said pharmaceutically acceptable salt thereof, wherein the AUC resulting from administration of the solid oral dosage is at least about 100% greater than the AUC resulting from administration of an immediate release dosage form having an equivalent amount of the compound and/or the pharmaceutically acceptable salt thereof.

45. The solid oral dosage form according to claim 43 comprising said the compound and/or the pharmaceutically acceptable salt thereof, wherein the AUC resulting from administration of the solid oral dosage is at least about 500% greater than the AUC resulting from administration of an immediate release dosage form having an equivalent amount of the compound and/or the pharmaceutically acceptable salt thereof.

46. The solid oral dosage form according to any one of claims 1 to 42, having an onset of release of the compound and/or the pharmaceutically acceptable salt thereof in the jejunum or ileum of the small intestine.

47. The solid oral dosage form according to any one of claims 3 to 45, wherein the irreversible covalent kinase inhibitor is chosen from ibrutinib, ACP196, acalabrutinib, BGB3111, HM71224, ONO-4059, RG7625, RG7880, MSC-2364447, CC-292, X-022, ABT-105, AC0025, EBI-1266, TP-4207, afatinib, mereletinib, osimertinib, rociletinib, neratinib, dacomitinib, poziotinib, spebrutinib, tarloxotinib, selinexor, verdinexor, PF-06747775, BLU-554, NSC-687852, VLX-1500, KU-113, NT-113, BLU-9931, KPT-350, and AZ-13767370.

48. The solid oral dosage form according to any one of claims 3 to 45, wherein the irreversible covalent kinase inhibitor is chosen from:

(R)-1-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one,

(R)-4-(8-amino-3-(1-(but-2-ynoyl)pyrrolidin-2-yl)imidazo[1,5-a]pyrazin-1-yl)-N-(pyridin-2-yl)benzamide,

(S)-7-(1-acryloylpiperidin-4-yl)-2-(4-phenoxyphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide,

(S)-7-(1-(but-2-ynoyl)piperidin-4-yl)-2-(4-phenoxyphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide,

N-(3-((2-((2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)thieno[3,2-d]pyrimidin-4-yl)oxy)phenyl)acrylamide,

1-(3-((2-((4-(4-methylpiperazin-1-yl)phenyl)amino)-[1,2,4]triazolo[1,5-a]pyridin-8-yl)oxy)phenyl)prop-2-en-1-one,

(R)-6-amino-9-(1-(but-2-ynoyl)pyrrolidin-3-yl)-7-(4-phenoxyphenyl)-7H-purin-8(9H)-one,

N-(2-((6-((5-(5-fluoro-2-(hydroxymethyl)-3-(4-oxo-6,7,8,9-tetrahydrobenzo[4,5]thieno[2,3-d]pyridazin-3(4H)-yl)phenyl)-1-methyl-2-oxo-1,2-dihydropyridin-3-yl)amino)pyridin-2-yl)amino)ethyl)acrylamide,

N-(3-((5-fluoro-2-((4-(2-methoxyethoxy)phenyl)amino)pyrimidin-4-yl)amino)phenyl)acrylamide,

6-(1-acryloylpiperidin-4-yl)-2-(4-phenoxyphenyl)nicotinamide,

(R)-1-(1-acryloylpiperidin-3-yl)-4-amino-N-(5-chlorobenzo[d]oxazol-2-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide,

(S,E)-N-(4-((3-chloro-4-fluorophenyl)amino)-7-((tetrahydrofuran-3-yl)oxy)quinazolin-6-yl)-4-(dimethylamino)but-2-enamide,

(R)-1-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one,

N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)phenyl)acrylamide,

N-(3-((2-((4-(4-acetylpiperazin-1-yl)-2-methoxyphenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)phenyl)acrylamide,

(E)-N-(4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-3-cyano-7-ethoxyquinolin-6-yl)-4-(dimethylamino)but-2-enamide,

(E)-N-(4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)-4-(piperidin-1-yl)but-2-enamide,

1-(4-((4-((3,4-dichloro-2-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)oxy)piperidin-1-yl)prop-2-en-1-one,

N-(3-((5-fluoro-2-((4-(2-methoxyethoxy)phenyl)amino)pyrimidin-4-yl)amino)phenyl)acrylamide,

(E)-4-((4-((3-bromo-4-chlorophenyl)amino)pyrido[3,4-d]pyrimidin-6-yl)amino)-N,N-dimethyl-N-((1-methyl-4-nitro-1H-imidazol-5-yl)methyl)-4-oxobut-2-en-1-aminium bromide,

(Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)-N′

-(pyrazin-2-yl)acrylohydrazide,

(Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)-N′

-(pyridin-2-yl)acrylohydrazide,

N-((3R,4R)-4-fluoro-1-(6-((3-methoxy-1-methyl-1H-pyrazol-4-yl)amino)-9-methyl-9H-purin-2-yl)pyrrolidin-3-yl)acrylamide,

N-((3S,4S)-3-((6-(2,6-dichloro-3,5-dimethoxyphenyl)quinazolin-2-yl)amino)tetrahydro-2H-pyran-4-yl)acrylamide,

(3E,5E)-1-acryloyl-3,5-bis(4-nitrobenzylidene)piperidin-4-one,

(E)-N-(7-((1R,5S,6s)-3-oxabicyclo[3.1.0]hexan-6-ylethynyl)-4-((3-chloro-4-fluorophenyl)amino)quinazolin-6-yl)-4-(dimethylamino)but-2-enamide,

(3E,5E)-1-acryloyl-3,5-bis(4-fluoro-3-nitrobenzylidene)azepan-4-one,

N-(2-((6-(2,6-dichloro-3,5-dimethoxyphenyl)quinazolin-2-yl)amino)-3-methylphenyl)acrylamide,

(Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)-N′

-pivaloylacrylohydrazide, and

N-(2-((2-((tetrahydro-2H-pyran-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)phenyl)acrylamide.

49. The solid oral dosage form according to any one of claims 3 to 45, wherein the irreversible covalent kinase inhibitor is chosen from:

50. A method of treating a disease treatable by inhibition of BTK, in a patient in recognized need thereof, which method comprises administering to the patient in single or multiple doses, a therapeutically effective amount of the compound and/or the pharmaceutically acceptable salt thereof, contained in a solid oral dosage form according to any one of claims 1 to 49.

51. The method of claim 50 wherein the disease is selected from an autoimmune disease, cancer, and an inflammatory disease.

52. The method of claim 50 wherein the disease is a leukemia or lymphoma.

53. The method of claim 51 wherein the leukemia is selected from chronic lymphocytic leukemia (CLL), small lymphocytic leukemia (SLL), multiple myeloma, mantle cell lymphoma, and B-cell non-Hodgkin lymphoma.

3. A solid oral dosage form comprising

(a) a compound that is an irreversible covalent kinase inhibitor, and/or a pharmaceutically acceptable salt thereof;

(b) means for release of the compound and/or the pharmaceutically acceptable salt thereof in one or more mammalian intestinal sites selected from the jejunum and ileum; and

,

(c) a pharmaceutically acceptable excipient.

4. A solid oral dosage form comprising:

(a) a compound that is an irreversible covalent kinase inhibitor, and/or a pharmaceutically acceptable salt thereof, and

(b) an enteric coating covering the core;

wherein the solid oral dosage form releases less than about 10% by weight of said compound and/or said pharmaceutically acceptable salt thereof, in about 1.5 hours in a dissolution vessel comprising an aqueous solution at a pH of less than about 3;

less than about 10% by weight of said compound and/or said pharmaceutically acceptable salt thereof, in about 1.5 hours in a dissolution vessel comprising an aqueous solution at a pH of from about 4.5 to about 5.5; and

, the solid oral dosage form releases not less than about 80% by weight of said compound and/or said pharmaceutically acceptable salt thereof, from about twenty minutes to about two hours in a dissolution vessel comprising an aqueous solution at a pH of from about 6.4 to about 7.4.