Forms of a pi3k delta selective inhibitor for use in pharmaceutical formulations

Patent metadata

Field	Value
Publication number	US-2021269446-A1
Application number	US-202017247806-A
Country	US
Kind code	A1
Filing date	Dec 23, 2020
Priority date	May 27, 2014
Publication date	Sep 2, 2021
Grant date	—

Abstract

The present invention relates to solid state forms of a p-toluenesulfonic acid salt (PTSA) of the selective PI3K delta inhibitor (S)-2-(1-(4-amino-3-(3-fluoro-4-isopropoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-6-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one (TGR-1202). The present invention also relates to methods of preparing the same, pharmaceutical compositions containing them, and methods of treating a PI3K kinase mediated disease or disorder, such as cancer, by administering the same.

First claim

1 - 43 . (canceled)

44 . A pharmaceutical composition comprising (i) a p-toluenesulfonic acid salt of (S)-2-(1-(4-amino-3-(3-fluoro-4-isopropoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-6-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one and (ii) a solubilizer, wherein the salt has a d(0.9) of from about 5 to about 50 μm.

45 . The pharmaceutical composition of claim 44 , wherein the solubilizer is hydroxypropyl betadex.

46 . The pharmaceutical composition of claim 44 , wherein the weight ratio of the p-toluenesulfonic acid salt to the solubilizer is from about 1.5:1 to about 1:1.5.

47 . The pharmaceutical composition of claim 45 , wherein the weight ratio of the p-toluenesulfonic acid salt to the solubilizer is from about 1.5:1 to about 1:1.5.

48 . The pharmaceutical composition of claim 44 , wherein the tablet further comprises one or more excipients selected from suspending agents, dispersing agents, disintegrants, lubricants, and any combination of any of the foregoing.

49 . The pharmaceutical composition of claim 44 , wherein the salt has a d(0.9) of from about 5 to about 25 μm.

50 . The pharmaceutical composition of claim 44 , wherein the salt has a d(0.9) of from about 5 to about 15 μm.

51 . The pharmaceutical composition of claim 44 , wherein the salt has a d(0.5) of from about 1 to about 10 μm.

52 . The pharmaceutical composition of claim 44 , wherein the salt has a d(0.5) of from about 2 to about 5 μm.

53 . A pharmaceutical composition comprising (i) a p-toluenesulfonic acid salt of (S)-2-(1-(4-amino-3-(3-fluoro-4-isopropoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-6-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one and (ii) a solubilizer, wherein the salt exhibits a XRPD pattern having one or more peaks selected from 5.0, 10.1, 22.1, and 24.5±0.2° 2Θ.

54 . The pharmaceutical composition of claim 44 , wherein the ratio of p-toluenesulfonic acid to (S)-2-(1-(4-amino-3-(3-fluoro-4-isopropoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-6-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one is about 1:1.

55 . A pharmaceutical composition comprising (i) 200 mg of a p-toluenesulfonic acid salt of (S)-2-(1-(4-amino-3-(3-fluoro-4-isopropoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-6-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one and (ii) a solubilizer, wherein the salt has a d(0.9) of from about 5 to about 50 μm.

56 . The pharmaceutical composition of claim 55 , wherein the solubilizer is hydroxypropyl betadex.

57 . The pharmaceutical composition of claim 55 , wherein the weight ratio of the p-toluenesulfonic acid salt to the solubilizer is from about 1.5:1 to about 1:1.5.

58 . The pharmaceutical composition of claim 56 , wherein the weight ratio of the p-toluenesulfonic acid salt to the solubilizer is from about 1.5:1 to about 1:1.5.

59 . The pharmaceutical composition of claim 55 , wherein the tablet further comprises one or more excipients selected from suspending agents, dispersing agents, disintegrants, lubricants, and any combination of any of the foregoing.

60 . The pharmaceutical composition of claim 55 , wherein the p-toluenesulfonic acid salt has a d(0.9) of from about 5 to about 25 μm.

61 . The pharmaceutical composition of claim 55 , wherein the p-toluenesulfonic acid salt has a d(0.9) of from about 5 to about 15 μm.

62 . The pharmaceutical composition of claim 55 , wherein the p-toluenesulfonic acid salt has a d(0.5) of from about 1 to about 10 μm.

63 . The pharmaceutical composition of claim 55 , wherein the p-toluenesulfonic acid salt has a d(0.5) of from about 2 to about 5 μm.

64 . The pharmaceutical composition of claim 55 , wherein the p-toluenesulfonic acid salt exhibits a XRPD pattern having one or more peaks selected from 5.0, 10.1, 22.1, and 24.5±0.2°2Θ.

65 . The pharmaceutical composition of claim 55 , wherein the ratio of p-toluenesulfonic acid to (S)-2-(1-(4-amino-3-(3-fluoro-4-isopropoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-6-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one is about 1:1.

66 . A method of treating indolent non-Hodgkin's lymphoma in a subject in need thereof comprising administering to the subject the pharmaceutical composition of claim 44 .

67 . A method of treating B-cell lymphoma in a subject in need thereof comprising administering to the subject the pharmaceutical composition of claim 44 .

68 . A method of treating follicular lymphoma in a subject in need thereof comprising administering to the subject the pharmaceutical composition of claim 44 .

69 . A method of treating indolent non-Hodgkin's lymphoma in a subject in need thereof comprising administering to the subject the pharmaceutical composition of claim 55 .

70 . A method of treating B-cell lymphoma in a subject in need thereof comprising administering to the subject the pharmaceutical composition of claim 55 .

71 . A method of treating follicular lymphoma in a subject in need thereof comprising administering to the subject the pharmaceutical composition of claim 55 .

72 . A pharmaceutical composition comprising (i) a p-toluenesulfonic acid salt of (S)-2-(1-(4-amino-3-(3-fluoro-4-isopropoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-6-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one and (ii) a solubilizer.

Assignees

• Rhizen Pharmaceuticals Sa

Inventors

• Vakkalanka Swaroop K

Classifications

• Y02A50/30

  Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change · CPC title

• C07C309/30

  of six-membered aromatic rings substituted by alkyl groups · CPC title

• C07B2200/13

  Crystalline forms, e.g. polymorphs · CPC title

• A61P29/00

  Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] · CPC title

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title