Pharmaceutical compositions

Patent metadata

Field	Value
Publication number	US-9376395-B2
Application number	US-201214345562-A
Country	US
Kind code	B2
Filing date	Sep 14, 2012
Priority date	Sep 18, 2011
Publication date	Jun 28, 2016
Grant date	Jun 28, 2016

Abstract

The present invention is directed to pharmaceutical compositions comprising: (a) a cyclopolysaccharide and (b) a compound of Formula (I) or its pharmaceutical acceptable salt:

wherein X 1 , X 2 , Q, Z, and m are defined herein. Also disclosed is a method for treating a neoplastic disease or an immune disease with these compositions.

First claim

What is claimed is:

1. A pharmaceutical composition comprising (a) a cyclopolysaccharide, and (b) a compound of Formula (I)

or a pharmaceutically acceptable salt thereof:
wherein
m is 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16;
Z is deleted, C(R a R b ), O, S, C(O), N(R a ), SO 2 , OC(O), C(O)O, OSO 2 , S(O 2 )O, C(O)S, SC(O), C(O)C(O), C(O)N(R a ), N(R a )C(O), S(O 2 )N(R a ), N(R a )S(O 2 ), OC(O)N(R a ), N(R a )C(O)O, N(R a )C(O)S, or N(R a )C(O)N(R b ), in which each of R a and R b , independently, is H, alkyl, alkenyl, or alkynyl;
X 1 and X 2 independently, is halo or OSO 2 R c , in which R c is alkyl, alkenyl, or alkynyl; and
Q is cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, or heteroaryl, each of which, independently, is optionally substituted with alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, heteroaryl, halo, nitro, oxo, —C═NH, cyano, alkyl-R d , OR d , OC(O)R d , OC(O)OR d , OC(O)SR d , SR d , C(O)R d , C(O)OR d , C(O)SR d , C(O)NR e R f , SOR d , SO 2 R d , NR e R f , or N(R e )C(O)R f , in which each of R d , R e , and R f , independently, is H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, halo, cyano, amine, nitro, hydroxy, or alkoxy.

2. The composition of claim 1 , wherein X 1 and X 2 independently, is halo; Z is deleted, CH 2 , O, CO, NH, SO 2 , OC(O), C(O)O, C(O)S, NHC(O), C(O)NH, OC(O)NH, NHC(O)O, or NHC(O)S; m is 5, 6, 7, or 8; and Q is a 9-10 membered aryl or heteroaryl.

3. The composition of claim 2 wherein the compound is represented by Formula(II)

in which R 1 and R 2 independently, is H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, halo, —C═NH, amine, cyano, hydroxy, or alkoxy.

4. The composition of claim 3 , wherein the compound is represented by Formula(III)

5. The composition of claim 1 wherein said pharmaceutically acceptable salt is a hydrochloride salt, hydrobromide salt, methanesulfonate, toluenesulfonate, acetate, fumarate, sulfate, bisulfate, succinate, citrate, phosphate, maleate, nitrate, tartrate, benzoate, biocarbonate, carbonate, sodium hydroxide salt, calcium hydroxide salt, potassium hydroxide salt, tromethamine(Tris) salt, or mixtures thereof.

6. The composition of claim 5 wherein said pharmaceutically acceptable salt is a hydrochloride salt, methanesulfonate, toluenesulfonate, acetate, succinate, citrate, maleate, tartrate, or mixtures thereof.

7. The composition of claim 6 wherein said pharmaceutically acceptable salt is an acetate salt.

8. The composition of claim 1 wherein the cyclopolysaccharide is a cyclodextrin.

9. The composition of claim 8 wherein said cyclodextrin is selected from the group consisting of α-cyclodextrin, βcyclodextrin, δ-cyclodextrin.

10. The composition of claim 9 wherein said cyclodextrin is β-cyclodextrin.

11. The composition of claim 10 wherein said β-cyclodextrin is a hydroxypropyl β-cyclodextrin, or sulfobutylether β-cyclodextrin.

12. The composition of claim 10 , wherein said β-cyclodextrin is a β-cyclodextrin substituted with 2-hydroxy-N,N,N-trimethylpropanammonium, carboxymethylated-β-cyclodextrin, O-phosphated-β-cyclodextrin, succinyl-(2-hydroxy)propyl-β-cyclodextrin, sulfopropylated-β-cyclodextrin, heptakis(6-amino-6-deoxy)-β-cyclodextrin, O-sulfated-β-cyclodextrin, and δ-monodeoxy-6-mono-(3-hydroxy)propylamino-β-cyclodextrin.

13. The composition of claim 1 wherein the composition further contains a pH adjusting agent selected from the group consisting of acids, bases and salts, or mixtures thereof, for adjusting the pH range of the composition.

14. The composition of claim 13 wherein said pH adjusting agent is sodium bicarbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, calcium hydroxide, tromethamine (Tris), or mixtures thereof.

15. The composition of claim 14 wherein said pH adjusting agent is a sodium bicarbonate, tromethamine (Tris), or mixtures thereof.

16. A composition comprising (a) a cyclodextrin, (b) a compound of Formula (III)

or a pharmaceutically acceptable salt thereof, and (c) a pH adjusting agent selected from the group consisting of acids, bases and salts, or mixtures thereof, for adjusting the pH range of the composition.

17. The composition of claim 16 wherein said cyclodextrin is β-cyclodextrin.

18. The composition of claim 17 , wherein said β-cyclodextrin is a β-cyclodextrin substitued with 2-hydroxy-N,N,N-trimethylpropanammonium, carboxymethylated-β-cyclodextrin, O-phosphated-β-cyclodextrin, succinyl-(2-hydroxy)propyl-β-cyclodextrin, sulfopropylated-β-cyclodextrin, heptakis(6-amino-6-deoxy)-β-cyclodextrin, O-sulfated-β-cyclodextrin, and 6-monodeoxy-6-mono-(3-hydroxy)propylamino-β-cyclodextrin.

19. The composition of claim 17 wherein said β-cyclodextrin is hydroxypropyl β-cyclodextrin, or sulfobutylether β-cyclodextrin.

20. The composition of claim 16 wherein said pharmaceutically acceptable salt is a hydrochloride salt, methanesulfonate, toluenesulfonate, acetate, succinate, citrate, maleate, tartrate, or mixtures thereof.

21. The composition of claim 16 wherein said pharmaceutically acceptable salt is an acetate salt.

22. The composition of claim 16 wherein said pH adjusting agent is bicarbonate, carbonate, sodium hydroxide, calcium hydroxide, potassium hydroxide, tromethamine, or mixtures thereof.

23. The composition of claim 16 wherein said pH adjusting agent is a sodium bicarbonate.

24. The composition of claim 17 wherein said β-cyclodextrin is a hydroxypropyl β-cyclodextrin or sulfobutylether β-cyclodextrin, said pharmaceutically acceptable salt is an acetate salt, and said pH adjusting agent is sodium bicarbonate.

25. The composition of claim 16 wherein the composition has a pH range from 6.0 to 9.0.

26. The composition of claim 25 in which the pH range of the composition is from 7.0 to 8.0.

27. The composition of claim 16 wherein the cyclodextrin is present at a concentration from 2.5% to 40% weight/volume.

28. The composition of claim 16 wherein the cyclodextrin is present at a concentration from 5% to 20% weight/volume.

29. A pharmaceutical dosage form comprising a pharmaceutical composition according to claim 16 , wherein the pharmaceutical dosage form comprises 5 mg to 500 mg of compound represented by Formula (III).

30. A lyophilized preparation of the composition according to claim 16 , wherein the preparation is packaged in a vial or other pharmaceutically acceptable container.

31. A method of treating a neoplastic disease or an immune disease comprising administering, either alone or in combination with other therapies, to a subject having the neoplastic disease or immune disease an effective amount of the composition according to claim 16 , wherein said neoplastic disease is lung cancer, head and neck cancer, central nervous system cancer, prostate cancer, testicular cancer, colorectal cancer, pan

Assignees

• Chen Yu
• Yang Lan
• Feng Feiyu
• Ge Qiufu
• Guo Dianwu
• Chen Yi
• Purdue Pharmaceuticals Products L P

Inventors

• Chen Yu
• Yang Lan
• Feng Feiyu
• Ge Qiufu
• Guo Dianwu
• Chen Yi

Classifications

• A61P35/02

  specific for leukemia · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title

• A61P37/02

  Immunomodulators · CPC title

• A61K9/0019

  Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner (non-active ingredients are additionally classified in A61K47/00) · CPC title