Crystalline freebase forms of a biphenyl compound

Patent metadata

Field	Value
Publication number	US-9415041-B2
Application number	US-201514955515-A
Country	US
Kind code	B2
Filing date	Dec 1, 2015
Priority date	Jul 15, 2009
Publication date	Aug 16, 2016
Grant date	Aug 16, 2016

Abstract

The invention provides two crystalline freebase forms of biphenyl-2-ylcarbamic acid 1-(2-{[4-(4-carbamoylpiperidin-1-ylmethyl)benzoyl]methylamino}ethyl)piperidin-4-yl ester. The invention also provides pharmaceutical compositions comprising the crystalline freebase or prepared using the crystalline freebases; processes and intermediates for preparing the crystalline freebases; and methods of using the crystalline freebases to treat a pulmonary disorder.

First claim

What is claimed is:

1. A pharmaceutical composition comprising a pharmaceutically acceptable dry powder excipient and a crystalline freebase of biphenyl-2-ylcarbamic acid 1-(2-{[4-(4-carbamoylpiperidin-1-ylmethyl)benzoyl]methylamino}-ethyl)piperidin-4-yl ester characterized by a powder x-ray diffraction pattern comprising diffraction peaks at 2θ values of 6.6±0.1, 13.1±0.1, 18.6±0.1, 19.7±0.1, and 20.2±0.1; and further characterized by having five or more additional diffraction peaks at 2θ values selected from 8.8±0.1, 10.1±0.1, 11.4±0.1, 11.6±0.1, 14.8±0.1, 15.2±0.1, 16.1±0.1, 16.4±0.1, 16.9±0.1, 17.5±0.1, 18.2±0.1, 19.3±0.1, 19.9±0.1, 20.8±0.1, 21.1±0.1, 21.7±0.1, and 22.3±0.1.

2. The composition of claim 1 , which further comprises an agent selected from β 2 adrenergic receptor agonists, steroidal anti-inflammatory agents, phosphodiesterase-4 inhibitors; or a pharmaceutically acceptable salt thereof and combinations thereof; wherein the crystalline form and the agent are formulated together or separately.

3. The composition of claim 2 , which comprises a β 2 adrenergic receptor agonist or a pharmaceutically acceptable salt thereof and a steroidal anti-inflammatory agent or a pharmaceutically acceptable salt thereof.

4. The composition of claim 1 , wherein the crystalline compound is in micronized form.

5. The composition of claim 1 , wherein the excipient is selected from lactose, starch, mannitol, dextrose, polylactic acid, polylactide-co-glycolide, and combinations thereof.

6. The composition of claim 1 , wherein the excipient is lactose.

7. The composition of claim 2 , which comprises a β 2 adrenergic receptor agonist, or a pharmaceutically acceptable salt thereof.

8. The composition of claim 2 , which comprises a steroidal anti-inflammatory agent, or a pharmaceutically acceptable salt thereof.

9. The composition of claim 2 , which comprises a phosphodiesterase-4 inhibitor, or a pharmaceutically acceptable salt thereof.

10. A pharmaceutical composition comprising dry lactose having a particle size between about 1 μm and about 100 μm and micronized particles of a crystalline freebase of biphenyl-2-ylcarbamic acid 1-(2-{[4-(4-carbamoylpiperidin-1-ylmethyl)benzoyl]methylamino}ethyl)piperidin-4-yl ester characterized by a powder x-ray diffraction pattern comprising diffraction peaks at 2θ values of 6.6±0.1, 13.1±0.1, 18.6±0.1, 19.7±0.1, and 20.2±0.1; and further characterized by having five or more additional diffraction peaks at 2θ values selected from 8.8±0.1, 10.1±0.1, 11.4±0.1, 11.6±0.1, 14.8±0.1, 15.2±0.1, 16.1±0.1, 16.4±0.1, 16.9±0.1, 17.5±0.1, 18.2±0.1, 19.3±0.1, 19.9±0.1, 20.8±0.1, 21.1±0.1, 21.7±0.1, and 22.3±0.1.

11. The composition of claim 1 , wherein the crystalline compound is characterized by a powder x-ray diffraction pattern comprising diffraction peaks at 2θ values selected from 6.6±0.1, 11.4±0.1, 13.1±0.1, 16.1±0.1, 17.5±0.1, 18.2±0.1, 18.6±0.1, 19.3±0.1, 19.7±0.1, 19.9±0.1, 20.2±0.1, 20.8±0.1, 21.1±0.1, 21.7±0.1, and 22.3±0.1.

12. The composition of claim 7 , wherein the β 2 adrenergic receptor agonist is formoterol or a pharmaceutically acceptable salt thereof.

Assignees

• Woollam Grahame
• Theravance Biopharma R&D Ip Llc

Inventors

• Woollam Grahame

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P11/08

  Bronchodilators · CPC title

• A61P11/00

  Drugs for disorders of the respiratory system · CPC title

• A61P11/06

  Antiasthmatics · CPC title

• C07D401/12 Primary

  linked by a chain containing hetero atoms as chain links · CPC title