Claims for Patent: 10,159,746

Summary for Patent: 10,159,746

Title:	Cyclodextrin complexation methods for formulating peptide proteasome inhibitors
Abstract:	This disclosure provides methods for formulating compositions comprising one or more peptide proteasome inhibitors and a cyclodextrin, particularly a substituted cyclodextrin. As well as cyclodextrin complexation methods of formulating a peptide proteasome inhibitor (e.g., a compound of formula (1)-(5) or a pharmaceutically acceptable salt thereof) with one or more cyclodextrins. Such methods substantially increase the solubility and stability of these proteasome inhibitors and facilitate both their manufacture and administration. For example, homogenous solutions of a compound of formula (5) (carfilzomib) can be obtained at a pharmaceutically useful pH (e.g., about 3.5) and at higher concentrations (e.g., about 5 mg/mL) than could be obtained without one or more cyclodextrins and the processes of complexation between the compound and one or more cyclodextrins provided herein. ##STR00001##
Inventor(s):	Lewis; Evan (Pacifica, CA), Shwonek; Peter (San Francisco, CA), Dalziel; Sean (San Francisco, CA), Jumaa; Mouhannad (Foster City, CA)
Assignee:	Onyx Therapeutics, Inc. (Thousand Oaks, CA)
Application Number:	14/399,582
Patent Claims:	1. A method for preparing a low chloride pharmaceutical composition for use in treating multiple myeloma, the method comprising: (i) providing a first combination comprising: (a) a compound having a structure: ##STR00015## or a pharmaceutically acceptable salt thereof; (b) a low chloride sulfobutyl ether beta cyclodextrin ("SBECD"); and (c) water; wherein the low chloride SBECD has a chloride ion content of 0.05% w/w or less and the first combination is heterogeneous and the compound or salt has a low solubility in the first combination; and (ii) contacting the first combination with a non-chloride acid to form a second combination, wherein the compound is more soluble in the second combination than in the first combination. 2. The method of claim 1, wherein the first combination comprises less than 0.5% w/v of organic solvent or buffer. 3. The method of claim 1, wherein the second combination comprises a complex of the compound and the SBECD. 4. The method of claim 1, wherein the acid is added in the form of an aqueous solution. 5. The method of claim 1, wherein the mole ratio of chloride ion to compound in the first combination is not more than 0.32. 6. The method of claim 1, wherein providing a first combination (step (i)) comprises adding the compound to a solution of the low chloride SBECD and the water. 7. The method of claim 6, wherein the compound is a crystalline form of the compound and has an X-ray powder diffraction pattern comprising 2 to 8 characteristic peaks expressed in degrees 2.theta. at 6.10, 9.32, 10.10, 12.14, 13.94, 18.44, 20.38, and 23.30. 8. The method of claim 1, wherein the first combination is a slurry or suspension and the method further comprises mixing the first combination, as a slurry or suspension, prior to contacting the first combination with an acid. 9. The method of claim 1, wherein the method further comprises mixing the second combination for a time sufficient to achieve a homogeneous third combination. 10. The method of claim 9, wherein the concentration of the compound in the third combination is from 1 mg/mL to 20 mg/mL. 11. The method of claim 9, wherein the pH of the third combination is from 2 to 4. 12. The method of claim 9, wherein the method further comprises filtering the third combination. 13. The method of claim 9, wherein the method further comprises lyophilizing the third combination to provide a lyophilizate. 14. The method of claim 13, wherein the method further comprises mixing the lyophilizate with sterile water for injection. 15. The method of claim 14, further comprising mixing the lyophilizate with citric acid. 16. A method for preparing a low chloride pharmaceutical composition, the method comprising: (i) providing a first combination comprising: (a) a compound having a structure: ##STR00016## or a pharmaceutically acceptable salt thereof; (b) low chloride SBECD; and (c) water for injection; wherein the low chloride SBECD has a chloride ion content of 0.05% w/w or less and the first combination is heterogeneous and the compound or salt has a low solubility in the first combination; and (ii) contacting the first combination with an aqueous solution of citric acid to form a second combination, wherein the compound is more soluble in the second combination than in the first combination. 17. The method of claim 16, wherein the first combination comprises less than 0.5% w/v of organic solvent or buffer. 18. The method of claim 16, wherein the second combination comprises a complex of the compound and the low chloride SBECD. 19. The method of claim 16, wherein the mole ratio of chloride ion to compound in the first combination is not more than 0.32. 20. The method of claim 16, wherein step (i) comprises adding the compound to a solution of the low chloride SBECD and the water. 21. The method of claim 20, wherein the compound is a crystalline form of the compound and has an X-ray powder diffraction pattern comprising 2 to 8 characteristic peaks expressed in degrees 2.theta. at 6.10, 9.32, 10.10, 12.14, 13.94, 18.44, 20.38, and 23.30. 22. The method of claim 16, wherein the method further comprises mixing the first combination prior to contacting the first combination with an acid. 23. The method of claim 16, wherein the method further comprises mixing the second combination for a time sufficient to achieve a homogeneous third combination. 24. The method of claim 23, wherein the concentration of the compound in the third combination is from 1 mg/mL to 20 mg/mL. 25. The method of claim 23, wherein the pH of the third combination is from 2 to 4. 26. The method of claim 23, wherein the method further comprises filtering the third combination. 27. The method of claim 23, wherein the method further comprises lyophilizing the third combination to provide a lyophilizate. 28. The method of claim 27, wherein the method further comprises mixing the lyophilizate with sterile water for injection. 29. The method of claim 28, further comprising mixing the lyophilizate with citric acid. 30. The method of claim 4, wherein the acid is citric acid.

Details for Patent 10,159,746

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Merck Sharp & Dohme Corp.	ZOSTAVAX	zoster vaccine live	For Injection	125123	05/25/2006		2032-05-08