content_image/944874.jpg content_image/944872.jpg content_image/944873.jpg content_image/944838.jpg content_image/944878.jpg content_image/944879.jpg content_image/944880.jpg content_image/944876.jpg content_image/944877.jpg
# (12) United States Patent 

# Lewis et al. 

# (54) CYCLODEXTRIN COMPLEXATION METHODS FOR FORMULATING PEPTIDE PROTEASOME INHIBITORS 

(71) Applicant: Onyx Therapeutics, Inc., South San Francisco, CA (US) 

(72) Inventors: Evan Lewis, Pacifica, CA (US); Peter Shwonek, San Francisco, CA (US); Sean Dalziel, San Francisco, CA (US); Mouhannad Jumaa, Foster City, CA (US) 

(73) Assignee: Onyx Therapeutics, Inc., Thousand Oaks, CA (US) 

( *) Notice: Subject to any disclaimer, the term ofthis patent is extended or adjusted under 35 U.S.C. 154(b) by O days. 

(21) Appl. No.: 14/399,582 

(22) PCT Filed: May 8, 2013 

(86) PCT No.: PCT /US2013/040127 § 371 (c)(l), (2) Date: Nov. 7, 2014 

(87) PCT Pub. No.: WO2013/169897 PCT Pub. Date: Nov. 14, 2013 

## (65) Prior Publication Data 

US 2015/0111838 Al Apr. 23, 2015 

(60) Provisional application No. 61/777,475, filed on Mar. 12, 2013, provisional application No. 61/644,122, filed on May 8, 2012. 

(51) Int. Cl. 

<img src='content_image/944874.jpg'>

(52) U.S. Cl. CPC ........ A61K 47/48969 (2013.01); A61K 38107 (2013.01); A61K 4716951 (2017.08); B82Y 5100 (2013.01) 

(58) Field of Classification Search None See application file for complete search history. 

## (56) References Cited 

<img src='content_image/944872.jpg'>

<img src='content_image/944873.jpg'>

Whalen et al. (’Specific effects of chloride ion in epoxide hydro› lysis. The pH-dependence of the rates and mechanisms for the 

## Related U.S. Application Data 

(Continued) 

## U.S. PATENT DOCUMENTS 

(Continued) 

## FOREIGN PATENT DOCUMENTS 

(Continued) 

## OTHER PUBLICATIONS 

<img src='content_image/944838.jpg'>

# (IO) Patent No.: US 10,159,746 B2 

# (45) Date of Patent: Dec. 25, 2018 

hydrolysis of indene oxide’ Journal of the American Chemical Society v98(24) Nov. 24, 1976 pp. 7859-7861).* 

Primary Examiner - Karlheinz R. Skowronek Assistant Examiner - Ronald T Niebauer (74) Attorney, Agent, or Firm - Marshall, Gerstein & Borun LLP 

## (57) ABSTRACT 

This disclosure provides methods for formulating composi› tions comprising one or more peptide proteasome inhibitors and a cyclodextrin, particularly a substituted cyclodextrin. As well as cyclodextrin complexation methods of formulat› ing 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. 

<img src='content_image/944878.jpg'>

<img src='content_image/944879.jpg'>

<img src='content_image/944880.jpg'>

<img src='content_image/944876.jpg'>

<img src='content_image/944877.jpg'>

## Specification includes a Sequence Listing. 

US010159746B2 

(Continued) 

## 30 Claims, 8 Drawing Sheets 

