US010159746B2  (IO)  Patent No.:  US 10,159,746 B2  (45)  Date of Patent:  Dec. 25, 2018  (12)  United States Patent  Lewis et al.  (54)  CYCLODEXTRIN COMPLEXATION  METHODS FOR FORMULATING PEPTIDE  PROTEASOME INHIBITORS  Specification includes a Sequence Listing.  OTHER PUBLICATIONS  FOREIGN PATENT DOCUMENTS  U.S. PATENT DOCUMENTS  (56)  References Cited  Related U.S. Application Data  (65)  Prior Publication Data  (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  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.  (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.  Whalen et al. (’Specific effects of chloride ion in epoxide hydro› lysis. The pH-dependence of the rates and mechanisms for the  30 Claims, 8 Drawing Sheets  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.  hydrolysis of indene oxide’ Journal of the American Chemical  Society v98(24) Nov. 24, 1976 pp. 7859-7861).*  (Continued)  (Continued)  (Continued)  4,522,811 A  5,831,081 A  6/1985 Eppstein et al.  ll/ 1998 Reuscher  WO  WO  WO-98/10779 Al  WO-2002/30455 A2  3/1998  4/2002  A61K  47140  A61K  47148  (2006.01)  (2006.01)  (Continued)  (1)  R,0~5yij0~Y  R 1  0  R 3  0  (2)  (3)  (5)  Primary Examiner  - Karlheinz R. Skowronek  Assistant Examiner  - Ronald T Niebauer  (74)  Attorney, Agent, or Firm  - Marshall, Gerstein &  Borun LLP  (57)  ABSTRACT 