# US 8,785,418 B2 · Lyophilization cakes of proteasome inhibitors > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 8,785,418 B2 - Document ID: US8785418B2 - Status: Granted - Kind: B2 - Application number: 13/248,398 - Filed: 2011-09-29 - Published: 2012-02-09 - Granted: 2014-07-22 - Earliest claimed: 2009-04-03 - Assignees: Cephalon, Inc. - Applicants: Denis Bricout; Helene Cambourieux; Michael L. Cappola; Nicole Frati; Piyush R. Patel - Inventors: Denis Bricout; Helene Cambourieux; Michael L. Cappola; Nicole Frati; Piyush R. Patel - Web page: https://patentgrep.com/patent/US8785418B2 ## CPC - A61K 9/19: lyophilised {, i.e. freeze-dried, solutions or dispersions (lyophilised products with subsequent particle size reduction A61K9/14; granules or pellets made by lyphilisation A61K9/1682; solid oral dosage forms made by lyophilisation A61K9/2095; lyophilisation additives A61K47/00)} - A61K 9/0095: {Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches (A61K9/0007 takes precedence; eatable gels or foams A61K9/0056; oral mucosa adhesive forms A61K9/006)} - A61K 31/69: Boron compounds - A61K 47/183: {Amino acids, e.g. glycine, EDTA or aspartame} - A61K 47/26: Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin - A61K 47/40: Cyclodextrins; Derivatives thereof - A61P 35/00: Antineoplastic agents - A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D) - A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS ## Abstract Lyophilized cakes of proteasome inhibitors are described, as well as methods for their production and use. ## Claims ### Claim 1 A lyophilized cake comprising: (a) a compound of Formula I or a pharmaceutically acceptable salt or ester thereof: wherein R1 is an optionally substituted 5-, 6-, or 10-membered heteroaryl having at least one N or R1 is an optionally substituted 6- or 10-membered aryl; (b) a cyclodextrin; and (c) a bulking agent comprising a monosaccharide. ### Claim 2 (depends on 1) The lyophilized cake of claim 1, wherein the compound of Formula I is ### Claim 3 (depends on 1) The lyophilized cake of claim 1, wherein the compound of Formula I is Compound 1 or a pharmaceutically acceptable salt or ester thereof. ### Claim 4 (depends on 3) The lyophilized cake of claim 3, wherein the drug is Compound 1. ### Claim 5 (depends on 3) The lyophilized cake of claim 3, further comprising a surfactant. ### Claim 6 (depends on 3) The lyophilized cake of claim 3, wherein the cyclodextrin is methyl-β-cyclodextrin, dimethyl-β-cyclodextrin, trimethyl-β-cyclodextrin, 2-hydroxymethyl-β-cyclodextrin, hydroxyethyl-β-cyclodextrin, 2-hydroxypropyl-β-cyclodextrin, 3-hydroxypropyl-β-cyclodextrin, β-cyclodextrin sulfate, β-cyclodextrin sulfonate, β-cyclodextrin sulfobutyl ether, or a mixture thereof. ### Claim 7 (depends on 3) The lyophilized cake of claim 3, wherein the lyophilized cake reconstitutes in about 90 seconds or less to provide a clear solution free of particulate matter. ### Claim 8 (depends on 3) The lyophilized cake of claim 3, further comprising a pH modifier. ### Claim 9 (depends on 8) The lyophilized cake of claim 8, wherein the pH modifier comprises an acid. ### Claim 10 (depends on 9) The lyophilized cake of claim 9, wherein the pH of the lyophilized cake is adjusted to a pH of about 4 or lower. ### Claim 11 (depends on 3) The lyophilized cake of claim 3, wherein the lyophilized cake exhibits a decrease in drug purity of no more than about 1% after storage for 6 months under accelerated conditions. ### Claim 12 (depends on 7) The lyophilized cake of claim 7, wherein the lyophilized cake exhibits a decrease in drug purity of no more than about 1% after storage for 6 months under accelerated conditions. ### Claim 13 (depends on 7) The lyophilized cake of claim 7, wherein the lyophilized cake exhibits a decrease in drug purity of no more than about 0.5% after storage for 6 month under accelerated conditions. ### Claim 14 A method for manufacturing a lyophilized cake comprising the steps of: (a) providing a first mixture comprising a cyclodextrin, a bulking agent comprising a monosaccharide, and water; (b) mixing a surfactant and a portion of the first mixture to form a second mixture; (c) combining a compound of Formula I, or a salt or ester thereof, and the second mixture to form a drug mixture; wherein R1 is an optionally substituted 5-, 6-, or 10-membered heteroaryl having at least one N or R1 is an optionally substituted 6- or 10-membered aryl; (d) mixing the remainder of the first mixture with the drug mixture to form a pre-lyophilization solution; and (e) lyophilizing the pre-lyophilization solution. ### Claim 15 A method for manufacturing a lyophilized cake comprising: (a) providing a first mixture containing a cyclodextrin, a bulking agent comprising a monosaccharide, and water; (b) providing a drug mixture containing a compound of Formula I, or a salt or ester thereof, and tert-butanol; wherein R1 is an optionally substituted 5-, 6-, or 10-membered heteroaryl having at least one N or R1 is an optionally substituted 6- or 10-membered aryl; (c) combining the first mixture and the drug mixture to provide a pre-lyophilization solution; and (d) lyophilizing the pre-lyophilization solution. ### Claim 16 (depends on 14) The method of claim 14, wherein the drug mixture contains Compound 10 ### Claim 17 (depends on 15) The method of claim 15, further comprising the step of adjusting the pH of the pre-lyophilization solution to a pH of about 4 or lower.