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WO 2017/095848 Al 8 June 2017 (08.06.2017) W P O P C T (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date WO 2017/095848 Al 8 June 2017 (08.06.2017) W P O P C T (51) International Patent Classification: DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, A61K 47/42 (2017.01) A61K 39/395 (2006.01) HN, HR, HU, ID, IL, IN, IR, IS, JP, KE, KG, KN, KP, KR, A61K 39/00 (2006.01) A61K 47/00 (2006.01) KW, KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, (21) International Application Number: OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, PCT/US20 16/064080 SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, (22) International Filing Date: TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, 30 November 2016 (30.1 1.2016) zw. (25) Filing Language: English (84) Designated States (unless otherwise indicated, for every kind of regional protection available): ARIPO (BW, GH, (26) Publication Language: English GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, (30) Priority Data: TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, 62/260,677 30 November 2015 (30. 11.2015) US TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, (71) Applicant: MEDIMMUNE, LLC [US/US]; One Medim- LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, mune Way, Gaithersburg, MD 20878 (US). SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, KM, ML, MR, NE, SN, TD, TG). (72) Inventors: PATEL, Sajal, M.; c/o Medimmune, LLC, One Medimmune Way, Gaithersburg, MD 20878 (US). Declarations under Rule 4.17 : PANSARE, Swapnil, K.; c/o Medimmune, LLC, One — as to applicant's entitlement to apply for and be granted a Medimmune Way, Gaithersburg, MD 20878 (US). patent (Rule 4.1 7(H)) (74) Agents: SCOTT, Derek et al; c/o Medimmune, LLC, One — as to the applicant's entitlement to claim the priority of the Medimmune Way, Gaithersburg, MD 20878 (US). earlier application (Rule 4.1 7(in)) (81) Designated States (unless otherwise indicated, for every Published: kind of national protection available): AE, AG, AL, AM, AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, — with international search report (Art. 21(3)) BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DJ, DK, DM, (54) Title: OPTIMIZED RATIOS OF AMINO ACIDS AND SUGARS AS AMORPHOUS STABILIZING COMPOUNDS IN PHARMACEUTICAL COMPOSITIONS CONTAINING HIGH CONCENTRATIONS OF PROTEIN-BASED THERAPEUTIC AGENTS : 77 C - — , ,—, , , , ,— , -—, , , Temperatu re (¾) Figure 1 (57) Abstract: The present invention relates to improved pharmaceutical compositions that contain high concentrations of one or more protein biomolecule(s). In particular, the invention relates to pharmaceutical compositions that include an optimized ratio of protein biomolecule to an amorphous stabilizing compound or compounds, especially a sugar, such as sucrose, trehalose, glucose, lactose or sorbitol, or mixtures thereof, or one or more amino acid molecules such as arginine, alanine, glycine, lysine or proline, or derivatives and salts thereof, or mixtures thereof. The inclusion of such amorphous stabilizing compound(s), at such optimized ratio, provides acceptable long-term stability of the protein biomolecule, and facilitates shorter lyophilization time, more specifically short er drying time, even more specifically shorter primary drying time. Title Of The Invention: Optimized Ratios of Amino Acids and Sugars as Amorphous Stabilizing Compounds in Pharmaceutical Compositions Containing High Concentrations of Protein-Based Therapeutic Agents Field Of The Invention [0001] The present invention relates to improved pharmaceutical compositions that contain high concentrations of one or more protein biomolecule(s). In particular, the invention relates to pharmaceutical compositions that include an optimized ratio of protein biomolecule to an amorphous stabilizing compound or compounds, especially a sugar, such as sucrose, trehalose, glucose, lactose or sorbitol, or mixtures thereof, or one or more amino acid molecules such as arginine, alanine, glycine, lysine or proline, or derivatives and salts thereof, or mixtures thereof. The inclusion of such amorphous stabilizing compound(s), at such optimized ratio, provides acceptable long-term stability of the protein biomolecule, and facilitates shorter lyophilization time, more specifically shorter drying time, even more specifically shorter primary drying time. Background Of The Invention [0002] Protein-based therapeutic agents (e.g., hormones, enzymes, cytokines, vaccines, immunotherapeutics, etc.) are becoming increasingly important to the management and treatment of human disease. As of 2014, more than 60 such therapeutics had been approved for marketing, with approximately 140 additional drugs in clinical trial and more than 500 therapeutic peptides in various stages of preclinical development (Fosgerau, K. et al. (2014) "Peptide Therapeutics: Current Status And Future Directions,'" Drug Discov. Today 20(1):122-128; Kaspar, A.A. et al. (2013) "Future Directions For Peptide Therapeutics Development," Drug Discov. Today 18:807- 817). [0003] One impediment to the use of such therapeutics is the physical instability that is often encountered upon their storage (US Patent No. 8,617,576; PCT Publications No. WO 2014/100143 and 2015/061584; Balcao, V.M. et al. (2014) "Structural And Functional Stabilization Of Protein Entities: State-Of-The-Art Adv. Drug Deliv. Rev. (Epub.): doi: 10.1016/j.addr.2014.10.005; pp. 1-17; Maddux, N.R. et al. (2011) "Multidimensional Methods For The Formulation Of Biopharmaceuticals And Vaccines,'" J. Pharm. Sci. 100:4171-4197; Wang, W. (1999) "Instability, Stabilization, And Formulation Of Liquid Protein Pharmaceuticals " Int. J. Pharm. 185:129-188; Kristensen, D. et al. (2011) "Vaccine Stabilization: Research, Commercialization, And Potential Impact," Vaccine 29:7122-7124; Kumru, O.S. et al. (2014) "Vaccine Instability In The Cold Chain: Mechanisms, Analysis And Formulation Strategies," Biologicals 42:237-259). Such instability may comprise multiple aspects. A protein-based therapeutic agent may, for example experience operational instability, such as an impaired ability to survive processing operations {e.g., sterilization, lyophilization, cryopreservation, etc.). Additionally or alternatively, proteins may experience thermodynamic instability such that a desired secondary or tertiary conformation is lost or altered upon storage. A further, and especially complex problem, lies in the stabilization of therapeutic agents that comprise multimeric protein subunits, with dissociation of the subunits resulting in the inactivation of the product. Kinetic instability is a measure of the capacity of a protein to resist irreversible changes of structure in in vitro non-native conditions. Protein aggregation and the formation of inclusion bodies is considered to be the most common manifestation of instability, and is potentially encountered in multiple phases of product development (Wang, W . (2005) "Protein Aggregation And Its Inhibition In Biopharmaceutics," Int. J. Pharm. 289:1-30; Wang, W. (1999) "Instability, Stabilization, And Formulation Of Liquid Protein Pharmaceuticals," Int. J. Pharm. 185:129-188; Arakawa, T. et al. (1993) "Factors Affecting Short-Term And Long-Term Stabilities Of Proteins," Adv. Drug Deliv. Rev. 10:1-28; Arakawa, T. et al. (2001) "Factors Affecting Short-Term And Long-Term Stabilities Of Proteins," Adv. Drug Deliv. Rev. 46:307-326). Such issues of instability can affect not only the efficacy of the therapeutic but its immunogenicity to the recipient patient. Protein instability is thus one of the major drawbacks that hinders the use of protein-based therapeutic agent (Balcao, V.M. et al. (2014) "Structural And Functional Stabilization Of Protein Entities: State-Of-The-Art," Adv. Drug Deliv. Rev. (Epub.): doi: 10. 1016/j.addr.2014. 10.005; pp. 1-17). [0004] Stabilization of protein-based therapeutic agents entails preserving the structure and functionality of such agents, and has been accomplished by establishing a thermodynamic equilibrium between such agents and their (micro)environment (Balcao, V.M. et al. (2014) "Structural And Functional Stabilization Of Protein Entities: State-Of-The-Art," Adv. Drug Deliv. Rev. (Epub.): doi: 10. 1016/j.addr.2014. 10.005; pp. 1-17). One approach to stabilizing protein- based therapeutic agents involves altering the protein to contain additional covalent (e.g., disulfide) bonds so as to increase the enthalpy associated with a desired conformation. Alternatively, the protein may be modified to contain additional polar groups so as to increase its hydrogen bonding with solvating water molecules (Mozhaev, V.V. et al. (1990) "Structure-Stability Relationships In Proteins: A Guide To Approaches To Stabilizing Enzymes " Adv. Drug Deliv. Rev. 4:387-419; Iyer, P.V. et al. (2008) "Enzyme Stability And Stabilization — Aqueous And Non-Aqueous Environment " Process Biochem. 43:1019-1032). [0005] A second approach to stabilizing protein-based therapeutic agents involves reducing the chemical activity of the water present in the protein's microenvironment, for example by freezing the water, adding specific solutes, or lyophilizing the pharmaceutical composition (see, e.g., Castronuovo, G. (1991) "Proteins In Aqueous Solutions. Calorimetric Studies And Thermodynamic Characterization " Thermochim. Acta 193:363-390). [0006] Employed solutes range from small
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