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WO 2018/144867 Al 09 August 2018 (09.08.2018) W!P O PCT

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WO 2018/144867 Al 09 August 2018 (09.08.2018) W!P O PCT (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 2018/144867 Al 09 August 2018 (09.08.2018) W!P O PCT (51) International Patent Classification: Diego, CA 92130 (US). LIN, Jui-chen; 8875 Costa Verde A61K 31/702 (2006.01) C12N 15/17 {2006.01) Blvd., Apt 1603, San Diego, CA 92122 (US). A61K 45/06 (2006.01) G01N 33/50 (2006.01) (74) Agent: LANGER, Michael, R. et al; Michael Best & CI2N 15/16 (2006.01) Friedrich LLP, 100 East Wisconsin Avenue, Suite 3300, (21) International Application Number: Milwaukee, W I 53218-4108 (US). PCT/US20 18/0 16647 (81) Designated States (unless otherwise indicated, for every (22) International Filing Date: kind of national protection available): AE, AG, AL, AM, 02 February 2018 (02.02.2018) AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DJ, DK, DM, DO, (25) Filing Language: English DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, (26) Publication Language: English HR, HU, ID, IL, IN, IR, IS, JO, JP, KE, KG, KH, KN, KP, KR, KW, KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, (30) Priority Data: MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, 62/454,613 03 February 2017 (03.02.2017) U S OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, (71) Applicant: VANDERBILT UNIVERSITY [US/US]; 305 SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, Kirkland Hall, 2201 West End Avenue, Nashville, TN TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. 37240 (US). (84) Designated States (unless otherwise indicated, for every (72) Inventors: CHERRINGTON, Alan; 8012 East Chase kind of regional protection available): ARIPO (BW, GH, Court, Nashville, TN 37221-4129 (US). MAGGS, David; GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, TZ, 6 Joy Street, Apt. 2, Boston, MA 02108 (US). GHOSH, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, Soumitra; 12334 Pathos Lane, San Diego, CA 92129 (US). TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, RHODES, Christopher, A.; 12868 Baywind Point, San EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM, (54) Title: SYSTEMS, COMPOSITIONS AND METHODS FOR TREATING DIABETES 100 Reservoir 150 Composition 201a 200 10 f ' 201b Pumping Mechanism 120 J FIG. 1 (57) Abstract: This disclosure provides methods for treatment comprising co-administering insulin and glucagon to a subject, and co- formulations comprising insulin and glucagon. [Continued on nextpage] WO 2018/144867 Al llll II II 11III II I 11II III I II II III II I II TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, KM, ML, MR, NE, SN, TD, TG). Published: SYSTEMS, COMPOSITIONS AND METHODS FOR TREATING DIABETES Cross Reference to Related Applications [001] This application claims the benefit of U.S. Provisional Application No. 62/454,613, filed February 3, 2017, the content of which is incorporated herein by reference in its entirety for all purposes. Field [002] The present disclosure provides systems, compositions and methods for treatment of a diabetic patient, and in particular to treatments including the co-administration of insulin and glucagon. Background [003] Treatment of a diabetic patient often includes delivery of insulin, such as via injections via syringe or an insulin delivery pump. Hypoglycemia is the complication feared most by patients with T1DM. It is a major barrier to effective treatment because people under dose insulin so as to avoid hypoglycemia. As a result, current treatments often result in inadequate glycemic control, involving undesired hypoglycemic and/or hyperglycemic events. [004] There is a need for systems, compositions, and methods that treat diabetic patients while reducing oscillations in blood glucose and hypoglycemic episodes. Summary [005] Embodiments of the systems, devices and methods described herein can be directed to systems, devices and methods for treatment of a diabetic patient. [006] In some aspects, the present disclosure provides methods of treatment comprising co-administering insulin and glucagon to a subject, wherein the insulin and glucagon are co administered at an insulin: glucagon molar ratio between about 1:1 and about 6:1, and wherein the insulin and glucagon are administered in an amount therapeutically effective to simultaneously treat or inhibit hyperglycemia and to inhibit hypoglycemia. For example, the insulin and glucagon may be co-administered at an insulin: glucagon molar ratio between about 1:1 and about 5 :1, between about 3 :1 and about 6 :1, or between about 3 :1 and about 5 :1. The subject may be hyperglycemic prior to co-administering the insulin and the glucagon. In some embodiments, co administering the insulin and the glucagon may comprise administering to the subject a co- formulation comprising insulin and glucagon. The co-formulation may comprise insulin at a concentration between about 1 mg/ml and about 10 mg/ml, and glucagon at a concentration between about 0.1 mg/ml and about 1 mg/ml. For example, the co-formulation may comprise insulin at a concentration between about 3 mg/ml and about 5 mg/ml, and glucagon at a concentration between about 0.1 mg/ml and about 0.8 mg/ml. The co-formulation may comprise a solvent that includes at least one non-aqueous solvent (e.g., an aprotic solvent, such as dimethyl sulfoxide and/or N-methylpyrrolidone). In some embodiments, between about 20% and about 60% of the solvent (v/v) consists of the one or more non-aqueous solvents. The solvent further may include one or more aqueous solvents. In some embodiments, no more than about 40% of the solvent (v/v) consists of the one or more aqueous solvents. In some embodiments, between about 10% and about 40% of the solvent (v/v) is propylene glycol (PG), glycerol or a combination of PG and glycerol. The co-administering of the insulin and the glucagon may comprise administering the insulin and the glucagon subcutaneously. Co-administering the insulin and glucagon may comprise administering insulin at a basal infusion rate of approximately 0.2-0.6 mU/kg/minute and administering glucagon at a basal infusion rate of approximately 1-4 ng/kg/minute. For example, the insulin may be administered at a basal infusion rate of approximately 0.3-0.5 mU/kg/minute, and/or the glucagon may be administered at a basal infusion rate of approximately 2-3 ng/kg/minute. [007] In some aspects, the present disclosure provides co-formulations comprising insulin at a concentration between about 1 mg/ml and about 10 mg/ml, and glucagon at a concentration between about 0.1 mg/ml and about 1 mg/ml, wherein the molar ratio of insulin: glucagon is between about 1:1 and about 6:1. For example, the molar ratio of insulin:glucagon may be between about 1:1 and about 5:1, between about 3:1 and about 6:1, or between about 3:1 and about 5:1. The insulin may be at a concentration between about 3 mg/ml and about 5 mg/ml, and the glucagon may be at a concentration between about 0.1 mg/ml and about 0.8 mg/ml. The co-formulations may further comprise a solvent that includes one or more aqueous solvents and one or more non-aqueous solvents (e.g. an aprotic solvent such as DMSO and/or NMP). In some embodiments, between about 20% and about 60% of the solvent (v/v) may consist of the one or more non-aqueous solvents. The solvent further may include one or more aqueous solvents. In some embodiments, no more than about 40% of the solvent (v/v) may consist of the one or more aqueous solvents. In some embodiments, between about 10% and about 40% of the solvent may be propylene glycol (PG), glycerol, or a combination of PG and glycerol. [008] The technology described herein, along with the attributes and attendant advantages thereof, will best be appreciated and understood in view of the following detailed description taken in conjunction with the accompanying drawings in which representative embodiments are described by way of example. Brief Description of the Drawings [009] Fig. 1 illustrates a system for delivering a composition to a patient, comprising a single pumping device with a single reservoir, consistent with the present inventive concepts. [010] Fig. 1A illustrates a system for delivering a composition to a patient, comprising a single pumping device with two reservoirs, consistent with the present inventive concepts. [Oil] Fig. IB illustrates a system for delivering a composition to a patient, comprising two pumping devices, consistent with the present inventive concepts. [012] Figs. 2-15 illustrate data from mammalian studies conducted by applicant, consistent with the present inventive concepts. [013] Fig. 16 illustrates a protocol of a mammalian study conducted by applicant, consistent with the present inventive concepts. [014] Figs. 17-46 illustrate data from mammalian studies conducted by applicant, consistent with the present inventive concepts. [015] Figs. 47-48 illustrates data from mammalian studies conducted by applicant in which a co-formulation of insulin and glucagon was used, consistent with the present inventive concepts. [016] Fig. 49 illustrates an experimental timeline of a mammalian study conducted by applicant to assess the ability of glucagon to increase and sustain increase glucose production when presented with insulin-induced hypoglycemia, consistent with the preset inventive concepts.
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