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(19) United States (12) Patent Application Publication (10) Pub US 20140221285A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2014/0221285 A1 BLEY et al. (43) Pub. Date: Aug. 7, 2014 (54) STABILIZED PHARMACEUTICAL (22) Filed: Feb. 4, 2014 FORMULATIONS OF INSULIN ANALOGUES AND/OR INSULIN DERIVATIVES Related U.S. Application Data (60) Provisional application No. 61/761,434, ?led on Feb. (71) Applicants:Oliver BLEY, Frankfurt am Main (DE); 6, 2013. Petra LOOS, Frankfurt am Main (DE); Bernd BIDLINGMAIER, Frankfurt am (30) Foreign Application Priority Data Main (DE); Walter KAMM, Frankfurt am Main (DE); Harald BERCHTOLD, Feb. 4, 2013 (EP) ................................ .. 133051268 Frankfurt am Main (DE) Publication Classi?cation (72) Inventors: Oliver BLEY, Frankfurt am Main (DE); Petra LOOS, Frankfurt am Main (DE); (51) Int. Cl. Bernd BIDLINGMAIER, Frankfurt am A61K 38/28 (2006.01) Main (DE); Walter KAMM, Frankfurt (52) U.S. Cl. am Main (DE); Harald BERCHTOLD, CPC .................................... .. A61K38/28 (2013.01) Frankfurt am Main (DE) USPC ......................................................... .. 514/6.4 (73) Assignee: SANOFI, Paris (FR) (57) ABSTRACT Stabilized pharmaceutical formulations of insulin analogues (21) Appl. No.: 14/172,151 and/or insulin derivatives are disclosed. Patent Application Publication Aug. 7, 2014 US 2014/0221285 A1 0104) FigureLC/MSofTRISbufferedformulation(formulation1:no. US 2014/0221285 A1 Aug. 7, 2014 STABILIZED PHARMACEUTICAL (Pharmaceutical Research, Vol. 7, No. 6, pp. 593-599, 1990) FORMULATIONS OF INSULIN ANALOGUES disclose chemical pathways of peptide degradation. Patel et AND/OR INSULIN DERIVATIVES al. (Pharmaceutical Research, Vol. 7, No. 7, pp. 703-711, 1990) disclose chemical pathways of peptide degradation. CROSS REFERENCE TO RELATED Tyler-Cross et al. (Journal of Biological Chemistry, Vol. 266, APPLICATION No. 33, Issue ofNovember 25, pp. 22549-22556, 1991) dis [0001] This application is related to and claims the bene?t close effects of amino acid sequence, buffers, and ionic of US. Provisional Patent Application Ser. No. 61/761,434 strength on the rate and mechanism of deamidation of aspar ?led Feb. 6, 2013, the entire contents of which are incorpo agine residues in small peptides. GB 840,870 discloses rated by reference herein. improvements in or relating to insulin preparations. US. Pat. No. 6,852,694 discloses stabilized insulin formulations. Gal INTRODUCTION loway et al. (DiabetesiThe Journal of the American Diabe tes Association, Vol. 21, No. Suppl.2, pp. 637-648, 1972) [0002] The present invention relates to a pharmaceutical disclose new forms of insulin. Jackson et al. disclose several formulation of at least one insulin analogue and/or insulin aspects with regard to neutral regular insulin (DiabetesiThe derivative, a process for preparing the pharmaceutical formu Journal of the American Diabetes Association, Vol. 21 , No. 4, lation of at least on insulin analogue and/ or insulin derivative, pp. 235-245, 1972). Lill (PharmaZie in unserer Zeit, No. 1, pp. and a related kit. It also relates to the pharmaceutical formu 56-61, 2001) discloses general aspects in connection with lation of at least one insulin analogue and/ or insulin derivative insulin formulations. The German product speci?cation of and to the related kit for use in the treatment of diabetes the medicinal product Berlinsulin® H Normal 3 mL Pen mellitus, hyperglycemia, and/or for use in lowering blood discloses a formulation containing human insulin, meta glucose levels. The present invention also relates to the use of cresol, glycerol, water and optionally hydrochloric acid and a medical device for administering the pharmaceutical for sodium hydroxide. The German product speci?cation of the mulation of at least one insulin analogue and/or insulin medicinal product Actrapid® discloses a formulation con derivative to an animal and/ or human. taining human insulin, Zinc chloride, glycerol, metacresol, sodium hydroxide, hydrochloric acid and water. BACKGROUND OF THE INVENTION [0007] The solubility of insulin, insulin analogues and/or [0003] Diabetes mellitus is a metabolic disorder in which insulin derivatives in aqueous media depends on the pH value. the ability to utilize glucose is more or less completely lost. For example, the lowest solubility is shown close to the iso [0004] For decades, insulin has been used in the treatment electric point which for human insulin is around pH 5.3 and of diabetes mellitus. Several insulin formulations have been 5.4. Very good solubility can be observed at pH values below developed, e.g. insulin Zinc (Zn (II)) suspension, formula 4 and above 7. However, insulin suffers from degradation at tions containing protamine, etc. Further, the active pharma strong acidic conditions and strong alkaline conditions. ceutical ingredient insulin itself has been modi?ed by devel Therefore, most of the medicinal products containing insulin, oping fast acting insulin analogues (e.g. insulin aspart, insulin insulin analogues and/or insulin derivatives have a pH value lispro, insulin glulisine) and long acting insulin analogues in the range of 7.2 to 7.4 and mostly buffering agents are used and derivatives (e.g. insulin detemir, insulin degludec, insulin to achieve and maintain the pH within this range. glargin). Fast acting insulin preparations are usually solutions [0008] It has now surprisingly been found that an altema of insulin, while long acting insulin preparations can be sus tive aqueous pharmaceutical formulation comprising at least pensions containing insulin in crystalline and/ or amorphous one insulin analogue and/or insulin derivative comprising form precipitated by the addition of Zinc (Zn(II)) salts (e.g. sodium chloride, without any additional buffering agent, Zinc chloride) alone or by addition of protamine or by a shows an excellent chemical and physical stability, which combination of both. quali?es this aqueous pharmaceutical formulation as a [0005] The chemical and physical stability of insulin for medicinal product having a de?ned shelf life. mulations is very important. Insulin formulations are often administered by using pen injection devices or insulin pumps SUMMARY OF THE INVENTION in which an insulin formulation is stored in cartridges until the [0009] One embodiment of the present invention relates to entire cartridge is empty. Insulin formulations may also be a pharmaceutical formulation comprising stored in vials, requiring a stable formulation with respect to chemical and physical stability across the shelf life of the (a). at least one analogue and/ or derivative of insulin; and formulation. [0006] The chemical and/or physical stability of insulin, (b). Zn(II); and insulin analogues and/ or insulin derivatives strongly depends [0010] (c). sodium chloride; and on the pharmaceutical formulation, e.g. the solvent, the pH (d). optionally protamine; value and the excipients. Brange et al. (Acta Pharm. Nord. 4(3), pp. 149-158, 1992) disclose several aspects in connec wherein the pharmaceutical formulation has a pH value in the tion with the chemical stability of insulin. WO 2004/080480 range of from 6.0 to 9.0 and is free of any additional buffering discloses pharmaceutical preparations comprising acid-sta agent. bilized insulin. GB 835,638 discloses insulin crystal suspen [0011] In another embodiment, the pharmaceutical formu sions having a protracted effect. WO 98/56406 discloses lation according to the present invention is an aqueous phar stable insulin formulations. US. Pat. No. 6,489,292 discloses maceutical composition. stable aqueous insulin preparations without phenol and [0012] In another embodiment, the pharmaceutical formu cresol. US. Pat. No. 6,211,144 discloses stable concentrated lation according to the present invention does not contain any insulin preparations for pulmonary delivery. Bhatt et al. additional buffering agent. US 2014/0221285 A1 Aug. 7, 2014 [0013] In another embodiment, the pharmaceutical formu In one embodiment, the pharmaceutical formulation accord lation according to the present invention does not contain any ing to the present invention comprises an analogue of insulin additional buffering agent other than the at least one analogue Which is insulin glulisine. and/ or derivative of insulin and the optionally present prota [0023] In another embodiment, the pharmaceutical formu mme. lation according to the present invention comprises a deriva [0014] In another embodiment, the pharmaceutical formu tive of insulin Which is selected from the group consisting of lation according to the present invention is free of any addi insulin detemir and/ or insulin degludec. In one embodiment, tional buffering agent selected from the group consisting of the pharmaceutical formulation according to the present 2-amino-2-hydroxymethyl-propane-1,3-diol (TRIS), phos invention comprises a derivative of insulin Which is insulin phate, citric acid or citrate salts, acetic acid and salts thereof, detemir. In one embodiment, the pharmaceutical formulation glycylglycine and methionin. according to the present invention comprises a derivative of insulin Which is insulin degludec. [0015] In another embodiment, the pharmaceutical formu lation according to the present invention does not contain any [0024] In another embodiment, the pharmaceutical formu additional buffering agent selected from the group consisting lation according to the present invention comprises at least of 2-amino-2-hydroxymethyl-propane-1,3-diol (TRIS), one analogue and/or derivative of insulin Which is present in phosphate,
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