Stabilized pharmaceutical formulations of insulin analogues and/or insulin derivatives

The present invention relates to a pharmaceutical preparation of at least one insulin analog and / or insulin derivative, a method for producing a pharmaceutical preparation of at least one insulin analog and / or insulin derivative, and a related kit. The present invention also relates to pharmaceutical formulations of at least one insulin analog and / or insulin derivative and related kits for use in the treatment of diabetes mellitus, hyperglycemia, and / or in lowering blood glucose levels. The present invention also relates to the use of medical devices for administering a pharmaceutical formulation of at least one insulin analog and / or insulin derivative to animals and / or humans.

Diabetes mellitus is a metabolic disorder in which the ability to utilize glucose is almost completely lost.

For decades, insulin has been used to treat diabetes mellitus. Several insulin preparations have been developed, such as zinc (Zn (II)) suspensions, protamine-containing preparations, and the like. In addition, the active pharmaceutical ingredient insulin itself develops fast-acting insulin analogs (eg insulin aspart, insulin lispro, insulin glargine) and long-acting insulin analogs and derivatives (eg insulin detemil, insulin degludec, insulin glargine). It has been improved by that. Fast-acting insulin preparations are usually solutions of insulin, whereas long-acting insulin preparations are made with the addition of zinc (Zn (II)) salts (eg, zinc chloride) alone, or with the addition of protamine, or. It can be a suspension containing insulin in crystalline and / or amorphous form precipitated by a combination of both.

The chemical and physical stability of insulin preparations is very important. Insulin preparation is often administered using a pen-type injection device or insulin pump in which the insulin preparation is stored in the cartridge until the cartridge is completely empty. Insulin preparations may also be stored in vials, and there is a need for a stable preparation with respect to the chemical and physical stability related to the shelf life of the preparation.

The chemical and / or physical stability of insulin, insulin analogs and / or insulin derivatives is strongly dependent on the pharmaceutical product, such as solvent, pH value and excipients. Brange et al. (Non-Patent Document 1) disclose several aspects in relation to the chemical stability of insulin. Patent Document 1 discloses a pharmaceutical preparation containing acid-stabilized insulin. Patent Document 2 discloses an insulin crystal suspending agent having a delaying action. Patent Document 3 discloses a stable insulin preparation. Patent Document 4 discloses a stable aqueous insulin preparation containing no phenol and cresol. Patent Document 5 discloses a stable concentrated insulin preparation for pulmonary delivery. Bhatt et al. (Non-Patent Document 2) disclose the chemical pathway of peptide degradation. Patel et al. (Non-Patent Document 3) disclose the chemical pathway of peptide degradation. Tyler-Cross et al. (Non-Patent Document 4) disclose the effects of amino acid sequences, buffers and ion concentrations on the rate and mechanism of amide degradation of asparagine residues in small peptides. Patent Document 6 discloses improvements in or related to insulin preparations. Patent Document 7 discloses a stabilized insulin preparation. Galloway et al. (Non-Patent Document 5) disclose a new form of insulin. Jackson et al. Disclose some aspects of neutral regular insulin (Non-Patent Document 6). Lill (Non-Patent Document 7) discloses a general aspect in relation to an insulin preparation. Pharmaceuticals Berlinsulin^(R)The German product specifications for the H Normal 3 mL Pen disclose formulations containing human insulin, metacresol, glycerol, water and optionally hydrochloric acid and sodium hydroxide. Pharmaceutical Actrapid^(R)German product specifications disclose formulations containing human insulin, zinc chloride, glycerol, metacresol, sodium hydroxide, hydrochloric acid and water.

The solubility of insulin, insulin analogs and / or insulin derivatives in an aqueous medium depends on the pH value. For example, the lowest solubility is shown near the isoelectric point near pH 5.3 and 5.4 for human insulin. Very good solubility can be observed at pH values below 4 and above 7. However, insulin is degraded under strong acid and alkaline conditions. Therefore, most pharmaceuticals containing insulin, insulin analogues and / or insulin derivatives have a pH value in the range of 7.2-7.4, and in most cases to reach and maintain pH within this range. , Insulin is used.

Here, surprisingly, an alternative aqueous pharmaceutical formulation containing at least one insulin analog and / or insulin derivative, containing sodium chloride, and no additional buffer exhibits excellent chemical and physical stability. Therefore, it was found that this aqueous pharmaceutical preparation is suitable as a drug having a definite shelf life.

<p><patcit num="1"><text>WO2004 / 080480</text></patcit><patcit num="2"><text>GB835,638</text></patcit><patcit num="3"><text>WO98 / 56406</text></patcit><patcit num="4"><text>US6,489,292</text></patcit><patcit num="5"><text>US6,211,144</text></patcit><patcit num="6"><text>GB840,870</text></patcit><patcit num="7"><text>US6,852,694</text></patcit></p>

<p><nplcit num="1"><text>Brange et al., Acta Pharm. Nord. 4 (3), pp. 149-158, 1992</text></nplcit><nplcit num="2"><text>Bhatt et al., Pharmaceutical Research, Vol. 7, No. 6, pp. 593-599, 1990</text></nplcit><nplcit num="3"><text>Patel et al., Pharmaceutical Research, Vol. 7, No. 7, pp. 703-711, 1990</text></nplcit><nplcit num="4"><text>Tyler-Cross et al., Journal of Biological Chemistry, Vol. 266, No. 33, Issue of November 25, pp. 22549-22556, 1991</text></nplcit><nplcit num="5"><text>Galloway et al., Diabetes --The Journal of the American Diabetes Association, Vol. 21, No. Suppl.2, pp. 637-648, 1972</text></nplcit><nplcit num="6"><text>Jackson et al., Diabetes --The Journal of the American Diabetes Association, Vol. 21, No. 4, pp. 235-245, 1972</text></nplcit><nplcit num="7"><text>Lill, Pharmazie in unserer Zeit, No. 1, pp. 56-61, 2001</text></nplcit></p>

<p> One embodiment of the invention is (a). Analogs and / or derivatives of at least one insulin; and (b). Zn (II); and (c). Sodium chloride; and (d). Possibly protamine; The pharmaceutical formulation comprising, wherein the pharmaceutical formulation has a pH value in the range of 6.0 to 9.0 and does not contain any additional buffer.</p><p> In another embodiment, the pharmaceutical preparation according to the present invention is an aqueous pharmaceutical composition.</p><p> In another embodiment, the pharmaceutical formulation according to the invention does not contain any additional buffer.</p><p> In another embodiment, the pharmaceutical formulation according to the invention does not contain any additional buffering agent other than at least one insulin analog and / or derivative and optionally protamine.</p><p> In another embodiment, the pharmaceutical formulation according to the invention comprises 2-amino-2-hydroxymethyl-propane-1,3-diol (TRIS), phosphate, citric acid or citrate, acetic acid and salts thereof, grease. It does not contain any additional buffer selected from the group consisting of sylglycine as well as methionine.</p><p> In another embodiment, the pharmaceutical formulation according to the invention comprises 2-amino-2-hydroxymethyl-propane-1,3-diol (TRIS), phosphate, citric acid or citrate, acetic acid and salts thereof, grease. It does not contain any additional buffer selected from the group consisting of sylglycine as well as methionine.</p><p> In another embodiment, the pharmaceutical formulation according to the invention comprises at least one insulin analog and / or derivative and optionally protamine, wherein the single component involved in any buffering activity is at least one insulin analog. And / or derivatives and optionally protamine.</p><p> In another embodiment, the pharmaceutical formulation according to the invention comprises at least one analog and / or derivative of insulin and optionally protamine, wherein the total concentration of any buffer in the present invention is 3.494 mg / mL ( Rounded: 3.5 mg / mL) to 3.996 mg / mL (Rounded: 4.0 mg / mL), 3.496 mg / mL (Rounded: 3.5 mg / mL) to 3.816 mg / mL (Rounded) : 3.8 mg / mL), or the total concentration of any buffer in the present invention is 3.496 mg / mL (rounded to the nearest 3.5 mg / mL).</p><p> In another embodiment, the pharmaceutical formulations according to the invention are: (a). Analogs and / or derivatives of at least one insulin; and (b) Zn (II); and (c). Sodium chloride; and (d). Possibly protamine; and (e). Metacresol; (f). Phenol; and (g). Polysorbate 20; and (h). Sodium hydroxide and sodium hydroxide to adjust the pH value to the range of 6.0 to 9.0. / Or hydrochloric acid; and (i). Consists of water.</p><p> In another embodiment, the pharmaceutical product according to the present invention is an aqueous pharmaceutical product.</p><p> In another embodiment, the pharmaceutical formulation according to the invention has an isoelectric point (IEP) in the range 4.0 to 6.0, 4.5 to 6.0, 4.5 to 5.5, 5.0 to 5.5, 5.0 to 5.2 or 5.1. Includes at least one insulin analog and / or derivative.</p><p> In another embodiment, the pharmaceutical formulation according to the invention has a pH value ranging from 6.5 to 8.5, 7.0 to 8.0, 7.0 to 7.8, 7.1 to 7.6, 7.2, 7.3, 7.4 or 7.5, or 7.4. Has.</p><p> In another embodiment, the pharmaceutical formulation according to the invention comprises at least one insulin analog selected from the group consisting of insulin aspart, insulin lispro and / or insulin gluricin. In one embodiment, the pharmaceutical formulation according to the invention comprises an analog of insulin, which is insulin lispro. In one embodiment, the pharmaceutical formulation according to the invention comprises an analog of insulin, which is insulin aspart. In one embodiment, the pharmaceutical formulation according to the invention comprises an analog of insulin, which is insulin gluricin.</p><p> In another embodiment, the pharmaceutical formulation according to the invention comprises a derivative of insulin selected from the group consisting of insulin detemir and / or insulin degludec. In one embodiment, the pharmaceutical formulation according to the invention comprises a derivative of insulin, which is insulin detemir. In one embodiment, the pharmaceutical formulation according to the invention comprises a derivative of insulin, which is insulin degludec.</p><p> In another embodiment, the pharmaceutical formulation according to the invention is 10 U / mL to 1000 U / mL, 10 U / mL to 600 U / mL, 10 U / mL to 300 U / mL, 50 U / mL to 300 U / mL, or Contains at least one insulin analog and / or derivative present at a concentration of 100 U / mL.</p><p> In another embodiment, the pharmaceutical formulation according to the invention is from 60 to 6000 nmol / mL, from 60 nmol / mL to 3600 nmol / mL, from 60 nmol / mL to 1800 nmol / mL, from 300 nmol / mL to 1800 nmol / mL, or 600 nmol / mL. Contains analogs and / or derivatives of insulin present at a concentration of mL.</p><p> In another embodiment, the pharmaceutical formulation according to the invention is 0.0100 mg / mL to 0.0600 mg / mL, 0.0150 mg / mL to 0.0500 mg / mL, 0.0150 mg / mL to 0.0300 mg / mL, 0.0150 mg / mL. Includes Zn (II) present at concentrations from 0.0196 mg / mL to 0.0200 mg / mL, or 0.0196 mg / mL.</p><p> In another embodiment, the pharmaceutical formulations according to the invention are 0.0100 mg / 100 U to 0.0600 mg / 100 U, 0.0150 mg / 100 U to 0.0500 mg / 100 U, 0.0150 mg / 100 U to 0.0300 mg / 100 U, 0.0150 mg / 100 U. Includes Zn (II) present at concentrations from to 0.0200 mg / 100 U, from 0.0190 mg / 100 U to 0.0200 mg / 100 U, or 0.0196 mg / 100 U.</p><p> In another embodiment, the pharmaceutical formulation according to the invention is 0.01 mg / mL to 15 mg / mL, 0.1 mg / mL to 15 mg / mL, 0.1 mg / mL to 10 mg / mL, 1 mg / mL to 10 mg / mL. From 2.0 mg / mL to 10 mg / mL, from 3.0 mg / mL to 9.0 mg / mL, from 4.0 mg / mL to 9.0 mg / mL, from 5.0 mg / mL to 9.0 mg / mL, from 6.0 mg / mL Up to 9.0 mg / mL, from 6.8 mg / mL to 8.3 mg / mL, 6.9 mg / mL, 7.0 mg / mL, 7.1 mg / mL, 7.2 mg / mL, 7.3 mg / mL, 7.4 mg / mL, 7.5 mg / At concentrations of mL, 7.6 mg / mL, 7.7 mg / mL, 7.8 mg / mL, 7.9 mg / mL, 8.0 mg / mL, 8.1 mg / mL, 8.2 mg / mL or 8.3 mg / mL, or 6.8 mg / mL Contains existing sodium chloride.</p><p> In another embodiment, the pharmaceutical formulation according to the invention comprises protamine or protamine sulfate present at concentrations from 0.10 to 0.15, 0.20, 0.25, 0.30, 0.32, 0.35, 0.40, 0.45 or 0.5 mg / mL.</p><p> In another embodiment, the pharmaceutical formulation according to the invention comprises a stabilizer, which in one embodiment is a surfactant, a polyoxyethylene derivative of sorbitan monolaurate (eg, polysorbate 20), polyethoxylethylene oleic acid. Derivatives (eg, polysorbate 80), poloxamers (which are polyoxyethylene-polyoxypropylene copolymers), or polysorbate 20 or polysorbate 80 or mixtures thereof. In another embodiment, the stabilizer is, in one embodiment, a surfactant, a polyoxyethylene derivative of sorbitan monolaurate (eg, polysorbate 20), a polyethoxylethylene derivative of oleic acid (eg, polysorbate 80), a poloxamer (which). Is a polyoxyethylene-polyoxypropylene copolymer), and in other cases polysorbate 20 or polysorbate 80 or a mixture thereof, from 0.01 to 0.05 mg / mL, 0.010 mg / mL, 0.015 mg / mL, 0.020 mg / It is present in concentrations of mL, 0.025 mg / mL, 0.03 mg / mL, or 0.02 mg / mL.</p><p> In another embodiment, the pharmaceutical formulation according to the invention comprises multiple analogs and / or derivatives of insulin, wherein one analog and / or derivative of insulin is fast-acting insulin, and one analog of insulin. And / or derivatives are long-acting insulin. In another embodiment, the pharmaceutical formulation according to the invention comprises fast-acting insulin and insulin glargine, insulin detemir and / or insulin degludec selected from the group comprising insulin aspart, insulin lispro and / or insulin gluricin. Includes long-acting insulin selected from the group.</p><p> In another embodiment, the pharmaceutical formulation according to the invention comprises one or more additional active pharmaceutical ingredients. In one embodiment, the additional active pharmaceutical ingredient is an anti-diabetic agent. In another embodiment, the pharmaceutical formulation according to the invention comprises a GLP-1 receptor agonist, a GLP-1 receptor / Glucagon receptor dual agonist, human FGF-21, FGF-21 analog, FGF-21 as additional active pharmaceutical ingredients. Includes one or more anti-diabetic agents selected from the group comprising derivatives, insulin, human insulin, insulin analogs, and insulin derivatives. In another embodiment, the pharmaceutical formulations according to the invention are insulin and insulin derivatives, GLP-1, GLP-1 analogs and GLP-1 receptor agonists, polymer-bound GLP-1 and GLP-1 analogs, dual GLP1 /. GIP agonist, dual GLP1 / Glucagon receptor agonist, PYY3-36 or its analog, pancreatic polypeptide or its analog, Glucagon receptor agonist or antagonist, GIP receptor agonist or antagonist, grelin antagonist or inverse agonist, xenin and its analog , DDP-IV inhibitor, SGLT2 inhibitor, dual SGLT2 / SGLT1 inhibitor, biguanidothiazolidinedione, dual PPAR agonist, sulfonylurea, meglycinide, alpha-glucosidase inhibitor, amylin and amylin analog, GPR119 agonist, GPR40 agonist, GPR120 agonist, GPR142 agonist, systemic or low-absorption TGR5 agonist, Cycloset, 11-beta-HSD inhibitor, glucokinase activator, DGAT inhibitor, tyrosine phosphatase 1 inhibitor, glucose -6- Phosphatase inhibitor, fructose-1,</p><p> In another embodiment, the pharmaceutical formulation according to the invention comprises multiple analogs and / or derivatives of insulin, wherein one analog and / or derivative of insulin is fast-acting insulin, and one analog of insulin. And / or derivatives are long-acting insulin.</p><p> In another embodiment, fast-acting insulin is selected from the group comprising insulin aspart, insulin lispro and / or insulin gluricin, and long-acting insulin is from the group comprising insulin detemir and / or insulin degludec. Be selected.</p><p> In another embodiment, the pharmaceutical formulations according to the invention are (a) .3.496 mg / mL insulin aspart (rounded: 3.5 mg / mL); and (b) 1.172 mg / mL metacresol; and (c) 1.150 mg / mL phenol; and (d) .0.04087 mg / mL Zn (II); and (e) .6.8 mg / mL sodium chloride; and (f) .0.02 mg / mL polysorbate 20; and (g). Consists of sodium hydroxide and / or hydrochloric acid and (h). Water adjusting the pH to 7.4.</p><p> In another embodiment, the pharmaceutical formulations according to the invention are (a) .3.496 mg / mL insulin aspart (rounded: 3.5 mg / mL); and (b) 1.172 mg / mL metacresol; and (c) 1.150 mg / mL phenol; and (d) .0.04087 mg / mL Zn (II); and (e) .6.8 mg / mL to 8.3 mg / mL sodium chloride; (f) .0.02 mg / mL polysorbate 20; (g) protamine sulfate from 0.1 mg / mL to 0.5 mg / mL; and (h). Sodium hydroxide and / or hydrochloric acid to adjust the pH to a pH in the range 7.1 to 7.6. And (i). Consists of water.</p><p> In another embodiment, the pharmaceutical formulations according to the invention are (a) 3.496 mg / mL insulin aspart (rounded: 3.5 mg / mL); and (b) 1.172 mg / mL metacresol; and ( c) 1.150 mg / mL phenol; and (d) .0.04087 mg / mL Zn (II); and (e) .6.8 or 6.9 or 7.0 or 7.1 or 7.2 or 7.3 or 7.4 or 7.5 or 7.6 or 7.7 or 7.8 or 7.9 or 8.0 or 8.1 or 8.2 or 8.3 mg / mL sodium chloride; (f) .0.02 mg / mL polysolvate 20; (g) 0.1 or 0.15 or 0.2 or 0.25 or 0.3 or 0.32 or 0.35 or 0.4 or 0.45 Or 0.5 mg / mL protamine sulfate; and (h). Consists of sodium hydroxide and / or hydrochloric acid and (i). Water for adjusting pH to 7.4.</p><p> The present invention also provides a pharmaceutical preparation for use in the treatment of diabetes mellitus, hyperglycemia, and / or for lowering blood glucose level.</p><p> The present invention is also a method of producing a pharmaceutical formulation according to the present invention, in which the ingredients are mixed together in the form of a solution or suspension, adjusted to the desired pH, and the mixture is brought to a final volume with water. Provide a way to do it.</p><p> The invention also relates to kits or combinations that include individual packages of pharmaceutical formulations and medical devices according to the invention. In one embodiment, the medical device is selected from the group comprising a syringe, an insulin injection system, an insulin infusion system, an insulin pump, an insulin pen injection device.</p><p> The invention also relates to a kit or combination comprising a pharmaceutical formulation according to the invention, at least one additional active pharmaceutical ingredient and optionally a separate package of medical device. In one embodiment, the medical device is selected from the group comprising a syringe, an insulin injection system, an insulin infusion system, an insulin pump, an insulin pen injection device.</p><p> The invention also comprises a kit or combination comprising a pharmaceutical formulation according to the invention, at least one additional active pharmaceutical ingredient and optionally a separate package of medical device, wherein the additional active pharmaceutical ingredient is an anti-diabetic agent. Regarding the combination.</p><p> The invention also comprises a kit or combination comprising a pharmaceutical formulation according to the invention, at least one additional active pharmaceutical ingredient and optionally a separate package of a medical device, wherein the additional active pharmaceutical ingredient is a GLP-1 receptor agonist. One selected from the group comprising GLP-1 receptor / Glucagon receptor dual agonist, human FGF-21, FGF-21 analog, FGF-21 derivative, insulin, human insulin, insulin analog, and insulin derivative. Includes more anti-insulin drugs. In another embodiment, the pharmaceutical formulations according to the invention are insulin and insulin derivatives, GLP-1, GLP-1 analogs and GLP-1 receptor agonists, polymer-bound GLP-1 and GLP-1 analogs, dual GLP1 /. GIP agonist, dual GLP1 / Glucagon receptor agonist, PYY3-36 or its analog, pancreatic polypeptide or its analog, Glucagon receptor agonist or antagonist, GIP receptor agonist or antagonist, grelin antagonist or inverse agonist, xenin and its analog , DDP-IV inhibitor, SGLT2 inhibitor, dual SGLT2 / SGLT1 inhibitor, biguanidothiazolidinedione, dual PPAR agonist, sulfonylurea, meglycinide, alpha-glucosidase inhibitor, amylin and amylin analog, GPR119 agonist, GPR40 agonist, GPR120 agonist, GPR142 agonist, systemic or low-absorption TGR5 agonist, Cycloset, 11-beta-HSD inhibitor, glucokinase activator, DGAT inhibitor, tyrosine phosphatase 1 inhibitor, glucose -6- Phosphatase inhibitor, fructose-1,</p><p> The present invention is also a kit or combination comprising a pharmaceutical formulation according to the invention, at least one additional active pharmaceutical ingredient and optionally a separate package of a medical device, wherein the kit comprises a plurality of analogs and / or derivatives of insulin. With respect to a kit or combination, one analog and / or derivative of insulin is fast-acting insulin, and one analog and / or derivative of insulin is long-acting insulin. In one embodiment, fast-acting insulin is selected from the group comprising insulin aspart, insulin lispro and / or insulin gluricin, and long-acting insulin comprises insulin glargine, insulin detemir and / or insulin degludec. Selected from the group.</p><p> The present invention also comprises a pharmaceutical formulation according to the invention, at least one additional active pharmaceutical ingredient and optionally a medical device for use in the treatment of diabetes mellitus, hyperglycemia and / or in lowering blood glucose levels. For kits or combinations that include individual packages of.</p><p> In another embodiment, the invention is a kit or combination comprising a pharmaceutical formulation according to the invention, at least one additional active pharmaceutical ingredient and optionally a separate package of medical device, the pharmaceutical formulation according to the invention and the further. The active pharmaceutical ingredient, in one embodiment, relates to a kit or combination in which the anti-diabetic agent is administered continuously, separately, over time and / or in stages.</p><p> The present invention also relates to the use of medical devices for administering pharmaceutical formulations to animals and / or humans. In one embodiment, the medical device is selected from the group comprising a syringe, an insulin injection system, an insulin infusion system, an insulin pump, an insulin pen type injection device.</p><p>Detailed Description As used herein, even the singular representation includes plural references unless explicitly stated otherwise. Thus, for example, a reference to a filler containing a "carrier" comprises one or more carriers, and a reference to an "additive" to one or more of such additives. Includes mention of.</p><p> As used herein, the term "active pharmaceutical ingredient" (API) provides any pharmacological action and is used in the treatment or prevention of a condition of any pharmaceutically active chemical or organism. Includes scientific compounds and any pharmaceutically acceptable salts thereof as well as any mixtures thereof. Exemplary pharmaceutically acceptable salts include hydrochloric acid, sulfuric acid, nitrate, phosphoric acid, hydrobromic acid, maleic acid, malic acid, ascorbic acid, citric acid, tartrate acid, pamoic acid, lauric acid, stearic acid, Includes palmitic acid, oleic acid, myristic acid, lauryl sulfate, naphthalene sulfonic acid, linoleic acid, linolenic acid, and the like. As used herein, the terms "active pharmaceutical ingredient," "drug," "activator," "active ingredient," "active substance," and "drug" mean that they are synonymous. It has the same meaning.</p><p> In one embodiment, the active pharmaceutical ingredient is an anti-diabetic agent. Examples of anti-diabetes drugs can be found in Rote Liste 2012, Chapter 12. Examples of anti-diabetic agents include (a) insulin, insulin analogs and insulin derivatives, (b) glucagon-like peptide 1 (GLP-1) and its analogs and receptor agonists, as described in detail below. Includes, but is not limited to, dual GLP-1 / GIP agonists and (d) dual GLP-1 / glucagon receptor agonists.</p><p>(a). Insulin, insulin analogs and insulin derivatives Examples of insulin, insulin analogs and insulin derivatives are insulin glargine (Lantus).^(R)), Insulin glulisin (Apidra)^(R)), Insulin detemir (Levemir)^(R)), Insulin lispro (Humalog)^(R)/ Liprolog^(R)), Insulin Degludec (Tresiba)^(R)), Insulin aspart (NovoLog)^(R)/ Novo Rapid^(R)), Basal insulin and analogs (eg LY2605541, LY2963016), PEGylated insulin lispro, Humulin^(R), Linjeta^(R), SuliXen^(R), NN1045, Insulin + Symlin^(R), Fast-acting and short-acting insulin (eg Linjeta)^(R), PH20 Insulin, NN1218, HinsBet^(R)), Oral, inhalation, transdermal and sublingual insulin (eg Exubera)^(R), Nasulin^(R), Afrezza^(R), Insulin tregopil, TPM-02 / insulin, Capsulin^(R), Oral-lyn^(R), Cobalamin^(R), Oral insulin, ORMD0801, NN1953, VIAtab^(R)) Is included, but not limited to them. Also included are those insulin derivatives bound to albumin or another protein by a bifunctional linker. (b). Glucagon-like peptide 1 (GLP-1), GLP-1 analog and GLP-1 receptor agonist Lixisenatide (AVE0010 / ZP10) is an example of GLP-1, GLP-1 analog and GLP-1 receptor agonist. / Lyxumia^(R)), Exenatide / Exenatide-4 (Byetta)^(R)/ Bydureon^(R)/ ITCA 650, Liraglutide / Victoza^(R)), Semaglutide, Taspoglutide, Albiglutide, Duraglutide, r Exendin-4, CJC-1134-PC, PB-1023, TTP-054, HM-11260C, CM-3, GLP-1 Eligen (GLP-) 1 Eligen), ORMD0901, NN9924, Nodexen, Viador-GLP-1, CVX-096, ZYOG-1, ZYD-1, MAR-701, ZP-2929, ZP-3022, CAM-2036, DA-15864, ARI- Includes, but is not limited to, 2651, ARI-2255, exenatide-XTEN and glucagon-XTEN, AMX-8089 + VRS-859 and polymer-bound GLP-1 and GLP-1 analogs. (c). Double GLP-1 / Glucoseotropic Insulinotropic Peptide (GIP) Agonist Examples of double GLP-1 / GIP agonists include MAR701, MAR-709, BHM081 / BHM089 / BHM098). , Not limited to them. (d). Double GLP-1 / glucagon receptor agonist Examples of dual GLP-1 / glucagon receptor agonists include OAP-189 (PF-05212389, TKS-1225), TT-401 / 402, ZP2929, LAPS-HMOXM25, MOD-6030). Not limited to.</p><p> Other suitable active pharmaceutical ingredients that may be included in the pharmaceutical formulations of the present invention include, but are not limited to: additional gastrointestinal peptides such as peptide YY3-36 (PYY3-36) or Its analog and pancreatic polypeptide (PP) or its analog. Glucagon receptor agonist or antagonist (GIP receptor agonist or antagonist) Ghrelin antagonist or inverse agonist and xenin and its analogs. Dipeptidyl peptidase-IV (DPP-4) inhibitor, eg alogliptin / Nesina^(R), Linagliptin / BI-1356 / Ondero^(R), / Trajenta^(R)/ Tradjenta^(R)/ Trayenta^(R), Saxagliptin / Onglyza^(R), Sitagliptin / Januvia^(R)/ Xelevia^(R)/ Tesavel^(R), Sitagliptin + Metformin / Janumet^(R)/ Velmetia^(R), Aildagliptin, anagliptin, aemigliptin, teneligliptin, melogliptin, toleragliptin, DA-1229, MK-3102, KM-223, KRP-104 and Ari-2243. Sodium-dependent glucose transporter 2 (SGLT2) inhibitors such as canagliflozin, dapagliflozin, remogliflozin, cergliflozin, empagliflozin, ipragliflozin, tofogliflozin (RO-4998452), luseogliflozin, LX-4211, Erzgriflozin (PF-04971729), EGT-0001442 and DSP-3235. Double SGLT2 / SGLT1 inhibitor. Biguanides (eg metformin, buformin, phenformin), thiazolidinediones (eg pioglycazone, riboglycazone, rosiglitazone, troglycazone), dual PPAR agonists (eg alegritazal, muragritazar, tesaglitazaal), sulfonylureas (eg tolbutamide, glibenclamide, glimepiride) / Amaryl^(R), Glipizide), meglitinide (eg nateglinide, repaglinide, mitiglinide), alpha-glucosidase inhibitors (eg acarbose, miglitol, boglibose), amylin and amylin analogs (eg pramlintide / symlin)^(R)). G-protein-coupled receptor 119 (GPR119) agonists (eg GSK-1292263, PSN-821, MBX-2982, APD-597, ARRY-981). GPR40 agonists (eg TAK-875, TUG-424, P-1736, JTT-851, GW9508). GPR120 agonist and GPR142 agonist. Systemic or low-absorption TGR5 (GPBAR1 = G-protein-coupled bile acid receptor 1) agonist (eg INT-777, XL-475, SB756050). Bromocriptine / Cycloset^(R), 11-Beta-hydroxysteroid dehydrogenase (11-beta-HSD) inhibitors (eg LY2523199, BMS770767, RG-4929, BMS816336, AZD-8329, HSD-016, BI-135585), glucokinase activation Inhibitors of substances (eg PF-04991532, TTP-399, GK1-399, ARRY-403 (AMG-151), TAK-329, ZYGK1), diacylglycerol O-acyltransferase (DGAT) (eg pradigastat) ) (LCQ-908), LCQ-908), Tyrosine phosphatase 1 inhibitor (eg Troduschemin), Glucose-6-phosphatase inhibitor, Fluctose-1,6-bisphosphatase inhibitor, Glucogen phosphorylase inhibitor, Phosphorylase carboxykinase inhibitor, glycogen synthase kinase inhibitor, pyruvate dehydrogenase kinase inhibitor, alpha 2 adrenaline-like action receptor antagonist, CC chemokine receptor type 2 (CCR-2) antagonist, glucose transporter- 4 modulators and somatostatin receptor 3 agonists (eg MK-4256).</p><p> Also, one or more lipid-lowering drugs, such as 3-hydroxy-3-methylglutaryl-coenzyme-A-reductase (HMG-CoA-reductase) inhibitors (eg, simvasstatin, atrovastatin, losbustatin), fibrato (eg For example, bezafibrate, phenofibrate), nicotinic acid and its derivatives (including niacin, delayed release preparations of niacin), nicotinic acid receptor 1 agonist (eg GSK-256073), peroxisome proliferator-activated receptor (PPAR-) ( Alpha, gamma or alpha / gamma) agonists or modulators (eg allegritazaal), PPAR-delta agonists, acetyl-CoA-acetyltransferase (ACAT) inhibitors (eg avasimib), cholesterol absorption inhibitors (eg ezetimib), bile acid -Binding substances (eg cholesterol, cholesterol), peroxisome proliferators (IBAT) (eg GSK-2330672), microsome triglyceride transfer protein (MTP) inhibitors (eg lomitapide (AEGR-733), SLx-4090, granotapid) (granotapide)), modulator of proprotein convertase subtilisin / kexin type 9 (PCSK9) (eg REGN727 / SAR236553, AMG-145, LGT-209, PF-04950615, MPSK3169A, LY3015014, ALD-306, ALN-PCS, BMS- 962476, SPC5001, ISIS-394814, 1B20, LGT-210, 1D05, BMS-PCSK9Rx-2, SX-PCK9, RG7652), LDL receptor upregulators such as hepatoselective thyroid hormone receptor beta agonists (eg epirotyrome (eg epirotyrome)) KB-2115), MB07811, Sobetarom (QRX-431), VIA-3196, ZYT1), HDL-elevating compounds, such as:CETP inhibitors (eg torcetrapib, anacetrapib (MK0859), dalcetrapib, evacetrapib, JTT-302, DRL-17822, TA-8995, R-1658, LY-2484595) or ABC1 regulators, lipid metabolism modulators (eg BMS-823778, TAP-301, DRL-21994, DRL-21995), phospholipase A2 (PLA2) inhibitors (eg dalcetrapib / Tyrisa)^(R), Valles prazib, liraprazib), ApoA-I enhancers (eg RVX-208, CER-001, MDCO-216, CSL-112, VRX-HDL, VRX-1243, VIRxSYS), cholesterol synthesis inhibitors (eg ETC-1002) and Lipid metabolism modulators (eg BMS-823778, TAP-301, DRL-21994, DRL-21995) and omega-3 fatty acids and their derivatives (eg Icosapentethyl (AMR101), Epanova)^(R), AKR-063, NKPL-66) are also suitable as active pharmaceutical ingredients.</p><p> Other suitable active agonist ingredients that may be included in the pharmaceutical formulation include, but are not limited to, sibutramine, tesofensin, oristat, cannabinoid receptor 1 (CB1) antagonists (eg TM-38837), melanin aggregation hormone. (MCH-1) antagonists (eg BMS-830216, ALB-127158 (a)), MC4 receptor agonists and partial agonists (eg AZD-2820, RM-493), neuropeptide Y5 (NPY5) or NPY2 antagonists (eg Berneperito) , S-234462), NPY4 agonist (eg PP-1420), beta-3-adrenalinergic receptor agonist, leptin or leptin mimetic, 5-hydroxytryptamine 2c (5HT2c) receptor agonist (eg lorcaserin), or Bupropion / Nartrexon (Contrave)^(R)), Bupropion / Zonisamide (Empatic)^(R)), Bupropion / Phentermine or Pramlintide / Metrereptin, Phentermine / Topiramate (Qsymia)^(R)) Combinations, lipase inhibitors (eg cetilistat / Cametor)^(R)), Angiogenesis inhibitors (eg ALS-L1023), histamine H3 antagonists (eg HPP-404), AgRP (agouti-related protein) inhibitors (eg TTP-435), triple monoamine uptake inhibitors (dopamine, norepinephrine and serotonin re-) Uptake) (eg tesofensin), methionine aminopeptidase 2 (MetAP2) inhibitor (eg beloranib), nasal preparation of the calcium channel blocker diltiazem (eg CP-404) and fibroblast growth factor receptor 4 (FGFR4) Antisense oligonucleotides (eg ISIS-FGFR4Rx) for the production of) or prohibitins targeting peptide-1 (eg Adipotide)^(R)) Includes one or more active substances for the treatment of obesity.</p><p> Further suitable active pharmaceutical ingredients that may be included in the pharmaceutical formulation include angiotensin II receptor blockers (eg, thermisartan, candesartan, balsartan, rosartan, aprosartan, ilbesartan, olmesartan, tasosartan, azil sartane), angiotensin converting enzyme (ACE) Inhibitors, Endoserin Converting Enzyme (ECE) Inhibitors, Diuretics, Beta Blockers, Calcium Antagonists, Central Action Hypertension Drugs, Alpha-2-Adrenalinergic Receptor Antagonists, Neutral Endopeptidase Inhibitors, Thrombocytopenia Inhibitors are included, but not limited to them, and others or combinations thereof are suitable.</p><p> As used herein, the terms "insulin analog" and "insulin analog" are used by deleting and / or exchanging at least one amino acid residue present in natural insulin, and / or at least one. It refers to a polypeptide having a structure of natural insulin, for example, a molecular structure that can be structurally derived from that of human insulin by adding one amino acid residue. The added and / or exchanged amino acid residues can be either encoding amino acid residues, or other natural residues, or pure synthetic amino acid residues. Examples of insulin analogs include, but are not limited to: (i). "Insulin alpart" is the amino acid B28 in human insulin (ie 28 in the B chain of human insulin). Proline, which is the number amino acid), is produced by recombinant DNA technology so that it is replaced by aspartic acid; (ii). "Insulin lispro" is the penultimate on the C-terminal of the B chain of human insulin. Recombinant DNA technology is used to reverse lysine and proline residues (human insulin: Pro)^B28Lys^B29Insulin lispro: Lys^B28Pro^B29); (iii). "Insulin glulisine" differs from human insulin in that the amino acid asparagine at position B3 is replaced with lysine and the lysine at position B29 is replaced with glutamic acid; (iv). "Insulin glulisine" Is different from human insulin in that asparagine at position A21 is replaced with lysine and the B chain is extended by two arginines at the carboxy terminus.</p><p> As used herein, the term "aqueous" refers to a solution in which the solvent is water and / or a suspension in which the external phase is water and / or an emulsion in which the dispersed or continuous phase is water. Say.</p><p> As used herein, the term "buffer" refers to the acidity (pH) of a solution, suspension and / or emulsion to be close to the value chosen after the addition of another acid or base. A weak acid or weak base used to maintain. The function of the buffer is to prevent sudden changes in pH value when an acid or base is added to the solution. In aqueous solutions, suspensions and / or emulsions, the buffer is present as a mixture of a weak acid and its conjugate base or a mixture of a weak base and its conjugate acid. Examples of buffers include, but are not limited to: sodium hydrogen carbonate; acetic acid or acetate (eg sodium acetate, zinc acetate); sulphonic acid or sulphonate; N-cyclohexyl- 2-Aminoethanesulfonic acid (CHES) or a salt thereof; 3-[[1,3-Dihydroxy-2- (hydroxymethyl) propan-2-yl] amino] Propan-1-sulfonic acid (TAPS) or a salt thereof; 2- (N-morpholino) ethanesulfonic acid (MES) and its salts; piperazin-N, N'-bis (2-ethanesulfonic acid (PIPES) and its salts; N- (2-acetamide) -2-aminoethane Sulfonic Acid (ACES) and its Salts; Collamine Chloride; BES; 2-[[1,3-Dihydroxy-2- (Hydroxymethyl) -Propan-2-yl] Amino] Ethan Sulfonic Acid (TES) and its Salts; 2- [4- (2-Hydroxyethyl) piperazin-1-yl] ethanesulfonic acid (HEPES) and its salts; acetamide glycine; N- (2-hydroxy-1,1-bis (hydroxyl-methyl) ethyl) glycine (Tricin); Glycinamide; 2- (bis (2-hydroxyethyl) amino) acetic acid (bisin) and its salts; propionate; 3-[[1,3-dihydroxy-2- (hydroxymethyl) propane-2 -Il] -amino] -2-hydroxy-propane-1-sulfonic acid (TAPSO) and its salts; 3-morpholinopropane-1-sulfonic acid (MOPS) and its salts;</p><p> Amino acids (having free basic or acidic functional groups, such as methionine, arginine) or peptides (having free basic or acidic functional groups) may also be used as buffers. As used herein, the term "buffer" also includes amino acids, peptides and proteins. Since insulin analogs and / or insulin derivatives and / or protamines are peptides or derivatives of peptides (ie, they both contain amino acids with free basic or acidic functional groups), they have some buffering capacity. Sometimes it is considered a buffer.</p><p> As used herein, the terms "fast-acting insulin" or "short-acting insulin" are insulin analogs whose insulin-mediated action is initiated within 5-15 minutes and remains active for 3-4 hours. / Or an insulin derivative. Examples of fast-acting insulin include, but are not limited to: (i). Insulin aspart; (ii). Insulin lispro, and (iii). Insulin gluricin.</p><p> As used herein, the terms "additional buffer-free" or "buffer-free" mean that there are no additional buffers other than insulin analogs and / or derivatives and optionally protamine. .. As mentioned above, insulin analogs and / or derivatives and protamine contain amino acids with acidic or basic side chains and are therefore also considered buffers. Regardless of the absence of any buffer, the aqueous pharmaceutical formulation according to the invention may optionally contain protamine.</p><p> As used throughout the description and claims of the present specification, the word "contains" and variations of that word, such as "contains" and "contains," exclude other additives, ingredients, integers or steps. Not intended to be.</p><p> As used herein, the terms "insulin derivative" and "insulin derivative" are natural, with one or more organic substituents (eg, fatty acids) attached to one or more amino acids. It refers to a polypeptide having a structure of insulin, for example, a molecular structure that can be structurally derived from that of human insulin. In some cases, one or more amino acids present in natural insulin may be deleted and / or replaced by other amino acids, including non-encoding amino acids. , Or amino acids, including those that cannot be encoded, may be added to the natural insulin. Examples of insulin derivatives include, but are not limited to: (i). C-terminal threonine at position B30 is removed and fatty acids are added to the epsilon-amino functional group of lysine at position B29. "Insulin detemir" differs from human insulin in that a residue (myristic acid) is bound. (ii). "Insulin degludec" differs from human insulin in that the last amino acid is deleted from the B chain and a glutamyl bond is added from LysB29 to hexadecanedioic acid.</p><p> As used herein, the term "FGF-21" means "fibroblast growth factor 21". The FGF-21 compound may be a human FGF-21, an analog of FGF-21 (referred to as "FGF-21 analog") or a derivative of FGF-21 (referred to as "FGF-21 derivative").</p><p> As used herein, the term "formulation" is used directly or indirectly from the combination of specified ingredients in specified amounts, as well as products containing the specified ingredients in predetermined amounts or proportions. It refers to any product obtained as a target. With respect to pharmaceutical formulations, the term refers to a product containing one or more active ingredients and, optionally, a carrier containing an inert ingredient, as well as a combination of any two or more of the ingredients, complex formation or It includes any product obtained directly or indirectly from aggregation, or from the dissociation of one or more of the components, or from other types of reactions or interactions of one or more of the components. In general, a pharmaceutical formulation uniformly associates an active pharmaceutical ingredient (ie, an analog and / or derivative of insulin) with a liquid carrier, a fine powder solid carrier, or both, and then, if necessary, forms the product into the desired formulation. Manufactured by The pharmaceutical formulation contains an amount of active pharmaceutical ingredient sufficient to produce the desired effect depending on the course or condition of the disease. As used herein, the term "formulation" can correspond to a suspension or emulsion in addition to a solution. As used herein, the terms "formulation" and "composition" mean synonymous, i.e., have the same meaning. Pharmaceutical compositions are manufactured according to conventional techniques of pharmaceutical technology, including mixing, filling and dissolving the ingredients as needed to obtain the desired oral, parenteral, rectal, transdermal or topical product. To.</p><p> As used herein, the term "GLP-1 receptor agonist" refers to a compound that has agonist activity at the glucagon-like peptide-1 receptor. Examples of GLP-1 receptor agonists include, but are not limited to: exenatide / exenatide-4, liraglutide, lixisenatide, duraglutide, albiglutide, semaglutide, taspoglutide, r exenatide-4. (rExendin-4), CJC-1134-PC, PB-1023, TTP-054, HM-11260C, CM-3, GLP-1 Eligen, ORMD0901, NN9924, Nodexen, Viador-GLP-1, CVX- 096, ZYOG-1, ZYD-1, MAR-701, ZP-2929, ZP-3022, CAM-2036, DA-15864, ARI-2651, ARI-2255, Exenatide-XTEN and Glucagon-XTEN, AMX-8089 + VRS-859 and polymer-bound GLP-1 and GLP-1 analogs.</p><p> As used herein, the term "double GLP-1 receptor / glucagon receptor agonist" refers to a compound that has agonist activity at both the GLP-1 receptor and the glucagon receptor. Examples of dual GLP-1 receptor / glucagon receptor agonists include, but are not limited to: oxintomodulin, MAR701, MAR-709 and BHM081 / BHM089 / BHM098.</p><p> As used herein, the term "human insulin" refers to a human hormone whose structure and properties are well known. Human insulin has a cysteine residue, two polypeptide chains (chains A and B) linked by a disulfide bridge between the A and B chains. Chain A is 21 amino acid peptides, and chain B is 30 amino acid peptides, 2 chains are 3 disulfide bridges: 1 is between the 6th and 11th cysteines of chain A; 2 The second is between the 7th cysteine in the A chain and the 7th cysteine in the B chain; and the third is bound by the 20th cysteine in the A chain and the 19th cysteine in the B chain. ing.</p><p> As used herein, the term "includes" is used to mean "include, but not limited to." "Including" and "including, but not limited to," are used interchangeably.</p><p> As used herein, the term "isoelectric point" (pI, IEP) refers to a pH value at which a particular molecule does not carry a net charge. The isoelectric point is a technique for separating different molecules by the difference in their isoelectric points, and can be determined by using isoelectric focusing, which is well known in the art. It can also be calculated (see, for example, Levene and Simms,'Calculation of isoelectric point' J. Biol. Chem., 1923, pp. 801-813).</p><p> As used herein, the term "kit" refers to a product (eg, a kit of drugs, parts) that contains one package or one or more individual packages: (i). A pharmaceutical formulation containing an ingredient and at least one additional active pharmaceutical ingredient and optionally a medical device. At least one additional active pharmaceutical ingredient may be present in the pharmaceutical formulation, i.e., the kit may include one or more packages, where each package contains two or more active pharmaceuticals. Contains one pharmaceutical product containing the ingredients. Also, additional active pharmaceutical ingredients may be present in additional pharmaceutical formulations, i.e., the kit may include separate packages of two or more pharmaceutical formulations, where each pharmaceutical formulation is one. Contains active pharmaceutical ingredients. Or (ii). A pharmaceutical preparation containing an active pharmaceutical ingredient and a medical device.</p><p> The kit may include only one package, or may include one or more individual packages. For example, the kit may be a product (eg, drug) containing two or more vials, each containing a defined pharmaceutical product, wherein each pharmaceutical product has at least one activity. Contains pharmaceutical ingredients. For example, the kit is (i) a vial containing the defined pharmaceutical formulation and (ii). an additional tablet, capsule, powder or any other oral dosage form containing at least one additional active pharmaceutical ingredient. May include. The kit may further include a package leaflet with instructions on how to administer the pharmaceutical formulation and at least one additional active pharmaceutical ingredient to administration.</p><p> As used herein, the term "medical device" is used in the diagnosis, prevention or treatment of diseases of other conditions, and any device that does not achieve its purpose through pharmacological action in the body or on the surface of the body. , Equipment, insert, in vitro reagent or similar or related article. As used herein, the medical device may be a syringe, an insulin injection system, an insulin infusion system, an insulin pump or an insulin pen type injection device. As used herein, medical devices may be mechanically or electromechanically driven.</p><p> As used herein, unless otherwise stated, the conjunction "or" is used in the general sense of "and / or" and not in the exclusive sense of "any / or". Absent.</p><p> As used herein, the terms "pH" and "pH value" refer to the decimal logarithm of the reciprocal of hydrogen ion activity in solution.</p><p> As used herein, the term "pharmaceutical" refers to its intended use in the medical diagnosis, cure, treatment and / or prevention of a disease.</p><p> As used herein, the term "pharmaceutically acceptable" means that it is physiologically well tolerated by a mammal or human.</p><p> As used herein, the term "protamine" refers to a mixture of strongly basic peptides. Initially it was isolated from salmon and other species of fish sperm, but now it is produced primarily by recombination by biotechnology. It contains more than 2/3 of L-arginine. Since protamine contains an amino acid having a free basic side chain, it has a certain buffering ability and is therefore considered to be a buffering agent. Protamine may be used as protamine sulfate or protamine hydrochloride.</p><p> Concentration, quantity, solubility, particle size, wavelength, pH value, mass, molecular weight, percent and other numerical dates may be expressed or presented in a range format herein. Such range formats are used for convenience and brevity only, so they do not include only those numbers that are clearly listed as range limits, but are each number and subrange clearly listed? It must be understood that it should be flexibly interpreted to include all individual numbers or subranges contained within that range, such as.</p><p> As used herein, the term "long-acting insulin" refers to insulin analogs and / or insulins, in which an insulin-mediated action is initiated within 0.5-2 hours and remains active for approximately 24 hours or more. It refers to a derivative. Examples of fast-acting insulin include, but are not limited to: (i). Insulin glargine; (ii). Insulin detemir, and (iii). Insulin detemir.</p><p> As used herein, the term "stability" refers to the chemical and / or physical stability of an active pharmaceutical ingredient, in particular an insulin analog and / or derivative. The purpose of the stability test is to provide evidence of how the quality of active pharmaceutical ingredients or dosage forms changes over time under the influence of various environmental factors such as temperature, humidity and light. And to establish shelf life and recommended storage conditions for active pharmaceutical ingredients or dosage forms. Stability studies can include testing those properties of active pharmaceutical ingredients that are susceptible to changes during storage and may affect quality, safety and / or efficacy. The tests are, as required, with respect to physical, chemical, biological and microbiological properties, preservative content (eg antioxidants, antibacterial preservatives), and functional tests (eg dose delivery systems). ) Can be included. The analytical method can be fully verified and can be an indicator of stability. In general, significant changes in active pharmaceutical ingredients and / or dosage forms with respect to stability are defined as: 5% change from its initial value in the assay; or biological or immunological methods. Does not meet efficacy criteria when used; Any degradation products that exceed those criteria; Appearance, physical properties and functional tests (eg, adhesion, phase, separation, resuspension, solidification, Criteria for hardness, dose delivery per operation) are not met; however, some changes in physical properties (eg, suppository softening, emulsion thawing) can be expected under accelerated conditions; and As required, with respect to dosage form: Does not meet the criteria for pH; or Does not meet the criteria for dissolution of 12 dose units.</p><p> Also, significant changes to established criteria may be assessed prior to the start of the stability assessment.</p><p> Criteria are from the monograph (eg, European Pharmacopeia, United States Pharmacopeia, British Pharmacopeia, or others), as well as active drugs used in preclinical and clinical studies. It can be derived from the analysis batch of ingredients and pharmaceutical products. Tolerance limits must be proposed and adjusted in light of the levels observed with the substances used in preclinical and clinical studies. Product properties may be visual appearance, purity, solution / suspension color and clarity, visible particulates in solution, and pH. As a non-limiting example, suitable criteria for insulin aspart preparations are shown below:</p><p><tables num="1"><img file="JP6445461B2_D0001.tif" /></tables></p><p> The criteria shown above are based on the monographed tolerance limits (eg, British Pharmacopoeia, Volume III, 2012 or Pharmacopoeial Forum, Volume 36 (6), Nov-Dec 2010) and / Or it is derived from extensive experience in the development of insulin preparations.</p><p> As used herein, the term "treatment" refers to any treatment of a mammalian, eg, human condition or disease, and (1) inhibiting the disease or condition, i.e. stopping its development. This includes (2) alleviating the disease or condition, that is, eliminating the condition, or (3) stopping the symptoms of the disease.</p><p> As used herein, the unit of measure "U" and / or "international unit" refers to the hypoglycemic activity of insulin and is defined (according to the World Health Organization, WHO) as follows: 1U is sufficient to reduce blood glucose levels in rabbits (having a weight of 2 to 2.5 kg) to 50 mg / 100 mL within 1 hour and to 40 mg / 100 mL within 2 hours (as defined by WHO). Corresponds to the amount of highly purified insulin. For human insulin, 1 U corresponds to about 35 μg (Lill, Pharmazie in unserer Zeit, No. 1, pp. 56-61, 2001). For insulin aspart, 100U is equivalent to 3.5mg (Product Information Novo Rapid)^(R)). For insulin lispro, 100 U is equivalent to 3.47 mg (Product Information Humalog)^(R)). For insulin glulisine, 100 U corresponds to 3.49 mg (Product Information Apidra)^(R)cartridge). For insulin detemir, 100U is equivalent to 14.2 mg (Product Information Levemir)^(R)). For insulin glargine, 100U is equivalent to 3.64mg (Product Information Lantus)^(R))。 </p><p> Further embodiments of the invention include:</p><p> In one aspect, the invention is described in (a). Analogs and / or derivatives of at least one insulin; and (b). Zn (II); and (c). Sodium chloride; and (d). In some cases protamine; Provided is a pharmaceutical formulation comprising, wherein the pharmaceutical formulation has a pH value in the range of 6.0 to 9.0 and does not contain any additional buffer.</p><p> In one aspect, the pharmaceutical preparation of the present invention is an aqueous pharmaceutical preparation.</p><p> In one aspect, the pharmaceutical formulation of the present invention has a pH value in the range of 7.0 to 7.8.</p><p> In one aspect, the pharmaceutical formulation of the present invention comprises an analog of insulin selected from the group consisting of insulin aspart, insulin lispro and insulin glulisine.</p><p> In one aspect, the pharmaceutical formulation of the present invention comprises a derivative of insulin which is insulin detemir and / or insulin degludec.</p><p> In one aspect, the pharmaceutical formulation of the present invention comprises an analog and / or derivative of insulin present at a concentration from 10 U / mL to 1000 U / mL.</p><p> In one aspect, the pharmaceutical formulation of the present invention comprises Zn (II) at an analog and / or derivative concentration of 0.0100 to 0.0600 mg / 100 U insulin.</p><p> In one aspect, the pharmaceutical formulation of the present invention comprises sodium chloride at a concentration from 0.01 to 15 mg / mL.</p><p> In one aspect, the pharmaceutical formulation of the present invention comprises sodium chloride at a concentration from 6.8 to 8.3 mg / mL.</p><p> In one aspect, the pharmaceutical formulation of the present invention comprises protamine sulfate at a concentration from 0.1 to 0.5 mg / ml.</p><p> In one aspect, the pharmaceutical formulation of the present invention comprises 2-amino-2-hydroxymethyl-propane-1,3-diol (TRIS), phosphate, citric acid, citrate, acetate, acetate, glycylglycine. And does not contain any additional buffer selected from the group consisting of methionine.</p><p> In one aspect, the pharmaceutical formulation of the present invention comprises one or more additional active pharmaceutical ingredients.</p><p> In one aspect, the pharmaceutical formulation of the present invention comprises an additional active pharmaceutical ingredient that is an antidiabetic agent.</p><p> In one aspect, the pharmaceutical formulations of the present invention are: (a) GLP-1 receptor agonist; (b) dual GLP-1 receptor / glucagon receptor agonist; (c) human FGF-21; (d) FGF- 21 Analogs; (e) FGF-21 Derivatives; (f) Insulin; (g) Human Insulin; (h) Insulin Analogs; Contains pharmaceutical ingredients.</p><p> In one aspect, the pharmaceutical formulation of the invention comprises multiple analogs and / or derivatives of insulin, wherein one analog and / or derivative of insulin is fast-acting insulin, and one analog and / or analog of insulin. Alternatively, the derivative is long-acting insulin.</p><p> In one aspect, the pharmaceutical formulation of the invention is a fast-acting insulin selected from the group consisting of insulin aspart, insulin lispro and insulin glulisin, and one selected from the group consisting of insulin detemir and insulin deglulis. Includes long-acting insulin, which is more insulin.</p><p> In one aspect, the pharmaceutical formulations of the invention are: (a) .3.5 mg / mL insulin aspart; (b) 1.172 mg / mL metacresol; (c) 1.50 mg / mL phenol; (d). .0.04087 mg / mL Zn (II); (e) .6.8 mg / mL sodium chloride; (f) .0.02 mg / mL polysolvate 20; (g) .Sodium hydroxide to adjust pH to 7.4 And / or hydrochloric acid, and (h). Consists of water.</p><p> In one aspect, the pharmaceutical formulations of the present invention are: (a) .3.5 mg / mL insulin aspart; (b) 1.172 mg / mL metacresol; (c) 1.50 mg / mL phenol; (d) .0.04087 mg / mL Zn (II); (e) .6.8 mg / mL to 8.3 mg / mL sodium chloride; (f) .0.02 mg / mL polysolvate 20; (g) from .0.1 mg / mL Protamine sulfate up to 0.5 mg / mL; (h). Sodium hydroxide and / or hydrochloric acid for adjusting the pH to a pH in the range 7.1 to 7.6; and (i). Consists of water.</p><p> In one aspect, the invention is a method of producing the pharmaceutical formulation of the invention, in which the ingredients are mixed together in the form of a solution or suspension, the pH is adjusted to reach the desired pH, and water is added. In addition, a method of reaching the final volume is provided.</p><p> In one aspect, the invention provides a kit comprising (a). The pharmaceutical formulation of the invention; and (b). One or more individual packages of medical devices.</p><p> In one aspect, the invention is described in (a). Pharmaceutical formulations of the invention; and (b). At least one additional active pharmaceutical ingredient; (c). And optionally one or more individual packages of medical devices. Provide a kit containing.</p><p> In one aspect, the kit of the present invention comprises an additional active pharmaceutical ingredient that is an anti-diabetic agent.</p><p> In one aspect, the kits of the invention are: (a). GLP-1 receptor agonist; (b). Double GLP-1 receptor / glucagon receptor agonist; (c). Human FGF-21; (d). Selected from the group consisting of .FGF-21 analogs; (e) .FGF-21 derivatives; (f) .insulin; (g) .human insulin; (h) .insulin analogs; and (i) .insulin derivatives Contains additional active pharmaceutical ingredients that are anti-diabetic drugs.</p><p> In one aspect, the kit of the invention comprises multiple analogs and / or derivatives of insulin, wherein one analog and / or derivative of insulin is fast-acting insulin, and one analog and / or of insulin. The derivative is long-acting insulin.</p><p> In one aspect, the kit of the present invention comprises fast-acting insulin selected from the group consisting of insulin aspart, insulin lispro and insulin glulisin, and a group selected from the group consisting of insulin glargine, insulin detemir and insulin deglulis. Includes effective insulin.</p><p> In one aspect, the invention provides a pharmaceutical formulation or kit for use in the treatment of diabetes mellitus.</p><p> In one aspect, the invention provides a pharmaceutical formulation or kit for use in the treatment of hyperglycemia.</p><p> In one aspect, the invention provides a pharmaceutical formulation or kit for use in lowering blood glucose levels.</p><p> In one aspect, the invention provides a method of treating diabetes mellitus in a subject in need thereof, comprising administering the pharmaceutical formulation of the invention.</p><p> In one aspect, the invention provides a method of treating hyperglycemia in a subject in need thereof, comprising administering the pharmaceutical formulation of the invention.</p><p> In one aspect, the invention provides a method of lowering blood glucose levels in a subject in need thereof, comprising administering the pharmaceutical formulation of the invention.</p><p> In one aspect, the invention provides a medical device for administering the pharmaceutical formulation of the invention to animals and / or humans.</p><p> The present invention will be described with reference to the following examples. However, it should be understood that the present invention is not limited to the specific details of these examples.</p>

[Example 1] Production method (a) Polysorbate solution A polysorbate solution was prepared by dissolving 1.00 g of polysorbate 20 in water for injection (according to Ph. Eur.) And filling it with water for injection up to a final volume of 1000 mL. (b) Zinc Chloride Solution A zinc chloride solution (containing Zn (II)) was prepared by dissolving 2.00 g of zinc chloride in water for injection and filling it with water for injection to a final volume of 1000 mL.

(c) Solution A The final composition of Solution A is shown in Table 1.<tables num="2"><img file="JP6445461B2_D0002.tif" /></tables>

Solution A was prepared as described below: 1. Starting with about 500 mL of water for injection. 2. With constant stirring, 34.00 g of sodium chloride, 7.5 g of phenol and 8.6 g of m-methacresol were dissolved. 3. Fill the solution with water for injection up to about 900 g. 4. The solution was stirred for about 15 minutes using a magnetic stirrer. 5. Checked the pH (pH should be 8.65, rounded to: pH 9.0). If the pH value was not 8.65, the pH was adjusted to the above range using 1N hydrochloric acid or 1N sodium hydroxide solution. 6. Fill the solution with water for injection up to 1026 g.

(d) Final solution Table 2 shows the final composition of the final solution:<tables num="3"><img file="JP6445461B2_D0003.tif" /></tables>

The preparation of the composition per 2000 mL is described below. Other volumes (eg, composition per 1000 mL) can be prepared in the same way (using the corresponding amounts of insulin aspart and additives).

The final solution was prepared as described below: 1. Starting with about 300 mL of water for injection (according to Ph. Eur.). 2. Insulin aspart with constant stirring<u style="single">6.992</u>g (rounded off<u style="single">7.0</u>g) was added to 300 mL of water for injection (a suspension of insulin aspart in the water for injection is formed). 3. The pH value was confirmed. Insulin aspart was dissolved by adding 4.0.1N hydrochloric acid or 0.02N sodium hydroxide solution to change the pH value to about 3.1-3.2. 5. The solution was stirred for about 15 minutes using a magnetic stirrer. 6. 40.866 g of zinc chloride solution was added to the solution with constant stirring. 7. 40 g of polysorbate solution was added with constant stirring. 8. Fill the solution with water for injection up to 600 g. 9. With constant agitation, 0.4 g of Solution A4 1 was added slowly and carefully. The pH was adjusted to 7.4 (range 7.2-7.6) with 10.0.1N hydrochloric acid or 0.02N sodium hydroxide solution. 11. The solution was filled to 2010 g (corresponding to 100% of the final solution).

Quality Control: The final solution was a clear, colorless solution with a pH value of 7.4 (plus / minus 0.2; at 20-25 ° C).

The final solution was sterile filtered using a'Sartopore Minisart high flow'filter (filter material: polyether sulfone; pore size: 0.2 μm; source: Sartorius).

The final solution after sterilization filtration was a clear, colorless solution with an osmolality of 260 mOsmol / kg (plus / minus 30).

The final solution after sterile filtration was filled into suitable vials (volumes: 5 and 10 mL; 13 mm; clear glass; glass type 1).

Vials containing the final solution after sterile filtration were stored between + 2 ° C and + 8 ° C and shielded from light.

[Example 2] Management of pharmaceutical product (a) Analytical method If applicable, the test was conducted using the analytical test method specified in the official standard. The concept of quality control has been established in consideration of the requirements of cGMP and the current status of the progress of ICH. The non-official chromatographic analysis methods used to control the formulation are summarized below:

Description A large number of containers were visually tested for compliance with the criteria.

Identification (HPLC) The identity of the active ingredient was confirmed by comparing the retention time of the drug product sample with the retention time of the standard sample using a reverse phase HPLC method. This method was also used for assay measurement of active ingredients, for measurement of related compounds and impurities, and for quantification of preservatives m-methacresol and phenol.

Quantitative (HPLC) tests were performed by reverse phase liquid chromatography (HPLC). This method was also used for the identification and quantitative measurement of active ingredients, for the measurement of related compounds and impurities, and for the quantification of preservatives m-methacresol and phenol. Column: Lichrosorb RP18, particle size 5 μm, pore size 100 Å (250 mm × 4.0 mm), thermostat adjusted at + 35 ° C. Autosampler: Thermostat adjusted at + 8 ° C. Mobile phase A: Sodium sulfate was dissolved in water (14 g / mL) and adjusted to pH 3.4 with phosphoric acid and sodium hydroxide. Mobile phase B: water / acetonitrile (50: 50v / v). The gradient is shown in Table 3.

<tables num="4"><img file="JP6445461B2_D0004.tif" /></tables>

Flow velocity: 1.0 ml / min. Injection volume: 10 μL. Detection: 214 nm (for active ingredients) and 260 nm (for m-metacresol and phenol). Typical execution time: 60 minutes. Quantification of the active ingredient, m-methacresol and phenol was calculated by external standardization. The impurities were calculated using the peak area percent method. Test solution: The product was used without any dilution or further treatment.

Related Compounds and Impurities (HPLC) For the measurement of related compounds and impurities, the same chromatography conditions as "quantitative (HPLC)" were used. Related compounds and impurities were calculated using the peak area percent method.

High Molecular Weight Proteins (HMWPs) High molecular weight proteins were measured using high pressure size exclusion chromatography (HPSEC). Column: Waters Insulin HMWP, particle size 5-10 μm, pore size 12-12.5 nm (300 mm × 7.8 mm), thermostat adjusted at room temperature. Autosampler: Thermostat adjusted at + 8 ° C. Mobile phase: 650 mL of arginine solution (1 g / L) was mixed with 200 mL of acetonitrile and 150 mL of glacial acetic acid. Constant composition elution flow rate: 1.0 ml / min. Injection volume: 100 μL. Detection: 276 nm. Typical execution time: 35 minutes. HMWPs were calculated using the peak area percent method. Test solution: The product was used without any dilution or further treatment.

Quantitative Antibacterial Preservatives For quantitative measurements of m-methacresol and phenol, the same chromatography conditions as "quantitative (HPLC)" were used, and m-methacresol and phenol were calculated by external standardization.

(b) Verification of analytical methods The HPLC analysis methods of formulations for identification and quantitative measurement and related compounds and impurities were verified to clarify specificity, linearity, detection limit and quantification limit, accuracy, accuracy and range. ..

(c) Reasons for criteria The tests and criteria are, as previously indicated, ICH Q6B and published monographs, the results of the analysis obtained, the accuracy of the method used, the pharmacopoeia and / or regulatory guidelines. It was selected based on, and was consistent with the standard limits at this stage of development.

[Example 3] Pharmaceutical stability (a) Pharmaceutical stability The pharmaceutical stability study was started according to the outline of the stability study plan described in the table below. The composition and manufacturing method of the stability batch was a representative example of the material. Stability profiles were evaluated for storage under long-term, accelerated and rigorous test conditions according to ICH guidelines. Samples were packed and stored in glass vials with insertion discs and flange caps with flip-off lids. Stability data obtained with this packaging material were representative for preliminary shelf life and storage instructions for both packaging shapes (10 mL glass vials and 3 mL cartridges). To date, 12-month stability data are available from batches filled in 10 mL vials and 12-month batches filled in 3 mL cartridges, and formulation stability studies are ongoing.

<tables num="5"><img file="JP6445461B2_D0005.tif" /></tables>

During the stability test, the following tests were performed: Appearance, Quantification, Related Impurities, High Molecular Weight Protein, pH, Particulate Matter (Visible and Invisible Particles), Antibacterial Preservatives (m-Metacresol and Phenol) Quantification , Zinc content. After 12 months of storage under long-term storage conditions of + 5 ° C, testing for physical and chemical properties confirms the stability of the formulation when stored under recommended storage conditions. Only very small changes in related impurities could be observed.

When stored at + 25 ° C / 60% RH for 3 months under accelerated conditions, related impurities and high molecular weight proteins increased, but were kept within current tolerance limits. When stored under harsh conditions (+ 40 ° C / 75% RH for 1 month), one of the related impurities increased above the criteria. The contents of the active ingredient, m-methacresol and phenol, remained essentially unchanged under accelerated conditions.

The results of the formulation stability study confirm the chemical and physical stability of the formulation.

Tables 5-12 show long-term stability results, where batch number "_0105" corresponds to the formulation according to the invention filled in a 10 mL vial, and batch number "_318" on a 3 mL cartridge. Corresponds to the filled formulation according to the present invention.

(b) Comparison of stability of the product without buffer compared to the buffered product The buffered product containing phosphate buffer showed physical instability due to the formation of inorganic particles (sodium zinc phosphate hydrate). Formation, Na₆(ZnPO₄)₆. 8H₂O, sodalite crystal structure). Another buffered formulation containing a citrate buffer became turbid after being exposed to mild physical stress and also showed physical instability. The buffered formulation containing 2-amino-2-hydroxymethyl-propane-1,3-diol (synonym: TRIS) showed an increase in related impurities when stored under accelerated conditions. In addition, buffered formulations containing 2-amino-2-hydroxymethyl-propane-1,3-diol (TRIS) have three additionals when stored under harsh conditions (+ 40 ° C / 75% RH). The impurities (confirmed by LC / MS), namely TRIS-adduct + 103 Da; corresponding Desamido-adduct + 104 Da; and formaldehyde adduct + 12 Da (see Figure 1) were shown. The pharmaceutical product according to the present invention does not show these impurities.

Table 13 shows the relevant items and analytical results tested after 1 month of stability under long-term, accelerated and harsh conditions with respect to physicochemical stability compared to the formulations according to the invention. After storing the product under long-term storage conditions (+ 5 ° C for 1 month), the product was subjected to mechanical stress (shaking) and thermal stress (+ 37 ° C). Turbidity was measured (turbidity analysis test).

The stability of the buffer-free formulation (ie, an alternative aqueous pharmaceutical formulation containing at least one insulin analog and / or insulin derivative, sodium chloride, and no additional buffer) is excellent chemical and chemical. It exhibits physical stability and is therefore suitable as a pharmaceutical product having a predetermined shelf life.

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