PHARMACEUTICAL COMPOSITION IN THE FORM OF AN INJECTABLE AQUEOUS SOLUTION INCLUDING AT LEAST A RAPID ACTING INSULIN ANALOG AND A GLUCAGON SUPPRESSOR WITH PRANDIAL ACTION

Abstract

A composition in the form of an injectable aqueous solution, the pH of which is from 3.0 to 4.4, including at least a rapid-acting insulin analog and at least one glucagon suppressor with prandial action. The glucagon suppressor with prandial action is selected from the group consisting of an amylin analog or an amylin receptor agonist or a GLP-1 analog or a GLP-1 receptor agonist (GLP-1 RA). The glucagon suppressor with prandial action is an amylin analog or an amylin receptor agonist. The glucagon suppressor peptide with prandial action is pramlintide.

Claims

1-20. (canceled)

21. A pharmaceutical composition in the form of an injectable aqueous solution, the pH of which is from 3.0 to 4.0, comprising pramlintide and a rapid-acting insulin analog is insulin aspart A21G, also called human insulin A21G,B28D.

22. The pharmaceutical composition according to claim 21, wherein it is free of zinc.

23. The pharmaceutical composition according to claim 21, wherein it comprises nicotinamide.

24. The pharmaceutical composition according to claim 21, wherein the concentration of insulin aspart A21G is from 2 to 20 mg/mL.

25. The pharmaceutical composition according to claim 21, wherein the concentration of insulin aspart A21G is 3.5 mg/mL.

26. The pharmaceutical composition according to claim 21, wherein the concentration of pramlintide is from 0.32 to 5 mg/mL.

27. The pharmaceutical composition according to claim 21, wherein the pH of the solution is from 3.2 to 3.8.

28. The pharmaceutical composition according to claim 21, for use in the treatment of diabetes, wherein it is administered as one or several boluses at mealtime.

29. The pharmaceutical composition according to claim 21, for use in the treatment of diabetes, wherein it is administered using a pump.

30. The pharmaceutical composition according to claim 21, for use in the treatment of diabetes, wherein it is administered to improve the control of postprandial glycemia.

31. The pharmaceutical composition according to claim 21, for use in the treatment of diabetes, wherein it is administered to improve the control of postprandial glycemia and to decrease the adverse effects of pramlintide.

32. The pharmaceutical composition according to claim 21, for use in the treatment of diabetes, wherein it enables to decrease the food consumption induced by insulin.

Description

EXAMPLE 1

[0205] Preparation of a Pharmaceutical Composition Comprising Insulin Aspart A21G 100 U/mL (3.5 mg/mL) and of Pramlintide 0.6 mg/mL Containing m-Cresol (25 mM), Glycerol (184 mM) and Acetic Acid/Sodium Acetate Buffer (18 mM) at Acidic pH of 3.5.

[0206] A concentrated solution of excipients (m-cresol, glycerol) is added to a concentrated solution of insulin aspart A21G in an acetic acid/sodium acetate buffer at pH 3.5. A concentrated solution of pramlintide (10 mg/mL at pH 3.5) is added to this concentrated solution of insulin aspart A21G and of excipients so as to obtain the intended final pharmaceutical composition. The final pH 3.5, is obtained by addition of an aqueous solution of NaOH. The solution obtained is clear and homogeneous; it is subjected to a 0.22 μm filtration and stored in glass cartridges (1 mL of solution per 3 mL cartridge). The composition is detailed in table 1.

EXAMPLE 2

[0207] Preparation of a Pharmaceutical Composition Comprising Insulin Aspart A21G 100 U/mL (3.5 mg/mL) and of Pramlintide 0.6 mg/mL Containing m-Cresol (25 mM), Glycerol (184 mM), Acetic Acid/Sodium Acetate Buffer (18 mM) and Tween 20 (10 μg/mL) at Acidic pH of 3.5.

[0208] A concentrated solution of excipients (m-cresol, glycerol) is added to a concentrated solution of insulin aspart A21G in an acetic acid/sodium acetate buffer at pH 3.5. A concentrated solution of pramlintide (10 mg/mL at pH 3.5) and a concentrated solution of Tween 20 are added to this concentrated solution of insulin lispro A21G and of excipients so as to obtain the intended final pharmaceutical composition. The final pH 3.5, is obtained by addition of an aqueous solution of NaOH. The solution obtained is clear and homogeneous; it is subjected to a 0.22 μm filtration and stored in glass vials (1.2 mL of solution per 2 ml vial). The composition is detailed in table 1.

EXAMPLE 3

Preparation of a Pharmaceutical Composition Comprising Insulin Aspart A21G and of Pramlintide or GLP-1 RA at Acidic pH of 3.4.

[0209] A concentrated solution of excipients (m-cresol, glycerol) is optionally added to a concentrated solution of insulin aspart A21G at pH 2-3.5. A concentrated solution of pramlintide (10 mg/mL at pH 2-3.5) or GLP-1 RA (5 mg/mL) and optionally a concentrated solution of Tween 20 are added to this concentrated solution of insulin lispro A21G and of excipients so as to obtain the intended final pharmaceutical composition. The final pH 3.4, is obtained by addition of an aqueous solution of NaOH. The solutions obtained are clear and homogeneous; each is subjected to a 0.22 μm filtration and stored in glass cartridges (1 mL of solution per 3 ml cartridge). The compositions are detailed in table 1.

TABLE-US-00001 TABLE 1 Compositions comprising Insulin aspart A21G and glucagon suppressor at acidic pH. Aspart A21G Pramlintide GLP-1 RA Visual Composition (U/ml) (mg/ml) (mg/ml) pH Excipients aspect CA1 100 0.6 3.5 m-cresol Clear (25 mM) glycerol (184 mM) Acetate buffer (18 mM) CA2 100 0.6 3.5 m-cresol Clear (25 mM) glycerol (184 mM) Acetate buffer (18 mM) Tween 20 (10 μg/mL) CA3-1 100 0.6 3.4 m-cresol Clear (20.8 mM) glycerol (184 mM) Tween 20 (10 μg/mL) CA3-2 100 0.4 3.4 m-cresol Clear (20.8 mM) glycerol (184 mM) Tween 20 (10 μg/mL) CA3-3 100 0.9 3.4 m-cresol Clear (20.8 mM) glycerol (184 mM) Tween 20 (10 μg/mL) CA3-4 100 3.4 m-cresol Clear (20.8 mM) glycerol (184 mM) Tween 20 (10 μg/mL) CA3-5 200 0.8 3.4 m-cresol Clear (20.8 mM) glycerol (184 mM) Tween 20 (10 μg/mL) CA3-6 200 1.2 3.4 m-cresol Clear (20.8 mM) glycerol (184 mM) Tween 20 (10 μg/mL) CA3-7 200 1.8 3.4 m-cresol Clear (20.8 mM) glycerol (184 mM) Tween 20 (10 μg/mL) CA3-8 100 0.6 3.4 Clear CA3-9 200 1.2 3.4 Clear CA3-10 100 Exenatide 3.4 m-cresol Clear (0.05) (25 mM) glycerol (184 mM) Acetate buffer (5 mM) Tween 20 (10 μg/mL) CA3-11 100 Lixisenatide 3.4 m-cresol Clear (0.125) (25 mM) glycerol (184 mM) Acetate buffer (5 mM) Tween 20 (10 μg/mL) CA3-12 100 Exenatide 3.4 m-cresol Clear (0.1) (25 mM) glycerol (184 mM) Acetate buffer (5 mM) Tween 20 (10 μg/mL) CA3-13 100 Lixisenatide 3.4 m-cresol Clear (0.25) (25 mM) glycerol (184 mM) Acetate buffer (5 mM) Tween 20 (10 μg/mL) CA3-14 100 Exenatide 3.4 m-cresol Clear (0.4) (25 mM) glycerol (184 mM) Acetate buffer (5 mM) Tween 20 (10 μg/mL) CA3-15 100 Lixisenatide 3.4 m-cresol Clear (1) (25 mM) glycerol (184 mM) Acetate buffer (5 mM) Tween 20 (10 μg/mL) CA3-16 200 Exenatide 3.4 m-cresol Clear (0.1) (25 mM) glycerol (184 mM) Acetate buffer (5 mM) Tween 20 (10 μg/mL) CA3-17 200 Lixisenatide 3.4 m-cresol Clear (0.25) (25 mM) glycerol (184 mM) Acetate buffer (5 mM) Tween 20 (10 μg/mL)

EXAMPLE 4: PHARMACOKINETIC AND PHARMACODYNAMIC STUDY IN PIGS

[0210] Pharmacokinetic and pharmacodynamic study in pigs of the composition CA3-4 consisting of insulin aspart A21G (3.5 mg/mL equivalent to 100 U/mL of insulin) alone or the composition CA3-1 the composition (100 U/mL) combined with pramlintide (0.6 mg/mL).

[0211] Domestic pigs weighing approximately 50 kg, catheterized beforehand in the jugular, were fasted for 2.5 hours before the start of the experiment. During the hour preceding the injection of insulin, 3 blood samples were drawn to determine the baseline level of glucose and of insulin.

[0212] The injection of the formulations of insulin aspart A21G (CA3-4) or of insulin aspart A21G combined with pramlintide (CA3-1) at the dose of 0.125 U of insulin/kg and 0.75 μg of pramlintide/kg is performed subcutaneously in the flank of the animal with the aid of an insulin pen (Novo, Sanofi or Eli Lilly) equipped with a 31 G needle.

[0213] In order to determine the concentrations of insulin in the plasma and glucose in the blood, blood samples are drawn at the following times: 0, 10, 20, 30, 45, 60, 90, 120, 180 and 240 minutes. After each drawing, the catheter is rinsed with a dilute heparin solution.

Pharmacokinetic Results of the Solution of Insulin Aspart CA3-4 and of the Solution of Insulin Aspart A21G and Pramlintide CA3-1 in Pigs

[0214] The pharmacokinetic parameters of formulations CA3-4 and CA3-1 are estimated based on baseline-adjusted insulin concentrations in the plasma. A standard non-compartmental analysis is carried out with the aid of the software Phoenix WinNonlin (version 8, Certara). The values of the parameters (mean±standard deviation) are reported in table 2.

TABLE-US-00002 TABLE 2 Pharmacokinetic parameters of insulin of compositions CA3-4 and CA3-1 AUC.sub.0-30 min t.sub.max AUC.sub.0-30 min insulin insulin insulin (% of Composition Peptides N (min) (min*mU/L) AUC.sub.0-last) CA3-4 Aspart A21G 14 60 ± 22 342 ± 337 9 ± 10 (100 U/mL) CA3-1 Aspart A21G 14 50 ± 16 533 ± 401 14 ± 9  (100 U/mL) pramlintide (0.6 mg/mL) where t.sub.max= time necessary to observe the maximum plasma concentration; AUC.sub.0-30 min= area under the curve of the plasma concentration versus time between 0 and 30 min after injection; AUC.sub.0-last= area under the curve of the plasma concentrations versus time between 0 and the last quantifiable concentration after injection.

[0215] The analysis of the parameters indicates that the combination of insulin aspart A21G and of pramlintide (formulation CA3-1) leads to a faster absorption of insulin compared to insulin aspart A21G alone (formulation CA3-4). Formulation CA3-1 leads to a time to plasma peak (t.sub.max) which is earlier (approximately 10 min) and to a fraction of plasma insulin exposure within 0-30 min (AUC.sub.0-30min/AUC.sub.0-last) which is significantly increased (approximately 63%, p<0.05) in comparison to formulation CA3-4.

Pharmacodynamic Results of the Solution of Insulin Aspart CA3-4 and of the Solution of Insulin Aspart A21G and Pramlintide CA3-1 in Pigs

[0216] The pharmacodynamic parameters of formulations CA3-4 and CA3-1 are estimated based on baseline-adjusted (% from baseline) glucose concentrations in the blood. A standard non-compartmental analysis is carried out with the aid of the software Phoenix WinNonlin (version 8, Certara). The values of the parameters (mean±standard deviation) are reported in table 3.

TABLE-US-00003 TABLE 3 Pharmacodynamic parameters of glucose of compositions CA3-4 and CA3-1 AUC.sub.0-60 min t.sub.min glucose glucose (min*% from Composition Peptides N (min) baseline) CA3-4 Aspart A21G 13 96 ± 42 1197 ± 864 (100 U/mL) CA3-1 Aspart A21G 14 88 ± 46 1586 ± 549 (100 U/mL) pramlintide (0.6 mg/mL) where t.sub.min= time necessary to observe the minimum blood concentration. AUC.sub.0-60 min= area between baseline and the curve of the blood concentration versus time between 0 and 60 min after injection.

[0217] The analysis of the parameters indicates that the combination of insulin aspart A21G and of pramlintide (formulation CA3-1) leads to a faster hypoglycemic effect compared to insulin aspart A21G alone (formulation CA3-4). Formulation CA3-1 leads to time to maximum hypoglycemic effect (t.sub.min) which is earlier (approximately 8 min) and to an early hypoglycemic effect (AUC.sub.0-60min) which is increased (approximately 32%) in comparison to formulation CA3-4.