Soluble pharmaceutical compositions for parenteral administration comprising a GLP-1 peptide and an insulin peptide of short time action for treatment of diabetes and bulimia

Abstract

Pharmaceutical composition for parenteral administration comprising a meal related insulin peptide and an insulinotropic peptide.

1 . A soluble pharmaceutical composition for parenteral administration, which comprises an insulinotropic peptide, a meal-related insulin peptide, a pharmaceutically acceptable preservative and optionally an isotonicity agent.  
     
     
         2 . The pharmaceutical composition according to  claim 1 , wherein the pH of said pharmaceutical composition or a reconstituted solution of said pharmaceutical composition is from about pH 7.0 to about pH 9.0.  
     
     
         3 . The pharmaceutical composition according to  claim 1 , wherein the pH of said pharmaceutical composition or a reconstituted solution of said pharmaceutical composition is from about pH 7.0 to about pH 8.0.  
     
     
         4 . The pharmaceutical composition according to  claim 1 , wherein the composition is a solution.  
     
     
         5 . The pharmaceutical composition according to  claim 1 , wherein the composition is a solid.  
     
     
         6 . The pharmaceutical composition according to  claim 5 , which is to be reconstituted with an aqueous solution such as a buffer or water for injection.  
     
     
         7 . The pharmaceutical composition according to  claim 1 , which is suitable for administration by injection or infusion.  
     
     
         8 . The pharmaceutical composition according to  claim 1 , wherein said meal-related insulin peptide has a time action of less than 4 hours.  
     
     
         9 . The pharmaceutical composition according to  claim 1 , wherein said meal-related insulin peptide is human insulin, an analogue of human insulin, a derivative of human insulin or a derivative of a human insulin analogue.  
     
     
         10 . The pharmaceutical composition according to  claim 9 , wherein said meal-related insulin peptide is human insulin.  
     
     
         11 . The pharmaceutical composition according to  claim 9 , wherein said meal-related insulin peptide is a human insulin analogue.  
     
     
         12 . The pharmaceutical composition according to  claim 11 , wherein said meal-related human insulin analogue is Asp B28 -human insulin.  
     
     
         13 . The pharmaceutical composition according to  claim 11 , wherein said meal-related human insulin analogue is Lys B28 , Pro B29 -human insulin.  
     
     
         14 . The pharmaceutical composition according to  claim 11 , wherein said meal-related human insulin analogue is Lys B3 , Glu B29 -human insulin.  
     
     
         15 . The pharmaceutical composition according to  claim 11 , wherein said meal-related human insulin analogue is des(B30) human insulin.  
     
     
         16 . The pharmaceutical composition according to  claim 9 , wherein said meal-related insulin peptide is a derivative of a human insulin analogue.  
     
     
         17 . The pharmaceutical composition according to  claim 1 , wherein the concentration of said meal-related insulin peptide is in the range from about 1.6 mg/mL to about 5.6 mg/mL.  
     
     
         18 . The pharmaceutical composition according  claim 1 , wherein the concentration of said meal-related insulin peptide is in the range from about 1 mg/mL to about 10 mg/mL.  
     
     
         19 . The pharmaceutical composition according to  claim 1 , wherein said composition comprises two different insulin peptides.  
     
     
         20 . The pharmaceutical composition according to  claim 1 , wherein said insulinotropic peptide is GLP-1(7-37) (SEQ ID NO. 1), a GLP-1(7-37) analogue, a derivative of GLP-1(7-37), or a derivative of a GLP-1(7-37) analogue.  
     
     
         21 . The pharmaceutical composition according to  claim 20 , wherein said GLP-1(7-37) analogue is selected from the group consisting of Arg 34 -GLP-1(7-37), Gly 8 -GLP-1(7-36)-amide, Gly 8 -GLP-1(7-37), Val 8 -GLP-1(7-36)-amide, Val 8 -GLP-1(7-37), Val 8 Asp 22 -GLP-1(7-36)-amide, Val 8 Asp 22 -GLP-1(7-37), Val 8 Glu 22 -GLP-1(7-36)-amide, Val 8 Glu 22 -GLP-1(7-37), Val 8 Lys 22 -GLP-1(7-36)-amide, Val 8 Lys 22 -GLP-1(7-37), Val 8 Arg 22 -GLP-1(7-36)-amide, Val 8 Arg 22 -GLP-1(7-37), Val 8 His 22 -GLP-1(7-36)-amide, Val 8 His 22 -GLP-1(7-37), Val 8 Trp 19 Glu 22 -GLP-1(7-37), Val 8 Glu 22 Val 25 -GLP-1(7-37), Val 8 Tyr 16 Glu 22 -GLP-1(7-37), Val 8 Trp 16 Glu 22 -GLP-1(7-37), Val 8 Leu 16 Glu 22 -GLP-1(7-37), Val 8 Tyr 18 Glu 22 -GLP-1(7-37), Val 8 Glu 22 His 37 -GLP-1(7-37), Val 8 Glu 22 Ile 33 -GLP-1(7-37), Val 8 Trp 16 Glu 22 Val 25 Ile 33 -GLP-1(7-37), Val 8 Trp 16 Glu 22 Ile 33 -GLP-1(7-37), Val 8 Glu 22 Val 25 Ile 33 -GLP-1(7-37), Val 8 Trp 16 Glu 22 Val 25 -GLP-1(7-37), analogues thereof and derivatives of any of these.  
     
     
         22 . The pharmaceutical composition according to  claim 20 , wherein said derivative of a GLP-1(7-37) analogue is GLP-1(7-36)-amide.  
     
     
         23 . The pharmaceutical composition according to  claim 1 , wherein said insulinotropic peptide is a derivative of GLP-1(7-37) or a derivative of a GLP-1(7-37) analogue having a lysine residue and wherein a lipophilic substituent optionally via a spacer is attached to the epsilon amino group of said lysine.  
     
     
         24 . The pharmaceutical composition according to  claim 23 , wherein said lipophilic substituent has from 8 to 40 carbon atoms.  
     
     
         25 . The pharmaceutical composition according to  claim 23 , wherein said spacer is present and is selected from an amino acid.  
     
     
         26 . The pharmaceutical composition according to  claim 1 , wherein said insulinotropic peptide is a dipeptidyl aminopeptidase IV protected GLP-1 compound.  
     
     
         27 . The pharmaceutical composition according to  claim 1 , wherein said insulinotropic peptide is a plasma stable GLP-1 compound.  
     
     
         28 . The pharmaceutical composition according to any one of  claim 20 , wherein said derivative of a GLP-1(7-37) analogue is Arg 34 , Lys 26 (N ε -(γ-Glu(N α -hexadecanoyl)))-GLP-1(7-37).  
     
     
         29 . The pharmaceutical composition according to  claim 20 , wherein said insulinotropic peptide has from 27 to 43 amino acid residues.  
     
     
         30 . The pharmaceutical composition according to  claim 20 , wherein the concentration of said insulinotropic peptide is from about 1 mg/mL to about 25 mg/mL.  
     
     
         31 . The pharmaceutical composition according to  claim 1 , wherein said insulinotropic peptide is exendin-4 (SEQ ID NO 2), an exendin-4 analogue, a derivative of exendin-4, or a derivative of an exendin-4 analogue.  
     
     
         32 . The pharmaceutical composition according to  claim 31 , wherein said insulinotropic peptide is exendin-4 (SEQ ID NO. 2).  
     
     
         33 . The pharmaceutical composition according to  claim 31 , wherein said exendin-4 analogue is exendin-3 or ZP-10 (HGEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPSKKKKKK-NH2, SEQ ID. NO. 3).  
     
     
         34 . The pharmaceutical composition according to  claim 31 , wherein said derivative of an exendin-4 analogue is an acylated exendin-4 analogue or a pegylated exendin-4 analogue.  
     
     
         35 . The pharmaceutical composition according to  claim 31 , wherein said insulinotropic peptide is a derivative of exendin-4 or a derivative of an exendin-4 analogue having a lysine residue, and wherein a lipophilic substituent optionally via a spacer is attached to the epsilon amino group of said lysine.  
     
     
         36 . The pharmaceutical composition according to  claim 35 , wherein said lipophilic substituent has from 8 to 40 carbon atoms.  
     
     
         37 . The pharmaceutical composition according to  claim 35 , wherein said spacer is present and is selected from an amino acid.  
     
     
         38 . The pharmaceutical composition according to  claim 1 , wherein said insulinotropic peptide is a dipeptidyl aminopeptidase IV protected exendin-4 compound.  
     
     
         39 . The pharmaceutical composition according to  claim 1 , wherein said insulinotropic peptide is a plasma stable exendin-4 compound.  
     
     
         40 . The pharmaceutical composition according to  claim 31 , wherein said insulinotropic peptide has from 30 to 48 amino acid residues.  
     
     
         41 . The pharmaceutical composition according to  claim 20 , wherein the concentration of said insulinotropic peptide is from about 5 μg/mL to about 10 mg/mL.  
     
     
         42 . The pharmaceutical composition according to  claim 1 , wherein the isoelectric point of said insulinotropic peptide is from 3.0 to 7.0.  
     
     
         43 . The pharmaceutical composition according to  claim 1 , said composition further comprising zinc.  
     
     
         44 . The pharmaceutical composition according to  claim 43 , wherein the molar ratio of zinc to insulin peptide is from ⅙ to ½ mole/mole.  
     
     
         45 . The pharmaceutical composition according to  claim 1 , wherein said meal-related insulin peptide is human insulin and said insulinotropic peptide is Arg 34 , Lys 26 (N ε -(γ-Glu(N α -hexadecanoyl)))-GLP-1(7-37).  
     
     
         46 . The pharmaceutical composition according to  claim 45 , wherein the concentration of Arg 34 , Lys 26 (N ε -(γ-Glu(N α -hexadecanoyl)))-GLP-1(7-37) is in the range from from about 5 mg/mL to about 15 mg/mL and the concentration of human insulin is in the range from about 3.2 mg/mL to about 4.0 mg/mL.  
     
     
         47 . The pharmaceutical composition according to  claim 1 , wherein said insulin peptide is Asp B28 -human insulin and said insulinotropic peptide is Arg 34 , Lys 26 (N ε -(γ-Glu(N α -hexadecanoyl)))-GLP-1(7-37).  
     
     
         48 . The pharmaceutical composition according to  claim 47 , wherein the concentration of Arg 34 , Lys 26 (N ε -(γ-Glu(N α -hexadecanoyl)))-GLP-1(7-37) is in the range from about 5 mg/mL to about 15 mg/mL and the concentration of Asp B28 -human insulin is in the range from about 3.2 mg/mL to about 4.0 mg/mL.  
     
     
         49 . The pharmaceutical composition according to  claim 47 , wherein the concentration of Arg 34 , Lys 26 (N ε -(γ-Glu(N α -hexadecanoyl)))-GLP-1(7-37) is in the range from about 5 mg/mL to about 15 mg/mL and the concentration of Asp B28 -human insulin is in the range from about 3.4 mg/mL to about 3.8 mg/mL.  
     
     
         50 . The pharmaceutical composition according to  claim 1 , wherein said insulin peptide is Lys B3 , Glu B29 -human insulin and said insulinotropic peptide is ZP-10 (HGEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPSKKKKKK-NH2, SEQ ID. NO. 3).  
     
     
         51 . The pharmaceutical composition according to  claim 50 , wherein the concentration of Lys B3 , Glu B29 -human insulin is in the range from about 3.2 mg/mL to about 4.0 mg/mL.  
     
     
         52 . The pharmaceutical composition according to  claim 50 , wherein the concentration of ZP-10 is in the range from about 0.1 mg/mL to about 3 mg/mL.  
     
     
         53 . The pharmaceutical composition according to  claim 1 , wherein said preservative is phenol, m-cresol or a mixture thereof.  
     
     
         54 . The pharmaceutical composition according to  claim 1 , wherein said pharmaceutical composition comprises a buffer.  
     
     
         55 . The pharmaceutical composition according to  claim 54 , wherein said buffer is phosphate, TRIS, HEPES, glycine, N-glycylglycine, citrate or a mixture thereof.  
     
     
         56 . The pharmaceutical composition according to  claim 1 , wherein said pharmaceutical composition comprises an isotonicity agent.  
     
     
         57 . The pharmaceutical composition according to  claim 56 , wherein said isotonicity agent is not a salt.  
     
     
         58 . The pharmaceutical composition according to  claim 57 , wherein said isotonicity agent is selected from mannitol, sorbitol, glycerol, propylene glycol or a mixture thereof.  
     
     
         59 . The pharmaceutical composition according to  claim 1 , wherein said composition further comprises a stabiliser.  
     
     
         60 . The pharmaceutical composition according to  claim 59 , wherein said stabiliser is selected from the group consisting of L-histidine, imidazole and L-arginine.  
     
     
         61 . The pharmaceutical composition according to  claim 59 , wherein said stabiliser is a polyethylene glycol.  
     
     
         62 . The pharmaceutical composition according to  claim 1 , wherein said composition further comprises a surfactant.  
     
     
         63 . The pharmaceutical composition according to  claim 62 , wherein said surfactant is a poloxamer.  
     
     
         64 . The pharmaceutical composition according to  claim 63 , wherein said surfactant is a poloxamer 188.  
     
     
         65 . The pharmaceutical composition according to  claim 63 , wherein said surfactant is selected from the group consisting of poloxamer 407, poloxamer 124, poloxamer 181, poloxamer 182, poloxamer 237, poloxamer 331 and poloxamer 338.  
     
     
         66 . The pharmaceutical composition according to  claim 62 , wherein said surfactant is a polysorbate 20 (Tween-20).  
     
     
         67 . The pharmaceutical composition according to  claim 62 , wherein the concentration of said surfactant is from about 5 mg/L to about 3000 mg/L.  
     
     
         68 . The pharmaceutical composition according to  claim 62 , wherein the concentration of said surfactant is from about 10 mg/L to about 500 mg/L.  
     
     
         69 . The pharmaceutical composition according to  claim 62 , wherein the concentration of said surfactant is from about 20 mg/L to about 300 mg/L.  
     
     
         70 . The pharmaceutical composition according to  claim 62 , wherein the concentration of said surfactant is from about 50 mg/L to about 200 mg/L.  
     
     
         71 . The pharmaceutical composition according to  claim 62 , wherein said composition comprises two different surfactants.  
     
     
         72 . The pharmaceutical composition according to  claim 71 , comprising poloxamer 188 and polysorbate 20 (Tween-20).  
     
     
         73 . A method for treatment of hyperglycemia comprising parenteral administration of an effective amount of the pharmaceutical composition according to  claim 1 .  
     
     
         74 . The method according to  claim 73 , wherein said effective amount of the pharmaceutical composition is from about 30 μL/day to about 600 μL/day.  
     
     
         75 . The method according to  claim 73 , wherein administration is by subcutaneous injection.  
     
     
         76 . The method according to  claim 73 , wherein administration is by a pump.  
     
     
         77 . The method according to  claim 73 , wherein administration is by a pump which delivers a discontinuous amount of said pharmaceutical composition.  
     
     
         78 . The method according to  claim 77 , wherein said discontinuous administration of said pharmaceutical composition is by a pulse dosing for a period of time which is less than the period of time between pulses.  
     
     
         79 . A method for treatment of binge eating or bulimia, said method comprising parenteral administration of an effective amount of the pharmaceutical composition according to  claim 1