Pharmaceutical formulation comprising incretin-insulin conjugates

An aqueous pharmaceutical formulation comprising (i) a therapeutically effective amount of an incretin-insulin conjugate which comprises an incretin peptide and an insulin molecule, (ii) a buffer, (iii) glycerin, (iv) phenol or m-cresol, and (v) L-arginine HCl,

• wherein the pharmaceutical formulation has a pH of about 6.9-7.5;
• wherein the incretin peptide has the structure:
• X1X2X3GX4FTSDX5SX6YLDX7XsAAX9X1oFVX11WLLX12X13GPSSGAPPPSX14
• wherein
• X1 is His, Tyr, or absent;
• X2 is aminoisobutyric acid;
• X3 is Glu or Gln;
• X4 is Thr or Ile;
• X5 is Tyr or Lys acylated with a C16 to C20 alkyl group optionally via a gamma Glu linker;
• X6 is Ile or Arg;
• X7 is Lys, Arg, or Glu;
• X8 is Gln or Arg;
• X9 is Gln or aminoisobutyric acid;
• X10 is Glu or Asp;
• X11 is Asn, Gln, or Ala;
• X12 is Ala or Asp;
• X13 is Ala or Gly;
• and
• X14 is absent, Lys, Lys acylated with a C16 to C20 alkyl group optionally via a gamma Glu;
• wherein the insulin molecule comprises an A chain polypeptide and a B chain polypeptide of human insulin, wherein the B chain is linked to said A chain through disulfide linkages and wherein the incretin peptide is linked to the insulin peptide via a linear chain spacer of 5 to 10 atoms, wherein the spacer comprises a disulfide linkage within the backbone of the spacer linear chain, wherein the linear chain spacer joining the incretin peptide to the insulin molecule comprises the general structure of:
• wherein R3 is H or CH3;
• wherein the cysteine of the linear chain spacer joining the incretin peptide to the insulin molecule is at the C-terminal end of the incretin peptide;
• wherein the aqueous pharmaceutical formulation comprises about 1-100 mg/mL of the incretin-insulin conjugate, about 4-6 mg/mL of m-cresol or about 5.0 mg/mL of phenol about 6.3 mg/mL of the incretin-insulin conjugate, about 16 mg/mL of glycerin, about 10 mM sodium phosphate dibasic, and about 10.53 mg/mL of L-Arginine HCl.