Compositions containing rapid-acting insulin analogues
A pharmaceutical composition comprises an effective amount of an insulin analogue comprising modified A-chain and B-chain polypeptides. The modified A chain comprises one or more substitutions relative to wild-type human insulin A-chain selected from a Gln, His or Glu substitution at position A8, a Glu or Ala substitution at position A14, and an Ala, Gln, Gly, or Thr substitution at position A21. The modified B-chain polypeptide comprises one or more modifications relative to wild-type human insulin B-chain selected from a deletion of the amino acid or amino acids at position B1, B1 and B2, or B1-B3, an Ala or Glu substitution at position B2, a Glu or Ala substitution at position B3, an Ala substitution at position B4; and a Glu or Lys substitution at position B29. The composition comprises one or more of iloprost, citrate, EDTA and a polyphosphate compound. The composition may be used to treat diabetes.
1 . A pharmaceutical composition comprising an effective amount of an insulin analogue comprising a modified A-chain polypeptide and a modified B-chain polypeptide, wherein the insulin analogue consists of the following modifications with respect to wild type human insulin: EA8, EA14, GA21, desB1, AB2, EB3, and EB29, and
wherein the composition comprises one or more of iloprost, citrate, EDTA and a polyphosphate compound.
2 . The pharmaceutical composition of claim 1 , wherein
the insulin analogue is monomeric or dimeric when formulated at U-500.
3 . The pharmaceutical composition of claim 2 , wherein the insulin analogue is formulated with a polyphosphate compound.
4 . The pharmaceutical composition of claim 3 , wherein the polyphosphate compound is one or more of a pyrophosphate, triphosphate, trimetaphosphate, and tetraphosphate.
5 . The pharmaceutical composition of claim 1 , wherein the insulin analogue is formulated with iloprost.
6 . The pharmaceutical composition of claim 5 , wherein the iloprost is present at a concentration of about 1 μg/mL to about 100 μg/mL.
7 . The pharmaceutical composition of claim 5 , wherein the insulin analogue is formulated with EDTA and citrate.
8 . The pharmaceutical composition of claim 1 , wherein the insulin analogue is formulated with less than 0.05 moles of zinc per mole of insulin.
9 . The pharmaceutical composition of claim 1 , wherein the insulin analogue is formulated with one or more of about 10 to about 100 mM Tris, about 0.1 mg/mL to about 10 mg/mL m-cresol, and about 0.1 mg/mL to about 25 mg/mL glycerin.
10 . The pharmaceutical composition of claim 7 , wherein the insulin analogue further comprises magnesium.
11 . The pharmaceutical composition of claim 1 , comprising iloprost at a concentration of about 5 μg/mL to about 50 μg/mL.
12 . A method for treating a subject with diabetes or prediabetes, the method comprising administering to the subject pharmaceutically effective amount of an insulin analogue comprising a modified A-chain polypeptide and a modified B-chain polypeptide, wherein the insulin analogue consists of the following modifications with respect to wild type human insulin: EA8, EA14, GA21, desB1, AB2, EB3, and EB29, and
wherein the composition comprises one or more of iloprost, citrate, EDTA and a polyphosphate compound.
13 . The pharmaceutical composition of claim 1 , comprising iloprost at a concentration of about 10 μg/mL to about 25 μg/mL.