Acidic insulin preparations having improved stability
The invention relates to a pharmaceutical formulation comprising a polypeptide selected from the group consisting of insulin, an insulin metabolite, an insulin analog, an insulin derivative and combinations thereof; a surfactant or combinations of two or more surfactants; optionally a preservative or combinations of two or more preservatives; and optionally an isotonicizing agent, buffers or further excipients or combinations thereof, the pharmaceutical formulation having a pH in the acidic range.
1. A pharmaceutical formulation comprising Gly(A21), Arg(B31), Arg(B32)-human insulin;
at least one chemical entity chosen from esters and ethers of polyhydric alcohols;
at least one preservative; and
water,
wherein the pharmaceutical formulation has a pH in the acidic range from 1 to 6.8.
2. The pharmaceutical formulation as claimed in claim 1 , wherein the at least one preservative is chosen from phenols.
3. The pharmaceutical formulation as claimed in claim 1 , wherein the at least one preservative is cresol.
4. The pharmaceutical formulation as claimed in claim 3 , further including zinc.
5. The pharmaceutical formulation as claimed in claim 1 , further including at least one isotonicizing agent.
6. The pharmaceutical formulation as claimed in claim 4 , wherein the pharmaceutical formulation has a pH in the acidic range from 3.5 to 6.8.
7. The pharmaceutical formulation as claimed in claimed 6 , wherein the pharmaceutical formulation has a pH in the acidic range from 3.5 to 4.5.
8. The pharmaceutical formulation as claimed in claim 1 , wherein the at least one preservative is chosen from phenol, cresol, chlorocresol, benzyl alcohol, and parabens.
9. The pharmaceutical formulation as claimed in claim 5 , wherein the at least one isotonicizing agent is chosen from mannitol, sorbitol, lactose, dextrose, trehalose, sodium chloride, and glycerol.
10. The pharmaceutical formulation as claimed in claim 1 , further comprising a buffer.
11. The pharmaceutical formulation as claimed in claim 10 , wherein the buffer is chosen from TRIS, phosphate, citrate, acetate, and glycylglycine.
12. The pharmaceutical formulation as claimed in claim 1 , wherein the Gly(A21), Arg(B31), Arg(B32)-human insulin is present in a concentration of 60-6000 nmol/ml.
13. The pharmaceutical formulation as claimed in claim 12 , wherein the Gly(A21), Arg(B31), Arg(B32)-human insulin is present in a concentration of 240-3000 nmol/ml.
14. The pharmaceutical formulation as claimed in claim 1 , wherein the at least one chemical entity is present in a concentration of 5-200 μg/ml.
15. The pharmaceutical formulation as claimed in claim 14 , wherein the at least one chemical entity is present in a concentration of 5-120 μg/ml.
16. The pharmaceutical formulation as claimed in claim 15 , wherein the at least one chemical entity is present in a concentration of 20-75 μg/ml.
17. The pharmaceutical formulation as claimed in claim 9 , wherein at least one isotonicizing agent is chosen from glycerol and mannitol and wherein said at least one isotonicizing agent is present in a concentration of 100-250 mM.
18. The pharmaceutical formulation as claimed in claim 1 , further comprising one or more excipients chosen from acids, alkalis and salts.
19. The pharmaceutical formulation as claimed in claim 18 , wherein the excipient is NaCl which is present in a concentration of up to 150 mM.
20. The pharmaceutical formulation as claimed in claim 10 , wherein said buffer is present in a concentration of 5-250 mM.