Rapid-acting insulin formulation comprising a substituted anionic compound

Patent metadata

Field	Value
Publication number	US-10646551-B2
Application number	US-201916687339-A
Country	US
Kind code	B2
Filing date	Nov 18, 2019
Priority date	Nov 13, 2012
Publication date	May 12, 2020
Grant date	May 12, 2020

Abstract

A composition in aqueous solution includes insulin and at least one substituted anionic compound chosen from substituted anionic compounds consisting of a backbone formed from a discrete number u of between 1 and 8 (1≤u≤8) of identical or different saccharide units, linked via identical or different glycoside bonds, the saccharide units being chosen from the group consisting of hexoses, in cyclic form or in open reduced form, said compound comprising partially substituted carboxyl functional groups, the unsubstituted carboxyl functional groups being salifiable. A pharmaceutical formulation including the composition is also set forth.

First claim

The invention claimed is:

1. A rapid acting insulin pharmaceutical composition suitable for injection having a pH of 7.4±0.4, comprising:
an insulin in hexameric form in the presence of zinc, wherein the insulin has a concentration between 100 to 200 IU/mL;
a polyanionic compound in a concentration between 9.3 mM and 30 mM, wherein the polyanionic compound is citric acid or the Na + , K + , Ca 2+ or Mg 2+ salt thereof;
zinc salts;
sodium chloride; and
a preservative;
wherein the insulin is insulin lispro, and the composition has a circular dichroism signal at 251 nm of −300 deg cm 2 dmol −1 or the insulin is human insulin, and the composition has a circular dichroism signal at 275 nm of −250 deg cm 2 dmol −1 and wherein the insulin pharmaceutical composition does not include EDTA.

2. The rapid acting insulin pharmaceutical composition of claim 1 , wherein the concentration of the citric acid or salt thereof is between 10 mM and 30 mM.

3. The rapid acting insulin pharmaceutical composition of claim 1 , wherein the concentration of the citric acid is 20 mM.

4. The rapid acting insulin pharmaceutical composition of claim 1 , wherein the concentration of the citric acid is 30 mM.

5. The rapid acting insulin pharmaceutical composition of claim 1 , wherein the concentration of the citric acid is 10 mM.

6. The rapid acting insulin pharmaceutical composition of claim 1 , wherein the preservative is selected from the group consisting of m-cresol, phenol, and a mixture thereof.

7. The rapid acting insulin pharmaceutical composition of claim 1 , wherein the polyanionic compound is sodium citrate.

8. The rapid acting insulin pharmaceutical composition of claim 1 , further comprising a surfactant.

9. The rapid acting insulin pharmaceutical composition of claim 1 , wherein the zinc salts have a concentration of up to 500 μM.

10. A rapid acting insulin lispro pharmaceutical composition suitable for injection and having a pH of 7.4±0.4, comprising:
an insulin lispro in hexameric form; wherein the insulin has a concentration between 100 to 200 IU/mL;
a polyanionic compound in a concentration between 9.3 and 30 mM, wherein the polyanionic compound is citric acid or the Na + , K + , Ca 2+ or Mg 2+ salt thereof; zinc salts; and a preservative; and
wherein the insulin pharmaceutical composition has a circular dichroism signal at 251 nm of less than −300 deg cm 2 dmol −1 .

11. The rapid acting insulin lispro pharmaceutical composition of claim 10 , further comprising sodium chloride.

12. The rapid acting insulin lispro pharmaceutical composition of claim 10 , further comprising a surfactant.

13. The rapid acting insulin pharmaceutical composition of claim 10 , wherein the concentration of the citric acid or salt thereof is between 10 mM and 30 mM.

14. The rapid acting insulin pharmaceutical composition of claim 10 , wherein the concentration of the citric acid is 20 mM.

15. The rapid acting insulin pharmaceutical composition of claim 10 , wherein the concentration of the citric acid is 30 mM.

16. A rapid acting human insulin pharmaceutical composition suitable for injection and having a pH of 7.4±0.4, comprising:
human insulin in hexameric form; wherein the insulin has a concentration between 100 to 200 IU/mL;
a polyanionic compound in a concentration between 9.3 and 30 mM, wherein the polyanionic compound is citric acid or the Na + , K + , Ca 2+ or Mg 2+ salt thereof; zinc salts; and a preservative; and
wherein the insulin pharmaceutical composition has a circular dichroism signal at 275 nm of less than −250 deg cm 2 dmol −1 .

17. The rapid acting human insulin pharmaceutical composition of claim 16 , further comprising sodium chloride.

18. The rapid acting human insulin pharmaceutical composition of claim 16 , further comprising a surfactant.

19. The rapid acting insulin pharmaceutical composition of claim 16 , wherein the concentration of the citric acid or salt thereof is between 10 mM and 30 mM.

20. The rapid acting insulin pharmaceutical composition of claim 16 , wherein the concentration of the citric acid is 20 mM.

21. The rapid acting insulin pharmaceutical composition of claim 16 , wherein the concentration of the citric acid is 30 mM.

22. A rapid acting insulin pharmaceutical composition suitable for injection having a pH of 7.4±0.4, comprising:
an insulin in hexameric form in the presence of zinc, wherein the insulin has a concentration between 100 to 200 IU/mL;
a polyanionic compound in a concentration between 9.3 mM and 30 mM, wherein the polyanionic compound is citric acid or the Na + , K + , Ca 2+ or Mg 2+ salt thereof;
a surfactant; and
a preservative;
wherein the insulin is insulin lispro, and the composition has a circular dichroism signal at 251 nm of −300 deg cm 2 dmol −1 or the insulin is human insulin, and the composition has a circular dichroism signal at 275 nm of −250 deg cm 2 dmol −1 wherein the insulin pharmaceutical composition does not include EDTA.

23. The rapid acting insulin pharmaceutical composition of claim 22 , further comprising a tonicity agent.

24. The rapid acting insulin pharmaceutical composition of claim 23 , wherein the tonicity agent is sodium chloride.

25. The rapid acting insulin pharmaceutical composition of claim 23 , further comprising zinc salts.

26. The rapid acting insulin pharmaceutical composition of claim 25 , wherein the zinc salts have a concentration up to 500 μM.

Assignees

• Adocia

Inventors

• SOULA GéRARD
• Alluis Bertrand

Classifications

• C08B37/0021

  Dextran, i.e. (alpha-1,4)-D-glucan; Derivatives thereof, e.g. Sephadex, i.e. crosslinked dextran · CPC title

• C07H3/06

  Oligosaccharides, i.e. having three to five saccharide radicals attached to each other by glycosidic linkages · CPC title

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61K47/183

  Amino acids, e.g. glycine, EDTA or aspartame · CPC title

• A61K47/34

  Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers (A61K47/10 takes precedence) · CPC title