RU2001113271A - STABLE CONCENTRATED DRUG FORMS OF INSULIN FOR DELIVERY THROUGH EASY - Google Patents

Claims (20)

1. An aqueous preparative form of insulin, comprising from 6 to 15 mm human insulin or its analogue or its derivative, less than 50 mm chloride, less than 10 mm any anion other than chloride and acetate, from 2 to 5 Zn ²⁺ ions per six molecules insulin and at least 3 phenolic molecules per six insulin molecules.  2. The insulin formulation of claim 1, comprising about 6 mM, about 9 mM, about 12 mM, or about 15 mM human insulin or an analogue or derivative thereof.  3. The preparative form of insulin according to claim 1 or 2, comprising up to 50 mM phenolic molecules, preferably from 3 to 12 phenolic molecules per six insulin molecules, more preferably from 3 to 9 phenolic molecules per six insulin molecules.  4. The preparative form of insulin according to any one of the preceding paragraphs, comprising less than 40 mm, preferably less than 30 mm chloride, more preferably from 5 to 20 mm chloride.  5. The preparative form of insulin according to any one of the preceding paragraphs, including up to 5 mm phosphate. 6. The preparative form of insulin according to any one of the preceding paragraphs, comprising from 2 to 4 Zn ²⁺ ions, preferably from 2.2 to 3.2 Zn ²⁺ ions per six insulin molecules.  7. The preparative form of insulin according to any one of the preceding paragraphs, further comprising from 5 to 150 mm zwitterionic amine, preferably glycylglycine or glycine.  8. The preparative form of insulin according to any one of the preceding paragraphs, further comprising from 5 to 50 mm Trishydroxymethylaminomethane.  9. The preparative form of insulin according to any one of the preceding paragraphs, including sodium ions, potassium ions, or a mixture thereof, as cations.  10. The preparative form of insulin according to any one of the preceding paragraphs, further comprising between 0.001 and 1 wt. % non-ionic surfactant, preferably Tween 20 or Polox 188.  11. A formulation of insulin according to any one of the preceding claims, further comprising from 1 mM to 10 mM anionic surfactant, preferably sodium taurocholate.  12. The preparative form of insulin according to any one of the preceding paragraphs, including human insulin.  13. The preparative form of insulin according to any one of the preceding paragraphs, comprising a human insulin analogue, wherein position B28 is Asp, Lys, Leu, Val or Ala, and position B29 is Lys or Pro; or des (B28-B30), des (B27) or des (B30) human insulin. 14. The insulin formulation of claim 13, comprising a human insulin analogue, wherein position B28 is Asp or Lys and position B29 is Lys or Pro, preferably Asp ^{B28 is} human insulin or Lys ^B28 Pro ^{B29 is} human insulin.  15. The preparative form of insulin according to any one of paragraphs. 1-11, comprising a derivative of human insulin having one or more lipophilic substituents, preferably acylated insulin. 16. The insulin formulation according to claim 15, wherein the insulin derivative is selected from the group consisting of B29-N ^ε- myristoyl des (B30) human insulin, B29-N ^ε- palmitoyl des (B30) human insulin, B29- N ^ε -mipictoil human insulin, B29-N ^ε -palmitoil human insulin, B28-N ^ε -mipictoilLys ^B28 Pro ^B29 chelovecheckogo insulin, B28-N ^ε -palminoilLus ^B28 Pro ^B29 human insulin, B30-N ^ε -miristoil-Thr ^B29 Lys ^B30 human insulin B ³⁰ -N ^ε -palmitoilThr ^B29 Lys ^B30 human ^{insulin, B29-N ε - (N} - palmitoyl-γ-glutamyl) -des (B30) human ^{insulin, B29-N ε - (N} - lit. holil-γ-glutamyl) -des (B30) human insulin, B29-N ^ε - (ω-karboksigeptadekanoil) -des (B30) human insulin and B29-N ^ε - (ω-karboksigeptadekanoil) human insulin. 17. The preparative form of insulin according to claim 16, wherein the insulin derivative is B29-N ^ε -myristoyl des (B30) human insulin or B29-N ^ε - (N-lithocholyl-γ-glutamyl) des (B30) human insulin .  18. The preparative form of insulin according to any one of the preceding paragraphs, including an insulin analogue or human insulin, as well as an insulin derivative.  19. The preparative form of insulin according to any one of the preceding paragraphs, in which the phenolic molecules are selected from the group consisting of phenol, m-cresol, chlorocresol, thymol, or any mixture thereof.  20. The preparative form of insulin according to any one of the preceding paragraphs, having a hydrogen index in the range from 7 to 8.5, preferably from 7.4 to 7.9.