Claims for Patent: 9,822,158

Summary for Patent: 9,822,158

Title:	Method for preparing crystalline insulin
Abstract:	A method for crystallizing insulin or insulin analogs under alkaline conditions and purifying the insulin or insulin analog crystals by filtering through a filter and drying the insulin or insulin analog crystals captured on the filter to produce crystalline insulin or insulin analog crystal compositions is described. In particular aspects, the method may be used to crystalize insulin glargine.
Inventor(s):	Ortigosa; Allison D. (Harrisonburg, VA), Perry; William (Longmont, CO), Sleevi; Mark C. (Longmont, CO), Sierra; Luis (Dunellen, NJ)
Assignee:	Merck Sharp & Dohme Corp. (Rahway, NJ)
Application Number:	15/038,495
Patent Claims:	1. A method for preparing insulin glargine crystals comprising: (a) providing a solution comprising the insulin glargine, a water miscible organic solvent, and a crystal stabilizing agent, wherein the solution has a pH that is at least 1 pH unit greater than the pI of the insulin glargine; and (b) adding a zinc salt to the solution and incubating the solution for a time sufficient for the insulin glargine to crystallize and produce the insulin glargine crystals. 2. The method in claim 1, wherein the solution comprises ammonium acetate. 3. The method in claim 1, wherein the insulin glargine is at a concentration in the range of 1.75 g/L to 2.25 g/L. 4. The method in claim 1, wherein the water miscible organic solvent is selected from the group consisting of ethanol, methanol, acetone, and isopropanol. 5. The method in claim 1, wherein the water miscible organic solvent is isopropanol. 6. The method in claim 1, wherein the water miscible organic solvent is present in an amount which corresponds to about 9.5% (v/v) to 10.5% (v/v) of the solution. 7. The method in claim 1, wherein the crystal stabilizing agent is a phenolic agent selected from the group consisting of resorcinol, cresol, meta-cresol, phenol, methyl p-hydroxybenzoate, and methyl 4-hydroxybenzoate. 8. The method in claim 1, wherein the crystal stabilizing agent is meta-cresol. 9. The method in claim 1, wherein the zinc salt is zinc chloride. 10. The method in claim 1, wherein the amount of zinc salt added to the solution is sufficient to provide at least two molecules of zinc per six molecules of insulin glargine. 11. The method of claim 1, wherein the pH of the solution is from about 9.1 to 9.3. 12. The method of claim 1, wherein the pH of the solution is about 9.2. 13. The method of claim 1, wherein the crystallization is performed at a temperature of about 17.degree. C. to 23.degree. C. 14. The method in claim 1, wherein a crystal slurry comprising the insulin glargine crystals is produced by allowing the insulin glargine crystals in the solution to settle in the solution and the solution is decanted from the settled insulin glargine crystals to produce a decanted crystal slurry. 15. The method in claim 14, wherein the insulin glargine crystals are allowed to settle for about five hours or more prior to decanting the solution to produce the decanted crystal slurry. 16. The method of claim 14, wherein the decanted crystal slurry is applied to a filter apparatus to remove the solution from the decanted crystal slurry to produce a crystal cake bed and drying the crystal cake bed to provide the insulin glargine crystals. 17. The method of claim 16, wherein the crystal cake bed is dried in the filter apparatus. 18. The method of claim 16, wherein the filter apparatus is a Nutsche filter. 19. The method of claim 1, wherein the insulin glargine crystals are 10 .mu.m or greater in size.

Details for Patent 9,822,158

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Sanofi-aventis U.s. Llc	LANTUS	insulin glargine	Injection	021081	04/20/2000		2033-12-04
Sanofi-aventis U.s. Llc	LANTUS	insulin glargine	Injection	021081	04/25/2007		2033-12-04
Eli Lilly And Company	BASAGLAR	insulin glargine	Injection	205692	12/16/2015		2033-12-04