Crystalline insulin-conjugates

• US 8,906,850 B2
• Filed: 01/27/2010
• Issued: 12/09/2014
• Est. Priority Date: 01/28/2009
• Status: Active Grant

• Current Assignee: SmartCells, Inc. (Merck & Co., Inc.)
• Original Assignee: SmartCells, Inc. (Merck & Co., Inc.)
• Inventors: Zion, Todd C., Lancaster, Thomas M.
• Primary Examiner(s): Lukton, David
• Application Number:
  US13/145,525
• Publication Number:
  US 20110281791A1
• Time in Patent Office: 1,777 Days
• Field of Search: 514/5.9, 530/345
• US Class Current: 514/5.9
• CPC Class Codes: A61K 38/28 Insulins
• CPC Class Codes: A61K 47/549 Sugars, nucleosides, nucleotides or nucleic acids
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: C07K 14/62 Insulins

Abstract

The present disclosure provides crystalline insulin-conjugates. The present disclosure also provides formulations, methods of treatment, methods of administering, and methods of making that encompass these crystalline insulin-conjugates.

Claims

1. A crystalline insulin-conjugate of formula (I):

2. The crystalline insulin-conjugate of claim 1, wherein the conjugate is of formula (IIIa):

3. The crystalline insulin-conjugate of claim 2, wherein the conjugate is of formula (IIIa-1), (III2-2), or (IIIa-3):

4. The crystalline insulin-conjugate of claim 1, wherein the conjugate is of formula (IIIb):

5. The crystalline insulin-conjugate of claim 4, wherein the conjugate is of the formula (IIIb-1), (IIIb-2), (IIIb-3), (IIIb-4), (IIIb-4), (IIIb-6), (IIIb-7):

6. The crystalline insulin-conjugate of claim 1, wherein the conjugate is of formula (IIIc):

7. The crystalline insulin-conjugate of claim 6, wherein the conjugate is of formula (IIIc-1) or (IIIc-2):

8. The crystalline insulin-conjugate of claim 1, wherein the insulin molecule is selected from the group consisting of insulin lispro, insulin aspart and insulin glulisine.

9. The crystalline insulin-conjugate of claim 1, wherein the insulin molecule is insulin glargine or insulin detemir.

10. The crystalline insulin-conjugate of claim 1, wherein the insulin molecule is conjugated via the epsilon-amino group of Lys^B29.

11. The crystalline insulin-conjugate of claim 1, the branched trisaccharide is a branched trimannose.

12. The crystalline insulin-conjugate of claim 1, wherein each occurrence of X is aminoethyltrimannose (AETM).

13. The crystalline insulin-conjugate of claim 1, wherein each occurrence of X is aminoethyltrimannose (AETM) conjugated to the conjugate framework via an alpha anomeric carbon;

and W^I is an insulin molecule conjugated to the conjugate framework via the epsilon amino group of Lys^B29.

14. A crystalline insulin-conjugate of formula (IIIb-3):

15. A crystalline insulin-conjugate comprising a formula selected from the group consisting of: