Conjugate based systems for controlled drug delivery

• US 9,579,391 B2
• Filed: 06/04/2015
• Issued: 02/28/2017
• 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): Cordero Garcia, Marcela M
• Application Number:
  US14/731,016
• Publication Number:
  US 20150265717A1
• Time in Patent Office: 635 Days
• US Class Current: 1/1
• CPC Class Codes: A61K 38/28 Insulins
• CPC Class Codes: A61K 47/549 Sugars, nucleosides, nucleotides or nucleic acids
• CPC Class Codes: A61K 47/61 the organic macromolecular compound being a polysaccharide or a derivative thereof
• CPC Class Codes: A61P 3/08 for glucose homeostasis pancreatic hormones A61P5/48
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 5/50 for increasing or potentiating the activity of insulin
• CPC Class Codes: A61P 7/12 Antidiuretics, e.g. drugs for diabetes insipidus ADH A61P5/10

Abstract

Conjugates which comprise a drug and a ligand which includes a first saccharide; wherein the conjugate is characterized in that, when the conjugate is administered to a mammal, at least one pharmacokinetic or pharmacodynamic property of the conjugate is sensitive to serum concentration of a second saccharide. Exemplary conjugates and sustained release formulations are provided in addition to methods of use and preparation.

Claims

1. A method for treating diabetes comprising:

administering to a mammalian patient in need thereof a therapeutically effective amount of a conjugate that includes an insulin molecule conjugated to one or more ligands wherein at least one ligand is aminoethyltrimannose (AETM) or aminoethylfucose (AEF), wherein the conjugate treats the diabetes.

2. The method of claim 1, wherein the insulin molecule is conjugated via the A1 amino acid residue, via the B1 amino acid residue, via the epsilon-amino group of Lys^B29, via the epsilon-amino group of Lys^B28, or via the epsilon-amino group of Lys^B3.

3. The method of claim 1, wherein the insulin molecule is truncated.

4. The method of claim 1, wherein the conjugate includes two or more separate ligands wherein at least one ligand is AETM or AEF.

5. The method of claim 1, wherein the conjugate includes two or more separate ligands wherein at least two ligands are AETM or AEF.

6. The method of claim 1, wherein the conjugate has the general formula (II):

7. The method of claim 6, wherein the conjugate is of the formula:

8. The method of claim 6, wherein the conjugate is of the formula:

9. The method of claim 6, wherein the conjugate is of the formula:

10. The method of claim 1, wherein the conjugate is provided in a sustained release formulation.

11. The method of claim 10, wherein the formulation comprises protamine and zinc.

21. The method of claim 1, wherein the conjugate is provided in a sustained release formulation.

22. The method of claim 21, wherein the formulation comprises protamine and zinc.

12. A method for treating hyperglycemia comprising:

administering to a mammalian patient in need thereof a therapeutically effective amount of a conjugate that includes an insulin molecule conjugated to one or more ligands wherein at least one ligand is aminoethyltrimannose (AETM) or aminoethylfucose (AEF), wherein the conjugate treats the hyperglycemia.

13. The method of claim 12, wherein the insulin molecule is conjugated via the A1 amino acid residue, via the B1 amino acid residue, via the epsilon-amino group of Lys^B29, via the epsilon-amino group of Lys^B28, or via the epsilon-amino group of Lys^B3.

14. The method of claim 12, wherein the insulin molecule is truncated.

15. The method of claim 12, wherein the conjugate includes two or more separate ligands wherein at least one ligand is AETM or AEF.

16. The method of claim 12, wherein the conjugate includes two or more separate ligands wherein at least two ligands are AETM or AEF.

17. The method of claim 12, wherein the conjugate has the general formula (II):

18. The method of claim 17, wherein the conjugate is of the formula:

19. The method of claim 17, wherein the conjugate is of the formula:

20. The method of claim 17, wherein the conjugate is of the formula: