Conjugate based systems for controlled drug delivery

• US 9,050,370 B2
• Filed: 01/27/2010
• Issued: 06/09/2015
• 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:
  US13/145,532
• Publication Number:
  US 20110301083A1
• Time in Patent Office: 1,959 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 conjugate comprising an insulin molecule conjugated to one or more ligands wherein at least one ligand is aminoethyltrimannose having the formula;

2. The conjugate of claim 1, wherein the saccharide in the serum is glucose or alpha-methyl mannose.

3. The conjugate of claim 1, wherein the drug is an insulin molecule 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 LysB3.

4. The conjugate of claim 1, wherein the insulin molecule is truncated.

5. The conjugate of claim 1, wherein the conjugate includes two or more separate ligands wherein at least one ligand is aminoethyltrimannose.

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

7. The conjugate of claim 6, wherein the conjugate is of the formula (VIa):

8. The conjugate of claim 7, wherein the conjugate is of the formula (VIa-1), (VIa-2), or (VIa-3):

9. The conjugate of claim 6, wherein the conjugate is of the formula (VIb):

10. The conjugate of claim 9, wherein the conjugate is of the formula (VIb-1), (VIb-2), (VIb-3), (VIb-4), (VIb-5), (VIb-6), or (VIb-7):

11. The conjugate of claim 6, wherein the conjugate is of the formula (VIc) or (VIc-2):

12. The conjugate of claim 11, wherein the conjugate is of the formula (VIc-1) or (VIc-2):

13. A sustained release formulation comprising the conjugate of claim 1.

14. The formulation of claim 13, wherein the formulation comprises protamine and zinc.

15. A pump delivery system comprising a conjugate of claim 1, wherein the pump delivery system operates by infusing the conjugate into a mammal.

16. A method of treating hyperglycemia comprising administering formulation of claim 13 to a mammalian patient in need thereof.

17. A method comprising administering conjugate of claim 1 for the treatment of diabetes.

18. The conjugate of claim 1, wherein the insulin molecule is conjugated to the one or more ligands by a non-polymeric framework.