Conjugate based systems for controlled drug delivery

• US 10,398,781 B2
• Filed: 08/18/2017
• Issued: 09/03/2019
• 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:
  US15/680,262
• Publication Number:
  US 20180064824A1
• Time in Patent Office: 746 Days
• 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 that are independently selected from the group consisting of aminoethylglucose (AEG), aminoethylmannose (AEM), aminoethylbimannose (AEBM), aminoethyltrimannose (AETM), and β

-aminoethyl-N-acetylglucosamine (AEGA), wherein the one or more ligands are indirectly conjugated to the insulin molecule via a conjugate framework.

2. The conjugate 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 or-via the epsilon-amino group of Lys^B3.

3. The conjugate of claim 1, wherein the insulin molecule is conjugated to two or more separate ligands.

4. The conjugate of claim 3, wherein the two or more separate ligands are conjugated to a single conjugate framework that is also conjugated to the insulin molecule.

5. The conjugate of claim 3, wherein the two or more separate ligands and insulin molecule are each located on a separate branch of a single branched conjugate framework.

6. The conjugate of claim 5, wherein the two or more separate ligands and insulin molecule are each located on termini of separate branches of a single branched conjugate framework.

7. The conjugate of claim 3, wherein the two or more separate ligands are conjugated to the insulin molecule via two or more different conjugation points.

8. The conjugate of claim 7, wherein the insulin molecule is conjugated via the A1 amino acid residue and the epsilon-amino group of Lys^B29.

9. The conjugate of claim 8, wherein the insulin molecule is conjugated to two separate conjugate frameworks that are each conjugated to one or more separate ligands.

10. The conjugate of claim 8, wherein the insulin molecule is conjugated to two separate branched conjugate frameworks that are each conjugated to two ligands.

11. The conjugate of claim 10, wherein the ligands are located on separate branches of the branched conjugate frameworks.

12. The conjugate of claim 11, wherein the ligands are located on termini of separate branches of the branched conjugate frameworks.

13. The conjugate of claim 3, wherein the two or more separate ligands are aminoethylglucose (AEG).

14. The conjugate of claim 3, wherein the two or more separate ligands are aminoethylmannose (AEM).

15. The conjugate of claim 3, wherein the two or more separate ligands are aminoethylbimannose (AEBM).

16. The conjugate of claim 3, wherein the two or more separate ligands are aminoethyltrimannose (AETM).

17. The conjugate of claim 3, wherein the two or more separate ligands are O-aminoethyl-N-acetylglucosamine (AEGA).

18. The conjugate of claim 1, wherein the insulin molecule is selected from the group consisting of human insulin, porcine insulin, and bovine insulin.

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

20. The conjugate of claim 1, wherein the insulin molecule is insulin glargine or insulin detemir.