Method for controllably releasing a drug conjugate within subcutaneous tissue in response to the local concentration of an indicator

• US 8,697,643 B2
• Filed: 02/06/2012
• Issued: 04/15/2014
• Est. Priority Date: 10/19/2005
• Status: Active Grant

• Current Assignee: SmartCells, Inc. (Merck & Co., Inc.)
• Original Assignee: SmartCells, Inc. (Merck & Co., Inc.)
• Inventors: Lancaster, Thomas M., Nalewanski, Matthew, Zion, Todd C.
• Primary Examiner(s): Chandra, Gyan
• Application Number:
  US13/366,744
• Publication Number:
  US 20120135919A1
• Time in Patent Office: 799 Days
• Field of Search: None
• US Class Current: 514/5.9
• CPC Class Codes: A61K 38/25 Growth hormone-releasing factor [GH-RF], i.e. somatoliberin
• CPC Class Codes: A61K 38/26 Glucagons
• CPC Class Codes: A61K 38/28 Insulins
• CPC Class Codes: A61K 47/60 the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
• CPC Class Codes: A61K 47/61 the organic macromolecular compound being a polysaccharide or a derivative thereof
• CPC Class Codes: A61K 47/6903 the form being semi-solid, e.g. an ointment, a gel, a hydrogel or a solidifying gel
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: C08B 30/18 Dextrin , e.g. yellow canari, white dextrin, amylodextrin or maltodextrin; Methods of depolymerisation, e.g. by irradiation or mechanically
• CPC Class Codes: C08B 37/00 Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof cellulose D21; microbiological processes C12P
• CPC Class Codes: C08B 37/003 Chitin, i.e. 2-acetamido-2-deoxy-(beta-1,4)-D-glucan or N-acetyl-beta-1,4-D-glucosamine; Chitosan, i.e. deacetylated product of chitin or (beta-1,4)-D-glucosamine; Derivatives thereof
• CPC Class Codes: C08B 37/0069 Chondroitin-4-sulfate, i.e. chondroitin sulfate A; Dermatan sulfate, i.e. chondroitin sulfate B or beta-heparin; Chondroitin-6-sulfate, i.e. chondroitin sulfate C; Derivatives thereof
• CPC Class Codes: C08B 37/0072 Hyaluronic acid, i.e. HA or hyaluronan; Derivatives thereof, e.g. crosslinked hyaluronic acid (hylan) or hyaluronates
• CPC Class Codes: C08B 37/0084 Guluromannuronans, e.g. alginic acid, i.e. D-mannuronic acid and D-guluronic acid units linked with alternating alpha- and beta-1,4-glycosidic bonds; Derivatives thereof, e.g. alginates
• CPC Class Codes: Y10S 436/827 Lectins

Abstract

A conjugate that includes a drug covalently linked to a polymer. Upon administration, the conjugate is digested by an enzyme that is present at the site of administration thereby releasing a therapeutic agent. The conjugate may demonstrate substantially the same pharmacokinetic and pharmacodynamic behavior as the drug itself. A material for controllably releasing a conjugate in response to the local concentration of a molecular indicator. The material includes a plurality of conjugates and a plurality of multivalent cross-linking agents. The polymers of the conjugates include an analog of the indicator within their covalent structure. The multivalent cross-linking agents include cross-link receptors that interact with the indicator analog and thereby cross-link the conjugates. These non-covalent interactions are competitively disrupted when an amount of the molecular indicator is present thereby causing the material to release the conjugate in a manner that is dependent on the local concentration of indicator.

Claims

1. A method for controllably releasing a conjugate within subcutaneous tissue in response to the local concentration of an indicator comprising subcutaneously administering, to a patient in need thereof, a material that comprises:

a plurality of conjugates that each include a drug covalently linked to a polymer that is a polysaccharide that includes repeating chains of 1,4-linked alpha-D-glucose residues or the polymer is covalently linked to said drug via a spacer that includes a plurality of 1,4-linked alpha-D-glucose residues, wherein said conjugates are susceptible to digestion by an enzyme present in the extracellular space of subcutaneous tissue; and

a plurality of multivalent cross-linking agents each containing two or more cross-link receptors, wherein said conjugates are cross-linked by said multivalent cross-linking agents through interactions between the indicator analogs and the cross-link receptors, wherein said interactions are competitively disrupted if an amount of the indicator is present, and wherein competitive disruption of the interactions between the indicator analogs and the cross-link receptors causes the material to release the conjugate in a manner that is dependent on the local concentration of the indicator.

2. The method of claim 1, wherein the material is an insoluble hydrogel.

3. The method of claim 1, wherein the drug is an antidiabetic agent.

4. The method of claim 3, wherein the antidiabetic agent is selected from the group consisting of insulin, insulin analogues, insulin secretagogues and insulin sensitizers.

5. The method of claim 4, wherein the antidiabetic agent is insulin.

6. The method of claim 1, wherein the indicator analog has essentially the same composition as the indicator.

7. The method of claim 1, wherein the indicator is glucose and the drug is an antidiabetic agent.

8. The method of claim 1, wherein the multivalent cross-linking agent is a multivalent glucose-binding molecule.

9. The method of claim 1, the multivalent cross-linking agent is selected from the group consisting of concanavalin A (Con A), succinylated Con A, Con A covalently modified with a polyethylene glycol, and succinylated Con A covalently modified with a polyethylene glycol.

10. The method of claim 1, wherein the indicator is glucose and the indicator analog is glucose or a derivative thereof.

11. The method of claim 1, wherein the indicator is glucose and the indicator analog is mannose or a mannose-containing sugar.

12. The method of claim 1, wherein the material is dissolved in a biocompatible aqueous solution and the solution is injected subcutaneously.

13. A method for treating diabetes comprising subcutaneously administering to a patient in need thereof, a material that comprises:

a plurality of conjugates that each include an antidiabetic agent covalently linked to a polymer that is a polysaccharide that includes repeating chains of 1,4-linked alpha-D-glucose residues or the polymer is covalently linked to said drug via a spacer that includes a plurality of 1,4-linked alpha-D-glucose residues, wherein said conjugates are susceptible to digestion by an enzyme present in the extracellular space of subcutaneous tissue;

a plurality of multivalent cross-linking agents each comprising containing two or more cross-link receptors, wherein said conjugates are cross-linked by said multivalent cross-linking agents through interactions between the glucose analogs and the cross-link receptors, wherein said interactions are competitively disrupted if an amount of glucose is present, and wherein competitive disruption of the interactions between the glucose analogs and the cross-link receptors causes the material to release the conjugate in a manner that is dependent on the local concentration of glucose.

14. The method of claim 13, wherein the material is an insoluble hydrogel.

15. The method of claim 13, wherein the multivalent cross-linking agent is a multivalent glucose-binding molecule.

16. The method of claim 13, wherein the multivalent cross-linking agent is selected from the group consisting of concanavalin A (Con A), succinylated Con A, Con A covalently modified with a polyethylene glycol, and succinylated Con A covalently modified with a polyethylene glycol.

17. The method of claim 16, wherein the multivalent glucose-binding molecule is Con A covalently modified with a polyethylene glycol.