Polymer-drug conjugates

• US 20070099820A1
• Filed: 10/19/2006
• Published: 05/03/2007
• Est. Priority Date: 10/19/2005
• Status: Abandoned Application

• Current Assignee: SmartCells, Inc. (Merck & Co., Inc.)
• Original Assignee: SmartCells, Inc. (Merck & Co., Inc.)
• Inventors: Zion, Todd, Lancaster, Thomas, Nalewanski, Matthew
• Application Number:
  US11/583,362
• Publication Number:
  US 20070099820A1
• Time in Patent Office: Days
• US Class Current: 514/1.3
• 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 conjugate that releases a therapeutic agent within the extracellular space of subcutaneous tissue comprising:

a drug; and

a polymer covalently linked to the drug, whereupon subcutaneous administration, the conjugate is digested by an enzyme present in the extracellular space of subcutaneous tissue thereby releasing a therapeutic agent.

2. The conjugate of claim 1, wherein the drug is directly linked to the polymer and the polymer is susceptible to digestion by the enzyme.

3. The conjugate of claim 1, wherein the drug is indirectly linked to the polymer via a spacer that is susceptible to digestion by the enzyme.

4. The conjugate of claim 1, wherein the therapeutic agent and the drug are the same.

5. The conjugate of claim 1, wherein the therapeutic agent includes the drug covalently linked to a portion of the polymer.

6. The conjugate of claim 1, wherein the therapeutic agent includes the drug covalently linked to a portion of the polymer spacer.

7. The conjugate of claim 1, whereupon subcutaneous administration, said conjugate releases the therapeutic agent with a serum concentration curve that is substantially the same as when an equivalent amount of unconjugated drug is administered.

8. The conjugate of claim 1, whereupon subcutaneous administration, said conjugate releases the therapeutic agent with a serum T_max that is substantially the same as when an equivalent amount of unconjugated drug is administered

9. The conjugate of claim 1, whereupon subcutaneous administration, said conjugate releases the therapeutic agent with a serum C_max that is substantially the same as when an equivalent amount of unconjugated drug is administered

10. The conjugate of claim 1, whereupon subcutaneous administration, said conjugate releases the therapeutic agent with a serum half-life that is substantially the same as when an equivalent amount of unconjugated drug is administered.

11. The conjugate of claim 1, wherein the polymer is selected from the group consisting of polysaccharides, polypeptides and polynucleotides and the enzyme is selected from the group consisting of saccharidases, peptidases and nucleases.

12. The conjugate of claim 1, wherein the polymer is selected from the group consisting of carboxylated polysaccharides, —

NH₂ pendant polysaccharides, hydroxylated polysaccharides, alginate, collagen-glycosaminoglycan, collagen, mannan, amylose, amylopectin, glycogen, cellulose, hyaluronate, chondroitin, dextrin and chitosan.

13. The conjugate of claim 1, wherein the polymer is selected from the group consisting of co-polymers of aminated and non-aminated amino acids, co-polymers of hydroxylated and non-hydroxylated amino acids, co-polymers of carboxylated and non-carboxylated amino acids, co-polymers of the above and adducts of the above.

14. The conjugate of claim 1, wherein the polymer is a polysaccharide that includes 1,4-linked alpha and beta glucose residues.

15. The conjugate of claim 14, wherein the polymer is glycogen.

16. The conjugate of claim 15, wherein the saccharidase is an amylase.

17. The conjugate of claim 13, wherein the drug is an antidiabetic agent.

18. The conjugate of claim 17, wherein the antidiabetic agent is selected from the group consisting of insulin, insulin analogues, insulin secretagogues and insulin sensitizers.

19. The conjugate of claim 17, wherein the antidiabetic agent is insulin.

20. The conjugate of claim 17, wherein the antidiabetic agent is a sulfonylurea.

21. The conjugate of claim 1, wherein the drug is selected from the group consisting of growth hormones, glucagon, leptin, glucagon-like peptide 1 (GLP-1) and GLP-1 analogues.

22. The conjugate of claim 1, wherein the conjugate is non-antigenic when administered subcutaneously.

23. The conjugate of claim 1, wherein the conjugate is more soluble in water than the unconjugated drug.

24. The conjugate of claim 1, wherein the conjugate is less prone to aggregation in water than the unconjugated drug.

25. The conjugate of claim 1, wherein the polymer is glycogen and the drug is insulin.

26. The conjugate of claim 1, wherein the polymer includes an indicator analog within its covalent structure and whereupon mixing of a plurality of conjugates with a plurality of multivalent cross-linking agents that each contain two or more cross-link receptors, said conjugates becomes cross-linked by the multivalent cross-linking agents through interactions between the indicator analog and the cross-link receptors and said interactions are competitively disrupted in a manner that is dependent on the concentration of indicator added to the mixture.

27. The conjugate of claim 26, wherein the indicator analog has essentially the same composition as the indicator.

28. The conjugate of claim 26, wherein the indicator analog has a higher affinity for the multivalent cross-linking agent than the indicator.

29. The conjugate of claim 26, wherein the indicator analog is a portion of a side group of the polymer.

30. The conjugate of claim 26, wherein the indicator analog is incorporated into the backbone of the polymer.

31. The conjugate of claim 26, wherein the indicator is glucose and the drug is an antidiabetic agent.

32. The conjugate of claim 26, wherein the multivalent cross-linking agent is a multivalent binding protein.

33. The conjugate of claim 26, wherein the multivalent cross-linking agent is a multivalent glucose-binding molecule.

34. The conjugate of claim 33, wherein the multivalent glucose-binding molecule is selected from the group consisting of phytohemoagglutinins, human mannan binding protein (MBP), human pulmonary surfactant protein A (SP-A), human pulmonary surfactant protein D, bovine serum lectin CL-43 and conglutinin.

35. The conjugate of claim 34, wherein the phytohemoagglutinin is selected from the group consisting of concanavalin A (Con A), succinylated Con A, and phytohemoagglutinins derived from pisum sativum (pea), lathyrus odoratus (sweet pea), lens culinaris (lentil), narcissus pseudonarcissus (daffodil), vicia faba (fava bean) and vicia sativa (garden vetch).

36. The conjugate of claim 26, wherein the multivalent cross-linking agent is comprised of a plurality of monofunctional binding proteins or binding fragments thereof linked to one another.

37. The conjugate of claim 36, wherein the monofunctional binding protein is a bacterial glucose/galactose binding protein.

38. The conjugate of claim 26, wherein the polymer is a polysaccharide and the multivalent cross-linking agent is a plant lectin or a mammalian analog of a plant lectin.

39. The conjugate of claim 38, wherein the lectin 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.

40. The conjugate of claim 26, wherein the polymer is glycogen, the drug is insulin, the multivalent cross-linking agent is a multivalent glucose-binding molecule and the indicator is glucose.

41. The conjugate of claim 40, wherein the multivalent glucose-binding molecule 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.

42. The conjugate of claim 41, wherein the multivalent glucose-binding molecule is Con A covalently modified with a polyethylene glycol.

43. A material for controllably releasing a conjugate within the extracellular space of subcutaneous tissue in response to the local concentration of an indicator, comprising:

a plurality of conjugates that each include a drug covalently linked to a polymer that includes an analog of the indicator within its covalent structure, 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 indicator.

44. The material of claim 43, wherein the material is a plurality of particles.

45. The material of claim 44, wherein the material is an insoluble hydrogel.

46. A method for controllably releasing a conjugate within subcutaneous tissue in response to the local concentration of an indicator comprising subcutaneously administering the material of claim 43 to a patient in need thereof.

47. The method of claim 46, wherein the material is dissolved in a biocompatible aqueous solution and the solution is injected subcutaneously.

48. A kit for producing a material that controllably releases a conjugate within the extracellular space of subcutaneous tissue in response to the local concentration of an indicator comprising:

a plurality of conjugates that each include a drug covalently linked to a polymer that includes an analog of the indicator within its covalent structure, 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 that each contain two or more cross-link receptors, whereupon mixing, said conjugates become 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 added to the mixture, and wherein said competitive disruption causes the material to release the conjugate in a manner that is dependent on the amount of indicator added to the mixture.

49-57. -57. (canceled)