Conjugate addition reactions for the controlled delivery of pharmaceutical active compounds

• US 20030220245A1
• Filed: 03/24/2003
• Published: 11/27/2003
• Est. Priority Date: 06/02/2000
• Status: Active Grant

• Current Assignee: Eidenossische Technische Hochschule Zurich, ETH Zurich, Universität Zürich
• Original Assignee: ETH Zurich, Universität Zürich
• Inventors: Hubbell, Jeffrey A, Schoenmakers, Ronald, Elbert, Donald
• Granted Patent: US 7,291,673 B2
• Time in Patent Office: Days
• US Class Current: 514/12
• CPC Class Codes: A61K 31/337 having four-membered rings, e.g. taxol
• CPC Class Codes: A61K 31/4745 condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines yohimbine derivatives, vinblastine A61K31/475; ergoline derivatives A61K31/48
• CPC Class Codes: A61K 31/56 Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
• CPC Class Codes: A61K 31/704 attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin digitoxin A61K31/7048
• CPC Class Codes: A61K 31/7072 having two oxo groups directly attached to the pyrimidine ring, e.g. uridine, uridylic acid, thymidine, zidovudine
• CPC Class Codes: A61K 31/7088 Compounds having three or more nucleosides or nucleotides
• 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 47/62 the modifying agent being a protein, peptide or polyamino acid
• 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: A61K 48/00 Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
• CPC Class Codes: A61L 2300/222 Steroids, e.g. corticosteroids
• CPC Class Codes: A61L 2300/416 Anti-neoplastic or anti-proliferative or anti-restenosis or anti-angiogenic agents, e.g. paclitaxel, sirolimus
• CPC Class Codes: A61L 2300/43 Hormones, e.g. dexamethasone
• CPC Class Codes: A61L 2300/602 Type of release, e.g. controlled, sustained, slow
• CPC Class Codes: A61L 24/0015 Medicaments; Biocides
• CPC Class Codes: A61L 24/0031 Hydrogels or hydrocolloids
• CPC Class Codes: A61L 27/52 Hydrogels or hydrocolloids
• CPC Class Codes: A61L 27/54 Biologically active materials, e.g. therapeutic substances A61L27/227 takes precedence

Abstract

The invention features polymeric biomaterials formed by nucleophilic addition reactions to conjugated unsaturated groups. These biomaterials may be used for medical treatments.

Claims

1. A biomaterial comprising a pharmaceutically active moiety, wherein said biomaterial has an ester or amide bond onto said pharmaceutically active moiety, said bond having a half-life of between 1 hour and 1 year in an aqueous solution at pH 7.4 and 37°

C.

2. The biomaterial of claim 1, wherein the half-life of the ester or amide bond onto said pharmaceutically active moiety is between 1 day and 9 months in an aqueous solution at pH 7.4 and 37°

C.

3. The biomaterial of claim 2, wherein the half-life of the ester or amide bond onto said pharmaceutically active moiety is between 2 days and 2 months in an aqueous solution at pH 7.4 and 37°

C.

4. The biomaterial of claim 1, wherein said pharmaceutically active moiety is derived from one of the group consisting of synthetic organic molecules, naturally occurring organic molecules, nucleic acid molecules, biosynthetic proteins or peptides, naturally occurring peptides or proteins, and modified naturally occurring peptides or proteins.

5. The biomaterial of claim 4, wherein said organic molecule is paclitaxel, doxorubicin, camptothecin, 5-fluorodeoxyuridine, estradiol, 2-methoxyestradiol, or a derivative thereof.

6. A biomaterial comprising a binding moiety, wherein said binding moiety has affinity for a pharmaceutically active compound, and wherein said biomaterial has an ester or amide bond onto said binding moiety, said bond having a half-life of between 1 hour and 1 year in an aqueous solution at pH 7.4 and 37°

C.

7. The biomaterial of claim 6, wherein the half-life of the ester or amide bond onto said binding moiety is between 1 day and 9 months in an aqueous solution at pH 7.4 and 37°

C.

8. The biomaterial of claim 7, wherein the half-life of the ester or amide bond onto said binding moiety is between 2 days and 2 months in an aqueous solution at pH 7.4 and 37°

C.

9. The biomaterial of claim 6, wherein said binding moiety is heparin, a heparin-binding moiety, a metal ion binding moiety, a carbohydrate moiety, a carbohydrate binding moiety, or a moiety that binds hydrophobic groups.

10. The biomaterial of claim 9, wherein said metal ion binding moiety is a Cu⁺² binding moiety, a Co⁺² binding moiety, or a Zn²⁺ binding moiety.

11. The biomaterial of claim 9, wherein said carbohydrate binding moiety is a phenylboronic acid.

12. The biomaterial of claim 11, wherein said phenylboronic acid is linked to said biomaterial through a secondary amine on the phenyl ring of said phenylboronic acid.

13. The biomaterial of claim 9, wherein said moiety that binds hydrophobic groups is a clycodextrin.

14. The biomaterial of claim 6, wherein a pharmaceutically active moiety or compound is bound to said binding moiety.

15. The biomaterial of claim 14, wherein said pharmaceutically active moiety or compound is derived from one of the group consisting of synthetic organic molecules, naturally occurring organic molecules, nucleic acid molecules, biosynthetic proteins or peptides, naturally occurring peptides or proteins, and modified naturally occurring peptides or proteins.

16. The biomaterial of claim 15, wherein said organic molecule is paclitaxel, doxorubicin, camptothecin, 5-fluorodeoxyuridine, estradiol, 2-methoxyestradiol, or a derivative thereof.

17. A biomaterial formed from the cross-linking of two or more precursor components, wherein at least one of said precursor components has the formula:

D-Y—

C(O)—

(CH₂)_n—

S—

(CH₂)₂—

COX—

P, D-Y—

C(O)—

(CH₂)_n—

NH—

(CH₂)₂—

COX—

P, D-Y—

C(O)—

(CH₂)_n—

NH—

U—

P, D-Y—

C(O)—

(CH₂)_n—

S—

U—

P, D-Y—

C(O)—

(CH₂)_n—

S-L-S—

CH₂—

CH₂—

CO—

X—

P, D-Y—

C(O)—

(CH₂)_n—

S-L-S—

U—

P, D-Y—

C(O)—

(CH₂)_n—

NH-L-S—

CH₂—

CH₂—

CO—

X—

P, D-Y—

C(O)—

(CH₂)_n—

NH-L-S—

U—

P, D-Y—

C(O)—

(CH₂)_n—

S-L-NH—

CH₂—

CH₂—

CO—

X—

P, D-Y—

C(O)—

(CH₂)_n—

S-L-NH—

U—

P, D-Y—

C(O)—

(CH₂)_n—

NH-L-NH—

CH₂—

CH₂—

CO—

X—

P, or D-Y—

C(O)—

(CH₂)_n—

NH-L-NH—

U—

P

wherein D is a pharmaceutically active moiety or a binding moiety;

n is 1, 2, or 3;

Y is O, NH, or N;

L is a linear or branched linker;

X is O or N;

P is a water-soluble polymer or a water-swellable polymer comprising one or more conjugated unsaturated groups; and

U is the product of the addition of a nucleophile to an electrophilic group that is attached to said polymer.

18. The biomaterial of claim 17, wherein said cross-linking occurs in the presence of a polymer that does not contain a pharmaceutically active moiety, said polymer comprising two or more conjugated unsaturated groups, wherein said polymer is incorporated into said biomaterial.

19. The biomaterial of claim 17, wherein said cross-linking occurs in the presence of a polymer that does not contain a binding moiety, said polymer comprising two or more conjugated unsaturated groups, wherein said polymer is incorporated into said biomaterial.

20. The biomaterial of claim 17, wherein said cross-linking occurs in the presence of a polymer that does not contain a pharmaceutically active moiety or a binding moiety, said polymer comprising two or more conjugated unsaturated groups, wherein said polymer is incorporated into said biomaterial.

21. The biomaterial of claim 17, wherein said biomaterial has an ester or amide bond onto a pharmaceutically active moiety, and wherein said biomaterial has an ester or amide bond onto a binding moiety.

22. The biomaterial of claim 17, wherein said cross-linking occurs in the presence of a targeting compound comprising two or more nucleophilic groups, wherein said targeting compound provides targeting to a cell, tissue, organ, organ system, or site within a mammal.

23. The biomaterial of claim 17, wherein said water-soluble or water-swellable polymer is selected from the group consisting of poly(ethylene glycol), poly(ethylene oxide), poly(vinyl alcohol), poly(acrylic acid), poly(ethylene-co-vinyl alcohol), poly(hydroxypropyl methacrylamide), poly(N-isopropylacrylamide), poly(dimethyl acrylamide), poly(vinyl pyrrolidone), poly(acrylic acid), poly(ethyloxazoline), poly(ethylene oxide)-co-poly(propylene oxide) block copolymers, or water-soluble or water-swellable copolymers comprising these polymers, and their derivatives comprising conjugated unsaturated groups.

24. The biomaterial of claim 17, wherein said unsaturated groups are not activated as to undergo nucleophilic substitution reactions.

25. The biomaterial of claim 17, wherein said conjugated unsaturated groups are selected from the group consisting of acrylates, methacrylates, acrylamides, methacrylamides, acrylonitriles, and quinones.

26. The biomaterial of claim 17, wherein said linker comprises an adhesion site, growth factor binding site, protease binding site, or enzymatically degradable site.

27. The biomaterial of claim 17, wherein said linker comprises a nucleophilic group that increases the rate of release of a pharmaceutically active compound or a binding moiety having the formula D-OH, D-NH₂, or D-NH by reacting with the ester or amide bond onto D at the —

OH, —

NH₂ or —

NH.

28. The biomaterial of claim 17, wherein n is 2 or 3.

29. The biomaterial of claim 17, comprising an encapsulated pharmaceutically active compound.

30. The biomaterial of claim 29, wherein said encapsulated pharmaceutically active compound is a protein.

36. The biomaterial of claim 17, wherein said pharmaceutically active moiety is derived from one of the group consisting of synthetic organic molecules, naturally occurring organic molecules, nucleic acid molecules, biosynthetic proteins or peptides, naturally occurring peptides or proteins, and modified naturally occurring peptides or proteins.

37. The biomaterial of claim 17, wherein said pharmaceutically active moiety is paclitaxel, doxorubicin, 5-fluorodeoxyuridine, estradiol, 2-methoxyestradiol, or a derivative thereof.

38. The biomaterial of claim 17, wherein the half-life of the ester or amide bond onto said pharmaceutically active moiety is between 1 hour and 1 year in an aqueous solution at pH 7.4 and 37°

C.

51. The biomaterial of claim 17, wherein said cross-linking occurs in the presence of a polymer comprising two or more nucleophilic groups.

52. The biomaterial of claim 51, wherein said nucleophilic groups are selected from the group consisting of thiols and amines.

31. A method of forming a biomaterial, said method comprising the steps of:

(a) attaching a pharmaceutically active compound or a binding compound to a linker molecule or incorporating a nucleophilic amine or thiol into a pharmaceutically active compound or a binding compound,

(b) removing any thiol-or amine-protecting groups in said linker,

(c) coupling a thiol, amine, or alkene group in said linker or incorporated into said pharmaceutically active compound or said binding compound to a water-soluble polymer or a water-swellable polymer comprising two or more conjugated unsaturated groups by a conjugate addition reaction to form a precursor component, and

(d) cross-linking the uncoupled conjugated unsaturated groups in one or more said precursor components.

32. The method of claim 31, wherein said cross-linking of said uncoupled unsaturated groups occurs at or near a site within the body of a mammal.

39. The method of claim 31, wherein said pharmaceutically active compound is derived from one of the group consisting of synthetic organic molecules, naturally occurring organic molecules, nucleic acid molecules, biosynthetic proteins or peptides, naturally occurring peptides or proteins, and modified naturally occurring peptides or proteins.

40. The method of claim 31, wherein said pharmaceutically active compound is paclitaxel, doxorubicin, 5-fluorodeoxyuridine, estradiol, 2-methoxyestradiol, or a derivative thereof.

41. The method of claim 31, wherein the precursor component includes an ester or amide bond with a half-life between 1 hour and 1 year in an aqueous solution at pH 7.4 and 37°

C.

50. The method of claim 32, wherein said mammal is a human.

33. A method of treating or preventing a disease, disorder, or infection in a mammal by administering to said mammal a biomaterial comprising a pharmaceutically active moiety, wherein said biomaterial has an ester or amide bond onto said pharmaceutically active moiety, said bond having a half-life of between 1 hour and 1 year in an aqueous solution at pH 7.4 and 37°

C.

35. The method of claim 33 or 34, wherein said mammal is a human.

42. The method of claim 33, wherein said pharmaceutically active moiety is derived from one of the group consisting of synthetic organic molecules, naturally occurring organic molecules, nucleic acid molecules, biosynthetic proteins or peptides, naturally occurring peptides or proteins, and modified naturally occurring peptides or proteins.

43. The method of claim 33, wherein said pharmaceutically active moiety is paclitaxel, doxorubicin, 5-fluorodeoxyuridine, estradiol, 2-methoxyestradiol, or a derivative thereof.

44. The method of claim 33, wherein the bond has a half-life between 1 hour and 1 year in an aqueous solution at pH 7.4 and 37°

C.

34. A method of treating or preventing a disease, disorder, or infection in a mammal by administering to said mammal a biomaterial comprising a binding moiety, wherein said biomaterial has an ester or amide bond onto said binding moiety, said bond having a half-life of between 1 hour and 1 year in an aqueous solution at pH 7.4 and 37°

C., and wherein a pharmaceutically active moiety or compound is bound to said binding moiety.

45. A pharmaceutically active compound of the formula D-O₂C—

(CH₂)_n—

SH or D-N(O)C—

(CH₂)_n—

SH, wherein n is 1 or 2 and D is a pharmaceutically active moiety.

46. The pharmaceutically active compound of claim 45 further comprising at least one polymer cross-linked to the pharmaceutically active compound by a conjugated addition reaction/between a thiol group of the pharmaceutically active compound and a conjugated unsaturated group of the polymer.

47. A method of forming a biomaterial, said method comprising the steps of:

(a) attaching a pharmaceutically active compound to a linker molecule or incorporating a nucleophilic amine or thiol into a pharmaceutically active compound,

(b) coupling the thiol or amine in said linker or incorporated into said pharmaceutically active compound to at least a first polymer comprising two or more conjugated unsaturated groups by a conjugate addition reaction to form a precursor component;

(c) providing at least a second precursor comprising nucleophilic groups; and

(d) cross-linking the conjugated unsaturated groups of the precursor of step b) to the nucleophilic groups of the precursor of step c) by a conjugated addition reaction.

48. The method of claim 47, wherein said cross-linking occurs at or near a site within the body of a mammal.

49. The method of claim 48, wherein said mammal is a human.