Phosphate based biodegradable polymers

• US 20020155092A1
• Filed: 03/10/2001
• Published: 10/24/2002
• Est. Priority Date: 03/10/2000
• Status: Active Grant

• Current Assignee: Johns Hopkins University
• Original Assignee: Johns Hopkins University
• Inventors: Mao, Hai-Quan, Leong, Kam, Jie, Wen, Zhuo, Ren-Xi
• Granted Patent: US 6,805,876 B2
• Time in Patent Office: Days
• US Class Current: 424/78.37
• CPC Class Codes: A61K 9/0024 Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue compositions for intravenous administration, normal injectable solutions or dispersions for, e.g. subcutaneous administration A61K9/0019; brain implants A61K9/0085; (coated) prostheses, catheters or stents A61L
• CPC Class Codes: A61K 9/1647 Polyesters, e.g. poly(lactide-co-glycolide)
• CPC Class Codes: A61L 2300/604 Biodegradation
• CPC Class Codes: A61L 27/18 obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
• CPC Class Codes: A61L 27/58 Materials at least partially resorbable by the body
• CPC Class Codes: A61L 31/16 Biologically active materials, e.g. therapeutic substances A61L31/047 takes precedence
• CPC Class Codes: C08G 79/04 Phosphorus linked to oxygen or to oxygen and carbon
• CPC Class Codes: C08L 85/02 containing phosphorus

Abstract

Featured are biodegradable polymers comprising repeat units derived from cyclic phosphate monomers and optionally further comprising repeat units derived from lactide or caprolactone monomers. Also featured are methods for preparing the biodegradable polymers of the invention and biodegradable polymer compositions comprising a biologically active substance and a biodegradable polymer. Additionally featured are articles and microspheres prepared from biodegradable polymers and polymer compositions of the invention. Further, methods for the controlled release of a biologically active substance using the biodegradable polymers of the invention are also described.

Claims

4. A biodegradable polymer comprising at least one repeat unit according to formula A:

5. A polymer of claim 4, wherein the polymer Mw is between about 1,000 and about 200,000.

6. A polymer of claim 4, wherein the polymer comprises polymer chains that are not crosslinked.

7. A polymer of claim 4, the polymer comprising repeat units as in formula I:

8. The polymer of claim 7, wherein

x is 2;

R is C_1-6-alkyl;

R¹ and R² are independently selected at each occurrence from the group consisting of hydrogen, methyl and ethyl;

R³ and R⁵ are hydrogen;

R⁴ is hydrogen or C_1-6-alkyl; and

,

R⁶ is C_1-6-alkyl.

9. The polymer of claim 7, wherein:

x is 2;

R is methyl or ethyl;

R⁴ and R⁶ are methyl; and

,

R¹, R², R³ and R⁵ are hydrogen.

10. The polymer of claim 7, wherein:

x is 2;

R is independently selected for each occurrence of R from the group consisting of hydrogen and C_1-6-alkyl, wherein at least some occurrence of R is hydrogen;

R⁴ and R⁶ are methyl; and

,

R¹, R², R³ and R⁵ are hydrogen.

11. A polymer of claim 4, the polymer comprising recurring monomeric repeat units in formula II:

12. The polymer of claim 11, wherein the polymer is prepared by a melt polymerization or a Lewis acid catalyzed polymerization.

13. A polymer of claim 4, the polymer comprising recurring monomeric repeat units in formula IIA:

14. The polymer of claim 13, wherein the polymer is prepared by a melt polymerization or a Lewis acid catalyzed polymerization.

15. A polymer of claim 4, the polymer comprising repeat units as in formula III:

16. The polymer of claim 15, wherein

x is 2;

M is hydrogen;

R is C_1-6-alkyl; and

,

R¹ and R² are independently selected at each occurrence from the group consisting of hydrogen, methyl and ethyl.

17. The polymer of claim 15, wherein:

L is —

(CH₂)_a—

{O(CH₂)_a}_b where a is between about 1 and about 7 and b is between about 1 and about 500;

x is 2;

R is methyl or ethyl; and

,

R¹ and R² are hydrogen.

18. A polymer of claim 4, the polymer comprising repeat units as in formula IV:

19. The polymer of claim 18, wherein

x is 2;

L is —

(CH₂)_a—

{O(CH₂)_a}_b where a is between about 1 and about 7 and b is between about 1 and about 500;

Y is alkyl or aryl;

Z is —

C(O)—

or —

C(O)NH—

;

R is C_1-6-alkyl; and

,

R and R² are independently selected at each occurrence from the group consisting of hydrogen, methyl and ethyl.

20. The polymer of claim 18, wherein:

x is 2;

L is —

(CH₂)_a—

{O(CH₂)_a}_b where a is between about 1 and about 7 and b is between about 1 and about 500;

Y is alkyl or aryl;

Z is —

C(O)—

or —

C(O)NH—

;

R is methyl or ethyl; and

,

R¹ and R² are hydrogen.

21. A polymer of claim 4, the polymer comprising repeat units as in formula V:

22. The polymer of claim 21, wherein

x is 2;

L is —

(CH₂)_a—

{O(CH₂)_a}_b where a is between about 1 and about 7 and b is between about 1 and about 500;

R is C_1-6-alkyl;

R¹ and R² are independently selected at each occurrence from the group consisting of hydrogen, methyl and ethyl;

R³ and R⁵ are hydrogen;

R⁴ is hydrogen or C_1-6-alkyl; and

,

R⁶ is C_1-6-alkyl.

23. The polymer of claim 21, wherein:

x is 2;

L is —

(CH₂)_a—

{O(CH₂)_a}_b where a is between about 1 and about 7 and b is between about 1 and about 500;

R is methyl or ethyl;

R⁴ and R⁶ are methyl; and

,

R¹, R², R³ and R⁵ are hydrogen.

25. The process of claim 24, wherein the glycolide derivative is a compound according to formula VI:

26. The process of claim 24, wherein R⁴ and R⁶ are methyl.

27. The process of claim 24, wherein the cyclic phosphate is a compound according to formula VII:

28. The process of claim 24, wherein:

R is methyl or ethyl;

R¹ and R² are hydrogen at each occurrence of R¹ and R^2;

and,

x is 2.

29. The process of claim 24, wherein the contacting step takes place at a temperature of between about 50°

C. and about 240°

C.

30. The process of claim 24, wherein a Lewis acid catalyst is present during the contacting and polymerizing steps.

31. The process of claim 24, wherein the contacting step takes place during a time between about 1 hour and about 7 days.

35. A process for preparing a biodegradable polymer comprising the recurring monomeric units of formula IV:

39. A process for preparing a biodegradable polymer comprising the recurring monomeric units of formula V:

24. A process for preparing a biodegradable polymer comprising the recurring monomeric units of formula I:

32. A process for preparing a biodegradable polymer comprising the recurring monomeric units of formula III:

33. The process of claim 32, wherein the cyclic phosphate is a compound according to formula VII:

34. The process of claim 32, wherein:

R is methyl or ethyl;

R¹ and R² are hydrogen at each occurrence of R¹ and R²; and

,

x is 2.

36. The process of claim 35, wherein the macromolecular monomer is a compound according to formula III:

37. The process of claim 35, wherein the compound with two functional groups capable of reacting with an alcohol is an A-Y-A compound wherein;

A is a functional group capable of reacting with an alcohol selected from the group consisting of acid chloride, isocyanate, epoxide, and sulfonyl chloride; and

,

Y is alkyl, C_2-20-alkenyl, optionally substituted heteroalkyl, C_2-20-alkynyl, C_5-8cycloalkyl, (CH₂)_a—

{O(CH₂)_a}_b where a is between about 1 and about 7 and b is between about 1 and about 100, aryl or heteroaryl.

38. The process of claim 35, wherein:

R is methyl or ethyl;

R¹ and R² are hydrogen at each occurrence of R¹ and R^2;

and,

x is 2.

40. The process of claim 39, wherein:

xis 2;

L is —

(CH₂)_a—

{O(CH₂)_a}_b where a is between about 1 and about 7 and b is between about 1 and about 500;

R is methyl or ethyl;

R⁴ and R⁶ are methyl; and

,

R¹, R², R³ and R⁵ are hydrogen.

41. The process of claim 39, wherein the glycolide derivative is a compound according to the formula VI:

42. A biodegradable polymer composition comprising:

(a) at least one biologically active substance; and

(b) a biodegradable polymer comprising at least one repeat unit according to formula A;

wherein

R is hydrogen, optionally substituted alkyl, optionally substituted C_2-12-alkenyl, optionally substituted heteroalkyl, optionally substituted C_2-12-alkynyl, or optionally substituted C_5-8-cycloalkyl;

R¹ and R² are each independently chosen from the group consisting of H, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted C_2-12-alkenyl, optionally substituted C_2-12-alkynyl, and optionally substituted alkoxy;

x is 2,3,or 4;

and

at least one repeat unit selected from the group consisting of alkyl, C_2-20-alkenyl, C_2-20-alkynyl, optionally substituted heteroalkyl, —

O(CR₁R₂), C(O)—

where c is between about 1 and about 10, —

(CH₂)_a—

{O(CH₂)_a}b—

where a is between about 1 and about 7 and b is between about 1 and about 500, aryl, and heteroaryl;

or at least one repeat unit according to formula B;

wherein

R³, R⁴, R⁵ and R⁶ are each independently chosen from the group consisting of H, optionally substituted alkyl, optionally substituted C_2-12-alkenyl, optionally substituted C_2-12-alkynyl, optionally substituted heteroalkyl, and optionally substituted alkoxy.

1. A biodegradable polymer comprising at least one phosphate monomer repeat unit and at least one second monomer repeat unit, the second monomer repeat unit selected from the group consisting of optionally substituted glycyl glycolate, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted alkyl hydroxy-ester and optionally substituted poly(ethylene glycol).

2. A polymer of claim 1 wherein the second monomer repeat unit is an optionally substituted glycyl glycolate.

3. A polymer of claim 1 wherein the second monomer repeat unit is an optionally substituted alkyl hydroxy-ester.

43. The polymer composition of claim 42, wherein the polymer comprising repeat units as in formula I:

44. The polymer composition of claim 43, wherein

x is 2;

R is methyl or ethyl;

R⁴ and R⁶ are methyl; and

,

R¹, R², R³ and R⁵ are hydrogen.

45. The polymer composition of claim 42, wherein the polymer comprising repeat units as in formula III:

46. The polymer composition of claim 45, wherein

L is —

(CH₂)_a—

{O(CH₂)_a}_b where a is between about 1 and about 7 and b is between about 1 and about 500;

x is 2;

R is methyl or ethyl; and

,

R¹ and R² are hydrogen.

47. The polymer composition of claim 42, wherein the polymer comprising repeat units as in formula IV:

48. The polymer composition of claim 47, wherein:

x is 2;

L is —

(CH₂)_a—

{O(CH₂)_a}_b where a is between about 1 and about 7 and b is between about 1 and about 500;

Y is alkyl or aryl;

Z is —

C(O)—

or —

C(O)NH—

;

R is methyl or ethyl; and

,

R¹ and R² are hydrogen.

49. The polymer composition of claim 42, wherein the polymer comprising repeat units as in formula V:

50. The polymer composition of claim 49, wherein:

xis 2;

L is —

(CH₂)_a—

{O(CH₂)_a}_b where a is between about 1 and about 7 and b is between about 1 and about 500;

R is methyl or ethyl;

R⁴ and R⁶ are methyl; and

,

R¹, R², R³ and R⁵ are hydrogen.

51. The polymer composition of claim 42, wherein the polymer is soluble in at least one of the solvents selected from the group consisting of acetone, dimethylene chloride, chloroform, ethyl acetate, DMAC, N-methylpyrrolidone, dimethylformamide and dimehtylsulfoxide.

52. The polymer composition of claim 42, wherein the biologically active substance is a therapeutic drug or pro-drug.

53. The polymer composition of claim 52, wherein the biologically active substance is selected from the group consisting of polysaccharides, growth factors, hormones, anti-angiogenesis factors, interferons or cytokines, and pro-drugs of these substances.

54. The polymer composition of claim 52, wherein the drug is selected from the group consisting of anti-neoplastic neoplastic agents, antibiotics, anti-virals, anti-fungals, anti-inflammatories and anticoagulants.

55. The polymer composition of claim 52, wherein the biologically active substance and the polymer form a homogeneous matrix.

57. An article of claim 56, wherein the polymer comprising repeat units as in formula I:

58. The article of claim 57, wherein

x is 2;

R is methyl or ethyl;

R⁴ and R⁶ are methyl; and

,

R¹, R², R³ and R⁵ are hydrogen.

59. An article of claim 56, wherein the polymer comprising repeat units as in formula III:

60. The article of claim 59, wherein

L is —

(CH₂)_a—

{O(CH₂)_a}_b where a is between about 1 and about 7 and b is between about 1 and about 500;

x is 2;

R is methyl or ethyl; and

,

R¹ and R² are hydrogen.

61. An article of claim 56, wherein the polymer comprising repeat units as in formula IV:

62. The article of claim 61, wherein:

x is 2;

L is —

(CH₂)_a—

{O(CH₂)_a}_b where a is between about 1 and about 7 and b is between about 1 and about 500;

Y is alkyl or aryl;

Z is —

C(O)—

or —

C(O)NH—

;

R is methyl or ethyl; and

,

R¹ and R² are hydrogen.

64. The article of claim 63, wherein:

x is 2;

L is —

(CH₂)_a—

{O(CH₂)_a}_b where a is between about 1 and about 7 and b is between about 1 and about 500;

R is methyl or ethyl;

R⁴ and R⁶ are methyl; and

,

R¹, R², R³ and R⁵ are hydrogen.

65. The article of claim 56, wherein the biologically active substance is a therapeutic drug or pro-drug.

66. The article of claim 65, wherein the biologically active substance is selected from the group consisting of polysaccharides, growth factors, hormones, anti-angiogenesis factors, interferons or cytokines, and pro-drugs of these substances.

67. The article of claim 65 wherein the drug is selected from the group consisting of anti-neoplastic neoplastic agnets, antibiotics, anti-virals, anti-fungals, anti-inflammatories and anticoagulants.

68. The article of claim 65 wherein the biologically active substance and the polymer form a homogeneous matrix.

70. A method of claim 69, wherein the biodegradable polymer having the recurring monomeric units shown in formula I:

71. The method of claim 70, wherein:

x is 2;

R is methyl or ethyl;

R⁴ and R⁶ are methyl; and

,

R¹, R², R³ and R⁵ are hydrogen.

72. A method of claim 69, wherein the biodegradable polymer having the recurring monomeric units shown in formula III:

73. The method of claim 72, wherein

L is —

(CH₂)_a—

{O(CH₂)_a}_b where a is between about 1 and about 7 and b is between about 1 and about 500;

x is 2;

R is methyl or ethyl; and

,

R¹ and R² are hydrogen.

74. A method of claim 69, wherein the biodegradable polymer having the recurring monomeric units shown in formula IV:

75. The method of claim 74, wherein:

x is 2;

L is —

(CH₂)_a—

{O(CH₂)_a}_b where a is between about 1 and about 7 and b is between about 1 and about 500;

Y is alkyl or aryl;

Z is —

C(O)—

or —

C(O)NH—

;

R is methyl or ethyl; and

,

R¹ and R² are hydrogen.

76. A method of claim 69, wherein the biodegradable polymer having the recurring monomeric units shown in formula V:

77. The method of claim 76, wherein:

x is 2;

L is —

(CH₂)_a—

{O(CH₂)_a}_b where a is between about 1 and about 7 and b is between about 1 and about 500;

R is methyl or ethyl;

R⁴ and R⁶ are methyl; and

,

R¹, R², R³ and R⁵ are hydrogen.

78. The method of claim 69, wherein the biologically active substance is a therapeutic drug or pro-drug.

79. The method of claim 78, wherein the biologically active substance is selected from the group consisting of polysaccharides, growth factors, hormones, anti-angiogenesis factors, interferons or cytokines, and pro-drugs of these substances.

80. The article of claim 78, wherein the drug is selected from the group consisting of anti-neoplastic neoplastic agents, antibiotics, anti-virals, anti-fungals, anti-inflammatories and anticoagulants.

56. An article useful for implantation, injection, or otherwise being placed totally or partially within a body, the article comprising a biodegradable polymer composition comprising:

(a) at least one biologically active substance; and

(b) a biodegradable polymer comprising at least one repeat unit according to formula A;

wherein

R is hydrogen, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted C_2-12-alkenyl, optionally substituted C_2-12-alkynyl, or optionally substituted C_5-8-cycloalkyl;

R¹ and R² are each independently chosen from the group consisting of H, optionally substituted alkyl, optionally substituted C_2-12-alkenyl, optionally substituted heteroalkyl, optionally substituted C_2-12-alkynyl, and optionally substituted alkoxy;

x is 2, 3, or 4; and

at least one repeat unit selected from the group consisting of optionally substituted alkyl, optionally substituted C_2-20-alkenyl, optionally substituted C_2-20-alkynyl, optionally substituted heteroalkyl, —

O(CR₁R₂)_cC(O)—

where c is between about 1 and about 10, —

(CH₂)_a—

{O(CH₂)_a}_b—

where a is between about 1 and about 7 and b is between about 1 and about 500, optionally substituted aryl, and optionally substituted heteroaryl;

or

at least one repeat unit according to formula B;

wherein

R³, R⁴, R⁵ and R⁶ are each independently chosen from the group consisting of H, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted C_2-12-alkenyl, optionally substituted C_2-12-alkynyl, and optionally substituted alkoxy.

62-1. An article of claim 56, wherein the polymer comprising repeat units as in formula V:

69. A method for the controlled release of at least one biologically active substance comprising the steps of:

(a) combining the biologically active substance with a biodegradable polymer comprising at least one repeat unit according to formula A;

wherein

R is hydrogen, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted C_2-12-alkenyl, optionally substituted C_2-12-alkynyl, or optionally substituted C_5-8-cycloalkyl;

R¹ and R² are each independently chosen from the group consisting of H, optionally substituted alkyl, optionally substituted C_2-12-alkenyl, optionally substituted heteroalkyl, optionally substituted C_2-12-alkynyl, and optionally substituted alkoxy;

x is 2,3,or 4;

and

at least one repeat unit selected from the group consisting of optionally substituted alkyl, optionally substituted C_2-20-alkenyl, optionally substituted C_2-20-alkynyl, optionally substituted heteroalkyl, —

O(CR₁R₂), C(O)—

where c is between about 1 and about 10, —

(CH₂)_a—

{O(CH₂)_a}_b—

where a is between about 1 and about 7 and b is between about 1 and about 500, optionally substituted aryl, and optionally substituted heteroaryl;

or

at least one repeat unit according to formula B;

wherein

R³, R⁴, R⁵ and R⁶ are each independently chosen from the group consisting of H, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted C_2-12-alkenyl, optionally substituted C_2-12-alkynyl, and optionally substituted alkoxy;

to form an admixture;

(b) forming said admixure into a shaped, solid article or microsphere; and

(c) implanting or injecting the solid article or microsphere in vivo at a preselected site, such that the solid implanted or injected matrix is in at least partial contact with a biological fluid.