What is claimed is:
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.
4. A biodegradable polymer comprising at least one repeat unit according to formula A:
52
wherein
R is hydrogen, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted alkenyl, optionally substituted alkynyl, or optionally substituted cycloalkyl;
R1 and R2 are each independently chosen from the group consisting of H, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted alkenyl, optionally substituted alkynyl, and optionally substituted;
x is 2, 3, or 4; and
at least one repeat unit selected from the group consisting of optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted alkenyl, optionally substituted alkynyl, O(CR1R2)cC(O)where c is between about 1 and about 10, (CH2)aO(CH2)abwhere 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:
53
wherein
R3, R4, R5 and R6 are each independently chosen from the group consisting of H, optionally substituted heteroalkyl, optionally substituted alkyl, optionally substituted C2-12-alkenyl, optionally substituted C2-12-alkynyl, and optionally substituted alkoxy.
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:
54
wherein
R is hydrogen, optionally substituted alkyl, optionally substituted C2-12-alkenyl, optionally substituted heteroalkyl, optionally substituted C2-12-alkynyl, or optionally substituted C5-8-cycloalkyl;
R1 and R2 are each independently chosen from the group consisting of H, optionally substituted alkyl, optionally substituted C2-12-alkenyl, optionally substituted heteroalkyl, optionally substituted C2-12-alkynyl, and optionally substituted alkoxy;
x is 2, 3, or 4;
n and m are non-negative integers;
nm is about 5 to about 2000; and
m:n is between about 1:100 to about 100:1.
8. The polymer of claim 7, wherein
x is 2;
R is C1-6-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 C1-6-alkyl; and,
R6 is C1-6-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 C1-6-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:
55
wherein
n and m are non-negative integers;
nm is about 5 to about 2000; and
m:n is between about 1:100 to about 100:1.
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:
56
IIA
wherein
R is methyl or ethyl;
n and m are non-negative integers;
nm is about 5 to about 2000; and
m:n is between about 1:100 to about 100:1.
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:
57
wherein
L is optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted C2-20-alkenyl, optionally substituted C2-20-alkynyl, -(CH2)aO(CH2)ab where a is between about 1 and about 7 and b is between about 1 and about 500, optionally substituted aryl, or optionally substituted heteroaryl;
x is 2,3, or 4;
R is hydrogen, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted C2-12-alkenyl, optionally substituted C2-12-alkynyl, or optionally substituted C5-8-cycloalkyl;
R1 and R2 are each independently chosen from the group consisting of H, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted C2-12-alkenyl, optionally substituted C2-12-alkynyl, and optionally substituted alkoxy;
M is H, Li, Na, or K;
n and m are non-negative integers;
nm is about 5 to about 2000; and
m:n is between about 1:100 to about 100:1.
16. The polymer of claim 15, wherein
x is 2;
M is hydrogen;
R is C1-6-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)aO(CH2)ab 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:
58
wherein
L is optionally substituted alkyl, optionally substituted C2-20-alkenyl, optionally substituted C2-20-alkynyl, optionally substituted heteroalkyl, (CH2)aO(CH2)ab where a is between about 1 and about 7 and b is between about 1 and about 500, optionally substituted aryl, or optionally substituted heteroaryl;
x is 2,3, or 4;
R is hydrogen, optionally substituted alkyl, optionally substituted C2-12-alkenyl, optionally substituted C2-12-alkynyl, optionally substituted heteroalkyl, or optionally substituted C5-8-cycloalkyl;
R1 and R2 are each independently chosen from the group consisting of H, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted C2-12-alkenyl, optionally substituted C2-12-alkynyl, and optionally substituted alkoxy;
n and m are non-negative integers;
nm is about 5 to about 2000;
m:n is between about 1:100 to about 100:1;
p is between about 2 and about 500;
Z is chosen from the group consisting of C(O), C(O)NH, C(OH)HCH2, and C(CH2OH)H-; and
Y is optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted C2-20-alkenyl, optionally substituted C2-20-alkynyl, optionally substituted C5-8cycloalkyl, (CH2)aO(CH2)ab where a is between about 1 and about 7 and b is between about 1 and about 100, optionally substituted aryl or optionally substituted heteroaryl;.
19. The polymer of claim 18, wherein
x is 2;
L is (CH2)aO(CH2)ab 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 C1-6-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)aO(CH2)ab 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:
59
wherein
L is optionally substituted alkyl, optionally substituted C2-20-alkenyl, optionally substituted C2-20-alkynyl, optionally substituted heteroalkyl, (CH2)aO(CH2)ab where a is between about 1 and about 7 and b is between about 1 and about 500, optionally substituted aryl, or optionally substituted heteroaryl;
x is 2,3, or 4;
R is hydrogen, optionally substituted alkyl, optionally substituted C2-12-alkenyl, optionally substituted C2-12-alkynyl, optionally substituted heteroalkyl, or optionally substituted C5-8-cycloalkyl;
R1 and R2 are each independently chosen from the group consisting of H, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted C2-12-alkenyl, optionally substituted C2-12-alkynyl, and optionally substituted alkoxy;
n and m are non-negative integers;
nm is about 5 to about 2000;
m:n is between about 1:100 to about 100:1;
c and d are non-negative integers;
cd is about 5 to about 2000; and
(mn):(cd) is between about 1:100 and 100:1.
22. The polymer of claim 21, wherein
x is 2;
L is (CH2)aO(CH2)ab where a is between about 1 and about 7 and b is between about 1 and about 500;
R is C1-6-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 C1-6-alkyl; and,
R6 is C1-6-alkyl.
23. The polymer of claim 21, wherein:
x is 2;
L is (CH2)aO(CH2)ab 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.
24. A process for preparing a biodegradable polymer comprising the recurring monomeric units of formula I:
60
wherein:
R is hydrogen, optionally substituted C2-12-alkenyl, optionally substituted heteroalkyl, optionally substituted C2-12-alkynyl, or optionally substituted alkyl;
R1, R2, R3, R4, R5 and R6 are each independently chosen from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted C2-12-alkenyl, optionally substituted C2-12-alkynyl, and optionally substituted alkoxy;
x is 2,3,or 4;
n and m are non-negative integers;
nm is about 5 to about 2000; and,
m:n is between about 1:100 to about 100:1;
wherein the process comprising the steps of:
contacting at least one glycolide derivative and at least one cyclic phosphate; and
polymerizing the glycolide derivative and the cyclic phosphate under conditions conducive to preparing the biodegradable polymer.
25. The process of claim 24, wherein the glycolide derivative is a compound according to formula VI:
61
wherein:
R4 and R6 are independently selected from the group consisting of hydrogen, alkyl,, C2-12-alkenyl, C2-12-alkynyl, and alkoxy such that both R4 and R6 are not hydrogen; and
R3 and R5 are hydrogen.
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:
62
wherein
R, independently selected at each occurrence from the group consisting of, optionally substituted alkyl, optionally substituted C2-12-alkenyl, optionally substituted heteroalkyl, optionally substituted C2-12-alkynyl, and optionally substituted alkoxy;
R1 and R2 are independently selected at each occurrence from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted C2-12-alkenyl, optionally substituted C2-12-alkynyl, and optionally substituted alkoxy; and
x is 2,3or 4.
28. The process of claim 24, wherein:
R is methyl or ethyl;
R1 and R2 are hydrogen at each occurrence of R1 and R2; 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.
32. A process for preparing a biodegradable polymer comprising the recurring monomeric units of formula III:
63
wherein:
R is hydrogen, optionally substituted C2-12-alkenyl, optionally substituted heteroalkyl, optionally substituted C2-12-alkynyl, or optionally substituted alkyl;
R1 and R2 are each independently chosen at each occurrence from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted C2-12-alkenyl, optionally substituted C2-12-alkynyl, and optionally substituted alkoxy;
L is chosen from the group consisting of optionally substituted C2-12-alkyl, optionally substituted heteroalkyl, optionally substituted C2-20-alkenyl, optionally substituted C2-20-alkynyl, or (CH2)aO(CH2)ab, wherein each a is 1-6 and b is 1-500;
n and m are non-negative integers;
nm is about 5 to about 2000;
x is 2,3or 4;and
M is independently chosen at each occurrence of M from the group consisting of H, Na, Li, and K;
the process comprising the steps of:
contacting at least one cyclic phosphate with an initiator compound, HOLOH;
polymerizing the cyclic phosphate with the initiator compound under conditions conducive to preparing the biodegradable polymer.
33. The process of claim 32, wherein the cyclic phosphate is a compound according to formula VII:
64
wherein
R is hydrogen, C2-12-alkenyl, C2-12-alkynyl, or alkyl;
R1 and R2 are independently selected at each occurrence from the group consisting of hydrogen, alkyl, C2-12-alkenyl, optionally substituted heteroalkyl, C2-12-alkynyl, and alkoxy; and
x is 2, 3 or 4.
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.
35. A process for preparing a biodegradable polymer comprising the recurring monomeric units of formula IV:
65
wherein
L is optionally substituted alkyl, optionally substituted C2-20-alkenyl, optionally substituted C2-20-alkynyl, (CH2)aO(CH2)ab where a is between about 1 and about 7 and b is between about 1 and about 500, aryl, or heteroaryl;
x is 2,3, or 4;
p is between about 2 and about 500;
R is hydrogen, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted C2-12-alkenyl, optionally substituted C2-12-alkynyl, or C5-8-cycloalkyl;
R1 and R2 are each independently chosen from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted C2-12-alkenyl, optionally substituted heteroalkyl, optionally substituted C2-12-alkynyl, and optionally substituted alkoxy;
n and m are non-negative integers;
nm is about 5 to about 2000;
m:n is between about 1:100 to about 100:1;
Z is chosen from the group consisting of C(O), C(O)NH, C(OH)HCH2, and C(CH2OH)H;
Y is alkyl, C2-20-alkenyl, optionally substituted heteroalkyl, C2-20-alkynyl, C5-8cycloalkyl, (CH2)aO(CH2)ab where a is between about land about 7 and b is between about 1 and about 100, aryl or heteroaryl; and,
the process comprising the steps of:
making the biodegradable polymer of claim 30;
contacting the biodegradable polymer of claim 30 with a compound with two functional groups capable of reacting with an alcohol to form a covalent bond; and
polymerizing the biodegradable polymer and the compound with two functional groups capable of reacting with an alcohol under conditions conducive to preparing the biodegradable polymer according to formula IV.
36. The process of claim 35, wherein the macromolecular monomer is a compound according to formula III:
66
wherein
R is hydrogen, optionally substituted C2-12-alkenyl, optionally substituted heteroalkyl, optionally substituted C2-12-alkynyl, or optionally substituted alkyl;
R1 and R2 are each independently chosen at each occurrence from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted C2-12-alkenyl, optionally substituted C2-12-alkynyl, and optionally substituted alkoxy;
L is chosen from the group consisting of optionally substituted C2-20-alkyl, optionally substituted C2-20-alkenyl, optionally substituted heteroalkyl, optionally substituted C2-20-alkynyl, or (CH2)aO(CH2)ab, wherein each a is between about 1 and about 7 and b is between about 1 and about 500;
n and m are non-negative integers;
nm is about 5 to about 2000;
x is 2, 3 or 4; and
M is hydrogen.
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, C2-20-alkenyl, optionally substituted heteroalkyl, C2-20-alkynyl, C5-8cycloalkyl, (CH2)aO(CH2)ab 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 R2; and,
x is 2.
39. A process for preparing a biodegradable polymer comprising the recurring monomeric units of formula V:
67
wherein
L is optionally substituted alkyl, optionally substituted C2-20-alkenyl, optionally substituted C2-20-alkynyl, (CH2)aO(CH2)ab where a is between about 1 and about 7 and b is between about 1 and about 500, optionally substituted aryl, or optionally substituted heteroaryl;
x is 2,3, or 4;
R is hydrogen, optionally substituted alkyl, optionally substituted C2-12-alkenyl, optionally substituted heteroalkyl, optionally substituted C2-12-alkynyl, or C5-8-cycloalkyl;
R1 and R2 are each independently chosen from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted C2-12-alkenyl, optionally substituted C2-12-alkynyl, optionally substituted heteroalkyl, and optionally substituted alkoxy;;
n and m are non-negative integers;
nm is about 5 to about 2000;
m:n is between about 1:100 to about 100:1;
c and d are non-negative integers;
cd is about 5 to about 2000;
(mn):(cd) is between about 1:100 and 100:1; and, the process comprising the steps of:
making at least one biodegradable polymer of claim 28;
contacting the biodegradable polymer of claim 28 with at least one glycolide derivative; and
polymerizing the glycolide derivative under conditions conducive to the preparing a biodegradable polymer according to formula V.
40. The process of claim 39, wherein:
xis 2;
L is (CH2)aO(CH2)ab 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:
68
wherein:
R4 and R6 are independently selected from the group consisting of hydrogen, alkyl, C2-12-alkenyl, optionally substituted heteroalkyl, C2-12-alkynyl, and alkoxy such that both R4 and R6 are not hydrogen; and
R3 and R5 are hydrogen.
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:
69
wherein
R is hydrogen, optionally substituted alkyl, optionally substituted C2-12-alkenyl, optionally substituted heteroalkyl, optionally substituted C2-12-alkynyl, or optionally substituted C5-8-cycloalkyl;
R1 and R2 are each independently chosen from the group consisting of H, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted C2-12-alkenyl, optionally substituted C2-12-alkynyl, and optionally substituted alkoxy;
x is 2,3,or 4;and
at least one repeat unit selected from the group consisting of alkyl, C2-20-alkenyl, C2-20-alkynyl, optionally substituted heteroalkyl, O(CR1R2), C(O)where c is between about 1 and about 10, (CH2)aO(CH2)abwhere 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:
70
wherein
R3, R4, R5 and R6 are each independently chosen from the group consisting of H, optionally substituted alkyl, optionally substituted C2-12-alkenyl, optionally substituted C2-12-alkynyl, optionally substituted heteroalkyl, and optionally substituted alkoxy.
43. The polymer composition of claim 42, wherein the polymer comprising repeat units as in formula I:
71
wherein
R is hydrogen, optionally substituted alkyl, optionally substituted C2-12-alkenyl, optionally substituted C2-12-alkynyl, optionally substituted heteroalkyl, or optionally substituted C5-8-cycloalkyl;
R1, R2, R3, R4, R5 and R6 are each independently chosen from the group consisting of H, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted C2-12-alkenyl, optionally substituted C2-12-alkynyl, and optionally substituted alkoxy;
x is 2,3,or 4;
n and m are non-negative integers;
nm is about 5 to about 2000; and
m:n is between about 1:100 to about 100:1.
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:
72
wherein
L is optionally substituted alkyl, optionally substituted C2-20-alkenyl, optionally substituted C2-20-alkynyl, optionally substituted heteroalkyl, (CH2)aO(CH2)ab where a is between about 1 and about 7 and b is between about 1 and about 500, optionally substituted aryl, or optionally substituted heteroaryl;
x is 2,3, or 4;
R is hydrogen, optionally substituted alkyl, optionally substituted C2-12-alkenyl, optionally substituted C2-12-alkynyl, optionally substituted heteroalkyl, or optionally substituted C5-8-cycloalkyl;
R1 and R2 are each independently chosen from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted C2-12-alkenyl, optionally substituted C2-12-alkynyl, and optionally substituted alkoxy;
M is H, Li, Na, or K;
n and m are non-negative integers;
nm is about 5 to about 2000; and
m:n is between about 1:100 to about 100:1.
46. The polymer composition of claim 45, wherein
L is (CH2)aO(CH2)ab 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:
73
wherein
L is optionally substituted alkyl, optionally substituted C2-20-alkenyl, optionally substituted C2-20-alkynyl, (CH2)aO(CH2)ab where a is between about 1 and about 7 and b is between about 1 and about 500, optionally substituted aryl, or optionally substituted heteroaryl;
x is 2,3, or 4;
p is between about 2 and about 500;
R is hydrogen, optionally substituted alkyl, optionally substituted C2-12-alkenyl, optionally substituted C2-12-alkynyl, optionally substituted heteroalkyl, or optionally substituted C5-8-cycloalkyl;
R1 and R2 are each independently chosen from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted C2-12-alkenyl, optionally substituted C2-12-alkynyl, and optionally substituted alkoxy;
n and m are non-negative integers;
nm is about 5 to about 2000;
m:n is between about 1:100 to about 100:1;
Z is chosen from the group consisting of C(O), C(O)NH, C(OH)HCH2, and C(CH2OH)H; and,
Y is optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted C2-20-alkenyl, optionally substituted C2-20-alkynyl, optionally substituted C5-8cycloalkyl, (CH2)aO(CH2)ab where a is between about 1 and about 7 and b is between about 1 and about 100, optionally substituted aryl or optionally substituted heteroaryl.
48. The polymer composition of claim 47, wherein:
x is 2;
L is (CH2)aO(CH2)ab 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:
74
wherein
L is optionally substituted alkyl, optionally substituted C2-20-alkenyl, optionally substituted C2-20-alkynyl, optionally substituted heteroalkyl, (CH2)aO(CH2)ab where a is between about 1 and about 7 and b is between about 1 and about 500, optionally substituted aryl, or optionally substituted heteroaryl;
x is 2,3, or 4;
R is hydrogen, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted C2-12-alkenyl, optionally substituted C2-12-alkynyl, or optionally substituted C5-8-cycloalkyl;
R1 and R2 are each independently chosen from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted C2-12-alkenyl, optionally substituted heteroalkyl, optionally substituted C2-12-alkynyl, and optionally substituted alkoxy;
n and m are non-negative integers;
nm is about 5 to about 2000;
m:n is between about 1:100 to about 100:1;
c and d are non-negative integers;
cd is about 5 to about 2000; and,
(mn):(cd) is between about 1:100 and 100:1.
50. The polymer composition of claim 49, wherein:
xis 2;
L is (CH2)aO(CH2)ab 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.
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:
75
wherein
R is hydrogen, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted C2-12-alkenyl, optionally substituted C2-12-alkynyl, or optionally substituted C5-8-cycloalkyl;
R1 and R2 are each independently chosen from the group consisting of H, optionally substituted alkyl, optionally substituted C2-12-alkenyl, optionally substituted heteroalkyl, optionally substituted C2-12-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 C2-20-alkenyl, optionally substituted C2-20-alkynyl, optionally substituted heteroalkyl, O(CR1R2)cC(O)where c is between about 1 and about 10, (CH2)aO(CH2)abwhere 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:
76
wherein
R3, R4, R5 and R6 are each independently chosen from the group consisting of H, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted C2-12-alkenyl, optionally substituted C2-12-alkynyl, and optionally substituted alkoxy.
57. An article of claim 56, wherein the polymer comprising repeat units as in formula I:
77
wherein
R is hydrogen, optionally substituted alkyl, optionally substituted C2-12-alkenyl, optionally substituted C2-12-alkynyl, optionally substituted heteroalkyl, or optionally substituted C5-8-cycloalkyl;
R1, R2, R3, R4, R5 and R6 are each independently chosen from the group consisting of H, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted C2-12-alkenyl, optionally substituted C2-12-alkynyl, and optionally substituted alkoxy;
x is 2, 3,or 4;
n and m are non-negative integers;
nm is about 5 to about 2000; and,
m:n is between about 1:100 to about 100:1.
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:
78
wherein
L is optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted C2-20-alkenyl, optionally substituted C2-20-alkynyl, (CH2)aO(CH2)ab where a is between about 1 and about 7 and b is between about 1 and about 500, optionally substituted aryl, or optionally substituted heteroaryl;
x is 2,3, or 4;
R is hydrogen, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted C2-12-alkenyl, optionally substituted C2-12-alkynyl, optionally substituted C5-8-cycloalkyl;
R1 and R2 are each independently chosen from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted C2-12-alkenyl, optionally substituted C2-12-alkynyl, and optionally substituted alkoxy;
M is H, Li, Na, or K;
n and m are non-negative integers;
nm is about 5 to about 2000; and
m:n is between about 1:100 to about 100:1.
60. The article of claim 59, wherein
L is (CH2)aO(CH2)ab 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:
79
wherein
L is optionally substituted alkyl, optionally substituted C2-20-alkenyl, optionally substituted C2-20-alkynyl, optionally substituted heteroalkyl, (CH2)aO(CH2)ab where a is between about 1 and about 7 and b is between about 1 and about 500, optionally substituted aryl, or optionally substituted heteroaryl;
p is between about 2 and about 500;
x is 2,3, or 4;
R is hydrogen, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted C2-12-alkenyl, optionally substituted C2-12-alkynyl, or optionally substituted C5-8-cycloalkyl;
R1 and R2 are each independently chosen from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted C2-12-alkenyl, optionally substituted C2-20-alkynyl, and optionally substituted alkoxy;
n and m are non-negative integers;
nm is about 5 to about 2000;
m:n is between about 1:100 to about 100:1;
Z is chosen from the group consisting of C(O), C(O)NH, C(OH)HCH2, and C(CH2OH)H; and,
Y is optionally substituted alkyl, optionally substituted C2-20-alkenyl, optionally substituted C2-20-alkynyl, optionally substituted heteroalkyl, optionally substituted C5-8cycloalkyl, (CH2)aO(CH2)ab where a is between about 1 and about 7 and b is between land about 500, optionally substituted aryl or optionally substituted heteroaryl.
62. The article of claim 61, wherein:
x is 2;
L is (CH2)aO(CH2)ab 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.
62. An article of claim 56, wherein the polymer comprising repeat units as in formula V:
80
wherein
L is optionally substituted alkyl, optionally substituted C2-20-alkenyl, optionally substituted heteroalkyl, optionally substituted C2-20-alkynyl, (CH2)aO(CH2)ab where a is between about 1 and about 7 and b is between about 1 and about 500, optionally substituted aryl, or optionally substituted heteroaryl;
x is 2,3, or 4;
R is hydrogen, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted C2-12-alkenyl, optionally substituted C2-12-alkynyl, or optionally substituted C5-8-cycloalkyl;
R1 and R2 are each independently chosen from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted C2-12-alkenyl, optionally substituted C2-12-alkynyl, and optionally substituted alkoxy;
n and m are non-negative integers;
nm is about 5 to about 2000;
m:n is between about 1:100 to about 100:1;
c and d are non-negative integers;
cd is about 5 to about 2000; and,
(mn):(cd) is between about 1:100 and 100:1.
64. The article of claim 63, wherein:
x is 2;
L is (CH2)aO(CH2)ab 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.
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:
81
wherein
R is hydrogen, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted C2-12-alkenyl, optionally substituted C2-12-alkynyl, or optionally substituted C5-8-cycloalkyl;
R1 and R2 are each independently chosen from the group consisting of H, optionally substituted alkyl, optionally substituted C2-12-alkenyl, optionally substituted heteroalkyl, optionally substituted C2-12-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 C2-20-alkenyl, optionally substituted C2-20-alkynyl, optionally substituted heteroalkyl, O(CR1R2), C(O)where c is between about 1 and about 10, (CH2)aO(CH2)abwhere 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:
82
wherein
R3, R4, R5 and R6 are each independently chosen from the group consisting of H, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted C2-12-alkenyl, optionally substituted C2-12-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.
70. A method of claim 69, wherein the biodegradable polymer having the recurring monomeric units shown in formula I:
83
wherein
R is hydrogen, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted C2-12-alkenyl, optionally substituted C2-12-alkynyl, or optionally substituted C5-8-cycloalkyl;
R1, R2, R3, R4, R5 and R6 are each independently chosen from the group consisting of H, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted C2-12-alkenyl, optionally substituted C2-12-alkynyl, and optionally substituted alkoxy;
x is 2,3, or 4;
n and m are non-negative integers;
nm is about 5 to about 2000; and
m:n is between about 1:100 to about 100:1;
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:
84
wherein
L is optionally substituted alkyl, optionally substituted C2-20-alkenyl, optionally substituted heteroalkyl, optionally substituted C2-20-alkynyl, (CH2)aO(CH2)ab where a is between about 1 and about 7 and b is between about 1 and about 500 optionally substituted, optionally substituted aryl, or optionally substituted heteroaryl;
x is 2,3, or 4;
R is hydrogen, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted C2-12-alkenyl, optionally substituted C2-12-alkynyl, or optionally substituted C5-8-cycloalkyl;
R1 and R2 are each independently chosen from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted C2-12-alkenyl, optionally substituted C2-12-alkynyl, and optionally substituted alkoxy;
M is H, Li, Na, or K;
n and m are non-negative integers;
nm is about 5 to about 2000; and
m:n is between about 1:100 to about 100:1.
73. The method of claim 72, wherein
L is (CH2)aO(CH2)ab 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:
85
wherein
L is optionally substituted alkyl, optionally substituted C2-20-alkenyl, optionally substituted heteroalkyl, optionally substituted C2-20-alkynyl, (CH2)aO(CH2)ab where a is between about 1 and about 7 and b is between about 1 and about 500, optionally substituted aryl, or optionally substituted heteroaryl;
x is 2,3, or 4;
p is between about 2 and about 500;
R is hydrogen, optionally substituted alkyl, optionally substituted C2-12-alkenyl, optionally substituted C2-12-alkynyl, optionally substituted heteroalkyl, or optionally substituted C5-8-cycloalkyl;
R1 and R2 are each independently chosen from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted C2-12-alkenyl, optionally substituted heteroalkyl, optionally substituted C2-12-alkynyl, and optionally substituted alkoxy;
n and m are non-negative integers;
nm is about 5 to about 2000;
m:n is between about 1:100 to about 100:1;
Z is chosen from the group consisting of C(O), C(O)NH, C(OH)HCH2, and C(CH2OH)H; and,
Y is optionally substituted alkyl, optionally substituted C2-20-alkenyl, optionally substituted C2-20-alkynyl, optionally substituted C5-8cycloalkyl, optionally substituted heteroalkyl, (CH2)aO(CH2)ab where a is between about 1 and about 7 and b is between about 1 and about 100, optionally substituted aryl or optionally substituted heteroaryl.
75. The method of claim 74, wherein:
x is 2;
L is (CH2)aO(CH2)ab 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:
86
wherein
L is optionally substituted alkyl, optionally substituted C2-20-alkenyl, optionally substituted C2-20-alkynyl, optionally substituted heteroalkyl, (CH2)aO(CH2)ab where a is between about 1 and about 7 and b is between about 1 and about 500, optionally substituted aryl, or optionally substituted heteroaryl;
x is 2,3, or 4;
R is hydrogen, optionally substituted alkyl, optionally substituted C2-12-alkenyl, optionally substituted C2-12-alkynyl, optionally substituted heteroalkyl, or optionally substituted C5-8-cycloalkyl;
R1 and R2 are each independently chosen from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted C2-12-alkenyl, optionally substituted heteroalkyl, optionally substituted C2-12-alkynyl, and optionally substituted alkoxy;
n and m are non-negative integers;
nm is about 5 to about 2000;
m:n is between about 1:100 to about 100:1;
c and d are non-negative integers;
cd is about 5 to about 2000; and,
(mn):(cd) is between about 1:100 and 100:1.
77. The method of claim 76, wherein:
x is 2;
L is (CH2)aO(CH2)ab 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.
The claims below are in addition to those above.
All refrences to claim(s) which appear below refer to the numbering after this setence.
1. A central nervous system (CNS) catheter assembly adapted for use as a ventriculostomy catheter and a spinal catheter, said CNS catheter assembly comprising:
a catheter body defining at least one lumen therethrough having at least a first branch and a second branch, said first branch and said second branch in fluid communication with said at least one lumen, said catheter body having an insertable portion for insertion within a ventricle space or spinal canal of a subject;
an opening in fluid communication with said at least one lumen disposed at a proximal end of said first branch;
an opening in fluid communication with said at least one lumen disposed at a proximal end of said second branch;
at least one opening in fluid communication with said at least one lumen disposed at a distal end of said main body;
an aseptic drug delivery filter assembly disposed in fluid communication with said first branch;
a first valve disposed in fluid communication with said second branch; and
a component in fluid communication with said at least one lumen, said component selected from the group consisting of: an intracranial pressureosmotic pressure monitoring system, a fluid drainage system, an attachable introduction aid, a patient surface attachment aid, a micromanipulator and an intracranial pressure evaluation and relief system.
2. A catheter assembly according to claim 1, further comprising a second valve disposed in fluid communication with said first branch.
3. A catheter assembly according to claim 1, wherein said filter assembly comprises a micro-pore filter.
4. A catheter assembly according to claim 1, wherein said filter assembly comprises a membrane filter.
5. A catheter assembly according to claim 4, wherein said membrane filter is a positron emission membrane filter.
6. A catheter assembly according to claim 2, wherein said second valve is a one-way flow valve.
7. A catheter assembly according to claim 1, wherein said catheter body has a single lumen.
8. A catheter assembly according to claim 1, wherein said catheter body has two lumens.
9. A catheter assembly according to claim 1, further comprising a first connector disposed at the proximal end of said first branch.
10. A catheter assembly according to claim 1, wherein said second branch comprises a second connector disposed at the proximal end thereof.
11. A catheter assembly according to claim 1 further comprising a third branch disposed in fluid communication with said catheter body.
12. A catheter assembly according to claim 11 further comprising a third valve disposed in fluid communication with said catheter body and said third branch.
13. A catheter assembly according to claim 1 wherein said first valve is a Y-valve.
14. A catheter assembly according to claim 1 wherein said first valve is a swing valve.
15. A catheter assembly according to claim 1 further comprising an external pump in fluid communication with said first branch.
16. A catheter assembly according to claim 15 wherein said external pump is battery powered.
17. A catheter assembly according to claim 15 wherein said external pump has a refittable pump chamber.
18. A central nervous system temperature control system adapted for use with a central nervous system catheter assembly, said system comprising:
a closed-loop heat exchanger operatively connected in fluid communication to a conduit which is placed in fluid communication with central nervous system fluid through a catheter assembly as set forth in claim 1.
19. A system according to claim 18, further comprising a thermistor.
20. A method for controlling the temperature of cerebrospinal fluid, said method comprising the steps of:
disposing a catheter in direct contact with the cerebrospinal fluid of a subject;
disposing a conduit within the catheter and in contact with the cerebrospinal fluid, the conduit connected in fluid communication to a temperature control system comprising a closed-loop heat exchanger;
measuring the temperature of the cerebrospinal fluid; and
circulating fluid through the conduit to control the temperature of the cerebrospinal fluid.
21. A method according to claim 20 further comprising the step of adjusting the temperature of the fluid circulating in the conduit.
22. A method according to claim 20 further comprising the step of adjusting the rate of flow of the fluid through the conduit.
23. A method for aseptic drug delivery to the central nervous system through a catheter and cerebrospinal fluid, and monitoring of intracranial pressure or intraspinal pressure, said method comprising the steps of:
inserting a catheter into at least one of: a ventricular space and a spinal canal, said catheter comprising:
a catheter body having a distal end and defining at least one lumen therethrough having at least a first branch having a first opening in fluid communication with said at least one lumen disposed at a proximal end of said first branch, a second branch having a second opening in fluid communication with said at least one lumen disposed at a proximal end of said second branch, and a third branch, said first branch, said second branch, and said third branch in fluid communication with said at least one lumen, said catheter body having an insertable portion for insertion within a ventricle space or spinal canal of a subject and at least one opening in fluid communication with said at least one lumen disposed at a distal end of said catheter body;
a filter assembly disposed in fluid communication with said first branch;
a first valve movable between a first position wherein fluid flows through the second branch and not the third branch and a second position wherein fluid cannot flow to the second branch and flows to the third branch disposed in fluid communication with said second branch and the third branch; and
a second valve movable between a first position wherein fluid flows through the first branch and not the second branch and a second position wherein fluid cannot flow to the first branch and flows to the second or the third branch; and
delivering a drug through the first branch by positioning the second valve in the first position without opening the catheter to the atmosphere.
24. A method according to claim 23 further comprising the step of monitoring intracranial or intraspinal pressure by connecting a pressure monitoring device to the second branch and positioning the first valve in the first position and the second valve in the second position.
25. A method according to claim 23 further comprising the step of removing cerebrospinal fluid through the third branch by positioning the second valve in the second position and the first valve in the second position without opening the catheter to the atmosphere.
26. A method according to claim 23 wherein said drug is delivered from an external pump through the first branch.