US2006239961A1PendingUtilityA1
Hydrolytically degradable alkylene oxide based polymers
Assignee: NEKTAR THERAPEUTICS AL CORPPriority: Feb 15, 2002Filed: Feb 14, 2003Published: Oct 26, 2006
Est. expiryFeb 15, 2022(expired)· nominal 20-yr term from priority
C08G 65/04A61K 9/06A61K 47/34C08G 64/183C08G 65/329C08G 65/333C08G 65/33337C08G 65/33344C08G 65/33396C08L 2203/02A61K 9/00
44
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Claims
Abstract
The present invention provides a water soluble, nonpeptidic polymer comprising two or more alkylene oxide-based oligomers linked together by hydrolytically degradable linkages such as carbonates. Typically, the oligomer portion of the polymer is an amphiphilic triblock copolymer having a central propylene oxide block or butylene oxide block positioned between two ethylene oxide blocks. The polymer can be hydrolytically degraded into oligomers under physiological conditions. In aqueous media, the polymer preferably forms thermally reversible, hydrolytically degradable hydrogels that can be used, for example, for drug delivery and related biomedical applications.
Claims
exact text as granted — not AI-modified1 . A hydrolytically degradable polymer comprising two or more oligomers covalently linked by a carbonate bond,
wherein each oligomer comprises a triblock copolymer having a central propylene oxide block or butylene oxide block positioned between two ethylene oxide blocks.
2 . The polymer of claim 1 , comprising a hydroxy terminus.
3 . The polymer of claim 1 , comprising a reactive terminal moiety.
4 . The polymer of claim 3 , wherein said reactive terminal moiety is selected from the group consisting of N-succinimidyloxycarbonyl, 1-benzotriazolyloxycarbonyl, p-nitrophenyloxycarbonyl, N-maleimidyl, aldehyde, acetal, tresyl, 1-imidazolylcarbonyl, vinylsulfone, acryloyl, iodoacetamide, N-succinimidylpropionate, N-succinimidylbutyrate, N-succinimidylacetate, and o-pyridyldithiyl.
5 . The polymer of claim 1 , wherein said oligomer possesses from about 6 to about 6000 monomer subunits.
6 . The polymer of claim 1 , wherein said central propylene oxide block or butylene oxide block possesses from about 2 to about 2000 monomer subunits.
7 . A polymer having the formula:
X—O—[(—CH 2 CH 2 —O—) n —(CHR 1 CHR 2 'O—) q —(CH 2 CH 2 —O) r —CO 2 ] m —(CH 2 CH 2 O) n —(CHR 3 CHR 4 —O—) q —(CH 2 CH 2 —O) r —Y
wherein:
n, q, and r are integers each independently ranging from about 2 to about 2,000,
m is an integer ranging from 1 to about 200,
R 1 , R 2 , R 3 , and R 4 are independently selected from alkyl or H, where
R 1 is H when R 2 is alkyl or R 1 is alkyl when R 2 is H,
R 3 is H when R 4 is alkyl or R 3 is alkyl when R 4 is H, and
X and Y are each independently selected from the group consisting of H, alkyl, alkenyl, aryl, or a reactive moiety.
8 . The polymer of claim 7 , wherein X and Y are independently selected from the group consisting of H, alkyl, alkenyl, aryl, acryloyl, methacryloyl, tresyl, N-succinimidyloxycarbonyl, 1-benzotriazolyloxycarbonyl, p-nitrophenyloxycarbonyl, N-maleimidyl, aldehydes, acetals, 1-imidazolylcarbonyl, vinylsulfone, iodoacetamide, and o-pyridyldithiyl.
9 . The polymer of claim 8 , wherein at least one of X and Y is 1-benzotriazolyloxy carbonyl.
10 . The polymer of claim 8 , wherein X and Y are selected from the group consisting of acryloyl and methacryloyl.
11 . The polymer of claim 8 , wherein at least one of X and Y is N-succinimidyl carbonyl.
12 . The polymer of claim 7 , wherein n is an integer of from about 5 to about 500.
13 . The polymer of claim 7 , wherein n is an integer of from about 80 to about 120.
14 . The polymer of claim 7 , wherein q is an integer of from about 40 to about 70.
15 . The polymer of claim 7 , wherein r is an integer of from about 5 to about 100.
16 . The polymer of claim 7 , wherein m is an integer of from 1 to about 5.
17 . The polymer of claim 7 , wherein:
R 1 is H when R 2 is methyl or ethyl, or R 1 is methyl or ethyl when R 2 is H; and R 3 is H when R 4 is methyl or ethyl, or R 3 is methyl or ethyl when R 4 is H.
18 . The polymer of claim 7 , wherein n is an integer of from about 80 to about 120, q is an integer of from about 40 to about 70, r is an integer of from about 10 to about 50, and m is an integer of from 1 to about 5.
19 . A method for preparing a hydrolytically degradable polymer comprising the following steps:
(i) providing an oligomer comprising a hydroxyl terminus and a terminus, —O—CO 2 -Z, capable of reacting with a hydroxyl group to form a carbonate linkage, wherein Z is a reactive leaving group, and said oligomer comprises a triblock copolymer having a central propylene oxide block or butylene oxide block positioned between two ethylene oxide blocks, and (ii) contacting two or more of said oligomers under conditions sufficient to provide a hydrolytically degradable polymer comprising two or more oligomers covalently linked to one another by a carbonate bond.
20 . The method of claim 19 , further comprising the step of activating said hydrolytically degradable polymer by covalently attaching at least one chemically reactive group thereto.
21 . The method of claim 19 , further comprising the step of purifying said hydrolytically degradable polymer.
22 . The method of claim 19 , wherein said oligomer comprises a central propylene oxide block.
23 . The method of claim 19 , wherein said hydrolytically degradable polymer corresponds to the structure:
H—O—[(—CH 2 CH 2 —O—) n —(CHR 1 CHR 2 —O—) q —(CH 2 CH 2 —O) r —CO 2 —] m —(CH 2 CH 2 O) n —(CHR 3 CHR 4 —O—) q —(CH 2 CH 2 —O) r —H
wherein:
n, q, and r are integers each independently ranging from about 2 to 2000,
m is an integer ranging from 1 to 200,
R 1 , R 2 , R 3 , and R 4 are independently selected from alkyl or H, where
R 1 is H when R 2 is alkyl or R 1 is alkyl when R 2 is H,
R 3 is H when R 4 is alkyl or R 3 is alkyl when R 4 is H, and
said oligomer corresponds to the structure:
HO—(CH 2 CH 2 —O—) n —(CHR 1 CHR 2 —O—) q —(CH 2 CH 2 —O) r —CO 2 -Z
wherein n, q, r, R 1 and R 2 are as defined above, and Z is a reactive leaving group.
24 . The method of claim 23 , wherein Z is selected from the group consisting of N-succinimidyl, 1-benzotriazolyl, and p-nitrophenyl.
25 . The method of claim 23 , wherein the contacting step is carried out in an organic solvent in the presence of a base, at a temperature ranging from about 37° C. to about 100° C.
26 . The method of claim 25 , wherein said solvent is selected from the group consisting of acetonitrile, dimethylformamide, dimethylsulfoxide, benzene, toluene, xylenes, chloroform, and methylene chloride.
27 . The method of claim 25 , wherein said base is an organic base.
28 . The method of claim 27 , wherein said organic base is selected from the group consisting of triethylamine, pyridine, quinoline, and 4,4-dimethylaminopyridine.
29 . The method of claim 23 , wherein the contacting step is conducted in a melt in the presence of a base, at a temperature ranging from about 37° C. to 100° C.
30 . The method of claim 29 , wherein said base is an organic base.
31 . The method of claim 30 , wherein said organic base is selected from the group consisting of triethylamine, pyridine, quinoline, and 4,4-dimethylaminopyridine.
32 . The method of claim 23 , wherein n is an integer ranging from about 5 to 500.
33 . The method of claim 23 , wherein n is an integer ranging from about 80 to 120.
34 . The method of claim 23 , wherein q is an integer ranging from about 40 to 70.
35 . The method of claim 23 , wherein r is an integer ranging from about 5 to 100.
36 . The method of claim 23 , wherein m is an integer ranging from 1 to about 5.
37 . The method of claim 23 , wherein:
R 1 is H when R 2 is methyl or ethyl, or R 1 is methyl or ethyl when R 2 is H; and R 1 is H when R 4 is methyl or ethyl, or R 3 is methyl or ethyl when R 4 is H.
38 . A method for preparing a polymer having the formula:
H—O—[(—CH 2 CH 2 —O—) n —(CHR 1 CHR 2 —O—) q —(CH 2 CH 2 —O) r —CO 2 —] m —(CH 2 CH 2 O) n —(CHR 3 CHR 4 —O—) q —(CH 2 CH 2 —O) r —H
wherein:
n, q, and r are integers each independently ranging from about 2 to 2000,
m is an integer ranging from 1 to about 200,
R 1 , R 2 , R 3 , and R 4 are independently selected from alkyl or H, where
R 1 is H when R 2 is alkyl or R 1 is alkyl when R 2 is H,
R 3 is H when R 4 is alkyl or R 3 is alkyl when R 4 is H, and
said method comprising:
(i) polymerizing an oligomer having the formula,
HO—(—CH 2 CH 2 —O—) n —(CH 2 R 1 CHR 2 —O—) q —(CH 2 CH 2 —O) r —CO 2 -1-benzotriazolyl,
wherein n, q, r, R 1 and R 1 are as defined above,
in the presence of dimethylaminopyridine at a temperature of from about 45° C. to 100° C., either in a melt or in anhydrous acetonitrile, to thereby form said polymer.
39 . A method for preparing a polymer having the formula:
H—O—[(—CH 2 CH 2 —O—) n —(CHR 1 CHR 2 —O—) q —(CH 2 CH 2 —O) r —CO 2 —] m —(CH 2 CH 2 O) n —(CHR 3 CHR 4 —O—) q —(CH 2 CH 2 —O) r —H
wherein:
n, q, and r are integers each independently ranging from about 2 to 2000,
m is an integer ranging from 1 to about 200,
R 1 , R 2 , R 3 , and R 4 are independently selected from alkyl or H, where
R 1 is H when R 2 is alkyl or R 1 is alkyl when R 2 is H,
R 3 is H when R 4 is alkyl or R 3 is alkyl when R 4 is H, and
comprising:
polymerizing an oligomer having the formula,
HO—(CH 2 CH 2 —O—) n —(CHR 1 CHR 2 —O—) q —(CH 2 CH 2 —O) r —CO 2 —N-succinimidyl,
wherein n, q, r, R 1 and R 2 are as defined above,
in the presence of dimethylaminopyridine at a temperature of from about 45° C. to 100° C., either in a melt or in anhydrous acetonitrile to thereby form said polymer.
40 . A method for preparing a hydrolytically degradable polymer comprising the steps of:
(i) providing a first oligomer comprising a first functional group, —O—CO 2 —W, at one terminus and, at another terminus, a second functional group, —O—CO 2 -Z, wherein each functional group is capable of reacting with a hydroxyl group to form a carbonate, and wherein Z and W are each independently reactive leaving groups; (ii) providing a second oligomer comprising at least two hydroxyl terminal groups; (iii) forming a reaction mixture comprising said first and second oligomers; and (iv) polymerizing said first and second oligomers under conditions effective to form a hydrolytically degradable polymer, wherein said hydrolytically degradable polymer comprises two or more of said oligomers covalently linked by a hydrolytically degradable carbonate bond, wherein each of said oligomers comprises a triblock copolymer having a central propylene oxide block or butylene oxide block positioned between two ethylene oxide blocks.
41 . The method of claim 40 , further comprising the step of activating said hydrolytically degradable polymer by covalently attaching at least one chemically reactive group thereto.
42 . The method of claim 40 , further comprising the step of purifying said hydrolytically degradable polymer.
43 . The method of claim 40 , wherein said polymer comprises a central propylene oxide block.
44 . The method of claim 40 , wherein the first oligomer has a functional group —O—CO 2 -Z at two termini, and the step of providing the first oligomer comprises:
providing a precursor of the first oligomer, which has two terminal hydroxyl groups; providing an activating molecule having the formula Z—O—CO 2 -Z; and reacting said precursor with said activating molecule to form said first oligomer.
45 . The method of claim 40 , wherein said polymer has the formula:
H—O—[(—CH 2 CH 2 —O—) n —(CHR 1 CHR 2 —O—) q —(CH 2 CH 2 —O) r —CO 2 —] m —(CH 2 CH 2 O) n —(CHR 3 CHR 4 —O—) q —(CH 2 CH 2 —O) r —H,
said first oligomer has the formula of
W—O 2 C—O—(—CH 2 CH 2 —O—) n —(CHR 3 CHR 2 CHR 4 —O—) q —(CH 2 CH 2 —O) r —CO 2 -Z,
said second oligomer has the formula of
HO—(—CH 2 CH 2 —O—) n —(CHR 3 CHR 4 —O—) q —(CH 2 CH 2 —O) r —H,
wherein:
n, q, and r are integers each independently ranging from about 2 to 2000,
m is an integer of from 1 to about 200,
R 1 , R 2 , R 3 , and R 4 are independently selected from alkyl or H, where
R 1 is H when R 2 is alkyl or R 1 is alkyl when R 2 is H,
R 3 is H when R 4 is alkyl or R 3 is alkyl when R 4 is H, and
W and Z are as previously defined.
46 . The method of claim 45 , wherein W and Z are independently selected from the group consisting of N-succinimidyl, 1-benzotriazolyl, and p-nitrophenyl.
47 . The method of claim 45 , wherein the polymerizing step is conducted in a solvent in the presence of a base, and at a temperature of from about 37° C. to 100° C.
48 . The method of claim 47 , wherein said solvent is selected from the group consisting of acetonitrile, dimethylformamide, dimethylsulfoxide, benzene, toluene, xylenes, chloroform, and methylene chloride.
49 . The method of claim 47 , wherein said base is an organic base.
50 . The method of claim 49 , wherein said organic base is selected from the group consisting of triethylamine, pyridine, quinoline, and 4,4-dimethylaminopyridine.
51 . The method of claim 45 , wherein n is an integer ranging from about 5 to 500.
52 . The method of claim 45 , wherein n is an integer ranging from about 80 to 120.
53 . The method of claim 45 , wherein q is an integer ranging from about 40 to 70.
54 . The method of claim 45 , wherein r is an integer ranging from about 5 to 100.
55 . The method of claim 45 , wherein m is an integer ranging from 1 to about 5.
56 . The method of claim 45 , wherein:
R 1 is H when R 2 is methyl or ethyl, or R 1 is methyl or ethyl when R 2 is H; and R 3 is H when R 4 is methyl or ethyl, or R 3 is methyl or ethyl when R 4 is H.
57 . The method of claim 45 , wherein W and Z are the same, and wherein said step of providing said second oligomer comprises:
providing an activating molecule having the formula of Z-O—CO 2 -Z; providing a precursor of said second oligomer having two terminal hydroxyl groups; and reacting said activating molecule and said precursor to form said second oligomer.
48 . A method for preparing a polymer having the formula of:
H—O—[(—CH 2 CH 2 —O—) n —(CHR 1 CHR 2 —O—) q —(CH 2 CH 2 —O) r —CO 2 —] m —(CH 2 CH 2 O) n —(CHR 3 CHR 4 —O—) q —(CH 2 CH 2 —O) r —H,
wherein:
n, q, and r are integers each independently ranging from about 2 to 2000,
m is an integer ranging from 1 to about 200,
R 1 , R 2 , R 3 , and R 4 are independently selected from alkyl or H, where
R 1 is H when R 2 is alkyl or R 1 is alkyl when R 2 is H,
R 3 is H when R 4 is alkyl or R 3 is alkyl when R 4 is H, and
said method comprising:
providing a first alkylene oxide oligomer having the formula of
HO—(—CH 2 CH 2 —O—) n —(CHR 1 CHR 2 —O—) q —(CH 2 CH 2 —O) r —H;
providing a second alkylene oxide oligomer having a formula of 1-benzotriazolyl-O 2 C—O—(—CH 2 CH 2 —O—) n —(CHR 3 CHR 4 —O—) q —(CH 2 CH 2 —O) r —CO 2 -1-benzotriazolyl wherein R 1 , R 2 , R 3 and R 4 are as previously defined; and
co-polymerizing said first and second alkylene oxide oligomers in the presence of dimethylaminopyridine and at a temperature of from about 45° C. to 100° C., either in a melt or in anhydrous acetonitrile as solvent, thereby forming said polymer.
59 . A method for preparing a polymer having the formula of:
H—O—[(—CH 2 CH 2 —O—) n —(CHR 1 CHR 2 —O—) q —(CH 2 CH 2 —O) r —CO 2 —] m —(CH 2 CH 2 O) n —(CHR 3 CHR 4 —O—) q —(CH 2 CH 2 —O) r —H,
wherein:
n, q, and r are integers each independently ranging from about 2 to 2000,
m is an integer ranging from 1 to about 200,
R 1 , R 2 , R 3 , and R 4 are independently selected from alkyl or H, where
R 1 is H when R 4 is alkyl or R 3 is alkyl when R 4 is H,
R 3 is H when R 4 is alkyl or R 3 is alkyl when R 4 is H, and
said method comprising:
providing a first alkylene oxide oligomer having the formula of
HO—(—CH 2 CH 2 —O—) n —(CHR 3 CHR 4 —O—) q —(CH 2 CH 2 —O) r —H;
providing a second alkylene oxide oligomer having a formula of
N-succinimidyl-O 2 C—O—(—CH 2 CH 2 —O—) n —(CHR 3 CHR 4 —O—) q —(CH 2 CH 2 —O) r —CO 2 —N-succinimidyl wherein R 1 , R 2 , R 3 and R 4 are as previously defined; and
co-polymerizing said first and second alkylene oxide oligomers in the presence of dimethylaminopyridine and at a temperature of from about 45° C. to 100° C., either in a melt or in anhydrous acetonitrile as solvent, thereby forming said polymer.
60 . A method for preparing a hydrolytically degradable polymer comprising:
providing an alkylene oxide oligomer comprising a triblock copolymer having a central propylene oxide block or butylene oxide block positioned between two ethylene oxide blocks, providing an activating molecule having the formula of Z-O—CO 2 -Z, wherein each Z is independently a reactive leaving group; and co-polymerizing said oligomer and said activating molecule at conditions sufficient to form said hydrolytically degradable polymer, wherein said polymer comprises two or more of said oligomers covalently linked by a hydrolytically degradable carbonate bond.
61 . The method of claim 60 , wherein said oligomer comprises a central propylene oxide block.
62 . The method of claim 61 , wherein said oligomer has the formula of
HO—(—CH 2 CH 2 —O—) n —(CHR 1 CHR 2 —O—) q —(CH 2 CH 2 —O) r —H,
wherein:
n, q, and r are integers each independently ranging from about 2 to 2000,
m is an integer of from 1 to about 200,
R 1 , R 2 , R 3 , and R 4 are independently selected from alkyl or H, where
R 1 is H when R 2 is alkyl or R 1 is alkyl when R 2 is H, and
R 3 is H when R 4 is alkyl or R 3 is alkyl when R 4 is H.
63 . The method of claim 62 , wherein Z is selected from the group consisting of N-succinimidyl, 1-benzotriazolyl, and p-nitrophenyl.
64 . The method of claim 62 , wherein the co-polymerizing step is conducted in a solvent in the presence of an organic base, and at a temperature of from about 37° C. to 100° C.
65 . The method of claim 62 , wherein said solvent is selected from the group consisting of acetonitrile, dimethylformamide, dimethylsulfoxide, benzene, toluene, xylenes, chloroform, and methylene chloride.
66 . The method of claim 65 , wherein the solvent is acetonitrile.
67 . The method of claim 65 , wherein the organic base is an amine.
68 . The method of claim 67 , wherein said organic base is selected from the group consisting of triethylamine, pyridine, quinoline, and 4,4-dimethylaminopyridine.
69 . The method of claim 65 , wherein n is an integer ranging from about 5 to 500.
70 . The method of claim 65 , wherein n is an integer ranging from about 80 to 120.
71 . The method of claim 65 , wherein q is an integer ranging from about 40 to 70.
72 . The method of claim 65 , wherein r is an integer ranging from about 5 to 100.
73 . The method of claim 65 , wherein m is an integer ranging from 1 to about 5.
74 . A method for preparing a polymer having the formula of:
H—O—[(—CH 2 CH 2 —O—) n —(CHR 1 CHR 2 —O—) q —(CH 2 CH 2 —O) r —CO 2 —] m —(CH 2 CH 2 O) n —(CHR 3 CHR 4 —O—) q —(CH 2 CH 2 —O) r —H,
wherein:
n, q, and r are integers each independently ranging from about 2 to 2000,
m is an integer ranging from 1 to 200,
R 1 , R 2 , R 3 , and R 4 are independently selected from alkyl or H, where
R 1 is H when R 2 is alkyl or R 1 is alkyl when R 2 is H, and
R 3 is H when R 4 is alkyl or R 3 is alkyl when R 4 is H
said method comprising
co-polymerizing disuccinimidylcarbonate and
HO—(—CH 2 CH 2 —O—) n —(CHR 1 CHR 2 —O—) q —(CH 2 CH 2 —O) r —H, wherein R 1 and R 2 are as previously defined, in the presence of dimethylaminopyridine and at a temperature of from about 45° C. to 100° C., either in a melt or in anhydrous acetonitrile as solvent, thereby forming said polymer.
75 . A method for preparing a polymer having the formula of:
H—O—[(—CH 2 CH 2 —O—) n —(CHR 1 CHR 2 —O—) q —(CH 2 CH 2 —O) r —CO 2 —] m —(CH 2 CH 2 O) n —(CHR 3 CHR 4 —O—) q —(CH 2 CH 2 —O) r —H,
wherein:
n, q, and r are integers each independently ranging from about 2 to 2000,
m is an integer ranging from about 1 to about 200,
R 1 , R 2 , R 3 , and R 4 are independently selected from alkyl or H, where
R 1 is H when R 2 is alkyl or R 1 is alkyl when R 2 is H, and
R 3 is H when R 4 is alkyl or R 3 is alkyl when R 4 is H,
said method comprising
co-polymerizing bis(1-benzotriazolyl carbonate) and
HO—(—CH 2 CH 2 —O—) n —(CHR 1 CHR 2 —O—) q —(CH 2 CH 2 —O) r —H wherein R 1 and
R 2 are as previously defined,
in the presence of dimethylaminopyridine and at a temperature of from about 45° C. to 100° C., either in a melt or in anhydrous acetonitrile as solvent, thereby forming said polymer.
76 . A gel comprising a hydrolytically degradable polymer, said polymer comprising two or more oligomers covalently linked by a carbonate bond, wherein each oligomer comprises a triblock copolymer having a central propylene oxide block or butylene oxide block positioned between two ethylene oxide blocks.
77 . The gel of claim 76 , wherein said gel is thermally reversible.
78 . The gel of claim 76 , further comprising a biologically active agent physically entrapped within said gel.
79 . The gel of claim 76 , wherein said gel is crosslinked.
80 . The gel of claim 76 , wherein said gel is substantially absent covalent crosslinks.
81 . The gel of claim 76 , wherein said biologically active agent is covalently linked to the hydrolytically degradable polymer.
82 . A conjugate comprising a biologically active agent covalently linked to a hydrolytically degradable polymer having the formula of:
X—O—[(—CH 2 CH 2 —O—) n —(CHR 1 CHR 2 —O—) q —(CH 2 CH 2 —O) r —CO 2 —] m —(CH 2 CH 2 O) n —(CHR 3 CHR 4 —O—) q —(CH 2 CH 2 —O) r —Y
wherein:
n, q, and r are integers each independently ranging from about 2 to 2000,
m is an integer ranging from 1 to 200,
R 1 , R 2 , R 3 , and R 4 are independently selected from alkyl or H, where
R 1 is H when R 2 is alkyl or R 1 is alkyl when R 2 is H,
R 3 is H when R 4 is alkyl or R 3 is alkyl when R 4 is H, and
X and Y are each independently H, alky, alkenyl, aryl, or a reactive moiety capable of reacting with an active moiety on said biologically active agent, and where at least one of X and Y is said reactive moiety.
83 . The conjugate of claim 82 , wherein X and Y are independently selected from the group consisting of H, alkyl, alkenyl, aryl, acryloyl, tresyl, N-succinimidyloxycarbonyl, 1-benzotriazolyloxycarbonyl, p-nitrophenyloxycarbonyl, N-maleimidyl, aldehydes, acetals, 1-imidazolylcarbonyl, vinylsulfone, iodoacetamide, and o-pyridyldithiyl.
84 . The conjugate of claim 82 , wherein at least one of X and Y is N-succinimidyloxycarbonyl, 1-benzotriazolyloxycarbonyl, p-nitrophenyloxycarbonyl.
85 . The conjugate of claim 82 , wherein n is an integer ranging from about 5 to 500.
86 . The conjugate of claim 82 , wherein n is an integer ranging from about 80 to 120.
87 . The conjugate of claim 82 , wherein q is an integer ranging from about 40 to 70.
88 . The conjugate of claim 82 , wherein r is an integer ranging from about 10 to 50.
89 . The conjugate of claim 83 , wherein m is an integer ranging from 1 to about 5.
90 . A method for preparing a gel having a biologically active agent contained within a hydrolytically degradable polymer matrix, said polymer comprising two or more oligomers covalently linked by a carbonate bond, wherein each oligomer comprises a triblock copolymer having a propylene oxide block or butylene oxide block positioned between two ethylene oxide blocks, said method comprising the steps of:
providing said hydrolytically degradable polymer in a liquid solution; providing a biologically active agent in said solution; and raising the temperature of the hydrolytically degradable polymer until a viscous gel forms, thereby resulting in biologically active agent contained within the hydrolytically degradable polymer matrix.
91 . The method of claim 90 , wherein said oligomer comprises a central propylene oxide block.
92 . The method of claim 90 , wherein the polymer has the formula of
H—O—[(—CH 2 CH 2 —O—) n —(CHR 1 CHR 2 —O—) q —(CH 2 CH 2 —O) r —CO 2 —] m —(CH 2 CH 2 O) n —(CHR 3 CHR 4 —O—) q —(CH 2 CH 2 —O) r —H,
wherein:
n, q, and r are integers each independently ranging from about 2 to 2000,
m is an integer ranging from 1 to about 200,
R 1 , R 2 , R 3 , and R 4 are independently selected from alkyl or H, where
R 1 is H when R 2 is alkyl or R 1 is alkyl when R 2 is H, and
R 3 is H when R 4 is alkyl or R 3 is alkyl when R 4 is H.
93 . The method of claim 92 , wherein n is an integer ranging from about 10 to 50.
94 . A method for delivering a biologically active agent into the body of a mammal, comprising administering the gel of claim 76 into said mammal.
95 . A method for delivering a biologically active agent into the body of a mammal, comprising administering the conjugate of claim 8 , into said mammal.
96 . A delivery system for delivering a biologically active agent comprising
a hydrolytically degradable polymer, said polymer comprising two or more oligomers covalently linked by a carbonate bond, wherein each oligomer comprises a triblock copolymer having an a central propylene oxide block or butylene oxide block positioned between two ethylene oxide blocks, and a biologically active agent in aqueous solution with the hydrolytically degradable polymer.
97 . The delivery system of claim 96 , wherein the components of the delivery system are in the form of an injectable solution below about 35° C., but are a gel at the body temperature of a mammal.
98 . The delivery system of claim 97 , wherein said biologically active agent is physically contained within the polymer matrix of the gel.
99 . The delivery system of claim 96 , wherein said biologically active agent has a molecular weight less than about 2000 Da.
100 . The delivery system of claim 96 , wherein said biologically active agent is a protein, peptide, oligonucleotide, or carbohydrate.
101 . The delivery system of claim 96 , wherein said biologically active agent is an anticancer drug, antiviral drug, antibacterial drug, antibiotic, analgesic, anti-inflammatory drug, anti-arrhythmic drug, vasodilating drug, or cardiovascular drug.
102 . The delivery system of claim 96 , wherein the polymer has the formula of
H—O—[(—CH 2 CH 2 —O—) n —(CHR 1 CHR 2 —O—) q —(CH 2 CH 2 —O) r —CO 2 —] m —(CH 2 CH 2 O) n —(CHR 3 CHR 4 —O—) q —(CH 2 CH 2 —O) r —H,
wherein:
n, q, and r are integers each independently ranging of from about 2 to about 2000,
m is an integer ranging from 1 to about 200
R 1 , R 2 , R 3 , and R 4 are independently selected from alkyl or H, where
R 1 is H when R 2 is alkyl or R 1 is alkyl when R 2 is H, and
R 3 is H when R 4 is alkyl or R 3 is alkyl when R 4 is H.
103 . The gel of claim 78 , wherein the biologically active agent is covalently attached to a water-soluble polymer.
104 . The gel of claim 78 , wherein the water-soluble polymer is a polyethylene glycol derivative.Join the waitlist — get patent alerts
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