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US 2003/0199654 A1Published application
Degradable crosslinkers, and degradable crosslinked hydrogels comprising them
AssigneeBiosphere Medical, Inc.
InventorsHongmin Zhang, Alexander Schwarz
Life of this patent
Estimating the term…
Abstract
One aspect of the present invention relates to base-labile crosslinkers. A second aspect of the present invention relates to degradable crosslinked polymers and hydrogels comprising a base-labile crosslinker. The present invention also relates to a method of influencing the degradation rate of a crosslinked polymer or hydrogel, comprising the step of incorporating uncharged acrylamides into the crosslinked polymer or hydrogel.
Claims84
A compound represented by 1:
- 9
- wherein
- X represents independently for each occurrence O or S;
- L represents independently for each occurrence —NH—O—Q, or —O—NH—Q;
- Q represents independently for each occurrence acryloyl, 2-alkylacryloyl, 3-alkylacryloyl, 2,3-dialkylacryloyl, 3,3-dialkylacryloyl, 2,3,3-trialkylacryloyl, acryloylO(CR2)nC(O)—, 2-alkylacryloylO(CR2)nC(O)—, 3-alkylacryloylO(CR2)nC(O)—, 2,3-dialkylacryloylO(CR2)nC(O)—, 3,3-dialkylacryloylO(CR2)nC(O)—, 2,3,3-trialkylacryloylO(CR2)nC(O)—, (diene)C(O)—, (vinyl)(CR2)nC(O)—, or (vinyl)ArC(O)—;
- R represents independently for each occurrence H or alkyl;
- Z represents (CR2)n(CR2)nJ(CR2)m, or (CR2)nAr(CR2)m;
- Ar represents independently for each occurrence aryl or heteroaryl;
- J represents independently for each occurrence O, S, NR, cycloalkyl, heterocyclyl, (CH2CH2O)n, or (CH2CH2N(R))n;
- n represents independently for each occurrence an integer in the range 1-10;
- and
- m represents independently for each occurrence an integer in the range 0-10.
9 more elements
A compound represented by 2:
- 10
- wherein
- X represents independently for each occurrence O or S;
- M represents independently for each occurrence —NH—O—Q, or —O—NH—Q;
- Q represents independently for each occurrence acryloyl, 2-alkylacryloyl, 3-alkylacryloyl, 2,3-dialkylacryloyl, 3,3-dialkylacryloyl, 2,3,3-trialkylacryloyl, acryloylO(CR2)nC(O)—, 2-alkylacryloylO(CR2)nC(O)—, 3-alkylacryloylO(CR2)nC(O)—, 2,3-dialkylacryloylO(CR2)nC(O)—, 3,3-dialkylacryloylO(CR2)nC(O)—, 2,3,3-trialkylacryloylO(CR2)nC(O)—, (diene)C(O)—, (vinyl)(CR2)nC(O)—, or (vinyl)ArC(O)—;
- R represents independently for each occurrence H or alkyl;
- Z represents (CR2)n, (CR2)nJ(CR2)m, or (CR2)nAr(CR2)m;
- Ar represents independently for each occurrence aryl or heteroaryl;
- J represents independently for each occurrence O, S, NR, cycloalkyl, heterocyclyl, (CH2CH2O)n, or (CH2CH2N(R))n;
- G represents (CR(4−t)), aryl, or heteroaryl;
- n represents independently for each occurrence an integer in the range 1-10;
- and
- t represents 3 or 4.
10 more elements
A polymer, comprising a monomer represented by 1:
- 11
- wherein
- X represents independently for each occurrence O or S;
- L represents independently for each occurrence —NH—O—Q, or —O—NH—Q;
- Q represents independently for each occurrence acryloyl, 2-alkylacryloyl, 3-alkylacryloyl, 2,3-dialkylacryloyl, 3,3-dialkylacryloyl, 2,3,3-trialkylacryloyl, acryloylO(CR2)nC(O)—, 2-alkylacryloylO(CR2)nC(O)—, 3-alkylacryloylO(CR2)nC(O)—, 2,3-dialkylacryloylO(CR2)nC(O)—, 3,3-dialkylacryloylO(CR2)nC(O)—, 2,3,3-trialkylacryloylO(CR2)nC(O)—, (diene)C(O)—, (vinyl)(CR2)nC(O)—, or (vinyl)ArC(O)—;
- R represents independently for each occurrence H or alkyl;
- Z represents (CR2)n, (CR2)nJ(CR2)m, or (CR2)nAr(CR2)m;
- Ar represents independently for each occurrence aryl or heteroaryl;
- J represents independently for each occurrence O, S, NR, cycloalkyl, heterocyclyl, (CH2CH2O)n, or (CH2CH2N(R))n;
- n represents independently for each occurrence an integer in the range 1-10;
- and
- m represents independently for each occurrence an integer in the range 0-10.
9 more elements
A polymer, comprising a monomer represented by 2:
- 12
- wherein
- X represents independently for each occurrence O or S;
- M represents independently for each occurrence —NH—O—Q, or —O—NH—Q;
- Q represents independently for each occurrence acryloyl, 2-alkylacryloyl, 3-alkylacryloyl, 2,3-dialkylacryloyl, 3,3-dialkylacryloyl, 2,3,3-trialkylacryloyl, acryloylO(CR2)nC(O)—, 2-alkylacryloylO(CR2)nC(O)—, 3-alkylacryloylO(CR2)nC(O)—, 2,3-dialkylacryloylO(CR2)nC(O)—, 3,3-dialkylacryloylO(CR2)nC(O)—, 2,3,3-trialkylacryloylO(CR2)nC(O)—, (diene)C(O)—, (vinyl)(CR2)nC(O)—, or (vinyl)ArC(O)—;
- R represents independently for each occurrence H or alkyl;
- Z represents (CR2)n, (CR2)nJ(CR2)m, or (CR2)n, Ar(CR2)m;
- Ar represents independently for each occurrence aryl or heteroaryl;
- J represents independently for each occurrence O, S, NR, cycloalkyl, heterocyclyl, (CH2CH2O)n, or (CH2CH2N(R))n;
- G represents (CR(4−t)), aryl, or heteroaryl;
- n represents independently for each occurrence an integer in the range 1-10;
- and
- t represents 3 or 4.
10 more elements
A method of preparing a compound represented by 1:
- 13
- wherein
- X represents independently for each occurrence O or S;
- L represents independently for each occurrence —NH—O—Q, or —O—NH—Q;
- Q represents independently for each occurrence acryloyl, 2-alkylacryloyl, 3-alkylacryloyl, 2,3-dialkylacryloyl, 3,3-dialkylacryloyl, 2,3,3-trialkylacryloyl, acryloylO(CR2)nC(O)—, 2-alkylacryloylO(CR2)nC(O)—, 3-alkylacryloylO(CR2)nC(O)—, 2,3-dialkylacryloylO(CR2)nC(O)—, 3,3-dialkylacryloylO(CR2)nC(O)—, 2,3,3-trialkylacryloylO(CR2)nC(O)—, (diene)C(O)—, (vinyl)(CR2)nC(O)—, or (vinyl)ArC(O)—;
- R represents independently for each occurrence H or alkyl;
- Z represents (CR2)n, (CR2)nJ(CR2)m, or (CR2)nAr(CR2)m;
- Ar represents independently for each occurrence aryl or heteroaryl;
- J represents independently for each occurrence O, S, NR, cycloalkyl, heterocyclyl, (CH2CH2O)n, or (CH2CH2N(R))n;
- n represents independently for each occurrence an integer in the range 1-10;
- and
- m represents independently for each occurrence an integer in the range 0-10;
- comprising:
- a) reacting at least 2 molar equivalents of a hydroxylamine with a diester or 2 molar equivalents of an acrylic ester, thereby forming a dihydroxamic acid or 2 moles of a hydroxamic acrylamide, respectively;
- and
- b) reacting said dihydroxamic acid with at least 2 molar equivalents of an acryloyl halide;
- or reacting said 2 moles of a hydroxamic acrylamide with one molar equivalent of an adipoyl chloride.
14 more elements
A method of preparing a compound represented by 2:
- 14
- wherein
- X represents independently for each occurrence O or S;
- M represents independently for each occurrence —NH—O—Q, or —O—NH—Q;
- Q represents independently for each occurrence acryloyl, 2-alkylacryloyl, 3-alkylacryloyl, 2,3-dialkylacryloyl, 3,3-dialkylacryloyl, 2,3,3-trialkylacryloyl, acryloylO(CR2)nC(O)—, 2-alkylacryloylO(CR2)nC(O)—, 3-alkylacryloylO(CR2)nC(O)—, 2,3-dialkylacryloylO(CR2)nC(O)—, 3,3-dialkylacryloylO(CR2)nC(O)—, 2,3,3-trialkylacryloylO(CR2)nC(O)—, (diene)C(O)—, (vinyl)(CR2)nC(O)—, or (vinyl)ArC(O)—;
- R represents independently for each occurrence H or alkyl;
- Z represents (CR2)n, (CR2)nJ(CR2)m, or (CR2)nAr(CR2)m;
- Ar represents independently for each occurrence aryl or heteroaryl;
- J represents independently for each occurrence O, S, NR, cycloalkyl, heterocyclyl, (CH2CH2O)n, or (CH2CH2N(R))n;
- G represents (CR4−t)), aryl, or heteroaryl;
- n represents independently for each occurrence an integer in the range 1-10;
- and
- t represents 3 or 4;
- comprising:
- a) reacting at least 3 molar equivalents of a hydroxylamine with either a triester, a tetraester, or with at least 3 equivalents of an acrylic ester, thereby forming a trihydroxamic acid, a tetrahydroxamic acid, or at least 3 moles of a hydroxamic acrylamide;
- and
- b) reacting said trihydroxamic or tetrahydroxamic acid with at least 3 molar equivalents of an acryloyl halide, or reacting said at least 3 moles of a hydroxamic acrylamide with one molar equivalent of a triacyl halide.
14 more elements
A method of preparing a polymer comprising a monomer represented by 1:
- 15
- wherein
- X represents independently for each occurrence O or S;
- L represents independently for each occurrence —NH—O—Q, or —O—NH—Q;
- Q represents independently for each occurrence acryloyl, 2-alkylacryloyl, 3-alkylacryloyl, 2,3-dialkylacryloyl, 3,3-dialkylacryloyl, 2,3,3-trialkylacryloyl, acryloylO(CR2)nC(O)—, 2-alkylacryloylO(CR2)nC(O)—, 3-alkylacryloylO(CR2)nC(O)—, 2,3-dialkylacryloylO(CR2)nC(O)—, 3,3-dialkylacryloylO(CR2)nC(O)—, 2,3,3-trialkylacryloylO(CR2)nC(O)—, (diene)C(O)—, (vinyl)(CR2)nC(O)—, or (vinyl)ArC(O)—;
- R represents independently for each occurrence H or alkyl;
- Z represents (CR2)n, (CR2)nJ(CR2)m, or (CR2)nAr(CR2)m;
- Ar represents independently for each occurrence aryl or heteroaryl;
- J represents independently for each occurrence O, S, NR, cycloalkyl, heterocyclyl, (CH2CH2O)n, or (CH2CH2N(R))n;
- n represents independently for each occurrence an integer in the range 1-10;
- and
- m represents independently for each occurrence an integer in the range 0-10;
- comprsing:
- a) reacting a monomer represented by 1 with a second monomer in the presence of an initiator.
11 more elements
A method of preparing a polymer comprising a monomer represented by 2:
- 16
- wherein
- X represents independently for each occurrence O or S;
- M represents independently for each occurrence —NH—O—Q, or —O—NH—Q;
- Q represents independently for each occurrence acryloyl, 2-alkylacryloyl, 3-alkylacryloyl, 2,3-dialkylacryloyl, 3,3-dialkylacryloyl, 2,3,3-trialkylacryloyl, acryloylO(CR2)nC(O)—, 2-alkylacryloylO(CR2)nC(O)—, 3-alkylacryloylO(CR2)nC(O)—, 2,3-dialkylacryloylO(CR2)nC(O)—, 3,3-dialkylacryloylO(CR2)n, C(O)—, 2,3,3-trialkylacryloylO(CR2)nC(O)—, (diene)C(O)—, (vinyl)(CR2)nC(O)—, or (vinyl)ArC(O)—;
- R represents independently for each occurrence H or alkyl;
- Z represents (CR2)n, (CR2)nJ(CR2)m, or (CR2)nAr(CR2)m;
- Ar represents independently for each occurrence aryl or heteroaryl;
- J represents independently for each occurrence O, S, NR, cycloalkyl, heterocyclyl, (CH2CH2O)n, or (CH2CH2N(R))n;
- G represents (CR4−t)), aryl, or heteroaryl;
- n represents independently for each occurrence an integer in the range 1-10;
- and
- t represents 3 or 4;
- comprising:
- a) reacting a monomer represented by 2 with a second monomer in the presence of an initiator.
12 more elements
A method of preparing a crosslinked gel, comprising a hydrophobic polymer, and a crosslinker represented by 1:
- 17
- wherein
- X represents independently for each occurrence O or S;
- L represents independently for each occurrence —NH—O—Q, or —O—NH—Q;
- Q represents independently for each occurrence acryloyl, 2-alkylacryloyl, 3-alkylacryloyl, 2,3-dialkylacryloyl, 3,3-dialkylacryloyl, 2,3,3-trialkylacryloyl, acryloylO(CR2)nC(O)—, 2-alkylacryloylO(CR2)nC(O)—, 3-alkylacryloylO(CR2)nC(O)—, 2,3-dialkylacryloylO(CR2)nC(O)—, 3,3-dialkylacryloylO(CR2)nC(O)—, 2,3,3-trialkylacryloylO(CR2)nC(O)—, (diene)C(O)—, (vinyl)(CR2)nC(O)—, or (vinyl)ArC(O)—;
- R represents independently for each occurrence H or alkyl;
- Z represents (CR2)n, (CR2)nJ(CR2)m, or (CR2)nAr(CR2)m;
- Ar represents independently for each occurrence aryl or heteroaryl;
- J represents independently for each occurrence O, S, NR, cycloalkyl, heterocyclyl, (CH2CH2O)n, or (CH2CH2N(R))n;
- n represents independently for each occurrence an integer in the range 1-10;
- and
- m represents independently for each occurrence an integer in the range 0-10;
- comprising:
- a) reacting a monomer represented by 1 with a hydrophobic monomer in the presence of an initiator.
11 more elements
A method of preparing a crosslinked gel comprising a hydrophobic polymer and a crosslinker represented by 2:
- 18
- wherein
- X represents independently for each occurrence O or S;
- M represents independently for each occurrence —NH—O—Q, or —O—NH—Q;
- Q represents independently for each occurrence acryloyl, 2-alkylacryloyl, 3-alkylacryloyl, 2,3-dialkylacryloyl, 3,3-dialkylacryloyl, 2,3,3-trialkylacryloyl, acryloylO(CR2)nC(O)—, 2-alkylacryloylO(CR2)nC(O)—, 3-alkylacryloylO(CR2)nC(O)—, 2,3-dialkylacryloylO(CR2)nC(O)—, 3,3-dialkylacryloylO(CR2)nC(O)—, 2,3,3-trialkylacryloylO(CR2)nC(O)—, (diene)C(O)—, (vinyl)(CR2)nC(O)—, or (vinyl)ArC(O)—;
- R represents independently for each occurrence H or alkyl;
- Z represents (CR2)n, (CR2)nJ(CR2)m, or (CR2)nAr(CR2)m;
- Ar represents independently for each occurrence aryl or heteroaryl;
- J represents independently for each occurrence O, S, NR, cycloalkyl, heterocyclyl, (CH2CH2O)n, or (CH2CH2N(R))n;
- G represents (CR(4−t)), aryl, or heteroaryl;
- n represents independently for each occurrence an integer in the range 1-10;
- and
- t represents 3 or 4;
- comprising:
- a) reacting a monomer represented by 2 with a hydrophobic monomer in the presence of an initiator.
12 more elements
A method of preparing a crosslinked hydrogel, comprising a hydrophilic polymer and a crosslinker represented by 1:
- 19
- wherein
- X represents independently for each occurrence O or S;
- L represents independently for each occurrence —NH—O—Q, or —O—NH—Q;
- Q represents independently for each occurrence acryloyl, 2-alkylacryloyl, 3-alkylacryloyl, 2,3-dialkylacryloyl, 3,3-dialkylacryloyl, 2,3,3-trialkylacryloyl, acryloylO(CR2)nC(O)—, 2-alkylacryloylO(CR2)nC(O)—, 3-alkylacryloylO(CR2)nC(O)—, 2,3-dialkylacryloylO(CR2)nC(O)—, 3,3-dialkylacryloylO(CR2)nC(O)—, 2,3,3-trialkylacryloylO(CR2)nC(O)—, (diene)C(O)—, (vinyl)(CR2)nC(O)—, or (vinyl)ArC(O)—;
- R represents independently for each occurrence H or alkyl;
- Z represents (CR2)n, (CR2)nJ(CR2)m, or (CR2)nAr(CR2)m;
- Ar represents independently for each occurrence aryl or heteroaryl;
- J represents independently for each occurrence O, S, NR, cycloalkyl, heterocyclyl, (CH2CH2O)n, or (CH2CH2N(R))n;
- n represents independently for each occurrence an integer in the range 1-10;
- and
- m represents independently for each occurrence an integer in the range 0-10;
- comprising:
- a) reacting a monomer represented by 1 with a hydrophilic monomer in the presence of an initiator.
11 more elements
A method of preparing a crosslinked hydrogel, comprising a hydrophilic polymer and a crosslinker represented by 2:
- 20
- wherein
- X represents independently for each occurrence O or S;
- M represents independently for each occurrence —NH—O—Q, or —O—NH—Q;
- Q represents independently for each occurrence acryloyl, 2-alkylacryloyl, 3-alkylacryloyl, 2,3-dialkylacryloyl, 3,3-dialkylacryloyl, 2,3,3-trialkylacryloyl, acryloylO(CR2)nC(O)—, 2-alkylacryloylO(CR2)nC(O)—, 3-alkylacryloylO(CR2)nC(O)—, 2,3-dialkylacryloylO(CR2)nC(O)—, 3,3-dialkylacryloylO(CR2)nC(O)—, 2,3,3-trialkylacryloylO(CR2)nC(O)—, (diene)C(O)—, (vinyl)(CR2)nC(O)—, or (vinyl)ArC(O)—;
- R represents independently for each occurrence H or alkyl;
- Z represents (CR2)n(CR2)nJ(CR2)m, or (CR2)nAr(CR2)m;
- Ar represents independently for each occurrence aryl or heteroaryl;
- J represents independently for each occurrence O, S, NR, cycloalkyl, heterocyclyl, (CH2CH2O)n, or (CH2CH2N(R))n;
- G represents (CR(4−t)), aryl, or heteroaryl;
- n represents independently for each occurrence an integer in the range 1-10;
- and
- t represents 3 or 4;
- comprising:
- a) reacting a monomer represented by 1 with a hydrophilic monomer in the presence of an initiator.
12 more elements
Dependencies are inferred from the claim text.