Conjugate addition reactions for the controlled delivery of pharmaceutically active compounds
First Claim
Patent Images
1. A biomaterial formed from the cross-linking of two or more precursor components, wherein at least one of said precursor components has the formula:
-
D—
Y—
C(O)—
(CH2)n—
S—
(CH2)2—
CO—
X—
P,
D—
Y—
C(O)—
(CH2)n—
NH—
(CH2)2—
CO—
X—
P,
D—
Y—
C(O)—
(CH2)n—
NH—
U—
P,
D—
Y—
(O)—
CH2n—
S—
U—
P,
D—
Y—
C(O)—
(CH2)2—
S—
L—
S—
CH2—
CH2—
CO—
X—
P,
D—
Y—
C(O)—
CH2)2—
S—
L—
S—
U—
P,
D—
Y—
C(O)—
CH2)2—
NH—
L—
S—
CH2—
CH2—
CO—
X—
P,
D—
Y—
C(O)—
(CH2)2—
NH—
L—
S—
U—
P,
D—
Y—
C(O)—
(CH2)2—
S—
L—
NH—
CH2—
CH2—
CO—
X—
P,
D—
Y—
C(O)—
CH2)2—
S—
L—
NH—
U—
P,
D—
Y—
C(O)—
(CH2)2—
NH—
L—
NH—
CH2—
CH2—
CO—
X—
P, or
D—
Y—
C(O)—
(CH2)2—
NH—
L—
NH—
U—
P, wherein D is a pharmaceutically active moiety;
n is 1 or 2;
is O, NH, or N;
L is a linear or branched linker;
X is O or N;
P is a water-soluble polymer comprising one or more conjugated unsaturated groups or a water-swellable polymer comprising one or more conjugated unsaturated groups; and
L is the product of the addition of a nucleophilc to an electrophilic group that is attached to said polymer.
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Abstract
The invention features polymeric biomaterials formed by nucleophilic addition reactions to conjugated unsaturated groups. These biomaterials may be used for medical treatments.
144 Citations
38 Claims
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1. A biomaterial formed from the cross-linking of two or more precursor components, wherein at least one of said precursor components has the formula:
-
D—
Y—
C(O)—
(CH2)n—
S—
(CH2)2—
CO—
X—
P,
D—
Y—
C(O)—
(CH2)n—
NH—
(CH2)2—
CO—
X—
P,
D—
Y—
C(O)—
(CH2)n—
NH—
U—
P,
D—
Y—
(O)—
CH2n—
S—
U—
P,
D—
Y—
C(O)—
(CH2)2—
S—
L—
S—
CH2—
CH2—
CO—
X—
P,
D—
Y—
C(O)—
CH2)2—
S—
L—
S—
U—
P,
D—
Y—
C(O)—
CH2)2—
NH—
L—
S—
CH2—
CH2—
CO—
X—
P,
D—
Y—
C(O)—
(CH2)2—
NH—
L—
S—
U—
P,
D—
Y—
C(O)—
(CH2)2—
S—
L—
NH—
CH2—
CH2—
CO—
X—
P,
D—
Y—
C(O)—
CH2)2—
S—
L—
NH—
U—
P,
D—
Y—
C(O)—
(CH2)2—
NH—
L—
NH—
CH2—
CH2—
CO—
X—
P, or
D—
Y—
C(O)—
(CH2)2—
NH—
L—
NH—
U—
P,wherein D is a pharmaceutically active moiety;
n is 1 or 2;
is O, NH, or N;
L is a linear or branched linker;
X is O or N;
P is a water-soluble polymer comprising one or more conjugated unsaturated groups or a water-swellable polymer comprising one or more conjugated unsaturated groups; and
L is the product of the addition of a nucleophilc to an electrophilic group that is attached to said polymer.- View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 13, 14, 15, 16, 17)
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9. A method of forming a biomaterial, said method comprising the step of:
-
(a) attaching a pharmaceutically active compound to a linker molecule or incorporating a nucleophilic amine or thiol into a pharmaceutically active compound, (b) removing any thiol—
or amine-protecting groups in said linker,(c) coupling a thiol, amine, or alkene group in said linker or incorporated into said pharmaceutically active compound to a water-soluble polymer or a water-swellable polymer comprising two or more conjugated unsaturated groups by a conjugated addition reaction to form a precursor component, and (d) cross-linking the uncoupled conjugated unsaturated groups in one or more of said precursor components. - View Dependent Claims (10, 18, 19, 20, 21, 22, 23)
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- 11. A method of treating or preventing a disease, disorder, or infection in a mammal by administering to said mammal a biomaterial comprising a pharmaceutically active moiety, wherein said biomaterial has an ester or amide bond onto said pharmaceutically active moiety, said bond having a half-life of between 1 day and 1 year in an aqueous solution at pH 7.4 and 37°
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29. A pharmaceutically active compound of the formula D—
- O2C—
(CH2)n—
SH or D—
N(O)C—
(CH2)n—
SH, wherein n is 1 or 2 and D is pharmaceutically active moiety. - View Dependent Claims (30)
- O2C—
-
31. A method of forming a biomaterial, said method of comprising the step of:
-
(a) attaching a pharmaceutically active compound to a linker molecule or incorporating a nucleophilic amine or thiol into a pharmaceutically active compound;
(b) coupling the thiol or amine in said linker or incorporated into said pharmaceutically active compound to a polymer comprising two or more conjugated unsaturated groups by a conjugated addition reaction to form a precursor component; and
(c) cross-linking the uncoupled conjugated unsaturated groups in one or more said precursor components. - View Dependent Claims (32)
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33. A method of forming a biomaterial, said method comprising the steps of:
-
(a) attaching a pharmaceutically active compound to a linker molecule or incorporating a nucleophilic amine or thiol into a pharmaceutically active compound;
(b) coupling the thiol or amine in said linker or incorporated into said pharmaceutically active compound to at least a first polymer comprising two or more conjugated unsaturated groups by a conjugate addition reaction to form a precursor component;
(c) providing at least a second precursor comprising nucleophilic groups; and
(d) cross-linking the conjugated unsaturated groups of the precursor of step b) to the nucleophilic groups of the precursor of step c) by a conjugated addition reaction. - View Dependent Claims (34, 35)
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Specification