Conjugate addition reactions for the controlled delivery of pharmaceutically active compounds
AssigneesEidgenossische Technische Hochschule Zurich, Univesitat Zurich
InventorsJeffrey A. Hubbell, Donald Elbert, Ronald Schoenmakers
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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.
Claims38
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.
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.
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° C.
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.
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.
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.
Dependencies are inferred from the claim text.