Composite hydrogel drug delivery systems
Compositions and methods are provided to control the release of relatively low molecular weight therapeutic species through hydrogels by first dispersing or dissolving such therapeutic species within relatively hydrophobic rate modifying agents to form a mixture. The mixture is formed into microparticles that are dispersed within bioabsorbable hydrogels, so as to release the water soluble therapeutic agents in a controlled fashion. Methods of using the compositions of the present invention in therapeutic systems are also provided.
1. A method of making a gel, the method comprising reacting one or more hydrophilic, synthetic macromers through covalent reactions to form a continuous, bioabsorbable, synthetic, covalently crosslinked hydrogel matrix in the presence of a hydrophobic material and a therapeutic agent, with a plurality of non-gaseous hydrophobic domains being formed from the hydrophobic material and dispersed in the continuous hydrogel matrix, with the therapeutic agent being associated with the hydrophobic domains.
2. The method of claim 1 , wherein the hydrophobic material comprises a release rate modifying agent.
3. The method of claim 2 , wherein the release rate modification agent is selected from the group consisting of capric acid, undecanoic, lauric acid, heneicosanoic, behenic acid, behenic acid ethyl ester, behenic acid methyl ester, tricosanoic acid, methyl ester tridecanoic acid, pentadecanoic acid, heptadecanoic acid, heptadecanoic, ethyl ester heptadecanoic, methyl ester nonadecanoic acid, myristic acid, myristic acid benzyl ester, myristic acid methyl ester, palmitic acid, palmitic acid benzyl ester, palmitic acid butyl ester, palmitic acid hexadecyl, palmitic acid methyl ester, palmitic acid myricyl ester, palmitic acid propyl ester, stearic acid, stearic acid benzyl ester, stearic acid butyl ester, stearic acid isobutyl ester, stearic acid cyclohexyl ester, stearic acid ethyl ester, stearic acid hexadecyl ester, stearic acid methyl ester, stearic acid 3-oxo ethyl ester, stearic acid 2-hydroxyethyl ester, stearic acid 6-oxo ethyl ester, stearic acid 10-oxo ethyl ester, stearic acid 12-oxy ethyl ester, stearic acid pentyl ester, stearic acid isopentyl ester, stearic acid phenyl ester, stearic acid isopropyl ester, and stearic acid tetrahydrofufuryl ester.
4. The method of claim 2 , wherein the release rate modification agent is selected from the group consisting of fatty acids and triglycerides.
5. The method of claim 1 wherein the therapeutic agent has a molecular weight of less than 100,000.
6. The method of claim 2 wherein the therapeutic agent has a molecular weight less than 20,000.
7. The method of claim 1 wherein the therapeutic agent has a water solubility of greater than 0.01 mg/mL.
8. The method of claim 1 wherein the therapeutic agent is hydrophobic.
9. The method of claim 1 wherein the therapeutic agent is a member of the group consisting of a growth factor, a cytokine, an antimitotic drug, a radiation source, and an antineoplastic agent.
10. The method of claim 1 wherein the therapeutic agent is a member of the group consisting of antiallergenic agents, cardiovascular agents, agents affecting respiratory organs, hormones, agents affecting metabolism, and antimicrobial agents.
11. The method of claim 1 wherein the therapeutic agent is a member of the group consisting of chemotherapeutic agents, local anesthetics, antihistaminic, antiphlogistics, astringents, vitamins, antifungal agents, peripheral nervous anesthetics, vasodilators, anti-inflammatory agents, and immunosuppressants.
12. The method of claim 1 , wherein the hydrophobic domains comprise microdroplets.
13. The method of claim 1 , wherein the hydrophobic domains comprise microparticles.
14. The method of claim 1 , wherein the hydrophobic domains comprise a compound having a melting point less than 65° C.
15. The method of claim 1 wherein the hydrophobic domains comprise surfactants.
16. The method of claim 1 wherein the hydrophobic domains are formed in situ as the hydrogel is formed from the macromers.
17. The method of claim 16 wherein the hydrophobic domains comprise micelles.
18. The method of claim 1 wherein the hydrophobic domains comprise the therapeutic agents.
19. The method of claim 1 wherein the hydrophobic domains have a size of from about 1 to about 10 microns.
20. The method of claim 1 further comprising forming the hydrogel matrix in-situ.
21. The method of claim 1 wherein one or more of the macromers comprise poly(ethylene glycol).
22. The method of claim 1 wherein one or more of the macromers further comprise a biodegradable portion.
23. The method of claim 1 wherein one or more of the macromers further comprise free functional groups that are free after the macromers are covalently crosslinked to form the hydrogel matrix.
24. The method of claim 1 wherein one or more of the macromers, before bonding, each comprise at least two electrophilic functional groups or at least two nucleophilic groups, and further comprising reacting the electrophilic functional groups with the nucleophilic groups in a covalent reaction to form the hydrogel matrix.
25. The method of claim 1 , further comprising a binding ligand disposed within the hydrogel matrix.