Document Type

Dissertation - University Access Only

Award Date

2008

Degree Name

Doctor of Philosophy (PhD)

Department / School

Chemistry

Abstract

Topically applied ocular drug therapy is severally limited by the bioavailability of the drug to the anterior or posterior of the eye. Improving the delivery of three currently marketed ocular formulations utilizing various modified chitosan matrices has been studied. The drugs are remarkably different in chemical properties and structure; the non-steroidal anti-inflammatory is water soluble (ketorolac tromethamine - KT), the steroidal anti-inflammatory has no aqueous solubility (prednisolone acetate - PA), and the prostaglandin analog has very limited aqueous solubility (bimatoprost - B). The chitosan matrix was modified to facilitate the solubilization and optimize the delivery of each compound. The KT and PA were delivered by topical application while reducing the drug concentration by 75% and 96.5% to achieve similar aqueous humor concentrations, respectively. The novel delivery of B combines the idea of a bio adhesive matrix along with the prodrug strategy. The drug is covalently tethered onto the matrix; this allows the drug modified matrix to be injected in the subconjunctival tissue where it will reside for up to 6 months. The drug will be released by the proteolytic hydrolysis of the incorporated tether by various enzymes present in eye. The KT was delivered from a chitosan matrix that had been modified by octane sulfonyl chloride; this matrix has shown even greater bioadhesive nature than unmodified chitosan. The drug is combined with the matrix to create a solution which was compared with the marketed formulation for drug delivery in a rabbit model. The chitosan matrix formulation was able to deliver comparable drug concentrations as the marketed formulation while using 75% less drug. The PA was delivered utilizing a chitosan matrix that was modified by cholic acid by acid chloride chemistry. Modification of the matrix with cholic acid creates hydrophobic regions on the chitosan that solubilize the drug. This combination allows for complete solubilization of a hydrophobic drug into a hydrophilic matrix. This matrix was able to deliver comparable aqueous humor concentrations as the marketed formulation while using 96% less drug. The prostamide B was tethered onto the matrix using a succinic anhydride linker. The anhydride was successfully coupled with the drug using the catalyst 4- dimethylatnino pyridine to create the cleavable ester linkage. This complex contains a carboxylic acid and is reacted with the amine on chitosan using an EDC/NHS catalyzed reaction to tether the drug onto the matrix. Mass spec, FTIR, and NMR data supports this successful attachment. Release of the drug is dependent on enzymatic hydrolysis of the linker; the drug linked matrix was incubated with porcine liver esterase in a benchtop model and showed successful release of the parent drug. Theoretical calculations indicate that this drug delivery system could provide sustained release up to 6 months where the marketed formulation is a once daily eye drop. These results show significant improvements compared to current topical ophthalmic drug formulations. By tailoring the modification of the chitosan matrix for each drug, it is possible to enhance the delivery profile.

Library of Congress Subject Headings

Ophthalmic drugs -- Bioavailability

Format

application/pdf

Number of Pages

158

Publisher

South Dakota State University

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