| A major problem in ocular therapeutics is the attainment of an optimal drug concentration at the site of action. Because of the specific structure of the eye, the treatment of ocular diseases is often a drug delivery problem. This dissertation represents a systematic study of molecular structure-property-performance relationship of chemically modified starch-based ocular drug delivery systems.;The specific polymers investigated were Dihydroxyl Starch (DHS) and DHS Esters including acetates and propionates. The DHS was prepared through a two-step method. Starch was first oxidized by NaIO4 to form Dialdehyde Starch (DAS) and DAS was reduced to form the corresponding hydroxyls with NaBH4. After this modification, polymers with increased solubility in water were obtained. By varying the ratio between starch and oxidant in the first step, the content of Dialdehyde groups was controlled; thereafter 20DHS, 60DHS, and 100DHS were prepared. Among them, 100DHS was further esterified to obtain DHS acetates (DHSA) and DHS Propionates (DHSP). During esterification, the degree of substitution (DS) of DHSA and DHSP was controlled and in this work DHSA and DHSP with DS equal to 0.1 and 0.4 were prepared.;The specific aspects investigated in this research were surface property, mucoadhesion, rheological behavior, controlled drug release, and their effects on ocular drug delivery systems' performance in animal tests. (1) Surface property. Previous work was focused on lowering surface tension (ST) to help spreading. In this work, we took the Weipeng Liu ST's effect on both spreading and adhesion into account and suggested an ideal ST should be moderately lower than that of the cornea. (2) Mucoadhesion. A strong adhesion with mucus in the eye helps a drug delivery system to achieve a prolonged retention time and form a strengthened network that sustains the release of drug. In this work, the mucoadhesion of synthesized polymers was studied through a typical rheological approach. (3) Rheological properties. Flow properties were thoroughly studied by other researchers. However, it is rare for ophthalmic solutions to undergo only steady state shear rate in situ. Thus, it was necessary to investigate their viscoelastic properties as well, which were omitted by previous researchers. Therefore, in this work both steady shear and dynamic behaviors of synthesized polymers were studied to investigate their effects on ocular drug delivery systems. (4) Controlled drug release. The drug release profile is important for achievement of sustained drug release and they were studied with a standard USP dissolution method in this work. None of the four concepts we investigated is new and some of them have been introduced to the study of ocular drug delivery systems, however, no work has been done to study their effects systematically. As the first work of systematic study of biopolymer-based ocular drug delivery systems, we studied how these properties were affected by molecular structures, how they should be designed by engineering chemical structures accordingly, and how they affected the performance of ocular drug delivery systems, both theoretically and experimentally. The work described in this dissertation helps fill the knowledge gaps, which exist for the design of effective ocular drug delivery systems with modified starch. |
