An injectable ocular biostimuli-degradable, spacer-based, polymer drug conjugate for targeted treatment of posterior segment inflammation

Abstract

The posterior segment of the eye presents a daunting task in relation to effective administration of therapeutic measures, due in part to its relative inaccessibility anteriorly and in part due to its protective blood-ocular barriers which do not allow for a significant amount of drug to be passed through. Posterior segment inflammatory disorders have a range of causes but the potential outcome for most of these disorders, if left untreated, is permanent blindness. Thus, the advantages of intravitreal polymeric drug delivery systems which release drug directly into the posterior segment for varying time periods are numerous. Current market formulations as well as ongoing research related to injectable, intravitreal injectable devices for posterior segment applications were critically reviewed. A potential way forward was researched: An injectable ocular biostimuli-degradable, spacer-based polymer drug conjugate for targeted treatment of posterior segment inflammation. This dissertation details the outcomes of this researchDesign of stimulus-responsive intravitreal drug delivery technologies are one step further in the right direction as these systems would potentially translate to more controlled drug release mechanisms. Several intravitreal devices have been formulated, however, there are certain drawbacks present such as the lack of biodegradability and the need for relatively complex surgical procedures. This research was focused on the pharmaceutical, rather than the therapeutic, perspective of the development of a biostimuli-responsive, biodegradable and injectable intravitreal drug delivery system for administration in inflammatory posterior segment disorders. The Schiff-base based formulation was synthesized, characterized and tested in vivo in a New Zealand White Albino rabbit eye model and evaluated for toxicity and enhanced drug release. The “intelligent” system was designed using a biocompatible methoxy polyethylene glycol polymer with a hydrazide cap; which served as a linker; and dexamethasone, an established anti-inflammatory drug. The product would form a pH-labile hydrazone bond, a type of Schiff base. In vitro release studies showed a slight enhancement of drug release in low pH conditions. The system was then moved ahead into the in vivo stage of testing. Post-in vitro investigations, the system was tested in vivo in a study group of 33 New Zealand White Albino rabbits. The system was tested in physiological inflammatory conditions and normal noninflammatory physiological conditions in a 10-day study and compared to negative and positive control groups which served as a reference. Results showed an enhanced release of drug during inflammatory (pH~ 5.5) conditions in the posterior segment which also translated to an increased anterior chamber concentration (Inflamed = 0.691μg/mL vs non-inflamed 0.0634μg/mL) and histomorphological analysis determined the formulation to be non-toxic to the ocular environment. Thus, this formulated system has potential to be utilized in posterior segment inflammatory diseases.