Preparation, Characterization and Toxicity Evaluation of a Novel Sustained Release Delivery System for a Hydrogen Sulfide Donor - GYY 4137

Open angle glaucoma is an ocular neurodegenerative disease that is characterized by elevated intraocular pressure (IOP) and neurodegeneration of retina ganglion cell (RGC) and optic nerve head (ONH), leading to blindness. Although the current therapies are aimed at decreasing IOP, a small proportion of open angle glaucoma patients exhibit normal IOP. Therefore, there is a need for therapeutic approaches that simultaneously reduce the elevated IOP and provide RGC protection. Hydrogen sulfide (H2S) reportedly displays both of these activities in a concentration range of 10-200 μM. It can be toxic at a higher concentration and its donors are unstable in water. Thus, a search for a hydrophobic, sustained release delivery system for H2S donors is warranted in order to harness its therapeutic potential. This study investigated the preparation and characterization of a non-aqueous in situ gelling sustained release delivery system for H2S donors. |A HPLC method was developed for quantification of H2S in aqueous medium. The accuracy (% error < 10%) and precision (% RSD < 5%) of the methods were in compliance with USP guidelines for validation of an assay method. The delivery system was prepared by dissolving 10% w/v poly (lactic-co-glycolic acid) in benzyl benzoate and benzyl alcohol (3:7). The formulation was prepared by dispersing model H2S donor, GYY 4137, into polymer solution. The formulation rapidly formed an in situ gel upon injecting in simulated tear fluid. Compared to aqueous GYY 4137 solution, the formulation sustained and extended the H2S release significantly (p < 0.05). Rheological study of the delivery system indicated a shear-thinning plastic flow with 43.89 ± 3.21 cP viscosity and 1.12 ± 0.15 Pa yield value which corroborates its easy syringeability and injectability. Karl Fisher titrimetry indicated presence of 0.66 ± 0.10 % weight of inherent water which does not hydrolyze GYY 4137. The NMR spectroscopic study indicated presence of 4-methoxyphenylphosphonic acid (a GYY 4137 degradation product) in STF confirming the mechanism of H2S release. Benzyl benzoate and benzyl alcohol solvent blend exhibited toxicity in Y79 retinoblastoma cells which should be substituted with less toxic solvent in a future extension of this study.

Grantor dc:publisher

Creighton University

Year dc:date.issued

2016

Author dc:creator

• Patil, Akash

Advisor dc:contributor.advisor

• Dash, Alekha K.

Statement dc:rights

• Copyright is retained by the Author. A non-exclusive distribution right is granted to Creighton University and to ProQuest following the publishing model selected above.

Language dc:language.iso

en_US

Identifier URI

http://dspace2-test.creighton.edu:8080/xmlui/handle/10504/89419

OAI identifier oai:identifier

oai:cdr.creighton.edu:10504/89419