Abstract
Glaucoma, an ocular neuropathy, is characterized by progressive degeneration of retinal neurons which can ultimately lead to blindness if left untreated. The current therapies for glaucoma provide only symptomatic management by reducing intraocular pressure (IOP), a prominent risk factor for glaucoma. Since glaucoma is reported even in normotensive patients, the ideal glaucoma medication should lower IOP and confer neuroprotection to retinal neurons. Hydrogen sulfide (H2S) has been reported to reduce IOP and elicit retinal neuroprotection in mammalian ocular tissues. However, its ocular delivery is a challenge due to its gaseous nature and narrow therapeutic index. Therefore, this study developed a novel lipid-based delivery system for Diallyl Trisulfide (DATS), a H2S donor, to provide sustained release of H2S up to 8-9 hours upon topical application on the cornea. A high-performance liquid chromatography (HPLC) method was developed and validated as per USP guidelines for the quantification of DATS. The solid lipid nanoparticles (SLNs) loaded with DATS were prepared by hot emulsification process and solvent evaporation method. DATS-SLNs characterized for particle size, zeta potential, drug loading, and encapsulation efficiency. DATS-SLNs were incorporated in PEG ointment bases, characterized for ease of corneal spreadability by rheometer, and release profile for DATS as well as H2S. A well resolved peak of DATS was detected at 2.8 mins run time. The method showed good linearity (R2 > 0.999) over the concentration range of 3.12-100 ug/mL. The interday and intraday standard deviations were < 10% whereas the accuracy was > 90%. Glyceryl monostearate was selected for preparing SLNs whose particle size, polydispersity index, zeta potential, drug loading, and encapsulation efficiency were 124 ± 2.67 nm, 0.189 ± 0.005, - 23.57 ± 3.22 mV, 2.16 ± 0.26%, and 79 ± 3.6 %, respectively. PEG ointment base incorporated with DATS-SLNs showed a sustained release of DATS up to 9 hours releasing 67.89 ± 2.04% of the initial loaded amount with corresponding H2S concentration of 112 ± 2.16 µM. Rheological data indicated the formulation exhibited a shear thinning flow and had a viscosity of 4,445 ± 123 Pa.s at 34℃ suggesting the ease in flowability of the delivery system developed. Future studies should focus on increasing drug load and evaluating its corneal permeability. Successful completion of this study will provide a better therapeutic strategy for glaucoma, a disease that affects 79.6 million patients worldwide.