(685e) Dispersion of Drug Particles and Emulsion Drops in Oleogels for Ophthalmic Drug Delivery

Authors: 
Macoon, R., University of Florida
Chauhan, A., Colorado School of Mines
Ophthalmic drugs are currently delivered to the back of the eye for treating retinal diseases via injections through the eyeball. The blood-retina barrier and clearance mechanisms which eliminate drug from tears and ocular tissue make systemic or topical delivery techniques ineffective. Consequently, intravitreal injections into the eye are the only viable option even though repeated monthly injections increase risk for infections and retinal detachment. A reduction in the frequency of injections through extended release drugs could have significant benefits. We have developed a novel approach to inject a device into the eye through an intravitreal injection similar to what is currently used. The device is designed to release drugs for an extended period of time lasting about six months, which would significantly reduce the frequency of injections from monthly to bi-annually reducing the potential for retinal damage as well as costs significantly.

Our device comprises of an oleogel formulation loaded with drugs above the solubility limit resulting in a dispersion of the drug particles in the gelled oil. As an example, a steroid dexamethasone is loaded at various concentrations ranging from the solubility limit of 4% to 40% (w/w). We specifically focus on soybean oil gelled via a number of different gelators including ethyl cellulose, lechtin, and phytosterols at about 10% (w/w) loading. The gelled oleogel retains its shape after it is expunged from the .413mm diameter syringe into a buffer for in vitro studies or into the vitreous humor in preliminary ex vivo studies. The release from the oleogels follows the Higuchi’s model for release from an ointment containing dispersed particulate drugs. Specifically, the soluble drug diffuses out into the surrounding liquid (buffer or vitreous humor) resulting in dissolution of the particles. The boundary layer near the surface from which the particles are dissolved grows inwards towards the center of the device with time. The dissolution of the particles however leaves voids in the oleogels that force the drug to diffuse out in a tortuous path resulting in a decrease in diffusivity with increasing particle loading. Growth of the boundary layer in which particles are replaced with voids are followed via imaging to determine the dynamics for comparison with model. The model incorporating the diffusion and dissolution after accounting for the tortuosity fits the data well for in vitro release of dexamethasone from the cylindrical oleogel. The release duration from the device depends on the particle loading reaching about six months for 40% loading of dexamethasone. Effect of gelator concentration and loading is also explored on the drug release dynamics and oleogel rheology. An alternative approach is developed for the hydrophilic drugs by dissolving the drugs in water-in-oil emulsions, followed by gelling the oil phase. The low solubility of the hydrophilic drugs in the oil phase results in a long release duration of a few months, though the total amount of drug loading is limited to about 1% w/w. This approach allows dual delivery of multiple hydrophobic drugs or combination of hydrophobic and hydrophilic drugs. The pressure required to inject the formulation into the eyes is high due to the high viscosity and so a spring loaded autoinjector is developed via 3D printing to precisely inject the oleogel formulations into the eyes.

The proposed approach of creating oleogel formulations to inject devices into the vitreous is a simple and scalable approach to inject a device into the eye that can release both hydrophobic and hydrophilic drugs for about 6-months resulting in significant reduction in the frequency of the intravitreal injections. While in vitro and preliminary ex vivo results in cadaver eyes are promising, in vivo animal studies are necessary to establish safety and efficacy of this approach.