Ophthalmic delivery of hydrophilic drugs through drug-loaded oleogels

Delivering ophthalmic drugs to the target tissues in eye is challenging due to transport barriers. Rapid tear clearance of the drug instilled as eye drops to treat anterior segment diseases results in a low ocular permeability of 1-5%. The blood-retina barrier and clearance mechanisms which eliminate drug from tears and ocular tissue make systemic or topical delivery techniques ineffective in delivering drugs to the back of the eye. Intravitreal injections into the eye are the only viable option even though repeated monthly injections increase risk for infections and retinal detachment. Controlled and sustained drug delivery could reduce the frequency of injections and lower the associated risk of side effects.

Oleogels comprising of 10% (w/w) ethyl cellulose as the gelator in soybean oil are loaded with metformin HCl and timolol maleate above the solubility limit resulting in a dispersion of the drug particles in the gelled oil. In an alternative approach, hydrophilic drugs are dissolved in the water phase of water-in-oil emulsions, followed by gelling the oil phase. Each formulation was expunged from one mL syringes with attached 22-gauge needles (0.4 mm inner diameter) into buffer to form a cylindrical rod that maintained its shape due to the high viscosity of the oleogel. Dynamic drug concentration was measured in the release medium to determine drug release profiles. Also, the devices were imaged to show the dispersal of drug particles as well as the degradation of the device over time. Effective drug diffusivity for both particle-based and emulsion-based approaches was determined by fitting data to dynamic drug concentration models. The effect of particle size and drug loading are explored.

The release durations for metformin HCl are 120 hours for the particulate formulation and almost 1400 hours for the gelled emulsion formulation. For particulate timolol maleate formulation, the release duration increases from about 400 to over 1000 hours as the drug loading is increased from 1% to 25%, while the gelled emulsion formulation releases drug for 2200 hours. Drug release from oleogels can be modeled by considering formulation properties such as diffusion and solubility, however, tortuosity within the gel due to void formation and binding of drug to gelator molecules must also be taken into account to accurately model particle-based systems.

Oleogel rods are useful devices for extended delivery of ophthalmic drugs. The release duration can be controlled by drug loading and partition coefficient. Release of the drugs from the oleogels results in voids that increase the tortuosity resulting in an increase in release duration. Binding of drugs to the gelator decreases the effective diffusivity further increasing the release duration.