In vitro release of hydrophobic drugs by oleogel rods with biocompatible gelators

Abstract Purpose Currently, invasive monthly intravitreal injections through the eyeball are required to deliver retinal drugs. Injections of oleogels into the vitreous have the potential for extended release of both hydrophobic and hydrophilic drugs for extended durations which could decrease the frequency of injections. The type of gelator used is critical because it may impact drug release and also the biocompatibility of the device. Methods Oleogels containing soybean oil as the liquid component and beeswax, a combination of β-sitosterol and lecithin, sorbitan monostearate, sunflower wax, ethyl cellulose, or a combination of γ-oryzanol with β-sitosterol as the gelator were loaded with the drugs dexamethasone, cyclosporine, triamcinolone, vancomycin above the solubility limit and expunged from a syringe to create cylindrical rods for extended drug delivery. Images of the devices were taken to observe the dispersal of drug particles. In vitro drug release in buffer solutions was measured and effective drug diffusivity was determined from a fitted model. Effect of molecular weight and drug binding to the gelator on diffusivity was explored. Results At loading above the solubility limit, the oleogel formulation contains drug particles that act as distributed depots resulting in extended release. The oleogels prepared with different gelators presented a wide range of drug release profiles. The release durations for 10% loading dexamethasone are 35 days for the β-sitosterol/lecithin gel and 135 days for the sorbitan monostearate gel. The γ-oryzanol/β-sitosterol gels released 81% after 135 days and the beeswax and sunflower wax gels released about 78% and 79% of the loaded dexamethasone after 30 days, respectively. In ethyl cellulose gels, the release duration of 28% cyclosporine was 13 days, 28% loaded dexamethasone released 66% after 125 days, 28% triamcinolone released 46% after 108 days, and vancomycin released 80% after 21 days. The solubility limit of the drug in the oleogel was increased in presence of gelator suggesting significant drug binding to the gelator. The effective diffusivity decreased with drug binding likely because the bound drug does not diffuse. The model based on accounting for drug particle depots fit the release data. Dissolution of the particles results in void formation that increases tortosity impacting effective diffusivity. Conclusions Oleogel based rods can provide extended release of many hydrophobic drugs. Solubility of drugs in the gels are affected by gelator type, which suggests some interaction between the drug and the gelling agent. Drug dissolution, diffusion, binding as well as tortuosity due to the formation of voids must be considered to model drug release. Hypothesis Currently, invasive monthly intravitreal injections through the eyeball are required to deliver retinal drugs. Consequently, oleogels have been explored as an extended release ocular implant for delivery of drug to the retina. The gelator component in these gels is ethyl cellulose, a polysaccharide that is not readily degradable in the eye. Comparing various biocompatible gelator molecules’ ability to form drug incorporated oleogel formulations and their effect on drug release profiles could provide significant insight into development of oleogel devices. Experiments Oleogels containing soybean oil as the liquid component and beeswax, a combination of β-sitosterol and lecithin, sorbitan monostearate, sunflower wax, ethyl cellulose, or a combination of γ-oryzanol with β-sitosterol as the gelator were loaded with the drugs dexamethasone, cyclosporine, triamcinolone, vancomycin above the solubility limit and expunged from a syringe to create cylindrical rods for extended drug delivery. Images of the devices were taken to observe the dispersal of drug particles. In vitro drug release in buffer solutions was measured and effective drug diffusivity was determined from a fitted model. Findings At sufficient loading concentrations, drug particles are suspended in the gel and slowly release. The oleogels prepared with different gelators presented a wide range of drug release profiles. The release durations for 10% loading dexamethasone are 35 days for the β-sitosterol/lecithin gel and 135 days for the sorbitan monostearate gel. The γ-oryzanol/β-sitosterol gels released 81% after 135 days and the beeswax and sunflower wax gels released about 78% and 79% of the loaded dexamethasone after 30 days, respectively. In ethyl cellulose gels, the release duration of 28% cyclosporine was 13 days, 28% loaded dexamethasone released 66% after 125 days, 28% triamcinolone released 46% after 108 days, and vancomycin released 80% after 21 days. Solubility of drugs in the gels are affected by gelator type, which suggests some interaction between the drug and the gelling agent. Drug dissolution, diffusion, as well as tortuosity due to the formation of voids must be considered to model drug release.