Topical noninvasive retinal drug delivery of a tyrosine kinase inhibitor: 3% cediranib maleate cyclodextrin nanoparticle eye drops in the rabbit eye.

PURPOSE: Tyrosine kinase inhibitors inhibit VEGF receptors. If delivered to the retina, they might inhibit oedema and neovascularization such as in age-related macular degeneration and diabetic retinopathy. The aim of this study was to formulate cediranib maleate, a potent VEGF inhibitor, as γ-cyclodextrin nanoparticle eye drops and measure the retinal delivery and overall ocular pharmacokinetics after a single-dose administration in rabbits. METHODS: A novel formulation technology with 3% cediranib maleate as γ-cyclodextrin micro-suspension was prepared by autoclaving method. Suitable stabilizers were tested for heat-stable eye drops. The ophthalmic formulation was topically applied to one eye in rabbits. The pharmacokinetics in ocular tissues, tear film and blood samples were studied at 1, 3 and 6 hr after administration. RESULTS: γ-cyclodextrin formed complex with cediranib maleate. The formation of γ-cyclodextrin nanoparticles occurred in concentrated complexing media. Combined stabilizers prevented the degradation of drug during the autoclaving process. Three hours after administration of the eye drops, treated eyes showed cediranib levels of 737 ± 460 nM (mean ± SD) in the retina and 10 ± 6 nM in the vitreous humour. CONCLUSIONS: Cediranib maleate in γ-cyclodextrin nanoparticles were stable to heat in presence of stabilizers. The drug as eye drops reached the retina in concentrations that are more than 100 times higher than the 0.4 nM IC50 value reported for the VEGF type-II receptor and thus, presumably, above therapeutic level. These results suggest that γ-cyclodextrin-based cediranib maleate eye drops deliver effective drug concentrations to the retina in rabbits after a single-dose administration.

Characterization and Evaluation of Ternary Complexes of Ascorbic Acid with γ-Cyclodextrin and Poly(vinyl Alcohol).

Ascorbic acid (AA) is a general antioxidant used in aqueous pharmaceutical formulations. However, in aqueous solutions, AA is unstable and easily oxidized when exposed to air, light and/or heat. Cyclodextrins are well known for their ability to form inclusion complexes with various compounds to improve their solubility and stability. Previous studies demonstrate that cyclodextrins preserve the antioxidant capacity of AA but data for γ-cyclodextrin (γCD) have not been reported. Poly(vinyl alcohol) (PVA) is a hydrophilic polymer widely used as a drug matrix in various pharmaceutical fields, but its application for drug stabilization is limited. This study aimed to investigate the protective ability of γCD on AA through the formation of ternary complexes with PVA. Binary (i.e., AA/γCD, AA/PVA and γCD/PVA) and ternary (i.e., AA/γCD/PVA) complexes were first confirmed. It was reported that those complexes were formed through interactions between the heterocyclic ring of AA, hydroxyl group of PVA and hydrophobic cavity of γCD. The hydrodynamic diameter of complexes was then studied. It was found that the diameter of γCD/PVA complexes increased with respect to the concentration of γCD. Higher γCD concentrations also resulted in increasing hydrodynamic diameters of the ternary complex. The presence of AA in ternary complexes interfered with the aggregation tendency of γCD/PVA binary complexes. Furthermore, the antioxidant capacity of AA in binary and ternary complexes was investigated. It was found that the presence of γCD preserved the antioxidant activity of AA, whereas PVA showed a contrasting effect. The influence of γCD and PVA concentration on antioxidant capacity was then studied through central composite design (CCD). Even though the concentration of γCD significantly affected the inhibition efficiency of the ternary complex, the insignificant influence of PVA could not be ignored. A promising protective ternary complex should consist of an optimized concentration of PVA and a high concentration of γCD.

Solvent exchange and drug release characteristics of doxycycline hyclate-loaded bleached shellac in situ-forming gel and -microparticle.

Doxycycline hyclate (DX)-loaded bleached shellac (BS) in situ forming gel (isg) and in situ microparticle (ism) were prepared using dimethyl sulfoxide (DMSO), N-methyl pyrrolidone (NMP) and 2-pyrrolidone (PYR) as solvents. Solvent and drug release characteristics of them were investigated. Diffusion rate of solvent applied in formulation was as following: DMSO > NMP > PYR. In situ forming systems comprising PYR had the slowest release rate of solvent and drug while water flowed into system in rank of solvent order as following: DMSO > NMP > PYR. Size and density of pores were increased by time similarly to release rate of solvent and drug. At steady state, total mass loss converted to PYR ≫ NMP > DMSO similarly to water content pattern. The solvent and DX release from ism were apparently slower than those from isg owing to barrier effect from oil component. The isg and ism prepared from DMSO exhibited the highly sponge-like structure than that using PYR which the later matrices eventually dissipated due to hydrolysis of BS which was accelerated by PYR-induced water accumulation. PYR was the most appropriated solvent for BS isg and ism because their formulations demonstrated the proper sustained drug release and preferable self-degradation.