Developing an in situ nanosuspension: A novel approach towards the efficient administration of poorly soluble drugs at the anterior eye

With about 50–60 million cases in the US alone, dry eye disease represents a severe health care problem. Cyclosporin A (CsA) would be a potent candidate for a causal therapy. However, CsA is not sufficiently water soluble to be administrated via simple eye drops. We developed an in situ nanosuspension (INS) as a novel approach towards the administration of CsA to the cornea. It precipitates upon contact with the tear fluid and creates CsA nanoparticles that enter the cornea and release the drug by dissolution. We selected two liquid poly(ethylene glycols) (PEG) that dissolve CsA and create nanoparticles by precipitation of CsA upon water contact. Aqueous solutions of PEG and Solutol, a non-ionic surfactant, were well tolerated by primary human epithelial cells in vitro. To determine the critical water content needed for a precipitation, the solubility of CsA was investigated in quaternary systems of drug, solvent, surfactant and water. The best INS formulation showed a particle size of 505 ± 5 nm, a polydispersity index (PdI) of 0.23 ± 0.03 and a neutral zeta potential of −0.07 ± 0.05 mV. After single administration to porcine eyes in vitro, 3165 ± 597 ngCsA/gcornea were detected in corneal tissue, while the levels of Restasis® a commercial formulation were, with 545 ± 137 ngCsA/gcornea, significantly lower (P < 0.01). These results demonstrate that an INS is a promising, novel approach towards the causal treatment of inflammatory diseases at the anterior eye.

A poorly soluble drug, a surface active additive and the maximum possible amount of water that does not induce a precipitation are solved in a non-aqueous, but water miscible solvent to generate a clear solution by gentle stirring. In combination with the tear fluid, the administered droplet exceeds the critical water content and with that the point of precipitation. The drug spontaneously precipitates into nanoparticles and is taken up by the tissue.Figure optionsDownload high-quality image (184 K)Download as PowerPoint slide