Cyclosporine A Loaded Solid Lipid Nanoparticles In Situ Gel Formulations Ocular Drug Delivery System

Cyclosporine A (CyA) is a cyclic undecapeptide produced by Tolypocladium inflattum Gams and other fungi imperfecti. This drug is now routinely used as an oral immunosuppressor for organ transplantation and to prevent recurrence of graft rejection after keratoplasty. Systemic use of CyA has deleterious side effects such as nephrotoxicity and hypertension. The main difficulty is that CyA cannot be prepared in formulations based on the commonly used aqueous ophthalmic vehicles because of both its hydrophobicity and its extremely low aqueous solubility. Therefore, in most studies, CyA was dissolved and administered in vegetable oils. However, these media are poorly tolerated, result in relatively low ocular availability, and have short shelf lives. Improving the ocular bioavailability of poorly water-soluble Cyclosporine A (CyA) to reduce toxicity and side effect was considered as main focus of this paper. A series of related researches were carried out, including preparation of CyA-loaded nanoparticles, surface modified SLNs, compounding the coated CyA-SLNs with thermosensitive gel to prepare a kind of multiple drug delivery systems and finally comparing the pharmacokinetic in the rabbit tears and the drug concentrations in the cornea of the different preparations.A novel solid lipid nanoparticles (SLNs) coated with charge modifier was prepared to increase the solubility and the in vitro binding with the cornea. Since epithelial corneal cells exhibit negative charges on their surface, a positively charged delivery system would interact with the corneal cells and prolong residence time on the surface of cornea. For the SLNs, a mixture of glyceryl monostearate and eompritol ATO 888 was chosen as lipid phase, poloxamer 188 as surfactants, double-distilled water as water phase and stearylamine as charge modifier. The effects of various formulation and process parameters on particle size, stability and entrapment efficiency were investigated.The SLNs loaded thermosensitive gel of poloxamer 407 (SLN-Gel) was developed for ophthalmic use. As the SLNs were added, the gel temperature of the polymer solution increased about 11℃. Characteristics of SLNs as well as SLN-Gel, including particle size, zeta potential, viscosity, pH value, osmotic pressure, DSC, IR and in vitro release, were assessed. A membraneless model was applied to study the gel dissolution and SLNs release. The SLNs release followed zero-order kinetics, and was controlled by gel dissolution.Four experiments in rabbit eyes, including pre-ocular residence study, isolated rabbit cornea permeability study, drug elimination in the tears and the drug concentration in the cornea, were performed. The result indicated positively charged SLNs liked to bind with cornea and eliminated slowly in the tears compared with negatively charged SLNs, it also showed a larger CyA concentration in the cornea. SLN-Gel preparation showed longer retention time than the other preparations, and was hoped to improve CyA ocular bioavailability.