Nanoscale Dispersed Eye Ointment For The Treatment Of Dry Eye Syndrome

Dry eye syndromes are mainly caused by the reduction of tear secretion and the excessive evaporation of tears. The common symptoms of dry eye syndromes include constant irritation, foreign body sensation, blurred vision, tear hyperosmolarity, ocular surface damage. As far as evaporative type of dry eye syndromes is concerned, an instability of tear film was often observed. And for the medium and severe dry eye syndromes, inflammation was often observed. The common therapies of dry eye syndromes were tear replacement such as artificial tears, anti-inflammation drugs and immunosuppressive agent (such as Cyclosporin A, CyA). However, the anatomic structure of eye poses a quite solid barrier for the drug to retain or be absorbed when administrated to the eye.In our investigation, we aimed to formulate a nanoscale dispersed eye ointment (NDEO). Eye ointment matrix was dispersed in the nanoscale oil drops forming a lipid nanodispersion (LND). And NDEO was produced after LND was dispersed in the water which contained moisturizer, thickening agent and other excipients. Compared to eye ointment, NDEO could avoid eyelid adhesion and blurred vision, and meanwhile it could make a longer retention for the lipids. Taking advantage of the application of lipids, the NDEO could lubricate the eyelids and restore the tear film which would facilitate the treatment of dry eye syndromes. And NDEO could also be used as a carrier for lipophilic drugs, such as cyclosporine, that could be administered to the eye for the treatment of dry eye syndromes. Our study could be divided into two parts. Part one focused on the study of NDEO and part two focused on the the study of cyclosporine A loaded NDEO.In the part of NDEO study, we selected yellow Vaseline and wool fat as solid lipids and medium chain triglycerides as liquid lipid and then a lipid nanodispersion was produced using high pressure homogenization method combining with solvent emulsification/evaporation method. Thereafter the lipid nanodispersion was mixed with the same volume water containing moisturizer, thickening agent and other excipients. To acquire an optimized formulation, single factor experiment and orthogonal optimization experiments were carried out. NDEO formulated by the high pressure homogenization combined with solvent emulsification/evaporation method had a mean size around 100 nm, a spherical shape and a narrow size distribution. The eye ointment matrix was dispered in the nanoscale dispersed oil drops. Long term stability and affecting factors experiments showed that NDEO was sensitive to temperature and light. Significant changes of the size and PDI of NDEO, containing different amount of eye ointment matrix, that stored at 25℃and 4℃ for 6 months were not observed, while a significant decrease of zeta potential was observed. The result of hemolytic experiment showed that NDEO that contained different amount of eye ointment matrix would not cause hemolysis though water bathed with the red cells suspension for 12 h. There was no significant difference of the human cornea cells’viability that were treated by NDEO and Tears Natural(?) Forte (Control). Finally, in vivo pharmacodynamic evaluation was carried out using mice that were induced by BAC to make them suffered with dry eye syndromes. The result showed that NDEO prolonged the tear film break-up time and cut down the fluorescein staining score of cornea significantly compared with a commercial available drug Tears Natural(?) Forte. Histological study showed that NDEO could help the restoration of the ocular epithelium and the number of the goblet cells.In the second part of our study, cyclosporine A (CyA) was incorporated into the NDEO as a model drug. Then the characterization of the cyclosporine A loaded NDEO (CyA-NDEO) was carried out.The results showed that CyA-NDEO had a mean size around 100 nm with a spherical shape and a narrow size distribution. More than 99% of the CyA was entrapped in the NDEO matrix. The XRD, DSC and TGA results showed that the drug was compatible with the matrix excipients. No significant cytotoxicity was observed for the CyA-NDEO formulation. The stability result showed that the size and PDI of CyA-NDEO didn’t changed a lot when stored at 25℃ and 4℃for 6months, while a significant decrease of zeta potential was observed.The drug incorporated in the NDEO matrix was quite stable too, there was no significant change of the drug concentration in the formulation when stored at 25℃ and 4℃for 6 months. The in vitro release behavior of CyA from NDEO-0.5, 0.1, MCT and emulsion in SLF that contained SDS showed a slow release rate for NDEO-0.5, fast release rate for NDEO-0.1, faster rate for MCT group and the fatest rate for CyA-Emulsion bought from hospital.In general, nanoscale dispersed eye ointment was developed using high pressure homogenization combining with solvent emulsification/evaporation method. NDEO showed a good performance in safety and eye irritation. A significant increase of BUT and decrease of FL score were seen after the treatment with NDEO. Then NDEO was used as a drug carrier for lipholipic drugs that would be administered to eyes to treat eye diseases. A good entrapment efficiency was achieved. A good stability of Cy-NDEO was observed. Compared the CyA-MCT solution with CyA-Emulsion, a significantly slow release profile was observed for the Cy-NDEO groups. Further study on the CyA-NDEO should be carried out in future.