Study On The Nanomicelle Eye Drops Constructed With Rebaudioside Aas Green Carrier

Ophthalmic drug delivery has received extensive interests because of the low transfer efficiency,but intraocular multiple barrier mechanism encourage researchers to explore a more rational and more effective system of eye administration.However,this barrier mechanism limits the application of the means of pharmaceutical preparations,and it is difficult to design dosage forms.Especially,this is more obvious in the application of insoluble drugs.According to this problem,researchers have developed new drug delivery systems,like solid dispersions;liposomes;microcapsules,etc.Micellar system,particularly nano micellar drug delivery system,can greatly improve the solubility of insoluble drugs and make them more dispersible,thus promoting the permeation and absorption of drug in the cornea.The conclusion that the smaller the size of micelle,the stronger the promoting effect on drug absorption were discussed in some literatures.Rebaudioside A(RA),which is a steviol glycoside extracted from the natural herb Stevia rebaudiana Bertoni,has been widely used in food and medicine,In recent years.However,RA is rarely used in ophthalmology.RA has both hydrophobic diterpene and hydrophilic sugar side chain(s)in its structure.Hence,the research takes advantage of this feature to structure the micellar system with RA as micellar carrier excipient,and to study the solubilization,function and mechanism of promoting absorption of drugs.RA-Cou6 micelle was prepared and optimized with coucouin-6(Cou6)as hydrophobic drug model,and then the in vivo and in vitro characteristics were evaluated,respectively.Then,pterostilbene was selected as the active drug to structure the active drug micelle system of RA and pterostilbene,the pharmacokinetics and pharmacodynamics evaluation of the micelle were carried out in vivo.Results show that RA self-assembled into micelles including Cou6 and pterostilbene with ultra-small particle size(< 4 nm)in a homogeneous distribution state(PDI < 0.3).Cou6 was highly encapsulated into the RA micelles according to the weight ratios of RA to Cou6.RA had good cellular tolerance without significantly causing apoptosis.RA-Cou6 micelle ophthalmic solution also had excellent cellular tolerance and in vivo ocular tolerance.On this basis,the absorption of free Cou6 andthe micelle of Cou6 in corneal tissues and cells was compared by various methods.The results showed that the absorption of the micelle of Cou6 was faster and higher than free Cou6.By observing the distribution of coumarin 6 in lysosomes,endoplasmic reticulum,mitochondria and other organelles,the results showed the distribution and process of the micelle after it was ingested.Then,the studies on corneal epithelial cells and in vitro ocular absorption pathways indicated that the cell uptake of Cou6 was significantly involved in an energy-independent and active intracellular endocytosis activity.Furthermore,in vitro experiments on the eye showed that the endocytosis pathway was significantly more complex than that in cell experiments.In the micelle system constructed by RA and pterostilbene,the absorption of the drug was consistent with the above results.Compared with free drug,the drug which was loaded in micelles had better absorption efficiency and was conducive to develop the pharmacological action of the drug itself.These results suggest that as a novel intraocular drug delivery system,RA micelle has great potential in improving the bioavailability of hydrophobic drugs.