Preparation And Study Of Compound Digitalis Leaf Extract Ion-sensitive In-situ-forming Gel For Ophthalmic Drug Delivery System

Objective：Digitoxin with treatment of fundus macular degeneration; Eye muscle type,the effect of nerve and adaptive eye fatigue. Enhancing vascular sealing,at theeye esculin leads to an increase in the capillary resistance both in the iris andciliary body. The combined action of these two ingredients results in theimprovement of retinal perfusion,Thus, a good treatment of eye diseases.Inview of traditional eye ophthalmic preparation before the cornea contact timeis short, and owing to the eye’s special physical barrier and protectionmechanisms, eye’s drops bioavailability decreased greatly. For this reareason,we prepared Compound digitalis leaf extract ion-sensitive in-situ-forming eyegel. In the hope to overcome the disadvantage of ordinary eye drops, show thesuperiority of ion-sensitive in-situ-forming eye gel. Meanwhile I hoped thispaper could be useful for future research of ocular drug delivery system.Methods:HPLC method was developed for determining the content of digitoxin andesculin. Optimization of the technology of extracting chemical constituentsfrom digitalis leaf was chosed by orthogonal experimental design,thus toobtain a total extract of digitalis leaf.Prescription screening and optimization:On the basis of scientificliteratures,we selected Gelrite as the main matrix of ion-sensitive in-situeye gel. Investigated the state of different concentrations of matrix material atroom temperature25℃and the state of which was diluted by STF at34℃.Took viscosity as index to screen the reasonable prescription.Studying theeffect of PH value for in situ gel viscosity, so as to optimize the prescription.The quality of Compound digitalis leaf extract ion-sensitive in-situ-forming eye gel made by myself was evaluated with several indexes,that were the content of preparation,pH,appearance, pH, irritation, stability,In itro vrelease and so on.Investigation of general characteristics:After centrifugation, freezing,heat and sterilization process, investigated the change of the character,pHvalue and contentof the preparation.The irritant effects of self-restraint preparation on rabbit eyes weretested．Single dosing eye irritation and multiple dosing eye irritation wereobserved, recorded and evaluated. The self-restraint preparation was topicallyadministrated to the left eyes and a solution of0.9％saline was administered tothe right eyes of6rabbit.The chemical and physical stability of preparation made by optimalformula was investigated under following circumstances: strong light andaccelerated stability experiments,and investigated the change of thecharacter,pH value and contentof the preparation.In vitro release study: Dialysis bag method is used to determine therelease of the drug in the gel. The release medium was artificial tears, sampleswere obtained at set time. The release behavior of durg in the gel was studied,at the same time the drug release mechanism was investigated.Usinghigh performance liquid chromatography (HPLC) method for releasing degreeand content inspection.preliminary study in eye: Rabbits were selected as laboratory animals,The self-restraint preparation was topically administrated to the right eyes andEsculin and digitalisglycosides eye drops was administered to the left eyes.The distribution of drugs in organization of rabbit eyes and drug retention timein rabbit eyes were studied.Results:According to orthogonal experimental design, we applied nine groupexperiments and took the amount of digitoxin in the extracts from digitalis leafas an index.Based on the K values of different factor,with the K valueincreasing,the yield of digitoxin was increasing. The optimum extraction technology was A1B1C3D3, which was90%ethanol as extractant; heatingtime was60min; Reflow temperature was80℃.Took viscosity as index to investigated the state of differentconcentrations of matrix material at room temperature25℃and the state ofwhich was diluted by STF at34℃. In combination with the studying theeffect of PH value for in situ gel viscosity, the optimum prescription wasGelrite as the main matrix,its concentration was0.5%;the concentration ofBoric acid was0.1mol/l.The pH value of homemaded preparation was5.34.Inspecting the quality of the preparation showed that the character, pHvalue of preparation were up to standard. When storing the stateof the homemade in situ gel was clear solution,while under physiologicalconditions its was a certain intensity of gel. Preparation after centrifugal,freezing, high temperature, sterilization treatment had no discoloration andstratification.The character, pH value and content of the preparation were nochange.The irritant effects：Single dosing and multiple dosing had no markedlyinfluences on tested rabbit eyes.Study of stability: The results of strong light and accelerated stabilityexperiments showed that the formulation was stable.In vitro release study:The cumulative release of drug to fit the zero order,first class equation, Higuchi model found that it conformed to first ordeModel.Animal studies showed that drug were mainly distributed in thecornea,vitreous-crystal and sclera-ciliary body. Compared with ordinary eyedrops, the homemade in situ gel could prolong the residence time of drug inthe ocular cavity.Conclusion：The content of compound digitalis leaf extract ion-sensitive in-situ-formingeye gel made by myself was up to standard. It showed a good stability andnon-stimulation and meet the requirement of eye ophthalmicpreparation.In vitro the drug coud release completely. Ion-sensitive in-situ-forming could prolong the residence time of drug in the ocular cavity.Compared with ordinary eye drops,it showed a great potential in ophthalmicapplication.