The Experimental Study Of Salvianolic Acid B Corneal Permeability And Novel Ophthalmic Delivery System

Objective:according to cataract medication need for the clinical treatment. to prolong drug and corneal contact time and improve the corneal penetration, with salvianolic acid B as a model drug which is water soluble components of Salvia miltiorrhiza, study on basic physicochemical properties, stability of salvianolic acid B, selecting the optimal penetration enhancers for salvianolic acid B’s corneal permeability, and taking Carbopol as main matrix, HPMC as tackifier to preparate pH sensitive eye gel, and the study of gel preparation properties, stability, irritation, to the further development of new drugs of traditional Chinese medicine in the treatment of cataract and lay a good experimental base.Methods:(1) with the extraction rate of salvianolic acid B as evaluation index and orthogonal test to select optimal process for percolation extraction of salvianolic acid B, by experimental methods for ethyl acetate extraction, silica gel column chromatography, crystallization to purify of salvianolic acid B.(2) study solubility, oil/water partition coefficient of the salvianolic acid B, the content changes in light, high temperature, high humidity conditions of salvianolic acid B powder, the effect stability of salvianolic acid B in water solution at different temperatures on the biodegradation constants and different additives.(3) by using the improved Franz diffusion cell, study of salvianolic acid B’s corneal permeability, the first selecting optimal concentration for salvianolic acid B through cornea, and adding three different concentrations of permeation enhancers (azone, poloxamer188, hydroxypropyl beta cyclodextrin), with the apparent coefficient as a index, selecting the best promotion of salvianolic acid B cornea permeation and study the stimulation for permeation enhancers’concentration in vivo, in vitro.(4) using liquidity, transparency, viscosity, gel capacity as an index, selecting pH sensitive gel matrix composition of salvianolic acid B, including Carbopol and tackifier types and dosage, and other additional ingredients for ophthalmic preparation.(5) establishment a content determination method of salvianolic acid B pH sensitive gel, and the gel preparation, in vitro release of rheology, corneal penetration amount, stability; in rabbit eye irritation response score control method, observation rabbit eye irritation for the single dose, repeated dosing at different time after the preparation.Results:(1) the best of salvianolic acid B percolation extraction process of30%ethanol soaking24h, to the flow rate of2mL/min, the ethyl acetate extraction, silica gel column chromatography, crystallization, final income of salvianolic acid B content is91.33%.(2) the salvianolic acid B easily soluble in water, phosphate buffer salt of pH is4,5,6,7.4, GBR reagent, artificial tears, oil-water partition coefficients as pH increases, in the neighborhood of pH5to a minimum, then cut flat; powder within10days of strong light, high temperature conditions comparison of stability, appearance, content of almost no change, but the powder is easy to moisture absorption and moisture absorption and rapid degradation; water solution with the first-order kinetic equation, Arrenius equation is Igk=-3.4529/T+7.6408(r=0.9816), degradation constant is1.132x104h-1, valid for38.80days; the different additives on effect of salvianolic acid B content, Vc can increase the stability of salvianolic acid B.(3) in vitro diffusion test,0.5%of salvianolic acid B cumulative release reached the highest; compared with the control group,0.05%azone make salvianolic acid B apparent permeability coefficient increased by5.91times,0.50%of poloxamer188make salvianolic acid B apparent permeability coefficient increased by3.91times,0.50%hydroxy propyl base-beta cyclodextrin that salvianolic acid B apparent permeability coefficient increased by2.36times; in the experiment all the selected concentration of Azone, hydroxypropyl beta cyclodextrin concentration,0.30%,0.50%of poloxamer188concentration groups were on the rabbit eye irritation,1%,2%,3%of poloxamer188concentrations in the group on the rabbit eye irritation.(4)to determine the gel composition is:0.5%of salvianolic acid B,0.14%Carbopol,0.3%HPMC,0.1%azone,0.2%Vc.(5) the establishment of salvianolic acid B pH sensitive gel content determination method study of conform to requirements, rheological results show that the gel pseudoplastic fluid; and homemade salvianolic acid B physiological salt solution, pH sensitive gel delay of salvianolic acid B in vitro release, increase of salvianolic acid B through the release quantity of cornea. Salvianolic acid B pH sensitive gel for eye use in high light condition, content has been reduced; under the condition of low temperature, gel properties of appearance, value of pH and the content of salvianolic acid B did not significantly change; under the condition of room temperature, gel properties of appearance, value of pH and the content of salvianolic acid B change; accelerated testing conditions, gel in appearance, value of pH and the content, has obvious change; the gel through single, multiple conjunctival period after administration, in rabbit eyes with no stimulation, indicating that the preparation without irritation.Conclusion:(1) the selection of the gel matrix prescription is reasonable in design, simple process, can delay the drug release, prolonged drug in corneas of retention time.(2) single, multiple rabbit eye test showed that the preparation of eye irritation, but in the preparation of salvianolic acid B instability, agents should be in low temperature, light storage condition.