Study On Montmorillonite-Eudragit As Carrier Material In Ocular Mucosal Drug Delivery System

Glaucoma is a multifactorial neurodegenerative disease associated with loss of retinal ganglion cells?RGC?.The pathology of the eyes,requires the accumulation of drugs in the eye tissue for a long time to achieve the best therapeutic effect,and reducing the dose and frequency of administration will undoubtedly improve the patient's medication compliance.In this study,an acrylic polymer Eudragit RL PO/Eudragit RS PO?EUD PO?was introduced to design mucosal administration that a nanostructured acid-modified montmorillonite-EUD PO nanoparticle?MT-BTH-EUD PO nanoparticle?.The physicochemical properties,in vitro release characteristics,mechanism,morphology and microstructure of the prepared MT-BTH-EUD PO nanoparticles were evaluated.Montmorillonite?MT?was modified to increase the specific surface area and cation exchange capacity?CEC?,betalol hydrochloride?BTH?as the model drug,and acid modified montmorillonite was loaded?MT-BTH?by solution intercalation method.The drug load of MT-BTH was?302±24?mg·g^-1.MT-BTH-EUD PO nanoparticles were prepared by emulsifying solvent volatilization method with 1%poloxamer 188?w/v?as surfactant.The suspension of MT-BTH-EUD PO nanoparticles was prepared with light blue opalescence.The encapsulation rate and drug loading of MT-BTH-EUD PO were?69.92±1.37?%and?7.54±0.54?%,respectively.The in vitro drug release curve of MT-BTH-EUD PO nanoparticles was determined by dynamic dialysis method.Meanwhile,kinetic equation fitting was performed on the data of in vitro drug release to explore the mechanism of drug release.Results shows that MT-BTH-EUD PO nanoparticles could significantly prolong the drug release time,and the cumulative drug release in vitro was about 72.35%at 10 h.Compared with the drug release curve of BTH-EUD PO nanoparticles?modified MT without drug loading?in vitro,the nanoparticles introduced with MT could significantly prolong the drug release.Freeze-drying of MT-BTH-EUD PO nanoparticles was carried out,and the types and dosage of freeze-drying protectant were screened.The results showed that 8%mannitol was the best protection agent for freezing drying.The microstructure of MT,acid-MT,MT-BTH and prepared MT-BTH-EUD PO nanoparticles were analyzed.The total specific surface area of Acid-MT measured by the specific surface area tester increased from69.79 cm³·g^-1 of the specific surface area of montmorillonite before acidification to 108.80 cm³·g^-1,indicating that modification of montmorillonite can significantly improve the specific surface area.However,the specific surface area of MT after drug loading decreased to11.30 cm³·g^-1.It can be found from the nitrogen-adsorption-desorption curve that the area under the nitrogen-adsorption-desorption curve of MT,Acid-MT and MT-BTH have hysteresis loops.The area under the acid-modified MT and the nitrogen-adsorption-desorption curve of MT after drug loading decreased,indicating that the pore channel or interlayer position of MT was occupied,and BTH has been successfully loaded into the interlayer domain or pore space of Acid-MT.The average particle size of MT-BTH-EUD PO nanoparticles was?82.27±8.08 nm?and the Zeta potential was+?30.55±2.39?mV.The nanoparticles of MT-BTH-EUD PO can be observed as spherical particles with uniform size under transmission electron microscope,and three different types of lattice fringes and bright diffraction spots can be observed.Combining with the peaks of X-ray powder diffractometer,it can be seen that the nanoparticles of MT-BTH-EUD PO exist in crystalline form.The results of ftir spectra showed that new absorption peaks appeared in the mt-bth spectrum due to the successful insertion of BTH into the interlayer of acid modified montmoronite,and new absorption peaks(e.g.3300,1734 and1460cm^-1)appeared at the same time that the bands at 3625,3431,1613 and1513 cm^-1 were disappeared due to the loading of BTH and MT-BTH–EUD PO nanoparticles.Thermal analysis result,MT-BTH-EUD PO nanoparticles exist two weightlessness?300?⁴00??,and the weightlessness BTH temperature is 300?,and compared with Acid-MT map,MT-BTH in temperature is 300?⁴00?in weightlessness peak,the result can be concluded that BTH is successfully loaded Acid modified MT and MT-BTH-EUD PO nanoparticles.The contact angle of the MT-BTH-EUD PO nanoparticles on the rabbit eye surface in vitro was measured by the contact Angle measuring instrument,and the adhesion property of the MT-BTH-EUD PO nanoparticles was determined by the interaction method between the MT-BTH-EUD PO nanoparticles and the intestinal mucosa of mice.The results showed that the suspension of MT-BTH-EUD PO nanoparticles could reduce the surface tension,and the contact Angle between the MT-BTH-EUD PO nanoparticles and the BTH-saline solution was?21.77±0.52?°,?36.61±0.7?°,respectively.Therefore,it is believed that the prepared MT-BTH-EUD PO nanoparticles can increase the wettability and extensibility of the nanoparticles on the ocular surface,so that the nanoparticle suspension can be better spread out on the ocular surface compared with the BTH liquid solution.By comparing the Zeta potential changes before and after the interaction between the MT-BTH-EUD PO nanoparticles and the intestinal mucosa of mice,it can be known that the positively charged MT-BTH-EUD PO nanoparticles have better mucosal adhesion.For the safety evaluation of MT-BTH-EUD PO nanoparticles,the methods of chicken embryo allantoic membrane vascular stimulation,"Draize rabbit eye stimulation"?single eye stimulation and multiple eye stimulation?,corneal hydration value and MTT cytotoxicity test based on human corneal epithelial cells were used.All the above experimental results indicated that the irritation of MT-BTH-EUD PO nanoparticles on the eyes was relatively small,and the toxicity of MT-BTH-EUD PO nanoparticles on human corneal epithelial cells was relatively low.