Study On The Properties Pharmacokinetics And Pharmacodynamics Of Ophthalmic Drug-loaded Montmorillonite-solid Lipid Nanoparticles

Glaucoma has become the second most common blind disease in the world.Due to the special physiological structure of the eye and the limitations of drug delivery,traditional treatment methods have low bioavailability and poor drug compliance for patients.The new nanometer drug delivery system has the advantages of slow release of drugs and prolonged retention time on the ocular surface,which is expected to improve bioavailability.In this study,betaolol hydrochloride was used as a model drug to prepare a drug-loaded montmorillonite-solid lipid nanoparticle（Mt-BH-SLNs）drug delivery system for ocular drug delivery through a high-temperature melting-low-temperature solidification method.Based on the previous research of the research group,the prepared Mt-BH-SLNs were evaluated in terms of particle size,dispersion coefficient,pH value,osmotic pressure,encapsulation efficiency,drug loading rate,X-ray photoelectron spectroscopy analysis and in vitro release behavior,etc.;through the Draize eye irritation experiment,Allantoic membrane angiogenesis-trypan blue staining test and cytotoxicity（MTT）test to evaluate the safety of Mt-BH-SLNs;then the rabbit eye corneal contact angle measurement and rose bengal test to investigate the pre-corneal behavior of Mt-BH-SLNs;finally,the pharmacokinetics of Mt-BH-SLNs were investigated through tear elimination experiment and aqueous humor microdialysis experiment,and the anterior chamber injection of compound carbomer solution induced high intraocular pressure model to investigate the effect of Mt-BH-SLNs in reducing intraocular pressure.The prepared Mt-BH-SLNs had a light blue opalescence in appearance,and the Tyndall effect was shown by laser pointer irradiation;the average particle size of Mt-BH-SLNs is（149.50±2.20）nm with the dispersion coefficient of 0.2850±0.0450;Zeta potential is+（20.15±0.01）m V;the osmotic pressure and pH are（276.0±7.0）m Osm·L^-1 and 6.88±0.30,respectively.The above data all showed that Mt-BH-SLNs had good pharmaceutical properties and were suitable for eyes administration.The encapsulation efficiency and drug loading rate were（84.98±1.53）%and（5.03±0.14）%,respectively.It meet the requirement in the 2020 edition of the Chinese Pharmacopoeia;X-ray photoelectron spectroscopy analysis results showed that BH molecules were successfully inserted into the interlayer domain of acidified montmorillonite to form Mt-BH complexes.In vitro release experiments showed that the in vitro release curves of Mt-BH-SLNs showed a slow and steady release compared with that of BH solution and BH-SLNs.The new drug release system can continuously release（85.00±1.53）%of the drug within 12 hours.Studies had shown that Mt-BH-SLNs was a release mechanism that combines erosion and diffusion.Attention should be paid to the potential toxicity of nano-carrier materials.All the safety test results showed that Mt-BH-SLNs showed lower irritation compared to BH solution.The carrier material of solid lipid nanoparticles was natural lipid material soybean phospholipid,which had good biocompatibility.The raw material drug BH had certain irritation.The preparation of BH into solid lipid nanoparticles could reduce the irritation of drug molecules to a certain extent.The contact angles of the aqueous solution and Mt-BH-SLNs were（37.37±0.14）°and（36.83±0.21）°,both below 90°,showing no significant difference（P>0.05）indicating that homemade Mt-BH-SLNs can quickly wet the cornea;the experimental results of Rose Bengal show that the water-soluble drug molecule BH deposited on the outer surface of the nanoparticle due to the decrease in the solubility of quenching when adsorbed and embedded on the surface of the nanoparticle or during the preparation of the SLN can improve the surface hydrophilicity of Mt-BH-SLNs This was beneficial for nanoparticles to adhere to and/or traverse the hydrophilic tear film mucin network structure,thereby prolonging their retention time on the ocular surface.This was corroborated by the results of subsequent tear elimination experiments:the retention time of the Mt-BH-SLNs carrier on the ocular surface in the tear elimination experiment was 300min,which was 3.33 times that of BH-physiological saline solution;the results of the ocular microdialysis experiment showed that compared with BH-physiological saline solution,Mt-BH-SLNs had longer T_max（4 times）（P<0.05）,MRT0-t（1.53 times）（P<0.05）and AUC_0-t（1.64 times）（P<0.05）,It showed that Mt-BH-SLNs can improve bioavailability.At the same time,the cornea could be used as a drug reservoir for eye drops,and its function was reflected in the mode of influencing drug penetration,resulting in inconsistent changes in the drug concentration of tears and aqueous humor over time,and the retention time of the drug in the aqueous humor was longer than the retention time in the ocular surface tears;the results of pharmacodynamics for lowering intraocular pressure showed that compared with BH-physiological saline solution,Mt-BH-SLNs had a long-lasting and stable effect of lowering intraocular pressure.In summary,self-made Mt-BH-SLNs had good pharmacological properties,were suitable for ocular administration,had good safety,could improve bioavailability,had a lasting and stable effect of lowering intraocular pressure,and had great potential in the field of glaucoma treatment.