Study On Ocular Drug Delivery Properties Of Solid Lipid Nanoparticles And Eudragit Microspheres

Glaucoma has become one of the three major causes of vision loss in the world.Due to the low bioavailability of traditional eye drops for immediate administration,it is difficult to meet the long-term treatment needs of glaucoma.Nanoparticles and microparticles have been used as eyedrop carriers in drug delivery studies.However,there are few studies on the differences in toxicity and drug tissue retention,and physiological barriers such as cornea,tear film and etc.,as well as special physiological behaviors such as tear renewal,drainage and etc.,cause more uncertainties in eye drops compared with other drug delivery methods.In addition,no more effective options have been developed for such delivery systems.We attempted to compare the application of novel ion-exchange micro-nano drug delivery system in the treatment of glaucoma,a chronic ocular disease,and to provide a certain research basis for the selection of novel drug delivery system.This study is based on the previous research of the research group.Firstly,montmorillonite(MT)is acidified,and then betaxolol hydrochloride(BHC)is loaded into the acidified montmorillonite by ion exchange,so as to obtain drug loaded Montmorillonite(MT-BHC).Then it was embedded into Eudragit microspheres and solid lipid nanoparticles to construct double sustainedrelease drug loaded Montmorillonite Eudragit microspheres(MT-BHC MPs)and double sustained-release drug loaded Montmorillonite Solid lipid nanoparticles(MT-BHC SLNs).Two new ocular drug delivery systems(DDS)(MT-BHC MPs eye drops and MT-BHC SLNs eye drops)with ion exchange characteristics were developed with appropriate excipients.BHC solution was used as control.The physical and chemical properties,in vitro release,safety evaluation,precorneal retention and pharmacodynamics of lowering intraocular pressure of MT-BHC MPs and MT-BHC SLNs eye drops were compared to explore the feasibility of using them in the treatment of eye diseases.The particle size and potential of MT-BHC SLNs were(547.7 ± 4.25)nm and +(7.84 ± 0.94)m V,respectively,and that of MT-BHC MPs were(9.82 ± 3.56)μm and +(8.58 ± 0.57)m V,respectively.The encapsulation rates of MT-BHC SLNs and MT-BHC MPs were 83.52 ± 0.91% and 85.43 ±1.27%,respectively.The drug loading of MT-BHC MPs and MT-BHC SLNs were 6.23 ± 0.07% and 4.55 ± 0.05%,respectively,that is,the former was1.37 times of the latter,MT-BHC MPs should be more suitable for the eye drug delivery system with the requirement of dosage.The osmotic pressure and p H value of MT-BHC MPs and MT-BHC SLNs eye drops meet the quality requirements of ophthalmic preparations in the 2020 Edition of Chinese Pharmacopoeia.The rheological behavior indicates that both are pseudoplastic fluids.In vitro release data showed that the cumulative release amounts of both were less than 40% at 0.5 h,indicating that they met the requirements of sudden release of delayed and controlled release preparations in Chinese Pharmacopoeia 2020 edition.Compared with BHC solution with a cumulative release of 100% at 2 h,the cumulative release of MT-BHC SLNs eye drops and MT-BHC MPs eye drops at 12 h were 87.78% and 80.43%,respectively,indicating that these two kinds of eye drops had better sustained release performance and met the design requirements of twice a day administration.At the same time,the release of both belong to Fick diffusion mechanism.In addition,physical parameters such as surface tension,contact Angle,diffusion time and hydrophobicity of MT-BHC MPs eye drops and MT-BHC SLNs eye drops were investigated,and the results showed that the surface tension of MT-BHC MPs(37.50 ± 0.51 m N/m)and MT-BHC SLNs(37.41 ± 0.05 m N/m)were both lower than that of BHC solution(43.09 ±0.59 m N/m),which were more likely to wet the lipid layer of tear film in front of cornea and the surface of hydrophobic corneal epithelium.In addition,it meets the requirements of general ophthalmic preparation for surface tension,which is beneficial to increase the interaction between micro/nano particles and tear mucin and the epithelium of cornea or conjunctiva,which is beneficial to prolong the retention time of eye drops on the surface of the eye.The contact angles of BHC solution,MT-BHC MPs eye drops and MT-BHC SLNs eye drops are all less than 90°,indicating that the three preparations have good wettability.The precorneal diffusion time of BHC MPs eye drops is longer than that of MT-BHC SLNs eye drops,which provides more interaction time for the interaction of particles with negatively charged mucin in the pre-corneal tear film and the corneal/conjunctival epithelium.Meanwhile,hydrophobicity results showed that the hydrophobicity of MTBHC MPs was significantly stronger than that of MT-BHC SLNs,which was conducive to the interaction between MT-BHC MPs and corneal/conjunctival epithelium with strong hydrophobicity,thus enhancing the precorneal retention ability of MT-BHC MPs.The safety of three kinds of ophthalmic preparations were investigated by Draize stimulation,tissue section observation and evaluation,and in vivo rabbit eye blink.The results showed that BHC solution,MT-BHC SLNs eye drops and MT-BHC MPs eye drops had relatively little irritation and good biocompatibility.Eye drops with sustained-release properties need to ensure slow drug release while still having the ability to prolong the retention time of preparations in front of the cornea.Therefore,precorneal fluorescence tracer experiment and tear elimination experiment were carried out to investigate the precorneal retention properties of BHC solution,MT-BHC SLNs eye drops and MT-BHC MPs eye drops.The results showed that in the fluorescence tracer experiment,the precorneal fluorescence retention time of MT-BHC MPs eye drops was significantly prolonged,which was 8.44 times of BHC solution and 3 times of MT-BHC SLNs eye drops.The tear elimination experiment showed that the precorneal retention time of MT-BHC MPs was10.67 times that of BHC solution and 1.33 times that of MT-BHC SLNs.The above experiments showed that MT-BHC SLNs eye drops and MT-BHC MPs eye drops had stronger precorneal retention than BHC solution.This may be due to the micro interaction between MT-BHC MPs and MT-BHC SLNs with appropriate particle size and positive charge and mucin layer network structure in tear film,which changes the control of tear water layer circulation into mucin layer circulation control for most drug removal.Thus,the precorneal retention of MT-BHC MPs eye drops and MT-BHC SLNs eye drops was enhanced.In addition,MT-BHC MPs eye drops have a stronger precorneal retention capacity than MT-BHC SLNs eye drops.Combining with physical parameters such as positive charge and hydrophobicity on particle surface and diffusion time of the preparation,our research group proposed an analysis from the perspective of micro-interaction between ocular micro/nano DDS and multi-layer biological mask: The longer precorneal diffusion time of MT-BHC MPs compared to MT-BHC SLNs wins more time for the particles to interact with the negatively charged mucin in the precorneal tear film and the epithelium of corneal or conjunctiva.Tear removal experiments showed that the retention time of drugs in MT-BHC MPs and MT-BHC SLNs eye drops was up to 480 min and 360 min respectively,which may be related to the 6-12 h circulation time of glycocalyx structure formed by polysaccharides extending from corneal epithelium.The retention time of MT-BHC MPs eye drops is longer,and the hydrophobicity of MT-BHC MPs is stronger than that of MT-BHC SLNs,while the angular conjunctival epithelium is hydrophobic,and its interaction with the angular conjunctival epithelium may play an important role.With the extension of time,it is possible that MT-BHC MPs gradually glides into the depth of mucin and even reaches the cornea/conjunctiva(bulbar conjunctiva and fornival conjunctiva)and interacts with the hydrophobic structure of its epithelium,further enhancing the precorneal retention capacity of MT-BHC MPs.Compared with MT-BHC SLNs eye drops,MT-BHC MPs eye drops show excellent precorneal retention,but whether they can produce positive treatment needs further confirmation.Therefore,we carried out the study on the pharmacodynamics of IOP.The study showed that compared with MTBHC SLNs eye drops,MT-BHC MPs eye drops had the most stable and lasting IOP lowering curve,and the IOP lowering effect lasted for 12 h,that is,the IOP can be lowered smoothly within the interval period of administration.In conclusion,MT-BHC MPs eye drops with good biocompatibility and more lasting and stable IOP lowering effect made by our research group have good application potential in the administration of glaucoma.From the perspective of micro/nano particles and precorneal multilayer biological mask,the microscopic interaction of analytical preparation with mucin of tear film and the epithelium of cornea or conjunctiva was synthesized by combining potential,diffusion time,hydrophobicity and other physical parameters.The research Angle and thought have certain novelty and innovation.Then,the above analysis principle of micro-interaction is applied to the IOP lowering effect of the preparation with the help of the bridge of precorneal retention capacity,so as to discuss the effective delivery of the preparation by linking the physical and chemical properties and physiological properties of the preparation.This idea is conducive to exploring the application potential of different DDS in the eye.