| Myricetin(Myr)is a natural ingredient that is widely found in many Myricaceae plants and it belongs to flavonoids.Myricetin has a wide range of biological and pharmacological activities,but it has the disadvantages of poor water solubility,rapid degradation and low bioavailability.These shortcomings greatly restrict its application in the treatment of eye diseases.In this paper,In order to increase the water solubility,stability and corneal permeability of myricetin,Polyoxyl 15 hydroxystearate(Kolliphor? HS15,HS15)and Polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer(Soluplus?,Soluplus)were used to construct nanomicelle eye drops respectively with myricetin.Then the two kinds of eye drops were evaluated in vivo and in vitro.HS15-Myr nanomicelle eye drops and Soluplus-Myr nanomicelle eye drops were prepared by solvent evaporation-hydration method.Based on entrapment efficiency,zeta potential,particle size and particle size dispersion,the optimal formulation of two kinds of excipients was selected.After that,the surface characteristics,chemical stability,short-term storage stability,eye tolerance,absorption in vitro and in vivo and efficacy of nanomicelle eye drops were further investigated.After screening and optimization,the mass ratio of HS15 and Myr was 21: 1.The encapsulation efficiency of this nanomicelle eye drops was 96.12 ± 0.31%,the average particle diameter was 12.17 ± 0.73 nm,and the particle size distribution was uniform.The polydispersity coefficient was 0.137 ± 0.013,and the surface charge potential of the nanomicelles eye drops was-[4.28 ± 0.42] mV.HS15-Myr nanomicelle eye drops had stronger ability to resist degradation compared with free myricetin.At pH6.5,its degradation rate was 4.8 times slower than free myricetin;HS15-Myr nanomicelle eye drops showed high storage stability at 4 ? and 25 ?,it could be stored stably for 12weeks;HS15-Myr nanomicelle eye drops were dropped into rabbit eyes,and no irritation and corneal damage were observed in the rabbit eyes,which indicated thatthe eye drops were highly safe.Coumarin 6 was used as a fluorescent probe for quantitative and qualitative research to show the absorption of prescriptions in mouse eye tissues,the results showed that HS15-Myr nanomicelles eye drops could significantly improve the penetration of the drug in the corneal tissue,the penetration efficiency was about 3.3 times that of free drugs in 30 min.Not noly that,compared with free myricetin,HS15-Myr nanomicelle eye drops showed it can increase the anti-oxidative activity of myricetin in vitro,and the more significant anti-inflammatory activity in rabbit eye tissue.The anti-inflammatory activity of 10mg/ m L HS15-Myr nanomicelle eye drops is similar to diclofenac sodium eye drops.For Soluplus-Myr nanomicelle eye drops,the optimal prescription ratio was when the mass ratio of Soluplus to Myricetin was 18: 1,and the encapsulation efficiency of nanomicelle eye drops was 99.5 ± 0.52%.The average diameter of the particle is 60.72± 1.09 nm,and the particle size distribution was uniform,the polydispersity coefficient was 0.140 ± 0.018,and the surface charge potential of the nanomicelle eye drops was-[2.29 ± 0.33] mV.Compared with free myricetin,Soluplus-Myr nanomicelle eye drops had a better resistance to myricetin degradation,which was about 38.88 times.The Soluplus-Myr nanomicelle eye drops also had good storage stability and had good tolerance when dropped it to rabbit eyes.The experimental results about drug absorption in vivo showed,the penetration efficiency of Soluplus-Myr nanomicelle eye drops in corneal tissue was about 12.0 times that of free drugs in 30 min.Soluplus-Myr nanomicelle eye drops also improved the antioxidative activity of myricetin in vitro and the anti-inflammatory activity in rabbit eye tissue.The effect was similar to HS15-Myr nanomicelle eye drops.Soluplus-Myr nanomicelle eye drops compared to HS15-Myr nanomicelle eye drops,Soluplus-Myr can improve the retention time of myricetin in the cornea,has better corneal absorption.10 mg / mL HS15-Myr nanomicelle eye drops and 4 mg / mL Soluplus-Myr nanomicelle eye drops showed similar anti-inflammatory activity,which was the same as the commercially available diclofenac sodium eye drops.In summary,the two myricetin nanomicelle eye drops prepared with the new materials HS15 and Soluplus were feasible.HS15-Myr and Soluplus-Myr effectively improved the solubility and stability of myricetin in water and promote the absorption of myricetin in the eyes.The result provided a theoretical basis for the ocular drug delivery of insoluble flavonoids such as myricetin. |
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