Objective: To prepare voriconazole (VCZ) sulfonated butyl ether-β-cyclodextrin (SBE-β-CD) inclusion compound and study the properties in vitro.Methods: VCZ SBE-β-CD inclusion compound was prepared respectively by a stirring method, an ultrasonic method and a grinding method, and the one with the highest inclusion rate and inclusion compound yield was chosen as the final preparation method.The formula and preparation process were optimized by an orthogonal design.The inclusion compound was identified by differential scanning calorimetry and solubility determination, and the in vitro dissolution was determined as well.Results: The stirring method had the highest inclusion rate and inclusion compound yield, and the optimal preparation and formula conditions were as follows: the inclusion temperature was 25℃, the stirring time was 4 h and the amount ratio of VCZ to SBE-β-CD was 1∶1.After the optimization, the inclusion rate was (86.14 ± 0.69)%, and the yield of inclusion compound was (97.11 ± 0.31)%.After the inclusion, the characteristic peak of VCZ disappeared and the solubility of VCZ increased significantly.Compared with those of VCZ, the dissolution rate and amount of VCZ inclusion compound both increased notably.Conclusion: VCZ SBE-β-CD inclusion compound can be prepared by the stirring method, which lays foundation for the further studies on VCZ eye drop.

Objective: To study the solubilization of sulfonated butyl ether-β-cyclodextrin (SBE-β-CD) and hydroxypropyl-β-cyclodextrin (HP-β-CD) for voriconazole (VCZ) to lay basis for the preparation of inclusion compounds of VCZ.Methods: The phase-solubility method was used, and the solubilization of SBE-β-CD and HP-β-CD at different concentrations for VCZ was studied at various temperatures and the inclusion constant (K) and such inclusion parameters as ΔG, ΔH and ΔS were calculated.Results: Both SBE-β-CD and HP-β-CD could improve the solubility of VCZ in water, while the solubilization of SBE-β-CD was more significant than that of HP-β-CD at the same concentration under the same temperature.The equilibrium phase-solubility diagram of SBE-β-CD vs VCZ was AN type, and that of HP-β-CD vs VCZ was AL type.With the increase of temperature, K of both β-CD decreased.ΔG, ΔH and ΔS were all negative for the inclusion process.Conclusion: Compared with that of HP-β-CD, the solubilization of SBE-β-CD for VCZ is better.The inclusion is spontaneously formed with exothermic process, and the main acting force is Van der Waals'' force.

Objective: To prepare 1% voriconazole ( VCZ) sulfonated butyl ether- β-cyclodextrin ( SBE-β-CD) inclusion com-pound eye drop and study the quality. Methods: VCZ SBE-β-CD inclusion compound was prepared with the molar ratio of VCZ to SBE-β-CD of 1 :1. Sodium chloride was used as the osmotic pressure regulator and benzalkonium bromide was employed as the pre-servative in the preparation of VCZ SBE-β-CD inclusion compound eye drop. The appearance, pH value, content stability and irritation of the eye drop were studied as well. Results:The eye drop was colorless and transparent solution with the pH value of 6. 44 ± 0. 20, 6. 50 ± 0. 15,6. 48 ± 0. 22 the osmotic pressure of (320 ± 4. 62),(316 ± 2. 88),(322 ± 2. 60)MOsm and the VCZ content of 1. 02% g ·ml-1 . The results of accelerated testing and long-term testing showed no notable changes in the quality indices. The eye drop exhibi-ted no significant irritation to the rabbit eyes. Conclusion:VCZ SBE-β-CD inclusion compound eye drop shows the properties of high VCZ content, stable quality and promising safety in eye application, which is worthy of further studies.

Objective: To prepare 1% voriconazole ( VCZ) sulfonated butyl ether- β-cyclodextrin ( SBE-β-CD) inclusion com-pound eye drop and study the quality. Methods: VCZ SBE-β-CD inclusion compound was prepared with the molar ratio of VCZ to SBE-β-CD of 1 :1. Sodium chloride was used as the osmotic pressure regulator and benzalkonium bromide was employed as the pre-servative in the preparation of VCZ SBE-β-CD inclusion compound eye drop. The appearance, pH value, content stability and irritation of the eye drop were studied as well. Results:The eye drop was colorless and transparent solution with the pH value of 6. 44 ± 0. 20, 6. 50 ± 0. 15,6. 48 ± 0. 22 the osmotic pressure of (320 ± 4. 62),(316 ± 2. 88),(322 ± 2. 60)MOsm and the VCZ content of 1. 02% g ·ml-1 . The results of accelerated testing and long-term testing showed no notable changes in the quality indices. The eye drop exhibi-ted no significant irritation to the rabbit eyes. Conclusion:VCZ SBE-β-CD inclusion compound eye drop shows the properties of high VCZ content, stable quality and promising safety in eye application, which is worthy of further studies.

Objective:To study the effects of voriconazole sulfonated butyl ether-β-cyclodextrin inclusion compound(VCZ-SBE) eye drop on fungal keratitis (FK) in rabbits. Methods:Aspergillus fumigatus was used for the establishment of FK model in rabbits. Totally 48 healthy rabbits were divided into four groups. The 12 right eyes in group A were inoculated with Aspergillus fumigatus with-out any treatment. The 12 right eyes in group B were inoculated with Aspergillus fumigatus,and then treated with 0.5% VCZ-SBE eye drop,those in group C were inoculated with Aspergillus fumigatus,and then treated with 1.0% VCZ-SBE eye drop,and those in group D were inoculated with Aspergillus fumigatus,and then treated with 0.5% fluconazole eye drop. The cornea of normal left eyes in the four groups was used for the blank control. Ulcer grading was performed for all the eyes in 0,1,4,7 and 14 d after the successful es-tablishment of FK model. Every 3 rabbits were sacrificed in 1,4,7 and 14 d,and then the cornea was obtained to evaluate the infiltra-tion degree of inflammatory cells and the invasion depth of hyphae into cornea. Results:After the successful establishment of FK mod-el,the ulcer grading among the groups showed no significant difference(P>0.05). Respectively after the 7,4 and 14-day treatment, the ulcer grading in group B,C and D was notably lower than that in group A (P<0.05). After the 4,7 and 14-day treatment,the ulcer grading,infiltration depth and necrosis degree in group C were all lower than those in group B and D(P<0.05),and after the 7 and 14-day treatment,those in group B were lower than those in group D(P<0.05). Conclusion:Compared with fluconazole eye drop at the same concentration,VCZ-SBE inclusion compound eye drop can decrease the ulcer grading of FK and reduce the infiltration depth in a concentration-dependent manner.