Studies On Itraconazole-Loaded Cubic Liquid Crystal Precursor For Vaginal Delivery

Objective:Itraconazole(ITZ)was used as the model drug,phytantriol(PYT)was used as a matrix material,and N,N-dimethylacetamide(DMAC)was used as an organic solvent to prepare ITZ-loaded cubic liquid crystal(LC)precursor for vaginal delivery.Cubic LC gels could be formed when the precursors contacted with water and achieves sustained release of the drug.A mouse model of Candida albicans vaginitis was established to investigate the therapeutic effect of ITZ-loaded cubic LC precursor on it.Methods:The basic composition of the blank cubic LC precursor was selected through the PYT-DMAC-water ternary phase diagram.The properties of the formulations including injectability,minimum water absorption V_m and gelation time T_g for phase inversion and stability was investigated to preliminary determine the prescription.The preparation process was optimized to determine the preparation method.Polarization microscope(PLM),small angle X-ray scattering(SAXS),and rheological properties were used to characterize the formulations(including precursors and cubic LC gels)to further clarify the internal structure and rheological properties of the preparations.Based on the in vitro drug release experiments of the preparations,the release behavior characteristics of the preparations were investigated and the final formulation was optimized.The vaginal appearance irritation score and observation of HE stained sections of vaginal tissue was used as indicators,to investigate the vaginal irritation of blank cubic LC precursor and ITZ-loaded cubic LC precursor.The retention time of ITZ in the vagina of mice was investigated to evaluate the in vivo retention time performance of ITZ-loaded cubic LC precursors.A mouse candida vaginitis model was constructed,and vaginal appearance,vaginal lavage fluid,secretions culture and pathological sections were used as evaluation indicators,miconazole nitrate cream wasused as a positive control to investigate the therapeutic effect of ITZ cubic LC precursor.Results:The optimal prescription of the ITZ-loaded cubic LC precursor was(PYT/DMAC/ITZ,70:30:0.9,w/w/w).The formulations had good fluidity and could be used for injection.The V_m was 60.59μL,and the T_g was 13.17s.It could be phase inverted to form LC gel in vivo and in vitro.In vitro release experiments showed that the formulations could keep a sustained release of ITZ for more than72 hours.The LC gels formed after phase conversion of the prepared precursor preparation were observed as a dark field under PLM,and the ratio of the Bragg peak of the SAXs test result was√2:√3:√4:√6:√8:√9,indicating that cubic LC gels were formed,and the addition of ITZ did not change the internal structure type of the cubic LC.The rheological test results showed that the cubic LCs had higher viscosity and viscoelastic properties,and has the characteristics of pseudo-plastic fluid of shear thinning.The results of vaginal irritation experiments showed that the blank cubic LC precursor and ITZ-loaded cubic LC precursor both produced less irritation to the vaginal mucosa of mice and caused a slight inflammatory response,while the irritation scores were consistent with clinically applied standards and lower than the commonly used miconazole nitrate cream.The results of the pharmacodynamic test showed that compared with the model group,the mice treated with ITZ-loaded cubic LC precursors were continuously administered for 7days,and the vaginal congestion and redness were significantly reduced or disappeared,and the vaginal secretions were significantly reduced.Microscopic observation of vaginal lavage fluid of mice was collected,in which the number of Candida spores was significantly reduced.Pathological sections of vaginal tissue showed that the structure of the vaginal mucosa was intact,there was no congestion of capillaries under the tissue,and inflammatory cell infiltration was reduced.Only individual cell infiltration and cell swelling were seen.And the therapeutic effect of ITZ cubic liquid crystal precursor is better than that of miconazole nitrate cream.Conclusion:The ITZ cubic LC precursor developed in this experiment has high biocompatibility,convenient administration and fast phase inversion.It can improve the solubility of ITZ,increase drug loading,and have a good sustained release effect.It is an excelent new dosage form of ITZ for local drug delivery.After administration,the vaginal retention time of the drug could be prolonged and the local drug concentration in the vagina was increased.The growth of Candida albicans was effectively inhibited.The ITZ-loaded cubic LC precursor had a good therapeutic effect on Candida albicans vaginitis in mice.This also provides new ideas and references for vaginal delivery of other drugs.