| Desonide（DES）is a synthetic sixth category,a low-potency,insoluble non-fluorinated topical corticosteroid that is difficult to dissolve in water,and it plays a vital role as a topical corticosteroid.A variety of desonide preparations are already on the market,including creams,lotions,ointments and hydrogels.However,there are some limitations with conventional preparations for local treatment,such as limited drug penetration,poor toxicity,high dosing frequency and low patient compliance.Long-term use can cause a variety of side effects,affecting the dermis and epidermis.Due to the risk of tolerance,local and systemic adverse reactions,the dosage,frequency and duration of use of desonide should be minimal to meet the required clinical efficacy.Therefore,it is considered to be prepared into desonide nanoemulsion preparation,so that it can easily pass through the skin barrier and exert a therapeutic effect.Nanoemulsion（NE）as a new type of carrier system has the incomparable advantages of traditional gels,creams,ointments,etc.Its transparent appearance,small particle size and stability,can solve the problem of insoluble drug absorption.However,the nanoemulsion has low viscosity and good fluidity,and it is not easy to adhere to the skin when used in topical preparations for transdermal administration.Therefore,in this project,the optimized nanoemulsion is loaded into the gel matrix to prepare desonide nanoemulsion gel（DES NE-gel）,on the one hand,it can increase the viscosity of the preparation and be easy to apply,so that the drug can be slowly released into the skin;on the other hand,the three-dimensional network skeleton of the hydrogel formed by physical cross-linking can prevent the Ostwald ripening of the nanoemulsion and make the nano Milk is more stable.The purpose of this subject is to prepare hydrogels based on desonide nanoemulsion,and to study its transdermal properties,therapeutic effects on eczema,safety and stability.The main research contents and results are as follows:1.Pre-prescription research:An accurate and reliable HPLC method for the determination of desonide content has been established.The oil-water distribution system of desonide was determined by the shake flask method.The results showed that the drug is highly lipophilic,and the diffusion of desonide in the epidermis and dermis limits its transdermal absorption,so o/w type nanoemulsion needs to be prepared.The constant temperature oscillation method was used to determine the solubility of DES in different oils and surfactants,laying a foundation for prescription screening and process research.2.The desonide nanoemulsion was prepared by the high-pressure homogenization method,and the particle size,PDI,encapsulation efficiency,and zeta potential were used as indicators to investigate the homogenization pressure,homogenization times,oil,surfactant,and surface aid through single factor experiments.The influence of the amount of active agent on the quality of nanoemulsion,the homogenization pressure is 900 bar,and the number of homogenization times is 3 as the preparation process.The factors that have a greater impact on the nanoemulsion are screened out,and the Box-Behnken response surface method is optimized.The best prescription composition is:eucalyptus oil:glyceryl triacetate（1:1,13.21%）,oleic acid（0.5%）,Tween 80（6.99%）,poloxamer 407（1.5%）,diethylene glycol Alcohol diethyl ether（1.85%）,purified water（75.05%）.3.Perform particle size,encapsulation efficiency,zeta,PDI,TEM,appearance,type of nanoemulsion,differential scanning calorimetry（DSC）,X-ray diffraction method,thermal stability experiment on the nanoemulsion prepared by the above prescription process,Speed up the quality evaluation of the experiment.The results show that the nanoemulsion is a translucent light blue opalescent emulsion.The morphology observed under TEM is spherical,and it is judged to be o/w type nanoemulsion by the dyeing method.By using Delsa Nano TMC particle size and The particle size measured by Zeta potential analyzer was38.3±1.47 nm,Zeta potential was 20.69±0.44 mv,PDI was 0.174±0.026,and the encapsulation efficiency measured by ultrafiltration centrifugation was 91.32±0.62%.The results of DSC and X-ray diffraction showed that the characteristic peaks of desonide in the nanoemulsion disappeared,indicating that the drug was dispersed in the carrier in a molecular state,and the encapsulation effect was good.Centrifugation,heating and cooling cycle experiments and accelerated stability experiments have proved that the nanoemulsion has good stability.4.Prepare desonide nanoemulsion gel with Carbomer 980 as the gel matrix.The Franz diffusion cell was used to study the in vitro release,in vitro permeation and retention of desonide nanoemulsion and gel in the skin.Confocal fluorescence microscopy（CLSM）was used to visually observe the penetration of the preparation,and HE staining,DSC,and infrared spectroscopy（ATR-FTIR）were used to study the transdermal mechanism of desonide nanoemulsion gel.The results show that:compared with the commercial desonate gel Desonate?,the release of desonide nanoemulsion gel follows the Higuchi model and has a slow-release effect.The cumulative penetration and retention of DES in the skin are significant（P<0.01）higher than that of desonide commercially available gels.CLSM results indicate that skin appendages（such as sweat ducts and hair follicles）also provide a way for desonide nanoemulsion gel to penetrate the skin.In addition,the results of fluorescence analysis can more intuitively observe the distribution of drugs in the skin.Nanoemulsions and nanoemulsions have significantly improved the penetration and retention of drugs,the penetration rate is fast,and the retention of drugs is large.The results of HE staining,DSC,and ATR-FTIR study indicate that the transdermal mechanism is mainly through changing the microstructure of the stratum corneum,increasing the fluidity between lipids and destroying the hydrogen bonds of the lipid bilayer,changing the structure of keratin in the stratum corneum and increasing the keratin.Hydration of the layer,thereby increasing the penetration of the drug.5.Use 2,4-dinitrofluorobenzene to establish a mouse model of chronic eczema and administer treatment.The experimental results show that desonide nanoemulsion gels have better effects than commercially available gels.Desonide nanoemulsion gel can significantly improve the thickening and swelling of the right ear tissue in chronic dermatitis-eczema mice,the cortex becomes thinner,the thymus and spleen index is reduced,the number of inflammatory cells is significantly reduced,and the pathology is improved,and there is a dose Dependency.6.Investigate the safety of desonide nanoemulsion gel.The safety of the preparation was evaluated by investigating the toxicity of desonide nanoemulsion gel on Ha Ca T cells and the effect on cell permeability.The irritation of the preparation on the normal skin and broken skin of New Zealand white rabbits was investigated through single skin administration and multiple skin administration.The experimental results show that the preparation has no effect on the survival rate of Ha Ca T cells at a concentration of 100μg·ml-1.Skin irritation experiments show that the desonide nanoemulsion gel has no obvious irritation to the skin after single or multiple administrations.7.To investigate the stability of desonide nanoemulsion gel through influencing factor experiments and accelerated experiments.The results of influencing factors indicate that the desonide nanoemulsion gel is stable to strong light,intolerant of high temperature and humidity.Commercial packaging has good stability within two months. |
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