Studies On Preparation And Efficacy Of Butenafine Hydrochloride Nanoemulsion

Objective: To offer a novel safe and effective transdermal drug for treatment of skinfungal infections, we developed butenafine hydrochloride nanoemulsion as a novel allylamineantifungal drug preparation and evaluated the quality, safety, transdermal effect andpreliminary clinical efficacy.Methods:(1) To formulate the butenafine hydrochloride nanoemulsion, we drafted thepseudo-ternary phase diagrams by water titration method, and determined the optimalformulation.(2) The quality of butenafine hydrochloride nanoemulsion was evaluated withstructure pattern, droplet size, particle size distribution, content, and stability.(3) The safetyof butenafine hydrochloride nanoemulsion for skin was evaluated by skin irritation withsingle or multiple dosing, skin sensitization, and skin acute toxicity with single dosing.(4)The transdermal effect of butenafine hydrochloride nanoemulsion was tested in mouse skin invitro, with comparation of accumulated transdermal quantity and retention volume amongbutenafine hydrochloride nanoemulsion and butenafine hydrochloride cream with addition of0%,1%or2%azone.(5) To evaluate the antifungal ability in vitro, the minimal inhibitoryconcentration of butenafine hydrochloride nanoemulsion for Trichophyton rubrum,Trichophyton mentagrophytes, Epidermophyton floccosum and Microsporum canis was testedby double broth dilution method, and was compared with butenafine hydrochloride cream andbifonazole cream.(6) The clinical pharmacodynamics of butenafine hydrochloridenanoemulsion was evaluated in guinea pig skin infected with Trichophyton mentagrophytesand was compared with butenafine hydrochloride cream and bifonazole cream.Results:(1) The optimal formulation of butenafine hydrochloride nanoemulsion was asfollows: ω (butenafine hydrochloride nanoemulsion)=1.2%, ω (Tween-80)=29.8%, ω(absolute ethyl alcohol)=10%, ω (isopropyl myristate)=2%, ω (polyethyleneglycol-400)=0.3%, ω (distilled water)=56.7%.(2) Butenafine hydrochloride nanoemulsion wastransparent and faint yellow liquid with the structure pattern of oil in water (O/W). Theaverage particle size was12.8nm, and the polydispersity index (PDI) was0.137, with anarrow and homogeneous particle size distribution. After a5-fold dilution, the average pHvalue was6.3±0.3, and the corresponding zeta potential was (-10.3±0.1) mV. Acceleration,centrifugation, illumination, and longterm storage test had no results of layering, separating out, flocculating and obvious content changing. The prepared nanoemulsion had a goodstability, and the period of validity was30months.(3) Butenafine hydrochloridenanoemulsion had no irritation effect on skin, except that high dosing group had slightirritation to damaged skin for the first three days. Test in the guinea pig skin indicatedbutenafine hydrochloride nanoemulsion was a weak sensitizing preparation with nosensitization incidence. In the acute toxicity test, butenafine hydrochloride nanoemulsion withmatrix had no obvious influence on rat growth, proved to be a safe preparation for externaluse.(4) The transdermal effect of butenafine hydrochloride nanoemulsion was significantlybetter than butenafine hydrochloride cream, as the percutaneous rate, accumulatedtransdermal quantity for the first12hours and retention volume were3.35,3, and2.6timesthat of butenafine hydrochloride cream, respectively. Addition of azone didn’t affect thetransdermal effect of butenafine hydrochloride nanoemulsion distinctly, but the transdermaleffect of butenafine hydrochloride cream was improved.(5) The minimal inhibitoryconcentration of butenafine hydrochloride nanoemulsion for the four types of fungi had3.96-33.33times of significant difference (P<0.05) compared with butenafine hydrochloride creamand bifonazole cream.(6) Within two weeks, the cure rate of butenafine hydrochloridenanoemulsion for guinea pig skin infected with Trichophyton mentagrophytes was highercompared with butenafine hydrochloride cream and bifonazole cream. The effect ofbutenafine hydrochloride nanoemulsion was quick, and all cases were cured at day12with norecurrence.Conclusion: The formulated butenafine hydrochloride nanoemulsion presented goodstability, safety, and efficacy, in accord with the quality requirements of nanoemulsionformulation.