Preparation Of Ketoconazole Polymer Mixed Micelles

Ketoconazole(KTZ)is a broad-spectrum antifungal imidazole,Belgium,Janssen Pharmaceutica,first synthesized in 1976 and 1978 for clinical application.Clinically for the treatment of a variety of different types of Candida,yeast,fungal skin diseases caused by,especially for superficial dermatophytes and Candida powerful antibacterial.In recent years,the drug adverse reactions reported during use more and more,especially in the oral administration,the presence of severe liver toxicity problems.Objective:To improving the solubility and stability of ketoconazole,optimizing the preparaton process,improving efficacy,we make ketoconazole into polymer mixed micelles.And on this basis,evaluate the preparation of the polymer mixed micelles quality,establish the appropriate content determination method,and investigate in vitro transdermal rate and skin irritation,and then observe its curative effect on animal ringworm of the body model.Study provide reference for the development of new polymeric micelles of hydrophobic drugs.Methods:Using water-soluble polymer material poloxamer F68 and F127 as the carrier material,prepared by film dispersion ketoconazole polymer mixed micelles.The L9(34)orthogonal was designed by the amount of drug,the amount of methanol,the rate of the two carrier materials encapsulating efficiency as index polymer mixed micelles.Using high performance liquid chromatography(HPLC)method to determine the content,and its stability were investigated.Freeze-drying the ketoconazole polymer mixed micelles to a solid powder,and evaluated the quality before and after freeze-drying.In vitro penetration test using TP-5 Intelligent transdermal diffusion instrument.Made mice tinea model of candida albicans,studied the effect of ketoconazole polymer mixed micelles.Results:The best preparation process of ketoconazole polymer mixed micelles are:the amount of ketoconazole is 10 mg,the amount of methanol to 5 mL,F127 and F68 ratio is 3:2,rotating at a bath temperature of 40 C steam 1 hour,the rotational speed of 40 r/m.Add 5 ml deionized water with the same temperature,hydration 15 min.Polymer mixed micelles obtained at this time is regular spherical shape,uniform size,no adhesions,an average particle diameter of 9.2 nm,Zeta potential was+65.60 mV.Detected by HPLC,ketoconazole resulting polymer micelle encapsulation efficiency was 85.32%.The final freeze-drying process is:2 mL polymer mixed micelle solution was added 4%PEG-6000,pre-freezing 12 h,-60? freeze-dried 36 h.In vitro transparent tests showed that the polymer mixed micelles formulation penetration effect of ketoconazole.By stimulating experiments showed that polymer mixed micelles had no stimulation to the skin.Antibacterial tests showed that ketoconazole polymer mixed micelles Candida albicans have obvious inhibitory effect.Pharmacodynamic results showed that ketoconazole polymer mixed micelle of tinea Mice with good effect,with the positive difference between the groups was not statistically significant(p>0.05),and the blank matrix group and untreated group comparison were statistically significant(p<0.05).Conclusion:Preparation of ketoconazole film dispersion polymer micelle process operation is simple and feasible,which are in line with the requirements of quality evaluation,physical and chemical properties more stable.Pharmacodynamic tests showed that ketoconazole polymer mixed micelles having antibacterial effect.