| ObjectivesOtomycosis externa is a common clinical ear disease in recent years.It often causes ear pruritus and pain,which seriously affects the quality of life of patients.However,there is a lack of suitable drug preparation for the treatment of the disease,and an ear drop with convenient use and definite efficacy against external auditory canal fungus is urgently needed in clinic.The aim of this research is to prepare the ear drops dosage form of voriconazole,optimize the formulation through process screening,establish the quality standard of the preparation and evaluate its safety and effectiveness,provide new preparations for the treatment of otomycosis externa.Methods(1)Orthogonal experimental design was used to investigate the effects of mass ratio of subject to object,inclusion time and inclusion temperature on inclusion rate and inclusion yield of voriconazole cyclodextrin inclusion complex.The types and dosage of stabilizer,preservative and p H regulator were screened by single factor influence experiment to optimize the formulation.(2)The quality standard of the preparation was determined according to the requirements of the Chinese Pharmacopoeia for ear drops,and the content of voriconazole in the preparation was determined and verified by high performance liquid chromatography(HPLC)external standard method.The related substances and voriconazole dextral isomers of the preparation were detected by HPLC.Furthermore,the contents,related substances,p H value,quantity and microbial limit of the preparation were investigated under accelerated(30℃),long-term(25℃)and cold storage(2～10℃)conditions for 6 months.(3)The safety of voriconazole ear drops was preliminarily evaluated by intact skin and damaged skin stimulation test of rabbit ear and allergic test of guinea pig.Besides,fungus from external auditory canal was isolated and cultured,and the sensitivity of pathogenic fungus to the preparation was detected by drug sensitivity test in vitro.Results(1)The optimum inclusion technology was as follows: voriconazole and sulfobutylether-β-cyclodextrin,the ratio of host to guest was 1:16,the inclusion time was 3 h,and the inclusion temperature was 40±2.5℃.In addition,voriconazole ear drops were formulated with voriconazole(0.2%)as main drug,sulfobutylether-β-cyclodextrin as solvent,ethanol as cosolvent,glycerol(30%)and propylene glycol(30%)as stabilizer,sodium benzoate(0.1%)as preservative and acetic acid as p H regulator.(2)HPLC methods were established respectively for the determination of voriconazole,related substances and dextral isomers.The results of recovery,precision,limit of detection and limit of quantification showed that the method of voriconazole content was specific and sensitive.Voriconazole ear drops were colorless and oily with p H ranging from 5.0to 6.5.The three batches of voriconazole ear drops remained stable for 6months under cold storage(2 to 10℃).(3)New Zealand rabbits were treated with voriconazole ear drops twice a day for 14 consecutive days,4-6 drops once,and ear bath.No stimulation reaction of voriconazole ear drops on intact skin and damaged skin of external auditory canal was observed.Guinea pigs were sensitized3 times and stimulated 1 time with preparation,no local or systemic allergic reaction was found.Most of the 52 strains were Aspergillus fungi and98.08%(n=51)were sensitive to voriconazole ear drops.ConclusionIn this study,we designed the voriconazole ear drops.The properties of voriconazole remained stable after 6 months storage in cold storage.Voriconazole ear drops had no significant irritation to ear skin or no local and systemic allergy.It has inhibitory effect on most pathogenic fungi of external auditory canal.The preparation is safe and easy to use.Thus,it is expected to be used as a hospital preparation for the treatment of otomycosis externa. |
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