| Ketoconazole(KCZ)belongs to the imidazoles antifungal drugs,and the mechanism of action is to inhibit ergosterol biosynthesis in the fungal cell membranes to achieve antifungal effect,which has been used clinically for the treatment of systemic fungal infection.But,because KCZ belongs to Biopharmaceutics Classification System class II,the absorption and bioavailability of KCZ are influenced or limited by the poor solubility.In this paper,starting from increasing drug solubility,KCZ nanocrystals were prepared by nanocrystal technology,so as to reduse diameter of particles,increase the drug solubility and dissolution rate and improve the drug absorption and bioavailability,thus reducing drug dose and liver toxicity.KCZ nanocrystals also can be used as intermediates for the development of topical preparations and other preparations.The UV and HPLC methods were established respectively in this paper for the analysis of the dissolution rate and the assay of KCZ.The results showed that the methods were accurate,reliable,stable and suitable for the quality control of KCZ.High pressure homogenization method was employed to prepare KCZ nanocrystals,and the technological conditions of this method were also studied with particle size and PI as evaluation index.The process parameters,such as drug concentrations,types and concentrations of stabilizer,the pressure of high-pressur homogenizer,homogenization circle numbers were investigated via single factor tests.On this basis,the process conditions were optimized in an orthogonal experiment of four factors and three levels.And the results indicated that the optimized process parameters were as follows: the concentration of stabilizer poloxamer 407 was 10%(relative to the drug amount),the concentration of drug was 10 mg/m L,the circulating pressure was 800 bar,and the circle index was 15 times.The pharmaceutical characteristics of KCZ nanocrystals were studied,such as particle size,appearance morphology,crystal form,solubility and dissolution rate,etc.The results indicated that the crystal form of self-made nanocrystals was regular with good dispersibility,the particle mean diameter was 120 nm with uniform particle size,and the chemical structure and crystal form of KCZ nanocrystals weren’t changed obviously.Furthermore,the solubility of KCZ nanocrystals was higher than bulk drug,and the results showed significant improvement in the dissolution rate of KCZ nanocrystals compared to bulk drug and commercially available capsules.In the study,the composition and processing technology of KCZ nanocrystals capsules were confirmed.The capsules formulation was composed of appropriate amount of dry KCZ nanocrystals and 3% talcum powder(relative to the amount of nanocrystals).The mixed contents were filled in capsule shell and corresponded to 200 mg KCZ.The quality of self-made capsules complied with the requirement of capsule in the appendix of Chinese Pharmacopoeia(secontd part,2010 edition)and the results showed a significant increase in the dissolution rates of KCZ nanocrystals compared to the control preparations.The wistar rats were selected as experimental animals and the HPLC method was established to determine plasma concentration of KCZ in the study.The pharmacokinetics of the self-made capsule was studied by single dose testing with bulk drug and commercially available capsules as contorl.The study results were as follows: after oral administration of the self-made capsules,bulk drug and the commercially available capsules,the peak concentration(Cmax)were 2232.26±30.16ng/m L,140.10±10.27ng/m L,1335.62±28.62 ng/m L,respectively,and the area under plasma drug concentration-time curve(AUC0-∞)were 20710±235.22ng·h/m L,1763±136.23ng·h/m L,11360±201.36ng·h/m L,respectively.The study results indicated that the self-made capsules improved the drug absorption and bioavailability and the relative bioavailability were1174.70% and 182.31%,respectively. |
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