The Pharmacokinetics Staudy Of Itraconazole Nanosuspensions With Cholic Acid As The Stabilizer

With the advances of combinational chemistry and high throughput screening,an increasing number of pharmacologically active compounds have been identified and developed.A significant proportion of those drug candidates are poorly watersoluble resulting in the limited absorption.Therefore,advanced formulation and processing technologies are required to overcome solubility issues.A number of methods have been extensively investigated for dissolution enhancement,such as particle size reduction,salt formation and lipid-based formulation,to increase the solubilization.ITRAconazole is belong to?biopharmaceutics classification system?BCS 2 class of drugs,whose dissolubility in water is poor(pH=7,less than 1 ng.ml^-1).In this paper,the preparation of nanoparticles suspension agent?Nanosuspension?was studied,and further,the prescription,preparation technology,the physical and chemical properties,and pharmacokinetic characteristics were systematically examined.Appropriate stabilizers are added to the nanosuspension to lower the free surface-energy of the nanoparticles and to prevent the agglomeration.The high free surface-energy of nanoparticles can be lowered by stabilizers that decrease the solid-liquid interfacial tension,while particle aggregation may be efficiently prevented or slowed down through forming electrostatic repulsion or steric barriers.Bile acids are natural compounds belonging to the structure of steroid.The important detergent properties of bile acids come from their facial amphiphilic nature,which is derived from convex hydrophobic b-side and the convex hydrophilic a-side.In previous reports,bile acid as a hydrophobic segment combined with other hydrophilic polymer segments to constitute the amphiphilic diblock or multiblock polymerization.The reports were few which acting as the stabilizer individually.In recent years,scientists have studied amphiphilic block copolymers of bile acids?Poly?bile acid?s amphiphilic block copolymer,“PBA-ABC”?include phospholipids-bile acids block copolymer?Sandeep Kumar,2015?,the bile acid-fluorouracil prodrug polymer?Diana Vivian,2014?,polyethylene glycol?peg?-cholic acid block copolymer?Kai Xiao,2009?,polyethylene glycol?peg?-cholic acid-vitamin E block copolymer?Wenzhe Huang,2014?,bile acid-polyethylene imine block copolymer?m.Wahab Amjad,2014?,etc.A kind of supramolecular gel is formed by cyclodextrin and bile acid?Yong-Guang Jia?.If it is used as a stabilizer for the nanosuspension,based on the amphiphilic properties of the molecular structure,the hydrophobic part can adsorb on the surface of drugs,and the hydrophilic side will stretch into the water around the drug,forming strong hydrophilic shell.The pure drug was stabled in the middle to form stable sub-micron drug particle suspensions.First analysis of ITRA in vitro was established.Specific chromatographic conditions wereThermo Syncronis C₁₈8 column?250×4.6mm,5?m?,85%methanol as the mobile phase,flow rate of 1.0mL·min^-1,detection wavelength of 263 nm,25?as the column temperature,injection volume of 10?L.By the study of methodology,ITRA has a good linear relationship in a concentration range of 0.1-25?g.mL^-1,with the average recovery of 99.56%and the RSD of 0.75%.After investigation on the prescription including the drug concentration,the ratio of stabilizer and drug and the technique containing the stirring speed of craft micro-precipitation,the homogeneous pressure and homogeneous times we confirmed 1:1 as the ratio of bile acids and ITRAconazole and 1mg.mL^-11 as the drug concentration.Microprecipitate-high pressure homogenization were used to prepareITRA-Nano.Freeze-dried powder were prepared by the method of freeze-drying.The amount of freeze-drying protection was investigated.Dry powder prepared by different concentrations of mannitol showed loose,and had no collapse phenomenon observed from the appearance.Lyophilized formulation prepared by mannitol with the amount of 5%had a minimum change in particle size and distribution after reconstitution.Next,the formulation properties of ITRA-Nano were research.By TEM,ITRA-Nano showed rod shape and evenly distributed.Particle size and distribution of ITRA-Nano was analyzed before and after lyophilization by DLS.It can be found that particle size of nanoparticles did not change significantly before and after the freeze-drying.The stability was excellent.DSC and X-ray diffraction revealed the changes of crystal form.They showed that the the presence of ITRAconazole nanosuspension was still the crystalline state,comparing with the crude drug.Slurry method was used to test the dissolution in vitro of the drug.The results showed that nano-suspensions can significantly improve the dissolution rate of the drug,with a cumulative dissolution of 80%after 30min.Finally,pharmacokinetics analysis method of ITRA was established.Dynamic behavior of two formulations by oral,namely ITRAconazole capsules and ITRA-Nano,were studied without food.The results showed that,AUC_?0-??and Cmax ofITRA-Nano was significantly higher than the capsules.It indicated that the preparation of ITRA nanoparticles can effectively improve its absorption in vivo.