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??OBJECTIVE To optimize the preparation process conditions of fanhuncaoin dry powder for inhalation by orthogonal design. METHODS Fanhuncaoin dry powder was prepared by spray-drying method. Following spray-drying, particle size analysis was performed by laser diffraction. Resultant powders were characterized using scanning electron microscopy. The aerosolisation performance was determined using twin-stage liquid impinger. And moisture content was examined by thermogravimetric analysis. The preparation process conditions were optimized with orthogonal design combined with multi-index test. The powder yield, aerodynamic diameter, moisture content and respirable fraction were used as indices for orthogonal design. RESULTS The results of optimized process parameters were confirmed with atomization pressure of 210 kPa, feed flow rate of 9.1 mL??min^-1, aspiration speed of 0.6 m³??min^-1 and inlet temperature of 130 ??. As a result,51.19% yield, 2.92 ??m aerodynamic diameter,4.18% moisture content and 54.45% respirable fraction are obtained by the optimal process conditions. CONCLUSION Orthogonal design combined with multi-index test can be used to optimize the preparation process of fanhuncaoin dry powder for inhalation.     

载体对粉雾剂粉末流动性的影响

目的　研究载体对粉雾剂粉末流动性的影响 ,确定适宜的粉雾剂载体和载体的介入方法。方法　以硫酸沙丁胺醇为模型药物 ,以休止角为流动性指标 ,研究不同类型、大小的乳糖载体 ,对物理混合型硫酸沙丁胺醇粉雾剂粉末流动性的影响 ;以乳糖、甘露醇、甘氨酸为内加载体 ,采用喷雾干燥微粉化方法 ,制备微粉型硫酸沙丁胺醇粉雾剂 ,并进一步考察泊洛沙姆对微粉流动性的影响。结果　重结晶乳糖休止角较市售乳糖小 ;在喷雾干燥工艺处方中 ,加入适量的泊洛沙姆 ,可明显增加以乳糖和甘氨酸为载体的粉雾剂微粉流动性 ,其中以甘氨酸为载体 ,含 2 %泊洛沙姆的微粉型硫酸沙丁胺醇粉雾剂休止角最小35 .5 1°± 0 .2 5° ,流动性最好。结论　采用内加载体直接喷雾技术 ,并加入适量泊洛沙姆 ,可制得流动性良好的粉雾剂     

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??OBJECTIVE To establish an HPLC method for the simultaneous determination of butorphanol tartrate, dextroisomer and benzethonium chloride which works as the bacteriostatic agent in butorphanol tartrate injection on a cyclodextrin chiral column. METHODS The HPLC analysis was performed on an Astec Cyclobond ?? cyclodextrin chiral column (4.6 mm??250 mm,5 ??m), with mobile phase consisting of 0.05 mol??L^-1 ammonium acetate solution (pH was adjusted to 4.1 by acetic acid) and acetonitrile using gradient elution at a flow rate of 1.0 mL??min^-1. The detection wavelength was set at 280 nm. RESULTS The method showed good linearity for the three components to be measured. The linear ranges were 0.04-2.0 mg??mL^-1 for butorphanol tartrate (r=0.999 9), 0.01-2.0 mg??mL^-1 for dextroisomer (r=1.000 0), and 0.02-1.0 mg??mL^-1 for benzethonium chloride (r=0.999 9), respectively. The average recoveries were 100.2%, 100.7%, and 99.4%, respectively. CONCLUSION The method is simple, accurate and reproducible. It can be used for the quality control of butorphanol tartrate injection.     

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??OBJECTIVE To establish a simple, sensitive method of liquid chromatographic-tandem mass spectrometric (LC-MS/MS) for determination of mirabegron in dog plasma, and to evaluate the pharmacokinetics for single dose of different formulations of mirabegron sustained-release tablets in dogs. METHODS The analyte mirabegron and internal standards (IS) tolbutamide were separated on a BEH C₁₈ column (2.1 mm??50 mm, 1.7 ??m) with mobile phase of 0.1% formic acid water solution-0.1% formic acid methyl cyanides solution using a gradient elution mode at a flow rate of 450 ??L??min^-1. In accordance with randomized two-period self crossover study, eight dogs were given single oral dose of the test preparation and reference preparation, then the concentration of mirabegron in plasma was determined, the pharmacokinetic parameters were calculated and the difference of the two preparations were evaluated. RESULTS The linear range of mirabegron in Beagle dogs plasma was 1-1 000 ng??mL^-1. The accuracy and the precisions of intra-day and inter-day also were qualified. After a single dose administration of the test preparation and reference preparation, the pharmacokinetic parameters were as follow:t_1/2 were(7.14??1.59) vs (7.13??1.78)h, ??_max were (144.4??77.5) vs (130.3??39.2)ng??mL^-1, t_max were (3.72??1.87) vs (4.64??1.55)h, AUC_0??48 were (1 021??439) vs (989??299)ng??h??mL^-1, AUC_0???? were (1 043??441) vs (1 010??301)ng??h??mL^-1. CONCLUSION The LC-MS/MS method is suitable for pharmacokinetic study of mirabegron. Moreover, there is no significant difference in the pharmacokinetic profiles between the two preparations of mirabegron.     

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??OBJECTIVE To determine the optimum ultrasonic-assisted extracting process of total flavonoids from Zingiber mioga by response surface methodology, and then study the antioxidant activity of the extract. METHODS On the basis of single factor experiments, a 4-factor, 3-level Box-Behnken center-united experiment was conducted. The Box-Behnken experiment analyzed and optimized the processing conditions by response surface methodology, then the antioxidant activity of the extract was determined. RESULTS The optimum conditions at ultrasonic power of 300 W were as follows treatment temperature 60 ??, ethanol concentration 85.99%, liquid-to-solid ratio 98.08 mL??g^-1, treatment time 15 min. Under the optimum conditions, the extraction rate of the total flavonoids was 37.01%, with a bias of 4.28% compared with the predicted value of 35.49%; the reducing power of the total flavonoids from Zingiber mioga at the concentration of 1.038 7 mg??mL^-1 was equal to that of vitamin C of 56.60 ??g??mL^-1; the ??OH radical scavenging ratio of the total flavonoids from Zingiber mioga was 73.07%, the DPPH radical scavenging ratio was 65.72%, and the inhibition rate of anti-lipid peroxidation was 49.94%. CONCLUSION The total flavonoids from Zingiber mioga can be developed as a new type of antioxidant agents, and regression analysis and parameter optimization of the extracting process can be conducted by using response surface methodology.     

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??OBJECTIVE To establish a method for determination of diclofenac sodium in human plasma under high-fat meal condition using two-dimensional liquid chromatography (2D-HPLC) coupled with trapping column, and to evaluate the bioequivalence and the bioavailability of diclofenac sodium sustain-released tablets in healthy volunteers. METHODS Under fed state, eighteen healthy male volunteers were divided into two groups by an open, randomized two period crossover design with a single dose of diclofenac sodium sustain-released tablets. The plasma concentrations were determined by 2D-HPLC method, and calculated pharmacokinetic parameters and bioavailability. RESULTS The main pharmacokinetic parameters of test and reference preparations after a single dose were: AUC_0??16 was (2 591.6 ?? 705.8 ) and (2 588.8??772.0) ng??h??mL^-1;AUC_0????was (2 896.4??839.7) and (2 700.3??806.1) ng??h??mL^-1; t_max was (4.6??0.7) and (4.4??0.9)h; ??_max was(1 332.8??912.5) and (1 325.7??706.3) ng??mL^-1, respectively. The relative bioavailability of test preparation in single dose was (102.4??15.1)%. CONCLUSION The 2D-HPLC method coupled with trapping column is a simple, rapid and specific for determination of diclofenac sodium in human plasma. The RESULTS of statistical analysis indicate that the two preparations are bioequivalent in healthy volunteers with a single dose under high-fat fed condition.     

Box-BehnkenЧӦ�淨�Ż������������׾���������Ĥ�Ĵ����о�

??OBJECTIVE To prepare and optimize meloxicam nanosuspensions fast dissolving sublingual films (MLX-NS-FDSFs) and to evaluate its in vitro dissolution characteristics. METHODS Meloxicam nanosuspensions (MLX-NS) were prepared by pH-dependent dissolving-precipitating/high speed shearing method and then transformed into fast dissolving sublingual films (FDSFs). The formulations of MLX-NS-FDSFs were optimized by employing Box-Behnken design-response surface methodology with the amount of HPMC-E30, PEG-400 and MLX-NS as investigation factors, and particle size of reconstituted nanoparticles from MLX-NS-FDSFs, disintegration time and stretch length as indexes. The morphology, content uniformity and in vitro dissolution of the optimal formulation were also evaluated. RESULTS The MLX-NS-FDSFs prepared by optimized formulation (35 mg??mL^-1 HPMC-E30, 40 mg??mL^-1 PEG-400, 10 mL MLX-NS) could fast disintegrate in (26.08??1.76) s, the tensile length was (1.51??0.13) mm, and the particle size of reconstituted nanoparticles from MLX-NS-FDSFs was (186.4??6.3) nm. There was a little deviation between the theoretically predicted value and the measured value. It showed that this model had a good prediction. Morphological analysis showed that well-dispersed MLX nanoparticles embedded in MLX-NS-FDSFs. The conformity of drug content was up to standard. MLX could be released in vitro as much as (91.75??8.05)% within five minutes. CONCLUSION Using Box-Behnken design and response surface method to optimize MLX-NS-FDSFs is effective and feasible. MLX-NS-FDSFs can significantly increase the cumulative dissolution of MLX.     

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??OBJECTIVE To develop an HPLC-ELSD method for determination of MPEG-DSPE and HSPC in doxorubicin hydrochloride liposome injection. METHODS The column was Waters Symmetry 300 C₁₈(4.6 mm??150 mm, 5 ??m;pore size:300). The mobile phase was methonal-tetrahydrofuran-0.17 mol??L^-1 ammonium acetate(93??6??1). The flow rate was 1.0 mL??min^-1. The column temperature was 25 ?? and the injection volume was 10 ??L. The ELSD conditions were as follows: Alltech 2000ES ELSD detector; drift temperature: 110 ??; rate: 2.6 L??min^-1. RESULTS This method had good specificity. The linear ranges of the calibration curves for MPEG-DSPE and HSPC were 0.03-0.48 mg??mL^-1 (r=0.999 8) and 0.1-1.0 mg??mL^-1 (r = 0.999 8), respectively. The average recovery rates of MPEG-DSPE and HSPC were 100.0% (n=3??3) and 101.0% (n=3??3), respectively. The LODs of MPEG-DSPE and HSPC were 13 and 52 ng, respectively. The repeatability and intermediate precision of MPEG-DSPE were 0.9% (n=5) and ??1.9%(n=3), respectively. The repeatability and intermediate precision of HSPC were 1.1%(n=5) and ??1.3%(n=3) , respectively. CONCLUSION The established method is accurate, reliable, repeatable and suitable for the determination of MPEG-DSPE and HSPC in doxorubicin hydrochloride liposome injection.     

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??OBJECTIVE To establisha simultaneous determination method of three main alkaloids in Plumula nelumbinis by high performance liquid chromatography(HPLC), including liensinine, isoliensinine and neferine, and optinize the ultrasonic-assisted extraction process of total alkaloids from Plumula nelumbinis by using response surface methodology based on Box-Behnken design. METHODS The alkaloids were separated on a RP-HPLC C₁₈ monolithic column(4.6 mm??50 mm, Merck, Darmstadt, German) with a mobile phase consisting of methanol-water-triethylamine-acetic acid(70??30??0.2??0.05), and the method was validated for linearity, sensitivity and extraction recovery. Based on the single-factor analysis, a mathematical model was constructed to analyze the effects of each factor of the ultrasonic-assisted extraction and their interactions on alkaloids yields of Plumula nelumbinis. The three independent variables were volume fraction of ethanol(A), solid-liquid ratio(B) and ultrasound extraction time(C), respectively. RESULTS The HPLC method used to separate three alkaloids within 5 min showed an excellent linear correlation (r²>0.999) in the range of 3.4-340 ??g??mL^-1(liensinine), 3.47-347 ??g??mL^-1(isoliensinine) and 3.47-347 ??g??mL^-1 (neferine). The limits of detection(LODs) of three alkaloids were 0.17, 0.69 and 0.69 ??g??mL^-1, and the limits of quantification were 0.34, 1.73 and 1.73 ??g??mL^-1, respectively. The intra-day and inter-day variations of RSD were less than 5%, and the extraction recovery rang from 97.06% to 104.12% with RSD ranging from 0.08% to 0.87%(n=6). The optimum extraction conditions were: solid-liquid ratio, 1??30.3; volume fraction of ethanol, 69.8%; ultrasound extraction time, 29.0 min. The yield under the optimum conditions was found to be(14.82??0.42) mg??g^-1, which was agreed closely with the predicted value of 14.70 mg??g^-1. CONCLUSION The HPLC method used to determine the three main alkaloids in Plumula nelumbinis shows ideal characteristics of quickness, accuracy, high sensitivity and good repeatability.The optimum ultrasonic extraction technology has expressed excellent extraction ability of alkaloids in Plumula nelumbinis which indicates the RSM result is reasonable and effective.