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??OBJECTIVE To establish an LC-MS/MS method to determine (S)-pantoprazole sodium in dog plasma and investigate its toxicokinetics. METHODS After protein precipitation with acetonitrile, the analyte and internal standard were separated on CHIRALCEL OJ-RH column (4.6 mm ??150 mm, 5 ??m) with acetonitrile-water (28??72) as mobile phase eluted at a flow rate of 0.6 mL??min^-1. Detection was carried out by electrospray positive ionization mass spectrometry in the multiple reaction monitoring (MRM) mode. The MRM transitions of m/z 384.0/199.8 and m/z 180.0/110.0 were used to quantify (S)-pantoprazole sodium and phenacetin, respectively. Beagle dogs were intravenously given (S)-pantoprazole sodium for 4 weeks at low, medium, and high dosages (10, 20, 40 mg??kg^-1??d^-1). RESULTS The calibration curve was linear over the concentration range of 50-30 000 ng??mL^-1. The RSDs were less than 15%, and the accuracy was in the range of 85%-115%. The AUC_{0-4 h} and ??_max of (S)-pantoprazole sodium were proportional to the dosages. CONCLUSION The established method can be applied to the determination of (S)-pantoprazole sodium in plasma of dogs and is suitable for the toxicokinetic study.     

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??OBJECTIVE To improve the dissolution and oral bioavailability of cinacalcet in fasted state by preparing cinacalcet nanoemulsion. METHODS The oil phase, emulsifiers and co-emulsifiers were selected by solubility test and phase diagram studies. The dissolution in vitro and bioavailability in Bealge dogs of cinacalcet nanoemulsion were evaluated. RESULTS The cinacalcet nanoemulsion was prepared with oleic acid(as oil phase), OP-10 (as emulsifier), PEG200 (as co-emulsifier) and water (W-W=3:8:4:15) and showed goog physical properties with regular round appearance. The average particle size of cinacalcet nanoemulsion was (24.1??3.8) nm. The poly-dispersity index (PDI) and Zeta potential were (0.261??0.032) and (-26.1??1.7) mV, respectively, which proved that the cinacalcet nanoemulsion formed a stable system. The in vitro dissolution of cinacalcet was significantly improved after being prepared into nanoemulsion. The pharmacokinetic study showed that the bioavailability of cinacalcet nanoemulsion was significantly enhanced in Beagle dogs in fasted state and the absorbtion of cinacalcet nanoemulsion had no difference in fed and fasted state. CONCLUSION Cinacalcet nanoemulsion is easy to prepare and has small particle size, which can significantly improve the dissolution and bioavailability of cinacalcet in fasted state.     

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??OBJECTIVE To prepare freeze-dried alprostadil lipid microspheres and investigate their stability and pharmacokinetic characteristics. METHODS The alprostadil lipid microspheres were prepared by two-step emulsifying method and then freeze-dried. The physicochemical properties were characterized. The stability in vitro and pharmacokinetics in Beagle dogs were also studied. RESULTS The freeze-dried alprostadil lipid microspheres presented a good appearance and the rehydrated time was short. The size after reconstruction was (164.1??3.9) nm, the encapsulation efficiency was (92.5??3.3)% and the content of PGA₁ was (1.38??0.21)%. It showed good stability after storing for 6 months as indicated by the size and contents of alprostadil and PGA₁. After intravenous injection in Beagle dogs, the half time and peak time were (7.5??3.7) and (7.6??2.9) min respectively, and the peak plasma concentration of PGE₁ was (105??40.4) ng??L^-1, which was similar to the reference formulation. CONCLUSION The freeze-dried alprostadil lipid microspheres can significantly improve the stability of alprostadil lipid microspheres with good pharmacokinetic characteristics, which indicates a promising prospect in clinic use.     

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??OBJECTIVE To prepare the tulobuterol crystal reservoir patch, and to evaluate morphology, stability and crystallization factors of the crystal in the patch, adhesive force, dissolution, transdermal properties in vitro and the pharmacokinetics in rabbits. METHODS The transdermal patch was prepared on the basis of drug recrystallization and characterized by morphology, stability and crystallization factors using microscope and adhesive force using initial adhesion tester, adhesion tester and peel tester. The dissolution and transdermal properties were evaluated by using the dissolution tester and transdermal tester. In addition, pharmacokinetics was studied using New Zealand rabbits as experimental animals. RESULTS The drug crystals were evenly distributed in the form of filaments, which had average width of (4.4??1.8)??m and kept stable at 2-40 ??. The crystallization in patches is affected by tulobuterol supersaturation and temperature. The adhesive force of patch was suitable and its dissolution matched standard which can be fitted by the Higuchi equation. In the diffusion cell in vitro, the drug penetrated through the skin in a Zero-order kinetic equation, and the cumulative penetration percentage and skin retention concentration were 92.04% and 10.36 ??g??cm^-2 with in 24 h. The pharmaceutic parameters showed that the tulobuterol blood concentration can be maintained within 24 h, whose t_max and ??_max were (6.67??3.06)h and (3.08??1.32) ng??mL^-1, respectively. CONCLUSION The tulobuterol crystal reservoir patch can be established by control of recrystallization conditions. The patch has good adhesive properties and sustained release characteristics in vitro and in vivo, which has the practical significance for further study.     

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??OBJECTIVE To compare the pharmacokinetic parameters of Xuesaitong dispersible tablets and common tablets in Beagle dogs. METHODS Using double cycle crossover trial, six Beagle dogs were treated with single oral dose of 100 mg of Xuesaitong dispersible tablets and conventional tablets and determining the pharmacokinetic parameters of ginsenoside Rb1 and Rg1 in Xuesaitong dispersible tablets and conventional tablets in Beagle dog plasma. RESULTS The ginsenoside Rb1 and Rg1 peak concentration of Xuesetong dispersible tablets in Beagle dog plasma was significantly higher than that of Xuesaitong tablets, the ginsenoside Rg1 peak time of Xuesaitong dispersible tablets in Beagle dog plasma was significantly earlier than that of Xuesaitong tablets. Additionally, the ginsenoside Rb1 peak time exhibited ahead of the trend, which is in line with the characteristics of rapid disintegration and absorption of preparation in vivo. CONCLUSION The plasma exposure in two preparation of ginsenoside Rb1 and Rg1 in Beagle dog holds fairly basic and no significant difference. But the ??_max of the main ingredients of Panax ginseng saponins Rb1 and Rg1 in Xuesaitong dispersed tablets, is significantly higher than that of the film coated tablets, and peak time is significantly shortened, which could promote the drug absorption.     

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??OBJECTIVE To study evodiamine complex nanoemulsion oil-in-water (EPBCN) in vitro and in vivo evaluation, about release in vitro and pharmacokinetics. METHODS Release in pH 1.2 hydrochloric acid and pH 6.8 PBS solutions and oral bioavailability in rats of EPBCN would be studied. The bioequivalence between evodiamine (ED) and EPBCN was judged. RESULTS In vitro release of EPBCN was about 2.61 times higher than that of ED. The oral bioavailability of EPBCN was 7.35 folds than that of ED. 90% confidence interval of area under concentration-time curve (AUC_{0-72 h}) and peak concentration (??_max) exceeded the standard range. CONCLUSION EPBCN can remarkably increase the release in vitro and oral bioavailability in rats, and they do not have bioequivalence.     

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??OBJECTIVE To study the pharmacokinetics and bioequivalence of hydroxysafflor yellow A (HSYA) and hydroxysafflor yellow A nanoemulsion (HYAN) in rats.METHODS Twelve male rats were randomly divided into two groups. The rats were administered intragastrically with HSYA or HYAN, respectively, and then blood was collected from the venous plexus at different time points. HPLC method was used for the determination of HSYA blood concentration.RESULTS The main pharmacokinetic parameters of HYAN were as follows: the area under curve (AUC_{0-24 h}), peak concentration (??_max), peak time (t_max) and clearance (CL) were (31.56??4.58) mg??L??h^-1, (12.75??2.64) mg??L^-1, (0.83??0.54) h and (1.89??0.93) L??h^-1??kg^-1, respectively. The AUC_{0-24 h}, ??_max and t_max of HYAN increased by 5.49, 10.22 and 2.50 times, respectively, and the CL of HYAN was only 1/4 of that of HSYA. The 90% confidence intervals for AUC_{0-24 h} and ??_max were not within the prescribed range of bioequivalence criteria.CONCLUSION Relative to HSYA, the high plasma concentration and prolonged peak time of HYAN in vivo can significantly improve the oral bioavailability of HSYA. HSYA solution and HYAN are not bioequivalent.     

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??OBJECTIVE To establish an LC-MS/MS method for the determination of levetiracetam to investigate the pharmacokinetics of levetiracetam extended-release tablets at fasted and fed states. METHODS The separation was achieved on a Waters Symmetry C₁₈ column (3.9 mm??150 mm,5 ??m) with mobile phase consisting of acetonitrile-5 mmol??L^-1 ammonium acetate and 0.3% formic acid aqueous solution (10/90, V/V). Two subjects were randomly assigned to receive single oral dose of levetiracetam extended-release tablets 1 000 mg after being fasted and fed by a randomized crossover design. The plasma concentrations of levetiracetam were measured by LC-MS/MS. RESULTS The calibration curve of levetiracetam in human plasma was linear over the concentration rang of 0.100 0-80.00 ??g??mL^-1. Under fasted and fed conditions, the main pharmacokinetic parameters of levetiracetam were as follows:??_max were 20.50 and 19.09 ??g??mL^-1, AUC_{0-48 h} were 345.4 and 336.3 ??g??h??mL^-1, t_max were 4.5 and 7.0 h, respectively. CONCLUSION The method is proved to be convenient, accurate and sensitive, and suitable for the pharmacokinetic study of 1 000 mg levetiracetam extended-release tablets in healthy Chinese volunteers after being fasted and fed. The result suggests that high fat and calories diet has effect on the pharmacokinetics of levetiracetam extended-release tablets, with t_max being delayed.     

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??OBJECTIVE To evaluate the effects of drug concentration and perfusion rate on the recoveries of self-made linear microdialysis probes for further ocular pharmacokinetic study. METHODS Brimonidine tartrate was selected as the model drug. The in vitro recovery was determined using positive dialysis and retrodialysis at different perfusion rates and drug concentrations. And the in vivo recovery was determined using retrodialysis method. RESULTS The microdialysis recoveries of brimonidine tartrate were inversely proportional to perfusion rate,while independent of drug concentration. The positive dialysis and retrodialysis recoveries in vitro were different at 1.0 ??L??min^-1, but no significant difference at 2.0 and 3.0 ??L??min^-1. The in vitro recoveries were greater than those in vivo. CONCLUSION The self-made microdialysis probe has stable recovery and can be used in ocular pharmacokinetic study of brimonidine tartrate.