| Lansoprazole is a new proton pump inhibitor (proton pump inhibitors, PPIs) which has accessed the French market in 1992. It is a second generation anti-peptic ulcer drug after Omeprazole has developed. Peptic ulcer is a kind of frequently-occurring common disease. Ulcers is usually single, which is called gastric ulcer in the stomach (gastric ulcer, GU), duodenal ulcer in the duodenum (duodenal ulcer, DU). More than 70% of duodenal and gastric ul-cers are caused by a bacterium called helicobacter pylori. According to the sta-tistics, more than 50% people of the world has infected with the H. pylori (Helicobacter pylori, HP).In China and other developing countries, the infection rate reaches to 70%90%. Where there is no acid, there is no ulcer. It is suggested that exces-sive stomach acid, weakened mucosal protection and Hp infection are the ma- jor causes of ulcer. Thus a medicine should be developed to treat Hp infection and peptic ulcers by decreasing the secretion of stomach acid and protecting the gastric mucosa. The proton pump inhibitors can block gastric acid secretion of in the last channel that lead to the inhibition of the secretion of gastric acid, histamine, acetylcholine and gastrin and acid secretion induced by physical stimulation through this channel. Therefore, the key measures to treat peptic ulcer is to inhibite the of secretion gastric acid. Lansoprazole can treat ulcer rapidly and efficiently through inhibiting gastric acid secretion and eradication Hp.Purpose:A highly simple, rapid and accurate assay was developped for determina-tion the concentration of Lansoprazole in human plasma by reverse-phase high performance liquid chromatography (HPLC) in order to support pharmacoki-netic studies and bioequivalent studies. On the basis, the anthropometric bioe-quivalence of Lansoprazole tablets produced by the Fourth Pharmaceutical Co.Ltd. of Zhonglian Group was evaluate. The reference agents was Lanso-prazole tablets produced by Yangtze River Pharmaceutical Group Pharmaceu-tical Co., Ltd. Sichuan Hairong. . The clinical data was provided to report to a higher authority of this drug. Meanwhile, scientific grounds were provided to guide the safe and reasonable clinical application, and references were also provided to research for drug experimentations.Method:The study included two parts. The first part was to establish a simple HPLC assay for determining the concentration of Lansoprazole in human plasma. In this part, conclude many choices about: chromatographic column, mobile phase, flow rate, internal standard, detectors and method of deal with human blood samples.Chromatographic conditions: the analytical column was an Agilent C18 ( 250 mm×5mm,5μm). The mobile phase consisted of a mixture of acetonitrile and phosphate buffer-triethylamine (pH =7.0)(v : v = 30 : 70). Flow rate: 1.0 mL·min-1; internal standard: Omeprazole; injection volume: 20μL; UV wave-length: 285nm. Meanwhile, we investigated the anylasis capability of chroma-tographic column C18 which was changed its heteropolarity and used in this study.Human plasma samples processing methods: precision drain plasma sam-ples, centrifugal, join internal standard omeprazole, then centrifugal, dry use-ing supernate liquid nitrogen gas. Join mobile phase after dissolving, feeding sample analysis.The second part was to study the pharmacokinetics and bioequivalence of Lansoprazole as well as reference agent following a single dose administration in healthy volunteers.In this study, standard two-stage self-control trial with crossover design was employed, and 20 healthy persons selected as volunteers were randomly divided into two groups.According to the chemical medicine clinical pharmacokinetic study , the technical guidance principle 20 cases of subjects were randomly divided into two groups, R/A two stages, pharmacokinetic and bioequivalence research. This experiment using internal standard method for plasma samples of the concentration of Lansoprazole in blood drug concentration time data via DAS2.1.1 pharmacokinetics, and statistical software processing 2.1.1 statistical software DAS analysis of variance and double unilateral t-test and (1-2α) % confidence interval analysis method with the tested preparations and prepara- tion does have the bioequivalence. Calculation other major pharmacokinetic parameters, Tmax, Cmax measured by using statistical moment, AUC calculation method.Results:1. In the present experiment, the number of theoretical plate of HPLC was 2350, and column efficiency is well. The Lansoprazole in serum was well sep-arated from the baseline, demonstrating its specificity. The linear relationship with peak area appeared from 50 ng·mL-1 to 2400 ng·mL-1 of Lansoprazole in serum (r =0.9992, n=6),The standard curve equation was Y = -0.011320 + 0.000755X,r = 0.9992。The lowest quantity limit was 50 ng·mL-1. The re-covery rates of the high, middle and low concentrations were (92.1 11.7)%, (106.6 14.3)%, (108.2 11.2)% respectively. The coefficients of inter-day were 12.43 %,0.925%,3.13 %, respectively and intra-day variations 9.27%, 6.99 %,4.81%, all less than 15%. Original serum samples were stable for 3 months at -20℃and the prepared to be tested sample 24h at room temper-ature, and the corresponding variant coefficients were both lower than 10%.2. The main pharmacokinetic parameters of Lansoprazole and reference formulation were as follows:Tmax were(2.52±0.80)and (2.82±0.69) h; Cmax were (854.82±249.70) ng·mL-1 and (813.22±289.59) ng·mL-1; AUC(0-12h) were (3779.90±1191.52) ng·h·mL-1 and (3513.00±742.25) ng·h·mL-1; AUC(0-∞)were (3742.635±749.854) ng·h·mL-1 and (4078.542±1171.173) ng·h·mL-1; T1/2Ke/h were (2.19±0.49)h and (2.38±0.48)h.3. Pharmacokinetics parameters were brought to logarithmic transformation, and analysis of variance in terms of AUC(0-12h), AUC(0-∞), Cmax and Tmax were carried out. No significant difference existed between two Lansoprazole prep-arations. Then double half analysis and (1-2α)% confidence interval analysis were applied to exhibit no significant difference in AUC(0-12h) and Cmax (P>0.05). Tested formulation AUC(0-12h) of 90% confidence interval is corre-sponding to reference formulation 88.4%～103.8%, 90% confidence interval of Cmax is corresponding to reference formulation 92.2%～127.2%.Conclusion:1. Established analysis Lansoprazole pharmacokinetic and human bioequiva-lence evaluation by HPLC method, which was highly specific and had high detection sensitivity and accuracy result characteristic. All performance index-es accord with pharmacokinetic and bioequivalence research test. And the op-eration is fast and simple, precision and high efficiency.The subject modified C18 column using polarity analysis of effects of Lansoprazole obtained the ex-pected results.2. This test on test preparation (Lansoprazole Tablets) and participation on the human body than preparations bioequivalence evaluation AUC(0-∞) was inves-tigated, and Cmax, T1/2, and AUC(0-12h), Tmax, many indexes, etc, get more than 2,200 effective experimental data. Conclusion: two preparations in healthy body has bioequivalence, relative bioavailability of localizing, two agents me-tabolise similar, can be in clinical safely and effectively use.3. This test on test preparation (Lansoprazole tables) and Lansoprazole prepa-rations pharmacokinetic studies, illuminates the Omeprazole in human absorp-tion, distribution, metabolism and excretion pharmacokinetic variation charac-teristics for the drug, declare to provide information, formulated for guide clinical safety, reasonable dosing, also provided the scientific basis for similar drug development to provide the reference. |
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