Analytical Methods Validation: Bioavailability,Bioequivalence and Pharmacokinetic Studies

Pharmaceutical Research -     

Formulation,Biological and Pharmacokinetic Studies of Sucrose Ester-Stabilized Nanosuspensions of Oleanolic Acid

Purpose  

The aim of this study was to develop sucrose ester (SE)-stabilized oleanolic acid (OA) nanosuspensions (NS) for enhanced delivery.     

Enhancement of Oral Bioavailability of Tripterine Through Lipid Nanospheres: Preparation,Characterization, and Absorption Evaluation

Oral delivery of anticancer drugs remains challenging because of limited water-solubility and/or poor permeability. Here, we aimed to enhance the oral bioavailability of tripterine (TRI, a plant-derived anticancer compound) using lipid nanospheres (LNs) and to determine the mechanisms of oral absorption. TRI-loaded LNs (TRI-LNs) were prepared by rapid dispersion of an ethanol mixture of TRI, lecithin, sodium oleate, and soybean oil into water. The obtained LNs were 150 nm in size with a high value of entrapment efficiency (99.95%). TRI-LNs were fairly stable and the drug release was negligible (< 0.2%) in simulated physiological fluid. The pharmacokinetic results showed that LNs significantly enhanced the oral bioavailability of TRI with a relative bioavailability of 224.88% (TRI suspensions was used as a reference). The mechanistic studies demonstrated that improved intestinal permeability and post-enterocyte lymphatic transport were mainly responsible for the enhanced oral absorption. Our findings suggested that LNs may be a viable oral carrier for poorly bioavailable drugs. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 103:171 1-1719, 2014     

奥硝唑在兔体内的药动学和生物利用度研究

目的　建立血清中奥硝唑(ornidazole,ONZ)浓度的HPLC检测方法;研究不同剂量的国产ONZ在家兔灌胃给药的绝对生物利用度和药动学。方法　采用甲硝唑作为内标,醋酸乙酯为萃取溶剂,流动相:甲醇水(2 5∶75 ) ,流速1mL·min-1,紫外检测波长312nm ,色谱柱NucleosilC18(4.6mm×15 0mm ,5 μm)。家兔给药后耳静脉采血,测定血清药物浓度;绝对生物利用度由等剂量下灌胃和静注后的药时曲线下面积之比而得。结果　以ONZ浓度和与内标的峰高比进行回归,回归方程:Y =0 .0 3796 + 0 .0 94 11X ,r =0 .9999,最低检出量为3.1ng。ONZ绝对回收率99.7%～10 1.3% ,日间和日内精密度的变异小于10 .3% ;ONZ 3个剂量组灌胃家兔,Tpeak、T1 2ka、T1 2ke、CL F、Vd F经检验无统计学差异。AUC和Cmax与剂量之间线性相关。30mg·kg-1剂量组ONZ在家兔灌胃的生物利用度在5 4.8%±2 8.6 %。结论　ONZ血清浓度检测方法得到建立,可参考此方法对ONZ在人体的药动学进行研究。     

提高难溶性药物口服生物利用度的方法

讨论了影响自胃肠道吸收药物生物利用度的因素，对提高难溶性药物口服生物利用度的方法进行了综述。     

Bio-International '92, Conference on Bioavailability,Bioequivalence and Pharmacokinetic Studies

Organized by International Pharmaceutical Federation (FIP) together with American Association of Pharmaceutical Scientists (AAPS), U.S. Food and Drug Administration (PDA), and Health Protection Branch, Canada (HPB). Cosponsored by Bundesgesundheitsamt (EGA), Germany, European Federation of Pharmaceutical Sciences (EUFEBS), Academy of Pharmaceutical Sciences and Technology, Japan (APSTJ), Dutch Medicines Evaluation Board (RIVM), The Netherlands, and Zentrallaborato-rium Deutscher Apotheker (ZL), Germany.     

葡萄糖酸锌兔体内药物动力学及生物利用度研究

本文介绍了用原子吸收分光光度法测定葡萄糖酸锌(Zinc Gluconate,ZG)兔体内血清锌浓度,用一室模型分析了ZG在家兔体内的药动学参数以及硫酸锌片剂,ZG水剂相对于ZG片剂对锌的生物利用度,硫酸锌片剂,ZG水剂相对于ZG片剂对锌的生物利用度分别为24.9％和62.1％。实验结果表明:ZG具有口服吸收快,维持时间长,峰浓度高的特点,是一优于硫酸锌的良好补锌剂。     

Enhanced Oral Bioavailability of Vinpocetine Through Mechanochemical Salt Formation: Physico-Chemical Characterization and In Vivo Studies

Purpose

Enhancing oral bioavailability of vinpocetine by forming its amorphous citrate salt through a solvent-free mechanochemical process, in presence of micronised crospovidone and citric acid.

Methods

The impact of formulation and process variables (amount of polymer and citric acid, and milling time) on vinpocetine solubilization kinetics from the coground was studied through an experimental design. The best performing samples were characterized by employing a multidisciplinary approach, involving Differential scanning calorimetry, X-ray diffraction, Raman imaging/spectroscopy, X-ray photoelectron spectroscopy, solid-state NMR spectroscopy, porosimetry and in vivo studies on rats to ascertain the salt formation, their solid-state characteristics and oral bioavailability in comparison to vinpocetine citrate salt (Oxopocetine^®).

Results

The analyses attested that the mechanochemical process is a viable way to produce in absence of solvents vinpocetine citrate salt in an amorphous state.

Conclusion

From the in vivo studies on rats the obtained salt was four times more bioavailable than its physical mixture and bioequivalent to the commercial salt produced by conventional synthetic process implying the use of solvent.     

Liquiritin-Hydroxypropyl-Beta-Cyclodextrin Inclusion Complex: Preparation,Characterization, Bioavailability and Antitumor Activity Evaluation

The pharmacological activities of liquiritin (LT) are greatly limited by its insolubility and low oral absorption. The purpose of this study was to prepare LT-hydroxypropyl-beta-cyclodextrin inclusion complex (LT-HP-β-CD) to increase water solubility, oral bioavailability and antitumor effect of LT. Herein, saturated aqueous solution method was applied to prepare the LT-HP-β-CD prior to characterization via scanning electron microscope (SEM), infrared radiation (IR) spectroscopy, X-ray diffraction analysis (XRD), and differential scanning calorimetry (DSC). Also, in vitro release and in vivo pharmacokinetics were evaluated. Moreover, the anti-tumor activity of the formulation was investigated in the A549 lung cancer cells. The results of SEM, IR, XRD and DSC showed that LT-HP-β-CD was successfully formulated. In vitro release and oral bioavailability of LT-HP-β-CD compared with the free LT was significantly higher. Successfully, antitumor effect of LT was remarkably enhanced by the preparation of LT-HP-β-CD. Altogether, the LT-HP-β-CD represents a potential carrier for enhancing the water solubility and oral bioavailability of LT coupled with antitumor activity enhancement.     

Comparison of Oral Absorption and Bioavailability of Drugs Between Monkey and Human

Purpose. To compare the oral absorption and bioavailability of numerous drugs with a wide variety of physicochemical and pharmacological properties between humans and monkeys and to explore potential reasons for the findings. Methods. Data for fraction of dose absorbed (F _a) and oral absolute bioavailability (F) were obtained by an extensive Medline database search. Inclusion and exclusion criteria were the same as those reported in our previous studies. A total of 43 and 35 drugs were selected for F _a and F comparison, respectively. The time to reach peak concentration (t _max), total clearance, and nonrenal clearance were evaluated for 15, 28, and 13 drugs, respectively. Results. F _a values in monkeys were similar or identical to those in humans. Additionally, similar t _max values were seen in monkeys and humans at comparable doses, thus indicating comparable absorption kinetics between the two species. Conversely, F values in monkeys were generally lower with coumarin being a marked exception. Both total and nonrenal clearances were evaluated and found to be generally greater in monkeys, supporting a generally higher first-pass metabolism and lower F in this species. This was also supported by published data suggesting greater in vitro hepatic drug metabolism for monkeys as compared to humans. Conclusions. Monkeys appear to be a good predictor of F _a in humans. However, a generally lower F makes monkeys a potentially poor predictor of human F. Higher reported metabolic clearances and hepatic enzyme activities in monkeys may account for this observation.     

染料木素共聚物纳米胶束冻干粉的制备及性质

目的制备染料木素共聚物纳米胶束冻干粉。方法以共聚物聚乙二醇-聚乳酸(PEG-PLA)为载体,采用改良溶剂挥发法制备染料木素共聚物纳米胶束,用真空冷冻干燥法制备染料木素共聚物纳米胶束冻干粉。通过考察制备的冻干粉特性来确定冻干保护剂的种类和用量。结果 5%蔗糖为最佳冻干保护剂,得到的冻干粉外观符合冻干制剂要求,粒径为(133.56±3.67) nm,Zeta电位为(-12.60±2.26) mV。冻干工艺为:真空度1 Pa,-60℃预冻5 h,-35℃恒定2 h,-33℃恒定5 h,-30℃恒定5 h,0℃恒定2 h,25℃恒定2 h。冻干粉在水中分散性良好,体系中染料木素浓度达到333.32μg·mL^-1。染料木素纳米共聚物胶束冻干粉具有生物活性,其对羟自由基(·OH)的清除作用在20～80μg·mL^-1范围内强于染料木素单体。结论通过冻干保护剂种类和用量的筛选及冻干工艺的优化,可得到较为稳定的染料木素共聚物纳米胶束冻干粉。     

中药静脉注射液不溶性微粒研究

目的 :考察复配中药针剂在静脉注射液中的不溶性微粒的变化及解决方法。方法 :将61种中药注射剂按治疗剂量溶配于0 9 %氯化钠注射液中 ,用库尔特仪计数该液中直径大于2 5、5 0、10 0、25 0μm的微粒数 ;对微粒进行理化性质显微鉴别 ;考察精密药液过滤器流速、流量、吸附性和截留作用。结果 :(1)26种中药注射剂微粒数超过《中国药典》 (2000年版 )标准 ,占实验总数42 6 % ;(2)不溶性微粒有玻璃渣、活性炭、橡胶屑、毛屑索条和药物残渣 ;(3)精密药液过滤器的流速、流量符合临床要求 ,截留率为88 5 % ,未见其有吸附作用。结论 :精密药液过滤器可截留中药输液的微粒 ,保证患者用药安全。     

Prediction of Human Bioavailability from Human Oral Administration Data and Animal Pharmacokinetic Data Without Data from Intravenous Administration of Drugs in Humans

Purpose  To predict the absolute oral bioavailabilities (BAs) of drugs in humans without using pharmacokinetic data from intravenous administration in humans. Methods  The distribution volume of the terminal phase () in humans was predicted by three methods using animal pharmacokinetic data. Then, total body clearance (CL_tot) was calculated by multiplying the elimination rate constant and , and the BA was calculated as a ratio between CL_tot and oral clearance. The predicted and observed values were compared for 67 drugs for which pharmacokinetic data after intravenous administration in humans were available. Results  For , predicted values within twice the observed value were obtained for 72.1% of drugs by both methods Ia and Ib, respectively, in which only rat pharmacokinetic data were used. The corresponding percentage was 75.0% for method II, in which pharmacokinetic data from animals other than rats were used. For BA, predicted values within 1.3 times the observed values were obtained for 66.7% and 57.4% of drugs by methods Ia and Ib, respectively, and 75.0% by method II. Conclusions  Using the present methods, it is possible to predict BA from human oral administration data combined with animal pharmacokinetic data to a certain level without using intravenous injection data. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

28种静脉用中药注射剂不溶性微粒的研究

28种静脉用中药注射剂按治疗剂量加入各自溶媒后不溶性微粒的检测表明：每种药物均含有不同粒径及数量的微粒。其中多数符合《中国药典》标准，但有4种药物≥10μm的微粒数在20个以上或≥25μm的微粒多于2个，超过《中国药典》标准。值得注意的是，中药静脉注射剂中小于10μm的微粒个数明显多于西药静脉注射液。提示中药静脉注射剂质控的难度和改善工艺质量的迫切性。本实验对国产精密药液过滤器的滤过作用亦作了考察。     

Preparation and Solidification of Redispersible Nanosuspensions

To test the feasibility of preparing redispersible powders from nanosuspensions without further addition of drying protectants, Lovastatin was processed into nanosuspensions and subsequently converted into a powder form using a spray-drying process. The effects of spray-drying process parameters and stabilizers on the properties of the spray-dried powders were evaluated. The inlet air temperature was found to have the most pronounced impact; a low-inlet air temperature consistently yielded dried powders with improved redispersibility. This was attributed to the low Peclet number associated with a low-inlet air temperature, making nanoparticles less prone to aggregation and coalescence during spray drying, as evidenced by the well-defined boundary shown between nanoparticles in the SEM photomicrographs of the spray-dried microparticles. The influence of atomization pressure is significant particularly at a low-inlet air temperature. The redispersibility index value of the powder is dependent on the type of stabilizers used in the nanosuspension formulation. Spray-dried powders with acceptable redispersibility were prepared with drug concentration as high as 3%. In conclusion, with optimized process parameters and selected stabilizers, spray drying is a feasible process in the solidification of nanosuspensions with high drug loading and acceptable redispersibility.