国产异丁司特缓释胶囊的人体相对生物利用度研究

目的 考察国产异丁司特缓释胶囊的人体相对生物利用度。方法 12 名男性健康受试者随机分为3组,分别口服单剂量日本产异丁司特缓释胶囊20 mg、国产异丁司特缓释胶囊20 mg、异丁司特原料药10mg,交叉自身对照。于服药后取静脉血,用HPLC 法测定血清异丁司特浓度。结果 三种制剂的Cm ax 分别为(54.9±9.7)、(60.7±9.1)、(62.2±11.5)μg · L^-1,t_max分别为(3.8±0.8)、(3.9±0.8)、(1.75±0.34)h,t_1/2(ke)为(11.5±1.4)、(12.1±1.0)、(3.5±0.5)h,AUC_(0~t)为(618.1±57.7)、(588.2±66.6)、(233.0±46.4)μg ·h·L^-1。以日本杏林公司产品作为参比制剂,国产异丁司特缓释胶囊的人体相对生物利用度为(95.6±11.0)%。结论 经双向单侧t检验,国产和进口缓释胶囊具有生物等效性,与原料药相比具有明显的缓释特性。     

Insights into the Pharmacokinetics and In Vitro Cell-Based Studies of the Imidazoline I2 Receptor Ligand B06

The impact of neurodegenerative diseases (ND) is becoming unbearable for humankind due to their vast prevalence and the lack of efficacious treatments. In this scenario, we focused on imidazoline I₂ receptors (I₂-IR) that are widely distributed in the brain and are altered in patients with brain disorders. We took the challenge of modulating I₂-IR by developing structurally new molecules, in particular, a family of bicyclic α-iminophosphonates, endowed with high affinity and selectivity to these receptors. Treatment of two murine models, one for age-related cognitive decline and the other for Alzheimer’s disease (AD), with representative compound B06 ameliorated their cognitive impairment and improved their behavioural condition. Furthermore, B06 revealed beneficial in vitro ADME-Tox properties. The pharmacokinetics (PK) and metabolic profile are reported to de-risk B06 for progressing in the preclinical development. To further characterize the pharmacological properties of B06, we assessed its neuroprotective properties and beneficial effect in an in vitro model of Parkinson’s disease (PD). B06 rescued the human dopaminergic cell line SH-SY5Y from death after treatment with 6-hydroxydopamine (6-OHDA) and showed a crucial anti-inflammatory effect in a cellular model of neuroinflammation. This research reveals B06 as a putative candidate for advancing in the difficult path of drug discovery and supports the modulation of I₂-IR as a fresh approach for the therapy of ND.     

Design and development of bioinspired calcium phosphate nanoparticles of MTX: pharmacodynamic and pharmacokinetic evaluation

The aim of this investigation is the management of rheumatoid arthritis (RA) by developing methotrexate-loaded calcium phosphate nanoparticles (MTX-CAP-NP) and to evaluate pharmacokinetic and pharmacodynamic behavior in adjuvant induced arthritis model. The nanoparticles were synthesized by wet precipitation method and optimized by Box-Behnken experimental design. MTX-CAP-NPs were characterized by TEM, FTIR, DSC and XRD studies. The particle size, zeta potential and entrapment efficiency of the optimized nanoparticles were found to be 204.90?±?64?nm, ?11.58?±?4.80?mV, and 88.33?±?3.74%, respectively. TEM, FTIR, DSC and XRD studies revealed that the developed nanoparticles were nearly spherical in shape and the crystalline structure of CAP-NP was not changed after MTX loading. The pharmacokinetic studies revealed that MTX-CAP-NP enhanced bioavailability of MTX by 2.6-fold when compared to marketed formulation (FOLITRAX-10). Under pharmacodynamic evaluation, arthritic assessment, radiography and histopathology studies revealed that CAP has ability to regenerate cartilage and bone therefore, together with MTX, MTX-CAP-NPs have shown significant reduction in disease progression. The overall work demonstrated that the developed nanodelivery system was well tolerated and more effective than the marketed formulation.     

Mannosylated Systems for Targeted Delivery of Antibacterial Drugs to Activated Macrophages

Macrophages are a promising target for drug delivery to influence macrophage-associated processes in the body, namely due to the presence of resistant microorganisms in macrophages. In this work, a series of mannosylated carriers based on mannan, polyethylenimine (PEI) and cyclodextrin (CD) was synthesized. The molecular architecture was studied using FTIR and ¹H NMR spectroscopy. The particle size, from small 10–50 nm to large 500 nm, depending on the type of carrier, is potentially applicable for the creation of various medicinal forms: intravenous, oral and inhalation. Non-specific capture by cells with a simultaneous increase in selectivity to CD206+ macrophages was achieved. ConA was used as a model mannose receptor, binding galactosylated (CD206 non-specific) carriers with constants of the order of 10⁴ M⁻¹ and mannosylated conjugates of 10⁶–10⁷ M⁻¹. The results of such primary “ConA-screening” of ligands are in a good agreement in terms of the comparative effectiveness of the interaction of ligands with the CD206+ macrophages: non-specific (up to 10%) absorption of highly charged and small particles; weakly specific uptake of galactosylated polymers (up to 50%); and high affine capture (more than 70–80%) of the ligands with grafted trimannoside was demonstrated using the cytometry method. Double and multi-complexes of antibacterials (moxifloxacin with its adjuvants from the class of terpenoids) were proposed as enhanced forms against resistant pathogens. In vivo pharmacokinetic experiments have shown that polymeric carriers significantly improve the efficiency of the antibiotic: the half-life of moxifloxacin is increased by 2–3 times in conjugate-loaded forms, bio-distribution to the lungs in the first hours after administration of the drug is noticeably greater, and, after 4 h of observation, free moxifloxacin was practically removed from the lungs of rats. Although, in polymer systems, its content is significant—1.2 µg/g. Moreover, the importance of the covalent crosslinking carrier with mannose label was demonstrated. Thus, this paper describes experimental, scientifically based methods of targeted drug delivery to macrophages to create enhanced medicinal forms.     

水解工艺对苦荞提取物中槲皮素含量的影响及其药代动力学研究

目的:以苦荞提取物为研究对象,通过正交实验设计优化苦荞提取物中芦丁被酸水解为槲皮素的工艺条件,并结合药代动力学研究探讨酸水解工艺对苦荞提取物中芦丁和槲皮素吸收的影响。方法:以盐酸百分含量、水解时间、乙醇百分含量、水解温度作为因素设计四因素三水平正交实验优化苦荞提取物中芦丁酸水解为槲皮素的工艺条件,以该工艺进行苦荞提取物酸水解,并在水解第1、2、4、6 h取样得到不同槲皮素含量的水解产物1、2、3、4。分别灌胃大鼠200 mg/kg的苦荞提取物及各水解产物,并在不同时间点采血,以黄芩素为内标,高效液相色谱(HPLC)测定血浆中槲皮素的浓度,DAS 2.0计算主要药代动力学参数。结果:苦荞提取物芦丁酸水解的最佳工艺参数为盐酸百分含量0.91%、水解时间6 h、乙醇百分含量50%、水解温度70 ℃,在该工艺条件下64.11%芦丁转化为槲皮素。苦荞提取物、水解产物1、2、3、4槲皮素的AUC_0-t分别为(17.604±5.422)、(42.175±9.435)、(87.917±19.347)、(116.706±46.256)、(178.509±49.478) mg/L·h,C_max分别为(2.743±1.217)、(7.109±2.603)、(12.438±3.197)、(15.727±4.68)、(20.044±5.736) mg/L。与苦荞提取物相比,其水解产物1、2、3、4的药代动力学参数AUC_0-t、C_max具有显著性差异(p<0.05)。结论:苦荞提取物经酸水解后部分芦丁转化为槲皮素,芦丁和槲皮素在大鼠体内的累计吸收量也相应提高。     

刺五加化学成分药动学特性及其体内代谢过程研究进展

刺五加作为吉林省大宗药材之一,具有益气健脾,补肾安神的功效,临床上有显著的抗疲劳作用。刺五加主要化学成分为苷类、黄酮类、香豆素类、多糖类、木脂素类等。刺五加化学成分的多样性,决定了其药动学的复杂性。通过对国内外大量文献的分析、归纳和整理,本文总结了刺五加化学成分的药动学特征及其在体内吸收、分布、代谢(肠道菌群代谢、肝脏代谢、体内代谢)情况,对刺五加化学成分的体内代谢过程进行深入挖掘与探索,为刺五加生物活性物质的开发和利用提供了参考。     

Enhanced bioavailability and hepatoprotectivity of optimized ursolic acid–phospholipid complex

Objective: To prepare and characterize an optimized phospholipid complex of Ursolic acid (UA) to overcome the poor pharmacokinetic properties and to investigate the impact of the complex on hepatoprotective activity and bioavailability in animal model.

Significance: UA is a potential phytoconstituent obtained from several plant sources, which has been explored for its diverse pharmacological activities including hepatoprotection. Its major limitation is poor absorption, rapid elimination, and hence low bioavailability after administration.

Methods: Response surface methodology was adopted to formulate an optimized (UA) complex. The complex was characterized by differential thermal analysis (DTA), Fourier transform-Infrared Spectroscopy, Powder X ray Diffraction, molecular docking, etc. The physico-chemical profile (solubility, oil/water partition coefficient) and in vitro dissolution profile was estimated. The formulation was then used to study hepatoprotective activity and bioavailability in animal models.

Results: Results showed that the phospholipid complex of UA has enhanced the hepatoprotective potential as compared to pure UA at the same dose level. The complex restored the levels of serum hepatic marker enzymes with respect to untreated group and increased the relative bioavailability of UA in rat plasma by 8.49-fold in comparison with pure compound at the same dose level. It enhanced the elimination half-life (t_{1/2 el}) from 0.69 ± 1.76 to 8.28 ± 1.98 h.

Conclusion: Complexation of UA with phospholipid markedly enhanced the hepatoprotective potential of UA by improving its bioavailability and pharmacokinetic parameters.

Novelty statement

The present article deals with rational optimization of the formulation parameters for phospholipid complex of ursolic acid by Response Surface Methodology analysis, characterizing the formulation by in silico approach apart from conventional instrumental techniques, and evaluating the in vitro dissolution, pharmacokinetics, and hepatoprotective activity of the complex in animals.

Novelty statement

The present article deals with rational optimization of the formulation parameters for phospholipid complex of ursolic acid by Response Surface Methodology analysis, characterizing the formulation by in silico approach apart from conventional instrumental techniques, and evaluating the in vitro dissolution, pharmacokinetics, and hepatoprotective activity of the complex in animals.     

测定犬血浆银杏黄酮类化合物含量的方法

To develop a reliable, reproductive hydrolysis method combined with LC-MS/MS quantification for measurement of ginkgo flavonoids, three aglycones quercetin (QCT), kaempferol (KMF) and isorhamnetin (ISR) in plasma. The newly developed hydrolytical method was evaluated in terms of hydrolysis stability, capability, matrix effect, as well as accuracy, precison, selectivity, sensitivity, and stability, which was further demonstrated its applicability in a pilot plasma pharmacokinetics study in beagle dogs receiving an single oral administration of three capsules. It was successfully applied to generate pharmacokinetic data for the disposition of flavonoids in beagles.     

Applications of accelerator mass spectrometry for pharmacological and toxicological research

The technique of accelerator mass spectrometry (AMS), known for radiocarbon dating of archeological specimens, has revolutionized high-sensitivity isotope detection in pharmacology and toxicology by allowing the direct determination of the amount of isotope in a sample rather than measuring its decay. It can quantify many isotopes, including 26Al, 14C, 41Ca, and 3H with detection down to attomole (10(-18)) amounts. Pharmacokinetic data in humans have been achieved with ultra-low levels of radiolabel. One of the most exciting biomedical applications of AMS with 14C-labeled potential carcinogens is the detection of modified proteins or DNA in tissues. The relationship between low-level exposure and covalent binding of genotoxic chemicals has been compared in rodents and humans. Such compounds include heterocyclic amines, benzene, and tamoxifen. Other applications range from measuring the absorption of 26Al to monitoring 41Ca turnover in bone. In epoxy-embedded tissue sections, high-resolution imaging of 14C label in cells is possible. The uses of AMS are becoming more widespread with the availability of instrumentation dedicated to the analysis of biomedical samples.     

In vitro and in vivo evaluation of controlled-release matrix tablets of highly water-soluble drug applying different mw polyethylene oxides (PEO) as retardants

The aim of the work presented is to prepare a controlled-release hydrophilic matrix tablet (CMT) controlling release of highly water-soluble drug applying pure combination of high- and low-Mw PEO as matrix materials, to avoid the lag time of drug release, and to overcome incomplete release in later stages. The influences of types and amounts of different Mw PEOs used, drug loading, pH of release medium and agitation rate on drug release were evaluated. The study of uptake and erosion of matrix was conducted and mechanism of improving drug release was discussed. In vivo pharmacokinetics of the CMT and reference preparation self-made controlled-release osmotic pump tablets (COPT) were performed in beagle dogs. The optimized formulation containing 43% PEO WSR 303 and 32% PEO N750 showed a zero order release from 1?h to 12?h. In vivo results demonstrated that the CMT had similar AUC_0-48?h and C_max with the COPT but smaller T_max than the COPT and provided a more stable therapeutic concentration compared to the COPT. In conclusion, hydrophilic matrix tablet combining only different Mw PEOs as matrix materials had very good potential to be developed into a controlled-release drug delivery system for highly water-soluble drug. Besides, its manufacturing processes were succinct which would be preferable for modern medicine industry.