萘普生肠溶微丸的制备及其体外特性研究

目的:研制萘普生肠溶微丸,评价其体外释药特性.方法:采用丸芯上药法制备萘普生含药微丸,以丙烯酸II号树脂为衣材进行包衣,采用释放度试验考察萘普生肠溶微丸的体外释药特性,并进行了稳定性试验.结果:本品在pH1.2盐酸溶液中2 h的溶出量低于10%,在pH6.8磷酸缓冲液中可迅速释放药物,45 min累积溶出量可达80%以上.结论:用丙烯酸Ⅱ号树脂为衣材制备萘普生肠溶微丸工艺可行,质量可靠.     

双氯芬酸钠肠溶微丸型片剂的研制

本文制备了双氯芬酸钠肠溶微丸型片剂。以丙烯酸树脂EudragitNE30D和EudragitL30D-55不同比例的混合物作为衣膜材料，对不同粒径大小的双氯芬酸钠速释丸芯进行不同增重水平的包衣，并与不同压缩特性和用量比例的缓冲微丸混合，压片。所得的双氯芬酸钠肠溶微丸型片剂在人工胃液中2 h内累积释放百分数<10%，在人工肠液中1 h内累积释放百分数为(83±2.42)%。结果表明EudragitNE30D与EudragitL30D-55以一定比例混合制备得到适合压片的肠溶微丸，硬脂酸制备的缓冲微丸可用于微丸型片剂的制备。     

5-氟尿嘧啶结肠定位释药微丸的研制及释药特性

采用流化床喷雾包衣法,研制了2种5-氟尿嘧啶结肠定位释药微丸.以羟丙甲纤维素为溶胀层,乙基纤维素水分散体为控制层,制备时间依赖型包衣微丸;另以肠溶型丙烯酸树脂Eudragit S100为包衣材料,制备pH依赖型微丸.测定了2种微丸在模拟胃肠道各区段pH环境下的释放度.结果表明,时间依赖型包衣微丸体外持续、缓慢释放;pH依赖型包衣微丸在模拟胃和小肠中上部pH的介质中基本不释药,在模拟回盲部区段pH介质中脉冲释药,即后者在体外显示出较好的结肠定位释药特性.     

布地奈德肠溶缓释微丸的体外释药特性及其在大鼠各肠段的药物残余量

目的制备布地奈德肠溶缓释微丸,并对其体外释药特性和大鼠灌胃后各肠段内容物中药物残余量进行比较研究。方法采用转篮法对制备的布地奈德肠溶缓释微丸进行体外释放度试验,比较微丸在不同释放介质中的释放曲线;测定微丸在大鼠灌胃后各肠段内容物中药物的残余量,并与对照制剂进行比较。结果试验组和对照组微丸在0.1 mol·L~(-1)HCI溶液中2h和PBS 6.8中10 h的释药曲线基本重合,f_2相似因子为90.1;在0.1 mol·L~(-1)HCl溶液12 h的累积释放率均<10%,在PBS 6.0、PBS 6.8和PBS 7.5缓冲液3种介质中12h的释药曲线f_2相似因子分别为54.2、50.3和57.8;两者在大鼠灌胃后2、4、6、8h各肠段残余总量和回结肠残余量的P值均>0.05。结论布地奈德肠溶缓释微丸与对照制剂具有相似的体外释药特性,大鼠灌胃后各肠段药物残余量无显著差异。     

盐酸地尔硫卓控释微丸的研究

采用包衣法制备含有速释和缓释两部分的地尔硫控释微丸。体外溶出试验表明，微丸在最初１ｈ溶出主药２０％之后以缓慢平稳的速度持续释药，其释药曲线与对照制剂恬尔心缓释胶囊接近，零级释药速率常数为７．２５％／ｈ。其释药速度受介质ｐＨ的影响，但受转速的影响较小。控释微丸在４０℃、相对湿度７５％时贮存３个月，质量稳定。     

4-氨基水杨酸钠结肠定位包衣片的制备与体外释放

目的:制备pH依赖和时间双重控制的4-氨基水杨酸钠结肠定位给药系统,并考察其体外释药行为。方法:以渗透型丙烯酸树脂EudragitRL与EudragitRS混和包衣液作为内层缓释层,pH依赖型丙烯酸树脂EudragitFS作为外层肠溶层,以柠檬酸三乙酯作为增塑剂,使用可调速糖衣机包衣,并研究包衣片在模拟人体胃肠道环境中的释放情况。结果:系统在0.1mol·L--1盐酸中2h无药物释放,在pH6.5的磷酸盐缓冲液中12h几乎无药物释放,在pH7.0和pH7.4时呈缓慢释放,且pH越高,释药时滞越短,肠溶层厚度的增加可延长释药时滞,12h内释药完全。结论:用渗透型丙烯酸树脂EudragitRL与EudragitRS的混合液作为缓释层,用pH依赖型丙烯酸树脂EudragitFS作为肠溶层可制备4-氨基水杨酸钠结肠定位包衣片。     

伊拉地平缓释胶囊的制备工艺及体外释药研究

目的:研究伊拉地平缓释胶囊制备工艺,并对其体外释药进行考察。方法:采用醇溶上药法(流化床底喷装置)制备伊拉地平微丸,并进行伊拉地平微丸质量评价及粉体学性质研究。用乙基纤维素(EC)和羟丙甲基纤维素(HPMC)为包衣材料,采用流化床进行包衣制备伊拉地平缓释微丸,对缓释微丸体外释放进行评价并考察不同热处理时间以及人工胃液对缓释微丸药物释放的影响,同时对批内和批间释药情况进行比较。结果:制备得到的伊拉地平微丸质量良好,不同热处理时间(1~12 h)对于伊拉地平缓释微丸的释药特性影响不大,在制备过程中可不进行热处理,干燥即可。人工胃液会显著地降低伊拉地平缓释微丸的释药速率,宜将其置于肠溶胶囊中。伊拉地平缓释微丸批间及批内重复性较好,在0.1%十二烷基二甲基氧化胺溶液12 h释放符合零级释药模型动力学过程。结论:制备得到的伊拉地平缓释胶囊缓释效果好,达到了释药要求。     

酒石酸美托洛尔延迟起释缓释微丸的制备

目的制备酒石酸美托洛尔延迟起释缓释微丸;研究该制剂的体外释放影响因素。方法采用挤出滚圆法制备含药丸芯,以丙烯酸树脂(Eudragit NE 30D)为内层包衣材料,乙基纤维素与丙烯酸树脂(Eudragit L100)的混合膜材为外层包衣材料制备延迟起释缓释微丸。通过改变内层包衣质量增加、外层包衣质量增加及外层包衣液中乙基纤维素与Eudragit L 100的质量比来达到一定时滞后缓慢释放药物的目的。考察了处方因素和溶出条件对体外释放度的影响。结果制得时滞为4 h,4、6、10、14 h的累积释放量分别为<10%、20%~35%、50%~70%、≥75%的延迟起释缓释微丸。结论内层包衣质量增加、外层包衣液中乙基纤维素与Eudragit L100的比例及外层包衣质量增加对延迟起释缓释微丸的释药时滞和释药速率具有显著影响,药物的体外释放情况不受溶出转速和溶出装置的影响。     

磷酸川芎嗪丙烯酸树脂水分散体包衣小丸的体外释放研究

目的：研究磷酸川芎嗪丙烯酸树脂水分散体包衣缓释小丸的体外释药。方法：采用丙烯酸树脂RS30D和丙烯酸树脂RL30D混合液包衣制备磷酸川芎嗪缓释小丸，并考察包衣混合液中两种丙烯酸树脂水分散体比例、包衣增重、溶出介质pH对磷酸川芎嗪包衣制剂体外释药的影响。结果：随着包衣液中丙烯酸树脂RL30D/丙烯酸树脂RS30D比例增大、包衣增重降低、溶出介质pH增大，释药速率加快。结论：包衣液中丙烯酸树脂RL30D/丙烯酸树脂RS30D比例、包衣增重、溶出介质pH均显著影响制剂药物释放。     

美沙拉嗪结肠靶向微丸的制备和体外评价

目的以结肠溶型丙烯酸树脂为包衣材料制备美沙拉嗪pH控制型结肠靶向微丸,评价其体外释药特性。方法挤出滚圆法制备美沙拉嗪微丸,采用L934正交设计实验优化工艺条件,流化床包衣机包衣,采用U884均匀设计试验优化工艺参数,考察了微丸圆整度、收率及体外释药特性。结果优化条件所得的微丸外观圆整,粒径分布均匀,收率高,在人工胃液中2h、人工小肠液中4h累计释放率<5%,人工结肠液1h累计释放率>95%,具有明显的结肠靶向释药特性。结论美沙拉嗪结肠靶向微丸具有良好的体外结肠靶向释药特性,可进一步进行体内释药行为考察。     

Effect of secondary structure on the rate of deamidation of several growth hormone releasing factor analogs

The objective of this study was to determine whether the rates of deamidation of Asn⁸ in selected growth hormone releasing factor (GRF) analogs were related to the peptide's secondary structures in solution. Bovine or human [Leu²⁷]GRF(1–32)NH₂ (both having Gly at position 15), [Ala¹⁵ Leu²⁷]bGRF(1–32)NH₂ and [Pro¹⁵ Leu²⁷]bGRF(1–32)NH₂ were used as model peptides. The peptide helical content (assessed by CD) increased with the increasing methanol concentration and was as follows: 7, 12 and 18% in 0% MeOH; 24, 48 and 52% in 40% MeOH; and 41, 77 and 81% in 80% MeOH for Pro¹⁵ Leu²⁷ bGRF(1–32)NH₂, [Leu²⁷]hGRF(1–32)NH₂, and Ala¹⁵ Leu²⁷ bGRF(1–32)NH₂, respectively. 2D NMR studies done in the presence of 40% CD₃OH indicated more helical structure for the Ala¹⁵ analog as compared to [Len²⁷]hGRF(1–32)NH₂. In both these peptides Asn⁸ was included in the helical region. In contrast, the lack of conformational information for the Pro¹⁵ analog indicated little helical structure around Asn⁸. The peptides’ deamidation rates decreased and their half-lives increased with increasing MeOH concentrations. At 40% MeOH, the least helical Pro¹⁵ bGRF analog (t_1/2= 10.78 h) deamidated 1.5 and 2 times faster than its Gly¹⁵ (t_1/2= 15.74 h) and Ala¹⁵ (t_1/2= 21.53 h) counterparts, respectively. This study indicates that helical environment around Asn⁸ in GRF makes this residue less prone to deamidation.     

Pharmacological characteristics of beta-adrenoceptor binding sites in intact and sympathectomized rat spleen

Summary [³H]-(-)-Dihydroalprenolol ([³H]-DHA) binds to rat spleen membranes with a dissociation equilibrium constant (K _D) of about 0.7 nM and a maximal number of binding sites of 272 fmoles x mg protein^–1. Approximately 90% of the sites labelled by 1 nM [³H]-DHA possess classical properties of beta-adrenoceptors. The labelled ligand is stereospecifically displaced by the isomers of propranolol and the order of potency of agonists is: isoprenaline>adrenaline >noradrenaline. Highly selective beta₁ antagonists such as practolol and atenolol displaced [³H]-DHA from spleen membranes in a biphasic manner indicating the co-existence of beta₁ and beta₂ sites (30–35% beta₁; 65–70% beta₂) in this tissue. Support for this classification was provided by the binding of the beta₂ agonist procaterol to spleen membranes. This drug possessed high affinity only for those sites that have low affinity for the beta₁, selective agents.Chemical sympathectomy induced by chronic 6-hydroxydopamine administration did not alter the number or the pharmacological properties of beta-adrenoceptor binding sites. The results suggest that both beta₁ and beta₂ adrenoceptors are probably postsynaptic in spleen.     

THE RELATIVE BIOAVAILABILITY OF TWO MARKETED CONTROLLED RELEASE DILTIAZEM DOSAGE FORMS AT STEADY STATE IN HEALTHY VOLUNTEERS

This study was conducted to determine the relative bioavailability of Dilacor^TM XR capsules compared to Cardizem^® CD capsules at both low (180 mg d⁻¹) and high (540 mg d⁻¹) dose levels. Trough and serial plasma samples were obtained and pharmacokinetic parameters were calculated from the steady state concentration—time profiles. Mean steady state plasma diltiazem concentrations (AUC_ss(0–24)) of Dilacor XR were 19% and 26% lower than those of Cardizem CD for the 180 mg d⁻¹ and 540 mg d⁻¹ dose levels, respectively. In addition, Dilacor XR had lower mean C_max,ss, T_max,ss, C_min,ss, and trough values than Cardizem CD with percentage differences ranging from 17% to 29%. The variability (%CV) in the data from the Dilacor XR treatments was higher for each calculated pharmacokinetic parameter compared to the Cardizem CD treatments. The %CV for Dilacor XR ranged from 34% to 104% while the %CV for Cardizem CD ranged from 21% to 49%. From these results, it may be concluded that Dilacor XR is not bioequivalent to Cardizem CD at steady state doses of 180 mg d⁻¹ and 540 mg d⁻¹.     

NMR and HPLC-NMR spectroscopic studies of futile deacetylation in paracetamol metabolites in rat and man

HPLC-NMR spectroscopy has been used to investigate the level of deacetylation followed by reacetylation (futile deacetylation) of metabolites of paracetamol detected in human and rat urine. This has been achieved through the synthesis and administration of paracetamol isotopically labeled at the acetyl group with C²H₃, ¹³CH₃ and ¹³CO-¹³CH₃. Using paracetamol-C²H₃ it had been shown that in the rat the sulphate metabolite present in the urine shows 10–13% futile deacetylation depending on the dose, whereas for paracetamol-¹³CO-¹³CH₃ the corresponding value was about 8%. After solid phase extraction, it was also possible to determine the level of futile deacetylation in the glucuronide metabolite using directly-coupled HPLC-NMR. This approach was facilitated by the use of acetonitrile-d₃ as an HPLC eluent and the HPLC-NMR analyses showed that the level of futile deacetylation in the sulphate and glucuronide metabolites were equal at about 9%. The glucuronide of paracetamol-C²H₃ was the predominant metabolite in man and following separation using HPLC-NMR, the level of futile deacetylation was shown to be 1% for the glucuronide and 2% for the sulphate, these values being equal within experimental error. This work demonstrates the utility of NMR and HPLC-NMR spectroscopy for isotope exchange studies.     

5-HT2受体介导大鼠DRG神经元膜GABA-激活电流的增强作用

目的探讨5-HT对大鼠DRG神经元膜GABA-激活电流的调节作用及其机制。方法在新鲜分离的大鼠DRG神经元标本上，以全细胞膜片钳技术记录膜电流，用排管快速换液装置行胞外给药，以胞内透析技术分析信号转导途径。结果给予GABA可使多数受检细胞产生浓度依赖性内向电流(I_GABA)。预加5-HT，可使I_GABA增加。此效应可被5-HT₂受体特异性激动剂α-methyl-5-HT(1×10^-6 mol·L^-1)所模拟，被5-HT₂受体选择性拮抗剂cyproheptadine所阻断。在部分细胞，5-HT本身可引起由5-HT₃受体介导的快速内向电流，但并未发现该电流与5-HT对I_GABA的增强作用有必然的联系。从GABA激活电流的量效曲线可见，预加5-HT后和对照曲线相比，阈浓度不变、EC₅₀值相近，I_GABA最大值增加33.6%。胞内透析GDP-β-S或H-7可取消5-HT增强I_GABA的效应，而透析H-9无效。结论5-HT可增强GABA-激活电流，其机制为5-HT₂受体激活后通过PKC引起GABA_A受体胞内磷酸化所致。     

An alternative and robust synthesis of [13C4]Baraclude® (entecavir)

Stable isotope‐labeled [¹³C₄]entecavir (1) was prepared in 11 steps. Commercially available [¹³C]guanidine hydrochloride and diethyl[1,2,3‐¹³C₃]malonate were condensed to yield 2‐amino[2,4,5,6‐¹³C₄]pyrimidine‐4,6‐diol (8). This was converted to the desired purine (7) in five steps. Introduction of the chiral epoxide was followed by subsequent deprotection to give [¹³C₄]entecavir (1), in an overall yield of 5.7% from labeled precursors. The chemical purity of the title compound was determined to be >99% by HPLC. The isotopic distribution was determined by mass spectrometry to be 282[M + 4], 98.4%; 281[M + 3], 1.6%; and 278[M + 0], <0.1%. Copyright © 2013 John Wiley & Sons, Ltd.     

Aflatoxin B1 Degradation by a Pseudomonas Strain

Aflatoxin B₁ (AFB₁), one of the most potent naturally occurring mutagens and carcinogens, causes significant threats to the food industry and animal production. In this study, 25 bacteria isolates were collected from grain kernels and soils displaying AFB₁ reduction activity. Based on its degradation effectiveness, isolate N17-1 was selected for further characterization and identified as Pseudomonas aeruginosa. P. aeruginosa N17-1 could degrade AFB₁, AFB₂ and AFM₁ by 82.8%, 46.8% and 31.9% after incubation in Nutrient Broth (NB) medium at 37 °C for 72 h, respectively. The culture supernatant of isolate N17-1 degraded AFB₁ effectively, whereas the viable cells and intra cell extracts were far less effective. Factors influencing AFB₁ degradation by the culture supernatant were investigated. Maximum degradation was observed at 55 °C. Ions Mn²⁺ and Cu²⁺ were activators for AFB₁ degradation, however, ions Mg²⁺, Li⁺, Zn²⁺, Se²⁺, Fe³⁺ were strong inhibitors. Treatments with proteinase K and proteinase K plus SDS significantly reduced the degradation activity of the culture supernatant. No degradation products were observed based on preliminary LC-QTOF/MS analysis, indicating AFB₁ was metabolized to degradation products with chemical properties different from that of AFB₁. The results indicated that the degradation of AFB₁ by P. aeruginosa N17-1 was enzymatic and could have a great potential in industrial applications. This is the first report indicating that the isolate of P. aeruginosa possesses the ability to degrade aflatoxin.     

Effects of presynaptic muscarinic cholinoreceptor blockade on neuromuscular transmission as assessed by the train‐of‐four and the tetanic fade response to rocuronium

This study investigated the effect of muscarinic M₁ and M₂ receptor antagonists on the rocuronium‐induced train of four (TOF ) fade and tetanic fade, respectively. Ex‐vivo phrenic nerves and diaphragms were obtained from adult Sprague‐Dawley rats and stabilized in Krebs buffer; the nerve‐stimulated muscle TOF fade was observed at 20 s intervals. For the TOF study, phrenic nerves and diaphragms were incubated with pirenzepine (an M₁ blocker) at concentrations of 0 nmol L^?1 (control), 10 nmol L^?1 (PZP 10), or 100 nmol L^?1 (PZP 100). Rocuronium was then administered incrementally until the first twitch tension had depressed by >95% during TOF stimulation. The mean TOF ratios were compared when the first twitch tensions were depressed by 40%‐50%. For the tetanic fade study, 50 Hz/5 s tetani was applied initially, 30 min after the administration of a loading dose of rocuronium and methoctramine (an M₂ receptor blocker, loaded at 0 μmol L^?1 [control], 1 μmol L^?1 [MET 1], or 10 μmol L^?1 [MET 10]). The EC ₉₅ of rocuronium was significantly lower in the PZP 10 group than in the control group. In the PZP 10 group, the TOF ratios at 50% and first twitch tension depression were significantly lower than those in the control group (P =.02). During tetanic stimulation, the tetanic fade was significantly enhanced in the MET 10 group compared to the other groups. This study shows that antagonists of muscarinic M₁ and M₂ receptors affect the rocuronium‐induced neuromuscular block as demonstrated by the reduced EC ₉₅ and TOF ratios (M₁ antagonist, pirenzepine) or the enhanced 50‐Hz tetanic fade (M₂ antagonist, methoctramine).     

Pharmacokinetics of thiopental after single and multiple intravenous doses in critical care patients

Thiopental was administered to neurosurgical patients for cerebral protection and its pharmacokinetic parameters were determined after a single bolus of 540, 1000 or 1500 mg (3 subjects) or after multiple doses of 250 mg (5 subjects) and 500 mg (2 subjects) every two hours for up to 7 days. The data were analysed by a two- or three- compartment model and linear kinetics. After a single IV bolus, the mean initial volume of distribution (V1) was 0.4811·kg^–1, and the steady-state volume of distribution (V_ss) was 2.16 1·kg^–1. The distribution (t_1/2) and elimination (t_1/2) half-lives were 0.590 and 5.89 h, respectively, and the mean residence time (MRT) was 7.44 h. The clearance was 5.41 ml·min^–1·kg^–1. With repeated injections, the pharmacokinetic parameters for each patient were estimated taking into account all administered doses and blood samples, which were taken whenever possible daily at steady state and after the last dose. The variability observed in the pharmacokinetic parameters of thiopental reflected by the coefficient of variation (CV%) was wide but was of similar magnitude within patients (CV_intra) as it was between patients (CV_inter). The steady-state trough plasma concentration (C_min obs) ranged from 4.8 to 30 mg·1^–1 (mean 16.0 mg·1^–1 and median 14.3 mg·1^–1). Peak concentrations (C_max obs) ranged from 8.35 to 45 mg·1^–1 (25.4 mg·1^–1, and median 23.3 mg·1^–1). The values of V1 and V_ss were similar to those obtained after a single dose. For V1, the mean was 0.333 1·kg^–1. The mean V_ss was 2.68 1·kg^–1, with a CV_intra of 12.6 to 56% and a CV_inter of 13.2%. A shorter distribution half-life t_1/2 was noted on multiple dosing; the mean value was 0.122 h. The elimination half-life t_1/2 and the mean residence time became longer due to a decrease in clearance. For t_1/2 the mean value was 16.3 h. The mean MRT was 21.9 h, CV_intra 9.19 to 48.5%, and the CV_inter 35.3%. The mean clearance was 2.16 ml·min^–1·kg^–1, CV_intra 7.28 to 25.5%, and the CV_inter 20.4%. This value is 50% lower than after a single dose.Identification of the kinetic parameters of thiopental allows simulation of the effects of doses on subsequent plasma levels and will permit a priori prediction of day to day adjustment of drug dosage.     

离子色谱法同时测定葡萄糖酸钙及其杂质(Cl-,SO42-)的含量

本文采用Waters ILC-1离子液相色谱仪,IC-PAK A50×4.6mm色谱柱,pH6.61×10^-3mol/L邻苯二甲酸溶液为流动相,430型电导检测器检测,由外标法和外标单点校正法同时测定了葡萄糖酸钙及其杂质(Cl^-,SO₄^2-)的含量。方法简便、快速,测定结果与中国药典法一致。外标法和外标单点校正法测定Cl^-,SO₄^2-的平均回收率为100.8%和100.2%,相关系数分别为0.9951(n=8)和0.9961(n=8)。