Effect of Anions on Adsorption of Bile Salts by Colestipol Hydrochloride

The Langmuir affinity constant and adsorptive capacity for the adsorption of citrate anion or cholate anion by colestipol hydrochloride at pH 7.5, 37°C, were similar. Prior exposure of colestipol hydrochloride to citrate anion caused the adsorption of cholate anion to decrease slightly in comparison to a control utilizing only cholate anion. The concentration of citrate anion was found to be directly related to the decrease in cholate anion adsorption. Simultaneous exposure of colestipol hydrochloride to citrate and cholate anions at pH 7.5, 37°C, resulted in the same adsorption of cholate anion as sequential exposure to citrate anion followed by cholate anion. Sequential exposure of colestipol hydrochloride to simulated gastric fluid and simulated intestinal fluid containing cholate anion resulted in a small decrease in cholate adsorption which was attributed to competition with phosphate anion in simulated intestinal fluid. Pepsin in the simulated gastric fluid did not affect adsorption of cholate anion from simulated intestinal fluid. Preexposure to components of tomato juice and orange juice also slightly reduced the adsorption of cholate anion by colestipol hydrochloride.     

Solubilization of Drugs by Physiological Mixtures of Bile Salts

Purpose. The solubilization of a number of steroids was determined in bile salt simple micelles and a bile salt/phospholipid micellar system to provide a better basis to predict the extent of drug solubilization in vivo. Methods. Excess solid drug was dispersed in taurodeoxycholate or mixed micelle solutions prepared with fixed mole ratios of taurocholate, taurodeoxycholate, taurochenodeoxycholate, glycodeoxycholate, glycocholate, and glycochenodeoxycholate with egg phosphatidylcholine. Drug concentrations were determined from the absorbance following centrifugation. Using NMR spectroscopy, the diffusivities of the simple and mixed micelles were 2 × 10^-6 and 8 × 10^-7 cm²/s, respectively. Results. From the change in the concentration of drug in solution with a change in the lipid concentration, the solubilization ratio (SR) was calculated. The SR and aqueous solubility were used to calculate the micelle/aqueous partition coefficients (K_m/w). K_m/w was correlated with octanol/water partition (P_o/w) for the TDC and mixed micelle data sets with correlation lines of logK_m/w = 0.74logP_o/w + 1.55 (r² = 0.91) and logK_m/w = 0.61 logP_o/w + 2.44 (r² = 0.95), respectively. Conclusions. With such data, a refined, predictive relationship between the in vitro and the in vivo solubilization with additional information concerning the bile salt/lipid concentration in the human intestine appears possible.     

Effect of Competing Anions on Binding of Bile Salts by Cholestyramine

The binding of bile salts by cholestyramine may be influenced by other anions, as the Langmuir adsorption coefficients for three bile salts tested were similar to the model anion, citrate. However, the selectivity coefficient indicated preferential binding of cholate anion in comparison to citrate anion. Binding experiments confirmed cholestyramine's preference for bile salts as the presence of other anions reduced but did not prevent the binding of cholate anion. Binding of cholate anion was reduced in direct relationship to the citrate anion concentration. Prior exposure of cholestyramine to citrate anion caused the binding of cholate anion to decrease slightly. Sequential exposure of cholestyramine to simulated gastric fluid and simulated intestinal fluid containing cholate anion resulted in a decrease in cholate binding which was attributed to competition with anions present in the gastrointestinal fluids. Components of tomato juice and orange juice, fluids commonly used to enhance ingestion of cholestyramine, also reduced the binding of cholate anion.     

In Vitro Binding of Lorazepam and Lorazepam Glucuronide to Cholestyramine,Colestipol, and Activated Charcoal

Pharmaceutical Research -     

大豆磷脂脂质载体与胆酸盐表面活性剂的体外相互作用

采用旋转薄膜蒸发法结合挤压过滤工艺制备大豆磷脂脂质体,所制得脂质体的平均粒径为217nm,跨距0．838,负染色脂质体经透射电镜观察,呈明显的双层膜圆球型结构。以胆酸钠盐和脱氧胆酸钠盐研究其与脂质体之间的相互作用,将500nm波长处的可见光吸收值评价胆盐-脂质体混悬液的浊度,测定脂质体的粒径变化情况。在胆酸盐加入的初期,由于胆酸盐和脂质体形成混合胶团,致使脂质体的粒径和浊度值稍有增加,进一步加入的胆酸盐使脂质体的粒径和浊度值下降。胆盐和脂质体问的相互作用经历了数个重排现象,使脂质体的粒径发生规律性的变化,这与脂质体的体内稳定性密切相关,也可反映脂质体的载药和释药特性。     

高效液相色谱法测定异丙嗪胆汁片中盐酸异丙嗪的含量

目的:建立高效液相色谱法测定异丙嗪胆汁片中盐酸异丙嗪的含量。方法:Diamonsil~(TM)C_(18)色谱柱(250 mm×4.6 mm,5μm,迪马公司);流动相:0.02mol·L~(-1)磷酸二氢钾缓冲溶液(取磷酸二氢钾2.72 g,加水700 mL 溶解,用磷酸调 pH 至3.0,加水至1000 mL)-乙腈-甲醇(55:20:25),流速:1.0 mL·min~(-1),检测波长:249nm,进样量:10μL。结果:盐酸异丙嗪在5.3-84.6μg·mL~(-1)浓度范围内线性关系良好,r=0.9998(n=6),平均回收率为99.90%,RSD=0.62%(n=5)结论:该法简便、灵敏、准确,专属性强,可用于异丙嗪胆汁片的质量控制。     

盐酸二甲双胍肠溶片体外释放度研究

目的考察不同厂家盐酸二甲双胍肠溶片的释放度，以评价其内在质量。方法采用转篮法，以紫外分光光度法测定二甲双胍的含量，并对释药参数T50，Td，m进行统计分析。结果两个厂家的二甲双胍肠溶制剂均符合制剂释放质量规定，但释药参数差异具有统计学意义（P〈0．01）。结论为了确保盐酸二甲双胍肠溶制剂的疗效，应对其进行体外溶出度的测定。     

托烷司琼注射液常见临床配伍稳定性考察

目的 考察注射用托烷司琼在注射器中与临床常见7种输液配伍的稳定性。方法 在室温下,将注射用盐酸托烷司琼加入到7种输液(果糖注射液、0.9%氯化钠注射液、乳酸钠林格注射液、5%葡萄糖注射液、复方氯化钠注射液、葡萄糖氯化钠注射液和转化糖注射液)中,模拟临床用药浓度,用液相色谱串联质谱测定配伍后不同时间配伍液的含量,同时检查配伍液的pH值、颗粒数和外观变化。结果 注射用盐酸托烷司琼与7种输液配伍后在18~25 ℃放置4 h,其外观、pH值和含量基本不变,≥10 μm和≥25 μm的颗粒数也符合规定要求。结论 注射用盐酸托烷司琼与7种输液配伍,在18~25 ℃下4 h内基本稳定。     

盐酸倍他洛尔阳离子脂质体原位凝胶的离体角膜滞留性研究

目的:考察盐酸倍他洛尔阳离子脂质体原位凝胶(BHCL-ISG)的离体角膜滞留性及生物相容性.方法:采用逆向蒸发法制备盐酸倍他洛尔脂质体(BHL),用季铵化程度为60％的N-三甲基壳聚糖(TMC60)对其包衣,得到阳离子脂质体(BHCL),再以泊洛沙姆407和188为温敏性原位凝胶(ISG)基质,用冷法制备BHCL-ISG.采用悬挂泡和束缚泡法对BHCL-ISG离体角膜接触角及表面解吸附动力学进行考察,并采用Draize评分法评价其兔角膜的刺激性.结果:BHCL-ISG外形圆整,粒径均匀,呈正电性.与BHL及BHL-ISG相比,BHCL-ISG与角膜的接触角较大,但角膜表面滞留时间明显延长(P＜0.05),同时未显示角膜刺激性.结论:BHCL-ISG可延长角膜滞留时间,并具有良好的生物相容性.     

盐酸克林霉素微囊的体外释药及其影响因素的考察

目的 采用液中干燥法制备盐酸克林霉素微囊,并考察其体外释药特性。方法 以乙基纤维素为囊材制备微囊．用浆法研究其体外释药的影响因素。结果 药物释放速率随微囊粒径减小而增加;囊材粘度增加,药物释放速率降低;附加剂滑石粉对药物释放的影响较复杂,随着滑石粉比例增加．药物释放速率增加．但至一定比例后．速率降低。与市售胶囊相比．有明显缓释作用。结论 液中干燥法制备的盐酸克林霉素微囊有显著的缓释作用．有良好的开发应用前景。     

Solubilization of Retinoids by Bile Salt/ Phospholipid Aggregates

Purpose. The capacity and specificity of bile salt (BS)/phosphatidylcholine (PC) mixed lipid aggregated systems in solubilizing four structurally related retinoids, etretinate, motretinid, fenretinide and N-ethyl retinamide, were determined. Methods. Excess solid drug was dispersed into sodium taurocholate (NaTC)/egg PC systems at lipid ratios of 10:0, 10:2 and 10 mM:10 mM in isotonic HEPES buffer, pH 6.5. A sensitive HPLC method was used to quantify the amount solubilized. The melting point and associated enthalpy change as well as the aqueous solubilities were also measured. Results. The retinoids had aqueous solubilities of less than 25 nM. The predicted aqueous solubility was less than 0.01 nM. The amount of retinoid in 10 mM NaTC was increased from three to four orders of magnitude relative to the aqueous solubility. Further increases in the amount solubilized were observed in the 10:10 mixed micelle dispersion. Fenretinide and N-ethyl retinamide were particularly well solubilized by BS and BS/PC aggregated systems which may be related to the presence of a cyclohexenyl ring. Conclusions. The discrepancy between the observed and predicted aqueous solubility may be due to self-association of the retinoids. Micellar/aqueous distribution ratios appear to be dominated by the hydrophobic effect, although specific interactions also are important. In considering intestinal absorption, the large increase in solubilization with BS/PC micelles would be capable of dramatically increasing the bioavailability in spite of the smaller effective diffusivity of the solubilized retinoid.     

盐酸尼卡地平缓释微丸的制备及其溶出度研究

目的:制备盐酸尼卡地平缓释微丸,并考察影响其溶出度的因素.方法:采用滚动凝聚法制备,用紫外分光光度法测定溶出度.结果:盐酸尼卡地平体外溶出度随着膜厚度及聚乳酸分子量增大而显著减小.结论:聚乳酸可用于制备口服盐酸尼卡地平缓释制剂.     

The Solubility-Modulated Osmotic Pump: In Vitro/in Vivo Release of Diltiazem Hydrochloride

A generalized method was investigated for conversion of controlled-porosity osmotic pump release profiles from first-order to zero-order kinetics using diltiazem · HC1 as a model drug. Diltiazem · HC1 has an aqueous solubility >590 mg/ml (37°C) and was released from controlled-porosity osmotic pump devices with first-order kinetics. This high solubility was markedly reduced (155 mg/ ml; 37°C) in the presence of NaCl (1 M). Based on theory for osmotically actuated drug release, this reduced solubility would be expected to result in a zero-order release profile of >80% of an initial diltiazem · HC1 load. Devices were prepared with cores that contained diltiazem · HC1 and sufficient NaCl granules coated with a microporous cellulose acetate butyrate 381-20 film to maintain a 1 M NaCl concentration within the drug compartment over a 16-hr period. This resulted in release of 75% of the initial diltiazem HC1 load with zero-order kinetics over a 14- to 16-hr period. The in vivo performance of these devices in beagle dogs was analyzed. The in vivo percentage diltiazem absorbed profiles were superimposable with the in vitro release profile. These results suggest that diltiazem release and absorption from the solubility modulated osmotic pump occur throughout the GI tract in a fashion predictable from in vitro dissolution data.     

The Nitrogen Adsorption Isotherm of Alpha-lactose Monohydrate

A complete nitrogen adsorption isotherm was measured for α-lactose monohydrate, from 0.001 to 0.995 relative pressure at 77 K. The isotherm was qualitatively classified as Type II, and was quantitatively analyzed for surface area, porosity, and surface heterogeneity. Surface area results revealed that the normal Brunauer Emmett Teller (BET) range of 0.05–0.35 relative pressure was not suitable for this grade of lactose, but having full isotherm data enabled a more appropriate analytical range to be found, illustrating the importance of measuring the entire isotherm as an essential step in method development. The isotherm was analyzed for micro and mesoporosity, both of which were found to be insignificant for lactose. The low relative pressure range 0.001–0.005 did not obey Henry's law, indicating the presence of surface heterogeneity. Density functional theory was exploited to quantitatively measure heterogeneity in the surface energy of lactose, using the full nitrogen adsorption profile. As expected for a crystalline material with multiple faces and likely presence of imperfections on the surface, the surface energy distribution function was broad with more than one mode.     

盐酸班布特罗的HPLC测定

采用HPLC测定盐酸班布特罗的含量。以十八烷基硅烷键合硅胶为固定相，以6.0mmol/L辛烷磺酸钠的甲醇溶液－乙腈－50mmol/L磷酸盐缓冲液（pH3.0)(34:11:35)为流动相，检测波长214nm，对乙酰氨基苯甲醚为内标。     

紫外分光光度法测定盐酸吗啡注射液的含量

本文采用紫外分光光度法测定盐酸吗啡注射液的含量。该法操作简便，重现性好，回收率为９９．７６％，ＣＶ０．２３％，经与《中国药典》１９９０年版方法比较，结果基本一致。     

中药饮片污染耐胆盐革兰阴性菌的考察

目的：考察中药饮片耐胆盐革兰阴性菌的污染状况。方法：依据2015年版《中国药典》微生物限度检查法草案中耐胆盐革兰阴性菌检查方法对中药饮片耐胆盐革兰阴性菌进行定性检查,对阳性样品进行定量检查,比较预培养2h和不预培养两种方法对耐胆盐革兰阴性菌定量检出的差异。结果：通过对17个品种174批中药饮片的考察,结果显示中药饮片耐胆盐革兰阴性菌污染比较严重,达81.0％。按2015年版《中国药典》中药饮片耐胆盐革兰阴性菌标准来判断,16.1％不合格,且预培养2 h和不预培养两种方法检验结果没有显著差异（ P＞0.05）。结论：本研究可为2015年版《中国药典》中药饮片耐胆盐革兰阴性菌限度标准的制定提供参考依据。     

Characterization of Interactions Between Bile Salts and Drugs by Micellar Electrokinetic Capillary Chromatography. Part I.

Purpose. The general properties of micellar electrokinetic capillary chromatography (MECC) were utilized to characterize the strength of interactions between bile salts and biological active substances. Methods. For that purpose various bile salts were used as micellar pseudostationary phase in the background electrolyte. Furthermore, a physicochemical model was applied and the effective partition coefficients between micellar and water phase were calculated in order to evaluate the strength of interactions between bile acids and the drugs. Results. It was found that the interactions between the selected drugs and bile salts depend both on the lipohilicity of the drugs and on the charge of the components. Only hydrophobic, cationic drugs such as quinine and propranolol are able to interact with these surface-active agents. Conclusions. MECC is a valuable methode to characterize interactions such occurring between drugs and bile salts.     

In Vitro Controlled Release of Alfuzosin Hydrochloride Using HPMC-Based Matrix Tablets and Its Comparison with Marketed Product

The present study is an attempt to formulate a controlled-release matrix tablet formulation for alfuzosin hydrochloride by using low viscous hydroxy propyl methyl cellulose (HPMC K-100 and HPMC 15cps) and its comparison with marketed product. Different batches of tablets containing 10 mg of alfuzosin were prepared by direct compression technique and evaluated for their physical properties, drug content, and in vitro drug release. All the formulations had a good physical integrity, and the drug content between the batches did not vary by more than 1%. Drug release from the matrix tablets was carried out for 12 hr and showed that the release rate was not highly significant with different ratios of HPMC K-100 and HPMC15cps. Similar dissolution profiles were observed between formulation F3 and the marketed product throughout the study period. The calculated regression coefficients showed a higher r² value with zero-order kinetics and Higuchi model in all the cases. Although both the models could be applicable, zero-order kinetics seems to be better. Hence, it can be concluded that the use of low viscous hydrophilic polymer of different grades (HPMC K-100 and HPMC 15cps) can control the alfuzosin release for a period of 12 hr and was comparable to the marketed product.     

Matrix-Type Transdermal Patches of Verapamil Hydrochloride: In Vitro Permeation Studies Through Excised Rat Skin and Pharmacodynamic Evaluation in Rats

The objectives of this study were to develop matrix-type transdermal patches of verapamil hydrochloride (VRP) with pectin as a matrix polymer to investigate the influence of several terpenes on in vitro permeation of VRP through rat skin and to evaluate pharmacodynamic activity of transdermal formulations in rats. Matrix-type transdermal patches containing VRP were prepared using pectin as a matrix agent and propylene glycol as a plasticizer agent. Terpenes such as nerolidol, d-limonene, eucalpytol, menthone, and menthol were also used as a chemical enhancer to improve the skin penetration of VRP. The permeation studies were perfomed using Franz-type diffusion cells and full-thickness excised abdominal rat skin. Effects of terpenes on the permeation parameters of VRP were evaluated. In vitro skin permeation studies showed that nerolidol was the most promising enhancer among the enhancers examined in the present study, followed by d-limonene. Pharmacodynamic activity of the transdermal patches containing nerolidol or d-limonene was evaluated in rats by the measurement of systolic blood pressure for 360 min with the use of the tail cuff method. VRP transdermal patches significantly decreased the systolic blood pressure after 30 min and transdermal patches containing nerolidol and d-limonene maintained the decrease in blood pressure during the observation of 360 min.