一种新型药用辅料——聚苯乙烯磺酸钠离子交换树脂的合成与表征

目的：制备一种新型药用辅料聚苯乙烯磺酸钠离子交换树脂并对其进行表征。方法：采用自由基聚合及磺化反应制备药用级聚苯乙烯磺酸钠离子交换树脂，并运用红外光谱法、差示扫描量热仪、X-射线衍射仪、激光衍射粒径分析仪等分析仪器对所制得的树脂及药物树脂复合物进行鉴别。结果：成功制备了粒径范围在60-200μm的聚苯乙烯磺酸钠离子交换树脂，并且证明药物与树脂通过化学键结合。结论：成功地制备了聚苯乙烯磺酸钠阳离子交换树脂。     

麦角甾苷固体脂质纳米粒处方筛选和理化性质研究

目的 研究不同种类药用辅料成分对麦角甾苷固体脂质纳米粒（SLN）理化性质的影响,为研究SLN的处方筛选提供依据。方法 采用乳化-固化法制备麦角甾苷-SLN,单一变量法考察山嵛酸甘油酯（Compritol ATO 888）、单硬脂酸甘油酯、大豆卵磷脂、Myrj52等辅料对麦角甾苷-SLN粒径、包封率、表征分散度（PDI）等理化性质的影响,采用透射电镜法观察麦角甾苷-SLN的形态,X-射线衍射（XRD）分析其药物晶体结构。结果 随Compritol ATO 888用量增加,麦角甾苷-SLN粒径不断减小,包封率逐渐减小,PDI逐渐增加;随单硬脂酸甘油酯的用量增加,粒径明显增大,包封率略有降低,PDI减小;随卵磷脂用量增加,粒径明显增大,包封率降低,PDI减小;随Myrj52用量明显增加,粒径减小,包封率增加,PDI增大;麦角甾苷-SLN外观圆整,呈球形;麦角甾苷以分子分散状态被包裹在SLN中。结论 不同辅料对麦角甾苷-SLN的理化性质均产生一定影响趋势,为制备SLN的处方筛选研究提供启示与思路。     

盐酸氨溴索药物树脂混悬剂的制备及物理稳定性的研究

目的:制备盐酸氨溴索药物树脂混悬剂并对其物理稳定性进行考察.方法:考察树脂微囊自身性质(粒径,湿真密度,荷电性,润湿性)和助悬剂性质(密度、流变特性),以沉降体积比和再分散性为评价指标对制得的混悬剂进行评价.结果:树脂微囊自身性质适合制备混悬剂,聚丙烯酸树脂(carbopol)和微晶纤维素(avicel)助悬效果好.结论:选取合适的树脂微囊与助悬剂可制得物理稳定性良好的盐酸氨溴索药物树脂混悬剂.     

海藻酸微囊的制备与评价

目的:探讨利用气体雾化技术(AAT)制备的脂溶性药物吲哚美辛和水溶性药物对乙酰氨基酚海藻酸微囊的理化特性.方法:采用筛分法测定微囊粒径,紫外分光光度法测定微囊的包封率及载药量,恒重法测定微囊中的含水量.结果:海藻酸钠浓度增加、输送速度增加和氮气压力增加与微囊粒径减小.微囊的包封率和载药量随着药物溶解度的增加而降低.微囊含水量最初随着冷冻干燥时间的延长急剧下降,当下降到一定程度后随着冷冻干燥时间的延长变化不大.结论:采用AAT方法制备海藻酸微囊方法简单,但是水溶性大的药物不宜用此法制备微囊.     

葡萄籽原花青素B2磷脂复合物的制备研究

目的 制备葡萄籽原花青素磷脂复合物,考察其理化性质,研究磷脂复合物制剂成型工艺.方法 以葡萄籽原花青素与磷脂的复合率为评价标准,再以复合率为指标确定复合物制备工艺;研究原花青素B2磷脂复合物的理化性质包括脂水分配系数及溶解性能等;探讨葡萄籽原花青素磷脂复合物的制剂成型工艺.结果 优化工艺的复合率可达97％.原花青素B2磷脂复合物的油水分配系数与原花青素B2相比明显增大,预示其体内吸收有可能提高.原花青素磷脂复合物流动性尚可,但黏性强,相对临界湿度小,引湿性较强.结论 确定了制备葡萄籽原花青素磷脂复合物的最佳工艺,该复合物明显改善了原药的理化性质.     

硫酸庆大霉素水分测定方法的改进

硫酸庆大霉素具引湿性,其纯度、稳定性、理化性质等均与含水量的多少密切相关.为了控制水分含量,中国药典的含水量测定方法为干燥失重.在105℃的条件下干燥至恒重.在干烤过程中,温度、恒重时间、放置时间对供试品有影响,从而不能充分地反映出该品种的含水量.因此,特进行了干燥失重和水分测定法的比较.     

多肽GRGDS修饰的紫杉醇长循环靶向脂质体的体外评价

目的:本研究以甘氨酸-精氨酸-甘氨酸-天冬氨酸-丝氨酸(glycine-arginine-glycine-aspartic acid-serine,GRGDS)五肽修饰的脂质体作为抗癌药物.紫杉醇的载体,对其体外理化性质和细胞毒作用进行评览价.方法:采用化学偶联合成DSPE-PEG-GRGDS,以此作为导向性材料,采用薄膜分散法制备载紫杉醇的PEG修饰长循环脂质体(GRGDS-SSL-PTX),并对脂质体的包封率、粒径和体外释放率等性质进行了考察,同时采用人卵巢癌SKOV-3细胞和人乳腺癌MCF-7细胞进行了体外细胞生长抑制的评价.结果:与普通紫杉醇长循环脂质体(SSL-PTX)相比,本研究制备的紫杉醇主动靶向脂质体(GRGDS-SSL-PTX)的粒径、包封率、载药量、体外释放及稳定性等理化性质无显著差异,包封率约为95%,平均粒径为(115.5±2.2)和(117.5±1.3)nm.冰冻蚀刻透射电镜观察结果表明,脂质体外观基本圆整且均匀分散.体外释放结果表明,12 h内分别有67.9%和72.3%的PTX从SSL-PTX和GRGDS-SSL-PTX中释放.体外细胞毒实验结果表明,GRGDS-SSL-PTX对人卵巢癌SKOV-3细胞和人乳腺癌MCF-7细胞的生长抑制作用均有增强,分别为SSL-PTX的1.42倍和2.12倍.结论:GRGDS五肽修饰的紫杉醇靶向脂质体成功制备,将有利于体内肿瘤的靶向治疗效果.     

姜黄素脂质体的制备及理化性质考察

目的:制备姜黄素脂质体,并进行理化性质初步研究。方法:选用薄膜法制备姜黄素脂质体,以单因素考察优选最佳制备工艺;观察脂质体粒径和形态特征,同时考察其贮存条件。结果:确定最佳工艺卵磷脂和胆固醇的比例为3∶1,磷酸缓冲盐溶液的pH值为6.6,离子浓度为0.01moL.L-1。姜黄素脂质体外观呈完整圆球形或椭圆形的球粒,粒径主要分布于140~425nm,表面电性为负,pH为(6.58±0.2),包封率为69.79%,最佳的贮存条件为3~5℃冷藏保存。结论:薄膜法制备姜黄素脂质体方法可行,其理化性质基本稳定,为进一步研究姜黄素在肿瘤治疗中的应用提供了理论基础。     

吡喹酮固体脂质纳米粒的制备及其理化性质研究

目的:制备吡喹酮固体脂质纳米粒(PZQ-SLN),并考察其理化性质。方法:以山嵛酸甘油酯和乙酸丁酯为脂质材料,超声分散法制备PZQ-SLN,透射电镜观察纳米粒形态,测定其粒径、Zeta电位和药物包封率,并进行体外释放试验及考察样品的稳定性。结果:所得脂质纳米粒为类圆球状,粒径分布较均匀。样品粒径为(100±21)nm,包封率为(79.3±0.69)%,平均Zeta电位值为—66.3mV。药物体外释放符合Weibull方程。4℃放置3mo后粒径、包封率和Zeta电位均无明显变化。结论:制备的PZQ-SLN理化性质较为理想,能使药物缓慢释放。4℃条件下贮存比较稳定。     

聚乳酸分子量对利福平聚乳酸微球性质的影响

目的 :考察聚乳酸分子量对利福平聚乳酸微球性质的影响。方法 :采用分散一溶媒扩散法制备利福平聚乳酸微球 ,测定微球的粒径分布和包封率 ,进行体外释药和稳定性试验。结果 :在本制备方法中 ,聚乳酸分子量对微球粒径分布的影响作用不明显 ;药物包封率随聚乳酸分子量增大而增加 ;聚乳酸分子量减小 ,微球体外释药速度加快。稳定性试验表明 ,微球在 4℃和室温 (2 0～ 2 5℃ )条件下性质稳定 :3 7℃条件下因聚乳酸软化 ,微球发生粘连聚集。结论 :应根据实验目的选择适宜分子量的聚乳酸 ,以获得所需性质的微球。     

Comparative efficacy of thallium adsorption by activated charcoal, prussian blue, and sodium polystyrene sulfonate

BACKGROUND: Although Prussian blue is considered the antidote of choice for thallium poisoning, the lack of a Food and Drug Administration-approved pharmaceutical formulation has led to the search for other adsorbents. Activated charcoal has been demonstrated to adsorb thallium in vitro, and the similarity between thallium and potassium has led some authors to consider the use of sodium polystyrene sulfonate as a potential adsorbent. This experiment was designed to compare the relative thallium binding efficacy of these agents in a standard isotherm model. METHODS: A standard aqueous solution of thallium acetate buffered to pH 7.0 was agitated at 25 degrees C with activated charcoal, Prussian blue, or sodium polystyrene sulfonate at adsorbent:thallium ratios ranging from 1.5:1 to 100:1. In order to further simulate physiologic conditions, all trials were repeated in a solution containing 4 mmol/L potassium phosphate. After thorough agitation, the mixtures were allowed to settle and were centrifuged and filtered through a 0.22-micron filter. Supernatant thallium concentrations were measured by atomic absorption spectrophotometry. Langmuir isotherms were used to calculate the maximal adsorptive capacity of each adsorbent, using linear regression with Pearson's correlation coefficients (r). Maximal adsorptive capacities were compared statistically with a p < 0.05 considered significant. RESULTS: The maximal adsorptive capacities defined as milligrams of thallium per gram of adsorbent (shown with linear regression p and r values) were as follows: activated charcoal, 59.7 mg/g (p = 0.005, r = 0.995); Prussian blue, 72.7 mg/g (p = 0.004, r = 0.996); and sodium polystyrene sulfonate, 713 mg/g (p = 0.049, r = 0.951). All three values were statistically different from each other. At a physiologic potassium concentration, the maximal adsorptive capacities for activated charcoal and Prussian blue were essentially unchanged (58.3 mg/g and 69.8 mg/g, respectively, p > 0.05 for each vs trials without potassium), while the maximal adsorptive capacity for sodium polystyrene sulfonate fell to 39.1 mg/g (p = 0.003, r = 0.997, p = 0.005 vs sodium polystyrene sulfonate without potassium). CONCLUSIONS: This in vitro study confirms the utility of Prussian blue and activated charcoal as thallium adsorbents. Although sodium polystyrene sulfonate demonstrates exceptional in vitro adsorption of thallium, its greater affinity for potassium probably renders it clinically ineffective.     

Efficacy of the cation exchange resin, sodium polystyrene sulfonate, to decrease iron absorption

BACKGROUND: Iron is not bound by charcoal; therefore, a method of binding iron in the gastrointestinal tract to prevent absorption in iron overdose is needed. This study investigated the efficacy and safety of sodium polystyrene sulfonate to prevent absorption of iron in human volunteers. METHODS: Six adult volunteers completed this prospective crossover trial. Following an oral dose of elemental iron 10 mg/kg, each subject received sodium polystyrene sulfonate 30 g or water as control. Baseline and serial serum iron samples were drawn to determine pharmacokinetic parameters. RESULTS: A trend toward increased time to peak following sodium polystyrene sulfonate compared to the control arm (5.7 vs 3.6 hours) was observed but was not statistically significant (p = 0.517). A trend toward smaller area-under-the-curve for the sodium polystyrene sulfonate was evident but was not statistically significant (p = 0.77). Iron concentration increased on average 298 mcg/dL and 370 mcg/dL above baseline in the treatment and control arms (p = 0.44). Sodium polystyrene sulfonate is not an effective method of decontamination for iron overdose.     

Effect of several adsorbents on the gastrointestinal absorption of paraquat

The effect of several adsorbents on paraquat poisoning was investigated (1) by measuring the saturated amount of the poison adhered on the adsorbentsin vitro and (2) by assaying the blood level of paraquat in the rat inin situ intestinal absorption experiments. Activated charcoal powder, natural aluminum silicate, and cationic exchange resins (calcium polystyrene sulfonate and sodium polystyrene sulfonate) were used as adsorbents. The steady-state blood level of paraquat in its absorption experiment with the cationic exchange resins was markedly lower than those without the resins or with other adsorbents. A good relationship was achieved between the calculated AUC or absorption rate (in situ) and the saturated adsorption amount (in vitro). The rank order of the effect was sodium polystyrene sulfonate>calcium polystyrene sulfonate>natural aluminum silicate>activated charcoal powder. The effect of sodium polystyrene sulfonate after intestinal washing with physiological saline was also measured, and a synergistic effect (marked decrease in blood paraquat level) was found as compared with the intestinal washing alone. The simultaneous use of G.I. washing and powerful adsorbent was scientifically proven to be most beneficial.     

卡络磺钠树脂复合物的制备及静态交换特性

目的制备卡络磺钠树脂复合物,研究其静态交换反应特性。方法以强碱性氯型阴离子交换树脂Duolite AP 143/1083为载体,静态法制备了卡络磺钠树脂复合物,考察了温度、药物初始浓度和树脂粒径对交换反应的影响,并研究了交换反应动力学和热力学。结果卡络磺钠与DuoliteAP 143/1083的离子交换反应符合二级动力学模型;升高温度可提高载药速度,但载药量下降;随着药物初始浓度的增加,载药量先增加然后达到饱和;减小树脂粒径可加快反应速度,但载药量基本不变。结论最优制备条件确定为温度298.2 K,药物初始质量浓度为1.0 g.L-1,树脂粒径60~75μm。     

The Influence of Product Brand-to-Brand Variability on Superdisintegrant Performance A Case Study with Croscarmellose Sodium

The purpose of this study is to investigate factors influencing croscarmellose sodium functionality with special emphasis on developing a discriminating model tablet formulation to evaluate product brand-to-brand variability. The particle size distribution, water uptake, and swelling properties of five brands of croscarmellose sodium in either neutral water or 0.1 N HCl were studied. Differences were observed in all properties between brands. Media with acidic pH had a negative impact, but to different extents, on both the water uptake and swelling of all croscarmellose sodium brands due to the presence of carboxymethyl sodium substituents. A tablet matrix composed of lactose (75% w/w) and dicalcium phosphate (25% wt/wt) was used to compare the functional equivalency of the five brands of croscarmellose sodium. The tablet disintegration times were inversely proportional to the swelling ability of superdisintegrant in the testing medium regardless of medium temperature and disintegrant concentration. In conclusion, the particle size, total degree of substitution, and the ratio of basic to acidic substituents are important factors that should be considered during product optimization. The tablet matrix composed of lactose and dicalcium phosphate at a weight ratio of 3:1 can be used as a model formulation for product lot-to-lot consistency and product brand-to-brand comparison purposes.     

The influence of product brand-to-brand variability on superdisintegrant Performance. A case study with croscarmellose sodium

The purpose of this study is to investigate factors influencing croscarmellose sodium functionality with special emphasis on developing a discriminating model tablet formulation to evaluate product brand-to-brand variability. The particle size distribution, water uptake, and swelling properties of five brands of croscarmellose sodium in either neutral water or 0.1 N HCl were studied. Differences were observed in all properties between brands. Media with acidic pH had a negative impact, but to different extents, on both the water uptake and swelling of all croscarmellose sodium brands due to the presence of carboxymethyl sodium substituents. A tablet matrix composed of lactose (75% w/w) and dicalcium phosphate (25% wt/wt) was used to compare the functional equivalency of the five brands of croscarmellose sodium. The tablet disintegration times were inversely proportional to the swelling ability of superdisintegrant in the testing medium regardless of medium temperature and disintegrant concentration. In conclusion; the particle size, total degree of substitution, and the ratio of basic to acidic substituents are important factors that should be considered during product optimization. The tablet matrix composed of lactose and dicalcium phosphate at a weight ratio of 3:1 can be used as a model formulation for product lot-to-lot consistency and product brand-to-brand comparison purposes.     

Effective parameters in determining cross-linked dextran microsphere characteristics: screening by Plackett–Burman design-of-experiments

This study aims to screen the effective parameters in preparing cross-linked dextran microspheres (CDMs) to make them controllable for obtaining microspheres with tunable properties. Microspheres were prepared by chemical crosslinking of dextran dissolved in internal phase of an inverse emulsion system (W/O) using epichlorohydrin (ECH). A Plackett–Burman design-of-experiments was employed as the screening methodology to investigate the effects of the kinetics and process parameters, i.e. the mixing speed and emulsification time on the resulting microsphere characteristics. Crosslinking reaction temperature and concentrations of the emulsion constituents including dextran, ECH and sodium hydroxide were the studied kinetic parameters. Equilibrium swelling ratio, mean particle size and size distribution of the resulting CDMs were measured and statistically analysed. It was found that dextran concentration is the most influential parameter on the particle size and swelling ratio of the obtained CDMs. Increasing dextran concentration in the aqueous phase leads to a significant increase in the mean particle size and decrement in water uptake capacity of the resulting microspheres, respectively.     

In-vitro study of the drug interactions between Miglitol, an alpha-glucosidase inhibitor, and adsorbents

The interactions between miglitol, an alpha-glucosidase inhibitor, and six adsorbents (carbon spheres, cholestyramine, colestimide, sevelamer hydrochloride, calcium polystyrene sulfonate, and sodium polystyrene sulfonate) were investigated in vitro. Miglitol corresponding to the minimum dose and adsorbents corresponding to the maximum dose were incubated at 37 degrees C for 180 min in solutions of pH 1.2 (gastric pH condition) and pH 6.8 (enteric pH condition), with and without the presence of carbohydrates, which were added to observe the effects on food adsorption. The adsorption ratio of miglitol to carbon spheres was 13.6% and 0% in pH 1.2 solution and 86.4% and 5.0% in pH 6.8 solution without and with the presence of carbohydrates, respectively. Thus, the adsorption ratio was higher in pH 6.8 solution. Adsorption of miglitol to calcium polystyrene sulfonate was nearly the same, 15.0-21.9%, at both pH. The adsorption ratio of miglitol to sodium polystyrene sulfonate was 43.4% and 45.5%, respectively, in pH 1.2 solution without and with carbohydrates. In the pH 6.8 solutions, however, the respective adsorption ratios were low (5.2% and 11.3%). Miglitol did not adsorb to cholestyramine, sevelamer hydrochloride or colestimide under any pH condition examined. The above results suggest that miglitol adsorbs to carbon spheres and polystyrene sulfonic acid cation exchange resins. However, considering that miglitol is taken just before eating and thus exists in gastointestinal fluids together with food, and that the site of its effect is the upper small intestine, the interactions between miglitol and these adsorbents will most likely not be a problem.     

Insulin Nanoparticles: A Novel Formulation Approach for Poorly Water Soluble Zn-Insulin

PURPOSE: To determine the feasibility of using wet milling technology to formulate poorly water soluble zinc-insulin as a stable, biologically active, nanoparticulate dispersion. METHODS: The feasibility of formulating zinc-insulin as a nanoparticulate dispersion using wet milling technology was studied. An insulin nanoparticulate formulation was reproducibly obtained after milling zinc-insulin in the presence of F68, sodium deoxycholate and water at neutral pH. The physical and chemical properties of these peptide particles were studied using electron microscopy, laser light scattering, HPLC and SDS-PAGE. To verify efficacy, hyperglycemic rats were dosed subcutaneously and intraduodenally with nanoparticles or solubilized insulin. Glucose and insulin levels were monitored on blood samples collected throughout the study. RESULTS: Zn-insulin (mean size = 16.162 microm) was processed using milling technology to form an aqueous-based nanoparticle dispersion with a mean particle size of less than 0.150 microm. The formulation was homogeneous and exhibited a unimodal particle size distribution profile using laser light diffraction techniques. Insulin, processed as a peptide-particle dispersion, was shown to be comparable to unprocessed powder using HPLC and SDS-PAGE. In addition, HPLC analyses performed on samples, heat-treated at 70 degrees C for 100 minutes, demonstrate that under conditions which effect the solubilized peptide, formulated as a peptide-particle dispersion, insulin was chemically stable. Also, when stored refrigerated, the insulin dispersion was chemically and physically stable. Finally, peptide particles of insulin, dosed subcutaneously and intraduodenally, were effective at lowering blood glucose levels of hyperglycemic rats. CONCLUSION: Water insoluble Zn-insulin can be formulated as a stable, biologically active nanometer-sized peptide particle dispersion using wet media milling technology.     

In Vitro Adsorption of Bile Salts by Colestipol Hydrochloride

The acid–base titration of colestipol hydrochloride exhibits no sharp inflection points, indicating a weakly basic anion-exchange copolymer. The swelling of colestipol hydrochloride in water and the adsorption of cholate anion are inversely related to pH and are, therefore, related to the ionization state of the copolymer. The Langmuir adsorption parameters at pH 7.5 and 37°C are similar for cholate, glycocholate, and taurocholate anions. Adsorption capacity was not related to particle size and exceeded the adsorptive capacity of the external surface by three orders of magnitude. Therefore, it is believed that the swelling of colestipol hydrochloride makes extensive internal surface area available for adsorption of bile salts. The rate of adsorption depends on the concentration of sodium cholate to which the colestipol hydrochloride is exposed. Adsorption was complete within 5 min when the concentration was below the adsorptive capacity. In contrast, adsorption at levels of sodium cholate at or above the adsorptive capacity was not complete within a 3-hr test period.