酒石酸美托洛尔片仿制药与原研药溶出曲线的相似性评价

目的:建立酒石酸美托洛尔片的溶出度测定方法,并评价仿制药与原研药的质量一致性。方法:采用桨法,转速为50r/min,分别以p H 1.2盐酸溶液、p H 4.5醋酸盐缓冲液和p H 6.8磷酸盐缓冲液为溶出介质,用光纤药物溶出度实时测定仪以10 mm的测定光程,分别测定酒石酸美托洛尔片仿制药与原研药的溶出曲线,并采用相似因子(f~2)法评价二者溶出曲线的相似性。结果:在3种溶出介质中,酒石酸美托洛尔片仿制药与原研药的f2分别为80.5、66.8、69.4,说明二者溶出曲线具有相似性。结论:所建立的实时溶出度过程分析方法适用于酒石酸美托洛尔片的溶出度测定;仿制药与原研药的体外溶出行为具有相似性,故其质量一致性较好。     

国产酒石酸美托洛尔片的溶出度质量评价

目的：通过考察国内7家不同生产企业的酒石酸美托洛尔片与参比制剂（商品名：倍他洛克^TM）的体外溶出情况评价药品质量。方法：参照日本《药品品质再评价工程拟定流程》中对溶出度试验条件的规定,分别考察不同厂家的酒石酸美托洛尔片在水、pH 1.2的氯化钠盐酸溶液、pH 4.0的醋酸盐缓冲液及pH 6.8的磷酸盐缓冲液4种介质中的体外溶出行为,溶出方法为浆法,转速为50 r·min^-1。采用相似因子法比较7家企业的酒石酸美托洛尔片与参比制剂溶出行为的差异。结果： 7家企业酒石酸美托洛尔片的溶出行为存在较大差异,C、F、G企业样品在4种溶出介质中的f₂值均小于50,溶出曲线与参比制剂不相似。结论：国内某些生产企业的酒石酸美托洛尔片与参比制剂的溶出行为有显著差异,仿制药品的质量应予以关注。     

酒石酸美托洛尔片制剂工艺及体外释放度研究

采用多条溶出曲线的方法 ,比较不同粘合剂浓度(酒石酸美托洛尔片)制剂的溶出度差异。通过不同溶出介质条件下相似因子的比较,分析不同制剂工艺的酒石酸美托洛尔片与参比制剂溶出度的相似因子。     

酒石酸美托洛尔片仿制与原研的溶出度比较

目的：对酒石酸美托洛尔片国产仿制药与原研药进行体外溶出度比较,为质量一致性评价提供依据。方法参照中国药典2010版二部酒石酸美托洛尔片的质量标准,选取50mg规格样品,采用4种不同的溶出介质对国内8家企业生产的仿制药和原研药进行体外溶出行为考察,并采用差异因子f1法、相似因子f2法和直接比较法来评价仿制药与原研药溶出行为的一致性。结果8家仿制药溶出行为参差不齐,按直接比较法只有1家仿制药在四种溶出介质中的溶出曲线均与原研药一致,只在两种或一种溶出介质中的溶出曲线与原研药一致的情况较多。结论国内企业生产的酒石酸美托洛尔片仿制药与原研药存在体外溶出行为不一致性,处方、制剂工艺、辅料的选用方面需要进一步研究,以达到仿制药与原研药体外溶出行为一致性和质量一致性。同时,要结合生物等效性试验,对该品种的国产仿制药和原研药的一致性作出综合的评价。     

酒石酸美托洛尔片溶出曲线的测定和评价

目的:比较受试片剂和不同厂家市售片剂的溶出行为.方法:依据中国药典2015版第四部通则0931第二法,结合高效液相色谱法测定受试片剂和市售片溶出度,采用f2相似因子评价不同制剂溶出曲线的相似度.结果:三种介质中,受试制剂溶出曲线f2因子均大于50,市售片A的溶出曲线f2因子均小于50,市售片B在pH 4.0介质中的溶出曲线f2因子大于50,但在pH 1.2和pH 6.8介质中小于50.结论:受试片在三种介质中的f2因子均符合一致性评价要求,两种市售片剂则不完全符合,相对而言,pH6.8介质中测定、计算获得的f2因子可以在一定程度上区分不同来源酒石酸美托洛尔片的溶出行为.     

不同厂家奈韦拉平片的溶出度对比研究

目的 考察国产奈韦拉平片与进口制剂的体外溶出度情况,并比较其体外溶出相似性.方法 分别考察各厂家奈韦拉平片在pH 2.0磷酸盐缓冲液中的溶出度,并比较了国产奈韦拉平片与进口制剂分别在pH 1.2盐酸水溶液、pH 2.0磷酸盐缓冲液、pH 4.5醋酸盐缓冲液、pH 6.8磷酸盐缓冲液4种介质中溶出行为相似性.结果 各厂家奈韦拉平片在pH 2.0磷酸盐缓冲液60min时溶出度均高于75%;有3个厂家的奈韦拉平片在4种溶出介质中的溶出曲线与进口制剂相似.结论不同厂家生产的奈韦拉平片溶出行为有显著差异,可能会影响药物在体内的生物利用度.     

异丙醇对阿替洛尔片溶出行为的影响

目的考察异丙醇用量对阿替洛尔片溶出行为的影响。方法以不同用量的异丙醇为润湿剂,通过湿法制粒制备阿替洛尔片(规格为每粒50 mg),分别测定其5,10,15,25,45,60 min时的累积溶出度,绘制溶出曲线并与参比制剂比较,计算其f2值。结果异丙醇用量对阿替洛尔片的溶出行为影响显著。结论随着异丙醇用量的增加,阿替洛尔的溶出速率加快;当异丙醇用量为0.080 mL/片时,阿替洛尔的溶出行为与参比制剂相似。     

盐酸丙卡特罗片溶出度测定方法的建立及与原研片一致性评价

摘 要：目的：建立盐酸丙卡特罗片溶出度测定方法，评价仿制片与原研片溶出行为的一致性。方法：采用桨板法，转速为50 r·min-1，高效液相色谱法测定累积溶出量。根据仿制药一致性评价要求，考察仿制片与原研片在5种不同溶出介质中的体外溶出行为并比较其相似性。结果：所建立的方法具有测定条件合理、适用性广、操作简便等特点，在5种不同介质中，3批仿制片与原研片15 min时溶出量均大于85%，属于快速溶出，可判定其溶出曲线具有相似性。结论：该方法适用于盐酸丙卡特罗片的溶出度测定，可为其质量一致性评价提供参考。     

酒石酸美托洛尔片溶出度曲线的研究

目的确定酒石酸美托洛尔片工艺改变对其溶出度曲线的影响。方法通过改变酒石美托洛尔片制粒过程中粘合剂预交化淀粉浆的浓度,改善颗粒的可压性,减少整粒时间长,粒度偏大、偏硬的问题,解决压片工序片重差异大的问题。结果工艺优化后酒石美托洛尔片试验样品,溶出度曲线与市售原研药基本一致。结论按照优化工艺生产的中试产品与原工艺生产的产品、原研药厂家市售的酒石酸美托洛尔片溶出度曲线基本一致,符合《中国药典》的相关要求。     

光纤药物溶出度实时测定仪在线监测阿昔洛韦片的溶出度

目的 建立考察阿昔洛韦片溶出过程的方法,初步评价其制剂质量.方法 用光纤药物溶出度实时测定仪在线监测阿昔洛韦片的溶出过程.结果 考察9个厂家阿昔洛韦片的溶出曲线,结果显示部分厂家产品溶出过程不相似,1个厂家产品片间差异很大.结论 光纤溶出度实时测定仪能够有效测定固体药物的体外溶出过程,为改进制剂工艺、监控制剂工艺稳定性提供有益的参考.     

酒石酸美托洛尔缓释片工艺研究

目的对酒石酸美托洛尔缓释片的处方工艺进行研究。方法运用正交设计法,通过测定不同时间酒石酸美托洛尔的释放率,来判断其缓释效果从而对缓释骨架材料、填充剂、粘合剂、润滑剂的种类、规格、用量及工艺等进行考察,并对确定的处方及工艺制备的3批样品测定其释放度。结果用HPMC作为骨架材料,微晶纤维素作为填充剂,硬脂酸镁作为润滑剂,3%EC乙醇溶液作为粘合剂制成酒石酸美托洛尔缓释片。结论本制剂工艺简单,所用各种辅料均为国产化,成本低.制得酒石酸美托洛尔缓释片释放度符合规定。     

A three-layer guar gum matrix tablet for oral controlled delivery of highly soluble metoprolol tartrate

The objective of the study is to design oral controlled drug delivery systems for highly water-soluble drugs using guar gum as a carrier in the form of a three-layer matrix tablet. Metoprolol tartrate was chosen as a model drug because of its high water solubility. Matrix tablets containing either 30 (M1), 40 (M2) or 50% (M3) of guar gum were prepared by wet granulation technique using starch paste as a binder. Three-layer matrix tablets of metoprolol tartrate were prepared by compressing on both sides of guar gum matrix tablet granules of metoprolol tartrate M1, M2 or M3 with either 50 (TL1M1, TL1M2 or TL1M3) or 75 mg (TL2M1, TL2M2 or TL2M3) of guar gum granules as release retardant layers. Both the matrix and three-layer matrix tablets were evaluated for hardness, thickness, drug content uniformity, and subjected to in vitro drug release studies. The amount of metoprolol tartrate released from the matrix and three-layer matrix tablets at different time intervals was estimated by using a HPLC method. Matrix tablets of metoprolol tartrate were unable to provide the required drug release rate. However, the three-layer guar gum matrix tablets (TL2M3) provided the required release rate on par with the theoretical release rate for metoprolol tartrate formulations meant for twice daily administration. The three-layer guar gum matrix tablet (TL2M3) showed no change either in physical appearance, drug content or in dissolution pattern after storage at 40 degrees C/75% RH for 6 months. The FT-IR study did not show any possibility of metoprolol tartrate/guar gum interaction with the formulation excipients used in the study. The results indicated that guar gum, in the form of three-layer matrix tablets, is a potential carrier in the design of oral controlled drug delivery systems for highly water-soluble drugs such as metoprolol tartrate.     

琥珀酸美托洛尔缓释片和酒石酸美托洛尔片对急性心肌梗死患者心率的影响

目的比较琥珀酸美托洛尔缓释片和酒石酸美托洛尔片对急性心肌梗死患者心率的影响。方法选择急性心肌梗死患者76例,在除外应用美托洛尔禁忌后,按1∶2比例随机分配到琥珀酸美托洛尔缓释片组25例和酒石酸美托洛尔片组51例。前者给予琥珀酸美托洛尔23.75 mg,日1次口服,后者给予酒石酸美托洛尔12.5 mg,日2次口服。在此基础上,两组均常规予阿司匹林、氯吡格雷、ACEI及他汀类药物治疗,分别记录用药前和用药后24、48、72 h静息状态的心率,比较用药后心率下降的程度和趋势。结果琥珀酸美托洛尔缓释片组在用药后24、48、72 h 3个时间点的心率分别下降了0、1%、9%,次数下降了0.5次/min、1.6次/min、7.6次/min,酒石酸美托洛尔片组心率分别下降了3%、5%、6%,次数下降了3.5次/min、4.1次/min、5.7次/min。P均<0.05,认为不同时间点上患者心率的差异有统计学意义;而因素心率和剂型的交互作用的P值均>0.05,尚不能认为剂型和心率有交互作用。两组患者服药后72 h内,心率变化的趋势无统计学意义,P均>0.05。结论急性心肌梗死患者应用琥珀酸美托洛尔缓释片或酒石酸美托洛尔片,72 h内心率降低的差异有统计学意义,但两组服药后72 h内,心率的降低程度差异无统计学意义,而且72 h内两组心率下降的趋势,差异也无统计学意义。     

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。     

Pharmacokinetic evaluation of guar gum-based three-layer matrix tablets for oral controlled delivery of highly soluble metoprolol tartrate as a model drug.

The objective of the present study is to carry out pharmacokinetic evaluation of oral controlled release formulation (guar gum-based three-layer matrix tablets) containing highly soluble metoprolol tartrate as a model drug. Six healthy volunteers participated in the study, and a two-way crossover design was followed. The plasma concentration of metoprolol tartrate was estimated by reverse-phase HPLC. The pharmacokinetic parameters were calculated from the plasma concentration of metoprolol tartrate versus time data. The delayed T(max) lower C(max) decreased K(a) unaltered bioavailability and prolonged t(1/2) indicated a slow and prolonged release of metoprolol tartrate from guar gum three-layer matrix tablets in comparison with the immediate release tablet dosage form. The results of the study indicated that guar gum three-layer matrix tablets were able to provide oral controlled delivery of highly water-soluble drug such as metoprolol tartrate in humans.     

Box-Behnken效应面法筛选聚氧乙烯骨架缓释片处方和释药机制的研究

目的：优化聚氧乙烯骨架片的处方并对释药机制进行研究。方法：以水溶性药物酒石酸美托洛尔为模型药物,釆用药物与聚氧乙烯等辅料混合均匀后直接压片的方法制备聚氧乙烯骨架片。以药物释放数据的零级方程拟合度R₀²和处方在1小时和24小时的累积释药百分率Q_1h、Q_24h为评价指标。用Box-Behnken效应面法筛选最优处方。获得最优处方的释放数据进行Higuchi equation、Korsmeyer equation、Peppas-Sahlin equation方程拟合。结果：优化处方是：酒石酸美托洛尔100 mg、聚氧乙烯170 mg、卡波姆65 mg、碳酸钠102 mg,按照该处方制备的酒石酸美托洛尔聚氧乙烯骨架片,对应的评价指标测得值与预测值的偏差小于5%。经验方程拟合和各种方法验证了骨架片的药物释放是扩散和溶蚀的协同作用。结论：利用Box-Behnken效应面法筛选酒石酸美托洛尔聚氧乙烯骨架片的处方的主方法是有效可行的,模型的预测值与理论值相符。药物的释放机制是扩散和溶蚀的协同作用。     

二甲双胍片治疗糖尿病合并高血压128例的疗效观察

目的观察二甲双胍片治疗糖尿病合并高血压的临床疗效。方法将128例糖尿病合并高血压患者,随机分为观察组（68例）和对照组（60例）,对照组服用美托洛尔片100mg/d,观察组在对照组给药基础上给予二甲双胍片1000mg/d;两组患者给药30d后,观察两组患者治疗前后血压、空腹血糖。结果观察组患者在收缩压、舒张压、空腹血糖、餐后两小时血糖几方面治疗前后比较具有显著性差异（P〈0.05）。结论二甲双胍片治疗糖尿病伴原发性高血压疗效明确。     

Use of natural gums and cellulose derivatives in production of sustained release metoprolol tablets

Metoprolol tartrate sustained-release tablets (100 mg) were prepared using xanthan/guar gums and also hydroxypropyl methyl cellulose (HPMC) carboxymethyl-Cellulose (CMC) polymers by direct compression method. Physical characteristics of the tablets and water uptake in addition to their dissolution profiles were compared with standard (Lopressor® SR) tablets. Dissolution test was performed in the phosphate buffer solution (pH 6.8) and the samples were analyzed spectrophotometerically in 275.7 nm. Dissolution studies showed that formulations containing 100 and 80% of HPMC, 100% of guar, and 20% of xanthan followed the Higuchi model, while those containing 60 and 40% HPMC and 100 and 80% xanthan followed a zero-order model. The tablets with 40% xanthen followed a Hixon-Crowell model. In cellulose derivatives the highest MDT and dissolution efficiency until 8 hr (DE₈%) belonged to tablets with 40% HPMC, increasing the amount of CMC decreased the drug release rate, and formulations containing 60 and 40% of HPMC had the USP dissolution standards. While, in the gum formulations, the highest mean dissolution time and the lowest DE₈% belonged to tablets with 100% xanthan, increasing the xanthan decreased the release rate of metoprolol, and formulations containing 80 and 100% xanthan had the USP dissolution standards. Results showed that natural gums are suitable for production of sustained-release tablets of metoprolol.     

Novel metrics to compare dissolution profiles

PURPOSE: To evaluate four novel metrics that compare dissolution profiles and assess their performance characteristics by comparing dissolution profiles of FAST and SLOW immediate release metoprolol tartrate tablets. METHODS: The four novel metrics (rho, rho m, delta a, and delta s), along with f2, were applied to dissolution data from FAST and SLOW metoprolol tartrate tablets. For example, rho m is defined as: [formula: see text] where Rt is the percent dissolved of the reference product at time t, Tt the percent dissolved of the test product at time t, and RATIOt the larger of either Rt/Tt or Tt/Rt. The mean metric values, upper (or lower) confidence limits, and skewness values were calculated, in order to characterize the performance of each metric. RESULTS: The mean values of rho, rho m, delta a, delta s, and f2 were 1.80, 0.80, 0.47, 0.36, and 19.6, respectively. The novel metrics indicate that greater than a 50% relative difference exists between the FAST and SLOW profiles. The upper 95% confidence limits for rho, rho m, delta a, and delta s were 1.84, 0.83, 0.48, and 0.38, respectively, with f2 having a lower limit of 19.1. Skewness values for ln-transformed rho, rho m, delta a, delta s, and f2 were 0.81, 0.71, 0.86, 0.47, and -0.94, respectively, suggesting favorable metric distribution properties. CONCLUSIONS: The direct curve comparison metrics rho, rho m, delta a, and delta s appear to be viable methods to compare dissolution profiles, particularly rho m.