Disintegrant Selection in Hydrophobic Tablet Formulations

The hydrophobicity of poorly soluble drugs can delay tablets disintegration. We probed here the influence of different disintegrants on the disintegration of challenging hydrophobic formulations. Tablets containing diluents, hydrogenated vegetable oil and either sodium starch glycolate (SSG), croscarmellose sodium (CCS) or crospovidone (XPVP) were prepared. The disintegration time of tablets was tested immediately and after storage at 40 °C and 75% RH in sealed bags. Results show that storage and compression force had a negative effect on disintegration, particularly with 1% disintegrant. The performance of the three disintegrants was in the following order: CCS (best) > SSG > XPVP. For example, tablets containing 1% CCS, SSG and XPVP, compressed at 20 kN, disintegrated in ≈3, ≈12 and ≈69 min, respectively, after two months storage. Settling volume, liquid uptake and effect of storage on physical properties of the pure disintegrants were also studied and revealed that the reduced performance of XPVP is related to: 1) its rapid, yet short-range expansion upon liquid exposure and 2) its change of behaviour on storage. In conclusion, CCS ensured rapid disintegration at low concentration across various compression forces and storage times. Thus, the use of CCS in hydrophobic tablet formulations is recommended.     

Performance of Diltiazem Tablet and Multiparticulate Osmotic Formulations in the Dog

The in vivo performance of two extended-release (ER) osmotic formulations of diltiazem were evaluated in the beagle dog. Both ER formulations had similar bioavailabilities (F) as the diltiazem solution. Although F was somewhat variable following ER administration, this variability may be related to the drug entity since intra- and interanimal variability of orally administered diltiazem solutions was substantial. Deconvolution of the ER plasma diltiazem data with absorption data from the orally administered diltiazem solutions provided an estimate of the in vivo drug release from the ER formulations. The two ER formulations, designed with different in vitro release profiles, reflected these differences in vivo, with nearly identical respective in vivo and in vitro release profiles.     

Spectrophotometric Estimation of Ketotifen Fumarate from Tablet Formulations

Two simple and sensitive visible spectrophotometric methods have been developed for the quantitative estimation of ketotifen fumarate from its tablet formulation. The developed methods are based on formation of chloroform extractable colored complex of with 2-nitroso- napthol-4- sulphonic acid and rhodizonic acid. The extracted complex of drug with 2-nitroso- napthol-4- sulphonic acid (method-I), showed absorbance maxima at 436.5 nm and with rhodizonic acid (method-II), showed absorbance maxima at 489.5 nm. The linearity range for both the developed methods was observed in the concentration range of 50-250 µg/ml of drug. Results of analysis for both the developed methods were validated statistically and by recovery studies.     

Intrinsic Dissolution Rates of Tablet Filler-Binders and Their Influence on the Dissolution of Drugs from Tablet Formulations

Intrinsic dissolution rates were determined for different grades of commonly used calcium salt fillers and lactose. Typical tablet formulations of low-dose drugs were studied to determine the influence of this property on drug dissolution.     

羟氨苄青霉素胶囊及片剂的溶出度考察

本文对国产几个厂家的羟氨苄青霉素胶囊及进口的弗莱莫星可溶片进行了体外溶出度测定，并对其溶出参数（Ｔ＿（５０）、Ｔｄ、ｍ）进行了统计处理。结果表明：同一厂家不同批号的胶囊或片剂以及不同厂家的胶囊和片剂之间，其溶出参数皆有显著性差别（ｐ＜０．０１）。     

老年人地高辛血药浓度监测及影响因素分析

目的 了解老年人地高辛血药浓度的影响因素,为临床地高辛的合理使用提供参考.方法 采用荧光偏振免疫法(FPIA)对地高辛血药浓度进行监测,并对我院2010年1月～2011年12月老年人群地高辛血药浓度监测结果进行回顾性分析.结果 男性181例次,女性162例次;男性、女性地高辛血药浓度无明显差异;80～94岁组地高辛血药浓度较高(P＜0.05);位于地高辛治疗窗内的有147例次,占总数42.86％,有152例次(44.31％)和44例次(12.83％)分别低于治疗窗和高于治疗窗,与60～69岁组相比,70～94岁组地高辛血药浓度高于治疗窗的比例升高.结论 地高辛血药浓度影响因素复杂,应对老年人尤其是高龄人群进行地高辛血药浓度监测,结合临床疗效,进行个体化给药,降低老年人群的用药风险.     

Single-Dose and Steady-State Pharmacokinetics of Diltiazem Administered in Two Different Tablet Formulations

Abstract: Single-dose and steady state pharmacokinetics of diltiazem administered in two different oral formulations were assesed with particular reference to rate and extent of absorption. Following single dose administration a significant difference in t_max was observed (2.9 ± 1.9 and 6.8 ± 2.6 hr respectively) whereas differences in AUC, t_1/2 and C_max were not significant. The AUC (mean ± S.D.) values following single dose administration of Cardil® and Cardizem® were 678.4 ± 321.5 and 948.6 ± 580.6 ng · ml^-1 · hr respectively. The mean and the 95% confidence limits for the observed ratio AUC_Cardil/ AUC_Cardizem are 0.89 and 0.44-1.34 respectively. At steady-state a significant difference between C_max/C_min and t_max was seen C_max/C_min being 4.9 and 3.2 respectively and T_max being 2.7 ± 2.0 and 6.0 ± 2.8 hr respectively, whereas C_max and AUC did not differ significantly. The AUC (mean ± S.D.) values in steady state of Cardil® and Cardizem® were 880.1 ± 399.8 and 1056.8 ± 509.8 ng · ml^-1 · hr respectively. The mean and the 95% confidence limits for the observed ratio AUC_Cardil/AUC_Cardizem are 0.96 and 0.66-1.26 respectively. Although the observed ratios AUC_Cardil/AUC_Cardizem in both the single-dose and the steady-state study do not differ significantly from 1.0, the confidence limits exceed the acceptable values given by Poulsen & Juul (personal communication 1990) (a 20% decrease or increase of the ratio to 0.8 or 1.2).     

Evaluation of the Pharmacokinetics and Safety of AMG 986 Tablet and Capsule Formulations in Healthy Adult Subjects: A Phase I,Open-Label,Randomized Study

Background and objectiveAMG 986 is a first-in-class, novel apelin receptor small molecule agonist initially developed for the treatment of heart failure. The current phase I study was conducted to evaluate the pharmacokinetics and safety of a single-dose 200-mg capsule formulation of AMG 986 relative to the tablet formulation in 12 healthy subjects.MethodsIn a two-period, two-way crossover design, eligible subjects were randomized 1:1 to tablet/capsule or capsule/tablet treatment sequences; each treatment sequence lasted for approximately 6 days and comprised six subjects.ResultsFollowing a single oral dose of AMG 986, the geometric mean maximum observed concentration (C_max) values were 9670 ng/mL and 6920 ng/mL and the geometric mean area under the curve from time zero to 120 h (AUC_0–120h) values were 68,000 ng*h/mL and 59,900 ng*h/mL for the tablet and capsule, respectively. The geometric least squares means (90% confidence interval [90% CI]) for the ratios of capsule/tablet were 0.88 (90% CI 0.81–0.96) and 0.72 (90% CI 0.57–0.91) for AUC_0–120h and C_max, respectively. AMG 986 had an acceptable safety profile; all adverse events were grade 1 or 2 in severity.ConclusionThere was a modest 12% decrease in AUC_0–120h and a 28% decrease in C_max with the AMG 986 capsule versus the tablet. These differences are not considered to be clinically relevant, suggesting the capsule formulation can be used in subsequent clinical studies of AMG 986.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40268-022-00388-1.     

依西美坦胶囊的人体生物等效性研究

目的 :研究依西美坦胶囊与依西美坦片的生物等效性。方法 :男性健康志愿者18名 ,采用自身交叉方式单剂量口服受试制剂依西美坦胶囊与参比制剂依西美坦片50mg ,以高效液相色谱法测定其血药浓度 ,计算其药动学参数及其相对生物利用度 ,评价其生物等效性。结果 :依西美坦胶囊和依西美坦片主要药动学参数T1/2(β) 分别为 (24 34±3 59)h和 (24 00±3 90)h ,Tmax 分别为(1 67±0 34)h和 (1 64±0 29)h ,Cmax 分别为 (26 34±13 82)ng/ml和 (25 19±11 94)ng/ml ,AUC0～t分别为 (323 00±97 50)ng/ (ml·h)和 (273 92±90 44)ng/ (ml·h) ,AUC0～∞分别为 (340 94±124 20)ng/ (ml·h)和 (288 64±113 60)ng/(ml·h)。两制剂的药动学参数无统计学差异。依西美坦胶囊的相对生物利用度为 (105 75±9 40) %。结论 :依西美坦胶囊与依西美坦片具有生物等效性     

氟他胺胶囊(片)药代动力学及其生物等效性评价

用HPLC法研究10名健康男性受试者单剂量口服500mg氟他胺胶囊和片后,血浆中羟基氟他胺浓度及其药代动力学指标。并以片剂为参比制剂,对胶囊的生物利用度及其生物等效性进行评价。结果显示受试者服药后,血浆中原型药物浓度低,且变异性大,并快速转化为羟基代谢物。测得的胶囊T_(max)2.7h,C_(max)2.22μg·ml~(-1),片剂的T_(max)3.3h,C_(max)2.00μg·ml~(-1)。两制剂的t1/2约为5.7h。AUC~(24)分别为20.93±4.01和19.43±5.35μg·ml~1。相对生物利用度为110.22±14.82％。经方差分析和双向单侧t检验显示两种剂型的AUC~(24)和AUC生物等效。     

Effect of Hydrophilic Diluents on the Release Profile of Griseofulvin from Tablet Formulations

Studies have shown that when compressing drugs with low aqueous solubility, the solubility of diluents selected is very crucial as it influences the disintegration, dissolution and bioavailability of such drugs. Based on these reports, the present study was undertaken to investigate the effect of some commonly used hydrophilic tablet diluents (lactose, sucrose, mannitol and dextrose) on the in vitro release properties of griseofulvin from compressed tablets. Griseofulvin granules and tablets were prepared using the wet granulation method. Tablet properties evaluated as a function of the diluents used include, hardness, friability, dissolution profile and dissolution efficiency at 60 min. Results obtained indicated variability in griseofulvin release in the presence of the diluents. The relative enhanced dissolution effects of the four hydrophilic diluents is in the order of dextrose>sucrose>lactose>mannitol. All the griseofulvin tablet batches produced exhibited a better drug release (in terms of rate and extent of release) than a commercially available tablet sample of griseofulvin (Fulcin^®). The results of the dissolution efficiency (DE_60min) are 91.7, 83.5, 48.7, 35.3 and 15.6% for dextrose, sucrose, lactose, mannitol and fulcin^®, respectively. The overall results indicated that dextrose or sucrose can be utilised to improve the in vitro release profile and hence in vivo bioavailability of griseofulvin from compressed tablets.     

盐酸左氧氟沙星片剂和胶囊剂人体生物等效性研究

目的:评价受试制剂盐酸左氧氟沙星片和胶囊与参比片剂人体生物等效性。方法:采用3制剂3周期的优化拉丁方试验设计,24名健康男性受试者分别口服单剂量3种左氧氟沙星制剂200 mg,HPLC法测定血浆中左氧氟沙星的浓度。结果:受试制剂盐酸左氧氟沙星片、盐酸左氧氟沙星胶囊和参比制剂的cm ax分别为(2.24±0.33)、(2.37±0.48)和(2.05±0.37)μg/m l;tm ax分别为(0.94±0.43)、(0.85±0.38)和(1.07±0.42)h;t1/2分别为(6.46±0.56)、(6.50±0.68)和(6.40±0.66)h;AUC0-24分别为(16.13±2.00)、(17.12±2.47)和(15.37±2.20)μg.h.m l-1;AUC0-∞分别为(17.46±2.34)、(18.53±2.83)和(16.63±2.59)μg.h.m l-1。受试制剂盐酸左氧氟沙星片和盐酸左氧氟沙星胶囊相对于参比制剂的生物利用度分别为(105.6±8.7)%和(112.0±11.6)%。结论:受试制剂盐酸左氧氟沙星片和盐酸左氧氟沙星胶囊与参比制剂盐酸左氧氟沙星片具有生物等效性。     

盐酸左氧氟沙星片剂和胶囊剂人体生物等效性研究

目的:评价受试制剂盐酸左氧氟沙星片和胶囊与参比片剂人体生物等效性.方法:采用3制剂3周期的优化拉丁方试验设计,24名健康男性受试者分别口服单剂量3种左氧氟沙星制剂200 mg,HPLC法测定血浆中左氧氟沙星的浓度.结果:受试制剂盐酸左氧氟沙星片、盐酸左氧氟沙星胶囊和参比制剂的cmax分别为(2.24±0.33)、(2.37±0.48)和(2.05±0.37)μg/ml;tmax分别为(0.94±0.43)、(0.85±0.38)和(1.07±0.42)h;t1/2分别为(6.46±0.56)、(6.50±0.68)和(6.40±0.66)h;AUC0-24分别为(16.13±2.00)、(17.12±2.47)和(15.37±2.20)μg·h·ml-1;AUC0-∞分别为(17.46±2.34)、(18.53±2.83)和(16.63±2.59)μg·h·ml-1.受试制剂盐酸左氧氟沙星片和盐酸左氧氟沙星胶囊相对于参比制剂的生物利用度分别为(105.6±8.7)%和(112.0±11.6)%.结论:受试制剂盐酸左氧氟沙星片和盐酸左氧氟沙星胶囊与参比制剂盐酸左氧氟沙星片具有生物等效性.     

阿斯匹林肠溶缓释胶囊的人体药代动力学及生物利用度研究

本文报道口服阿斯匹林肠溶缓释胶囊及肠溶片后体内水杨酸盐的高效液相色谱测定法及正常人药代动力学和生物利用度研究的结果。12名健康志愿者，随机分为两组，分别交叉口服阿斯匹林肠溶缓释胶囊和肠溶片各600mg。阿斯匹林在体内迅速转化为活性代谢产物水杨酸，测定口服给药后不同时间血中水杨酸的浓度，使用3P87实用药代动力学程序对药一时曲线进行处理，结果表明，水杨酸在体内的代谢过程符合一室模型。单剂空腹口服阿斯匹林肠溶缓释胶囊和肠溶片后，体内水杨酸的平均峰浓度为35．52±8．28mg／L和30．32±8．96mg／L；平均达峰时间为5．70±1．25h和7．40±2．17h开均药-时曲线下面积为328.4±92．2mg／（Lh）和316．0±70．95mg／（L·h)）;消除半衰期为3．11±1．25h和3．84±1．72h；吸收迟滞时间为2．33±0．65h和3．35±1．16h。肠溶缓释胶囊的达峰时间明显短于肠溶片。缓释胶囊对片剂的相对生物利用度为103．9％。     

奥硝唑片、奥硝唑胶囊人体生物等效性研究

目的 :比较试验制剂国产奥硝唑片及国产奥硝唑胶囊与参比制剂进口奥硝唑片的生物等效性。方法 :18名健康志愿者 ,单剂三交叉口服试验制剂奥硝唑片、奥硝唑胶囊和参比制剂 1.5 g ,于药前和药后0 .5 ,1,1.5 ,2 ,3,4 ,6 ,8,12 ,2 4 ,36 ,4 8,72h取肘静脉血 ,用高效液相色谱法测定奥硝唑经时血药浓度 ,数据经 3P97处理得药代动力学参数 ,根据试验制剂和参比制剂AUC计算相对生物利用度。同时对主要药代动力学参数进行方差分析、双单侧t检验和 (1- 2α)置信区间分析 ,评价试验制剂和参比制剂的生物等效性。结果 :试验制剂奥硝唑片、奥硝唑胶囊和参比制剂主要药代动力学参数t1/ 2 ( β) 分别为 (16 .2 9± 2 .199) ,(16 .0 8± 2 .317)和 (15 .84 9± 2 .2 6 4 ) ,tpeak分别为 (1.75± 0 .4 93) ,(1.75± 0 .4 93)和 (1.75± 0 .4 79)h ,Cmax分别为(2 1.5 34± 3.5 3) ,(2 1.936± 3.314 ) ,(2 0 .85± 5 .939) μg·ml-1,AUC0～ 72 分别为 (44 4 .5 6± 5 5 .872 ) ,(44 6 .4 98± 5 5 .138)、(433.30 9± 5 8.5 2 1) μg·ml-1·h-1,AUC0～∞ 分别为 (46 2 .94 9± 5 5 .35 4 ) ,(46 5 .2 2 1± 5 6 .73) ,(45 1.6 6 8± 5 7.971) μg·ml-1·h-1,奥硝唑片、奥硝唑胶囊相对生物利用度分别为 10 2 .91± 8.93%     

地高辛在老年慢性心功能不全患者中的应用及其血药浓度变化研究

目的：观察地高辛治疗老年慢性心功能不全的临床疗效,探讨地高辛血药浓度监测的价值。方法：选取2012年10月—2014年6月在广州市番禺区何贤纪念医院应用地高辛治疗的老年慢性心功能不全住院患者146例,观察其临床疗效,并测定地高辛稳态血药浓度。结果：心力衰竭缓解患者地高辛稳态血药浓度为（1．64±0．87）ng／ml,心力衰竭未缓解患者为（0．82±0．41） ng／ml,差异有统计学意义（P＜0．05）;地高辛血药浓度越高,中毒反应发生率越高,差异有统计学意义（P＜0．05）;患者年龄、给药剂量、联合用药等均对地高辛血药浓度存在影响。结论：地高辛血药浓度个体差异较大,血药浓度监测对减少地高辛中毒和实现个体化给药具有重要意义。     

苦参素片、苦参素胶囊人体生物等效性研究

目的: 比较苦参素片剂与胶囊剂的生物等效性.方法: 20名男性健康志愿者,双交叉于试验当日晨空腹一次口服试验制剂苦参素片、参比制剂苦参素胶囊 600 mg,于药前和药后0.25,0.5,1.0,1.25,1.5,2.0,2.5,3.0,3.5,4.0,5.0,6.0,8.0 h取肘静脉血,高效液相色谱法测定主要成分氧化苦参碱血药浓度.氧化苦参碱血药浓度-时间数据经3P97处理,得药动学参数,参数进行方差分析、双单侧t检验和(1-2α)置信区间分析,并计算相对生物利用度评价两种制剂的生物等效性.结果: 苦参素片和苦参素胶囊氧化苦参碱主要药代动力学参数t1/2分别为(2.144±0.453)h 和(2.066±0.439)h,tmax 分别为(2.275±0.716)h和(2.175±0.654)h,Cmax 分别为(0.384±0.144)μg·ml-1 和(0.370±0.132)μg·ml-1,AUC0-8h分别为(1.098±0.278)μg·ml-1·h和(1.094±0.280)μg·ml-1·h,AUC0-∞分别为(1.216±0.292)μg·ml-1·h和(1.200±0.271)μg·ml-1·h.试验制剂苦参素片相对生物利用度F(以氧化苦参碱计)为100.403%±6.281%,两制剂具有生物等效性.结论: 苦参素片和苦参素胶囊为生物等效制剂.     

Quantitative Correlation of the Effect of Process Conditions on the Capping Tendencies of Tablet Formulations

Capping is a mechanical defect in tablet formulation and manufacture. Understanding what influences tablet capping in terms of process variables and formulation properties and developing specialized techniques to correlate these variables with mechanical failures are practical interests of the pharmaceutical industry. Tablet compression emulator was used to rank order capping tendencies of a diverse sample set. The compression forces of 5–25 kN were used to compress round, beveled edge, and oval shape tablets. Compression speeds of 25, 40, and 80 rpm were chosen as representative ranges for bench-to-manufacturing-scale processing. Tablets were tested by in-house developed nondestructive ultrasonic method. The measurements revealed that elastic modulus vary with different testing orientations that indicated elastic modulus anisotropy in tablets. It was shown that altering process conditions such as tooling, compression force, and compression speed significantly impact the capping tendencies of formulations. A systematic approach has been applied to develop a predictive tool to assess capping tendencies of formulations. The developed tool is fast, material sparing, and has potential to flag the risk of manufacturability issues and provide insight into the performance of formulations during early development. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 103:1652–1663, 2014