Formulation,Bioavailability, and Pharmacokinetics of Sustained-Release Potassium Chloride Tablets

The release of potassium chloride incorporated into hydrogenated vegetable oil and hydroxypropyl methylcellulose matrix tablets was studied in vitro. The formulations containing 20% hydrogenated vegetable oil and hydroxypropyl methylcellulose showed a sustained-release profile comparable to that of a standard commercially available sustained-release preparation, containing 8 mEq potassium chloride embedded in a wax material. The formulated and standard sustained-release potassium chloride tablets were compared to a conventional enteric-coated potassium chloride tablet in 10 healthy subjects. Mean recoveries in 24-hr urine potassium levels from four dosage forms (after subtracting normal urine potassium excretion levels) were 76 ± 32% from hydroxypropyl methylcellulose, 95 ± 22% from hydrogenated vegetable oil-incorporated matrix tablets, 91 ± 29% from commercially available sustained-release tablets, and 97 ± 13% from enteric-coated tablets. There was no significant difference (P > 0.05) in the time to reach maximum excretion rates among the three sustained-release tablets. No significant adverse effect was experienced with any of the preparations.     

Succinylated whey protein isolate as a sustained-release excipient of puerarin derivative oral tablets: Preparation,optimization and pharmacokinetics

This work was done to investigate succinylated commercial whey protein isolate (S-WPI) as an oral sustained-release delivery carrier for puerarin 5 (PR-5). The succinylation conditions were established for S-WPIs by optimization of single factor study and Box–Beehnken design. The effect of succinylation degree on S-WPIs solubility was evaluated. Physicochemical properties of S-WPIs dried by different three methods on their flow ability, particle size, morphology and in vitro release behavior were studied. After preparing PR-5 sustained release protein tablets with S-WPIs as the carrier by direct powder compression method, the drug release were studied in vitro and the oral pharmacokinetics and bioavailability was evaluated using in vivo dog model. It was observed that concentration of substrate has a significant effect on succinylation. Release behavior in vitro showed spry dried S-WPIs with 100% succinylation rate and 30% drug loading would be applied to the preparation of PR-5 sustained-release protein tablets based on the swelling mechanism (protein loss). Compared with PR-5 conventional tablet with oral administration, T_max value of PR-5 sustained-release protein tablets was approximately 1.58 fold greater than those of the conventional tablets as further evidenced by the significantly prolonged MRT and T_1/2. The findings demonstrated that spray-dried S-WPIs has potential as a promising functional excipient for the design of PR-5 oral sustained-release tablets which can fully improve sustained-release effect and oral bioavailability.     

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。     

Comparison of serum levels of two sustained- release preparations of lithium carbonate

Summary

Concentrations of lithium in serum were compared during treatment of 18 chronic schizophrenic patients with 2 sustained-release forms of tablet containing lithium carbonate (‘Priadel’ and Lithium'Phasal’). Doses were given once daily at 7pmor8am. ‘Priadel’ gave higher concentrations at 9?pm after dosage at 7?pm, and higher at 12 noon when the drugs were given at 8 am. When the drugs were given at 7?pm mean values between 9 am and 6?pm were similar for the two formulations.

In general, the two preparations were satisfactory sustained-release forms of a lithium salt. ‘Phasal’ might have been slightly less likely to give side-effects than ‘Priadel’, but this disadvantage with the latter drug might be avoided by giving it later at night. The findings supported the view that for once-a-day administration it is better to give sustained-release forms of lithium salts at night rather than in the morning, so that any peaks in serum concentration should be during sleep, but twice-a-day dosage would be preferable.     

The Effect of Formulation Composition and Dissolution Parameters on the Gel Strength of Controlled Release Hydrogel Tablets

The impact of hydrogel polymers and dissolution media on tablet gel strength, Γ, of controlled release (CR) hydrogel tablets was investigated. CR tablets containing either hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), or carbomer were formulated with theophylline and Fast Flo® lactose, to produce tablets with a polymer content of 8, 15, and 30% w/w. Γ was measured using a previously reported method. The drug dissolution profiles were similar, irrespective of polymer type or dissolution media (DI water, 0.1 N HCl, and pH 6.8 phosphate buffer), at the same % w/w level of polymer. Γ, however, showed large and significant differences (p≤0.05) between tablets containing different polymers and between different dissolution media. Γ values were HPMC K100MP > HPC HXF > carbomer 971P (same % w/w) with absolute Γ values at 30% w/w in DI water of 6600, 4600, and 1600 ergs/cm³, respectively. Γ for HPMC based tablets was independent of changes in dissolution media, while the Γ values for HPC tablets were 18% lower in acid and buffer than in DI water. Of the polymers tested, carbomer based tablets had the lowest Γ values in all dissolution media and an unexpected 58% lower Γ in buffer compared with DI water or acid. Γ provides a quantitative measure of the effect of formulation and dissolution parameter changes on tablet gel layer strength, under in vitro stress conditions that may parallel in vivo tablet performance, but which cannot be deduced from a comparison of dissolution profiles or polymer viscosity.     

盐酸普萘洛尔缓释片与常释片的生物利用度比较研究

目的：通过双交叉试验证明盐酸普萘洛尔缓释片有缓释作用。方法：用HPLC方法,测定血清中普萘洛尔浓度,进行盐酸普萘洛尔缓释片与常释片的生物利用度比较及峰谷浓度波动研究。结果：12位健康男性受试者一次交叉口服缓释片和常释片(均为40 mg)后的C_max分别为62.4±23.3和95.9±12.6 ng.mL^-1,AUC分别为360.2±80.6和383.5±74.2 ng.h.mL^-1,缓释片相对于常释片的相对生物利用度为95%;12位受试者连续服缓释片和常释片后平均稳态浓度分别为42.2±12.2和32.7±7.1 ng.mL^-1,波动度(DF)分别为0.90±0.35和2.09±0.34。结论：两种制剂具生物等效性,且缓释片比常释片有峰谷浓度差异小、血药浓度波动幅度小的特点。     

Application of Curdlan to Controlled Drug Delivery. I. The Preparation and Evaluation of Theophylline-Containing Curdlan Tablets

To study the use of curdlan, a natural -l,3-glucan, in drug delivery, in vitro release studies were carried out with curdlan tablets containing theophylline. Tablets were readily prepared by compressing three different curdlan and theophylline mixtures, namely, a physical mixture, spray-dried curdlan particles with theophylline powder, and spray-dried particles of curdlan/theophylline solution. Drug release from the tablets prepared from spray-dried particles of curdlan/theophylline was lowest. The release rate was constant from 1 to 8 hr, and 59% cumulative release was obtained at 8 hr. Drug release from curdlan tablets was unaffected by pH or various ions; these curdlan tablets might also control drug release in vivo after oral administration. Application of Higuchi's equation indicated that drug release from curdlan tablets was diffusion-controlled. The release profiles of the curdlan tablets were compared to those of a commercial theophylline sustained-release tablet.     

醋氯芬酸缓释片治疗膝骨关节炎的疗效观察

目的探讨醋氯芬酸缓释片治疗膝骨关节炎的临床疗效。方法选取2018年1月—2019年12月在天津市第一中心医院治疗的96例膝骨关节炎患者作为研究对象,按照不同治疗方法将所有患者分为常规片组、缓释片组,每组各48例。常规片组口服醋氯芬酸片,100 mg/次,2次/d。缓释片组口服醋氯芬酸缓释片,200 mg/次,1次/d。两组患者连续治疗4周。观察两组的临床疗效,比较两组治疗前后视觉模拟评分法(VAS)评分、关节功能评分、日常生活能力评分。结果治疗后,缓释片组患者的总有效率(97.9%)明显高于常规片组(87.5%),两组数据组间差异具有统计学意义(P0.05)。治疗后,两组患者VAS评分、关节功能评分、日常生活能力评分均显著降低(P0.05),且缓释片组患者VAS评分、关节功能、日常生活能力评分明显低于常规片组(P0.05)。结论醋氯芬酸缓释片治疗骨关节炎具有较好的临床疗效,能够缓解患者疼痛,改善患者关节功能、日常生活能力。     

二甲双胍亚硝胺杂质研究及亲水凝胶骨架材料的筛选

目的 探讨不同亲水凝胶骨架材料与盐酸二甲双胍(metformin hydrochloride,MET)降解生成N-二甲基亚硝胺(N-dimethylnitrosamine,NDMA)之间的相关性,筛选合适的骨架材料用于制备MET缓释片。方法 以高效液相色谱-三重四极杆串联质谱为NDMA监测手段,通过原辅料相容性考察确定产生NDMA风险较低的骨架材料,而后考察溶胀性能,确定溶胀作用与参比制剂相似的骨架材料,将筛选出的骨架材料制备缓释片后考察其体外溶出和剂量倾泻的行为。结果 原辅料相容性考察发现羟丙甲纤维素(hypromellose,HPMC)是引起MET降解产生NDMA的主要原因,并筛选出溶胀作用与HPMC相似的卡波姆,以其为骨架材料制备缓释片可获得与参比制剂相似的溶出曲线,且剂量倾泻风险较低,产品稳定性良好。结论 卡波姆可作为HPMC的替代材料,用于制备MET缓释片。     

Delivery of didanosine from enteric-coated,sustained-release bioadhesive formulation

The aim of our study is to assess the release characteristics, in vitro permeation, and stability of an enteric-coated, bioadhesive, sustained-release formulation of didanosine (ddI). Enteric-coated tablets of ddI, containing Polyox® WSRN-303 and Methocel K4M, were prepared using hydroxypropylmethylcellulose phthalate (HPMCP 5.5). The enteric-coated formulation was resistant to dissolution in 0.1 N HCl solution but dissolved within 10 min ( ±2 min) in pH 7.4 phosphate buffered saline. The release profiles were linear with square root time. Stability studies indicate that the formulations were stable at 4°C, room temperature, and 40°C upon storage for 6 months. Polyox® WSRN-303 tablets exhibited a higher ddI permeation ratio across live intestinal tissue compared with conventional tablets. Enteric-coated, sustained-release, bioadhesive tablets deliver ddI in small doses and at the same time prevent acid-induced degradation and hence hold a potential to improve ddI's oral bioavailability.     

Assessing the risk of alcohol-induced dose dumping from sustained-release oral dosage forms: in vitro–in silico approach

Abstract

Consumption of alcoholic beverages with sustained-release oral dosage forms may pose a risk to patients due to potential alcohol-induced dose dumping (ADD). Regulatory guidances recommend in vitro dissolution testing to identify the risk of ADD, but the question remains whether currently proposed test conditions can be considered biopredictive. The purpose of this study was to evaluate different dissolution setups to assess ADD, and the potential of combined in vitro–in silico approach to predict drug absorption after concomitant alcohol intake for hydrophilic and lipophilic sustained-release tablets containing ibuprofen or diclofenac sodium. According to the obtained results, the impact of ethanol was predominantly governed by the influence on matrix integrity, with the increase in drug solubility being less significant. Hydrophilic matrix tablets were less susceptible to ADD than lipophilic matrices, although the conclusion on formulation ethanol-vulnerability depended on the employed experimental conditions. In silico predictions indicated that the observed changes in drug dissolution would not result in plasma concentrations beyond therapeutic window, but sustained-release characteristics of the formulations might be lost. Overall, the study demonstrated that in vitro–in silico approach may provide insight into the effect of ADD on drug clinical performance, and serve as a tool for ADD risk assessment.     

Evaluation of theophylline tablets compacted by means of a novel ultrasound-assisted apparatus

A model formulation containing theophylline and Eudragit® RL was compacted, at energies ranging between 15 and 150 J, by means of a laboratory-scale, novel tabletting machine in which compaction was effected by ultrasound, rather than by mechanical energy. Comparison of the technological and physico-chemical characteristics of the resulting tablets with those of tablets obtained with a conventional tabletting machine evidenced significant differences, suggesting sintering as the main mechanism operating in ultrasound-assisted compaction. The ultrasound-compacted tablets released the drug at lower rates with respect to conventional tablets. The novel technique migh prove useful for the development of sustained-release oral dosage forms containing theophylline or other suitable drugs.     

盐酸羟考酮缓释片口服和直肠给药治疗中重度癌痛有效性和安全性的系统评价

目的 系统评价盐酸羟考酮缓释片口服和直肠给药治疗中、重度癌痛的有效性和安全性。方法 计算机检索PubMed、Cochrane图书馆、CNKI、VIP、CBM、万方等数据库公开发表的盐酸羟考酮缓释片口服和直肠给药治疗中、重度癌痛的随机对照试验（RCT）,检索年限均为自建库至2016年3月。文献质量评价参照Cochrane系统评价员手册。结果 共纳入10项研究,合计642例患者,主要结局指标为临床疗效,次要结局指标为不良反应（恶心呕吐、便秘、嗜睡）。由于纳入研究质量不高且存在发表偏倚,因此只做描述性分析。系统评价结果显示,盐酸羟考酮缓释片直肠给药治疗中、重度癌痛的临床疗效与口服给药相较无差异,且恶心呕吐、便秘和嗜睡的发生率更低。结论 盐酸羟考酮缓释片口服与直肠给药治疗中、重度癌痛具有相同的疗效,且直肠给药不良反应发生率更低,但受限于纳入研究的质量和数量,尚需今后开展更多大样本、高质量的RCT加以验证。     

消炎汤调节肠道微生态改善大鼠慢性盆腔炎的研究

目的探讨消炎汤通过调节肠道微生态的变化对慢性盆腔炎大鼠的治疗作用。方法采用子宫内注射苯酚胶浆建立大鼠慢性盆腔炎模型,造模2周后ig消炎汤5、10、20 g/kg,连续14 d,观察大鼠子宫内膜形态,qPCR检测子宫组织中细胞间黏附分子(ICAM-1mRNA)表达情况,并采用16SrRNA高通道测序观察慢性盆腔炎大鼠肠道菌群的构成和比例。结果各给药组中充血水肿现象少见,且炎症浸润程度好于妇科千金片组。与模型组相比,消炎汤各剂量组子宫组织中ICAM-1mRNA的表达均有下调,尤以消炎汤20 g/kg组为甚(P0.01)。与模型组相比,消炎汤20 g/kg组Simpson指数显著上升(P0.05)。给予消炎汤治疗后肠道菌群多样性、丰度均得到一定程度改善,但未见统计学差异。与模型组相比,消炎汤10、20g/kg组乳杆菌、梭状芽孢杆菌OUT比例有不同程度升高。治疗后,消炎汤20、10g/kg组OUT比例较模型组明显下降。结论消炎汤能够明显改善慢性盆腔炎大鼠子宫的炎症程度,有效减少黏连的发生,作用机制与其调节肠道微生态影响雌激素代谢有关。     

In Vitro and in Vivo Evaluation of Whole and Half Tablets of Sustained-Release Adinazolam Mesylate

The mechanism of release from sustained-release adinazolam mesylate tablets was assessed by the Higuchi equation and by analysis of drug release profiles through 60% released using the Peppas equation. Computed values of the diffusional exponent, n, ranged from 0.59 to 0.66. Values of n in this range are consistent with a mixed mechanism of release, with diffusion of drug through the hydrated polymer matrix and relaxation of this matrix being the principal processes controlling release. The rate of in vitro drug release was increased for half tablets relative to whole tablets and is attributed to an increase in the surface to volume ratio of half tablets of about 16%. This increase in surface-to-volume ratio of half tablets was reflected by an increase in the constant, k, from the Peppas equation of 20–23% and by an increase in the slope of Higuchi plots of 12–18% for four lots of tablets. In vivo/in vitro relationships from two bioavailability studies were thoroughly evaluated. Using either a linear or a quadratic relationship, an in vivo/in vitro correlation exists for sustained-release adinazolam mesylate tablets.     

原子吸收法测定碳酸锂缓释片的含量

目的:建立碳酸锂缓释片中测定碳酸锂含量的原子吸收法.方法:采用火焰原子吸收对照品比较法,仪器条件:检测波长:670.8 nm;灯电流:5 mA;狭缝:0.8 nm;背景:不扣背景;乙炔:70 L·h-1;空气:460 L·h-1;燃烧头高度:6 mm.结果:本法精密度、重复性和耐用性良好,平均回收率为100.3％(n=...     

The effect of media and other variables on the BP solution rate test for slow lithium carbonate tablets

The British Pharmacopoeial test for assessing the solution rate of slow lithium carbonate tablets has been evaluated using ‘controlled release’ tablets containing 400 mg of lithium carbonate. No significant differences in lithium release were found when the volume of media used in the test was reduced from 250 ml to 200 ml, the final stage of the test in pH 6.8 phosphate buffer reduced from 5 to 3 h, the number of tablets in each thimble reduced from three to one, or the prescribed phosphate buffers replaced with phthalate and Tris, respectively. A four-fold increased concentration of phosphate in the phosphate buffers used resulted in a significant retardation in lithium solution rate. This was not attributable to an ionic strength effect but possibly to the formation of trilithium phosphate at the interface. Dissolution studies using the USP Basket Method showed a significantly slower release rate of one tablet into 900 ml of phosphate buffer compared with Tris buffer. This difference was markedly increased when three tablets were investigated in 200 ml of similar media. These differences were considered to be due to the formation of the much less soluble trilithium phosphate in the phosphate buffers.     

The effect of formulation composition and dissolution parameters on the gel strength of controlled release hydrogel tablets.

The impact of hydrogel polymers and dissolution media on tablet gel strength, Gamma, of controlled release (CR) hydrogel tablets was investigated. CR tablets containing either hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), or carbomer were formulated with theophylline and Fast Flo lactose, to produce tablets with a polymer content of 8, 15, and 30% w/w. Gamma was measured using a previously reported method. The drug dissolution profiles were similar, irrespective of polymer type or dissolution media (DI water, 0.1 N HCl, and pH 6.8 phosphate buffer), at the same % w/w level of polymer. Gamma, however, showed large and significant differences (p < or = 0.05) between tablets containing different polymers and between different dissolution media. Gamma values were HPMC KI00MP > HPC HXF > carbomer 971P (same % w/w) with absolute Gamma values at 30% w/w in DI water of 6600, 4600, and 1600 ergs/cm3, respectively. Gamma for HPMC based tablets was independent of changes in dissolution media, while the Gamma values for HPC tablets were 18% lower in acid and buffer than in DI water. Of the polymers tested, carbomer based tablets had the lowest Gamma values in all dissolution media and an unexpected 58% lower Gamma in buffer compared with DI water or acid. Gamma provides a quantitative measure of the effect of formulation and dissolution parameter changes on tablet gel layer strength, under in vitro stress conditions that may parallel in vivo tablet performance, but which cannot be deduced from a comparison of dissolution profiles or polymer viscosity.     

Swellable matrices for the controlled-release of diclofenac sodium: formulation and in vitro studies

Oral administration has been the most usual and convenient employed route of drug delivery systems. Particularly, oral sustained-release systems for the delivery of drugs by a process of continuous swelling of the polymeric carrier have been investigated. Thus, the goal of this study was to evaluate the effects of hydroxypropyl methylcellulose (HPMC) and carboxypolymer (Carbopol 934) on the release behavior of diclofenac sodium (DS) from a swellable matrix tablet system. Nine different DS controlled-released tablets were compressed by using the wet-granulation technology. The influence of the polymer content, the polymer ratio, the polymeric swelling behavior, and the pH changes on the release rate of DS was investigated. There was no significant difference in drug release when total polymer concentration was 10%. When the tablets were formulated having 20% or 30% of HPMC/carbomer, it was observed that a more rapid release of DS occurred as the carboxypolymer ratio within the matrices increased. In agreement with previous results, the dissolution studies demonstrated that the combination of these two polymeric matrix formers resulted in near zero-order release rate of DS. The DS release from all these matrix tablets was pH dependent, being markedly reduced at lower pH, and could be attributed to the poor solubility of DS at this pH value. In HCl 0.1 N solution, HPMC controlled drug release because the carbomer has a low solubility at this pH. As the pH increased, the carbomer became ionized, being able to interact with HPMC to control the drug release.     

复方氢氯噻嗪双层片中酒石酸美托洛尔缓释片的处方筛选

目的:筛选复方氢氯噻嗪双层片中酒石酸美托洛尔缓释片处方。方法:以体外释放度为主要考察指标,并以羟丙基甲基纤维素(HPMC)与卡波姆的总用量(A)及二者的质量比(B)、微晶纤维素用量比例(C)、聚丙烯吡咯烷酮(PVP)无水乙醇溶液浓度(D)为因素进行正交试验优选处方。结果:优化处方确定A为30%,B为1∶2,C为20%,D为5%。优化后所制3批酒石酸美托洛尔缓释片1h内的累积释放度均在25%～45%,4h内的累积释放度均在40%～75%,8h内的累积释放度均>75%,24h累积释放度均>90%。结论:所选酒石酸美托洛尔缓释片的处方合理、工艺简单。