Plasma levels of aspirin following effervescent and enteric coated tablets,and their effect on platelet function

Summary Oxcarbazepine (oxcarb) 600 and 900 mg (2360 and 3540 μmol) was taken by 3 volunteers (2 ♀, 1 ♂; 45–67 kg; age 22–34 years) after an overnight fast. Blood, saliva and urine were collected for the next 72 h for assay of oxcarb, 10,11-dihydro-10-hydroxy-carbamazepine (OHcarb), and 10,11-dihydrotrans-10,11-dihydroxy-carbamazepine (diol). Oxcarb reached a maximum level of about 1 μg/ml (3.93 μmol/l) within 1 h and dropped below the detection limit (0.1 μg/ml=0.39 μmol/l) within 3 h. The active metabolite OHcarb appeared in the blood before oxcarb and reached the higher maximum level of 7.4 μg/ml (29 μmol/l) after 7 h. Thereafter serum levels decreased with a t_1/2 of about 25 h, and after 40 h with a t_1/2 of 9 h, the latter agreeing with the renal excretory t_1/2 calculated from the urine data (10 h). The ratio of OHcarb concentration in saliva to that in plasma varied considerably (0.3–1.7; median 1; r>0.9), whereas that of blood to plasma was 1.25 with only small variation (r>0.98); OHcarb concentrations in erythrocytes were 50% higher than in plasma. Diol was detected in blood (maximum level 0.5 μg/ml=1.84 μmol/l) in 2 volunteers. 45% of the dose could be recovered in urine (Oxcarb 5%, OH-carb 36%, Diol 4%). Whereas Oxcarb was completely conjugated, only 25% of OHcarb was conjugated and diol was unconjugated.     

不同厂家阿司匹林肠溶片中游离水杨酸的考查考查分析

目的:考查国内14个不同厂家生产的阿司匹林肠溶片的游离水杨酸,对不同厂家的同一药物制剂的质量进行评价,为临床用药提供参考.方法:根据《中国药典》中阿司匹林肠溶片的检验标准,采用高效液相色谱法测定阿司匹林肠溶片中游离水杨酸的含量并进行方法学考查.结果:14个生产厂家共计44批阿司匹林肠溶片中,有4批次游离水杨酸的限度超过《中国药典》的规定.结论:不同厂家以及部分同一厂家不同批次的的阿司匹林肠溶片,其游离水杨酸含量均存在一定差异.生产企业应筛选合理的处方和制备工艺,运输及经营环节控制好温湿度,以保证药物的质量及稳定性.     

Absorption of enteric and non-enteric coated prednisolone tablets.

1. Relative rates of absorption of enteric and non-enteric preparations of prednisolone were measured in five renal transplant recipients. 2. The absorption of the enteric coated preparation is delayed and the peak plasma concentration is much lower than that attained using the same dose of the uncoated material. 3. The therapeutic implications of these observations are discussed.     

双氯芬酸钠肠溶片质量考察

利用RP-HPLC,以卡马西平(CZ)为内标,对国内3个厂家生产的双氯芬酸钠(D5)肠溶片进行了崩解度、释放度、含量测定的研究。结果表明:不同厂家的DS肠溶片释放度差异极为显著(P<0.01)、崩解度与释放度之间有较好的相关性(r=0.9103)。     

双氯芬酸钠肠溶片的制备及其处方优化

目的：制备更优质的双氯芬酸钠肠溶片。方法采用粉末直接压片及高效包衣机包衣法制备了双氯芬酸钠肠溶片,从片芯及包衣层两方面对处方进行筛选及优化。结果所制得的双氯芬酸钠肠溶片在人工胃液中耐酸力良好,在人工肠液中的溶出迅速且完全。结论研制了双氯芬酸钠肠溶片,解决了双氯芬酸钠对胃部刺激较大的问题,重现性好,工艺可行。     

The permeability of enteric coatings and the dissolution rates of coated tablets

The effect of an increasing concentration of plasticizer and pigment on the permeability to both water vapour and simulated gastric juice of cellulose acetate phthalate and polyvinyl acetate phthalate has been evaluated. There were significant differences between the permeability coefficients of each polymer, particularly with regard to water vapour. The presence of additives within the film coatings had a greater effect on the properties of cellulose acetate phthalate than those of polyvinyl acetate phthalate. Suitable formulations of each polymer were used to enteric coat 325 mg aspirin tablets, which were subsequently subjected to both the Disintegration Test for Enteric Coated Tablets B.P. and a dissolution procedure to monitor the release of drug in simulated gastric juice and simulated intestinal fluid. Both polymers demonstrated their suitability for producing enteric coatings. However, polyvinyl acetate phthalate yielded a faster release of aspirin in simulated intestinal fluid than did cellulose acetate phthalate.     

二甲双胍肠溶片人体药动学和生物利用度研究

目的：研究二甲双胍肠溶片生物利用度。方法：HPLC法测定血浆中二甲双胍浓度。30名健康受试者随机交叉单剂量口服二甲双胍肠溶片参比药物和试验药物1 000 mg,测定不同时间血浆中二甲双胍浓度,DAS软件处理药时数据。结果：与参比药物相比,试验药物相对生物利用度F₀^t：（97.3±14.9）%,F₀^∞：（94.9±13.9）%;试验药物与参比药物的主要药动学参数t_max分别为：（2.20±0.49）h;（2.42±0.58）h,C_max分别为：（1 733±379）ng·mL^-1;（1 620±396）ng·mL^-1,t_1/2ke分别为：（2.48±0.40）h;（2.50±0.20）h,AUC₀^t分别为：（11 402±2 402）ng·h·mL^-1;（10 701±2 011）ng·h·mL^-1,AUC₀^∞分别为：（12 258±2 401）ng·h·mL^-1;（11 299±2 321）ng·h·mL^-1;对两制剂间AUC₀^t、AUC₀^∞、C_max、t_max药动学参数进行双向单侧t检验,P值分别为：0.050 86、0.059 02、0.063 85、0.058 34,均大于0.05,无统计学意义。结论：二药物生物等效。     

巴戟甲素亲水凝胶骨架肠溶缓释片的质量研究

目的:建立巴戟甲素亲水凝胶骨架肠溶缓释片质量控制方法。方法:按中国药典附录ⅠA片剂项下要求依次检查片重,采用转篮法检查制剂的释放度;采用薄层色谱法鉴别制剂中巴戟甲素,采用高效液相-蒸发光色谱法(HPLC-ELSD)测定巴戟甲素含量。结果:制剂片重和释放度均符合制剂通则标准;制剂巴戟甲素薄层行为良好,且阴性对照无干扰;测得5批制剂中巴戟甲素含量在38.33～40.89 m.g片-1之间,为标示量的93.0%～107.0%。结论:制剂指标检查符合制剂通则标准;所建立的薄层色谱法可准确鉴别制剂中的巴戟甲素;制剂中巴戟甲素含量符合规格要求,研制的骨架肠溶包衣缓释片质量可控、稳定。本方法准确、可靠、重复性好,可用于巴戟甲素亲水凝胶骨架肠溶缓释片的质量控制。     

无时滞非达霉素肠溶片的制备及溶出评价

目的: 制备无时滞非达霉素肠溶片,考察其溶出特性。方法: 采用湿法制粒工艺,通过正交实验进行片芯优化,以甲基丙烯酸与丙烯酸乙酯共聚物为肠溶包衣材料,制备非达霉素肠溶片,以体外释放度为指标,考察其溶出行为。结果: 片芯中羟丙甲纤维素和交联羧甲基纤维素钠的用量分别为1.2%和4.5%,微晶纤维素和淀粉的比例为3:1,肠溶层共聚物的比例为50%时,制备的非达霉素肠溶片在pH1.0盐酸中2h释放度小于10%,在pH4.5醋酸盐缓冲液中可以崩解释放,在pH6.8磷酸盐缓冲液中快速释放,10min释放度大于60%。结论: 制备的非达霉素肠溶片与普通肠溶片相比无时滞效应,有望进行工业化生产。     

HPLC法测定氨糖美辛肠溶片中吲哚美辛的含量

目的：建立ＨＰＬＣ法测定氨糖美辛肠溶片中吲哚美辛的含量。方法：采用ＳＰＨＥＲＩ－５Ｒｐ－１８色谱柱,以甲醇－水－乙腈－磷酸（６０：２５：１５：０．０４）为流动相。结果：吲哚美辛在１０～６０μｇ／ｍｌ范围内深度与峰面 良好的线必ｒ＝０．９９９９）,平均回收率为９９．５６％,ＲＳＤ为０．６５％。结论：本法准确、快速、重现性好。     

Influence of aqueous coatings on the stability of enteric coated pellets and tablets.

Pancreatin pellets, placebo pellets and tablets containing vitamin B2 were coated with various aqueous and organic enteric polymers, HPMCAS, HP, Eudragit L 100-55, Eudragit L 30 D-55, CAP, CAT, CMEC and PVAP, comparatively investigated and tested for storage stability. With the exception of Eudragit L 100-55 and Eudragit L 30 D-55, higher amounts of coating material were needed to achieve gastro-resistance with aqueous coating than with organic coating. Film formation from aqueous dispersions of micronized HP 55 was affected by the degree of micronization and was improved by reducing the particle size of the polymer. Undercoating was another suitable measure to decrease the amount of coating material required. The choice of plasticizer was of special importance in the aqueous dispersions, and type and quantity must be appropriate for the polymer applied. Non-polymeric plasticizers such as triethyl citrate (TEC) evaporated along with water during the spraying or drying process and high temperatures promoted such losses. The moisture-sensitive pancreatic enzymes were damaged both by humidity and heat during aqueous coating. The extent of damage was dependent on the coating equipment used. Upon storage, coatings obtained from aqueous dispersions showed changes in enteric performance or release characteristics as a consequence of three chemical/physical mechanisms: hydrolysis of ester linkages in the polymer or plasticizer, evaporation of the plasticizer, delayed film formation. The active ingredient pancreatin induced hydrolysis of the ester based film-former hydroxypropyl methylcellulose acetate succinate (HPMCAS). However, even without the influence of enzymes, the phthalic ester groups of aqueous hydroxypropyl methylcellulose phthalate (HP) were partly cleaved after 11 months storage. In HPMCAS-coated pancreatin pellets, the plasticizer glyceryl triacetate was almost completely hydrolyzed by the enzymes, whilst triethyl citrate was lost by evaporation through permeable packaging material at elevated temperatures. Open storage at elevated temperatures and humidities caused changes in the surface structure of HPMCAS coatings, consisting of a smoothing of the originally somewhat porous film and sticking. When applied to vitamin B2 tablets, Eudragit L 100-55, Opadry enteric (PVAP) and Aqoat (HPMCAS) proved to be quite stable aqueous enteric coatings, whereas cellulose acetate phthalate CAP or cellulose acetate trimellitate CAT coatings as ammonia-neutralized aqueous solution or as water-based pseudolatex Aquateric were unstable when stored under stress conditions.     

Understanding the in vivo performance of enteric coated tablets using an in vitro-in silico-in vivo approach: Case example diclofenac

Individual pharmacokinetics after administration of enteric coated tablets are often highly variable and this has been ascribed to the interaction of the dosage form with the physiology of the gastrointestinal tract. This research aimed to explore the influence of interactions between enteric coated tablets and physiological factors such as gastric and intestinal pH as well as gastric emptying on the release of drug from the dosage form and the subsequent plasma profile, using diclofenac as a case example.A physiologically based pharmacokinetic (PBPK) model for monolithic enteric coated dosage forms was designed and coupled with biorelevant dissolution results to predict PK profiles of diclofenac from Voltaren® tablets in both fasted and fed humans. The paddle method was used to obtain the dissolution profiles of diclofenac in biorelevant media. The Noyes–Whitney model was employed to describe the dissolution kinetics. The PBPK model was set up using STELLA® software. A single unit enteric coated tablet was assumed to be emptied from stomach only with the house-keeping wave. Timing of the emptying was simulated using a random number generator to statistically estimate gastric emptying times after ingestion. The lag times and the dissolution rate used as input parameters in the STELLA® model were adjusted according to the pre-exposure period. The oral PK profiles were predicted for each virtual subject individually, and then the mean profiles and standard deviations were calculated.The dissolution profiles were highly affected by the period of pre-exposure in FaSSGF. A long period of pre-exposure of the tablet prolonged the lag time and decreased the dissolution rate. The results of the pharmacokinetic simulations showed that not only the mean profiles in the fasted state but also the variability could be predicted successfully using data generated for the individual virtual subjects. The results emphasize the importance of accounting for the range of pH profiles and gastrointestinal transit in the target population when predicting plasma profiles of enteric coated dosage forms and point to problems in demonstrating bioequivalence for dosage forms of this type.     

Gastrointestinal transit and disintegration of enteric coated magnetic tablets assessed by ac biosusceptometry.

The oral administration is a common route in the drug therapy and the solid pharmaceutical forms are widely used. Although much about the performance of these formulations can be learned from in vitro studies using conventional methods, evaluation in vivo is essential in product development. The knowledge of the gastrointestinal transit and how the physiological variables can interfere with the disintegration and drug absorption is a prerequisite for development of dosage forms. The aim of this work was to employing the ac biosusceptometry (ACB) to monitoring magnetic tablets in the human gastrointestinal tract and to obtain the magnetic images of the disintegration process in the colonic region. The ac biosusceptometry showed accuracy in the quantification of the gastric residence time, the intestinal transit time and the disintegration time (DT) of the magnetic formulations in the human gastrointestinal tract. Moreover, ac biosusceptometry is a non-invasive technique, radiation-free and harmless to the volunteers, as well as an important research tool in the pharmaceutical, pharmacological and physiological investigations.     

Comparative bioavailability of aspirin and paracetamol following single dose administration of soluble and plain tablets

Summary

In this study, the bioavailability of aspirin and paracetamol was compared in plain and soluble combination formulations in fasting, healthy volunteers. Blood samples were taken and C_max, T_max and AUC measured at various times following administration of single doses of the two formulations in 12 subjects.

The rapidity of uptake of aspirin following administration of a soluble formulation suggests significant absorption from the stomach. There was no significant difference in the pharmacokinetic parameters of paracetamol derived from a soluble or plain formulation. A comparison of the uptake of aspirin from the soluble aspirin formulation with paracetamol from either plain or soluble tablets showed that aspirin entered the plasma and achieved peak levels significantly more quickly. However, the half life of paracetamol was significantly longer than that of aspirin.

These findings suggest that onset of analgesia should be more rapid following dosing with soluble aspirin, a conclusion supported by comparative efficacy studies conducted with differing formulations of aspirin.     

Evolution of a physiological pH 6.8 bicarbonate buffer system: Application to the dissolution testing of enteric coated products

The use of compendial pH 6.8 phosphate buffer to assess dissolution of enteric coated products gives rise to poor in vitro-in vivo correlations because of the inadequacy of the buffer to resemble small intestinal fluids. A more representative and physiological medium, pH 6.8 bicarbonate buffer, was developed to evaluate the dissolution behaviour of enteric coatings. The bicarbonate system was evolved from pH 7.4 Hanks balanced salt solution to produce a pH 6.8 bicarbonate buffer (modified Hanks buffer, mHanks), which resembles the ionic composition and buffer capacity of intestinal milieu. Prednisolone tablets were coated with a range of enteric polymers: hypromellose phthalate (HP-50 and HP-55), cellulose acetate phthalate (CAP), hypromellose acetate succinate (HPMCAS-LF and HPMCAS-MF), methacrylic acid copolymers (EUDRAGIT® L100-55, EUDRAGIT® L30D-55 and EUDRAGIT® L100) and polyvinyl acetate phthalate (PVAP). Dissolution of coated tablets was carried out using USP-II apparatus in 0.1 M HCl for 2 h followed by pH 6.8 phosphate buffer or pH 6.8 mHanks bicarbonate buffer. In pH 6.8 phosphate buffer, the various enteric polymer coated products displayed rapid and comparable dissolution profiles. In pH 6.8 mHanks buffer, drug release was delayed and marked differences were observed between the various coated tablets, which is comparable to the delayed disintegration times reported in the literature for enteric coated products in the human small intestine. In summary, the use of pH 6.8 physiological bicarbonate buffer (mHanks) provides more realistic and discriminative in vitro release assessment of enteric coated formulations compared to compendial phosphate buffer.     

The dissolution of aspirin and aspirin tablets

An attempt has been made to standardize the “beaker” method of measuring in vitro dissolution rates of tablets against published data for aspirin. An unexpected problem arose when it was found that samples of commercial aspirin have different intrinsic dissolution rates. The form of aspirin used in tablet manufacture is likely therefore to be of significance from the viewpoint of in vivo dissolution and drug availability.     

硫酸氢氯吡格雷联合阿司匹林肠溶片对非ST段抬高型急性心肌梗死患者炎症因子及左室重构的影响

目的分析硫酸氢氯吡格雷联合阿司匹林肠溶片对非ST段抬高型急性心肌梗死患者炎症因子及左室重构的影响。方法将180例非ST段抬高型急性心肌梗死患者随机分为两组,均给予基础治疗,参照组(90例)采用硫酸氢氯吡格雷治疗,观察组(90例)采用硫酸氢氯吡格雷联合阿司匹林肠溶片治疗,对比两组患者治疗前后血清炎症因子IL-33、IL-8、hs-CRP;心超测定左室重构LVEDd、LVESd、LAD、PWT、LVEF的变化情况。结果治疗后,两组患者血清IL-33、IL-8、hs-CRP水平均下降(P<0.05),且观察组治疗后血清IL-33、IL-8、hs-CRP水平低于参照组(P<0.05);治疗后,两组患者LVEDd、LVESd、LAD、PWT明显降低(P<0.05),LVEF明显升高(P<0.05),且观察组治疗后LVEF高于参照组(P<0.05),LVEDd、LVESd、LAD、PWT水平低于参照组(P<0.05)。结论硫酸氢氯吡格雷联合阿司匹林可明显抑制非ST段抬高型急性心肌梗死患者左室重构和炎症反应水平。     

6种市售阿司匹林肠溶片的体外溶出试验比较

目的：考察６种市售阿司匹林肠溶片的体外溶出,以评价其内在质量。方法：采用转篮法进行体外溶出试验,用紫外分光光度法检测溶出液中药物浓度,计算累积释放量。以威布尔分布拟合溶出参数,由双侧ｔ检验对组间溶出参数进行统计学分析。结果：６种阿司匹林肠溶片在酸性介质（０．１ｍｏｌ／Ｌ盐酸）及ｐＨ ６．８磷酸盐缓冲液中的溶出均符合中国药典要求;拜阿司匹灵与其他５种阿司匹林肠溶片的体外释放速度具有显著性差异（Ｐ＜０．０５）,前者慢于后者。结论：６种制剂的体外溶出均符合中国药典的要求,但制剂间体外释放速度存在显著差异。