Physiological parameters of the gastrointestinal fluid impact the dissolution behavior of the BCS class IIa drug valsartan

Abstract

The objective of this study was to investigate the effect of the physiological parameters (pH, buffer capacity, and ionic strength) of the gastrointestinal (GI) fluid on the dissolution behavior of the class II weakly acidic (BCS class IIa) drug valsartan. A series of in vitro dissolution studies was carried out on Diovan^® immediate release tablets using media that cover the physiological range of pH (1.2–7.8), buffer capacity (0–0.047?M/ΔpH), and ionic strength (0–0.4?mol/L) of the GI fluid during fasted and fed states using the conventional USP II apparatus. Valsartan exhibited pH- and buffer capacity-dependent dissolution behavior, where valsartan release was slow and incomplete in media simulating gastric fluid with low pH, and fast and complete in media simulating intestinal fluid with high pH. In addition, the rate of valsartan release increased with increasing the buffer capacity of the dissolution medium. In water and NaCl solutions, valsartan release was incomplete and the dissolution profiles were similar regardless of the ionic strength of the medium, indicating an ionic strength-independent dissolution behavior. These results highlight the significant effect of the physiological parameters of the GI fluid on the dissolution behavior of BCS class IIa drugs.     

秋水仙碱片溶出度一致性评价

目的建立秋水仙碱片溶出度测定方法,评价国内5个厂家23批次秋水仙碱片溶出曲线相似性。方法采用《中华人民共和国药典》2015年版溶出度测定第三法测定秋水仙碱片溶出度,使用纯水、pH值4.5醋酸盐缓冲液与pH值6.8磷酸盐缓冲液3种溶出介质,考察秋水仙碱片溶出行为,并通过计算相似因子评价溶出曲线相似性。结果秋水仙碱片在pH值6.8磷酸盐缓冲液中溶出效果较好。国内市售5个厂家秋水仙碱片在3种溶出介质中溶出曲线均相似(f2>50)。结论该方法适用于秋水仙碱片溶出曲线测定,可为秋水仙碱片质量一致性评价提供参考。     

不同厂家生产的硝苯地平片体外溶出度的比较

目的：比较国内不同厂家生产的硝苯地平片的体外溶出度。方法：以紫外分光光度法测定硝苯地平的含量,分别根据《英国药典》2010年版、《美国药典》第34版和《中华人民共和国药典》2010年版的方法,对5个厂家生产的硝苯地平片的溶出度进行考察,并比较硝苯地平片在水、pH4.5乙酸钠缓冲液以及pH6.8磷酸盐缓冲液中的溶出度。运用相似因子f2法,比较硝苯地平片在不同溶出介质中溶出曲线的相似性。结果：5个厂家生产的硝苯地平片的溶出度按《中华人民共和国药典》2010年版方法测定,在60min时均〉75%;按《英国药典》2010年版方法测定,45min时均〈75%;按《美国药典》第34版方法测定,20min时均〈80%。以0.1mol/L盐酸溶液为对照,硝苯地平片在人工胃液（不含胃蛋白酶）、水、pH4.5乙酸钠缓冲液和pH6.8磷酸盐缓冲液中的溶出曲线的相似因子f2为50.93～77.45;以0.25%十二烷基硫酸钠溶液为对照,相似因子f2远〈50,表明溶出曲线不相似。结论：5个厂家生产的硝苯地平片的体外溶出度符合《中华人民共和国药典》的要求,但达不到《英国药典》和《美国药典》的标准。国内厂家生产的硝苯地平片溶出度检查标准有待提高。     

采用计算机模拟技术结合Caco-2细胞模型与溶出度试验考察国产盐酸曲美他嗪片的生物等效性

目的：采用计算机模拟技术结合Caco-2细胞模型和溶出度试验，对国产盐酸曲美他嗪生物等效性进行研究。方法：首先基于Caco-2单层细胞膜模型考察盐酸曲美他嗪的渗透性，获得其表观渗透系数P_app；第二步采用HPLC法测定溶出曲线来比较10家国产企业与原研生产的盐酸曲美他嗪片在5种不同pH条件下体外溶出行为的差异；最后采用Gastrol Plus^TM软件，导入本试验实测P_app，通过该软件转化为P_eff值，建立准确的体外溶出曲线与体内药动学曲线之间的相关性模型，基于该模型预测国产盐酸曲美他嗪片的药动学曲线，对其生物等效性进行体内外相关的研究。HPLC测定法：C₁₈柱，以0.287%无水庚烷磺酸钠-甲醇（55：45）为流动相，检测波长为231 nm，流速1.0 mL·min^-1；溶出度方法：分别以0.05 mol·L^-1盐酸溶液，pH 1.2、pH 4.0、pH 6.8缓冲盐溶液和水为溶出介质，桨法50 r·min^-1，溶出体积900 mL，分别考察片剂在上述5种溶出介质中5，10，5，20，30，45，60，90 min取样的溶出曲线。结果：盐酸曲美他嗪的表观渗透系数P_app值随着药物浓度的增加反而下降，属于中等渗透的药物；不同pH的溶出介质对盐酸曲美他嗪片的溶出行为无区分性；但在每种溶出介质中，国外原研片剂溶出较慢，与国产片剂的溶出行为存在明显差异，多数国产片剂快速溶出；采用Gastrol Plus^TM软件从药物在体内具有不同释放速率时的体内吸收情况与通过体外溶出曲线模拟体内吸收情况两个方面进行模拟研究，结果显示现有的国产盐酸曲美他嗪片与原研片剂在体内能够生物等效。结论：尽管国产盐酸曲美他嗪片的体外溶出曲线与原研片剂存在差别，但体内生物等效的可能性极大。Gastrol Plus^TM软件能够预测口服固体制剂与原研制剂的生物等效性，可在一致性评价工作中推广应用。     

硝苯地平片剂溶出度的考察

目的考察不同生产企业生产的硝苯地平片剂的体外溶出度。方法分别以0.1 mol.L-1盐酸溶液、人工胃液(不含胃蛋白酶)、pH 4.5醋酸钠缓冲液、pH 6.8磷酸盐缓冲液和蒸馏水为溶出介质,采用紫外分光光度法检查;以质量分数为0.25%十二烷基硫酸钠为溶出介质,采用HPLC法检查,比较不同厂家硝苯地平片剂的体外溶出度。用相似因子法评价硝苯地平片剂在0.1 mol.L-1盐酸溶液、人工胃液(不含胃蛋白酶)、pH 4.5醋酸钠缓冲液、pH 6.8磷酸盐缓冲液和蒸馏水中的溶出行为。结果在质量分数为0.25%十二烷基硫酸钠溶液中,硝苯地平的溶出度在60 min均大于65%,而在其他溶出介质中的溶出度均达不到《英国药典》及《美国药典》中规定的标准。相似因子f2均在50~100之间。结论溶出介质的pH值对硝苯地平的溶出度没有影响。从整体来看,国产硝苯地平片剂的体外溶出行为与国外制剂相比有很大差距。     

苯磺酸左旋氨氯地平片在不同介质中的溶出度

目的：考察苯磺酸左旋氨氯地平片在盐酸溶液（9→1000）、醋酸-醋酸钠缓冲液（pH4．5）、磷酸盐缓冲液（pH6．8）、水等介质中的溶出度。方法：采用《中国药典》2010年版二部附录XC第三法操作,转速为50r／min,以紫外分光光度法测定溶液的光密度并计算溶出度。结果：两厂家苯磺酸左旋氨氯地平片在不同溶出介质中的溶出曲线基本一致,在盐酸溶液（9→1000）中的累积溶出度最高。结论：苯磺酸左旋氨氯地平片为碱性物质,溶出速率受介质的pH影响较大。     

Application of a radiotelemetric system to evaluate the performance of enteric coated and plain aspirin tablets

The bioavailability of enteric coated and plain aspirin tablets was studied in four beagle dogs. Blood sampling for enteric coated tablets was planned with the aid of a radiotelemetric system. The release of aspirin from its dosage form was detected by monitoring the change in intestinal pH. Aspirin and salicylic acid levels in plasma obtained from the enteric coated dosage form exhibited familiar concentration versus time absorption profiles. Variation in the plasma concentrations of these two compounds within each dog studied (four runs each) was relatively small when time zero was adjusted to the commencement of tablet dissolution. The plasma levels obtained from plain aspirin (three runs each), however, show atypical absorption. The estimated absolute bioavailability was 0.432 +/- 0.0213 and 0.527 +/- 0.0260 for enteric coated and plain aspirin, respectively. Other pharmacokinetic parameters for these two dosage forms such as the highest observed plasma concentration (Cmax) (10.9 +/- 0.535 microgram/mL versus 13.6 +/- 1.88 micrograms/mL) and the time to reach Cmax (tmax) (26.6 +/- 1.94 min versus 31.0 +/- 7.04 min) agree well. The mean values for gastric emptying time, in vivo coating dissolution time, and in vivo disintegration/dissolution time of the tablet core for enteric coated aspirin are 48.7 +/- 7.23 min, 44.3 +/- 3.80 min, and 34.7 +/- 2.04 min, respectively.     

阿奇霉素片溶出曲线一致性评价研究

摘要：目的 建立阿奇霉素片溶出曲线测定方法,评价国产仿制阿奇霉素片与原研药在4种不同pH的溶出介质中的体外溶 出行为。方法 采用桨法,转速为75r/min,分别以pH2.0盐酸溶液、pH4.5磷酸盐缓冲液、pH6.0磷酸盐缓冲液和pH6.8磷酸盐缓 冲液为溶出介质,溶出介质体积为900mL;采用UPLC法测定阿奇霉素溶出度,并计算累积溶出量,绘制溶出曲线;评价溶出 曲线的相似度。结果 在4种不同pH的溶出介质中,国产和原研阿奇霉素片均在15min内溶出量达到了85%以上,说明两批国内 仿制产品与原研药溶出行为基本一致,判定相似。结论 本方法适用于阿奇霉素片仿制药的溶出曲线测定,可为阿奇霉素片的 质量一致性评价提供参考。     

不同厂家洛索洛芬钠片溶出度比较

目的 比较5个厂家洛索洛芬钠片在4种溶出介质中的溶出曲线,以评价该药品的质量。方法 采用桨法、转速50 r·min^-1、溶出介质900 mL进行体外溶出试验,分别考察不同厂家洛索洛芬钠片在盐酸溶液、pH 4.5醋酸盐缓冲液、水和pH 6.8磷酸盐缓冲液4种溶出介质中的体外溶出行为,测定溶出曲线并采用相似因子法与原研药进行比较分析。结果 5个厂家洛索洛芬钠片在盐酸溶液中的溶出曲线基本一致,4个厂家的样品与原研药在水中的溶出曲线差异较大,2个厂家样品批间差异明显。结论 仿制药厂家生产的药品与原研药存在质量差异,建议结合生物等效性试验改进处方及生产工艺,提高该药品质量。     

Biopharmaceutical evaluation of a tablet dosage form made from ethyl cellulose encapsulated aspirin particles

Ethyl cellulose encapsulated aspirin particles, suitable for preparation of direct compression tablets were prepared by the solvent evaporation method. Ethyl acetate was used as a solvent for the polymer in combination with a saturated solution of aspirin as the dispersing medium to prevent partitioning and drug loss. This resulted in a high yield of free-flowing, non-aggregated particles. In vitro-in vivo evaluations of the experimental aspirin tablets (made by direct compression of ethyl cellulose encapsulated particles) and three different commercial aspirin products (a conventional tablet, a timed-release tablet, and a timed-release caplet) were undertaken. Comparison of the dissolution in acidic media at pH 1.2 showed different release profiles for these products. While the conventional tablet and the timed-release caplet showed the highest and the lowest rate of release, respectively; the timed-release tablet and the experimentally made tablet revealed an intermediate rate and very similar release profiles. The cumulative urinary excretion data collected in a complete crossover study, using five healthy subjects further indicated that the experimental tablet has an in vivo availability identical to that of the timed-release tablet.     

Matrix tablets based on a carrageenan with the modified-release of sodium riboflavin 5′-phosphate

Abstract

The focus of this work was to produce modified-release monolithic matrix tablets containing sodium riboflavin 5′-phosphate (vitamin B₂) as active pharmaceutical ingredient (API). Riboflavin 5′-phosphate is absorbed from the upper gastrointestinal tract by a specific transport mechanism. The aim of this work was the development of modified-release tablets from which most or the entire API can dissolve within 5?h. The dissolution was started in medium pH 1.2 (gastric juice) and finished in medium pH 4.5. The matrix former was iota-carrageenan combined with microcrystalline cellulose (MCC) and lactose in different ratios. Factorial design was used in this work so as to study the effects of the MCC/lactose ratio on the parameters of the tablets, and especially on the dissolution process. The dissolution data were subjected to statistical analysis, and the release profiles were fitted with different models. It was found that the MCC/lactose ratio influenced the quality of the tablets to a high degree. The Korsmeyer–Peppas model proved to characterize the total dissolution profile best, but fitting of the separate sections was also possible with a linear model.     

不同厂家盐酸伐昔洛韦片的体外溶出曲线比较

目的比较3个厂家盐酸伐昔洛韦片在4种溶出介质中溶出曲线的相似性。方法采用《中国药典》2010年版溶出度测定方法第一法装置,转速为50r/min,分别以pH1.2盐酸溶液、pH4.5醋酸盐缓冲液、pH6.8磷酸盐缓冲液和水为溶出介质,在252nm波长处测定吸光度,绘制3个厂家盐酸伐昔洛韦片的体外溶出曲线,并采用f2相似因子法考察其相似性。结果在4种不同溶出介质中,3个厂家的盐酸伐昔洛韦片溶出曲线的f2值差异较大,有1厂家产品只在一种介质中的溶出曲线与参比制剂相似,而另1厂家产品只在一种介质中的溶出曲线与参比制剂不相似。结论不同厂家的辅料、生产工艺和生产规模导致了盐酸伐昔洛韦片溶出度的差异。     

Comparison of WHO and US FDA biowaiver dissolution test conditions using bioequivalent doxycycline hyclate drug products

Objectives The dissolution characteristics of immediate‐release doxycycline hyclate products with certified in‐vivo bioequivalence to the innovator product were tested with a view to possible application of biowaiver‐based approval. Methods Five products were tested using US Pharmacopeia Apparatus 2: Antodox 100 mg hard gelatin capsules, Doxycyclin AL 100 T tablets, Doxycyclin‐ratiopharm 100 soft gelatin capsules, Doxycyclin STADA 100 mg tablets and Doxy‐Wolff 100 mg tablets. Three compendial buffers were used as dissolution media: simulated gastric fluid without pepsin, pH 1.2, acetate buffer, pH 4.5, and simulated intestinal fluid without pancreatin, pH 6.8. Results were obtained at two paddle speeds recommended for biowaiver applications: 75 rpm (World Health Organization; WHO) and 50 rpm (US Food and Drug Administration; US FDA). Key findings The results for the tablets and hard gelatin capsules indicate that a paddle speed of 75 rpm is more representative than 50 rpm, since 75 rpm generates dissolution profiles corresponding more closely to the in‐vivo profiles than those at 50 rpm. For evaluating soft gelatin capsule formulations with lipid fill, both US FDA and WHO methods were found to be over‐discriminating. Conclusions Bioequivalence of immediate‐release doxycycline hyclate tablets and hard gelatin capsules, but not soft gelatin capsules, can be evaluated in vitro using the biowaiver dissolution test conditions specified by the WHO.     

影响石杉碱甲骨架片体外释放因素的研究

目的自制石杉碱甲骨架缓释片（HA-MT），考察石杉碱甲骨架片中释放的体外释放特性。方法考察通过释放度实验研究不同制片工艺、测定方法、释放介质的pH值、搅拌转速对骨架片释药的影响，并考察其释药机制。结果制片方法、测定方法对释药行为影响不明显，但转速和溶出介质有明显影响。药物释放曲线符合HIGUCHI方程。结论制备的HA-MT工艺简易，释药达到缓控释要求，释药机制为扩散和溶蚀机制协同作用。     

Influence of Dissolution Media and Presence of Alcohol on the In Vitro Performance of Pharmaceutical Products Containing an Insoluble Drug

The purpose of this investigation is to determine how the dissolution media may influence the release rate of an insoluble drug in in vitro conditions. Some oral dosage forms containing ibuprofen, a molecule that shows pH-dependent solubility, are tested. They are evaluated in different media to simulate the gastrointestinal transit at paddle rotation speeds of 50 and 100 rpm. Moreover, the potential effect of different ethanol concentrations on drug release is tested. The dissolution profiles of the tablets show a similar behavior in water (pH 1.0) and phosphate buffer (pH 4.5) where the 2 doses are not completely dissolved. The soft capsules show a different behavior: a certain amount of ibuprofen, which is in solution inside the capsule, reprecipitates in water and in the pH 4.5 buffer. Instead, ibuprofen dissolves rapidly in the pH 6.8 buffer from all the formulations. In the water-ethanol solutions, the dissolution curves show a valuable increase in the drug dissolved at higher ethanol concentrations.     

Optimization of matrix tablets controlled drug release using Elman dynamic neural networks and decision trees

The main objective of the study was to develop artificial intelligence methods for optimization of drug release from matrix tablets regardless of the matrix type. Static and dynamic artificial neural networks of the same topology were developed to model dissolution profiles of different matrix tablets types (hydrophilic/lipid) using formulation composition, compression force used for tableting and tablets porosity and tensile strength as input data. Potential application of decision trees in discovering knowledge from experimental data was also investigated. Polyethylene oxide polymer and glyceryl palmitostearate were used as matrix forming materials for hydrophilic and lipid matrix tablets, respectively whereas selected model drugs were diclofenac sodium and caffeine. Matrix tablets were prepared by direct compression method and tested for in vitro dissolution profiles. Optimization of static and dynamic neural networks used for modeling of drug release was performed using Monte Carlo simulations or genetic algorithms optimizer. Decision trees were constructed following discretization of data. Calculated difference (f(1)) and similarity (f(2)) factors for predicted and experimentally obtained dissolution profiles of test matrix tablets formulations indicate that Elman dynamic neural networks as well as decision trees are capable of accurate predictions of both hydrophilic and lipid matrix tablets dissolution profiles. Elman neural networks were compared to most frequently used static network, Multi-layered perceptron, and superiority of Elman networks have been demonstrated. Developed methods allow simple, yet very precise way of drug release predictions for both hydrophilic and lipid matrix tablets having controlled drug release.     

Impact of pharmaceutical dosage form on stability and dissolution of roxithromycin

The behavior of dispersible tablets containing enteric-coated pellets and oral suspension, both containing roxithromycin, was investigated using dissolution tests in different media. The dissolution test was performed under different pH conditions. For both dosage forms investigated, the test was conducted at pH 1.2, 4.5, and 6.8. Additionally, for dispersible tablets, the test involving increasing pH was performed at pH 1.2 (acid stage) and afterwards at pH 6.8 (buffer stage). The extent of dissolution was measured using high-performance liquid chromatography (HPLC). In all cases tested, roxithromycin underwent rapid degradation at pH 1.2. Dispersible tablets displayed the features of modified release preparations with a non-complete dissolution during the test times in all media. Conversely, the oral suspension behaved as an immediate release preparation, with degradation at pH 1.2. However, the dissolution of the oral suspension at pH 4.5 and 6.8 was rapid and complete. The role of enteric-coated pellets is to mask the bitter taste of the active substance upon administration. However, the coating showed lack of resistance to media at pH 1.2. Therefore, dispersible tablets containing enteric-coated pellets are not pharmaceutically equivalent to the immediate-release oral suspension.     

小檗碱生物黏附缓释片的制备及体外评价

目的 测定小檗碱生物黏附缓释片和大鼠离体胃组织的黏附力,探究其体外释药作用,制备小檗碱生物黏附缓释片。方法 以羟丙基甲基纤维素(HPMC)和卡波姆(carbopol,CP)为生物黏附材料,通过正交试验对辅料用量进行优化。测定生物黏附缓释片的释放度,溶出介质为人工胃液(pH=1.2)。通过自制黏附力测定装置测定、比较小檗碱生物黏附缓释片和盐酸小檗碱片对大鼠离体胃组织的黏附力。结果 每片生物黏附缓释片中974P/971P为1/3,卡波姆用量为20 mg,羟丙基甲基纤维素为15 mg。生物黏附缓释片的体外释放达到缓释制剂要求,与普通片剂相比其对大鼠离体胃组织的黏附力更大。结论 小檗碱生物黏附缓释片的处方和工艺能够达到设计要求。     

不同厂家盐酸地芬尼多片溶出曲线相似性考察

目的：考察8个厂家盐酸地芬尼多片在不同溶出介质中的溶出曲线,比较不同厂家药品内在品质,为药品质量控制提供参考.方法：采用高效液相色谱法测定8个厂家盐酸地芬尼多片在水、pH1.2、pH4.0和pH6.8四种介质中的溶出曲线,结合AV值对溶出曲线得相似性进行比较分析.结果：在pH1.2、pH4.0和水三种溶出介质中各厂家盐酸地芬尼多片溶出量均符合药典规定,但溶出曲线差异性较大;在pH6.8中溶出量偏低.结论：仅1家企业4条溶出曲线均与原研厂家标准溶出曲线相似,企业仍需进一步改进处方及生产工艺以提高产品质量.     

生理药动学模型结合体外溶出试验评价瑞格列奈片的生物等效性

目的 评价国产瑞格列奈片(规格:1.0 mg)的生物等效性并探索体内外相关性更好的溶出条件.方法 分别测定4个厂家制剂在5种溶出介质中的溶出曲线,采用GastroPlusTM软件建立瑞格列奈片的生理药动学模型,利用计算机技术模拟分析研究瑞格列奈片的体内外相关性,并基于不同厂家产品的体外溶出结果,利用Weibull函数,...