Influence of granulation temperature on particle size distribution of granules in twin-screw granulation (TSG)

This study investigated an influence of granulation temperature during twin-screw granulation (TSG) on particle size distributions (PSDs). The influence of the granulation temperature on granule size distributions varied, depending on the liquid to solid (L/S) ratio, the kind of binders, the method of binder addition, and the filler material. The PSD of granules was broad and bimodal at a barrel temperature of 30?°C. Granules size distributions became narrow and second height decreased at high barrel temperature. While the L/S ratio had an effect on the sharpness of granule size distributions, this effect was minor compared to the granulation temperature. Granule size distributions were influenced by binder addition methods. When the binder was added as solution, PSD became broad. In formulations using lactose as filler, PSD became broad and bimodal at 90?°C. Much lactose was dissolved in granulation solution at high temperature, because the solubility of lactose rises significantly with the solution temperature leading to higher effective L/S ratio in the granulator. Hence, granulation was proceeded and large granules were formed. From these results, the granulation temperature is one of important parameters to obtain mono-modal PSD in TSG.     

An investigation into the effect of formulation variables and process parameters on characteristics of granules obtained by in situ fluidized hot melt granulation

The aim of this study was to investigate the influence of binder content, binder particle size, granulation time and inlet air flow rate on granule size and size distribution, granule shape and flowability, as well as on drug release rate. Hydrophilic (polyetilenglycol 2000) and hydrophobic meltable binder (glyceryl palmitostearate) were used for in situ fluidized hot melt granulation. Granule size was mainly influenced by binder particle size. Binder content was shown to be important for narrow size distribution and good flow properties. The results obtained indicate that conventional fluid bed granulator may be suitable for production of highly spherical agglomerates, particularly when immersion and layering is dominant agglomeration mechanism. Granule shape was affected by interplay of binder content, binder particle size and granulation time. Solid state analysis confirmed unaltered physical state of the granulate components and the absence of interactions between the active and excipients. Besides the nature and amount of binder, the mechanism of agglomerate formation seems to have an impact on drug dissolution rate. The results of the present study indicate that fluidized hot melt granulation is a promising powder agglomeration technique for spherical granules production.     

美乐托宁缓释片在不同介质中的释放试验

目的:制备美乐托宁缓释片,以国外上市制剂美乐托宁缓释片为参比制剂,考察自研制剂和参比制剂在不同pH释放介质中体外释放行为的相似性及体外释药机制。方法:采用释放度测定法转篮法的装置进行体外释放实验,用HPLC法测定释放度,采用f2相似因子对2种制剂释放曲线的相似度进行评价,并进行释放行为模型的拟合。结果:在不同pH的释放介质中,自制制剂释放度曲线与参比制剂比较,f2相似因子均大于50;美乐托宁缓释片在4种释放介质中体外释药拟合模型更接近一级方程、Higuchi方程和Peppas方程。结论:参比制剂与自制制剂在不同pH释放介质中的体外释放一致,释放机制为扩散释药。     

The consequence of the chemical composition of HPMC in matrix tablets on the release behaviour of model drug substances having different solubility

This study investigates the effect of the chemical heterogeneity of hydroxypropyl methylcellulose (HPMC) on the release of model drug substances from hydrophilic matrix tablets. The hypothesis was that the release of drug substances could be influenced by possible interactions with HPMC batches having different chemical heterogeneity. The cloud point of the most heterogeneous batch was more affected by the model drug substances, methylparaben and butylparaben, and most by butylparaben with the lowest solubility. The different clouding behaviour was explained by the heterogeneously substituted batches being more associative and the more lipophilic butylparaben being able to interact more efficiently with the hydrophobic HPMC transient crosslinks that formed. Interestingly, tablet compositions of the heterogeneously substituted HPMC batches released the more soluble methylparaben at lower rates than butylparaben. The explanation is that the hydrophobic HPMC interactions with butylparaben made the gel of the tablet less hydrated and more fragile and therefore more affected by erosional stresses. In contrast, drug release from compositions consisting of the more homogeneously substituted batches was affected to a minor extent by the drugs and was very robust within the experimental variations. The present study thus reveals that there can be variability in drug release depending on the lipophilicity of the drug and the substituent heterogeneity of the HPMC used.     

盐酸维拉帕米脉冲释放片体内外释药特性

目的：研究盐酸维拉帕米脉冲释放片体内外释药特性。方法：用干法压制包衣技术制备盐酸维拉帕米脉冲释放片，调整包衣中致孔剂用量，通过体外释放度试验考查时滞，并用HPLC法测定家兔血药浓度，考查体内外时滞的相关性。结果：体内外时滞基本相符。结论：可用体外时滞预测体内的时滞。     

卡托普利渗透泵控释片的制备及体外释放度考察

目的研究卡托普利渗透泵控释片的制备工艺及体外释药影响因素。方法以比色法为分析方法 ,采用综合评分法评价体外释放行为。结果卡托普利渗透泵控释片的体外释药符合零级释放规律 ,释药速率受HPMCK1 5含量、渗透压促进剂用量影响较大 ,在一定范围内 ,释药孔大小和片芯硬度对其影响较小 ,与溶出方法、介质 pH值、桨转速无关。 结论体外释放规律符合控释制剂要求 ,可进一步进行体内释药行为考察     

盐酸二甲双胍缓释片释放度的比较

目的制备盐酸二甲双胍缓释片,并与国外相同缓释片的释放度进行比较。方法以HPMC（K4M）和CMC-Na为缓释材料制备盐酸二甲双胍缓释片,采用相似因子法对实验室自制的和国外进口的盐酸二甲双胍缓释片的释放度进行考察。结果自制缓释片和进口缓释片1h的累计释放百分率分别为27．71％±0．97％和25．30％±2．03％,6h的累计释放百分率分别为67．47％±1．45％和70．34％±1．17％,12h的累计释放百分率分均大于85％;两种样品释放曲线的f2为（84．18±4．67）。结论自制的缓释片具有12h缓释效果;两种制剂的缓释曲线经相似因子法f2比较不存在显著性差异。     

卡托普利联合硝苯地平缓释片治疗高血压的效果观察

目的分析卡托普利联合硝苯地平缓释片治疗高血压的效果。方法随机将本院收治的100例高血压患者分为对照组和观察组,对照组患者采用硝苯地平缓释片治疗,观察组患者采用卡托普利联合硝苯地平缓释片治疗,观察两组治疗效果。结果观察组患者收缩压以及舒张压的下降程度明显高于对照组．差异有统计学意义（P〈0．05）,观察组的治疗的总有效率为96．0％,对照组治疗的总有效率为78．0％,差异有统计学意义（P〈0．05）。结论卡托普利联合硝苯地平缓释片治疗高血压的效果明显,且不良反应少,安全性高,值得临床推广使用。     

Effect of calcium ions on the gelling and drug release characteristics of xanthan matrix tablets

Xanthan is a well-known biopolymer. It is an anionic polysaccharide, whose primary structure depends on the bacterial strain and fermentation conditions. Xanthan was extensively studied in combination with galactomannans, and over 90 patents cover the technology of this preparation. Our aim was to investigate the relation between the physical properties of a xanthan matrix in the absence or presence of calcium ions and its influence on the release of pentoxifylline. The release of pentoxifylline from xanthan tablets in purified water was shown to be very slow and governed by the process of polymer relaxation. The presence of calcium ions significantly increased the drug release, changing the release mechanism into a more diffusion controlled one. Xanthan matrices showed substantially faster and more extensive swelling in water than in the presence of Ca2+ ions. Surprisingly, negative correlation between drug release and degree of swelling was obtained for xanthan: the higher the swelling, the slower the drug release. Higher ionic strength led to lower erosion of xanthan tablets, and the gel layers formed were more rigid and of firmer texture, as shown by rheological experiments and textural profiling. The results indicate that the presence of Ca2+ ions in the solution or in matrices does not cause crosslinking of xanthan polymers, but causes charge screening of ionized groups on the trisaccharide side chains of xanthan, leading to lower inter-molecular repulsion and changing water arrangement. The understanding of the parameters influencing drug release leads to the conclusion that xanthan is suitable for controlled release formulations, especially with the incorporation of certain small counterions.     

丙戊酸镁缓释片对难治性精神分裂症患者认知功能的影响

目的探讨丙戊酸镁缓释片对治疗难治性分裂症患者的认知功能的影响。方法采用入院顺续分层随机法，将80例难治性精神分裂症患者平均分为研究组（丙戊酸镁缓释片＋利培酮）和对照组（利培酮＋安慰剂）。在治疗前和治疗后2、4、8、12周末，用阳性症状及阴性症状量表（PANSS），不良反应量表（TESS）评定疗效及不良反应，用韦氏成人智力量表（WAIS-R）、韦氏记忆量表（WMS）和威斯康星卡片分类测验（WCST）平定治疗前后患者认知功能的改变。分析量表中各领域的计分。结果两组PANSS总分在治疗后与治疗前比较差异有统计学意义，（P〈0．05），研究组有效率72．5％，显效率20％；对照组有效率52．5％，显效率12．5％。两组间疗效差异有统计学意义，（P〈0．05），且两组言语量表、操作量表、全量表和记忆量表分比治疗前明显提高，研究组与对照组比较差异有统计学意义，（P〈0．05）。治疗后2、4、8、12周末TESS评分，两组差异无统计学意义（P〉0．05）。结论丙戊酸镁缓释片合并利培酮治疗难治性精神分裂症疗效确切，且安全性高，对认知功能的改善彻底。     

曲匹地尔缓释片的制备与体外释放度测定

目的:研制曲匹地尔缓释片。方法:用高分子化合物作辅料制备缓释片,测定释放度。结果:该处方、制备工艺简单,体外 释药符合缓释片的规律。结论:曲匹地尔缓释片剂可作为曲匹地尔的新制剂开发。     

Effect of different polymers and their combinations on the release of metoclopramide HCl from sustained-release hydrophilic matrix tablets

Metoclopramide HCl (MTC) is commonly used for the management of gastrointestinal disorders. It has a short biological half-life and is usually administered four times daily to maintain effective concentrations throughout the day. The aim of this study is to develop sustained-release hydrophilic matrix tablet formulations of drug to achieve reproducible and predictable release rates, extended duration of activity, decreased toxicity, reduction of required dose, optimized therapy, and improved patient compliance. Hydroxypropylmethyl cellulose (HPMC), carboxymethylcellulose sodium (NaCMC), chitosan and Carbopol 981 were incorporated in the matrix system separately or in combinations as release controlling factor by direct compression technique. Compatibility among the formulation components was assessed by DSC and FTIR analysis. MTC release from matrix was evaluated by using the US Pharmacopeia dissolution apparatus II. All formulations met the criteria of pharmacopeial requirements. Dissolution studies show that polymer type and concentration are important parameters on drug release. Chitosan, carbopol and NaCMC formulations exhibited pH-dependent drug release profile whereas HPMC did not. All the formulations containing 1:1 ratio of HPMC and chitosan exhibited desired drug release showing that all active substance releases progressively in a period of whole dissolution time and therefore it can be regarded as worthy of consideration for the manufacture of sustained-release MTC product.     

盐酸氨溴索缓释片体内外相关性研究

目的考察盐酸氨溴索缓释片体外释放度与体内吸收的相关性。方法应用释放度测定法研究盐酸氨溴索缓释片体外释药行为 ,采用HPLC法测定盐酸氨溴索缓释制剂在家犬体内的血药浓度 ,按照Wagner Nelson公式计算药物的吸收分数。 结果 3种自制盐酸氨溴索缓释片与参比制剂生物等效 ,以药物累积吸收百分数 f(t)与相应时刻的体外累积释放百分数F(t)建立的一元线性回归方程 ,参比制剂与 3种自制制剂的体内外相关系数分别为 0 969、0 979、0 970和 0 983。结论盐酸氨溴索缓释片的体外释放度与体内吸收具有显著的相关性。     

双氯芬酸钾HPMC骨架片体外释药影响因素研究

目的：研究药物／HPMC比、HPMC粘度、HPMC粒径、压片压力及桨转速对双氯芬酸钾HPMC骨架片体外释放行为的影响。方法：以HPMC为骨架材料,制备双氯芬酸钾缓释片,测定其体外释放度。结果：药物／HPMC比和HPMC粘度显著影响双氯芬酸钾缓释片的释药速率,HPMC粒径、压片压力和桨转速对双氯芬酸钾缓释片释药速率影响较小。结论：通过使用不同粘度HPMC、调节药物／HPMC比可制得较为理想的双氯芬酸钾缓释片。     

沙丁胺醇包合物缓释片的制备及其体外释放研究

目的研究沙丁胺醇 乙基化 β 环糊精包合物缓释片的制备方法 ,并考察其体外释放 ,筛选出适宜处方。方法采用粉末直接压片法制备沙丁胺醇 乙基化 β 环糊精包合物缓释片 ,含量测定采用紫外法 ,释放度测定采用《中华人民共和国药典》2 0 0 0版二部释放度测定法中的第 3法 ,用显色法测定释放介质中沙丁胺醇的浓度。结果增加淀粉用量可使 1∶1包合物缓释片的释药加快 ,但对1∶2包合物缓释片影响较小 ;1 %～ 5 %的硬脂酸镁可明显加速缓释片的药物释放 ,3%～ 7%的滑石粉对药物释放影响较小 ;压片压力、搅拌速度、释放介质对缓释片的药物释放影响较小。结论以乙基化β 环糊精为载体制成的沙丁胺醇包合物缓释片具有较好的缓释作用。     

贝那普利联合硝苯地平缓释片治疗高血压疗效观察

目的观察贝那普利联合硝苯地平缓释片治疗高血压的临床效果。方法将门诊确诊的68例高血压患者随机分为治疗组和对照组,治疗组采用贝那普利联合硝苯地平缓释片治疗,对照组采用硝苯地平缓释片治疗。疗程6周。结果贝那普利联合硝苯地平缓释片在降压效果方面优于对照组。结论贝那普利和硝苯地平缓释片联合治疗高血压疗效显著,值得临床选择使用。     

Effects of verapamil,diltiazem and ryosidine on the release of dopamine and acetylcholine in rabbit caudate nucleus slices

Summary Slices of the rabbit caudate nucleus were preincubated with ³H-dopamine or ³H-choline and then superfused with label-free medium. Release of ³H-dopamine and ³H-acetylcholine was elicited by either electrical stimulation at 8 (in one series 2) Hz, or an increase in the K⁺ concentration by 50 mmol/l, or addition of L-glutamate 1 mmol/l. Verapamil 1 mol/l, diltiazem 1 and 10 mol/l, and ryosidine 1 mol/l failed to the reduce the electrically-, K⁺- and glutamate-evoked overflow of tritium. Verapamil 1 mol/l and diltiazem 10 mol/l also failed to reduce the electricallyevoked overflow (2 Hz) when dopamine receptors, neuronal dopamine uptake, and neuronal choline uptake were blocked by domperidone, nomifensine and hemicholinium, respectively. Inhibition of the evoked overflow of tritium was only obtained when concentrations were increased to verapamil 10 mol/l, diltiazem 100 mol/l and ryosidine 10 mol/l. The inhibition was generally small. It was more evident for slices preincubated with ³H-choline than for those preincubated with ³H-dopamine, because in the latter verapamil, diltiazem and (much less) ryosidine accelerated the basal efflux of tritium. The inhibition of the K⁺-evoked overflow of tritium was probably due to blockade of Ca²⁺ channels because this overflow was Ca²⁺-dependent but tetrodotoxin-resistant. In contrast, the inhibition of the electrically- and glutamateevoked overflow possibly involved blockade of Na⁺ channels as well. The results indicate that three calcium antagonists from different chemical classes are very weak inhibitors of Ca²⁺ entry into, and hence transmitter release from, the terminal axons of central dopaminergic and cholinergic neurones. The function of the high affinity calcium antagonist binding sites that have been identified in brain remains unknown.     

参松养心胶囊联合琥珀酸美托洛尔缓释片治疗室性早搏的疗效观察

目的：观察参松养心胶囊联合琥珀酸美托洛尔缓释片治疗室性早搏的临床疗效。方法选取2012年4月－2013年9月收治的室性早搏患者100例,随机分为治疗组与对照组各50例。2组患者在常规治疗原发病的基础上,均停用所服用的抗心律失常药物7d以上,对照组给予琥珀酸美托洛尔缓释片口服;治疗组在对照组的基础上加服参松养心胶囊4粒／次,3次／d;2组均治疗1个疗程（4周为1个疗程）。观察其疗效及不良反应。结果治疗组总有效率92．0％明显高于对照组的78．0％,差异有统计学意义（ P＜0．05）;治疗组动态心电图症状改善效果总有效率84．0％明显高于对照组的62．0％,差异有统计学意义（P＜0．05）。结论参松养心胶囊联合琥珀酸美托洛尔缓释片剂治疗室性期前收缩可提高疗效且安全性较好,值得在临床推广使用。     

药物溶出/吸收仿生系统研究丹酚酸B缓释片释放规律

目的：应用药物溶出/吸收仿生系统（drug dissolution/absorption simulating system,DDASS）研究丹酚酸B缓释片的体外释放规律,为中药活性成分缓控释制剂的设计提供新技术。方法：分别采用DDASS法和我国药典收载的桨法对丹酚酸B固体制剂进行体外释放度试验,高效液相色谱法定量,SPSS软件对累积释放度进行释放模型拟合。改进DDASS装置使研究对象从药物固体粉末或颗粒剂扩展到片剂、胶囊剂等多种剂型,分别评价丹酚酸B缓释片DDASS改进前、后和桨法中释放规律的相关性。结果：丹酚酸B原料药及其缓释片在改进前DDASS模型中释药过程符合Weibull方程;而丹酚酸B缓释片在改进后DDASS模型中释药过程符合一级动力学方程,与桨法评价结果一致。DDASS改进前、后与桨法释药规律相关性水平r值分别为0.7884（r5,0.05〈r前〈r5,0.001）和0.9982r后〉r5,0.001）。结论：丹酚酸B缓释片释药规律研究显示改进后DDASS法与桨法之间存在更为显著相关性。较之桨法,DDASS法模拟了一个连续动态的、更接近人体消化道环境的释药过程,表明该法评价药物固体制剂释药特性研究的合理性,为药物剂型设计研究提供了新的技术平台。