Preparation and evaluation of sustained-release diltiazem hydrochloride pellets

In this study,diltiazem hydrochloride(DTZ)pellets were prepared successfully by extrusionespheronization method.Then methacrylic acid and ethylcellulose coating formulations were employed to make the DTZ pellets sustained release.The pellets with different coatings were investigated by in vitro dissolution tests.At last,the pellets with the best coating copolymer were subjected to pharmacokinetic studies in beagle dogs.The dissolution profiles of pellets coated with Eudragit
NE30D were similar to Herbesser
,one of the marketed sustained release capsules.In the bioavailability study,the principal pharmacokinetic parameters of self-made pellets and the marketed ones were comparable;the relative bioavailability of DTZ sustained release capsules compared with Herbesser
was 98.5
36.4%.All the data indicated self-made sustained pellets could prolong the release of DTZ,decrease the fluctuation of drug level in vivo,and increase the compliance of patients.

Preparation and evaluation of tamsulosin hydrochloride sustained-release pellets modified by two-layered membrane techniques

The aim of the present study was to develop tamsulosin hydrochloride sustained-release pellets using two-layered membrane techniques.Centrifugal granulator and fluidizedbed coater were employed to prepare drug-loaded pellets and to employ two-layered membrane coating respectively.The prepared pellets were evaluated for physicochemical characterization,subjected to differential scanning calorimetry(DSC)and in vitro release of different pH.Different release models and scanning electron microscopy(SEM)were utilized to analyze the release mechanism of Harnual■ and home-made pellets.By comparing the dissolution profiles,the ratio and coating weight gain of Eudragit■ NE30D and Eudragit■ L30D55 which constitute the inside membrane were identified as 18:1 and 10%-11%.The coating amount of outside membrane containing Eudragit■ L30D55 was determined to be 0.8%.The similarity factors(f_(2))of home-made capsule and commercially available product(Harnual■)were above 50 in different dissolution media.DSC studies confirmed that drug and excipients had good compatibility and SEM photographs showed the similarities and differences of coating surface between Harnual■ and self-made pellets before and after dissolution.According to Ritger-Peppas model,the two dosage form had different release mechanism.

Optimizing pH-sensitive and time-dependent polymer formula of colonic pH-responsive pellets to achieve precise drug release

Time-sensitive and pH-dependent polymers are generally employed to prepare colon-site delivery system, and their coating thickness and order are very important in controlling the drug release. The traditional colon-site delivery systems consist of time-dependent polymers as inner layer and pH-sensitive polymers as outer layer. However, they suffer from low drug-loading rate and immature drug release. In this study, total alkaloids of sophora alopecuroides(TASA)-loaded pellets were prepared by extrusion-spheronization method and coated with Eudragit RS30D and Eudragit S100. Pellets using Eudragit RS30D as inner layer and Eudragit S100 as outer layer were named as ERS-ES100 TCO, while pellets with Eudragit S100 as inner layer and Eudragit RS30D as outer layer were ES100-ERS NCO. Both types of formulations with varying coating ratios and orders of Eudragit S100 and Eudragit RS30D were designed and prepared. The following in vitro drug release and SEM studies indicated that ERS-ES100 TCO(F2) with 12.8% Eudragit RS30D as inner layer and 21% Eudragit S100 as outer layer released up to 42% drug in 5 h. Interestingly, ES100-ERS NCO(F4) coated with 12.8% Eudragit S100 and 14.8% Eudragit RS30D showed optimal drug release in colon. In conclusion, ES100-ERS NCO colonic delivery system achieved reduced coating thickness and improved colonic targeting compared with traditional delivery system(ERS-ES100 TCO). In addition, the similarity factors( f 2) value of sophoridine and matrine for investigated formulation were within 50–100 and > 80, demonstrating that sophoridine and matrine in all formulations achieved a synchronous release.

Preparation and bioavailability in healthy volunteers of cefaclor modified-release capsules

Aim To investigate whether modified-release cefaclor capsules could lead to a more suitable pharmacokinetic profile in the plasma. Methods Cefaclor pellets were prepared by extrusion/spheronization and coated by Eudragit L30D-55 or Eudragit NE30D, then the two sorts of pellets were filled to capsules in a 35：65 ratio to made a modified-release （MR） capsules. The bioavailability of the MR capsules was studied in 24 healthy volunteers after oral administration in a fast state using a commercially available immediate release （IR） capsule as a reference. Results The results showed that the MR formulation had a relatively good bioavailability compared with the commercial capsules, as well as a longer time keeping drug level above MIC than immediate release capsule. The relative bioavailability of the MR capsules was 97.4- 12.1%. Conclusion The data of the present study indicate that time of cefaclor plasma concentration above MIC can be substantially prolonged if cefaclor is administered as a modified- release product.

Preparation and in vitro-in vivo evaluation of intestinal retention pellets of Berberine chloride to enhance hypoglycemic and lipid-lowing efficacy

Berberine chloride(BBR) is a pharmacokinetic profile of drug with poor bioavailability but good therapeutic efficacy,which is closely related to the discovery of BBR intestinal target.The major aim of this paper is to develop BBR intestinal retention type sustained-release pellets and evaluate their in vivo and in vitro behaviors base on the aspect of local action on intestinal tract. Here,wet milling technology is used to improve dissolution and dissolution rate of BBR by decreasing the particle size and increasing the wettability. The pellets are prepared by liquid layer deposition technology,and then the core pellets are coated with Eudragit~?L30 D-55 and Eudragit~?NE30 D aqueous dispersion. The prepared pellets show high drug loading capacity,and the drug loading up to 93%. Meanwhile,it possesses significant sustained drug release effect in purified water which is expected to improve the pharmacokinetic behavior of BBR. The pharmacokinetics results demonstrate that the halflife of BBR was increased significantly from 24 h to 36 h and the inter-and intra-subject variability are decreased compared to commercial BBR tablets. The retention test results indicate that the pellet size and Eudragit~?NE30 D plays an important role in retention time of the pellet,and it is found that the pellets with small particle size and high Eudragit~?NE30 D coating content can stay longer in the intestine than the pellets with large particle size. All in all,BBR intestinal retention type pellets are prepared successfully in this study,and the pellets show satisfactory in vivo and in vitro behaviors.

Impact of release characteristics of sinomenine hydrochloride dosage forms on its pharmacokinetics in beagle dogs

AIM： To investigate the effect of release behavior of sustained-release dosage forms of sinomenine hydrochloride （SM·HCl） on its pharmacokinetics in beagle dogs. METHODS： The in vitro release behavior of two SM·HCl dosage forms, including commercial 12-h sustained-release tablets and 24-h sustained-release pellets prepared in our laboratory, was examined. The two dosage forms were orally administrated to beagle dogs, and then the in vivo SM.HCI pharmacokinetics was investigated and compared. RESULTS： The optimal SM·HCl sustained-release formulation was achieved by mixing slow- and rapidrelease pellets （9：1, w/w）. The SM·HCl release profiles of the sustained-release pellets were scarcely influenced by the pH of the dissolution medium. Release from the 12-h sustained-release tablets was markedly quicker than that from the 24-h sustained-release pellets, the cumulative release up to 12-h was 99.9% vs68.7%. From a pharmacokinetic standpoint, the 24-h SM.HCI sustainedrelease pellets had longer tmax and lower Cmax compared to the 12-h sustained-release tablets, the tmax being 2.67±0.52 h vs 9.83±0.98 h and the Cmax being 1334.45±368.76 ng/mL vs 893.12±292.55 ng/mL, respectively. However, the AUC0-tn of two SM·HCl dosage forms was comparable and both preparations were statistically bioequivalent. Furthermore, the two preparations had good correlations between SM·HCl percentage absorption in vivoand the cumulative percentage release in vitro. CONCLUSION： The in vitro release properties of the dosage forms strongly affect their pharmacokinetic behavior in vivo. Therefore, managing the in vitro release behavior of dosage forms is a promising strategy for obtaining the optimal in vivo pharmacokinetic characteristics and safe therapeutic drug concentration-time curves.

琥珀酸美托洛尔缓释微丸保护性衣层对其缓释片形成的影响与初步评价

目的评价羟丙纤维素及羟丙甲纤维素对琥珀酸美托洛尔缓释微丸的机械保护作用及差异。方法用不同分子量等级的羟丙纤维素和羟丙甲纤维素对琥珀酸美托洛尔缓释微丸进行包衣,通过检测微丸负压载荷、微丸完整性、体外溶出曲线,评价两种高分子材料对微丸的保护效果。通过制备了羟丙纤维素和羟丙甲纤维素薄膜并考察两种高分子材料薄膜的抗张强度、延展率、韧性和弹性模量等方面的机械性能差异。结果包被羟丙纤维素和羟丙甲纤维素的琥珀酸美托洛尔微丸,断裂载荷增加,压片后微丸完整性提高,机械性能提升,药物泄漏率降低。结论羟丙纤维素和羟丙甲纤维素保护层包衣对琥珀酸美托洛尔片释放单元有一定的机械保护作用,羟丙纤维素具有相对更高的保护能力,可以为多单元微丸药物释放系统的微丸保护策略提供借鉴。

盐酸伊伐布雷定缓释微丸的制备工艺及其药动学研究

目的制备盐酸伊伐布雷定缓释微丸,考察其载药率、体外释放度及其在大鼠体内的药动学特征。方法采用流化床包衣法制备盐酸伊伐布雷定缓释微丸,以载药率为评价指标,通过正交试验设计优化载药层工艺参数,以体外释放度为评价指标,通过响应面实验设计优化缓释层处方。健康雄性SD大鼠随机分成2组:盐酸伊伐布雷定缓释微丸组和盐酸伊伐布雷定片组,单次给药后,测定不同时间点的血药浓度,运用Das20软件计算药动学参数。结果载药层处方:盐酸伊伐布雷定原料药075 g、羟丙基甲基纤维素180 g、水40 g,流化床工艺参数:进风量13 m^(3)·h^(-1)、进风温度50℃、雾化压力12 bar、蠕动泵流速09 mL·min^(-1);缓释层处方:乙基纤维素78%、聚乙二醇400091%、柠檬酸三乙酯20%。平均载药率924%,12 h累计释放度为9237%;盐酸伊伐布雷定缓释微丸较普通片剂的相对生物利用度为13559%。结论盐酸伊伐布雷定缓释微丸制备工艺重现性良好,体内外缓释效果明显,生物利用度显著提高,为盐酸伊伐布雷定缓释制剂的研究提供了基础。

碳热还原法制备碳化硼原料缓释脱水研究

为改善传统碳热还原法制备碳化硼因直接高温(1 800~2 000℃)剧烈脱水导致硼酸原料挥发严重进而产品纯度低和结晶差等弊端,本文以硼酸和石油焦为原料,研究了原料存在形式(球团、粉末)、脱水温度、加热时间及升温速率对缓释脱水过程的影响,确定了适宜的缓释脱水参数,同时研究了缓释脱水过程的动力学。研究表明,较优的缓释脱水参数为:原料压制球团、脱水温度300℃、脱水时间40 min、升温速率5℃/min。此外,通过XRD和化学成分分析,原料经过缓释脱水过程可提高B4C纯度约9.01%,降低游离碳含量7.95%。由此可知,原料缓释脱水有利于维持原料配比平衡,从而提高碳热还原法的反应程度。

Preparation of Colon‐specific and Synchronous Release Pellet Containing Total Alkaloids of Sophora alopecuroides

Objective To deliver multiple component drugs to colon site and sustain a synchronous release for better therapeutic effect. For achieving this purpose, colon specific pellet containing total alkaloids of Sophora alopecuroides （TASA） was prepared. Methods The pellet was prepared by extrasion-spheronizing and subsequently coated with three layers of two polymers. Results The pellet core consisted of 40% TASA, 1：2 in ratio of Bletilla striata polysaccharide （BSP）, an enzyme-degradable material, to microcrystalline cellu{ose （MCC）, filler, and 1% CMC-Na solution as binder by optimization. Concerning of the three coated layers, the outer layer was coated with Eudragit RS30D for controlling drug release in colon, the intermediate layer and the inner layer were coated with same polymer, Eudragit $100, for preventing drug release in upper gastrointestinal tract, which required 23.2%, 21.7%, and 9.3% weigh gain, respectively. The coated pellets released 1.20% of sophoridine and 1.98% of matrine in media mimicking the stomach condition for 2 h, and 23.88% of sophoridine and 22.91% of matrine in media mimicking the intestine for 3 h and finally 90.25% of sophoridine and 89.94% of matrine in colonic conditions within 24 h, And the similarity factor f2 of sophoridine and matrine of release curve for investigated formulation was internal in （50-100） and 〉 80, demonstrating that sophoridine and matrine in formulation achieved a synchronous release. Conclusion The coated pellets achieve a certain colon-specific release and synchronous release.

双黄连pH依赖型梯度释药微丸的研究

目的制备pH依赖型梯度释药的双黄连微丸,以实现药物在体内的梯度脉冲释放。方法将酸中溶解度低的指标性成分黄芩苷制备成固体分散体,采用挤出滚圆法分别制备双黄连素丸和双黄连固体分散体微丸,选择Eudragit L30D-55和Eudragit L100/S100为包衣材料,采用流化床进行包衣。将固体分散体微丸、Eudragit L30D-55包衣微丸和Eudragit L100/S100包衣微丸按照比例混合即得。结果双黄连固体分散体微丸在pH>1.2的介质中释药,Eudragit L30D-55包衣微丸在pH>5.5的介质中开始释药,Eudragit L100/S100包衣微丸在pH>6.8的介质中开始释药。三种微丸按照比例混合之后在模拟人体胃肠道pH环境变化的体外释放介质中呈现良好的pH依赖型释药特性,且指标性成分黄芩苷和绿原酸的体外释放行为相似。结论利用人体胃肠道pH变化,采用多元定位释药技术制备的双黄连pH依赖性梯度释药微丸可以在长效释放的同时达到同步释放,满足中医药理论下的用药思想和整体观念。

双嘧达莫缓释微丸的研制及其体外释放特性

目的 :制备双嘧达莫 pH非依赖型缓释微丸 ,使药物释放不受胃肠道pH值变化及个体差异的影响。 方法 :采用固体分散技术 ,将药物与联合载体 (EudragitL、EC和PEG 60 0 0 )的混和有机液喷包于微晶纤维素 (MCC)空白丸芯上形成膜衣骨架型共沉淀物结构 ,以正交设计进行处方优化 ,考察不同pH条件下缓释微丸的释放特性。结果 :缓释微丸的体外药物释放呈pH非依赖型释放特征 ,符合一级动力学方程。结论 :具有溶解度pH依赖性的药物 ,以固体分散技术处理 ,通过不同性质载体的调节作用 ,可以制成pH非依赖型的缓释制剂。

灯盏花素缓释微丸制备工艺与处方优化的研究

目的 考察灯盏花素缓释微丸的制备工艺和最优处方 ,并对释药机制进行探讨。方法 利用挤出滚圆法制备骨架型微丸 ,采用单因素考察和正交设计筛选最优处方 ,通过方程拟合探讨释药机制。结果 所得微丸的制备工艺简单 ,微丸大小均匀 ,载药量大且药物含量均匀 ,能达到缓释 12 h的试验设计要求 ;释药机制以药物扩散为主 ,兼有骨架溶蚀。结论 利用挤出滚圆法制备灯盏花素缓释微丸方法简单 ,适于工业化生产。

多元定位释药技术制备舒胸缓释胶囊的研究

目的采用多元定位释药技术制备舒胸缓释胶囊。方法将处方药材精制后制备成舒胸微丸,然后分别采用HPM C、Eudrag it L 30D-55、Eudrag it L 100-Eudrag it S100混合物(1∶5)制备成3种包衣微丸,并按一定比例混合装入胶囊中。结果HPM C包衣微丸在任何pH值条件下均可释药,Eudrag it L 30D-55包衣微丸在pH≥5.5时开始释药,Eudrag it L 100-Eudrag it S100(1∶5)包衣微丸在pH≥6.8时开始释药。由3种包衣微丸混合制备而成的缓释胶囊,在模拟人体胃肠道pH变化条件下,呈现出一种pH依赖型梯度缓释特征,而且处方中的主要成分三七总皂苷、红花黄色素、阿魏酸、川芎嗪的释放度差异无显著性。结论采用定位释药技术制备而成的舒胸缓释胶囊中理化性质不同的各成分在缓释的同时可以达到同步释放,遵循了中药制剂复方配伍的整体观和用药思想。

微丸的进展

通过查阅近年国内外有关文献，对微丸的释药机制、制备方法及辅料作了综述。

双氯芬酸钠脉冲控释微丸的研究

目的 制备双氯芬酸钠脉冲控释微丸 (DS PRP)并考察体内外释药特性。方法 采用水溶胀性材料为内包衣溶胀层 ,乙基纤维素水分散体为外包衣控释层制备DS PRP ,考察影响其体外释药的因素 ,并进行体内药代动力学研究。结果 溶胀层材料类型、溶胀层和控释层包衣厚度、释放介质中十二烷基硫酸钠 (SDS)的加入对DS PRP的释药时滞和释药速率有显著影响 ,在 0 1%SDS溶液中释药时滞T0 1 为 3 1h ,体内释药时滞Tlag为 2 8h ,与DS丸芯的相对生物利用度为 ( 91± 12 ) %。结论 DS PRP在体内外均具有脉冲释药特性。

双氯芬酸钠肠溶微丸型片剂的研制

本文制备了双氯芬酸钠肠溶微丸型片剂。以丙烯酸树脂Eudragit NE30D和Eudragit L30D-55不同比例的混合物作为衣膜材料,对不同粒径大小的双氯芬酸钠速释丸芯进行不同增重水平的包衣,并与不同压缩特性和用量比例的缓冲微丸混合,压片。所得的双氯芬酸钠肠溶微丸型片剂在人工胃液中2 h内累积释放百分数<10%,在人工肠液中1 h内累积释放百分数为(83±2.42)%。结果表明Eudragit NE30D与Eudragit L30D-55以一定比例混合制备得到适合压片的肠溶微丸,硬脂酸制备的缓冲微丸可用于微丸型片剂的制备。

左金胃漂浮缓释片中小檗碱、巴马汀、吴茱萸碱和吴茱萸次碱的体外释放规律和机制研究

目的探讨左金胃漂浮缓释片体外多成分释放的规律和机制。方法采用转篮法以人工胃液为介质,以HPLC法测定左金胃漂浮缓释片中小檗碱、巴马汀、吴茱萸碱和吴茱萸次碱在8 h内的体外累积释放率,通过相似因子比较法、Higuchi方程,零级、一级释放方程等释放模型拟合法以及Peppas方程研究左金胃漂浮缓释片多成分释放的规律。结果左金胃漂浮缓释片中4种生物碱的平均释放曲线相互之间的相似因子均大于80%,均以Higuchi释放模型为最佳拟合模型,释放机制均为扩散协同骨架溶蚀作用。结论左金胃漂浮缓释片中生物碱类成分的释放具有均衡缓释性。

挤出滚圆法制备复方丹参速释微丸

目的制备复方丹参速释微丸,使理化性质差异较大的各成分达到同步释放。方法采用挤出滚圆法制备复方丹参速释微丸,以丹酚酸B、三七总皂苷和冰片为体外溶出考察的指标性成分,对微丸中加入的崩解剂种类、用量,黏合剂和表面活性剂的用量进行了筛选,并采用正交试验设计对处方进行了优化。结果在处方中加入20%泡腾崩解剂、5%羧甲基淀粉钠(CMS-Na)和2%十二烷基硫酸钠(SDS)后,复方丹参速释微丸中冰片的溶出效率增加,且3种指标成分基本达到了同步快速释放。结论通过加入复合崩解剂,可以使采用挤出滚圆法制备的微丸迅速崩解,从而使复方中药中理化性质差异较大的各成分达到同步释放。

盐酸青藤碱缓释组合微丸系统的研究

目的:建立线性叠加组合微丸释药模型,以盐酸青藤碱为模型药,进行模型验证和预测。方法:采用挤出滚圆法制备速释丸,流化床底喷包衣制备肠溶和缓释微丸。根据各种微丸的释药机制选择适宜的释放模型,利用Matlab的曲线拟合工具箱进行拟合,根据相关统计参数选择最佳拟合方程,将各种微丸释药方程进行线性叠加,得到组合微丸理论释药方程。根据预期的24h释放要求,利用Matlab解析线性不等式或线性方程组,预测各种微丸所需用量并实际组合,将释放试验结果与预测值进行对比验证。结果:对组合系统释药行为的数学解析结果显示,预测值(组合微丸理论释药方程)与实测值较接近,说明组合系统的释药行为是可控的,能较好地预测组合各种微丸所需的用量以满足不同释放行为的需要。结论:有预见性地组合不同的微丸或为不同组合比例提供了一种设计缓释系统的新方法。