单硝酸异山梨酯脉冲控释微丸的研究
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摘要
随着时辰生物学、时辰药理学的发展,以及临床的需求,传统的药物释放模式(如:药物以恒速释放)不能满足许多具有生物节律性疾病的要求。其瓶颈限制主要就是制剂与生物的节律性不相吻合,研究具有时辰给药的制剂可以解决这个问题。单硝酸异山梨酯是硝酸异山梨酯在体内的活性代谢产物,临床上主要用于心绞痛的治疗,由于心绞痛易在凌晨发作,本研究以单硝酸异山梨酯为模型药物,制备脉冲释药微丸,适于晚上睡前服用,经过一定的时滞后于次日凌晨释放出药物,以满足临床的需要。
本文所研究的微丸由内向外可分为含药丸芯、溶胀层、控释层。其原理为通过控释层控制体液的进入,水分不断经控释层到达溶胀层,溶胀层不断吸水膨胀直至大于控释层的阻力时,控释膜破裂,此时药物迅速释放出来,达到时滞的目的。
建立了高效液相色谱法作为单硝酸异山梨酯体外分析的方法,包括药物的释放、含量测定以及理化性质的研究等。单硝酸异山梨酯在5~50μg.mL~(-1)范围内药物浓度与峰面积呈良好的线性关系,该方法平均回收率为99.96%,RSD为0.92%(n=5),日内及日间精密度≤1%,说明本方法简便、准确、重现性好,可作为本制剂研究的质量控制方法。
本文以MCC、乳糖作为填充剂,水为粘合剂,采用挤出滚圆法制备了单硝酸异山梨酯的载药丸芯,并对成丸过程的三个主要因素:滚圆转速、滚圆时间、挤出转速进行了正交优化,结果表明,滚圆转速是影响微丸成形的最主要因素,并制得了在5min内释药达95%的丸芯。
采用流化床包衣技术,对丸芯进行两层包衣;本研究考察了流化床的各个参数,优化了条件,保证包衣的质量。且对溶胀层增重、控释层增重、微丸的粒径大小进行了考察,最后确定对20～24目丸的含药丸芯进行包衣,分别是CCNa和Surelease作为溶胀层和控释层。溶胀层增重20%、控释层增重23%,所制备的微丸的时滞时间为4h左右,开始释药后1.15h内释药达到80%。并对微丸的制备进行了重现性实验,结果表明,微丸的包衣及体外释放度重现性良好。本文通过对不同pH值的释放介质、搅拌速度和释放方法进行了考察,结果发现,在本研究所考察的范围内,三者对微丸的释药行为影响均较小;最后确定以转篮法测定其释放度,测定条件为:以水为释放介质,转篮转速为100rpm。
根据中国药典(2005年版)标准,对单硝酸异山梨酯脉冲控释微丸的稳定性进行了初步研究,包括影响因素实验,加速实验,以制剂外观、主药含量、释药行为为考察指标,考察在高温、高湿、强光照射对单硝酸异山梨酯脉冲控释微丸的影响。结果发现,该制剂对湿度比较敏感,应在阴凉干燥的环境中贮存。
本文建立了以硝酸异山梨酯为内标,测定家犬体内单硝酸异山梨酯血药浓度的气相色谱法。单硝酸异山梨酯在25～800ng.mL~(-1)范围内线性关系良好,相关系数r=0.9998,绝对回收率平均值为80.23%,方法回收率为99.89%,日内日间精密度均小于5%,最低检测浓度为10ng.mL~(-1),能满足家犬体内血药浓度的测定。
本文采用自身交叉给药,对单硝酸异山梨酯片(参比制剂)和单硝酸异山梨酯脉冲控释微丸(实验制剂)进行家犬体内药代动力学考察,药动学参数分别如下:参比制剂和受试制剂的Tlag分别为0.25h和4.094h,T_(max)分别为1.165h和5.277h,C_(max)分别为552.086 ng.mL~(-1)和479.216 ng.mL~(-1), AUC_(0-t)分别为3994.378 ng.mL~(-1).h和4185.622 ng.mL~(-1).h, AUC_(0-∞)分别为4373.492 ng.mL~(-1).h和4392.542 ng.mL~(-1).h.相对生物利用度为100.43%。
Due to advances in chronobiology, chronopharmacology, and the requirement of clinical therapy, the traditional goal of pharmaceutics (e.g. design drug delivery systems with a constant drug release rate) is becoming obsolete. However, the major bottleneck in the development of drug delivery systems that match the circadian rhythm (chronopharmaceutical drug delivery systems: ChrDDS) may be the availability of appropriate technology. Isosorbide 5-mononitrate (5-ISMN), an active metabolite of isosorbide dinitrate (ISDN), is a long-acting organic nitrate vasodilator used in the treatment of angina pectoris. According to the fact that angina pectoris usually happens in early morning, the Isosorbide-5-mononitrate pulsed controlled release pellets are devised to be administered at bedtime and reach its plasma concentration in midnight.
Our research of the preparation design is based on: The pulsed controlled release pellets consist of three laminar layers from center to outside: the core with drug, the swelling layer and the controlled layer. The theory of the pulsed controlled release pellets was controlled penetration of liquid to control the lag time. The swollen power exceeds the resistance of controlled layer when enough liquid penetrates. Then the controlled layer bursts and drug release.
Reversed phase high-performance liquid chromatography (RP-HPLC) method was developed for assay during the study of physicochemical properties, content and drug release. This method was proved to be simple, accurate, reliable and reproducible.
The core pellets were prepared by extrusion-spheronization in this paper. Pulsed release pellets (PRP) of ISMN were prepared by using croscarmellose sodium (CCNa) as inner layer and aqueous ethylcellulose dispersion (Surelease) as outer controlled layer on a fluidized spray coater. The factors which affect the lag time and the drug release profile were investigated, such as the type and the thickness of the inner and the outer layer. Furthermore full experiment design was chosen to optimize the formulations and the optimum formulation is as follow: a 20% CCNa coating level, 23% Surelease coating level. The prepared pellets release the drug after a lag time of about 4 hours and the accumulative release arrived 80% within 1.15h.
Followed Chinese Pharmacopoeia (edition 2005), the stability of the ISMN pulsed release pellets was investigated, which included influence factors and acceleration test. The appearance of pellets, release and drug content were major items investigated under the condition of strong light, high temperature, high humidity. The results showed that the coating membrane of pellets was sensitive to high humidity, but stable for temperature and light. Therefore the preparations should be preserved away from humidity.
The quantitative determination of ISMN in dogs’plasma was performed by GC with agilent micro-electron capture detector (micro-ECD) and the ISDN was chosen to be the internal standard. The standard curve was linear in the range of 25~800ng.mL~(-1) with a correlation efficient r value of 0.9998. It was proved that the recovery and the within day and between day precision of this method conformed to specification. The lower detection concentration was found to be 10ng.mL~(-1), indicating that the GC method was accurate.
The behavior in vivo of the pellets was evaluated in 6 dogs after an oral administration of ISMN tablets (reference formulation) or pulsed release pellets (test formulation). The pharmacokinetic parameters of the reference and test formulation were as below: Tlag were 0.25h and 4.094h, T_(max) were 1.165h and 5.277h, C_(max) were 552.086 ng.mL~(-1) and 479.216 ng.mL~(-1), AUC_(0-t) were 3994.378 ng.mL~(-1).h and 4185.622 ng.mL~(-1).h, AUC_(0-∞)were 4373.492 ng.mL~(-1).h,and 4392.542 ng.mL~(-1).h. The relative bioavailability was 100.43%.
本文所研究的微丸由内向外可分为含药丸芯、溶胀层、控释层。其原理为通过控释层控制体液的进入,水分不断经控释层到达溶胀层,溶胀层不断吸水膨胀直至大于控释层的阻力时,控释膜破裂,此时药物迅速释放出来,达到时滞的目的。
建立了高效液相色谱法作为单硝酸异山梨酯体外分析的方法,包括药物的释放、含量测定以及理化性质的研究等。单硝酸异山梨酯在5~50μg.mL~(-1)范围内药物浓度与峰面积呈良好的线性关系,该方法平均回收率为99.96%,RSD为0.92%(n=5),日内及日间精密度≤1%,说明本方法简便、准确、重现性好,可作为本制剂研究的质量控制方法。
本文以MCC、乳糖作为填充剂,水为粘合剂,采用挤出滚圆法制备了单硝酸异山梨酯的载药丸芯,并对成丸过程的三个主要因素:滚圆转速、滚圆时间、挤出转速进行了正交优化,结果表明,滚圆转速是影响微丸成形的最主要因素,并制得了在5min内释药达95%的丸芯。
采用流化床包衣技术,对丸芯进行两层包衣;本研究考察了流化床的各个参数,优化了条件,保证包衣的质量。且对溶胀层增重、控释层增重、微丸的粒径大小进行了考察,最后确定对20～24目丸的含药丸芯进行包衣,分别是CCNa和Surelease作为溶胀层和控释层。溶胀层增重20%、控释层增重23%,所制备的微丸的时滞时间为4h左右,开始释药后1.15h内释药达到80%。并对微丸的制备进行了重现性实验,结果表明,微丸的包衣及体外释放度重现性良好。本文通过对不同pH值的释放介质、搅拌速度和释放方法进行了考察,结果发现,在本研究所考察的范围内,三者对微丸的释药行为影响均较小;最后确定以转篮法测定其释放度,测定条件为:以水为释放介质,转篮转速为100rpm。
根据中国药典(2005年版)标准,对单硝酸异山梨酯脉冲控释微丸的稳定性进行了初步研究,包括影响因素实验,加速实验,以制剂外观、主药含量、释药行为为考察指标,考察在高温、高湿、强光照射对单硝酸异山梨酯脉冲控释微丸的影响。结果发现,该制剂对湿度比较敏感,应在阴凉干燥的环境中贮存。
本文建立了以硝酸异山梨酯为内标,测定家犬体内单硝酸异山梨酯血药浓度的气相色谱法。单硝酸异山梨酯在25～800ng.mL~(-1)范围内线性关系良好,相关系数r=0.9998,绝对回收率平均值为80.23%,方法回收率为99.89%,日内日间精密度均小于5%,最低检测浓度为10ng.mL~(-1),能满足家犬体内血药浓度的测定。
本文采用自身交叉给药,对单硝酸异山梨酯片(参比制剂)和单硝酸异山梨酯脉冲控释微丸(实验制剂)进行家犬体内药代动力学考察,药动学参数分别如下:参比制剂和受试制剂的Tlag分别为0.25h和4.094h,T_(max)分别为1.165h和5.277h,C_(max)分别为552.086 ng.mL~(-1)和479.216 ng.mL~(-1), AUC_(0-t)分别为3994.378 ng.mL~(-1).h和4185.622 ng.mL~(-1).h, AUC_(0-∞)分别为4373.492 ng.mL~(-1).h和4392.542 ng.mL~(-1).h.相对生物利用度为100.43%。
Due to advances in chronobiology, chronopharmacology, and the requirement of clinical therapy, the traditional goal of pharmaceutics (e.g. design drug delivery systems with a constant drug release rate) is becoming obsolete. However, the major bottleneck in the development of drug delivery systems that match the circadian rhythm (chronopharmaceutical drug delivery systems: ChrDDS) may be the availability of appropriate technology. Isosorbide 5-mononitrate (5-ISMN), an active metabolite of isosorbide dinitrate (ISDN), is a long-acting organic nitrate vasodilator used in the treatment of angina pectoris. According to the fact that angina pectoris usually happens in early morning, the Isosorbide-5-mononitrate pulsed controlled release pellets are devised to be administered at bedtime and reach its plasma concentration in midnight.
Our research of the preparation design is based on: The pulsed controlled release pellets consist of three laminar layers from center to outside: the core with drug, the swelling layer and the controlled layer. The theory of the pulsed controlled release pellets was controlled penetration of liquid to control the lag time. The swollen power exceeds the resistance of controlled layer when enough liquid penetrates. Then the controlled layer bursts and drug release.
Reversed phase high-performance liquid chromatography (RP-HPLC) method was developed for assay during the study of physicochemical properties, content and drug release. This method was proved to be simple, accurate, reliable and reproducible.
The core pellets were prepared by extrusion-spheronization in this paper. Pulsed release pellets (PRP) of ISMN were prepared by using croscarmellose sodium (CCNa) as inner layer and aqueous ethylcellulose dispersion (Surelease) as outer controlled layer on a fluidized spray coater. The factors which affect the lag time and the drug release profile were investigated, such as the type and the thickness of the inner and the outer layer. Furthermore full experiment design was chosen to optimize the formulations and the optimum formulation is as follow: a 20% CCNa coating level, 23% Surelease coating level. The prepared pellets release the drug after a lag time of about 4 hours and the accumulative release arrived 80% within 1.15h.
Followed Chinese Pharmacopoeia (edition 2005), the stability of the ISMN pulsed release pellets was investigated, which included influence factors and acceleration test. The appearance of pellets, release and drug content were major items investigated under the condition of strong light, high temperature, high humidity. The results showed that the coating membrane of pellets was sensitive to high humidity, but stable for temperature and light. Therefore the preparations should be preserved away from humidity.
The quantitative determination of ISMN in dogs’plasma was performed by GC with agilent micro-electron capture detector (micro-ECD) and the ISDN was chosen to be the internal standard. The standard curve was linear in the range of 25~800ng.mL~(-1) with a correlation efficient r value of 0.9998. It was proved that the recovery and the within day and between day precision of this method conformed to specification. The lower detection concentration was found to be 10ng.mL~(-1), indicating that the GC method was accurate.
The behavior in vivo of the pellets was evaluated in 6 dogs after an oral administration of ISMN tablets (reference formulation) or pulsed release pellets (test formulation). The pharmacokinetic parameters of the reference and test formulation were as below: Tlag were 0.25h and 4.094h, T_(max) were 1.165h and 5.277h, C_(max) were 552.086 ng.mL~(-1) and 479.216 ng.mL~(-1), AUC_(0-t) were 3994.378 ng.mL~(-1).h and 4185.622 ng.mL~(-1).h, AUC_(0-∞)were 4373.492 ng.mL~(-1).h,and 4392.542 ng.mL~(-1).h. The relative bioavailability was 100.43%.
引文
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51 Kojda G, Stein D, Kottenberg E, et al. In vivo effects of pentaerythrityl-tetranitrate and isosorbide-5-mononitrate on the development of atherosclerosis and endothelial dysfunction in cholesterol-fed rabbits. J Cardiovasc Pharmacol, 1995,25(5):763-73.
52 Lauro-Marty C, Lartigue-Mattei C, Chabard JL, et al. Gas chromatographic-mass spectrometric determination of isosorbide 5-mononitrate in human plasma. J Chromatogr B Biomed Appl, 1995,663(1):153-9.
53 Txeng TB, Fung HL. Gas chromatographic analysis of isomeric organic mononitrates in plasma. J. Chromatogr. Bioned Appl, 1991,571(1):109.
54 Gremeau I,Sauton V, Pinon V,et al. Solid-phase extraction of isosorbide dinitrate and two of its metabolites from plasma for gas chromatographic analysis. J Chromatogr Biomed Appl, 1995,995(2):399.
55 Stepanovic-Petrovic RM, Tokic-Vujosevic Z, Milovanovic S, et al. Comparison of the relaxant effects of a new oxime-nitrate derived from isosorbide-5-mononitrate and the parent drug. Arzneimittelforschung2004,54(4): 195-202.
56 Hutt V, Theodor R, Pabst G, et al. Evaluation of bioavailability and pharmacokinetics of two isosorbide-5-mononitrate preparations in healthy volunteers. J Clin Pharmacol , 1992,32(6):553-7.
57 孙学惠,郭涛,宋洪涛.等. 单硝酸异山梨酯定时脉冲控释片的研究. 解放军药学学报, 2005,21(4):258-261.
[1] ZHOU L G.The method of prepare pellets[J].Chin J Pharm(中国医药工业杂志),2005,36(02):127 -128.
[2] VERVAET C,BAERT L,REMON J P.Extrusion-speronisation a literature review[J].Int.J.Pharm,1995, 116:131-146.
[3] ZHANG Y X,CHAO D Y,ZHANG L,et al.Preparation of compound captopril sustained-release pellets and examination of drug release[J].Chin J Hosp Pharm(中国医院药学杂志),2005,25(11):1044-1045.
[4] SONG H T,GUO T,ZHANG Y X,et al.Preparation of salbutamol sulfate pulsatile controlled-release pellet[J].J Shengyong Pharm Univ( 沈 阳 药 科 大 学 学报),2003,20(02):97-115.
[5] SANTOS H,VEIGA F,PINA M,et al.Physical properties of chitosan pellets produced by extrusion-spheronisation: influence of formulation variables[J].Int J Pharm, 2002, 246(1-2):153-169.
[6] THO I,ANDERSSEN E,DYRSTAD K,et al.Quantum chemical descriptors in the formulation of pectin pellets produced by extrusion/spheronisation[J].Eur J Pharm Sci,2002,16(3):143-149.
[7] THO I,SANDE S A,KLEINEBUDDE P.Pectinic acid,a novel excipient for production of pellets by extrusion/spheronisation: preliminary studies[J].Eur J Pharm Biopharm,2002,54(1):95-99.
[8] TUNON A,BORJESSON E,FRENNING G,et al.Drug release from reservoir pellets compacted with some excipients of different physical properties[J].Eur J Pharm Sci,2003,20(4-5):469-479.
[9] PARIKH D M.Handbook of Pharmaceutical Granulation Technology[M].New York:Marcel Dekker:334-366.
[10] BASHAIWOLDU A B,PODCZECK F,NEWTON J M.The application of non-contact laser profilometry to the determination of permanent structural changes induced by compaction of pellets. I. Pellets of different composition[J].Eur J PharmSci,2004,21(2-3):143-154.
[11] HENG P W,KOO O M.A study of the effects of the physical characteristics of microcrystalline cellulose on performance in extrusion spheronization[J].Pharm Res,2001,18(4):480-487.
[12] SINHA V R,AGRAWAL M K,KUMRIA R.Influence of formulation and excipient variables on the pellet properties prepared by extrusion spheronization[J].Curr Drug Deliv,2005,2(1):1-8.
[13] BASIT A W,NEWTON J M,LACEY L F.Formulation of ranitidine pellets by extrusion-spheronization with little or no microcrystalline cellulose[J].Pharm Dev Technol,1999,4(4):499-505.
[14] SOUTO C,RODRIGUEZ A,PARAJES S,et al.A comparative study of the utility of two superdisintegrants in microcrystalline cellulose pellets prepared by extrusion-spheronization[J].Eur J Pharm Biopharm,2005,61(1-2):94-99.
[15] BOUTELL S,NEWTON J M,BLOOR J R,et al.The influence of liquid binder on the liquid mobility and preparation of spherical granules by the process of extrusion/spheronization[J].Int J Pharm,2002,238(1-2):61-76.
[16] ROUGH S L,BRIDGWATER J,WILSON D I.Effects of liquid phase migration on extrusion of microcrystalline cellulose pastes[J].Int J Pharm,2000,204(1-2):117-126.
[17] LUSTIG-GUSTAFSSON C,KAUR JOHAL H,PODCZECK F,et al.The influence of water content and drug solubility on the formulation of pellets by extrusion and spheronisation[J].Eur J Pharm Sci, 1999,8(2):147-152.
[18] TOMER G,NEWTON J M.Water movement evaluation during extrusion of wet powder masses by collecting extrudate fractions[J].Int J Pharm,1999,182(1):71-77.
[19] DREU R,SIRCA J,PINTYE-HODI K,et al.Physicochemical properties of granulating liquids and their influence on microcrystalline cellulose pellets obtained by extrusion-spheronisation technology[J].Int J Pharm,2005,291(1-2):99-111.
[20] SCHRODER M,KLEINEBUDDE P.Structure of disintegrating pellets with regard to fractal geometry[J].Pharm Res,1995,12(11):1694-1700.
[21] LUTCHMAN D,DANGOR C M,PERUMAL D.Formulation of rate-modulating pelletsfor the release of ibuprofen: an extrusion-spheronization process[J].J Microencapsul, 2005,22(6):643-659.
[22] LIANG C F,OU Y Y,CHENG P.Effect of Moistening and Binding Agents on Pellets Preparation[J].Chin J Pharm(中国医药工业杂志),2000,31(4):159-161.
[23] LIEW C V,GU L,SOH J L,et al.Functionality of cross-linked polyvinylpyrrolidone as a spheronization aid:a promising alternative to microcrystalline cellulose[J].Pharm Res,2005,22(8):1387-1398.
[24] PODCZECK F,KNIGHT P.The evaluation of formulations for the preparation of pellets with high drug loading by extrusion/spheronization[J].Pharm Dev Technol,2006,11(3):263-274.
[25] TOMER G,PODCZECK F,NEWTON J M.The influence of model drugs on the preparation of pellets by extrusion/spheronization: II. Spheronization parameters[J].Int J Pharm, 2002,231(1):107-119.
[26] WANG L M,PAN J J,GUO C L,et al.Experimental Study on Pellet Preparation of Chinese Medicine Concrete[J].China pharma(中国药业),2005,14(08):47-48.
[27] LI Q B,YOU J,YANG L,et al.Preparation of Gegen Qinlian Pellets by extrusion-spheronization method[J].Chin Tradit Herbal Drugs( 中 草 药 ), 2005,36(10):1473-1476.
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34 Lustig-Gustafsson C, Kaur Johal H, Podczeck F, et al. The influence of water content and drug solubility on the formulation of pellets by extrusion and spheronisation. Eur J Pharm Sci, 1999,8(2):147-52.
35 Vervaet C, Remon JP. Bioavailability of hydrochlorothiazide from pellets, made by extrusion/spheronisation, containing polyethylene glycol 400 as a dissolution enhancer. Pharm Res JT - Pharmaceutical research, 1997,14(11):1644-6.
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49 Pressmar F, Neidlein R, Strein K, et al. Pharmacokinetics of the organic nitrates trans-2-amino-2-methyl-N-(4- nitroxycyclohexylmethyl)-propionamide in dogs, and of 4-(2-nitroxyethyl)-piperidine in dogs and in monkeys. Arzneimittelforschung, 1992,42(10):1186-91.
50 Reis F, Rocha L, Ponte L, et al. Effect of preventive and regressive isosorbide5-mononitrate treatment on catecholamine levels in plasma, platelets, adrenals, left ventricle and aorta in cyclosporin A-induced hypertensive rats. Life Sci JT, 2005,77(20):2514-28.
51 Kojda G, Stein D, Kottenberg E, et al. In vivo effects of pentaerythrityl-tetranitrate and isosorbide-5-mononitrate on the development of atherosclerosis and endothelial dysfunction in cholesterol-fed rabbits. J Cardiovasc Pharmacol, 1995,25(5):763-73.
52 Lauro-Marty C, Lartigue-Mattei C, Chabard JL, et al. Gas chromatographic-mass spectrometric determination of isosorbide 5-mononitrate in human plasma. J Chromatogr B Biomed Appl, 1995,663(1):153-9.
53 Txeng TB, Fung HL. Gas chromatographic analysis of isomeric organic mononitrates in plasma. J. Chromatogr. Bioned Appl, 1991,571(1):109.
54 Gremeau I,Sauton V, Pinon V,et al. Solid-phase extraction of isosorbide dinitrate and two of its metabolites from plasma for gas chromatographic analysis. J Chromatogr Biomed Appl, 1995,995(2):399.
55 Stepanovic-Petrovic RM, Tokic-Vujosevic Z, Milovanovic S, et al. Comparison of the relaxant effects of a new oxime-nitrate derived from isosorbide-5-mononitrate and the parent drug. Arzneimittelforschung2004,54(4): 195-202.
56 Hutt V, Theodor R, Pabst G, et al. Evaluation of bioavailability and pharmacokinetics of two isosorbide-5-mononitrate preparations in healthy volunteers. J Clin Pharmacol , 1992,32(6):553-7.
57 孙学惠,郭涛,宋洪涛.等. 单硝酸异山梨酯定时脉冲控释片的研究. 解放军药学学报, 2005,21(4):258-261.
[1] ZHOU L G.The method of prepare pellets[J].Chin J Pharm(中国医药工业杂志),2005,36(02):127 -128.
[2] VERVAET C,BAERT L,REMON J P.Extrusion-speronisation a literature review[J].Int.J.Pharm,1995, 116:131-146.
[3] ZHANG Y X,CHAO D Y,ZHANG L,et al.Preparation of compound captopril sustained-release pellets and examination of drug release[J].Chin J Hosp Pharm(中国医院药学杂志),2005,25(11):1044-1045.
[4] SONG H T,GUO T,ZHANG Y X,et al.Preparation of salbutamol sulfate pulsatile controlled-release pellet[J].J Shengyong Pharm Univ( 沈 阳 药 科 大 学 学报),2003,20(02):97-115.
[5] SANTOS H,VEIGA F,PINA M,et al.Physical properties of chitosan pellets produced by extrusion-spheronisation: influence of formulation variables[J].Int J Pharm, 2002, 246(1-2):153-169.
[6] THO I,ANDERSSEN E,DYRSTAD K,et al.Quantum chemical descriptors in the formulation of pectin pellets produced by extrusion/spheronisation[J].Eur J Pharm Sci,2002,16(3):143-149.
[7] THO I,SANDE S A,KLEINEBUDDE P.Pectinic acid,a novel excipient for production of pellets by extrusion/spheronisation: preliminary studies[J].Eur J Pharm Biopharm,2002,54(1):95-99.
[8] TUNON A,BORJESSON E,FRENNING G,et al.Drug release from reservoir pellets compacted with some excipients of different physical properties[J].Eur J Pharm Sci,2003,20(4-5):469-479.
[9] PARIKH D M.Handbook of Pharmaceutical Granulation Technology[M].New York:Marcel Dekker:334-366.
[10] BASHAIWOLDU A B,PODCZECK F,NEWTON J M.The application of non-contact laser profilometry to the determination of permanent structural changes induced by compaction of pellets. I. Pellets of different composition[J].Eur J PharmSci,2004,21(2-3):143-154.
[11] HENG P W,KOO O M.A study of the effects of the physical characteristics of microcrystalline cellulose on performance in extrusion spheronization[J].Pharm Res,2001,18(4):480-487.
[12] SINHA V R,AGRAWAL M K,KUMRIA R.Influence of formulation and excipient variables on the pellet properties prepared by extrusion spheronization[J].Curr Drug Deliv,2005,2(1):1-8.
[13] BASIT A W,NEWTON J M,LACEY L F.Formulation of ranitidine pellets by extrusion-spheronization with little or no microcrystalline cellulose[J].Pharm Dev Technol,1999,4(4):499-505.
[14] SOUTO C,RODRIGUEZ A,PARAJES S,et al.A comparative study of the utility of two superdisintegrants in microcrystalline cellulose pellets prepared by extrusion-spheronization[J].Eur J Pharm Biopharm,2005,61(1-2):94-99.
[15] BOUTELL S,NEWTON J M,BLOOR J R,et al.The influence of liquid binder on the liquid mobility and preparation of spherical granules by the process of extrusion/spheronization[J].Int J Pharm,2002,238(1-2):61-76.
[16] ROUGH S L,BRIDGWATER J,WILSON D I.Effects of liquid phase migration on extrusion of microcrystalline cellulose pastes[J].Int J Pharm,2000,204(1-2):117-126.
[17] LUSTIG-GUSTAFSSON C,KAUR JOHAL H,PODCZECK F,et al.The influence of water content and drug solubility on the formulation of pellets by extrusion and spheronisation[J].Eur J Pharm Sci, 1999,8(2):147-152.
[18] TOMER G,NEWTON J M.Water movement evaluation during extrusion of wet powder masses by collecting extrudate fractions[J].Int J Pharm,1999,182(1):71-77.
[19] DREU R,SIRCA J,PINTYE-HODI K,et al.Physicochemical properties of granulating liquids and their influence on microcrystalline cellulose pellets obtained by extrusion-spheronisation technology[J].Int J Pharm,2005,291(1-2):99-111.
[20] SCHRODER M,KLEINEBUDDE P.Structure of disintegrating pellets with regard to fractal geometry[J].Pharm Res,1995,12(11):1694-1700.
[21] LUTCHMAN D,DANGOR C M,PERUMAL D.Formulation of rate-modulating pelletsfor the release of ibuprofen: an extrusion-spheronization process[J].J Microencapsul, 2005,22(6):643-659.
[22] LIANG C F,OU Y Y,CHENG P.Effect of Moistening and Binding Agents on Pellets Preparation[J].Chin J Pharm(中国医药工业杂志),2000,31(4):159-161.
[23] LIEW C V,GU L,SOH J L,et al.Functionality of cross-linked polyvinylpyrrolidone as a spheronization aid:a promising alternative to microcrystalline cellulose[J].Pharm Res,2005,22(8):1387-1398.
[24] PODCZECK F,KNIGHT P.The evaluation of formulations for the preparation of pellets with high drug loading by extrusion/spheronization[J].Pharm Dev Technol,2006,11(3):263-274.
[25] TOMER G,PODCZECK F,NEWTON J M.The influence of model drugs on the preparation of pellets by extrusion/spheronization: II. Spheronization parameters[J].Int J Pharm, 2002,231(1):107-119.
[26] WANG L M,PAN J J,GUO C L,et al.Experimental Study on Pellet Preparation of Chinese Medicine Concrete[J].China pharma(中国药业),2005,14(08):47-48.
[27] LI Q B,YOU J,YANG L,et al.Preparation of Gegen Qinlian Pellets by extrusion-spheronization method[J].Chin Tradit Herbal Drugs( 中 草 药 ), 2005,36(10):1473-1476.
[28] ISKANDARANI B,SHIROMANI P K,CLAIR J H.Scale-up feasibility in high-shear mixers: determination through statistical procedures[J].Drug Dev Ind Pharm,2001,27(7):651-657.
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