吲哚美辛多单元结肠靶向迷你片的制备及体内外评价

党云洁, 敖惠, 王勇, 孙梦娟, 曹德英, 杜青

河北医科大学药学院药剂教研室,石家庄 050024

DANG Yunjie^,, AO Hui, WANG Yong, SUN Mengjuan, CAO Deying, DU Qing^,

Pharmaceutical Staff Room, College of Pharmacy, Hebei Medical University, Shijiazhuang 050024, China

通信作者杜青(1963-),女,教授,博士,主要从事药物新技术与新剂型的研究。E-mail:qingdu2002@sina.com。

作者简介党云洁(1984-),女,河北石家庄人,讲师,博士,主要从事药物新型给药系统的研究。电话:0311-86265591,E-mail:dangyunjie@yeah.net。

基金资助: 国家科技重大专项(2014ZX09507001)

中图分类号: R971.1 文献标识码: B 文章编号: 1004-0781(2017)02-0196-06

摘要: 目的制备酶触发型多单元吲哚美辛结肠靶向迷你片,提高吲哚美辛治疗结肠疾病的靶向性。方法筛选不同比例肠溶层和壳聚糖层优化处方,采用直接压片法制备结肠靶向迷你片,考察制剂在不同释放液中的释药行为;采用大鼠模型考察其在体内的组织分布情况,并以比格犬为动物模型进行药动学研究和生物利用度评价。结果优选壳聚糖层处方:包衣液浓度为2%,增塑剂柠檬酸三乙酯(TEC)用量为15%,抗黏剂滑石粉用量为30%,包衣增重为5%;肠溶层处方:包衣液固含量20%,增塑剂TEC用量为5%,抗黏剂滑石粉用量为40%,包衣增重为3%。壳聚糖多单元结肠靶向制剂在大鼠胃、小肠中均无释放,在结肠处缓慢释放,比格犬体内药动学:C_max=(3.25±0.672) mg·L^-1,t_max=(2.00±0.014) h,AUC_(0-∞)=(10.2±0.871) mg·L^-1·h, MRT_(0-∞)=(2.82±0.180) h,CL=(2.46±0.202) L·h^-1·kg^-1,自制结肠靶向迷你片的释药时间显著延长,血药浓度平稳。结论制备的吲哚美辛酶触发型多单元结肠靶向迷你片具有较好的结肠靶向性和缓释效果,可为吲哚美辛治疗结肠疾病的制剂开发提供重要参考。

关键词: 吲哚美辛 ; 结肠靶向迷你片 ; 壳聚糖 ; pH值依赖 ; 酶触发

Abstract:

ObjectiveEnzyme triggered multi unit colon targeting mini tablet of indomethacin were prepared, in order to improve the target treatment of colon disease. MethodsDifferent proportion of enteric layer and chitosan layer were screened to optimize the prescription. The colon targeting mini tablets were prepared by direct compression method. The drug release properties were investigated in different release medium. Rats were used to investigate the distribution of tissue in vivo. The Beagle dogs were used to study the pharmacokinetics and bioavailability. ResultsThe optimum chitosan layer prescription: coating liquid concentration was 2%, plasticizer three citric acid ethyl ester (TEC) was 15%, an anti sticking agent amount of talc was 30%, coating weight was 5%; Enteric layer prescription: coating liquid solid content was 20%, plasticizer content of TEC was 5%, anti sticking agent talc powder dosage was 40%, coating weight was 3%. The chitosan multi unit colon targeted preparation seldom released in rat stomach and small intestine, released slowly in colon. The pharmacokinetics parameters in Beagle dogs were: C_max=(3.25 + 0.672) mg·L^-1, t_max= (2.00 + 0.014) h, AUC_(0-∞) = (10.2 +0.871) mg·L^-1·h, MRT _(0-∞) = (2.82 + 0.180) h, CL= (2.46 + 0.202) L·h^-1·kg^-1. The release time of mini tablets for colon targeted was significantly prolonged and preserved stable blood concentration. ConclusionThe enzyme triggered multi unit colon targeting mini tablet of indomethacin showed good target to colon and sustained release effect, providing an important reference for the development of preparation of indomethacin for the treatment of colon disease.

Key words: Indomethacin ; Colon targeting mini tablets ; Chitosan ; pH dependency ; Enzyme triggered

口服结肠靶向给药系统(oral colon-specific drug delivery system,OCDDS),是一种新型的制剂技术,由于载体材料的特殊性质,可以直接将药物运送到结肠部位,避免在胃、小肠等胃肠道上端崩解或蚀解而释放药物。结肠靶向给药系统将药物运送到结肠处才开始崩解或蚀解并释放药物,可发挥局部或全身治疗作用^[1-3]。根据载体材料释药的性质不同,OCDDS主要有pH值依赖型^[4]、时间控制型^[5]、压力控制型^[6]和菌群/酶触发型^[7]。其中菌群/酶触型OCDDS因其定位性好、可预测性高等特点,成为广大研究者关注的热点,是近年应用最为广泛的一种口服结肠靶向给药系统。吲哚美辛是最强的环氧化酶(COX)抑制药之一,主要用于急性风湿性及类风湿关节炎,并对结肠癌和直肠癌也有一定的治疗作用。但是吲哚美辛长期服用后药物不良反应(ADR)发生率较高,最常见的是胃肠道ADR,发生率为35%~50%^[8-9]。通过先进的制剂手段改善吲哚美辛的溶解性,提高其体内生物利用度,并降低其对胃肠道的刺激,在结肠癌及其其他癌症的临床治疗上具有重要意义。

笔者以吲哚美辛为主药,壳聚糖^[10-12]为酶触发型结肠靶向材料,采用pH值依赖和酶触发型原理相结合制备一种多单元结肠靶向迷你片(直径为3 mm的小片),避免采用单一释药原理存在的个体差异影响较大的问题,并且体内外实验均表明具有良好的结肠靶向性,可以为吲哚美辛治疗结肠疾病的制剂研究提供重要参考。

1 材料

1.1 实验动物

健康雄性Wistar大鼠,无特定病原体(SPF)级,体质量190~210 g,由河北医科大学动物实验中心提供,实验动物生产许可证号:SCXK(冀)2005-1003,合格证号:1512482;健康雄性比格犬,体质量10~11 kg,由河北医科大学新药安全评价研究中心提供,实验动物生产许可证号:SCXK(京)2011-0003,合格证号:11400600000678,给药前12 h起禁食,自由饮水,采样期间正常饮水,动物饲养室温度20~25 ℃,相对湿度60%~70%。

1.2 仪器

DP30A型单冲式压片机(北京国药龙立科技有限公司);BY300A型小型包衣机(上海黄海药检仪器厂);ZRS-8L智能溶出实验仪(天津市天大天发科技有限公司);KH-100B型超声波清洗器(昆山禾创超声仪器有限公司);LC-20A高效液相色谱仪,检测器SPD-20A(日本岛津公司)。

1.3 试药

吲哚美辛(湖北兴银河化工有限公司,批号:20130130);吲哚美辛胶囊(石药集团河北永丰药业有限公司,批号:20140219,);胃蛋白酶(郑州鸿祥化工有限公司,批号:20141022);胰酶(武汉康宝泰生物科技有限公司,批号20140720);壳聚糖酶(酷尔生物,批号:2015201v);磷酸二氢钾(天津博迪化工股份有限公司);乙腈、甲醇(美国天地试剂公司,色谱纯);纯净水(杭州娃哈哈集团有限公司)。

2 方法与结果

2.1 释放度测定方法

本实验以2010年版《中华人民共和国药典》二部溶出度实验第一法(篮法)为基础综合考虑结肠靶向制剂在体内转运过程中的生理环境和体内影响因素, 采用3步释放度实验法用于评价吲哚美辛结肠靶向迷你片的体外释药行为。

人工胃液(artificial gastric juice,AGJ)、人工小肠液(artificial intestinal juice,AIJ)和人工结肠液(artificial colon juice,ACJ)的配制参照文献[13]方法。

以AGJ 1 000 mL为释放介质,转速100 r·min^-1,依法操作,2 h后取样2 mL,滤过。取续滤液采用高效液相色谱(HPLC)法测定吲哚美辛;弃去AGJ,以AIJ 250 mL为释放介质,转速100 r·min^-1,依法操作,于4,6 h分别取样5 mL,同法测定吲哚美辛释放量;弃去AIJ,以ACJ为释放介质,转速100 r·min^-1,依法操作,于7,8,9,10,12 h分别取样5 mL,同法测定吲哚美辛释放量。

2.2 测定方法研究

2.2.1 色谱条件色谱柱:Hypersil GOLD C₁₈色谱柱(4.6 mm×25.0 mm,5 μm);流动相:乙腈-冰醋酸(0.1 mol·L^-1)(60∶40);检测波长:320 nm;柱温:25 ℃;流速:1.0 mL·min^-1;进样量:20 μL。

2.2.2 线性范围与标准曲线取干燥至恒重的吲哚美辛25 mg,精密称定,置100 mL量瓶中,加入适量流动相,超声溶解,并用流动相稀释至刻度制得储备液。配制吲哚美辛浓度分别为0.2,0.5,1,5,10,20,30,50 μg·mL^-1的系列溶液,以样品浓度(C,μg·mL^-1)为横坐标,样品峰面积(A)为纵坐标,进行线性回归,得到吲哚美辛在3种释放介质中的回归方程为:A=54 036 C+6 340.2, r=0.999 8(AGJ);A=62 553C+8 501.2, r=0.999 6(AIJ); A=63 821C+9 417.5, r=0.999 8(ACJ);吲哚美辛线性范围均为0.2~50 μg·mL^-1。

2.2.3 回收率实验分别用3种释放介质配制吲哚美辛浓度为0.2,25和50 μg·mL^-1,连续测定,计算回收率。AGJ的回收率为:99.41%(RSD=1.62%),99.3%(RSD=1.32%),99.31%(RSD=1.21%);AIJ的回收率为:99.57%(RSD=1.23%),99.49%(RSD=1.06%),99.52%(RSD=1.54%),ACJ的回收率为:99.67%(RSD=1.40%),99.61%(RSD=1.20%),99.83%(RSD=1.25%),均符合要求。

2.2.4 精密度实验分别用3种释放介质配制吲哚美辛浓度为0.2,25和50 μg·mL^-1低、中、高3种浓度的溶液各6份测定,吲哚美辛在AGJ、AIJ、ACJ中日内精密度RSD分别为0.87%,1.81%,1.91%;日间精密度RSD分别为1.28%,1.76%,1.89%,均符合要求。

2.2.5 溶液稳定性考察用3种释放介质分别配置20 μg·mL^-1吲哚美辛溶液,室温下放置12 h,分别于0,2,4,8,10,12 h取样测定,RSD分别为0.29%,0.33%,0.39%,表明放置12 h内药物溶液稳定。

2.3 结肠靶向迷你片的制备

2.3.1 片芯的制备将吲哚美辛固体分散体、乳糖、微晶纤维素(MCC)分别过筛孔内径0.150 mm(100目)筛,并按处方比例混合,并加入1%硬脂酸镁手工混合10 min,使用单冲压片机压制片芯,冲模直径为3.0 mm,片芯质量在(16±1) mg范围内,片剂硬度适当。

2.3.2 壳聚糖层的制备取处方量壳聚糖,溶于处方量5%醋酸溶液中,加入抗黏剂、增塑剂(以下提到的添加剂的用量均为壳聚糖用量为基准的百分数),搅拌均匀备用。将片芯置于包衣锅内,调节包衣锅适当转速,先让片芯在包衣锅中打磨5 min,控制包衣温度在60~70 ℃,然后调节喷液速度,进行包衣。

①包衣液中壳聚糖用量的选择:固定增塑剂柠檬酸三乙酯(TEC)用量为10%,抗黏剂滑石粉用量为20%,分别配制壳聚糖用量为1%,2%,3%的包衣液进行片芯的包衣,以包衣过程中片芯的状态(包衣增重情况、片芯粘连情况、片芯吸水情况)及包衣片外观作为考察指标。结果壳聚糖用量为3%的包衣液黏度很大,包衣过程中会使喷枪堵塞影响包衣进度,且包衣过程中片芯易出现黏连;使用壳聚糖用量为1%的包衣液进行片芯的包衣,片芯包衣增重过于缓慢,且包衣温度相对较高,个别片芯会吸水颜色加深。因此选择壳聚糖用量为2%。

②包衣液中增塑剂TEC用量的选择:固定壳聚糖用量为2%,抗黏剂滑石粉用量为20%,分别配制TEC用量为5%,10%和15%的包衣液进行片芯的包衣,以包衣片在pH值=6.8磷酸盐缓冲液中4 h的累积释放量及随后在CEL中6 h的累积释放量为考察指标。发现包衣膜中TEC用量为10%的包衣片释放效果最好。结果见图1。

图1 不同用量TEC对药物释放率的影响(n=6)

Fig.1 Influence of different dose of TEC on the drug release (n=6)

③包衣液中抗黏剂种类的选择:固定壳聚糖用量为2%,增塑剂TEC用量为10%,分别配制微粉硅胶与滑石粉用量均为20%的包衣液进行片芯的包衣,以包衣片在pH值=6.8磷酸盐缓冲液中4 h的累积释放量及随后在CEL中6 h的累积释放量为考察指标。结果显示滑石粉作为抗黏剂能使药物释放影响更小,见图2。

图2 不同抗黏剂对药物释放度的影响(n=6)

Fig.2 Influence of different antiadherent on the drug release (n=6)

④抗黏剂滑石粉用量的选择:固定壳聚糖用量为2%,TEC用量为10%,分别配制滑石粉用量为10%,20%和40%的包衣液进行片芯的包衣,以包衣片在pH值=6.8磷酸盐缓冲液中4 h的累积释放量及随后在CEL中6 h的累积释放量为考察指标。结果显示滑石粉含量为20%时药物释放度符合要求,滑石粉含量为40%时会引起药物提前释放,见图3。

图3 滑石粉用量对药物释放度的影响(n=6)

Fig.3 Influence of the dose of talcum on the drug release (n=6)

⑤壳聚糖薄膜包衣片包衣增重的选择:固定壳聚糖用量为2%,增塑剂TEC用量为10%,抗黏剂滑石粉用量为20%配制包衣液进行片芯的包衣,制得包衣增重为3%,5%,8%和12%的包衣片。然后进行释放度的测定,发现包衣增重为5%时不会提前释药,也不会出现药物迟释和释放不完全的情况,释放度符合要求,结果见图4。

图4 壳聚糖膜增重对药物释放度的影响(n=6)

Fig.4 Influence of chitosan coating weight on the drug release (n=6)

2.3.3 肠溶层的制备将EudragitFS 30D 加入到适量(约占溶液总体积的20%)纯化水中,搅匀,作为 A 相;在剩余纯化水中加入TEC、滑石粉,搅拌均匀,作为B相。将B相缓缓倾入A相中,室温下搅拌30 min,筛孔内径0.180 mm(80目)筛滤过,得固含量为20%肠溶衣包衣液备用^[13]。采用此包衣液控制包衣温度约在40 ℃,然后调节喷液速度和包衣锅转速,对壳聚糖薄膜包衣片进行二次包衣。

使用“2.1”项下包衣液处方,制得肠溶层包衣增重分别为1%,3%,7%,10%的双层包衣片,以其在SSL中2 h的累积释放量为考察指标。结果除肠溶层包衣增重为1%的双层包衣片在SSL中有药物释放外,其他几种不同肠溶层增重的双层包衣片在SSL中2 h内均不释药。

2.3.4 正交实验根据单因素考察结果,选取对吲哚美辛结肠靶向迷你片质量及药物释放影响较大的崩解剂MCC用量(A)、壳聚糖包衣液中TEC用量(B)及壳聚糖包衣液中滑石粉用量(C)3个因素,按L₉(3³)正交表设计实验,筛选最优处方。

以Y(Y=100-Fa-Fb+Fc)为评价指标,对A、B、C3个因素进行考察。Fa、Fb、Fc分别为药物在SSL中2 h、IBL中4 h和CEL中6 h的累积释放率。Y值越大表示结肠靶向效果越好。对各个因素进行方差分析,通过综合分析筛选出最佳处方。通过极差分析表明,所得优化组合为崩解剂MCC 5%,TEC15%,滑石粉30%。

2.3.5 处方确定取吲哚美辛固体分散体5 mg,加入乳糖7 mg,MCC3 mg,硬脂酸镁1%制备片芯,按照壳聚糖层处方(包衣液浓度为2%,增塑剂TEC 15%,抗黏剂滑石粉30%,包衣增重5%)和肠溶层处方(包衣液固含量为20%,增塑剂TEC 5%,抗黏剂滑石粉40%,包衣增重3%),按照“2.3.2”和“2.3.3”项方法进行包衣,制备3批直径为3.0 mm迷你圆形小片,每批含量均匀度(A+1.80s)分别为2.60,2.65,3.22,符合《中华人民共和国药典》2010年版规定。

2.4 影响因素实验

取自制吲哚美辛结肠靶向迷你小片装胶囊后置于培养皿中。①高温实验:60 ℃放置10 d,于第5和第10天取样进行药物含量检测。②高湿实验:在室温下和相对湿度为92.5%条件下放置10 d,第5和第10天取样进行测定。③强光实验:于照度(4 500±500)lx条件下放置10 d,第5和第10天取样进行测定。各实验条件下的样品的含量和释放度测定结果,在实验期间,所有的考核指标未发生明显变化。

2.5 吲哚美辛结肠迷你片体外释放结果

按照“2.1”项释放度测定方法测定释放度,另配制pH值为7.4的磷酸盐缓冲液代替ACJ作为对照组,同法进行释放度实验。结果见图5。由图5可知,本实验所制备的吲哚美辛壳聚糖结肠靶向迷你片在人工胃液和人工肠液中累积释放量不超过10%,5 h后在人工结肠液中开始缓慢释放,累积释放量均超过90%,在不含结肠内容物的释放介质中没有药物释放,表明壳聚糖层在结肠液环境下的降解作用下,衣膜上生成孔道,随着壳聚糖层的逐渐降解,药物从片芯中释放出来。体外释放实验表明吲哚美辛自制结肠靶向片具有较好的结肠定位特性。

2.6 吲哚美辛结肠靶向迷你片的大鼠体内组织分布

取体质量为190~210 g的Wistar大鼠,大鼠喂食吲哚美辛壳聚糖包衣结肠靶向迷你片(每片1.25 mg,注射用水1 mL送服)和未包衣迷你片,喂药后大鼠正常饮食。分别于给药后1,2,4,5,6,8,10 h后处死每组大鼠3只,打开腹腔,剖开消化道观察有无完整药片存在,然后分离胃、小肠和大肠组织。另取未饲药的大鼠,处死,分离各个组织,用于制备空白组织液。

图5 吲哚美辛结肠靶向制剂的释放曲线(x̅±s,n=6)

Fig.5 Release profile of the colon targeting tablet of indomethacin (x̅±s,n=6)

将大鼠处死,在胃部发现完整的片剂,在小肠中段片剂仍然以完整的形态存在,只是表面层有溶胀现象,在结肠部位未发现片剂,可能是壳聚糖层在酶的作用下降解,片芯暴露后发生崩解,药片已经混入到大鼠粪便中已无法辨别。大鼠口服未包衣迷你片后,在其胃、小肠和结肠组织内均检测到药物(图6),说明片剂在胃部就发生崩解,药物释放吸收入血。大鼠服用壳聚糖包衣的迷你片后,在其胃和小肠内均没有检测到药物,只在结肠组织检测到药物(图6),并且结肠组织内的药物浓度明显高于对照组,说明由于肠溶层和壳聚糖层的保护,吲哚美辛在结肠部位实现了靶向释放,结肠部位的浓度高于普通制剂,对于结肠部位疾病的治疗具有重要意义。

图6 吲哚美辛在大鼠体内的组织分布(x̅±s,n=3) A.未包衣迷你片;B.壳聚糖包衣迷你片

Fig.6 Tissue distribution of indomethacin in rats (x̅±s,n=3) A.uncoated mini tablets;B.chitosan coated mini tablets

精密吸取血浆样品500 μL 置于 10 mL 带刻度的离心管中。加入10%磷酸二氢钾溶液(pH值=3)100 μL后,涡旋震荡1 min。加入二氯甲烷5 mL,于涡旋震荡器上提取1 min。将提取后样品于4 000 r·min^-1离心 10 min。精密吸取下层二氯甲烷溶液置于另一试管中,氮气流吹干。使用流动相200 μL溶解,进样 20 μL。结果见图7,表1。

药物	C_max/(mg·L^-1)	t_max/h	AUC_(0-∞)/(mg·L^-1·h)	MRT_(0-∞)/h	CL/(L·h^-1·kg^-1)
市售制剂	1.40±0.06	16.2±0.50	11.3±1.17	16.6±1.04	2.22±0.25
结肠靶向迷你片	3.25±0.67	2.00±0.01	10.2±0.87	2.82±0.18	2.46±0.20

表1 吲哚美辛制剂在比格犬体内的药动学参数

Tab.1 Pharmacokinetic parameter of indomethacin preparations in beagle dogs x̅±s,n=6

2.7 吲哚美辛结肠靶向迷你片的比格犬体内生物利用度考察

采用两制剂双周期自身交叉实验法,选取6只健康比格犬,随机分成A、B两组,每组3只。实验前14 d未用任何药物,禁食12 h后,A组犬喂食自制吲哚美辛结肠靶向迷你片(实验制剂)20片(每片1.25 mg),B组犬喂食市售吲哚美辛胶囊(参比制剂)1粒(每粒25 mg),均以温水200 mL送服,服药4 h后统一进食,分别于给药前及给药后0.5,1,2,3,4,5,6,7,8,10,12,14,16,18,20,22,24 h由前肢静脉取血3 mL置于含肝素钠的采血管中,4 000 r·min^-1离心15 min,分离血浆,冷冻保存待测。两次给药间隔时间为1周,作为清洗期,1周后A、B两组犬交换服用,同法实验。

图7 两种吲哚美辛制剂在比格犬体内的血药浓度-时间曲线图(x̅±s,n=6)

Fig.7 Concentration-time curve of two indomethacin preparations in Beagle dogs (x̅±s,n=6)

3 讨论

由于肠溶层和壳聚糖层的保护作用,自制吲哚美辛结肠靶向迷你片在通过胃肠道时,药物被保留在片芯,随着肠溶层的溶解和壳聚糖层的溶胀,迷你片达到结肠后,在结肠多种酶的作用下,壳聚糖发生降解反应,原本致密的衣膜上形成了大量释药孔道和裂缝,吲哚美辛才开始释放并吸收入血,并随着时间的延长,衣膜完全降解,药物全部释放出来。因此与普通片相比,靶向迷你片的T_max明显延迟,结果与大鼠体内结果一致,表明本研究所制备的吲哚美辛壳聚糖迷你片具备良好的结肠靶向性。

与市售普通胶囊比较,自制吲哚美辛结肠靶向迷你片的药-时曲线的峰型较钝,体内血药浓度较平稳,推测应是填装到胶囊中的迷你小片到达结肠的时间不同,且在结肠中壳聚糖包衣层的酶解过程较缓慢,导致各个小片开始释药的时间也不尽相同,因此其体内释放是所有迷你片释放效果的综合反映,这也是迷你片多单元制剂的优点所在,通过多个释药单元释药行为的综合,避免一单元制剂可能出现的“全”或“无”的情况,大大增加用药安全性。

本制剂中使用壳聚糖作为结肠靶向材料,因其属于天然多糖类化合物,具有价格低廉、安全无毒、生物相容性优良,降解时只能被结肠菌群所产生的特有糖苷酶系所降解等优点,提高制剂的安全可靠性,降低辅料对人体造成的潜在安全风险^[13] 。吲哚美辛壳聚糖结肠靶向迷你片外层肠溶衣可避免胃酸对内层壳聚糖层的破坏,待药片进入小肠后,肠溶衣逐渐溶解,壳聚糖衣层在小肠中缺乏相应的酶而不会发生水解,进一步保护药物在小肠中不会提前释药,到达结肠后,壳聚糖衣层被结肠中大量存在的酶类水解,片芯崩解,使药物释放出来^[15]。

笔者在本研究设计的多单元给药制剂,将制备的壳聚糖结肠靶向迷你片每20片装入一粒0号普通明胶胶囊中,与普通片剂比较,有一定的优势,如药物服用后可较均匀地分散成多个释药单位,从而减少食物、个体差异和病理条件对制剂的影响,同时避免出现给药“全或无”的现象;在药物到达释药部位后较散的分布可以减轻对结肠的刺激性同时增大吸收面积,有利于药物吸收利用。在制备工艺方面,小片为双层包衣片,与常见的多单元给药系统如微丸比较,制备工艺简单,更有利于工业生产。

The authors have declared that no competing interests exist.

参考文献

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[2]	RAHMAN S, ABDULLAH M, MASUM A A, et al.Formulation and evaluation of bi-layered sustained release matrix tablets of tramadol hydrochloride[J]. J Appl Pharm Sci, 2012,2(6): 129-134. Abstract Bi-layer tablets of tramadol hydrochloride were prepared by direct compression technique incorporating an immediate release layer and a sustained release layer. An immediate release layer was successfully designed to release the bolus dose instantaneously. Water soluble Xanthan gum, water insoluble Kollidon SR and Eudragit L 100 were used as carriers in the sustained release layer of the matrix tablet. All the tablets were evaluated for thickness, diameter, weight variation, hardness and friability. The in vitro drug release was studied for eight hour, first two hours dissolution in acidic medium followed by six hour dissolution in buffer medium. Matrix tablet showed a sustained release rate with a controlled fashion as a function of the quantity of polymer used. The in vitro drug release data were fitted with several mathematical models and mean dissolution time along with fractional dissolution time values (T 25% , T 50% and T 80%) were calculated. Xanthan gum was found to be the most effective rate retarding agent compared to Kollidon SR and Eudragit L 100, when used at same ratio in the formulations. DOI:10.7324/JAPS.2012.2638 URL [本文引用:0]
[3]	ZHANG L, LIU X J, ZHAI G X.Progress on oral colon-specific drug delivery system[J]. Chin J New Drugs Clin Remed, 2011, 30(8): 574-579. Oral colon-specific drug delivery system(OCDDS)has gained increased importance for the delivery of drugs for the treatment of local diseases associated with the colon in recent years.In this article,the recent development of OCDDS was summarized,and in vitro and in vivo evaluation methods were also discussed. URL [本文引用:1]
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[6]	RUJIVIPAT S, BODMEIER R.Improved drug delivery to the lower intestinal tract with tablets compression-coated with enteric/nonenteric polymer powder blends[J]. Eur J Pharm Biopharm,2010, 76(3): 486-492. <p id="sp005">The objective of this study was to develop pH-erosion-controlled compression-coated tablets for potential colonic drug delivery with improved gastric resistance and pulsatile release based on compression-coatings of powder blends of the enteric polymer Eudragit® L100-55 and the extended release polymer ethylcellulose. Tablet cores containing model drugs of varying solubilities (acetaminophen, carbamazepine and chlorpheniramine maleate) were compression-coated with different ratios of Eudragit® L100-55:ethylcellulose 10cP FP at different compression forces and tablet core:compression-coat ratios. The compression-coated tablets were characterized by drug release, media uptake, erosion behaviour and wettability. All drugs were released in a pulsatile fashion in higher pH-media after a lag time, which was controlled by the erosion properties of the Eudragit L:ethylcellulose compression-coating. The addition of ethylcellulose avoided premature drug release in lower pH-media and significantly increased the lag time in higher pH-media because of a reduction in wettability, media uptake and erosion of the compression-coatings. Importantly, ethylcellulose also reduced the pH-dependency of the erosion process between pH 5.5 and 7.4. The lag time could also be increased by increasing the compression force and decreasing the core:compression-coat ratio. In conclusion, tablets compression-coated with blends of Eudragit L and ethylcellulose resulted in excellent release properties for potential targeting to the lower intestinal tract with no release in lower pH-media and rapid release after a controllable lag time in higher pH-media.</p> DOI:10.1016/j.ejpb.2010.09.004 Magsci [本文引用:1]
[7]	GULBAKE A, JAIN S K.Chitosan: a potential polymer for colon-specific drug delivery system[J]. Exp Opin Drug Deliv, 2012, 9(6): 713-729. There is an enormous growth and awareness of the potential applications of natural polymers for colon delivery of therapeutic bioactives. Chitosan (CH), a cationic polysaccharide, has a number of vital applications in the field of colon delivery and has attracted a great deal of attention from formulation scientists, academicians and environmentalists due to its unique properties.CH has been widely explored for the delivery of drugs, peptides, proteins and genes to the colon for different therapeutic applications. Sustained and controlled delivery can be achieved with CH-based formulations like CH-coated tablets, capsules, beads, gels, microparticles and nanoparticles. This review mainly focuses on various aspects of CH-based formulations, particularly development of colon-specific delivery of drug.The vital properties of CH make it a versatile excipient, not only for sustained/controlled release applications but also as biodegradable, biocompatible, bioadhesive polymer. The colon is recognized as the preferred absorption site for orally administered protein and peptide drugs. The main problem associated with CH is limited solubility at higher pH due to reduced cationic nature, which also reduces mucoadhesiveness. The application of newer targeting moiety with CH-based formulations for highly site-specific delivery of bioactive has to be evaluated for further improvement of therapeutic index (bioavailability). DOI:10.1517/17425247.2012.682148 PMID:22530707 URL [本文引用:1]
[8]	PACIFICI G M.Differential renal adverse effects of ibuprofen and indomethacin in preterm infants: a review[J]. Clin Pharmacol,2014, 31(6): 111-116. Abstract Objective The objective of this study was to evaluate the extent of renal adverse effects caused by ibuprofen or indomethacin in order to choose the safer drug to administer to preterm infants. Methods The following three parameters of renal function were taken into consideration: 1) the urine output; 2) the serum creatinine concentration; and 3) the frequency of oliguria. The bibliographic search was performed using PubMed and Embase databases as search engines. Results Urine output ranged from 3.5±1.2 to 4.0±1.4 mL/kg/h after ibuprofen treatment, and from 2.8±1.1 to 3.6±1.4 mL/kg/h after indomethacin treatment. The values for ibuprofen are significantly (P<0.05) higher than those for indomethacin. The serum creatinine concentrations ranged from 0.98±0.24 to 1.48±0.2 mg/dL after ibuprofen treatment, and from 1.06±0.24 and 2.03±2.10 mg/dL after indomethacin treatment. The values for ibuprofen are significantly (P<0.05) lower than those for indomethacin. The frequency of oliguria ranged from 1.0% to 9.6% (ibuprofen) and from 14.8% to 40.0% (indomethacin), and was significantly lower following ibuprofen than indomethacin administration. In infants with body weight lower than 1,000 g, oliguria appeared in 5% (ibuprofen) and 40% (indomethacin; P=0.02). Conclusion Indomethacin is associated with more severe renal adverse effects than ibuprofen. Ibuprofen is less nephrotoxic than indomethacin and should be used to treat patent ductus arteriosus in preterm infants. Immaturity increases the frequency of adverse effects of indomethacin. DOI:10.2147/CPAA.S59376 PMID:25114597 URL [本文引用:1]
[9]	PU Y J.Literature analysis of 137 ADR induced by indometacin oral preparation[J]. China Pharmacy, 2010, 21(36):3435-3436. OBJECTIVE: To analyze the clinical features and correlation factors of ADR caused by Indometacin oral preparation and to provide references for rational use of drugs.METHODS: Retrieved from CBM Database,CNKI and Chinese Periodical Fulltext Database,literatures on ADR caused by Indometacin oral preparation during 1994锝2009 were analyzed.RESULTS: 137 ADR cases were enrolled.The number of male patients was more than female.Main manifestation of ADR were injury of digestive system(26 cases,18.98%),followed by general impairment of body(124 cases,17.52%),injurg of circulatory system(19 case,13.78%)and lesion of skin and its appendants(17 cases,12.40%).The situation of ADR was severe relatively.CONCLUSION: The occurrence of ADR causes by many factors.We should pay attention to f hemorrhage of digestive tract and shock. URL [本文引用:1]
[10]	KUSHWAHA P, FAREED S, NANDA S et al. Design and fabrication of tramadol HCL loaded multiparticulate colon targeted drug delivery system[J]. J Chem Pharm Res, 2011(3): 584-595. The aim of the present study is to develop a multiparticulate system containing pectin microspheres for the colon targeted delivery of Tramdol HCl (TMD) for the treatment of irritable bowel syndrome. This work combines pH-dependent solubility of shellac polymers and microbial degradability of pectin polymers. Pectin microspheres containing TMD were prepared by emulsion cross linking method using different ratios of TMD and pectin (1:2 to 1:5), stirring speeds (500-2000 rpm) and emulsifier concentrations (1.0% - 2.0% wt/vol). The yield of preparation and the encapsulation efficiencies were high for all pectin microspheres. Microspheres prepared by using drug: polymer ratio 1:3, stirring speed 1000 rpm, and 1.25% wt/vol concentration of emulsifying agent were selected as an optimized formulation. Shellaccoating of pectin microspheres was performed by oil-in-oil solvent evaporation method using coat: core ratio (5:1). Microspheres were evaluated for surface morphology, particle size and size distribution, swellability, percentage drug entrapment, and in vitro drug release in simulated gastrointestinal fluids (SGF). The release profile of TMD from Shellac-coated pectin microspheres was pH dependent. In acidic medium, the release rate was much slower; however, the drug was released quickly at pH 7.4. It is concluded from the present investigation that Shellac-coated pectin microspheres are promising controlled release carriers for colon-targeted delivery of TMD. URL [本文引用:1]
[11]	GADALLA H H,SOLIMAN G M,MOHAMMED F A,et al.Development and in vitro/in vivo evaluation of Zn-pectinate microparticles reinforced with chitosan for the colonic delivery of progesterone[J]. Drug Deliv,2016,23(7): 2541-2554. [本文引用:0]
[12]	CHAUDHARY A, TIWARI N, JAIN V,et al.Microporous bilayer osmotic tablet for colon-specific delivery[J]. Eur J Pharm Biopharm,2011, 78(1): 134-140. Microporous bilayer osmotic tablet bearing dicyclomine hydrochloride and diclofenac potassium was developed using a new oral drug delivery system for colon targeting. The tablets were coated with microporous semipermeable membrane and enteric polymer using conventional pan-coating process. The developed microporous bilayer osmotic pump tablet (OPT) did not require laser drilling to form the drug delivery orifice. The colon-specific biodegradation of pectin could form in situ delivery pores for drug release. The effect of formulation variables like inclusion of osmogen, amount of HPMC and NaCMC in core, amount of pore former in semipermeable membrane was studied. Scanning electron microscopic photographs showed formation of in situ delivery pores after predetermined time of coming in contact with dissolution medium. The number of pores was dependent on the amount of the pore former in the semipermeable membrane. In vitro dissolution results indicated that system showed acid-resistant, timed release and was able to deliver drug at an approximate zero order up to 24 h. The developed tablets could be effectively used for colon-specific drug delivery to treat IBS. (C) 2011 Elsevier B.V. All rights reserved. DOI:10.1016/j.ejpb.2011.01.004 Magsci [本文引用:1]
[13]	UR-REHMAN T, TAVELIN S, GROBNER G.Chitosan in situ gelation for improved drug loading and retention in poloxamer 407 gels[J]. Int J Pharm, 2011, 409(1/2) : 19-29. A method for the in situ gelation of poloxamers and the mucoadhesive polymer chitosan has been developed by exploiting the tendency of poloxamer solution to form gel at physiological temperatures and of chitosan (CT) to form ionotropic gel structures in the presence of sodium tripolyphosphate (TPP). Novel poloxamer gels containing CT–TPP complex formed in situ during the administration were prepared by mixing poloxamer–CT and poloxamer–TPP solutions in double syringes. The micellization and gelation of poloxamer 407 in the presence of chitosan and/or TPP were studied using differential scanning calorimetry and tube inversion; both additives were found to reduce the critical micellization temperature and critical gelation temperature of poloxamer aqueous solution. The poloxamer gels containing CT–TPP complex formed in situ were found to exhibit reduced dissolution rate and superior release characteristics with three different drugs – metoprolol, doxycycline and flufenamic acid. Furthermore, by varying the compositions of the two solutions independently, it is possible to control the pH in a way to suit the solubilization of a drug as well as the specific environment of a particular application site. By varying the concentrations of chitosan, TPP and poloxamer, the delivery system can be fine-tuned to afford gels with specific properties, ranging from nanoparticle suspensions to semisolid gels. These in situ gels have the potential to increase the utility of thermo-reversible poloxamers in drug delivery. DOI:10.1016/j.ijpharm.2011.02.017 PMID:21335076 URL [本文引用:2]

Colon-specific delivery of trsveratrol: optimization of multi-particulate calcium-pectinate carrier

2010

... 口服结肠靶向给药系统(oral colon-specific drug delivery system,OCDDS),是一种新型的制剂技术,由于载体材料的特殊性质,可以直接将药物运送到结肠部位,避免在胃、小肠等胃肠道上端崩解或蚀解而释放药物.结肠靶向给药系统将药物运送到结肠处才开始崩解或蚀解并释放药物,可发挥局部或全身治疗作用^[1-3].根据载体材料释药的性质不同,OCDDS主要有pH值依赖型^[4]、时间控制型^[5]、压力控制型^[6]和菌群/酶触发型^[7].其中菌群/酶触型OCDDS因其定位性好、可预测性高等特点,成为广大研究者关注的热点,是近年应用最为广泛的一种口服结肠靶向给药系统.吲哚美辛是最强的环氧化酶(COX)抑制药之一,主要用于急性风湿性及类风湿关节炎,并对结肠癌和直肠癌也有一定的治疗作用.但是吲哚美辛长期服用后药物不良反应(ADR)发生率较高,最常见的是胃肠道ADR,发生率为35%~50%^[8-9].通过先进的制剂手段改善吲哚美辛的溶解性,提高其体内生物利用度,并降低其对胃肠道的刺激,在结肠癌及其其他癌症的临床治疗上具有重要意义. ...

Formulation and evaluation of bi-layered sustained release matrix tablets of tramadol hydrochloride

2012

Progress on oral colon-specific drug delivery system

2011

Formulation and evaluation of diltiazem HCl colon targeted tablets

2013

Optimization of preparation process for pH dependent-time Lag herba euphorbiae humifusae pellets for colon-specific delivery based on artificial neural network and particle swarm optimization algorithm

2012

Improved drug delivery to the lower intestinal tract with tablets compression-coated with enteric/nonenteric polymer powder blends

2010

Chitosan: a potential polymer for colon-specific drug delivery system

2012

Differential renal adverse effects of ibuprofen and indomethacin in preterm infants: a review

2014

Literature analysis of 137 ADR induced by indometacin oral preparation

2010

... 笔者以吲哚美辛为主药,壳聚糖^[10-12]为酶触发型结肠靶向材料,采用pH值依赖和酶触发型原理相结合制备一种多单元结肠靶向迷你片(直径为3 mm的小片),避免采用单一释药原理存在的个体差异影响较大的问题,并且体内外实验均表明具有良好的结肠靶向性,可以为吲哚美辛治疗结肠疾病的制剂研究提供重要参考. ...

Development and evaluation of Zn-pectinate microparticles reinforced with chitosan for the colonic delivery of progesterone

2016

Microporous bilayer osmotic tablet for colon-specific delivery

2011

Chitosan in situ gelation for improved drug loading and retention in poloxamer 407 gels

2011

... 2.3.3 肠溶层的制备将EudragitFS 30D 加入到适量(约占溶液总体积的20%)纯化水中,搅匀,作为 A 相;在剩余纯化水中加入TEC、滑石粉,搅拌均匀,作为B相.将B相缓缓倾入A相中,室温下搅拌30 min,筛孔内径0.180 mm(80目)筛滤过,得固含量为20%肠溶衣包衣液备用^[13].采用此包衣液控制包衣温度约在40 ℃,然后调节喷液速度和包衣锅转速,对壳聚糖薄膜包衣片进行二次包衣. ...

... 本制剂中使用壳聚糖作为结肠靶向材料,因其属于天然多糖类化合物,具有价格低廉、安全无毒、生物相容性优良,降解时只能被结肠菌群所产生的特有糖苷酶系所降解等优点,提高制剂的安全可靠性,降低辅料对人体造成的潜在安全风险^[13] .吲哚美辛壳聚糖结肠靶向迷你片外层肠溶衣可避免胃酸对内层壳聚糖层的破坏,待药片进入小肠后,肠溶衣逐渐溶解,壳聚糖衣层在小肠中缺乏相应的酶而不会发生水解,进一步保护药物在小肠中不会提前释药,到达结肠后,壳聚糖衣层被结肠中大量存在的酶类水解,片芯崩解,使药物释放出来^[15]. ...