盐酸倍他司汀缓释骨架片的制备及体外释药特性研究

摘 要 目的： 制备盐酸倍他司汀缓释骨架片。方法: 采用亲水性高分子材料HPMC为骨架,制备盐酸倍他司汀缓释片,并用单因素试验考察其释药特征。正交试验优化处方工艺。结果:以60% HPMC K15M为骨架材料,磷酸氢钙为填充剂,用10%PVP的90%乙醇溶液为黏合剂,湿法制粒压片为最佳工艺,片重为500 mg。药物体外释放接近Higuchi模型,能实现药物12 h内缓慢释放。结论: 本品制备工艺简便,具有缓解特性。     

曲尼司特缓释片的制备及其释药影响因素研究

目的 制备了曲尼司特凝胶骨架片。方法 采用HPMC K4M、K15M为凝胶骨架材料，进行了处方研究；通过测定制剂体外释放度，评价了该缓释片处方。结果 曲尼司特缓释片体外释药符合Higuchi方程，其释药速率常数Kr为0．193h^1/2。影响缓释片体外释药的因素有骨架材料的种类、用量、粘合剂的种类和释药介质的pH等。结论 缓释片具有明显的缓释作用，可缓慢释药12h。     

烟酸凝胶骨架缓释片的处方工艺研究

目的:优化烟酸凝胶骨架缓释片处方工艺。方法:采用亲水凝胶骨架材料羟丙基甲基纤维素(HPMC)的2种型号K15M、E15-LV及辅料磷酸氢钙的处方用量为因素设计正交试验,以体外释放度为考察指标,优化烟酸凝胶骨架缓释片的处方,并进行批内和批间体外释放度验证试验。结果:优化处方为HPMC(K15M、E15-LV)分别为4%、40%,磷酸氢钙为25%。所制烟酸凝胶骨架缓释片可持续释药12h,批内释放均一性及批间重现性均良好。结论:所选烟酸凝胶骨架缓释片处方合理,工艺简单。     

星点设计-效应面法优化甘草总黄酮骨架缓释片处方

目的:制备甘草总黄酮骨架缓释片,并对其体外释药情况进行考察。方法:以HPMC K4M、PVP K30及PEG4000为载体材料对甘草总黄酮进行固体分散,加入填充剂后混合压片,以甘草总黄酮的累积溶出率为指标,对甘草总黄酮的体外释药情况进行考察。结果:通过单因素试验结合星点设计实验优选的处方为:HPMC K4M占处方量15.42%,PVP K30占处方量32.65%,PEG4000占处方量14.65%,乳糖为填充剂。制备的甘草总黄酮缓释片释药规律符合Higuchi方程。结论:甘草总黄酮骨架缓释片的处方设计可行,该缓释片在体外12 h内的释药情况良好,将甘草总黄酮进行固体分散后,在水中的溶解度增加,以确保其体外释药完全。     

利格列汀双层缓释片的制备及体外释放研究

目的 制备一种新型利格列汀双层缓释片，并考察其体外释放行为。方法 以羟丙基甲基纤维素（hydroxyl propyl methyl cellulose，HPMC）为骨架材料、黄原胶为黏合剂，采用单因素设计筛选处方，进行利格列汀双层缓释片的制备，并绘制处方在pH 6.80介质中的体外溶出曲线；采用常规Ritger-Peppas、Higuchi、一级、零级释放曲线方程进行拟合，分析样品释药原理。结果 经优化后的样品由含药缓释层和含药速释层构成。缓释层由主成分利格列汀3 mg、缓释骨架材料HPMC（型号：K4M及K100M，用量均50 mg）、填充剂微晶纤维素100 mg、凝胶缓释基质黄原胶15 mg、润滑剂硬脂酸镁1 mg组成；速释层由主成分利格列汀2 mg、填充剂微晶纤维素10 mg、崩解剂交联聚乙烯吡咯烷酮15 mg、润滑剂硬脂酸镁1 mg组成。最终结果与零级释放方程匹配度最高，极具相关性，拟合结果r²无限接近于1。结论 成功制得利格列汀双层缓释片，并实现零级释放。     

酒石酸美托洛尔骨架缓释片的制备及释放度测定

目的：制备酒石酸美托洛尔缓释骨架片。方法：采用亲水性高分子材料HPMC为骨架，制备酒石酸美托洛尔缓释片，采用正交试验法以药物体外释药百分率为指标优选制剂处方。结果：最佳处方为30％HPMC K4M作阻滞剂、淀粉和乳糖（1：1）为填充剂，10％PVP乙醇液为黏合剂，1％硬脂酸镁为润滑剂，采用湿法制粒，压片。结论：本品制备工艺简便，药物体外释放符合Higuchi模型，自制缓释骨架片较市售缓释片具有更好的缓释效果，能维持药物12h内缓慢释放。     

盐酸美金刚缓释片的制备及其体外释放度考察

目的制备盐酸美金刚缓释片,并对其体外释放行为进行考察。方法以HPMC K15M和HPMC K4M为骨架材料压制缓释片。以HPMC(X1)用量和HPMC K15M/K4M用量之比(X2)为考察因素,以盐酸美金刚在2,6和10h的累积释放度Y2h,Y6h,Y10h为考察指标,利用2因素3水平中心复合设计-效应面法优化处方。在4种介质中考察了盐酸美金刚缓释片的体外释药行为。结果最终优化处方中的HPMC用量为片质量的60.0%,HPMCK15M/K4M用量之比为70∶30,所得缓释片在2,6和10h三点的累积释放度符合20%≤Y2h≤30%,40%≤Y6h≤60%和Y10h≥80%的要求,在12h内释放平稳、完全。结论采用中心复合设计-效应面法优化的处方预测性良好,制得的盐酸美金刚缓释片体外释放符合要求。     

阿普唑仑缓释片的处方筛选及体外释放度考察

目的:优选阿普唑仑缓释片处方,并对制剂进行体外释放度考察。方法:以羟丙基甲基纤维素(HPMC)、乙基纤维素、乳糖在处方中的用量百分比及HPMC的规格为考察因素,体外释放度为考察指标,经正交试验优化缓释片最佳处方,并对优化后处方所制制剂进行体外释放度考察。结果:优化处方中HPMC、乙基纤维素和乳糖用量百分比分别为30%、4%、15%,HPMC的规格为K4M;优化后所制制剂可持续释药24h,释药特性符合Higuchi方程。结论:所筛选的阿普唑仑缓释片处方合理并具有体外缓释性。     

乙肝清HPMC K4M/PVP K30骨架缓释片的研制与体外评价

目的进行乙肝清HPMC K4M/PVP K30骨架缓释片的研制与体外评价。方法以中药赶黄草和贯叶连翘的提取物为原料药,以HPMC K4M和PVP K30两种粘度不同,水合行为差异较大的亲水高分子材料联合使用作为骨架材料,制备缓释12 h的"乙肝清骨架缓释片"。以"HPMC+PVP K30"总量在处方中的百分量和HPMC在"HPMC+PVP K30"总量中的百分量为考察因素,通过处方单因素考察和星点设计—效应面法进行优化,得到最佳的制剂处方。并通过均一性实验和体外释药行为研究进行体外评价。结果本片剂优化处方中最低HPMC K4M与PVP K30用量不得低于20%。最佳制剂处方为骨架材料HPMC+PVP K30总量占片剂质量的27.03%,HPMC占HPMC+PVP K30总量的49.04%。本处方具有良好的重现性与稳定性;片剂药物释放符合一级释放模型。结论制备了载药量40%的乙肝清提取物缓释片,并优化得到了其最佳的制剂处方。     

马钱子碱双层渗透泵控释片的研制及处方优化

目的 制备马钱子碱双层渗透泵控释片,通过正交试验优化处方,并探讨最佳处方的释药机制。方法 以累积释放度及释药曲线是否呈线性作为评价指标,单因素试验考察PEO N750、PEO Coagulant和致孔剂PEG 4000用量以及包衣增重对马钱子碱双层渗透泵控释片体外释药情况的影响。设计正交试验优化马钱子碱双层渗透泵控释片处方,并对最佳处方体外释药行为进行模型拟合。结果 正交试验结果表明,PEO N750用量对马钱子碱双层渗透泵控释片体外释药行为有显著性影响（P<0.05）,最佳处方：PEO N750 175 mg,PEO Coagulant 65 mg,PEG 4000用量为11%,包衣增重7%。马钱子碱双层渗透泵控释片最佳处方在12 h内释药速率恒定,12 h内累积释放度达93.14%。结论 研制的马钱子碱双层渗透泵控释片在12 h内具有明显的零级释放特征,可有效控制马钱子碱缓慢、恒速释放。     

正交试验优选盐酸伐昔洛韦缓释片处方

目的:以羟丙甲基纤维素为主要材料,制备盐酸伐昔洛韦水溶性骨架片.方法:通过正交设计优化伐昔洛韦缓释片处方,按中国药典2000年版所载溶出方法的第一法测其释放度.结果:所制备的盐酸伐昔洛韦缓释片优选处方2 h体外累积释放量为24.67%,控制在规定的15%～40%之间,5 h体外累积释放量为69.61%,10 h体外累积释放量在90%以上.结论:经正交设计优化的盐酸伐昔洛韦缓释片处方可行.     

正交试验法优选双氯芬酸锌缓释片处方

目的:以HPMC为主要材料,制备水溶性骨架片缓释片。方法:通过正交设计优化双氯芬酸锌缓释片处方,按中国药典2000年版所载,溶出方法的第一法测其释放度。结果:所制备的缓释片优选处方2h体外累积释放量为24.67%,控制在药典规定的15%~40%之间,5h体外累积释放量为69.61%,10h体外累积释放量在90%以上。结论:经正交设计优化的双氯芬酸锌缓释片处方可行。     

延胡索乙素固体脂质纳米粒缓释片制备及工艺优化

目的：制备延胡索乙素固体脂质纳米粒缓释片，并研究延胡索乙素固体脂质纳米粒缓释片的释药模型和释药机理。方法：乳化-溶剂挥发法制备延胡索乙素固体脂质纳米粒，以乳糖作为冻干剂，羟丙基甲基纤维素（HPMC）为缓释材料进一步制备缓释片。在单因素考察的基础上，设计正交试验优化延胡索乙素固体脂质纳米粒缓释片处方，并对缓释片体外释药模型和释药机理进行探讨。结果：延胡索乙素固体脂质纳米粒缓释片最佳处方为缓释材料HPMC K4M和HPMC K15M比例为1：1，用量为40 mg，PEG 4000的用量为20 mg，硬脂酸镁用量为片芯质量的0.5%。延胡索乙素固体脂质纳米粒缓释片最佳处方的体外释放行为符合Higuchi释药模型，释药方程为：Mt/M_∞=0.286 8 t^1/2-0.073 8（r=0.990 8），12 h内累积释放度为93.56%，缓释片释药机理为扩散和溶蚀共存。结论：制备的延胡索乙素固体脂质纳米粒缓释片，工艺重复性较好，其释药行为符合Higuchi释药模型。     

西罗莫司缓释片的制备及其释药因素考察

目的制备西罗莫司缓释片并对其释药因素进行考察。方法采用羟丙基甲基纤维素（HPMC）为基本骨架材料制备了西罗莫司凝胶骨架片,对影响释药的因素,如采用羟丙基甲基纤维素（HPMC）规格、用量、填充剂种类、致孔剂用量、压片压力及释放介质等进行了考察。结果以30%羟丙基甲基纤维素（HPMC K4M）为骨架材料、2%乳糖为致孔剂、微晶纤维素（MCC）为填充剂时,缓释片呈明显一级释放特征。结论该制剂在体外具有良好的缓释效果,且制备工艺简单易行。     

二甲双胍亚硝胺杂质研究及亲水凝胶骨架材料的筛选

目的 探讨不同亲水凝胶骨架材料与盐酸二甲双胍(metformin hydrochloride,MET)降解生成N-二甲基亚硝胺(N-dimethylnitrosamine,NDMA)之间的相关性,筛选合适的骨架材料用于制备MET缓释片。方法 以高效液相色谱-三重四极杆串联质谱为NDMA监测手段,通过原辅料相容性考察确定产生NDMA风险较低的骨架材料,而后考察溶胀性能,确定溶胀作用与参比制剂相似的骨架材料,将筛选出的骨架材料制备缓释片后考察其体外溶出和剂量倾泻的行为。结果 原辅料相容性考察发现羟丙甲纤维素(hypromellose,HPMC)是引起MET降解产生NDMA的主要原因,并筛选出溶胀作用与HPMC相似的卡波姆,以其为骨架材料制备缓释片可获得与参比制剂相似的溶出曲线,且剂量倾泻风险较低,产品稳定性良好。结论 卡波姆可作为HPMC的替代材料,用于制备MET缓释片。     

Imperatorin sustained-release tablets: <Emphasis Type="Italic">In Vitro</Emphasis> and pharmacokinetic studies

We prepared and evaluated imperatorin (IMP) sustained-release tablets. IMP is an active compound in Angelica dahuricae, a Chinese herbal medicine. We used different polymers, such as hydroxypropyl methylcellulose (HPMC K4M, K15M, and K100M), carbopol 934P, sodium carboxymethyl cellulose (CMC-Na), and their combinations to prepare the matrix tablets and achieve the desired sustained release profile. The in vitro release profiles of these formulations were examined and fit to various kinetic release models. We also tested the effects of polymer combination ratios on the in vitro release rate. In vivo studies were performed for the optimized formulation in six beagle dogs, and pharmacokinetic parameters were compared with plain IMP tablets. IMP sustained-release tablets exhibited a more sustained plasma concentration than the plain tablets, with a relative bioavailability of 127.25%. The in vitro releases rates and in vivo absorption correlated for the initial 8 hours. These results demonstrate that the sustained-release tablet system can effectively control the release of IMP.     

Formulation development and optimization of bilayer tablets of aceclofenac

Objective: The objective of the present study was to develop bilayer tablets of aceclofenac that are characterized by initial burst drug release followed by sustained release of drug.

Methods: The fast-release layer of the bilayer tablet was formulated using microcrystaline cellulose (MCC) and HPMC K4M. The amount of HPMC E4M (X₁) and MCC (X₂) was used as independent variables for optimization of sustained release formulation applying 3² factorial design. Three dependent variables were considered: percentage of aceclofenac release at 1 h, percentage of aceclofenac release at 12 h, and time to release 50% of drug (t_50%). The composition of optimum formulation of sustained release tablets were employed to formulate double layer tablets.

Results: The results indicate that X₁ and X₂ significantly affected the release properties of aceclofenac from sustained release formulation. The double layer tablets containing fast-release layer showed an initial burst drug release of more than 30% of its drug content during first 1 h followed by sustained release of the drug for a period of 24 h.

Conclusion: The double layer tablets for aceclofenac can be successfully employed as once-a-day oral-controlled release drug delivery system characterized by initial burst release of aceclofenac for providing the loading dose of drug.     

Development of gastroretentive drug delivery system for cefuroxime axetil: In vitro and in vivo evaluation in human volunteers

The objective of this investigation was to develop the cefuroxime axetil sustained-release floating tablets to prolong the gastric residence time and compare their pharmacokinetic behavior with marketed conventional tablets (Zocef). The floating tablets were developed using polymers like HPMC K4M and HPMC K100M alone, and polymer combination of HPMC K4M and Polyox WSR 303 by effervescent technique. Tablets were prepared by slugging method and evaluated for their physical characteristics, in vitro drug release, and buoyancy lag time. The best formulation (F10) was selected based on in vitro characteristics and used in vivo radiographic and bioavailability studies in healthy human volunteers. All the formulations could sustain drug release for 12 h. The dissolution profiles were subjected to various kinetic release models and it was found that the mechanism of drug release followed Peppas model. The in vivo radiographic studies revealed that the tablets remained in stomach for 225±30 min. Based on in vivo performance, the developed floating tablets showed superior bioavailability than Zocef tablet. Based on in vivo performance significant difference was observed between C_max, t_max, t_1/2, AUC_0–∞, and mean residence time of test and reference (p<0.05). The increase in relative bioavailability of test was 1.61 fold when compared to reference.