Preparation and Characterization of Metoprolol Controlled-Release Solid Dispersions

In recent years, great attention has been paid to using solid dispersions to make sustained-release drugs. The objective of this study is to produce sustained-release systems of metoprolol tartrate using solid dispersion techniques and to evaluate their physicochemical characteristics. The solid dispersions were produced by melting and solvent methods, containing 7%, 15%, or 25% of the drug and different ratios of Eudragit RLPO and RSPO in ratios of 0:10, 3:7, 5:5, 7:3, and 10:0. Drug release profiles were determined by USP XXIII rotating paddle method in phosphate buffer solution (pH 6.8). XRD, DSC, IR, and microscopic observations were performed to evaluate the physical characteristics of solid dispersions. Results showed that the drug release from dispersions was at a slower rate than pure drug and physical mixtures. Moreover, the formulations containing greater ratios of Eudragit RSPO showed slower release rates and smaller DE_8% but larger mean dissolution time than those containing greater ratios of Eudragit RLPO. Dispersions with particle size of less than 100 μm containing 7% of metoprolol and Eudragit RL:RS 5:5 (solvent method) and those with the ratio of 3:7 (melting method) had similar release pattern to Lopressor® sustained-release tablets by zero-order and Higuchi kinetics, respectively.     

泛昔洛韦缓释微丸的研制

以Eudragit RSPO和RLPO为缓释材料,采用流化床包衣技术制备了泛昔洛韦缓释微丸.采用单因素试验筛选了增塑剂种类及用量、抗黏剂粒度、Eudragit RSPO和RLPO的配比及老化时间.所得优化参数为两种包衣材料配比19∶1,增塑剂为10％聚乙二醇6000,抗黏剂为20％滑石粉(1250目),包衣增重25％,老化12h.所制缓释微丸在1.5 h(0.1 mol/L盐酸)、3h和8 h(pH 6.8磷酸盐缓冲液)的累积释放度分别为10％～30％、30％～70％和70％以上.药动学研究表明,本品与泛昔洛韦普通片相比具有明显的缓释特征.     

Formulation optimization of solid dispersion of mosapride hydrochloride

Mosapride citrate (MSP) is a gastroprokinetic agent that acts as a selective 5-HT₄ agonist and accelerates the gastric emptying, and is used for the treatment of acid reflux, irritable bowel syndrome, and functional dyspepsia. The purpose of this study is to investigate the solid dispersion formulations of MSP with controlled release characteristic using various polymers, elucidate the release mechanism, and characterize the interaction patterns between MSP and polymers. Solid dispersions of MSP with different drug-to-polymer ratios were prepared by a solvent evaporation method and characterized in comparison with the simple physical mixtures. Eudragit RSPO, Eudragit RLPO, hydroxypropylmethylcellulose (HPMC) or Kollidon SR® was used as a controlled-release polymer along with polyvinylpyrrolidone (PVP) as a carrier. Characterization of MSP solid dispersion was performed using thermal analysis (DSC), powder X-ray diffraction (XRD), Fourier transform-infrared (FT-IR) spectroscopy, where the drug was converted from the crystalline state to amorphous state in all polymeric carriers used. In vitro dissolution studies showed that the drug release has been extended up to 24 h by using Eudragit RSPO or HPMC. Moreover, the formulations containing higher polymer content ratio showed better slow-release profile. These results indicate that the solid dispersion formulation containing PVP/Eudragit RSPO or HPMC mixture could serve as a good controlled-release system for MSP.     

酒石酸美托洛尔缓释微丸的制备及处方因素考察

目的：选用Eudragit RS 30 D与Eudragil RL30D两种包衣材料，制备日服2次的酒石酸美托洛尔缓释徽丸，并对其处方因素进行考察。方法：采用Glatt流化床底喷溶液上药法制备载药微丸，考察缓释聚合物Eudragit RS 30D与Eudragit RL 30D的不同质量配比（2：3，7：3和9：1）、聚合物包衣增重（10％，20％和30％）以及增塑利嗣量（10％，20％和40％）和放置时间对药物释放的影响。结果：当Eudragit RS 30D与Eudragit RL 30D的质量比为9：1，聚合物包衣增重为20％，增塑剂用量为20％时，药物的释放行为符合中国药典对缓释制剂释放度的相关规定。结论：通过调整Eudragit RS 30D与Eudragit RL 30D之间的比例，或提高聚合物包衣增重等手段，能使酒石酸美托洛尔载药徽丸具备较理想的缓释效果。     

Influence of formulation and process variables on in vitro release of theophylline from directly-compressed Eudragit matrix tablets

Extended-release theophylline (TP) matrix tablets were prepared by direct compression of drug and different pH-dependent (Eudragit L100, S100 and L100-55) and pH-independent (Eudragit RLPO and RSPO) polymer combinations. The influence of varying the polymer/polymer (w/w) ratio and the drug incorporation method (simple blend or solid dispersion) was also evaluated. Drug release, monitored using the Through Flow Cell system, markedly depended on both the kind of Eudragit polymer combinations used and their relative content in the matrix. Maintaining a constant 1:1 (w/w) drug/polymers ratio, the selection of appropriate mixtures of pH-dependent and pH-independent polymers enabled achievement of a suitable control of TP release. In particular, matrices with a 0.7:0.3 w/w mixture of Eudragit L100-Eudragit RLPO showed highly reproducible drug release profiles, with an almost zero-order kinetic, and allowed 100% released drug after 360 min. As for the effect of the drug incorporation method, simple blending was better than the solid dispersion technique, which not only did not improve the release data reproducibility, but also caused, unexpectedly, a marked slowing down in drug release rate.     

Release modulation of highly water soluble drug using solid dispersion: impact of dispersion and its compressed unit

In present day, availability of various carriers, innovative techniques of production and plenty of solvents support the growth of solid dispersion (SD) technology in pharmaceutical industries to overcome many issues. The present study was aimed to develop SD based sustained release system of Milnacipran HCl (MH). The SD containing ethyl cellulose, Eudragit RLPO and Eudragit RSPO at drug–polymer ratios of 1:1, 1:2, and 1:3 were developed using solvent evaporation technique and different waxes at ratio of 1:1, 1:1.25, 1:1.5 and 1:1.75 with drug were developed by melting method. The physicochemical properties of SD were evaluated using Fourier transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC) and X-ray diffraction (XRD). The desired SD batch was further compressed into tablet unit to achieve predetermined once a day drug release. Tablets prepared were evaluated for physicochemical parameters, in vitro drug release, drug release kinetics and scanning electron microscopy. Out of selected carriers, bees wax had shown maximum release retardation. The results of FTIR, DSC and XRD studies exhibited poor interaction amongst MH–bees wax and retention of crystalline state of MH in SD system. The presence of Benecel^® (HPMC K 200 M; 75 mg) in tablets comprising SD (1:1.25, MH:bees wax) revealed remarkable drug release extension and it was considered an optimal. The later was submitted to short term stability study and its results indicated the stable characteristic of system. Drug release from optimized formulation fitted well into Higuchi model with anomalous diffusion. The compressed unit of SD system of highly water soluble drug can be successful single day regimen.     

布洛芬缓释干混悬剂的制备及大鼠体内药代动学研究

目的 制备布洛芬口服缓释干混悬剂,以期为一些吞咽困难的患者提供自主给药、方便的新剂型.方法 采用湿法制粒技术制备含药微粒,分别以累积释放度、沉降体积比和再分散性为评价指标筛选缓释载体种类及比例、助悬剂种类及用量,制备布洛芬口服缓释干混悬剂,并对其大鼠体内药动学进行研究.结果 布洛芬(ibuprofen,IBU)缓释干混...     

Design,optimization and evaluation of mesalamine matrix tablet for colon drug delivery system

The aim of the present investigation was to develop and evaluate matrix tablet of mesalamine for colonic delivery by using Eudragit RSPO, RLPO and combination of both. The tablets were further coated with different concentration of pH-dependent methacrylic acid copolymers (Eudragit S100), by dip immerse method. The physicochemical parameters of all the formulations were found to be in compliance with the pharmacopoeial standards. The in vitro drug release study was conducted using sequential dissolution technique at pH 1.2 (0.1N) HCl, phosphate buffers pH 6.8 and 7.4, with or without rat cecal content mimicking different regions of gastro intestinal tract. The result demonstrated that the tablet containing Eudragit RLPO coated with Eudragit S100 (1 %) showed a release of 94.91 % for 24 h whereas in the presence of rat cecal content the drug release increases to about 98.55 % for 24 h. The uncoated tablets released the drug within 6 h. The in vitro release of selected formulation was compared with marketed formulation (Octasa MR). In vitro dissolution kinetics followed the Higuchi model via non-Fickian diffusion controlled release mechanism. The stability studies of tablets showed less degradation during accelerated and room temperature storage conditions. The enteric coated Eudragit S100 coated matrix of mesalamine showing promising site specific drug delivery in the colon region.     

阿昔洛韦缓释微丸的研制

目的制备阿昔洛韦缓释微丸,并对其体外释药情况进行研究。方法采用离心造粒技术制备阿昔洛韦素丸,在流化床内采用丙烯酸树脂水分散体对其包衣,制备阿昔洛韦缓释微丸。对包衣材料种类、配比及用量进行选择,对包衣微丸体外释药机理进行研究。结果包衣材料EudragitNE30D与L30D-55质量比为12∶1、增重8%时包衣微丸在pH6.8的磷酸盐缓冲液中呈现良好的缓释效果,体外释药过程基本符合Higuchi方程:Y=0.405+30.021t(r=0.9912)。结论采用离心造粒技术和丙烯酸树脂流化床包衣,成功地制备了阿昔洛韦缓释微丸,其体外释药缓慢、持续、平稳。     

甲磺酸双氢麦角毒碱缓释微丸的研制

目的：制备甲磺酸双氢麦角毒碱缓释微丸,并研究其体外释药情况。方法：采用离心造粒法制备甲磺酸双氢麦角毒碱素丸,在流化床内采用丙烯酸树脂水分散体对其包衣,制备甲磺酸双氢麦角毒碱缓释微丸。用释放度测定法考察影响药物释放的各种因素,研究包衣微丸体外释药机制。结果：所制微丸体外释药过程基本符合Higuchi方程：Y=0．41＋29．22t1/2（r=0．9782）。结论：甲磺酸双氢麦角毒碱缓释微丸体外释药缓慢、平稳。     

Preparation of Eudragit E100 microspheres by modified solvent evaporation method

The objective of this investigation was to develop the hollow microspheres as a new dosage form of floating drug delivery system with prolonged stomach retention time. Hollow microspheres containing ranitidine hydrochloride were prepared by solvent evaporation method using Eudragit RLPO dissolved in a mixture of dichloromethane and ethanol. The maximum yield and drug loading amount of hollow microspheres were 88.45% and 80 +/- 4.0%, respectively. The in vitro release profiles showed that the drug release rate decreased with increasing viscosity of Eudragit RLPO, while diameter of hollow microspheres increased with the increase of drug polymer weight ratio. Hollow microspheres could prolong drug release time (approximately 24 h) and float over stimulate gastric fluid for more than 12 h. These results demonstrated that ranitidine HCl hollow microspheres were capable of sustained delivery of the drug for longer period with increased bioavailability.     

热熔挤出法增加布洛芬的溶出度并掩盖其苦味

目的:制备布洛芬固体分散体,以增加布洛芬的溶出度并掩盖其苦味。方法:取布洛芬原料药与丙烯酸树脂Eudragit EPO,以1∶1.5(w/w)混合,采用热熔挤出法制备布洛芬固体分散体。用差示扫描量热法和粉末X射线衍射法分析布洛芬在Eudragit EPO中的分散状态。测定固体分散体、物理混合物和市售布洛芬片剂的溶出度,并评价布洛芬固体分散体的掩味效果。结果:布洛芬晶体结构的特征峰在差示扫描量热和粉末X射线衍射图中消失。在磷酸盐缓冲液中,固体分散体的溶出速度大于物理混合物和布洛芬片。志愿者对布洛芬固体分散体的味觉评价优于物理混合物和布洛芬原料。结论:热熔挤出法制备的Eudragit EPO固体分散体能增加布洛芬的溶出度,并有明显的掩味效果。     

Iron oxide induced enhancement of mucoadhesive potential of Eudragit RLPO: formulation,evaluation and optimization of mucoadhesive drug delivery system

Objectives: The objective of the study was to investigate the effect of iron oxide in the development of mucoadhesive tablets of cinnarizine using Eudragit RLPO polymer. A simplex lattice design was employed for optimizing the drug delivery system.

Methods: Different concentrations of Eudragit RLPO (X₁), iron oxide (X₂) and PVP K 30 (X₃) were taken as independent variables and mucoadhesive strength, t_50%, t_90%, MDT and tablet tensile strength were the selected response variables. Contour and 3D plots were drawn to portray the relationship between independent and response variables. Ex vivo studies were performed for the determination of mucoadhesive strength of formulated tablets employing texture analyzer. ATR-FTR, DSC and zeta potential determination were conducted for drug-excipient and ionic interaction studies.

Results: Friability, hardness and tensile strength of mucoadhesive tablet formulation were found to be 0.42 ± 0.21%, 3.93 ± 1.57 kg/cm² and 0.65 ± 0.26 mN/m², respectively. Mucoadhesive strength was found to be ranging between 5.75 ± 4.41 and 42.85 ± 3.94 g. Value of release exponent (n) was found to be 0.65 ± 0.22, indicating anomalous drug release behavior from the formulations. Numerical optimization using the desirability approach was employed for developing optimized formulation by setting constraints of the dependent and independent variables. The mucoadhesive tablet formulation composition consisting of 8.58% w/w Eudragit RLPO, 7.02% w/w iron oxide and 7.26% w/w PVP K 30 fulfilled maximum requirements of an optimum formulation with better regulation of the selected constraints.

Conclusions: Eudragit RLPO and iron oxide combination showed high level potential for fabricating gastroretentive as well as mucoadhesive drug delivery systems.     

豆腐果素缓释微丸包衣工艺的研究

分别以Surelease、Eudragit RS30D／RL30D为包衣材料，制备豆腐果素缓释微丸，筛选包衣工艺的优化参数。结果表明，用Surelease、Eudragit两种包衣材料均可得到在12h内缓慢释放的微丸，后者有近1h的时滞。     

Enhanced release of solid dispersions of etodolac in polyethylene glycol

This work examines the release of etodolac from various molecular weight fractions of polyethylene glycol (PEG) solid dispersions. Solid dispersions of etodolac were prepared in different molar ratios of drug/carrier by using solvent and melting methods. The release rate of etodolac from the resulting complexes was determined from dissolution studies by use of USP dissolution apparatus 2 (paddle method). The physical state and drug:PEG interaction of solid dispersions and physical mixtures were characterized by X-ray diffraction (XRD), infrared spectroscopy (IR) and differential scanning calorimetry (DSC). The dissolution rate of etodolac is increased in all of the solid dispersion systems compared to that of the pure drug and physical mixtures. The solid dispersion compound prepared in the molar ratio of 1:5 by the solvent method was found to have the fastest dissolution profile. The physical properties did not change after 9 months storage in normal conditions.     

Formulation and evaluation of a sustained-release tablets of metformin hydrochloride using hydrophilic synthetic and hydrophobic natural polymers

Metformin hydrochloride has relatively short plasma half-life, low absolute bioavailability. The need for the administration two to three times a day when larger doses are required can decrease patient compliance. Sustained release formulation that would maintain plasma level for 8-12 h might be sufficient for daily dosing of metformin. Sustained release products are needed for metformin to prolong its duration of action and to improve patient compliances. The overall objective of this study was to develop an oral sustained release metformin hydrochloride tablet by using hydrophilic Eudragit RSPO alone or its combination with hydrophobic natural polymers Gum copal and gum damar as rate controlling factor. The tablets were prepared by wet granulation method. The in vitro dissolution study was carried out using USP 22 apparatus I, paddle method and the data was analysed using zero order, first order, Higuchi, Korsmeyer and Hixson-Crowell equations. The drug release study revealed that Eudragit RSPO alone was unable to sustain the drug release. Combining Eudragit with gum Copal and gum Damar sustained the drug release for more than 12 h. Kinetic modeling of in vitro dissolution profiles revealed the drug release mechanism ranges from diffusion controlled or Fickian transport to anomalous type or non-Fickian transport. Fitting the in vitro drug release data to Korsmeyer equation indicated that diffusion along with erosion could be the mechanism of drug release.     

pH依赖—缓释型美沙拉秦结肠靶向小丸的制备与体外评价

以肠溶型和渗透型丙烯酸树脂为包衣材料制备ｐＨ依赖－缓释型美沙拉秦结肠靶向小丸,评价其体外释放特性。结果表明,包衣小丸在０．１ｍｏｌ／ＬＨＣｌ中２ｈ几乎不释放药物,在ｐＨ７．５缓冲液中具有较好的缓释作用。在模拟胃肠道各区段最高的和最低的ｐ变化的释放度试验中,均在对应小肠区段时开始缓慢释药。分别有４０％和７０％的药物进入结肠后释放。优于单独的肠溶或缓释制剂。     

Development of Extended-Release Solid Dispersions of Nonsteroidal Antiinflammatory Drugs with Aqueous Polymeric Dispersions: Optimization of Drug Release via a Curve-Fitting Technique

Extended-release solid dispersions of nonsteroidal antiinflammatory drugs were prepared by using aqueous polymeric dispersions of Eudragit RS30D and Eudragit RL30D as the inert carriers. The effects of different polymer ratios of Eudragit RS30D and Eudragit RL30D, different particle sizes, and different combination of various formulations of solid dispersions on the in vitro release kinetics of drugs from the dosage forms were investigated. A computer curve-fitting process was developed to choose the optimum formulation of the solid dispersion with the desired drug release profile. This process might offer the advantages of efficiency and simplicity in the formulation development of extended-release solid dispersions.     

盐酸文拉法辛缓释微丸的制备及体外释放度试验

目的制备盐酸文拉法辛缓释微丸,并对其体外释药行为进行研究。方法先用文拉法辛溶液对空白微丸进行上药,通过EC包衣制得速释微丸,然后用速释微丸为丸芯,用EudragitEudragitNE30D,水分散体为包衣材料制备缓释微丸,再将速释微丸和缓释微丸以1:2的比例混合得到最后的缓释微丸。并分别考察了包衣增重对体外释药行为的影响。结果对制备过程中不同阶段的微丸进行了体外释放研究,表明增重20%,速释微丸和缓释微丸以1:2的比例配比结果最为理想。结论盐酸文拉法辛缓释微丸具有较好的释药性能及良好的缓释效果。     

Design and evaluation of sustained release bilayer tablets of propranolol hydrochloride

The objective of the present research was to develop a bilayer tablet of propranolol hydrochloride using superdisintegrant sodium starch glycolate for the fast release layer and water immiscible polymers such as ethylcellulose, Eudragit RLPO and Eudragit RSPO for the sustaining layer. In vitro dissolution studies were carried out in a USP 24 apparatus I. The formulations gave an initial burst effect to provide the loading dose of the drug followed by sustained release for 12 h from the sustaining layer of matrix embedded tablets. In vitro dissolution kinetics followed the Higuchi model via a non-Fickian diffusion controlled release mechanism after the initial burst release. FT-IR studies revealed that there was no interaction between the drug and polymers used in the study. Statistical analysis (ANOVA) showed no significant difference in the cumulative amount of drug release after 15 min, but significant difference (p < 0.05) in the amount of drug released after 12 h from optimized formulations was observed.