Comparison of novel granulated pellet-containing tablets and traditional pellet-containing tablets by artificial neural networks

Abstract

Novel granulated pellets technique was adopted to prepare granulated pellet-containing tablets (GPCT). GPCT and traditional pellet-containing tablets (PCT) were prepared according to 29 formulations devised by the Design Expert 7.0, with doxycycline hydrochloride as model drug, blends of Eudragit FS 30D and Eudragit L 30D-55 as coating materials, for the comparison study to confirm the superiority of GPCT during compaction. Eudragit FS 30D content, coating weight gain, tablet hardness and pellet size were chosen as influential factors to investigate the properties and drug release behavior of tablets. The correlation coefficients between the experimental values and the predicted values by artificial neural networks (ANNs) for PCT and GPCT were 0.9474 and 0.9843, respectively, indicating the excellent prediction of ANNs. The similarity factors (f₂) for release profiles of GPCT and the corresponding original pellets were higher than those of PCT, suggesting that the excipient layer of granulated pellets absorbed the compressing force and protected the integrity of coating films during compaction.     

Compressibility of floating pellets with verapamil hydrochloride coated with dispersion Kollicoat SR 30 D.

The purpose of this study was to work out a method of compression of floating pellets with verapamil hydrochloride (VH) in a dose of 40 mg. It was assumed that this form should reside in the stomach floating for several hours and gradually release the drug in a controlled way. Compression of pellets into tablets, being a modern technological process, is much more perfect than enclosing them in a hard gelatin capsule. Kollicoat SR 30 D was selected for coating. In experiments three plasticizers were examined-propylene glycol, triethyl citrate and dibuthyl sebecate (all at concentration of 10%). It was found that VH release from pellets coated by the films of the same thickness (70 microm), however, containing plasticizers is considerably different. Pellets were prepared by wet granulation of powder mixture, spheronization of the granulated mass and coating of the cores with a sustained release film. Two kinds of cellulose, microcrystalline and powdered, and sodium hydrocarbonate were the main components of pellet core. Proper pellet coating film thickness, ensuring obtaining desirable VH release profile and flotation effect, was defined. X compositions of tablets with pellets were examined in order to obtain formulation, from which VH release would mostly approximate pellets before compressing. The best formulation was evaluated taking into account the effect of compression force an tablet hardness and friability, and pellet agglomeration and flotation. Tablet cross-section photographs were taken confirming necessary coating film thickness preventing their deformation caused by compressing into tablets.     

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。     

Influence of film additives on stabilizing drug release rates from pellets coated with acrylic polymers.

The objective of this study was to investigate the influence of talc and triethyl citrate (TEC) on stabilizing the drug release rates following curing and storage at elevated temperature of pellets coated with an aqueous acrylic polymeric dispersion. Core pellets containing anhydrous theophylline (20%), microcrystalline cellulose, and polyvinylpyrrolidone were prepared by extrusion-spheronization. The aqueous dispersions were prepared by adding up to 30% TEC as a plasticizer and talc up to 200% as an antiadherent to a mixture of Eudragit RS 30D/RL 30D (95:5). The theophylline pellets were coated in a fluidized-bed coating unit and then cured at elevated temperatures. Theophylline pellets were successfully coated with the Eudragit dispersions that contained up to 200% talc, based on the dry polymer weight, and the coating efficiency was greater than 93%. Our results demonstrated that the polymer, which was plasticized by TEC, was able to function as a film-forming agent for dispersions containing high levels of talc. No sticking of the coated pellets was observed during the coating process or during the curing or equilibrating phase, even with high levels of TEC in the film. The dissolution rate of theophylline from the coated pellets was delayed when the film coating dispersion contained high levels of talc. Additionally, the stability of the drug release profiles from the coated pellets after storage was significantly improved. Furthermore, a modified dissolution testing used to simulate mechanical stresses that may be encountered in vivo showed the film coated pellets would have sufficient strength. The results of this study demonstrated that high levels of film additives in the acrylic dispersion contributed to the stabilization of the drug release rates as well as the reproducibility of the coating process.     

Tableting of coated ketoprofen pellets

Ketoprofen pellets were prepared by the method of extrusion-spheronization, and a film coating of guar gum and Eudragit NE was applied to drug cores using pan technology. In an attempt to design a tablet which, on peroral administration, disintegrates rapidly, releasing intact coated pellets which maintain the integrity of both the cores and their release retarding membrane, Avicel PH101, lactose DT and magnesium stearate were used as excipients to prepare tablets comprising ketoprofen pellets or microcapsules. Preliminary experiments were conducted on uncoated pellets to determine the optimum compression force required to prepare tablets of satisfactory mechanical properties and release profiles. Coated pellets containing ketoprofen were used to investigate the influence of excipients levels. In an attempt to minimize problems associated with blending and segregation of microcapsules and excipients, placebo spheres of Avicel PH101 and lactose DT were produced by the method of extrusion-spheronization. The use of placebo spheres produced tablets with improved drug content uniformity and disintegration time. The tensile strength of such compacts was enhanced by excluding magnesium stearate from the mixes without significant problems of sticking or picking. The use of placebo pellets resulted in significant damage to drug microcapsules, which was attributed to the higher hardness and density of the excipients pellets. The role of membrane coating in protecting the drug core during compression was also evaluated.     

Suitability of κ-carrageenan pellets for the formulation of multiparticulate tablets with modified release

κ-Carrageenan is a novel pelletisation aid with high formulation robustness and quick disintegration leading to fast drug release unlike the matrix-like release from non-disintegrating microcrystalline cellulose pellets. Compression of pellets into tablets is cost effective. The feasibility of formulating multiparticulate tablets with coated κ-carrageenan pellets was investigated. Pellets containing a highly soluble drug in acid, namely bisacodyl and κ-carrageenan or MCC as pelletisation aid were prepared, enteric coated with a mixture of Kollicoat(?) MAE 30 DP and Eudragit(?) NE 30 D and compressed using silicified microcrystalline cellulose as embedding powder. The effect of coating level, type of pellet core, compression force and punch configurations on drug release were studied. A sufficient coating thickness for κ-carrageenan pellets was necessary to obtain multiparticulate tablets with adequate resistance in the acid stage regardless of the compression pressure used. While κ-carrageenan pellets and their tablets released over 80% of the drug during the neutral stage only about 20-24% was released from MCC pellets and their tablets. The type of punches used (oblong or round) did not significantly influence the drug release from the prepared tablets. Moreover, sufficient prolonged release properties were obtained with κ-carrageenan pellets containing theophylline as a model drug and coated with Kollicoat(?) SR 30 D using Kollicoat(?) IR as pore former. A lower coating level and higher amount of pore former were needed in case of theophylline pellets formulated with MCC as pelletisation aid. The sustained release properties of both coated pellet formulations were maintained after compression at different compression pressures.     

复方盐酸伪麻黄碱缓释微丸的制备及其释放度考察

目的制备含萘普生钠和盐酸伪麻黄碱的复方缓释微丸,考察理论聚合物包覆量、抗黏剂用量、热处理时间等因素对盐酸伪麻黄碱缓释微丸释放度的影响。方法采用挤出滚圆法制备萘普生钠速释微丸及盐酸伪麻黄碱含药丸芯,采用丙烯酸树脂水分散体(EudragitRS 30D)流化床包衣技术制备盐酸伪麻黄碱缓释微丸,采用紫外分光光度法测定萘普生钠的含量及溶出度,采用HPLC法测定盐酸伪麻黄碱的含量及释放度。结果萘普生钠、微晶纤维素、硫酸钠质量比为10∶9∶1时,制得的萘普生钠速释微丸圆整度好,脆碎度低,10 min累积释药大于90%;当盐酸伪麻黄碱缓释微丸的理论聚合物包覆量为50%、滑石粉用量为聚合物质量的40%、热处理时间为24 h时,药物释放过程接近零级释药模型。结论所制备的萘普生钠速释微丸及盐酸伪麻黄碱缓释微丸体外释药均符合速释和缓释要求,后者的体外释药过程接近零级释药模型。     

Controlled drug release from pellets containing water-insoluble drugs dissolved in a self-emulsifying system.

The aim of the study was to provide a controlled release system, which could be used for the oral administration of highly water-insoluble drugs. Pellets have been prepared by extrusion/spheronization containing two model drugs (methyl and propyl parabens) of low water solubility. One type of pellets contained the drugs mixed with lactose and microcrystalline cellulose (MCC) and the other types of pellets contained the model drugs dissolved in a self-emulsifying system (4.8%) consisting of equal parts of mono-diglycerides and polysorbate 80 and MCC. Pellets of all types in the same size fraction (1.4-2.0 mm) were coated to different levels of weight gain, with ethylcellulose, talc and glycerol. A sample of pellets containing methyl parabens in the self-emulsifying system was pre-coated with a film of hydroxypropylmethyl cellulose from an aqueous solution and then coated as above. Dissolution experiments established that the presence of the self-emulsifying system enhanced the drug release of both model drugs and that the film coating considerably reduced the drug release from pellets made with just water, lactose and MCC. The coating reduced the drug release from the pellets containing the self-emulsifying system to a lesser extent but in relation to the quantity of coat applied to the pellets. The application of a sub-coating of hydroxypropylmethyl cellulose was able to reduce the release rate of methyl parabens self-emulsifying system ethyl cellulose coated pellets. Thus, the formulation approach offers the possibility of formulating and controlling the in vitro release of water-insoluble drugs from solid oral dosage forms.     

硫酸沙丁胺醇缓释微丸的制备及其释放度研究

目的制备硫酸沙丁胺醇缓释微丸并考察其体外释放度。方法采用流化床底喷包衣技术,在已有处方工艺研究的基础上,进一步考察致孔剂用量及缓释层增重对其释放度影响。用高效液相色谱法测定其释放度。结果致孔剂在缓释层中的用量占该固体总量的0.22%,缓释层增重为8.55%时,所制备微丸的释放度最优,该微丸释药行为符合一级方程。结论方法简单,工艺可行,质量稳定,释放度符合药典规定要求。     

丙烯酸树脂水性包衣工艺制备氯化钾缓释片的研究

目的:研究氯化钾缓释片的优化工艺.方法:采用丙烯酸树脂水性包衣工艺,通过体外溶出试验对工艺参数进行筛选.结果:包衣后热处理、包衣处方因数(聚合物配比、增塑剂、包衣增重等)都对缓释片释放度有影响,而浆法转速和介质渗透压对缓释片释放度几乎无影响.结论:本研究缓释片的体外释放按零级模式释药.     

离心造粒法制备托拉塞米缓释小丸胶囊及其释放度考察

目的:制备托拉塞米缓释小丸胶囊。方法:采用离心造粒粉末层积法制备托拉塞米小丸,用丙烯酸树脂水分散体包衣,并对包衣小丸的释药特征进行探讨。结果:微晶纤维素(MCC)空白母核32～40目的收率约80.2%,含药素丸20～24目收率约87.6%,使用Eudragit NE30D包衣液,包衣增重10%。托拉塞米缓释胶囊体外释药行为较好地符合Higuchi方程。结论:在优化的工艺条件下可制得表面光滑、圆整度高的托拉塞米缓释小丸。     

离心造粒法制备双嘧达莫缓释微丸

目的制备双嘧达莫缓释微丸,考察包衣量对体外释放度的影响。方法采用离心造粒法制备双嘧达莫缓释微丸。结果所得的微丸圆整度良好,Eudragit NE30D包衣增重为7%时,所得微丸表现出缓释特征,相对生物利用度为（104.7±17.2）%,与参比制剂相比吸收程度等效,吸收速度不等效。结论离心造粒法适全双嘧达莫缓释微丸的制备。     

Preparation and evaluation of 1-deoxynojirimycin sustained-release pellets vs conventional immediate-release tablets

1-Deoxynojirimycin sustained-release pellets, which exhibit known release and absorption profiles, are used for the treatment of diabetes mellitus. In this study, a fluidised bed coater was employed to prepare new, drug-loaded pellets. In the dissolution test, it was found that 1-DNJ pellets exhibited a sustained release effect after being coated with hydroxypropyl methyl cellulose phthalate-55?S. For sustained-release pellets and immediate-release pellets, there was significant difference in the mean cumulative drug concentration profile in different media evaluation. In the bioavailability study, the ratio of mean relative bioavailability of the SR pellets to the IR tablets was calculated by the DAS from the AUC_0-24?h of 1-DNJ and was found to be 117.3%. This suggested that the behaviour in vivo of the 1-DNJ SR pellets was superior to the IR tablets, which indicated the designed preparation method of the 1-DNJ SR pellets was acceptable for achieving sustained release of 1-DNJ with enhanced bioavailability.     

离心造粒法制备罗红霉素缓释小丸

目的：制备罗红霉素缓释小丸,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微晶纤维素空白丸核和罗红霉素含药丸芯,以聚丙烯酸树脂Eudragit NE30D为包衣液制成膜控缓释小丸,考察包衣增重、致孔剂用量等因素对缓释小丸释放度的影响。结果：通过单因素考察确定了包衣液处方,所制备的小丸具有明显的缓释特征,体外释药过程符合一级动力学模型。结论：制备的罗红霉素缓释小丸符合12h缓释要求。     

盐酸青藤碱缓释微丸的研制

目的制备盐酸青藤碱缓释微丸,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微晶纤维素空白丸核和盐酸青藤碱含药丸芯,以聚丙烯酸树脂Eudragit NE 30D为包衣液制成膜控缓释微丸,考察包衣增重、抗粘剂用量等因素对缓释微丸释放度的影响。结果通过单因素考察确定了包衣液处方,所制备的微丸具有明显的缓释特征,体外释药过程符合一级动力学模型。结论用聚丙烯酸树脂Eudragit NE30D作为包衣材料所得缓释微丸符合24 h缓释要求。     

酮洛芬缓释胶囊剂制备工艺正交设计实验及其体外释放特性研究

采用小丸包衣工艺,利用正交设计实验对胶囊的处方、工艺进行筛选与优化,制备酮洛芬缓释胶囊,并测定其释放特征。结果表明:以优选的处方和工艺制备的缓释胶囊,体外释药缓释特征明显,持续释药达12h以上。该缓释胶囊处方合理,工艺简单,适合于工业化生产。     

盐酸普拉克索缓释片的制备及其释药性的研究

目的 制备盐酸普拉克索缓释微丸片.方法 采用流化床包衣法制备盐酸普勒克索微丸,再将微丸与一定的辅料昆合后压制成片.利用正交试验确定了微丸的最终处方.结果 最优处方为10％碳酸氢钙用量、3％包衣增重率、25％柠檬酸三乙酯用量.自制缓释微丸片在分割后其释放行为与整片相似.结论 自制缓释微丸片与市售缓释片的释放行为相似.     

西罗莫司单层高分子渗透泵控释片的制备及其体外释放特性研究

目的:制备西罗莫司单层高分子渗透泵控释片并考察其体外释放特性。方法:通过对片芯组成中的释药载体聚氧乙烯(PEO)的分子量、用量,促渗剂种类及氯化钠(NaCl)用量,包衣液中的聚乙二醇400(PEG400)用量,衣膜增重等设计单因素试验进行初步筛选,在此基础上以NaCl用量、衣膜增重、PEG400用量为因素,以释药方程的相关系数r为评价指标设计正交试验,考察并优化制剂处方及工艺,同时对其体外释放特性进行评价。结果:以PEO(Mw20000)30mg、NaCl70mg为片芯辅料,PEG4000.14g为包衣材料,衣膜增重12mg时制得的片剂最优,其零级释放特征显著,r=0.9954。结论:该制剂制备工艺简单,在体外可近恒速缓慢释放药物。     

盐酸文拉法辛缓释片的制备及其家犬体内药动学初步研究

 　目的：研制盐酸文拉法辛(venlafaxine hydrochloride,VH)缓释片,并评价其家犬药动学特性及生物利用度。方法：以Kollidon SR为基本骨架材料制备缓释片芯,用Kollicoat SR 30D包衣混悬液包衣,采用单因素考察法优化VH缓释片。以RP-HPLC测定VH血药浓度,对6只家犬进行药动学和生物利用度初步研究。结果：VH缓释片优化处方中片芯骨架材料为Kollidon SR 80%,以Kollicoat SR 30D包衣混悬液包衣增重为1%时,具有良好的缓释特征;单剂量口服自制VH缓释片与市售VH缓释胶囊的AUC0~36 h分别为(1 107.25±202.85)和(1 172.54±276.05) ng?h?mL-1;Tmax为(7.2±0.8)和(6.7±0.8) h;Cmax为(106.57±19.40)和(102.00±34.00) ng?mL-1;缓释片的相对生物利用度为(96.04±13.20)%。结论：盐酸文拉法辛缓释片具有缓释特征,同市售缓释胶囊生物等效。