Quality by design, part II: application of NIR spectroscopy to monitor the coating process for a pharmaceutical sustained release product

Ammonio methacrylate copolymers are commercially available as Eudragit RL/RS; they differ in the degree of quaternary ammonium group substitution, which gives them different permeabilities. These closely related polymers can be combined in various ratios to control release rate; consequently, release rate is controlled by the polymer composition and coating thickness. Therefore, predicting drug release from methacrylate copolymers using near infrared spectroscopy (NIRS) can be technically difficult. Thus, the objective of this study is to use NIRS to develop multivariate calibration models to predict tablet coat thickness and release rate for tablets coated with varying polymer ratios. A series of sustained release orbifloxacin formulations were developed with varying polymer ratios. Partial least squares (PLS) models were developed to predict coat thickness; samples from these formulations were pooled and a combined calibration was generated. To assess dissolution, tablets were coated using Eudragit RL and RS with ratios of 0:5, 1:4, 2:3, 3:2, 4:1, and 5:0. The amount released at set time-points was used to build PLS models. For the first time, NIRS has been successfully used to monitor Eudragit polymer coat thickness and drug release from tablets coated with various RL:RS ratios, which demonstrates the potential of NIRS as tool for coating process.     

Preparation and in vitro evaluation of slow release ketoprofen microcapsules formulated into tablets and capsules

Abstract

Ketoprofen powder was encapsulated with Eudragit RL/RS polymer solutions in isopropanol-acetone 1:1, using a simple and rapid method. Microcapsules were prepared using Eudragit solutions with different RL/RS ratios. The encapsulation process produces free-flowing microcapsules with good drug content and marked decrease in dissolution rate. The retardation in release profile of ketoprofen from microcapsules was a function of the polymer ratio employed in the encapsulation process. In vitro release of ketoprofen from microcapsules either filled in gelatin capsules or compressed into tablets, using calcium sulphate as diluent, confirmed the efficiency of the encapsulation process for preparing prolonged release medication. A capsule formulation with optimum sustained-release profile was suggested.     

磷酸川芎嗪丙烯酸树脂水分散体包衣小丸的体外释放研究

目的：研究磷酸川芎嗪丙烯酸树脂水分散体包衣缓释小丸的体外释药。方法：采用丙烯酸树脂RS30D和丙烯酸树脂RL30D混合液包衣制备磷酸川芎嗪缓释小丸，并考察包衣混合液中两种丙烯酸树脂水分散体比例、包衣增重、溶出介质pH对磷酸川芎嗪包衣制剂体外释药的影响。结果：随着包衣液中丙烯酸树脂RL30D/丙烯酸树脂RS30D比例增大、包衣增重降低、溶出介质pH增大，释药速率加快。结论：包衣液中丙烯酸树脂RL30D/丙烯酸树脂RS30D比例、包衣增重、溶出介质pH均显著影响制剂药物释放。     

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.     

Optimization of methacrylic acid ester copolymers blends as controlled release coatings using response surface methodology

The aim of this study was to statistically optimize the use of blends of methacrylic acid ester copolymers with different permeability properties as controlled-release coating systems for tablets to produce predictable predesigned release profiles. A full factorial design was used to study and optimize the use of methacrylic acid ester copolymers Eudragit RS 30D and Eudragit RL 30D as coating materials for controlled release. Directly compressed theophylline tablets were coated with aqueous dispersions containing different proportions of the two copolymers using a side-vented coating pan (Accela Cota). The effect of polymer loading level at 5, 7.5, and 10% weight gain and curing time at 50 degrees C for 12 and 24 hours were also evaluated. Coated tablets were tested for their drug release in water using a United States Pharmacopeia (USP) dissolution apparatus #2. The results showed that increasing the content of the lower permeability copolymer Eudragit RS 30D, increasing the polymer load, and increasing curing time at 50 degrees C resulted in slower drug release. A statistical model that describes and predicts the drug release properties of the coated tablets as a function of the copolymers ratio in the coating dispersion, polymer load, and curing time at 50 degrees C was developed. The most significant factor affecting drug release was found to be the ratio of the two copolymers in the coating dispersion followed by the curing time at 50 degrees C and the polymer loading level. Good correlations were observed between the model fitted values andthe experimental values. An optimized formula prepared by superimposing two-dimensional contour plots was prepared; its release profile was found to be in agreement with the prediction obtained from the model.     

Permeability and swelling studies on free films containing inulin in combination with different polymethacrylates aimed for colonic drug delivery.

The aim of this study was to assess some permeability and swelling characteristics of free films prepared by combination of inulin as a bacterially degradable system and time- or pH-dependent polymers as a coating formulation for colonic drug delivery. Different free films were prepared by casting and solvent evaporation method. Formulations containing inulin with Eudragit RS, Eudragit RL, Eudragit RS-Eudragit RL, Eudragit FS and Eudragit RS-Eudragit S with different ratios of inulin were prepared. After preparation, free films were evaluated by water vapor transmission test, swelling experiment and permeability to indomethacin and theophylline in different media. Formulations containing Eudragit FS had high resistance to water vapor permeation; but were unable to protect premature swelling and drug release in simulated small intestine media. Also, combination of Eudragit RS and Eudragit S had no suitable characteristics for colon delivery. However, Eudragit RS and Eudragit RL in combination with inulin made free films which had more swelling and permeation of drug in the colonic medium rather than the other media. It was shown that formulations containing sustained release polymethacrylates in combination with inulin have more potential as a coating system for specific colon delivery compared with pH-dependent polymers.     

Thermal treating as a tool for sustained release of indomethacin from Eudragit RS and RL matrices

Eudragit RS and RL are biocompatible non-swelling polymers that widely used in the preparation of sustained release drug delivery systems. In this study, the effect of thermal treating on the tensile strength of tablets and release of indomethacin from Eudragit RS and RL matrices were investigated. The results showed that thermal treating at 40 degrees C has no effect on the release of the drug, whereas heat-treating at temperatures higher than 50 or 60 degrees C decreases the release rate of indomethacin from Eudragit RS or RL, respectively. It was shown that the duration of the heat treatment was also an important factor in controlling the release rate of indomethacin from Eudragit matrices. The results showed that an increase in the duration of the heat treatment from 2 to 24 h resulted in a reduction in the release rate of the drug. The heating of the matrices over 24 h had no significant effect on the release rate of indomethacin. It was shown that heat treatment of the matrices over the glass transition temperature of the polymer can prolong the drug release but had no significant effect on the tensile strength of tablets.     

快速崩解茶碱包衣小丸骨架片的研制

用挤出／滚圆法以茶碱主模型药物研制快速崩解包衣小丸骨架片,以Ｅｕｄｒａｇｉｔ ＮＥ３０Ｄ或ＲＬ／ＲＳ３０Ｄ为包衣材料,用底喷式流化床包衣,再压制成骨架片,对包衣材料的种类、压片辅料的组成和用量,压片力等因素进行了考察优化,得到了符合美国药典释放度要求的包衣小丸骨架片。     

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.     

Preparation and in vitro evaluation of slow release ketoprofen microcapsules formulated into tablets and capsules.

Ketoprofen powder was encapsulated with Eudragit RL/RS polymer solutions in isopropanol-acetone 1:1, using a simple and rapid method. Microcapsules were prepared using Eudragit solutions with different RL/RS ratios. The encapsulation process produces free-flowing microcapsules with good drug content and marked decrease in dissolution rate. The retardation in release profile of ketoprofen from microcapsules was a function of the polymer ratio employed in the encapsulation process. In vitro release of ketoprofen from microcapsules either filled in gelatin capsules or compressed into tablets, using calcium sulphate as diluent, confirmed the efficiency of the encapsulation process for preparing prolonged release medication. A capsule formulation with optimum sustained-release profile was suggested.     

An Investigation into Formulation and Processing Strategies to Drive Gastroretention of Gabapentin Tablets

Purpose

The aim of the present work was to develop gastroretentive drug delivery system of gabapentin from different matrices prepared by hot melt or conventional wet granulation, which may enhance drug bioavailability. The influence of core type, granulation process, and coating level on the drug release rates was investigated.

Methods

Tablet cores were prepared from hydrophilic system of hypermellose, carboxy melthyl celloulse, and Avicel or hydrophobic system of ethyl cellulose, alginic acid, and stearic acid. The tablets were coated by Eudragit RL with triethyl citrate and compressed directly. These tablets were evaluated according to their in vitro dissolution profiles and release mechanisms.

Results

Hydrophobic matrices allowed the control of drug release. Hot melt granulation was an effective tool over wet granulation or coating for slowing release rates from hydrophobic tablets. Both hydrophobic polymer ratio and coating level influenced the drug release mechanism. The drug release of samples with minor proportion of ethyl cellulose and stearic acid or low Eudragit RL level was driven by anomalous transport and the increase of their proportions contributed to the erosion of the matrix.

Conclusions

Hydrophobic core tablet prepared from hot melt granulation and coated by Eudragit RL has shown to be a promising formulation intended to gastroretentive gabapentin delivery system.

     

氯化钾缓释片的处方工艺研究

目的尝试用骨架与膜衣相结合的方法对水易溶性药物释放速度的控制 ,调整体外释药行为 ,应用EUDRAGIT系列辅料进行氯化钾控释片的研究。方法用RSPO和NE 30D与KCl压制成水不溶蚀性骨架片 ,再用RL10 0 ,RS10 0包衣制得。结果体外释放度研究表明其释药行为是 :第2 ,4 ,6h的溶出量分别为标示量的 2 0 %～ 4 0 % ,30 %～ 6 0 % ,75 %以上。结论水易溶性药物 ,通过骨架和膜衣双重控制 ,体外释药行为效果较好     

The Influence of Buffer Species and Strength on Diltiazem HC1 Release from Beads Coated with the Aqueous Cationic Polymer Dispersions,Eudragit RS,RL 30D

Purpose. Eudragit RL and RS 30D are pseudolatexes frequently used in the coating of solid dosage forms. They are based on cationic copolymers stabilized with quaternary ammonium groups (poly(ethylacrylate-methylmethacrylate-trimethylammonioethyl methacrylate chloride). A pH-independent drug release is expected because of the quaternary nature of the cationic groups. The objective was to explain a distinct “pH-dependent” drug release in various buffer media with coated diltiazem beads. Methods. The diltiazem HC1 release from and water uptake of Eudragit RS/RL-coated beads was determined in various buffers of different buffer species, pH or concentration. Results. The drug release in the different buffer media was in the following order: pH 5.0 acetate > pH 3.5 formate > pH 7.4 phosphate buffer > 0.1M HC1). This “pH-dependent” drug release could be explained with an anion exchange process; the chloride counterions of the quaternary groups were exchanged with the anionic buffer species during the dissolution study. The water uptake of the coated beads correlated well with the drug release from the beads. Increasing the buffer strength (acetate buffer) first increased and then decreased the drug release, while increasing the ionic strength of different buffers with NaCl decreased the drug release and eliminated the observed buffer effects because of the excess of chloride ions. Conclusions. The anionic buffer species and not the pH had a significant effect on the hydration and hence on the drug release from beads coated with the cationic polymers, Eudragit RS and RL.     

氯化钾缓释片处方和工艺的优化

目的采用中心组合设计法优化氯化钾缓释片的处方。方法以EudragitRS100,RL100为缓释包衣材料,包复在以聚维酮为骨架的氯化钾片芯外,制成氯化钾缓释片。本试验将氯化钾缓释片在2,4,8h时的累积体外药物释放百分数为优化目标值,即因变量;以包衣液中聚合物EudragitRS100和EudragitRL100的比例和包衣用量为自变量,采用2因素5水平中心组合设计,试验结果进行多元线性回归,通过重叠等值线图法选取优化处方,并对预测值进行实验验证。结果优化处方为包衣材料RS100与RL100的配比为57∶43,包衣增重为2%~2.5%。结论用中心组合设计法优化处方和工艺,具有高效率、简便、预测性好的优点,能定量地揭示制剂工艺或组分各因素与制剂性质之间的关系,经验证,释放度预测值和实测值非常接近,证明以该法优化的处方是科学和可靠的。     

Design and study of ibuprofen disintegrating sustained-release tablets comprising coated pellets.

One challenge in tableting of sustained-release multiparticulates is maintaining the desired drug release after compaction. The aim of this study was to design sustained-release ibuprofen tablets which upon oral ingestion rapidly disintegrate into sustained-release pellets in which the integrity of the pellet core and/or coat is preserved. First free films composed of Eudragit RS 30D and RL 30D in 4:1 ratio and containing different levels of triethyl citrate (TEC) were prepared and tested to optimize the plasticizer level. Cured Eudragit based pellets with 60% ibuprofen loading which in our previous study showed proper mechanical properties for compression were coated with Eudragit RS 30D/RL 30D (4:1) containing 20% triethyl citrate at different coating levels. The mechanical properties of the coated pellets were tested. Polymer coated pellets were compacted into tablets either alone or with a blend of excipients comprising Avicel, PEG 4000, cross-linked PVP. A 3(2) full factorial design was used to optimize the filler blend composition. Effects of pellet to filler ratio, compression force and granulation of filler on tablet characteristics were investigated. Results of mechanical test showed that the coating of cured pellets had no significant effect on yield point and elastic modulus of the pellets. In the case of 5% coating level sustained release of ibuprofen over a period of 24h was achieved. The results obtained from tableting procedure showed that by selecting suitable filler blend (60% Avicel, 10% cross-linked PVP and 30% PEG 4000), compression force, and granulation of filler it was possible to prepare sustained-release tablets containing high ratio of coated pellets (even 80%) with desirable strength, disintegration time, and drug release rate. It was observed that compression force, pellet to filler ratio, composition of filler blend and granulation of fillers had no effect on drug release rate from compacted pellets but had significant influence on tablet strength, friability, and disintegration time. SEM graphs and in vitro release profiles for compacted pellets showed no apparent damage to the coated pellets as a result of the compaction process.     

Eudragit®: a technology evaluation

Introduction: Eudragit is the brand name for a diverse range of polymethacrylate-based copolymers. It includes anionic, cationic, and neutral copolymers based on methacrylic acid and methacrylic/acrylic esters or their derivatives.

Areas covered: In this review, the physicochemical characteristics and applications of different grades of Eudragit in colon-specific/enteric-coated/sustained release drug delivery and taste masking have been addressed.

Expert opinion: Eudragits are amorphous polymers having glass transition temperatures between 9 to > 150^oC. Eudragits are non-biodegradable, nonabsorbable, and nontoxic. Anionic Eudragit L dissolves at pH > 6 and is used for enteric coating, while Eudragit S, soluble at pH > 7 is used for colon targeting. Studies in human volunteers have confirmed that pH drops from 7.0 at terminal ileum to 6.0 at ascending colon, and Eudragit S based systems sometimes fail to release the drug. To overcome the shortcoming, combination of Eudragit S and Eudragit L which ensures drug release at pH < 7 has been advocated. Eudragit RL and RS, having quaternary ammonium groups, are water insoluble, but swellable/permeable polymers which are suitable for the sustained release film coating applications. Cationic Eudragit E, insoluble at pH ≥ 5, can prevent drug release in saliva and finds application in taste masking.     

硝苯地平膜控型控释微丸的制备及体外评价

目的研究硝苯地平(NF)膜控型24 h控释微丸的处方与工艺,并考察其体外释放特性。方法采用液相层积、丸芯上药法制备载药速释微丸,以Eudragit RL100、RS100为包衣材料,流化床悬浮包衣法制备膜控型控释微丸,并对影响微丸释放的处方因素进行了考察。通过与市售渗透泵片拜新同的体外释放度的对比研究,探讨硝苯地平膜控型控释微丸的体外释药特征。结果调整Eudragit RL100、RS100的比例、衣层厚度、致孔剂的用量,可以改变药物的释放速率。当Eudragit RL100、RS100的比例为3∶7,包衣增重为6%时,制备的控释微丸体外释药与市售渗透泵片相似(f2=62.8),具有良好的零级释放特性。结论以丸芯上药法,Eudragit RL100、RS100为控释材料制备的NF膜控型控释微丸,具有良好的零级释放特性,结果可为硝苯地平多单元控释制剂的研究开发提供参考。     

Quality by design, part III: study of curing process of sustained release coated products using NIR spectroscopy

This study investigated the potential of near infrared spectroscopy (NIRS) to assess film coat curing for tablets coated with methacrylate copolymers. The ability of NIRS to monitor film coat curing was studied and compared to conventional methods like differential scanning calorimetry (DSC) and hot-stage microscopy (HSOM). This study showed that variation in the curing temperature and duration affected the NIR spectra for all formulations. These results and the DSC and HSOM results showed that the spectral changes are due to polymer curing. In addition, glass beads, theophylline and orbifloxacin tablets were coated using Eudragit RL, RS, and L 30-D with varying ratios. Principal component analysis (PCA) was performed on the NIR spectra to investigate the effect of curing time and temperature on cast films, uncoated tablets, coated tablets and coated glass beads. Score plots showed that curing duration and temperature affected coated glass beads, uncoated and coated tablets significantly. The amount of drug released at 250 min, and the NIR spectra of cured tablets were used to develop and validate a 7-factor partial least square (PLS) regression calibration for theophylline tablets coated with Eudragit RL:RS 30-D (1:4). This study demonstrated the potential of NIRS in film coat curing and release monitoring.     

不同包衣条件下银杏缓释微丸体外释放考察

目的考察不同包衣条件下银杏缓释微丸的体外释放。方法采用单因素考察及正交设计法。结果以丙烯酸树脂EudragitRL30D和EudragitRS30D为包衣材料,质量比为4∶1,包衣增重10 % (w) ,增塑剂的用量为2 0 % (w ) ,无需熟化,可满足2 4h缓释的要求。结论包衣量、衣膜中两种丙烯酸树脂的配比和包衣温度是影响药物释放的关键因素     

Central composite design for the formulation and optimization of a multi-unit potential colonic drug delivery system of budesonide for ulcerative colitis

Budesonide is a potent glucocorticoid with high affinity for the glucocorticoid receptor, which is used for the treatment of inflammatory bowel diseases. Current oral formulations of budesonide present low efficacy against ulcerative colitis because of the premature drug release in the upper part of the gastrointestinal tract. The objective of this study was to develop a colon specific delivery system for budesonide to increase the efficacy in the treatment of ulcerative colitis using a statistical procedure. Pellets were prepared by powder layering of budesonide on nonpareils (0.5-0.6 mm) in a coating pan. Drug-layered pellets were coated with an inner layer of a combination of Eudragit RL PO and RS PO and an outer layer of Eudragit FS in a fluidized-bed apparatus. Central composite design was used to study the effect of three independent variables. The independent variables selected were amount of Eudragit FS outer coating (X1), proportion of Eudragit RL PO in the inner coating (X2), amount of Eudragit RL PO-RS PO inner coating (X3). Fifteen batches were prepared and evaluated for amount of drug released in 6 h (Y1), amount of drug released in 12h (Y2). The proportion of the more hydrophilic polymer Eudragit RL PO had the most significant effect on drug release - higher proportion gave faster release; the amount of inner and outer coat did not have a significant effect on the rate of drug release at either 6 or 12 h in the range studied. The computer optimization process and contour plots predicted the levels of independent variables X1, X2, and X3 (0.79, 0.69 and 0.35 respectively), for colon targeting.