Matrix formation in sustained release tablets: possible mechanism of dose dumping

Conditions under which poly(ethyl acrylate, methyl methacrylate) 2:1 (poly(EA-MMA), Eudragit NE) forms a stable matrix were investigated in tablets with diclofenac sodium (DS) as an active substance. DS was granulated with the aqueous polymer dispersion. Granules and/or tablets were cured under various temperature and humidity conditions. A six position rotating disk (200 rpm) apparatus was used for the release studies conducted in 37 degrees C acid then phosphate buffer (0.4 M) pH 6.8 or buffer only as the dissolution media. Morphological characteristics of the tablet surface were observed under SEM. Changes in tablet structure upon curing were evaluated through changes in tablet mechanical characteristics. Modulus of rupture, Young's modulus, AUC, AUC(max), where AUC=AUC(max), were determined by the three-point bending test. Some poorly cured tablets dose-dumped when placed directly into buffer but not if first placed in acid and then buffer. A higher content of polymer in the matrix, led to formation of a stronger polymer network upon higher curing temperature and/or longer curing duration, whereas relative humidity had a minor effect.     

Insulin encapsulation in reinforced alginate microspheres prepared by internal gelation.

Insulin-loaded alginate microspheres prepared by emulsification/internal gelation were reinforced by blending with polyanionic additive polymers and/or chitosan-coating in order to increase the protection of insulin at simulated gastric pH and obtain a sustained release at simulated intestinal pH. Polyanionic additive polymers blended with alginate were cellulose acetate phtalate (CAP), Eudragit L100 (EL100), sodium carboxymethylcellulose (CMC), polyphosphate (PP), dextran sulfate (DS) and cellulose sulfate (CS). Chitosan-coating was applied by using a one-stage procedure. The influence of additive polymers and chitosan-coating on the size distribution of microspheres, encapsulation efficiency and release profile of insulin in simulated gastrointestinal pH conditions was studied. The mean diameter of blended microspheres ranged from 65 to 106 microm and encapsulation efficiency of insulin varied from 14 to 100%, reaching a maximum value when CS and DS were incorporated in the alginate matrix. Insulin release, at pH 1.2, was almost prevented by the incorporation of PP, DS and CS. When uncoated microspheres were transferred to pH 6.8, a fast dissolution occurred, independently of the additive polymer blended with alginate, and insulin was completely released. Increasing the additive polymer concentration in the alginate matrix and/or chitosan-coating the blended alginate microspheres did not promote a sustained release of insulin from microspheres at pH 6.8.     

硝苯地平片剂溶出度的考察

目的考察不同生产企业生产的硝苯地平片剂的体外溶出度。方法分别以0.1 mol.L-1盐酸溶液、人工胃液(不含胃蛋白酶)、pH 4.5醋酸钠缓冲液、pH 6.8磷酸盐缓冲液和蒸馏水为溶出介质,采用紫外分光光度法检查;以质量分数为0.25%十二烷基硫酸钠为溶出介质,采用HPLC法检查,比较不同厂家硝苯地平片剂的体外溶出度。用相似因子法评价硝苯地平片剂在0.1 mol.L-1盐酸溶液、人工胃液(不含胃蛋白酶)、pH 4.5醋酸钠缓冲液、pH 6.8磷酸盐缓冲液和蒸馏水中的溶出行为。结果在质量分数为0.25%十二烷基硫酸钠溶液中,硝苯地平的溶出度在60 min均大于65%,而在其他溶出介质中的溶出度均达不到《英国药典》及《美国药典》中规定的标准。相似因子f2均在50~100之间。结论溶出介质的pH值对硝苯地平的溶出度没有影响。从整体来看,国产硝苯地平片剂的体外溶出行为与国外制剂相比有很大差距。     

Effect of anionic polymers on the release of propranolol hydrochloride from matrix tablets.

Anionic polymers, namely Eudragit S, Eudragit L 100-55, and sodium carboxymethylcellulose, were incorporated into hydroxypropylmethylcellulose (HPMC K100M) to modify the drug release from HPMC matrices. The effects of changing the ratio of HPMC to anionic polymers were examined in water and in media with different pH. The dissolution profiles were compared according to release rates. The interaction between propranolol hydrochloride and anionic polymers was confirmed using the UV difference spectra method. The drug release was controlled with the type of anionic polymer and the interaction between propranolol hydrochloride and anionic polymers. The HPMC-anionic polymer ratio also influenced the drug release. The matrix containing HPMC-Eudragit L 100-55 (1:1 ratio) produced pH-independent extended-release tablets in water, 0.1 N HCl, and pH 6.8 phosphate buffer.     

Electrospun diclofenac sodium loaded Eudragit® L 100-55 nanofibers for colon-targeted drug delivery

Eudragit? L 100-55 nanofibers loaded with diclofenac sodium (DS) were successfully prepared using an electrospinning process, and characterized for structural and pharmacodynamic properties. The influence of solvent and drug content on fiber formation and quality was also investigated. Fiber formation was successful using a solvent mixture 5:1 (v/v) ethanol:DMAc. XRD and DSC analysis of fibers confirm electron microscopic evidence that DS is evenly distributed in the nanofibers in an amorphous state. FTIR analysis indicates hydrogen bonding occurs between the drug and the polymer, which accounts for the molecular integration of the two components. In vitro dissolution tests verified that all the drug-loaded Eudragit? L 100-55 nanofibers had pH-dependent drug release profiles, with limited, less than 3%, release at pH 1.0, but a sustained and complete release at pH 6.8. This profile of properties indicates drug-loaded Eudragit? L 100-55 nanofibers have the potential to be developed as oral colon-targeted drug delivery systems.     

A comparative in vitro assessment of the drug release performance of pH-responsive polymers for ileo-colonic delivery

The aim of this study was to investigate the in vitro dissolution characteristics of pH-responsive polymers in a variety of simulated fluids. Prednisolone tablets were fabricated and coated with the following polymer systems: Eudragit S (organic solution), Eudragit S (aqueous dispersion), Eudragit FS (aqueous dispersion) and Eudragit P4135 (organic solution). Dissolution tests were conducted using a pH change method whereby tablets were transferred from acid to buffer. Three different buffer media were investigated: two compendial phosphate buffers (pH range 6.8-7.4) and a physiological buffer solution (Hanks buffer) with very similar ionic composition to intestinal fluid (pH 7.4). There was considerable drug release from tablets coated with Eudragit P4135 in acid, prompting discontinuation of further investigations of this polymer. Eudragit S (organic solution), Eudragit S (aqueous dispersion) and Eudragit FS on the other hand prevented drug release in acid, though subsequent drug release in the buffer media was found to be influenced by the duration of tablet exposure to acid. At pH 7.4 drug release rate from the polymer coated tablets was similar in the two compendial media, however in the physiological buffer, they were found to differ in the following order: Eudragit S (aqueous dispersion)>Eudragit FS>Eudragit S (organic solution). The results indicate that the tablets coated with the newer Eudragit FS polymer would be more appropriate for drug delivery to the ileo-colonic region in comparison to the more established Eudragit S. More importantly, however, dissolution in the physiological buffer was found to be markedly slower for all the coated tablets than in the two compendial buffers, a result akin to reported slower dissolution of enteric coated tablets in vivo. There is therefore the need to adequately simulate the ionic composition of the intestinal fluid in the dissolution media.     

Design of pH-independent controlled release matrix tablets for acidic drugs

The rate and extent of drug release from most controlled release systems are influenced by the pH of the dissolution medium for drugs with pH-dependent solubility. This dependency of drug release on pH may lead to additional inter- and intra-subject variability in drug absorption. In the present study, a pH-independent controlled release matrix system for acidic drugs was designed by incorporating release-modifiers in the formulation. Controlled release matrix tablets were prepared by compression of divalproex sodium, Methocel K4M and Eudragit E 100 or Fujicalin as the release-modifier. For formulations without any release-modifier, the extent and rate of drug release at pH 6.8 was much higher than that at pH 1.0. Formulations containing Eudragit E 100 provided drug release that was essentially independent of pH. This was achieved because Eudragit E 100 significantly increased the drug release in acidic medium and slightly decreased the release rate at higher pH. The increased release in the acidic medium can be attributed to the elevation of the micro-environmental pH in the swollen polymer gel layer. Formulations containing Fujicalin were less effective than those containing Eudragit E 100. This was attributed to the relative inability to elevate the pH and shorter residence time of Fujicalin in the matrix relative to Eudragit E 100.     

Preliminary assessment of selected methacrylic acid--acrylic acid copolymers as factors buffering triethanolamine interacting with artificial skin sebum

To allow cleaning of sebum ducts for acne prophylaxis the authors suggest use of triethanolamine buffered with anionic polymers of acrylic and methacrylic acid. In these preliminary researches addition of Eudragit L-100, Eudragit L-100-55 or Eudragit S-100 implicates decrease of pH of 1.49% triethahnolamine solution from 10.06 even to 7.20. Triethanolamine penetrates into the artificial skin sebum, gains hydrophylic properties, and reacted sebum increase in volume allowing mechanical remove of lipid bed. The highest triethanolamine penetration and the highest volume increase were observed after application of Eudragit S-100 complexes. Eudragit L-100 and L-100-55 proved milder action. These complexes may be applied for further examinations on acne prevention.     

Physical characterization and dissolution properties of ibuprofen: Eudragit coprecipitates.

Ibuprofen:Eudragit coprecipitates were prepared in 10:3 ratios and their physical properties and related dissolution characteristics were determined. The Eudragit polymers used for the studies were three anionics (Eudragit L100, Eudragit L100-55, and Eudragit S-100), one anionic:cationic mixture used in a 1:1 ratio (Eudragit S100 + E100), and four zwitterionics (Eudragits RL 100, RS 100, RSPM, and RLPM). Physical characterizations were made using qualitative and quantitative X-ray diffractometry, IR spectrophotometry, and differential scanning calorimetry (DSC). Except for Eudragit S100 + E100 coprecipitates, no sizeable interaction at a molecular level was detected between the drug and the polymer. The crystalline structure of the drug was slightly modified in the coprecipitates. Regardless of the lack of interaction, dissolution of ibuprofen was retarded from all the coprecipitates studied (except Eudragit L100), especially in the pH 6.8 to 7.5 media in which the drug is freely soluble. The dissolution rate constants of the coprecipitates, calculated using Higuchi equation, demonstrated that dissolution decreased in the order of anionics greater than zwitterionic greater than anionic + cationic mixtures. The data obtained suggest that the release mechanisms involved are the swelling and slower dissolution of the polymer matrix relative to precipitated ibuprofen. The coprecipitates possess improved flow properties compared with ibuprofen with the exception of Eudragit RLPM and Eudragit RSPM. Eudragit coprecipitates can be useful tools in preparing ibuprofen sustained-release tablets. The coprecipitation technique used is simple and minimizes the use of organic solvents.     

Preparation and in vitro evaluation of mebeverine HCl colon-targeted drug delivery system

Mebeverine HCl is a water soluble drug commonly used to treat irritable bowel syndrome by acting directly on the smooth muscles of the colon. This work was aimed at the formulation and in vitro evaluation of a colon-targeted drug delivery system containing mebeverine HCl. Matrix tablets were prepared using ethyl cellulose (EC), Eudragit RL 100 either solely or in combination by wet granulation technique. Dissolution was carried out in 0.1 N HCl for 2?h followed by pH 6.8 phosphate buffer for eight hours. Uncoated forms released more than 5% drug in 0.1 N HCl therefore, Eudragit L100 was used as a coat. The results indicated very slow release profile. As a result, single retardant was used to prepare the matrix and coated by Eudragit L 100. The matrix containing 7% Eudragit RL 100 and 6% of binder was subjected to further studies to assess the effect of different coats (Eudragit L 100-55 and cellulose acetate phthalate) and different binders (pectin and sodium alginate) on the release profile. Eudragit L 100 and pectin were the best coating agent and binder, respectively. The final formula was stable and it can be concluded that the prepared system has the potential to deliver mebeverine HCl in vivo to the colon.     

Statistical optimization of indomethacin pellets coated with pH-dependent methacrylic polymers for possible colonic drug delivery

The objective of this study was to evaluate the effect of two factors (ratio of Eudragit S100 and Eudragit L100 and the coating level) on indomethacin release from pellets in order to optimize coating formulations for colonic delivery. Coating formulations were designed based on the full factorial design. Two independent variables were the ratio of Eudragit S100:Eudragit L100 (1:4, 1:1 and 1:0) and the level of coating (10%, 15% and 20%, w/w), respectively. The evaluated responses were lag time prior to drug release at pH 6.8 (the time required for drug release up to 2%) and percent of drug release at pH 6.8 in 5h. Polymers were coated onto the pellets containing 20% (w/w) indomethacin, using a fluidized bed coating apparatus. Dissolution test was carried out in media with different pH (1.2, 6.5, 6.8 and 7.2). The dissolution data revealed that the level of coating and the ratio of polymers are very important to achieve optimum formulation. Using responses and resulted statistical equations, optimum formulation consisted of Eudragit S100:L100 in 4:1 ratio and the level of coating (20%) was predicted. Practical results showed that the pellets prepared according to above formulation released no indomethacin at pH 1.2 (simulating stomach pH) and pH 6.5 (simulating proximal part of small intestine pH); drug release was slowly at pH 6.8 (simulating lower part of small intestine pH), but it was fast at pH 7.2 (simulating terminal ileum pH). The results of this study revealed that factorial design is a suitable tool for optimization of coating formulations to achieve colon delivery. It was shown that coating formulation consisted of Eudragit S100:Eudragit L100 in 4:1 ratio at 20% coating level has potential for colonic delivery of indomethacin loaded pellets. The optimized formulation produced dissolution profiles that were close to predicted values.     

Release performance of a poorly soluble drug from a novel, Eudragit-based multi-unit erosion matrix

Mechanisms governing the release of drugs from controlled delivery systems are mainly diffusion, osmosis and erosion. For poorly soluble drugs, the existing mechanisms are limited to osmosis and matrix erosion, that are commonly observed in single unit matrix dosage forms. This study reports formulation and dissolution performance of Eudragit L 100 55 and Eudragit S 100 based multi-unit controlled release system of a poorly soluble thiazole based leukotriene D(4) antagonist, that was obtained by an extrusion/spheronization technique. Effect of triethyl citrate, that was incorporated in the matrix, on the dissolution performance of the drug was also evaluated. In vitro matrix erosion and drug release from the pellets were determined by the use of USP Dissolution Apparatus I, pH 6.8 phosphate buffer, gravimetry and UV spectrophotometry, respectively. Results obtained demonstrated that matrix erosion and drug release occurred simultaneously from the pellets. Pellets eroded with a consequent reduction in size without any change in the pellet geometry for over 12 h. Matrix erosion and drug release followed zero order kinetics. Data obtained strongly suggested a polymer controlled, surface erosion mechanism.     

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.     

自制阿托伐他汀钙片与立普妥的体外溶出行为相似性评价

测定了自制阿托伐他汀钙片与立普妥在水、pH l.2盐酸、pH 4.5乙酸盐缓冲液、pH 6.8磷酸盐缓冲液4种溶出介质中的溶出曲线,并进行相似性评价.结果表明,自制片与立普妥在水、pH 4.5乙酸盐缓冲液、pH 6.8磷酸盐缓冲液中,15min时溶出度均达85％以上,在pH 1.2盐酸中相似因子f2为75.1.提示自制阿托伐他汀钙片与立普妥体外溶出行为相似.     

盐酸洛美沙星分散片体外溶出度测定方法的建立

目的:建立盐酸洛美沙星分散片体外溶出度的测定方法。方法:分别以水、磷酸盐缓冲液(pH6.8)、醋酸盐缓冲液(pH4.0)和盐酸溶液(0.1mol.L-1)为介质,篮法、转速100r.min-1条件下测定盐酸洛美沙星分散片在不同时间点的累积溶出率,采用紫外分光光度法在287nm波长下测定含量,确定溶出度的测定方法。结果:以盐酸溶液(0.1mol.L-1)为介质时,样品溶出更快、更平稳;确定溶出度检查取样时间为15min,限度标准为80%。结论:建立的盐酸洛美沙星分散片的体外溶出度测定方法可行。     

Evaluation of xanthan and highly substituted galactomannan from M. scabrella as a sustained release matrix

A highly substituted galactomannan (G) from Mimosa scabrella Bentham (Man:Gal 1.1:1), isolated from the seeds of a Brazilian leguminous tree and xanthan (X), an exopolysaccharide secreted by Xanthomonas campestris (Keltrol), were evaluated as a hydrophilic matrix system (XG) for controlled release (CR) of diclofenac sodium (DS) in tablets and capsules. The performance of XG (2:1) matrices containing 50 mg (A) or 100 mg (B) of DS was compared with a commercial CR product of DS. The drug release studies were carried out using a dissolution apparatus (paddle method) with gradual increase of pH values, from pH 1.4, to pH 4.0 (after 1 h) and to pH 6.8 (after 2 h). The results suggested the potential of XG systems as release retarding materials, which released 78.6 and 35.1% of drug after 24 h for capsules (A) and tablets (A), respectively. Drug release decreased with the increase of amount of drug and it is dependent of dosage form. Analysis of release data indicate a rather zero-order drug release with the erosion mechanism playing a dominant role.     

Diclofenac sodium loaded-cellulose acetate butyrate: Effect of processing variables on microparticles properties,drug release kinetics and ulcerogenic activity

The aim of this study was to develop and characterize diclofenac sodium loaded-cellulose acetate butyrate microparticles in order to obtain a controlled-release system. The influence of the type of polymer, the volume and composition of the internal phase, drug loading, surfactant concentration and additive added on microparticles characteristics (particle size, encapsulation efficiency, surface morphology and in vitro release profiles) was studied to optimize the microparticles system. The resultant microparticles were evaluated for the recovery, average particle size, drug loading and incorporation efficiency. The microparticles exhibited good flowing nature and compressibility index when compared to pure drug. Dissolution rate of diclofenac sodium in phosphate buffer (pH 6.8) increased with increases in initial drug loading, surfactant concentration and addition of alcohol as co-solvent but decreased with increases in the concentration of additives such as Gantrez® AN or Eudragit S100 in the internal phase. The dissolution data showed a Higuchi diffusion pattern for most of the formulations. About 56–81% reduction in ulcerogenic activity was observed with microparticles containing Eudragit S100 17–25%, based on total polymer concentration, when compared with pure diclofenac sodium.     

Diclofenac sodium loaded-cellulose acetate butyrate: effect of processing variables on microparticles properties, drug release kinetics and ulcerogenic activity

The aim of this study was to develop and characterize diclofenac sodium loaded-cellulose acetate butyrate microparticles in order to obtain a controlled-release system. The influence of the type of polymer, the volume and composition of the internal phase, drug loading, surfactant concentration and additive added on microparticles characteristics (particle size, encapsulation efficiency, surface morphology and in vitro release profiles) was studied to optimize the microparticles system. The resultant microparticles were evaluated for the recovery, average particle size, drug loading and incorporation efficiency. The microparticles exhibited good flowing nature and compressibility index when compared to pure drug. Dissolution rate of diclofenac sodium in phosphate buffer (pH 6.8) increased with increases in initial drug loading, surfactant concentration and addition of alcohol as co-solvent but decreased with increases in the concentration of additives such as Gantrez AN or Eudragit S100 in the internal phase. The dissolution data showed a Higuchi diffusion pattern for most of the formulations. About 56-81% reduction in ulcerogenic activity was observed with microparticles containing Eudragit S100 17-25%, based on total polymer concentration, when compared with pure diclofenac sodium.     

不同载体对缬沙坦纳米骨架载药系统溶出行为和生物利用度影响的研究

目的 通过调节纳米骨架载药系统（NDDS）中载体类型和比例实现对缬沙坦体外溶出和体内生物利用度的调控。方法 以缬沙坦作为模型药物,分别选取酸性敏感材料Eudragit E100（E100）、碱性敏感材料Eudragit L100-55（L100-55）作为载体材料,介孔二氧化硅Sylysia 350（S350）、Aerosil 200（A200）作为纳米骨架,通过调节载体和骨架材料的类型和比例筛选出具有pH 1.2、6.8敏感释放行为的纳米骨架载体处方,考察缬沙坦在pH 1.2、6.8环境中释放和在大鼠体内的药动学行为特征。结果 筛选的pH 1.2敏感释放缬沙坦NDDS处方缬沙坦、S350、E100比例为1∶3∶1,pH 6.8敏感释放缬沙坦NDDS处方为缬沙坦、A200、L100-55比例为1∶1∶3。pH 6.8敏感释放处方可调控缬沙坦在肠道pH 6.8条件下特异性溶出;pH 1.2敏感释放处方在保持缬沙坦在pH 6.8高溶出特性的同时可特异性地提高胃部酸性条件下的药物释放。pH 1.2、6.8敏感释放缬沙坦NDDS均一定程度上改善了缬沙坦的生物利用度,其中pH 6.8敏感释放缬沙坦NDDS提高生物利用度的幅度更高,血药浓度变化比较平缓。结论 NDDS可以调控缬沙坦的体外溶出和生物利用度,有望应用于pH值敏感性难溶药物的递送。     

Preparation and in vitro dissolution profile of zidovudine loaded microspheres made of Eudragit RS 100, RL 100 and their combinations

The objective of present investigation was to evaluate the entrapment efficiency of the anti-HIV drug, zidovudine, using two Eudragit polymers of different permeability characteristics and to study the effect of this entrapment on the drug release properties. In order to increase the entrapment efficiency optimum concentration of polymer solutions were prepared in acetone using magnesium stearate as droplet stabilizer. The morphology of the microspheres was evaluated using a scanning electron microscope, which showed a spherical shape with smooth surface. The mean sphere diameter was between 1000-3000 microm and the entrapment efficiencies ranged from 56.4-87.1%. Polymers were used separately and in combination to prepare different microspheres. The prepared microspheres were studied for drug release behavior in phosphate buffer at pH 7.4, because the Eudragit polymers are independent of the pH of the dissolution medium. The release profiles and entrapment efficiencies depended strongly on the structure of the polymers used as wall materials. The release rate of zidovudine from Eudragit RS 100 microspheres was much lower than that from Eudragit RL 100 microspheres. Evaluation of release data reveals that release of zidovudine from Eudragit RL 100 microspheres followed the Higuchi rule, whereas Eudragit RS 100 microspheres exhibited an initial burst release, a lag period for entry of surrounding dissolution medium into polymer matrix and finally, diffusion of drug through the wall material.