改善难溶性药物功效的一种新型给药系统——干酏剂的研究进展

干酏剂是一种将乙醇和药物同时包裹入水溶性聚合物壳内的固态微囊.乙醇的潜溶剂作用及喷雾干燥工艺可能产生的无定形药物,有利于包裹于干酏剂中的水难溶性药物快速分散并溶解于水性介质中,从而提高其溶出速率和生物利用度.本文综合近年来干酏剂研究的主要文献,从干酏剂的制剂成型工艺及机制、对难溶性药物体外溶出、体内吸收及生物利用度的影响,以及基于干酏剂的剂型设计及应用做一综述.     

Evaluation of the sustained release properties of Eudragit RS, RL and S (acrylic resins) microcapsules containing ketoprofen in beagle dogs

Eudragit RS, RS-RL, RL and S microcapsules containing ketoprofen were prepared by the solvent evaporation process in oil phase. The sustained release effect of these microcapsules and Oruvail, the representative commercial product of ketoprofen, was evaluated by the pH shift dissolution method and in beagle dogs, respectively. The dissolution patterns of ketoprofen from Eudragit RS, RS-RL and RL microcapsules were independent of the pH of the dissolution medium, and its dissolution rate increased with increasing content of ketoprofen in microcapsules. But the dissolution pattern of ketoprofen from Eudragit S microcapsules and Oruvail was found to depend on the pH of the dissolution medium. The rank order of the dissolution rate of ketoprofen from Eudragit RS, RS-RL and RL microcapsules containing 30 and 40 per cent (w/w) ketoprofen was sufficiently clear as to enable prediction of the relative bioavailability of ketoprofen from these microcapsules. In vivo evaluation using beagle dogs, sustained release effects of Eudragit RL and Eudragit S microcapsules containing 30 per cent (w/w) ketoprofen and Eudragit RS-RL microcapsules containing 40 per cent (w/w) ketoprofen were almost the same as or slightly superior to that of Oruvail.     

Design and evaluation of sustained release microspheres of potassium chloride prepared by Eudragit.

The aim of the present work was to prepare and evaluate the sustained release of potassium chloride formulations. Eudragit RS and/or RL loaded with potassium chloride microspheres were prepared by a solvent evaporation method. The effect of sustained release of Eudragit microspheres was evaluated by an in vitro dissolution test and in vivo oral absorption study, and the results were compared to a commercial product (Slow-K). The results showed that Eudragit microspheres loaded with potassium chloride can be easily prepared and satisfactory results obtained considering the size distribution and shapes of microspheres by incorporating aluminum stearate. The encapsulation efficiency and loading capacity were about 84-90% and 27%, respectively. Moreover, the Eudragit RS (30-45 mesh) and Eudragit RS/RL (20-30 mesh) microspheres showed a similar sustained release effect of commercial product via in vitro dissolution and in vivo oral absorption study.     

Development of coated nifedipine dry elixir as a long acting oral delivery with bioavailability enhancement

To develop the long acting nifedipine oral delivery with bioavailability enhancement, a nifedipine dry elixir (NDE) containing nifedipine ethanol solution in dextrin shell was prepared using a spray-dryer, and then coated nifedipine dry elixir (CNDE) was prepared by coating NDE with Eudragit acrylic resin. The physical characteristics and bioavailability of NDE and CNDE were evaluated, and then compared to those of nifedipine powder. NDE and CNDE, which were spherical in shape, had about 6.64 and 8.68–8.75 μm of geometric mean diameters, respectively. The amount of nifedipine dissolved from NDE for 60 min increased about 7- and 40-fold compared to nifedipine powder in pH 1.2 simulated gastric fluid and pH 6.8 simulated intestinal fluid, respectively. Nifedipine released from CNDE was retarded in both dissolution media compared with that from NDE. After oral administration of NDE, the C_max and AUC_0→8h of nifedipine in rat increased about 13- and 7-fold, respectively, and the Tmax of nifedipine was reduced significantly compared with those after oral administration of nifedipine powder alone. The AUC_0→8h and T_max of nifedipine in CNDE increased markedly and the C_max of nifedipine in CNDE was significantly reduced compared to those in NDE. It is concluded that CNDE, which could lower the initial burst-out plasma concentration and maintain the plasma level of nifedipine over a longer period with bioavailability enhancement, might be one of potential alternatives to the marketed long acting oral delivery system for nifedipine.     

Influence of an enteric polymer on drug release rates of theophylline from pellets coated with Eudragit RS 30D

The purpose of this research study was to investigate the influence of an enteric polymer on the drug release properties of theophylline pellets coated with Eudragit RS 30D. Theophylline pellets were coated with aqueous colloidal dispersions of Eudragit RS 30D containing various amounts of Eudragit L 100-55. The effect of storage conditions on the release of drug from coated pellets was determined as a function of the pH of the dissolution medium. The results from the dissolution study showed significant changes in the dissolution rate of theophylline from pellets coated with Eudragit RS 30D when cured at 40 degrees C for 4 days. No change in the drug release rate was observed when Eudragit L100-55 was present in the Eudragit RS 30D dispersion. Increasing the ratio of Eudragit L100-55 to Eudragit RS 30D resulted in faster drug release rates from the coated pellets. An increase in the pH of the dissolution medium was found to enhance drug release from the pellets coated with Eudragit RS 30D containing Eudragit L 100-55. Theophylline pellets when coated with Eudragit RS 30D containing the enteric polymer Eudragit L100-55 demonstrated no aging effects when stored at elevated temperatures. The overcoating of the pellets with Eudragit RD 100 did not affect the drug release profiles and prevented the particles from agglomerating during curing and storage.     

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。     

Eudragit FS based colonic microparticls of metoprolol tartrate

Metoprolol, a cardioselective β-blocker, is well absorbed in colon after oral administration with mean elimination half life of 3 h with bioavailability 50% due to extensive first pass effect, thus it was aimed to develop its modified release dosage form to reduce dosing frequency. Metoprolol tartrate loaded Eudragit FS microparticles were formulated using solvent evaporation technique by varying polymer contents and then compressing into tablets. The dissolution test was performed in simulated gastrointestinal fluid. All tabletted microparticles were tested for stability after storage in accelerated conditions. As a result of various analytical tests like FTIR, XRD and DSC analyses, drug was found stable in the microparticles. Metoprolol tartrate loaded Eudragit FS tabletted microparticles were stable in accelerated storage conditions. The release behavior of pH-dependent formulations was affected by the dissolution medium pH and the concentration of polymer used. There was a decrease in drug release rate with the increase in polymer concentration. In vitro drug release data (except test formulation F3) were best fitted to zero order model, which indicated the controlled release nature of formulation, while the Korsmeyer-Peppas model explored that drug release occurred according to case II relaxation transport mechanism (n > 0.89). Based on the results, it can be concluded that Eudragit FS is a suitable polymer to design pH dependent microparticles using solvent evaporation technique for the release of drug in colon and T2 can be considered as an optimum formulation on the basis of model independent (f2 test) kinetic interpretation of dissolution results (f2 < 50 for T2 versus reference).     

A new formulation of controlled release amitriptyline pellets and its in vivo/in vitro assessments

Controlled-release amitriptyline pellets (ATP) were formulated and its oral bioavailability was assessed in human volunteers after oral administration under fasting conditions. Core pellets were prepared using a CF granulator by two different methods (powder layering and solvent spraying) and coated with Eudragit RS or RL 100. Physical characteristics and dissolution rates of core pellets and coated pellets were evaluated to optimize the formulation. Powder layering method resulted in a better surface morphology than solvent spraying method. However, physical properties of the products were poorer when prepared by powder layering method with respect to hardness, friability and density. The dissolution profile of amitriptyline coated with Eudragit RS 100 was comparable to that of commercially available amitriptyline enteric-coated pellets (Saroten retard). After the oral administration of both products at the dose of 50 mg, the mean maximum concentrations (Cmax) were 36.4 and 29.7 ng/mL, and the mean areas under the concentration-time curve (AUC(0-96)) were 1180.2 and 1010.7 ng.h/mL for ATP and Saroten retard, respectively. The time to reach the maximum concentrations (Tmax) was 6 h for both formulations. Statistical evaluation suggested that ATP was bioequivalent to Saroten retard.     

国产右旋布洛芬缓释胶囊在大鼠体内的药动学及生物利用度研究

目的 考察自制和市售右旋布洛芬缓释胶囊在大鼠体内的药动学性质与生物等效性.方法建立反相高效液相色谱法,测定右旋布洛芬在血浆中的浓度,进行药动学和相对生物利用度研究.结果自制和市售右旋布洛芬缓释胶囊的主要药动学参数C_max分别为(1 173.87±281.68),(1 186.06±268.79) μg.mL^-1;AUC_(0-t)分别为(4 276.53±578.59),(4 489.83±645.73) mg.L^-1.h;AUC_(0-∞)分别为(5 095.58±683.82),(5 466.37±753.35) mg.L^-1.h;t_max分别为(1.33±0.26),(1.58±0.49) h;各参数间比较差异无统计学意义(P>0.05),以AUC_(0-∞)计算自制右旋布洛芬缓释胶囊的相对生物利用度为(93.2±12.5)%.结论自制右旋布洛芬缓释胶囊与市售制剂之间生物等效.     

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 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.     

Properties of tablets containing granulations of ibuprofen and an acrylic copolymer prepared by thermal processes.

The objective of this study was to investigate the properties of tablets containing granulations of ibuprofen (Ibu) and Ammonio Methacrylate Copolymer, Type B (Eudragit RS PO) prepared by hot-melt processing. Tablets were compressed from granules prepared by hot-melt granulation (HMG) or direct compression (DC). For the hot-melt extrusion (HME) process, tablets were prepared by cutting the extrudate, manually. The physicochemical properties of tablets were investigated using thermal analysis, powder X-ray diffraction analysis, tablet hardness, and drug dissolution. The effect of thermal treatment of tablets on the dissolution characteristics of Ibu was also investigated. The results demonstrated that the Ibu lowered the glass transition temperature (Tg) of the Eudragit RS PO and the softened polymer functioned as a thermal binder in the granulation. Ibu was demonstrated to be an effective plasticizer for Eudragit RS PO in the thermal processes. The efficiency of the granulation process increased with increasing levels of Eudragit RS PO in the powder blend. Higher levels of Eudragit RS PO in the tablets prepared by HMG or HME resulted in a decrease in the dissolution rate of the Ibu. An increase in the amount of Ibu in the tablets prepared by HMG or DC led to a decrease in the initial dissolution rate of the Ibu. Following the thermal treatment of the Ibu tablets prepared by HMG, the dissolution rate was significantly decreased due to structural changes in the tablets that resulted from the fusion and coalescence of plasticized polymer particles, causing a reduction in tablet porosity. The Ibu tablets prepared by HME demonstrated minimal changes in their release properties following thermal treatment even at temperatures higher than the Tg of the polymer. HME was shown to be a novel method to prepare matrix tablets and stable dissolution properties were obtained when tablets were stored at 40 degrees C for 30 days.     

Non-traditional plasticization of polymeric films

The objective of this study was to investigate the influence of methylparaben, ibuprofen, chlorpheniramine maleate and theophylline on the thermal and mechanical properties of polymeric films of Eudragit RS 30 D. The effects of methylparaben and ibuprofen in the film coating on the rate of drug release from Eudragit RS 30 D coated beads were also studied. The physical and mechanical properties of the cast films and coated beads were investigated using thermal analysis, tensile testing, X-ray diffraction analysis and dissolution testing. The results demonstrated that the glass transition temperature of the Eudragit RS 30 D decreased with increasing levels of methylparaben, ibuprofen and chlorpheniramine maleate in the film. Theophylline exerted no influence on the thermal properties of the polymer. The higher levels of the ibuprofen and methylparaben incorporated into the film resulted in a decrease in the tensile strength of the film. The decrease in Young's modulus of Eudragit RS 30 D coated beads was attributed to an increase in the flexibility of the polymeric films when the level of methylparaben or ibuprofen in the polymeric dispersion was increased. The dissolution data demonstrated that the rate of release of the ibuprofen from coated beads was decreased by increasing the amount of ibuprofen and methylparaben in the polymeric film coating.     

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/in vivo evaluation of sustained-release metformin hydrochloride pellets.

In this study, metformin hydrochloride (MH) sustained-release pellets were successfully prepared by centrifugal granulation. Seed cores preparation, drug layering, talc modification and coating of polymeric suspensions were carried out in a centrifugal granulator. Talc modification was performed before coating in order to overcome the high water solubility of metformin. The influence of surface modification by talc, the effects of Eudragit types and ratios, as well as the correlation between in vitro release and in vivo absorption were investigated in detail. Experimental results indicated that talc modification made a decisive contribution to controlling the drug release by avoiding drug dumping. Three dissolution media: 0.1 M HCl, distilled water and pH 6.8 phosphate buffer were employed to determine the in vitro release behaviors of the above metformin hydrochloride pellets. The relative bioavailability of the sustained-release pellets was studied in 12 healthy volunteers after oral administration in a fast state using a commercially available immediate release tablet (Glucophage) as a reference. Following coating with a blend of Eudragit L30D-55 and Eudragit NE30D (1:20), at 7% or 10% coating level, respectively (referred to as F-2, F-3), the pellets acquired perfect sustained-release properties and good relative bioavailability. The Cmax, Tmax and relative bioavailability for F-2 and F-3 coated pellets were 1.21 microg/ml, 6 h, 97.6% and 1.65 microg/ml, 8 h, 165%, respectively. Combined use of two Eudragit polymers with different features as coating materials produced the desired results. Restricted delivery of metformin hydrochloride to the small intestine from differently coated pellets resulted in increased relative bioavailability and a sustained release effect. The adoption of several different pH dissolution media established a better relationship between the in vitro release and in vivo absorption of the sustained-release pellets.     

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。     

Properties of Tablets Containing Granulations of Ibuprofen and an Acrylic Copolymer Prepared by Thermal Processes

The objective of this study was to investigate the properties of tablets containing granulations of ibuprofen (Ibu) and Ammonio Methacrylate Copolymer, Type B (Eudragit RS PO) prepared by hot-melt processing. Tablets were compressed from granules prepared by hot-melt granulation (HMG) or direct compression (DC). For the hot-melt extrusion (HME) process, tablets were prepared by cutting the extrudate, manually. The physicochemical properties of tablets were investigated using thermal analysis, powder X-ray diffraction analysis, tablet hardness, and drug dissolution. The effect of thermal treatment of tablets on the dissolution characteristics of Ibu was also investigated. The results demonstrated that the Ibu lowered the glass transition temperature (T_g) of the Eudragit RS PO and the softened polymer functioned as a thermal binder in the granulation. Ibu was demonstrated to be an effective plasticizer for Eudragit RS PO in the thermal processes. The efficiency of the granulation process increased with increasing levels of Eudragit RS PO in the powder blend. Higher levels of Eudragit RS PO in the tablets prepared by HMG or HME resulted in a decrease in the dissolution rate of the Ibu. An increase in the amount of Ibu in the tablets prepared by HMG or DC led to a decrease in the initial dissolution rate of the Ibu. Following the thermal treatment of the Ibu tablets prepared by HMG, the dissolution rate was significantly decreased due to structural changes in the tablets that resulted from the fusion and coalescence of plasticized polymer particles, causing a reduction in tablet porosity. The Ibu tablets prepared by HME demonstrated minimal changes in their release properties following thermal treatment even at temperatures higher than the T_g of the polymer. HME was shown to be a novel method to prepare matrix tablets and stable dissolution properties were obtained when tablets were stored at 40°C for 30 days.     

Combination of time-dependent and pH-dependent polymethacrylates as a single coating formulation for colonic delivery of indomethacin pellets

The objective of this study was to evaluate the combination of pH-dependent and time-dependent polymers as a single coating for design of colon delivery system of indomethacin pellets. Eudragit S100 and Eudragit L100 were used as pH-dependent polymers and Eudragit RS was used as a time-dependent polymer. A statistical full factorial design was used in order to optimize formulations. Factors studied in design were percent of Eudragit RS in combination with Eudragit S and L and coating level. Dissolution studies of pellets in the media with different pH (1.2, 6.5, 6.8 and 7.2) showed that drug release in colon could be controlled by addition of Eudragit RS to the pH-dependent polymers. The lag time prior to drug release was highly affected by coating level. With combination of two factors, i.e. the percent of Eudragit RS and coating level, the optimum formulation was found to be the one containing 20% Eudragit RS, 64% Eudragit S and 16% Eudragit L, and a coating level of 10%. This formulation was reproduced and tested in continuous condition of dissolution, and also separately at pH 7.5. The results of in vitro experiments indicate that the proposed combined time-dependent and pH-dependent polymethacrylate polymer coating may provide a colonic delivery system for indomethacin.     

丙烯酸聚合物包衣制备控释微丸

以渗透性丙烯酸聚合物（EudragitRS)为包衣材料制备盐酸地尔硫Zhuo控释微丸,体外释放度呈零级释放,释药速率常数为0.0635h^-1。释放度符合美国药典XXⅢ版规定,微丸经3个月加速试验。质量稳定。     

Relationship of film properties to drug release from monolithic films containing adjuvants.

The rate of drug release from a polymeric matrix system was influenced by the physical and chemical properties of the monolithic films. The model drugs, salicylic acid and chlorpheniramine maleate, and two poly(methyl methacrylate) copolymers of different permeabilities (Eudragit RL and Eudragit RS), with and without additional adjuvants, were used to form monolithic matrix films for controlled drug release. Adjuvants, including polyethylene glycols (PEG 400 and PEG 8000) and poly(vinylpyrrolidones) (PVP-K15 and PVP-K90), were incorporated into films of Eudragit RL PM and Eudragit RS PM. The moisture permeation constant, glass transition temperature (Tg), tensile strength, and drug release profiles were determined for each acrylic resin slab to correlate the physicochemical and physicomechanical film properties to observed drug release. Faster rates of drug diffusion were observed with the addition of PEG 400 to the films, because of its plasticizing effect and the resultant increased moisture permeability of the matrix. An exception existed with the Eudragit RL PM film containing salicylic acid where drug-polymer interactions inhibited drug diffusion. The small changes in moisture permeability, Tg, and tensile strength observed with incorporation of the PVPs had an insignificant influence on the dissolution results for salicylic acid from Eudragit RS PM films. Increases in the tensile strength and Tg after addition of PVP to the Eudragit RS PM matrix support the observed decreased rate of diffusion for chlorpheniramine maleate. The pores formed by migration of the hydrophilic adjuvants from the films altered the diffusion kinetics of the matrix, compared with that of the nonporous polymer, when only the antihistamine was present.