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。     

Mechanical Properties of Dry and Wet Cellulosic and Acrylic Films Prepared from Aqueous Colloidal Polymer Dispersions Used in the Coating of Solid Dosage Forms

The mechanical properties of dry and wet polymeric films prepared from various aqueous polymeric dispersions were evaluated by a puncture test. They were studied with respect to type of polymer dispersion [cellulosic: Aquacoat and Surelease; acrylic: Eudragit NE, L, RS, and RL 30 D], plasticizer type (water-soluble or water-insoluble), drying or curing conditions, method of film preparation (pseudolatex- vs solvent casting) and ratio of Eudragit RS/RL 30 D in mixed Eudragit RS/RL films. Dry and wet mechanical strengths of the polymeric films depended primarily on the types of the colloidal polymer dispersion and the plasticizer. Films prepared from ethylcellulose dispersions resulted in very weak and brittle films when compared to the acrylic films. Pseudolatex-cast ethylcellulose films showed lower puncture strength and elongation values when compared to those of the solvent-cast films. Curing of the pseudolatex-cast ethylcellulose films had minimal effects on their mechanical properties. Eudragit L 30D, an enteric polymer dispersion, resulted in brittle films in the dry state, but in very flexible films in the wet state because of the plasticization effect of water. Wet Eudragit RS 30 D polymer films plasticized with water-insoluble plasticizers were significantly more flexible than the corresponding wet films plasticized with water-soluble plasticizers. The water-soluble plasticizers leached from the films during exposure to the aqueous medium, while the water-insoluble plasticizers were almost completely retained within the wet films. The low permeability of a water-soluble drug, chlorpheniramine maleate, and the weak mechanical properties of Aquacoat films could suggest osmotic driven/rupturing effects as the release mechanisms from Aquacoat-coated dosage forms.     

Comparison of physicomechanical properties of films prepared from organic solutions and aqueous dispersion of Eudragit RL

BACKGROUND AND THE PURPOSE OF THE STUDY: Mechanical properties of films prepared from aqueous dispersion and organic solutions of Eudragit RL were assessed and the effects of plasticizer type, concentration and curing were examined. METHODS: Films were prepared from aqueous dispersion and solutions of Eudragit RL (isopropy alcohol-water 9:1) containing 0, 10 or 20% (based on polymer weight) of PEG 400 or Triethyl Citrate (TEC) as plasticizer using casting method. Samples of films were stored in oven at 60°C for 24 hrs (Cured). The stress-strain curve was obtained for each film using material testing machine and tensile strength, elastic modulus, %elongation and work of failure were calculated. RESULTS AND MAJOR CONCLUSION: The films with no plasticizer showed different mechanical properties depending on the vehicle used. Addition of 10% or 20% of plasticizer decreased the tensile strength and elastic modulus and increased %elongation and work of failure for all films. The effect of PEG 400 on mechanical properties of Eudragit RL films was more pronounced. The differences in mechanical properties of the films due to vehicle decreased with addition of plasticizer and increase in its concentration. Curing process weakened the mechanical properties of the films with no plasticizer and for films with 10% plasticizer no considerable difference in mechanical properties was observed before and after curing. For those with 20% plasticizer only films prepared from aqueous dispersion showed remarkable difference in mechanical properties before and after curing. Results of this study suggest that the mechanical properties of the Eudragit RL films were affected by the vehicle, type of plasticizer and its concentration in the coating liquid.     

Tackiness of acrylic and cellulosic polymer films used in the coating of solid dosage forms.

The objective was to determine the tackiness of acrylic and cellulosic polymer films in order to make predictions on the tackiness (agglomeration) of coated dosage forms during coating and curing. Force-displacement curves of the detachment process of two polymeric films were used as a measure of tackiness. Various polymers (cellulosic (Aquacoat and acrylics (Eudragit RS 30D, L 30D, NE 30D)), plasticizers (triacetin, triethyl citrate, tributyl citrate, acetyltributyl citrate) and anti-tacking agents (talc and glyceryl monostearate) were investigated. The order of tackiness for films prepared from the different aqueous polymer dispersions was in order of Eudragit NE 30D > RS 30D > RL 30D > Aquacoat. The tackiness increased with increasing plasticizer concentration due to the softening of the polymer. A correlation between the minimum film formation temperature and the tackiness was observed, however, no correlation between the tackiness and the lipophilicity of the plasticizer was seen. Talc and glyceryl monostearate (GMS) reduced the tackiness of the films significantly, with GMS being effective at much lower concentrations. Curing of Eudragit RS 30D-coated theophylline beads at temperatures higher than 40 degrees C in an irreversible agglomeration of the beads and damage of the coating upon separation of the beads. This resulted in a faster release than with uncured beads. Blending the beads with talc just prior to the curing step eliminated the agglomeration and therefore film damage, even at a curing temperature of 60 degrees C.     

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.     

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.     

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.     

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。     

顶喷式流化床包衣效果的影响因素研究

选择平均粒径为250μm的石英砂作为模型,分别用Eudragit NE30D水分散体与Eudragit RL乙醇溶液包衣,用正交设计考察流化床顶喷过程中各因素对包农效果的影响.结果表明,用Eudragit NE30D水分散体包衣时,包衣液流速和雾化压力对包衣效果影响较大,用Eudragit RL乙醇溶液包衣时则是增塑剂浓度的影响较大.     

Preparation and in vitro evaluation of Eudragit microspheres containing acetazolamide

The aim of this study was to prepare and evaluate Eudragit (RS and RL) microspheres containing acetazolamide. Microspheres were prepared by solvent evaporation method using acetone/liquid paraffin system. The influence of formulation factors (stirring speed, polymer:drug ratio, type of polymer, ratio of the combination of polymers) on particle size, encapsulation efficiency and in vitro release characteristics of the microspheres were investigated. The yields of preparation and the encapsulation efficiencies were high for all formulations the microspheres were obtained. Mean particle size changed by changing the polymer:drug ratio or the stirring speed of the system. Although acetazolamide release rates from Eudragit RS microspheres were very slow and incomplete for all formulations, they were fast from Eudragit RL microspheres. When Eudragit RS was added to Eudragit RL microsphere formulations, release rates slowed down and achieved the release profile suitable for peroral administration.     

Influence of selected surfactants on the tackiness of acrylic polymer films

Anti-tacking agents are always necessary in polymeric film coating formulations in order to prevent substrate agglomeration. The objective of this study was to investigate the abilities of certain nonionic surfactants in a group of sorbitan ester in reducing the tackiness of the films obtained from aqueous acrylic polymer dispersions (Eudragit), compared with those of talc and glyceryl monostearate (GMS). The results from the peel tests demonstrated that GMS, Span 60 and Span 40 could significantly reduce the tackiness of both Eudragit NE 30D and Eudragit RS 30D films. The mechanisms in reducing the film tackiness were investigated by analyzing the film compositions, using attenuated total internal reflectance infrared spectroscopy (ATR-IR) and optical microscopy. The storage modulus of the films was also examined. The results indicated that GMS, Span 60, and Span 40 could reduce the film tackiness by decreasing the polymer contents at the film surfaces, resulting in a notable reduction in the contact area of the polymers between the surfaces. The use of only 5% (w/w) of either GMS, Span 60 or Span 40 in the coating formulations is enough to prevent pellet agglomeration without adverse effects on film flexibility. The pellets coated with Eudragit RS 30D/RL 30D (9:1, w/w) did not exhibit any difference in the drug release profiles when either 100% (w/w) talc or 5% (w/w) GMS was used, whereas the formulations containing Span 60 or Span 40 gave a slightly faster release rate.     

Effect of formulation variables on in vitro drug release and micromeritic properties of modified release ibuprofen microspheres

Modified release microspheres of the non-steroidal anti-inflammatory drug, ibuprofen, were formulated and prepared using the emulsion solvent diffusion technique. The contribution of various dispersed phase and continuous phase formulation factors on in vitro drug release and micromeritic characteristics of microspheres was examined. The results demonstrated that the use of Eudragit RS 100 and Eudragit RL 100 as embedding polymers modified the drug release properties as a function of polymer type and concentration. Eudragit RS 100 retarded ibuprofen release from the microspheres to a greater extent than Eudragit RL 100. The drug/polymer concentration of the dispersed phase influenced the particle size and drug release properties of the formed microspheres. It was found that the presence of emulsifier was essential for microsphere formation. Increasing the concentration of emulsifier, sucrose fatty acid ester F-70, decreased the particle size which contributed to increased drug release properties. Scanning electron microscopy revealed profound distortion in both the shape and surface morphology of the microspheres with the use of magnesium stearate as added emulsifier. The application of an additional Eudragit RS 100 coat onto formed microspheres using fluid bed technology was successful and modulated the drug release properties of the coated microspheres.     

Effect of formulation variables on in vitro drug release and micromeritic properties of modified release ibuprofen microspheres.

Modified release microspheres of the non-steroidal anti-inflammatory drug, ibuprofen, were formulated and prepared using the emulsion solvent diffusion technique. The contribution of various dispersed phase and continuous phase formulation factors on in vitro drug release and micromeritic characteristics of microspheres was examined. The results demonstrated that the use of Eudragit RS 100 and Eudragit RL 100 as embedding polymers modified the drug release properties as a function of polymer type and concentration. Eudragit RS 100 retarded ibuprofen release from the microspheres to a greater extent than Eudragit RL 100. The drug/polymer concentration of the dispersed phase influenced the particle size and drug release properties of the formed microspheres. It was found that the presence of emulsifier was essential for microsphere formation. Increasing the concentration of emulsifier, sucrose fatty acid ester F-70, decreased the particle size which contributed to increased drug release properties. Scanning electron microscopy revealed profound distortion in both the shape and surface morphology of the microspheres with the use of magnesium stearate as added emulsifier. The application of an additional Eudragit RS 100 coat onto formed microspheres using fluid bed technology was successful and modulated the drug release properties of the coated microspheres.     

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。     

银杏内酯缓释微丸的制备及释放度研究

目的制备可4种成分同步释放的银杏总内酯缓释微丸,并对其体外释放进行评价。方法以Eudragit RS 30D/RL 30D为包衣材料,制备银杏内酯缓释微丸,以银杏内酯A、B、C和白果内酯为指标进行体外释放度评价,高效液相色谱法进行含量测定,筛选优化包衣处方及工艺参数。结果当EudragitRS 30D和RL 30D的比例为8∶2,增塑剂和抗黏剂的用量分别为20%和50%、包衣增重为10%时,制备得到的微丸可实现4种成分同步12 h缓释释放。结论本研究微丸制备工艺快速、简便、高效,适合工业化生产。     

Influence of fumed silicon dioxide on the stabilization of Eudragit RS/RL 30 D film-coated theophylline pellets

The objective of this study was to investigate the influence of various grades of fumed silicon dioxide on the drug release rate and physical aging of theophylline pellets coated with Eudragit RS 30 D and RL 30 D. Free films were assessed for both physicomechanical properties and water vapor permeability with respect to time and storage conditions. The release rate of theophylline was influenced by the physical properties of the silicon dioxide employed. As the particle size of the silica dioxide decreased, there was an increase in dispersion viscosity, as well as a decrease in the theophylline release rate from the coated pellets. Films prepared from formulas containing Aeroperl 300 had twice the water vapor transmission rate of films prepared from formulas containing Aerosil 200 VV and Cab-O-Sil M-5P and showed consistent moisture permeability values during storage for up to 1 month at 25 degrees C/0% relative humidity (RH). Scanning electron microscopy (SEM) imaging of pellets coated with a formulation containing Aerosil 200 VV or Cab-O-Sil M-5P demonstrated film structures that were homogenous, while those coated with a formulation containing Aeroperl 300 produced heterogeneous films with large particles of the excipient present within the polymeric matrix of the film. Stability in the drug release rate exhibited by pellets coated with a formulation containing Eudragit RS 30 D, 15% triethyl citrate (TEC), and 30% Aeroperl 300 was attributed to the stabilization of the moisture vapor transmission rate of the acrylic films. Increasing the concentration of Aeroperl 300 in the coating formulation increased the theophylline release rate from coated pellets.     

Influence of plasticizer level on the drug release from sustained release film coated and hot-melt extruded dosage forms

In the current study, the influence of plasticizer level on drug release was investigated for solid dosage forms prepared by hot-melt extrusion and film coating. The properties of two highly water-soluble compounds, diltiazem hydrochloride (DTZ) and chlorpheniramine maleate (CPM), and a poorly water-soluble drug, indomethacin (IDM), were investigated in the melt extrudates containing either Eudragit RSPO or Eudragit RD 100 and triethyl citrate (TEC) as the plasticizer. In addition, pellets containing DTZ were film coated with Eudragit RS 30D and varying levels of TEC using a fluidized bed coating unit. Differential scanning calorimetry (DSC) demonstrated that both CPM and IDM exhibited a plasticization effect on the acrylic polymers, whereas no plasticizing effect by DTZ on Eudragit RSPO was observed. Thermogravimetric analysis (TGA) was used to investigate the thermal stability of the DTZ, Eudragit RSPO and TEC at 140 degrees C, the maximum temperature used in the hot-melt extrusion process. The chemical stability of DTZ and IDM in the extrudate following hot-melt processing was determined by high pressure liquid chromatography (HPLC). Drug release rates of both DTZ and CPM from hot-melt extrudates increased with an increase in the TEC level in the formulations, while the release rate of DTZ from the Eudragit RS 30D-coated pellets decreased with an increase in TEC in the coating dispersion. This phenomenon was due to the formation of a reservoir polymeric structure as a result of the thermal stress and shear stress involved in the hot-melt extrusion process regardless of the TEC level. In contrast, coalescence of the polymer particles in the film coating process was enhanced with higher levels of TEC, as demonstrated by scanning electron microscopy (SEM). The addition of TEC (0% to 8%) in the IDM hot-melt extrudate formulation had no influence on the drug release rate as the drug release rate was controlled by drug diffusion through the inside of the polymeric materials rather than between the polymer particles.     

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.     

丹酚酸膜缓控释滴丸的制备及其体外释放度

目的研究丹酚酸缓释滴丸的制备方法。方法通过固体分散技术,以聚乙二醇6000(polyeth-ylene-glycol 6000,PEG-6000)和聚乙二醇400(polyethylene-glycol 400,PEG-400)为滴丸基质制备滴丸丸心,以乙基纤维素(ethyl cellulose,EC)、丙烯酸树脂高渗(eudragit RL100)、丙烯树脂低渗(eud-ragit RS100)、邻苯二甲酸二乙酯(diethyl phthalate,DEP)为包衣材料,体积分数为95%的乙醇溶液为包衣溶剂进行包衣,利用均匀设计优化处方,制得具有良好缓释效果丹酚酸缓释滴丸。结果以PEG-6000和PEG-400为固体分散辅料可制得外观圆整,质地均匀的丹酚酸滴丸,包衣处方中以乙基纤维素3.0 g、丙烯酸树脂RL100和RS100 1.0 g、邻苯二甲酸二乙酯2.5 mL、体积分数为95%的乙醇溶液100 mL、包衣增质量分数为3%能达到最佳的释放效果。结论所制备的丹酚酸缓释滴丸具有良好的释放效果。     

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.