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.     

pH依赖—缓释型美沙拉秦结肠靶向小丸的制备与体外评价

以肠溶型和渗透型丙烯酸树脂为包衣材料制备ｐＨ依赖－缓释型美沙拉秦结肠靶向小丸,评价其体外释放特性。结果表明,包衣小丸在０．１ｍｏｌ／ＬＨＣｌ中２ｈ几乎不释放药物,在ｐＨ７．５缓冲液中具有较好的缓释作用。在模拟胃肠道各区段最高的和最低的ｐ变化的释放度试验中,均在对应小肠区段时开始缓慢释药。分别有４０％和７０％的药物进入结肠后释放。优于单独的肠溶或缓释制剂。     

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.     

A novel pH- and time-based multi-unit potential colonic drug delivery system. I. Development

A novel delivery system was developed for delivering drugs to the colon by selecting polymethacrylates with appropriate pH dissolution characteristics for the distal end of the small intestine and relying upon the relatively constant transit time of the small intestine. Pellets were prepared by powder layering of 5-aminosalicylic acid (5-ASA) on nonpareils (0.5-0.6 mm) in a conventional coating pan. Drug-layered pellets were coated with an inner layer of a combination of two pH-independent polymers Eudragit RL and RS (2:8), and an outer layer of a pH-dependent polymer, Eudragit FS. Scanning electron micrograph (SEM) pictures of the coated pellets showed the uniformity of both the coatings. The release profile of 5-ASA was studied in three phosphate buffers after a simulated gastric pre-soak for 2 h in pH 1.2 media. There was no drug release for 12 h at pH 6.5. There was a sustained release of 5-ASA for over 12 h both at pH 7.0 and 7.5 after a lag time at pH 7.0 and no lag time at pH 7.5. The release rate was faster at pH 7.5 than at pH 7.0. The delivery system demonstrated its potential for colonic delivery by resisting drug release until pH 6.5 and the combination of Eudragit RL and RS proved successful for the sustained delivery of 5-ASA at the expected pH of the colon.     

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.     

5-氟尿嘧啶结肠定位释药微丸的研制及释药特性

采用流化床喷雾包衣法,研制了2种5-氟尿嘧啶结肠定位释药微丸.以羟丙甲纤维素为溶胀层,乙基纤维素水分散体为控制层,制备时间依赖型包衣微丸;另以肠溶型丙烯酸树脂Eudragit S100为包衣材料,制备pH依赖型微丸.测定了2种微丸在模拟胃肠道各区段pH环境下的释放度.结果表明,时间依赖型包衣微丸体外持续、缓慢释放;pH依赖型包衣微丸在模拟胃和小肠中上部pH的介质中基本不释药,在模拟回盲部区段pH介质中脉冲释药,即后者在体外显示出较好的结肠定位释药特性.     

Design and evaluation of pH modulated controlled release matrix systems for colon specific delivery of indomethacin

Indomethacin, a potent non steroidal anti-inflammatory drug (NSAID), is indicated for the local treatment of colorectal carcinoma. The aim of the present study was to design and investigate various matrix systems for controlled and site specific delivery of indomethacin to the colon. Various pH sensitive and hydrophobic polymers were investigated for their effect on drug release and site specificity. Effect of proportion of Eudragit L100 and Eudragit S100 in matrix either alone or in combination was evaluated. Effect of hydrophobic non-swellable polymer ethyl cellulose on the release pattern of drug from the Eudragit bases was also investigated. Matrix tablets prepared with Eudragit showed pH dependent release profile with the formulations of Eudragit L100 showing faster rate of drug release than Eudragit S100 in alkaline pH. The release profile from matrix tablets containing Eudragit L100 and Eudragit S100 in combination or with ethyl cellulose correlated well with the relative proportion of the two polymer types in the matrix base. Selected formulations when evaluated in simulated gastric fluid pH without enzymes showed negligible to low drug release (less than 10%) in the first 4-6 h followed with controlled release for 14-16 h. It was concluded that pH sensitive matrix bases in combination with a hydrophobic polymer like ethyl cellulose canbe ideal for site specific delivery of drugs to colon with controlled release profile.     

Statistical optimisation of diclofenac sustained release pellets coated with polymethacrylic films

The objective of the present study was to evaluate three formulation parameters for the application of polymethacrylic films from aqueous dispersions in order to obtain multiparticulate sustained release of diclofenac sodium. Film coating of pellet cores was performed in a laboratory fluid bed apparatus. The chosen independent variables, i.e. the concentration of plasticizer (triethyl citrate), methacrylate polymers ratio (Eudragit RS:Eudragit RL) and the quantity of coating dispersion were optimised with a three-factor, three-level Box-Behnken design. The chosen dependent variables were cumulative percentage values of diclofenac dissolved in 3, 4 and 6 h. Based on the experimental design, different diclofenac release profiles were obtained. Response surface plots were used to relate the dependent and the independent variables. The optimisation procedure generated an optimum of 40% release in 3 h. The levels of plasticizer concentration, quantity of coating dispersion and polymer to polymer ratio (Eudragit RS:Eudragit RL) were 25% w/w, 400 g and 3/1, respectively. The optimised formulation prepared according to computer-determined levels provided a release profile, which was close to the predicted values. We also studied thermal and surface characteristics of the polymethacrylic films to understand the influence of plasticizer concentration on the drug release from the pellets.     

Targeted enteral delivery of insulin to rats

The aim of the present work was to investigate the effectiveness of a dosage form approach for monitoring both the inactivation and the absorption processes by targeting insulin delivery to the colon. The dosage form design is based on incorporating insulin into small, soft gelatin capsules coated with polyacrylic polymer (Eudragit) having pH-dependent properties. The capsules were filled with 100 mg of the following formulation: 8 units (u) porcine insulin and 20 mg of surfactant mixture (sodium laurate: cetyl alcohol 2 : 8) in arachis oil, and were coated with mixtures of various ratios of Eudragit RS, L and S. The in vitro pH-dependent release rates of coated capsules were tested by scintillation counting using [¹²⁵I]insulin and two formulations which released the drug the most between pHs 7.5 and 8.0 (RS1 and RS2) were chosen for further studies in rats. Insulin absorption was measured by its hypoglycemic effect. Blood glucose concentrations were determined at 610 nm using the GOD-Perid method. The oral administration of the two chosen insulin-containing formulations gave significant (P<0.01) hypoglycemia when compared with controls. However, the duration, course and the intensity of effect were different for each formulation: the longest effect was obtained with formulation RS1 while the maximum glucose level reduction (up to 45% of initial value) occurred with formulation RS2. It was interesting to observe that the preadministration of a surfactant capsule did not change the glycemic profile; however, its post-administration prolonged the effect of RS2 by one hour.     

The effect of pectin on swelling and permeability characteristics of free films containing Eudragit RL and/or RS as a coating formulation aimed for colonic drug delivery

BACKGROUND AND THE PURPOSE OF THE STUDY: The potential of pectin as a bacterially degradable polysaccharide for colon drug delivery has been demonstrated. Due to the high solubility and swelling properties of pectin in aqueous media, it is frequently used in combination with water insoluble polymers for targeting drugs to the colon. The aim of this study was to evaluate free films containing pectin as a bacterially-degradable polysaccharide in combination with Eudragit RL (ERL) and/or RS (ERS) as a coating formulation for colonic drug delivery. METHODS: Isolated free films comprising 20% pectin and 80% ERL or ERS and their combination in 1:1 ratio were prepared by casting method. Then, free films were evaluated by water vapor transmission (WVT), swelling and permeability experiments for theophylline and indomethacin in different media. RESULTS: Formulations containing ERL exhibited higher WVT, swelling and permeability compared with formulations containing ERS. The permeability of theophylline through free films composed of pectin and eudragit polymers in simulated colonic media was not significantly different from those obtained in other media. However indomethacin free films containing pectin and ERL showed higher permeation in simulated colonic fluid (SCF) compared to the other media. MAJOR CONCLUSION: Formulation containing pectin and ERL may be suitable as a coating formulation for colon targeted delivery of drugs of low solubility such as indomethacin.     

氧化苦参碱缓释微丸的制备及包衣处方因素的考察

目的:探讨制备氧化苦参碱缓释微丸的影响因素。方法:以挤出滚圆法制备含药丸芯,采用流化床包衣法,分别以HPMC E5及Eudragit RS 30D作为隔离层及控释层的包衣材料进行包衣,考察隔离层包衣增重,控释层增塑剂的种类、用量,以及包衣增重对微丸释放行为的影响。结果:优选出以2%的HPMC E5作为隔离层包衣液,并加入0.2%的PEG 400作为增塑剂,隔离层包衣增重10%;控释层包衣处方为Eudragit RS 30D 6%,滑石粉2%,增塑剂邻苯二甲酸二丁酯(DBP)2%,水90%,包衣增重10%。所制备的氧化苦参碱缓释微丸与普通微丸相比,表现出明显的缓释行为。结论:该工艺处方所制备的氧化苦参碱缓释微丸具有良好的缓释特性。     

Influence of hydroxyethylcellulose on the drug release properties of theophylline pellets coated with Eudragit RS 30 D.

The objective of this study was to investigate the influence of a hydrophilic polymer, hydroxyethylcellulose (HEC), on the release properties of theophylline from pellets coated with Eudragit RS 30 D, and the physicochemical properties of Eudragit RS 30 D cast films. The release rate of theophylline from Eudragit RS 30 D coated pellets decreased during storage at 25 degrees C/60% RH due to the further coalescence of colloidal acrylic particles. In addition, water-vapor permeability and tensile strength of Eudragit RS 30 D cast film decreased after 1-month storage at 25 degrees C/60% RH. The presence of 10% hydroxyethylcellulose in the coating formulation was shown to stabilize the drug release rate from coated pellets, the water-vapor permeability and the tensile strength of free films. Atomic force microscopy and scanning electronic microscopy were used to demonstrate that the HEC was immiscible with Eudragit RS 30 D in the cast films. The stabilization effect of HEC was investigated and determined to be due to the formation of an incompatible phase between the latex particles which impaired further coalescence of the colloidal acrylic particles.     

Effect of pectinolytic enzymes on the theophylline release from pellets coated with water insoluble polymers containing pectin HM or calcium pectinate

Theophylline pellets were coated with cellulosic (Aquacoat ECD 30, Surelease clear) or acrylic (Eudragit NE30D, RS30D) polymer aqueous dispersions, containing 10% (related to the insoluble polymer content) of pectin HM or calcium pectinate, using a Uni-Glatt fluidized-bed coating apparatus. When commercial pectinolytic enzymes were added to the dissolution media (0.05 M acetate - phosphate buffer, pH 6.0), the release of theophylline from the coated pellets was generally slower than that observed in the media without enzymes. The enzymatic slowing down of the drug release, depending on the type of the aqueous polymer dispersion used, is more important with mixed Eudragit NE/calcium pectinate coated pellets. The results obtained have been examined with regard to the validity of the approach based on the combination of pectins and the insoluble polymer aqueous dispersions intended for specific-delivery of drugs to the colon. The mechanism of the hydrophilic drug release from pellets coated with insoluble polymer aqueous dispersions containing an aqueous gel-forming polymer has been also discussed.     

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。     

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.     

Dry polymer powder coating and comparison with conventional liquid-based coatings for Eudragit) RS, ethylcellulose and shellac.

Drug-layered pellets were coated with micronized polymer powders (Eudragit) RS, ethylcellulose, and shellac) by a dry powder coating technique as an alternative to organic- and aqueous-based coatings (Eudragit) RS 30D, Aquacoat) ECD) were investigated. High plasticizer concentrations (40%) and a thermal after-treatment (curing) were necessary for the coalescence of the polymer particles and good film formation. Ethylcellulose required a higher curing temperature and time than Eudragit) RS because of its higher glass transition temperature (133 versus 58 degrees C). A smaller polymer particle size also promoted film formation. In general, pellets coated with polymer powders required higher coating levels to obtain similar drug release patterns as pellets coated with organic polymer solutions and aqueous polymer dispersions.     

Preparation and characterization of ibuprofen pellets based on Eudragit RS PO and RL PO or their combination

The aim of this study was to assess the application of Eudragit RL PO and RS PO and their combination for production of ibuprofen pellets by extrusion-spheronization. The pellets were prepared based on full factorial design. Independent variables were % ibuprofen (40, 60, 80), the ratio of Eudragit RS to Eudragit RL (1:0, 1:1, 0:1) and % PVP (1, 3, 5). The evaluated responses were mean dissolution time (MDT), crushing strength and elastic modulus of pellets. Surface characteristics, sphericity and aspect ratio of pellets were also evaluated. Linear regression and response surface modeling was used for analyzing results. It was shown that the amount of water required to prepare a proper wet mass was affected by composition of formulations. The required amount of water decreased with increasing drug load and percent of PVP. It was also shown that formulations containing Eudragit RL need more water. Increasing percent of PVP slightly decreased MDT and elastic modulus but had negligible effect on crushing strength. Increasing the percent of ibuprofen up to 60% decreased MDT but beyond that increased MDT. Increasing the percent of ibuprofen also decreased elastic modulus of pellets. Eudragit RL PO compare with Eudragit RS PO resulted in pellets with high crushing strength; however, Eudragit type did not have a significant effect on elastic modulus.     

Relationship between drug dissolution and leaching of plasticizer for pellets coated with an aqueous Eudragit S100:L100 dispersion

In order to investigate the relationship between drug dissolution and leaching of plasticizer, theophylline pellets coated with 30% (w/w) Eudragit S100:L100 (1:1) plasticized with different levels of triethyl citrate (TEC) were prepared. The influence of storage conditions on the dissolution profile of theophylline and leaching of TEC was determined. Theophylline was found to dissolve completely from pellets coated with Eudragit S100:L100 (1:1) plasticized with 50% TEC at pH 6.0 after 2h. The shape of the pellets was maintained during dissolution testing. Cracks due to the leaching of TEC were observed in the scanning electron micrographs (SEMs) following dissolution testing at pH 6.0. Both the dissolution of theophylline and the leaching of TEC decreased during storage due to further coalescence of the acrylic polymers. The dissolution profiles of theophylline showed a biphasic pattern and the lag times were estimated as the time points at which a second, rapid release of theophylline was initiated. Subsequently, the percent of TEC leached at the lag time was calculated. While the lag time was increased by storage time and humidity, the percent of TEC leached at the lag time was unchanged as a function of storage condition and was dependent on the initial TEC levels in the films. In conclusion, the plasticizer content in the film coating influenced the dissolution profile of theophylline from pellets coated with Eudragit S100:L100 (1:1). A large amount of the TEC was leached from the enteric films before drug release was initiated and a TEC level of approximately 30% in the films, based on the polymer weight, was the critical amount of TEC for initiating drug release during dissolution testing at pH 6.0. While enteric films are more soluble and dissolve faster at higher pH values, the kinetics of plasticizer release was one of the important factors controlling the dissolution of drugs at pH 6.0, at which pH the enteric polymers were insoluble.     

Engineering polymer blend microparticles: An investigation into the influence of polymer blend distribution and interaction

The aim of this work was to understand the influence of polymer interaction and distribution on drug release from microparticles fabricated from blends of polymers. Blends of pH dependent polymer (Eudragit S, soluble above pH 7) and pH independent polymer (Eudragit RL, Eudragit RS or ethylcellulose) were incorporated into prednisolone loaded microparticles using a novel emulsion solvent evaporation method. Microparticles fabricated from blends of Eudragit S and Eudragit RL or RS did not modify drug release compared to microparticles fabricated from Eudragit S alone. This can be attributed to the high degree of miscibility of Eudragit S with Eudragit RS or Eudragit RL within the microparticles as confirmed by glass transition temperature measurements and confocal laser scanning microscopy. In contrast, microparticles prepared from blends of Eudragit S (75%) and ethylcellulose (25%) extended the release of prednisolone at pH 7.4 (compared to Eudragit S microparticles). This change in release profile was related to the immiscibility of Eudragit S and ethylcellulose as assessed by thermal analysis, and confirmed by microscopy which showed pores within the microparticle structures following dissolution of the Eudragit S domains. The ability of water insoluble polymers to extend drug release from enteric polymer microparticles is dependent on the miscibility and interaction of the polymers. This knowledge is important in the design of pH responsive microparticles capable of extending drug release in the gastrointestinal tract.     

pH依赖型尤特奇应用研究进展

鉴于药用辅料尤特奇所展现出的多功能性和特殊性质,现已成为国内外制剂研究的重要辅料。尤特奇根据溶解特性主要分为pH依赖型和渗透型两大类,主要用作缓控释制剂、口服定位释药系统、微球与微囊等制剂中的包衣材料及载体,可达到缓控释或定位释放的目的,还可起到掩味、增溶、防潮防辐、提高药物稳定性或生物利用度等作用。本文在文献调研的基础上,综述了pH依赖型尤特奇的理化性质及其在药物制剂领域应用的最新进展。