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。     

Studies of chitosan/organic acid/Eudragit RS/RL-coated system for colonic delivery

Prednisolone (PDS) beads were coated sequentially with (i) innermost hydrophobic layer of Eudragit RS/RL, (ii) middle drug release-triggering layer of chitosan, organic acid and Eudragit RS/RL, and (iii) outermost enteric coating layer. Continuous dissolution studies were carried out in artificial gastric fluid (pH 1.2), followed by intestinal fluid (pH 6.8), and finally in colonic fluid (pH 4 and 6) with and without beta-glucosidase. While drug release was prevented in the gastric and small-intestinal fluids, a continuous release was observed in the colonic fluid. Succinic acid provided the fastest rate of release in the colonic fluid compared to citric, tartaric or malic acid. A combined mechanism of drug release is proposed, which considers the swelling of chitosan and Eudragit RS/RL in the presence of succinic acid possibly via electrostatic interaction between the amine groups of chitosan/quaternary ammonium groups of Eudragit RS/RL and the carboxyl groups of succinic acid in aqueous medium. The results of plasma pharmacokinetic studies in Sprague-Dawley rats showed that the developed system provided a significant delay (T(max) 9.3 h) in the absorption profile of PDS compared with simple enteric-coated (T(max) 4 h) or powder (T(max) 1 h) formulation that was taken as proof for the colon-targeted delivery.     

Eudragit®: a technology evaluation

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

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

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

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 relative humidity on the mechanical and drug release properties of theophylline pellets coated with an acrylic polymer containing methylparaben as a non-traditional plasticizer.

The purpose of this study was to investigate the influence of relative humidity (RH) on the mechanical and dissolution properties of theophylline pellets coated with Eudragit((R)) RS 30 D/RL 30 D containing methylparaben (MP) as a non-traditional plasticizer. The coated beads were stored at 23 degrees C and at different relative humidities (0, 29, 51, 75 and 84% RH). The effect of storage conditions on the rate of drug release from coated beads was determined in pH 7.4 phosphate buffer solution. The mechanical properties, including tensile strength and Young's modulus, of individual beads were determined by a diametral compression method with a Chatillon((R)) tension/compression apparatus. The morphology of the intact and fractured beads was investigated using scanning electron microscopy (SEM). The moisture content of the polymeric films was determined using a Karl Fischer coulometric moisture analyzer. The results from the mechanical studies demonstrated that an increase in the relative humidity resulted in a decrease in the tensile strength and Young's modulus of the coated beads. SEM photographs showed that coated beads stored at 0% RH exhibited brittle fracture failure. The coated beads stored at 84% RH showed ductile behavior, which was attributed to the hydroplasticization effect on the acrylic polymer due to the uptake of moisture. The moisture content in the films was also shown to influence the rate of drug release from Eudragit((R)) RS 30 D/RL 30 D coated beads containing MP as the plasticizer. The change in release profiles could be minimized when the relative humidity was reduced to zero. The dissolution rate of theophylline from the coated beads decreased when stored at high relative humidities. This trend was reversed when the coated beads that were stored at 84% RH for 5 weeks, were then equilibrated at 0% RH.     

Design,formulation and evaluation of Azithromycin binary solid dispersions using Kolliphor series for the solubility and in vitro dissolution rate enhancement

The main purpose of this investigation is increasing of the solubility and dissolution rate of Azithromycin by solid dispersion technique using Kolliphor P 237, Kolliphor P 338 and Kolliphor P 407. Kolliphor (P 237, P 338 and P 407) in various properties by weight {(1:0.5), (1:1), (1:1.5) and (1:2)}, utilizing solvent evaporation method. Dissolution studies carried out in phosphate buffer with pH 6.0 according to US pharmacopoeia method. The drug release profiles were studied, so we found that the dissolution rate of the drug (by calculating the dissolution parameters) was significantly increase compared to pure drug, also solubility of physical mixtures as well as solid dispersions increased compared to the intact drug. For example solubility of the drug increased from 85–753 μg mL^?1 (for Kolliphor P 237; 8 times more). The best results were as follows: Kolliphor P 237 > Kolliphor P 338 > Kolliphor P 407. IR spectra revealed no chemical incompatibility between drug and polymer. Drug-polymer interactions were investigated using differential scanning calorimetry, powder X-ray diffraction and scanning election microscopy. The dissolution rate and solubility of Azithromycin solid dispersions was improved significantly using Kolliphor. In addition, the simplicity of this method is very effective and have been met the project objectives.     

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.     

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.     

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.     

Preparation and evaluation of slow-release pan-coated indomethacin granules

Abstract

Granules containing indomethacin crystals are coated with Eudragit solutions of different RL/RS ratios using a pan coating technique. The process is reproducible with regard to drug content, inexpensive and the formed granules were directly compressed into tablets. In vitro release of indomethacin from coated granules, tablets and capsules was studied as a function of different ratios of Eudragit RL/RS in the coating solution. The release of the drug was significantly reduced by the coating process in comparison with a formulation made from uncoated granules, prepared using 10 per cent gelatin solution as a binder. Release data were found to follow a diffusion-controlled model.     

Reversible redox system-based drug design,synthesis, and evaluation for targeting nitrogen mustard across brain

Target drug delivery of nitrogen mustard anticancer agents for a brain tumor is still a challenge due to their high hydrophilicity, poor physicochemical properties, and toxicity to normal tissues. The present study is, therefore, an attempt to investigate the possibility of improving the targeting potential and sustained release of nitrogen mustard alkylating agent to brain by employing reversible redox chemical delivery system approach. Various redox derivatives CDS-L-M (4a–c) based on dihydropyridine ? quaternary pyridinium ion redox system were synthesized and characterized by IR, (¹H and ¹³C)-NMR, and CHN elemental studies. The potential of these CDS derivatives (4a–c) to penetrate the blood–brain barrier was computed through an online software program and the values analyzed lay between the ranges those are required for good brain penetration. The results of storage stability study, in vitro chemical oxidation (silver nitrate) and pharmacokinetic studies in human blood, rat blood and brain homogenate for all CDS-L-M (4a–c) demonstrated that all derivatives could be oxidized into corresponding quaternary salts at an adequate rate, which suggested that brain targeting could be possible with more stable CDS-L-M (4c). The in vivo study on rats showed that administration of the CDS-L-M (4c) resulted in the sustained level of the corresponding salt (3c) in the brain, while blood levels of the oxidized metabolite rapidly fell. The in vitro NBP alkylating activity of quaternary salt (3c) of CDS-L-M (4c) was comparable to the known drug chlorambucil among all the synthesized derivatives.     

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

Purpose

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

Methods

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

Results

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

Conclusions

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

     

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.     

Release of diltiazem from Eudragit microparticles prepared by spray-drying

Microparticles containing diltiazem hydrochloride were prepared by the spray-drying technique using acrylatemethacrylate copolymers, Eudragit RS and Eudragit RL, as coating materials. The choice of solvent used during spray-drying determined the structure of the resultant microparticles. Spray-drying using dichloromethane as the solvent resulted in microspheres where the drug was distributed in the coating polymer matrix, whereas using toluene gave microcapsules with the drug coated by the polymer. The particle size distribution for both microspheres and microcapsules was narrow, with mean particle size below 10 μm. DTA-analysis showed that the drug was amorphous in the microspheres but crystalline in the microcapsules. The release pattern of diltiazem hydrochloride was affected by microparticle structure, whether the structure was matrix (microspheres) or reservoir (microcapsules). The results indicate that spray-drying is a method that can be used to prepare microparticles from the Eudragit acrylic resins RL and RS with a narrow particle size distribution. It is concluded that drug release rate can be controlled by choice of polymer type and production conditions during spray-drying.     

硝苯地平膜控型控释微丸的制备及体外评价

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

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。     

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

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

Preparation and characterization of free mixed-film of pectin/chitosan/Eudragit RS intended for sigmoidal drug delivery.

Polyelectrolyte complex (PEC) film between pectin as an anionic polyelectrolyte and chitosan as a cationic species was prepared by blending two polymer solutions at weight ratio of 2:1 and then solvent casting method. Besides pectin/chitosan PEC film, Eudragit RS, pectin/Eudragit RS and pectin/chitosan/Eudragit RS films were also prepared by aforementioned method. In mixed-film formulations, a fixed weight ratio of 1:5 of pectin or pectin/chitosan complex to Eudragit RS was used. Characterizations of pectin/chitosan interaction in solution were investigated by turbidity and viscosity measurement and in the solid state by Fourier transform infrared (FTIR) spectroscopy, wide angle X-ray diffraction (WAXRD) and thermogravimetric analysis (TGA). It was observed that the swelling profile of pectin/chitosan film was pH-dependent and its swelling ratio in phosphate buffer solution (PBS) pH 7.4 was about 2.5-fold higher than that of PBS pH 6.0. Formulation containing only pectin/chitosan could not protect free film from high swelling in the aqueous media, therefore, Eudragit RS as a water-insoluble polymer must be included in the mixed-film. The formation of PEC between pectin and chitosan resulted in a decrease in the crystallinity and thermal stability caused by the interactions between polyions. Drug permeation or diffusion studies were carried out using Plexiglas diffusion cell consisting of donor and acceptor compartments. Theophylline was selected as a model drug to measure permeability coefficient. Drug permeation through pectin/chitosan/Eudragit RS showed a sigmoidal pattern; whereas drug diffusion through pectin/Eudragit RS and Eudragit RS films followed a linear characteristic. The drug permeation through the ternary mixed-film showed a burst release upon exposure to PBS pH 6.0. This mixed-film formulation showed the potential for sigmoidal drug delivery with an initial, controllable slow release followed by a burst release immediately after the change in pH. The burst drug permeation might possibly be due to change in film's porosity.     

Infection-Responsive Drug Delivery from Urinary Biomaterials Controlled by a Novel Kinetic and Thermodynamic Approach

Purpose

The pH-dependent physicochemical properties of the antimicrobial quinolone, nalidixic acid, were exploited to achieve ‘intelligent’ drug release from a potential urinary catheter coating, poly(2-hydroxyethylmethacrylate) (p(HEMA)), in direct response to the elevated pH which occurs at the onset of catheter infection.

Methods

p(HEMA) hydrogels, and reduced-hydrophilicity copolymers incorporating methyl methacrylate, were loaded with nalidixic acid by a novel, surface particulate localization method, and characterized in terms of pH-dependent drug release and microbiological activity against the common urease-producing urinary pathogen Proteus mirabilis.

Results

The pH-dependent release kinetics of surface-localized nalidixic acid were 50- and 10-fold faster at pH 9, representing the alkaline conditions induced by urease-producing urinary pathogens, compared to release at pH 5 and pH 7 respectively. Furthermore, microbiological activity against P. mirabilis was significantly enhanced after loading surface particulate nalidixic acid in comparison to p(HEMA) hydrogels conventionally loaded with dispersed drug. The more hydrophobic methyl methacrylate-containing copolymers also demonstrated this pH-responsive behavior, but additionally exhibited a sustained period of zero-order release.

Conclusions

The paradigm presented here provides a system with latent, immediate infection-responsive drug release followed by prolonged zero-order antimicrobial delivery, and represents an ‘intelligent’, infection-responsive, self-sterilizing biomaterial.     

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.