The use of Eudragit RS 100/cyclodextrin nanoparticles for the transmucosal administration of glutathione

The aim of this work was to develop and characterize new nanoparticle systems based on Eudragit RS 100 and cyclodextrins (CDs) for the transmucosal administration of glutathione (GSH). For this purpose, nanoparticles (NPs) with the mucoadhesive properties of Eudragit RS 100 and the penetration enhancing and peptide protective properties of CDs were prepared and evaluated. The quasi-emulsion solvent diffusion technique was used to prepare the NPs with natural and chemically modified (HP-β-CD and Me-β-CD) CDs. The NPs prepared showed homogeneous size distribution, mean diameters between 99 and 156 nm, a positive net charge and spherical morphology. Solid state FT-IR, thermal analysis (DSC), and X-ray diffraction studies suggest that the nanoencapsulation process produces a marked decrease in crystallinity of GSH. The encapsulation efficiency of the peptide was found to be between 14.8% and 24%. The results indicate that mean diameters, surface charges and drug-loaded NPs were not markedly affected by the CD, whereas the presence of the latter influences drug release and to some extent peptide stability and absorption. Finally, it has been shown that CD/Eudragit RS 100 NPs may be used for transmucosal absorption of GSH without any cytotoxicity using the epithelial human HaCaT and murine monocyte macrophage RAW264.7 cell lines.     

Eudragit RL100 based microspheres for ocular administration of azelastine hydrochloride

In the present study, potential of polymeric microspheres for treatment of allergic conjunctivitis was investigated. Azelastine hydrochloride loaded Eudragit RL100 microspheres were prepared by solvent evaporation technique. The change in drug–polymer ratio on the particle size, zeta potential, entrapment efficiency and in vitro drug release was investigated. As Eudragit concentration ranged from 40 to 80?mg/ml the size range obtained was 4.18–7.36?µm with positive zeta potential. With the increase in drug polymer ratio, the entrapment efficiency was increased with maximum 14.56%. In vitro release studies demonstrated prolonged release of the drug over the period of 6?hr. Scanning electron micrographs showed that microspheres were spherical with distinct solid dense structure. Fourier transform infrared and differential scanning calorimetry studies concluded slight change in peak intensities of drug in microspheres. In vivo studies in rat model indicated that reduction in eosinophil count number was more pronounced in azelastine hydrochloride microspheres than marketed formulation, Azelast®.     

Preparation and analgesic activity of Eudragit RS100 microparticles containing diflunisal

Two different techniques, the quasi-emulsion solvent diffusion method and spray drying that provide polar and nonpolar preparation environments, were used to prepare microspheres from Eudragit RS100^® (RS) (acrylic/methacrylic copolymer) incorporating the nonsteroidal anti-inflammatory drug diflunisal. The effects of pH on the preparation medium and drug/polymer ratio on production yield and drug incorporation, as well as on the in vitro drug release at pH 1.2 and 6.8 from tabletted microparticles, were evaluated. The drug-polymer interactions and the effect of diflunisal incorporation in the polymer matrix on drug crystallinity have been evaluated by using differential scanning calorimetry, IR and ultraviolet spectroscopy, x-ray diffraction, and microscopy analysis. A preliminary biological assay confirmed that diflunisal maintains its analgesic activity after intraperitoneal administration to rats.     

Preparation and characterization of a powder containing an oily liquid drug with Eudragit EPO or L100 copolymer

Oily liquid drugs are not convenient for oral administration. We developed a powder containing clofibrate (CF), a model of an oily drug, using aminoalkyl methacrylate copolymer (EPO) or methacrylic acid copolymer (L100). CF or a mixture of CF and soybean oil was emulsified with EPO or L100 aqueous solution. Using a high-pressure homogenizer, a stable emulsion was obtained, and a powder was then obtained by lyophilization of the emulsion. The content of CF in the powder depended on the formulation, with the highest contents being 24.6% and 27.1% for EPO and L100, respectively. The incorporation ratio of CF was higher for L100 than for EPO. The powder using EPO was sticky because of leaked CF and the low glass transition temperature of EPO. The powder using L100 was a typical powder obtained by lyophilization. The leakage of CF from the powder was <2%, lower than for EPO powder. The dissolution of CF from powder using EPO was fast, regardless of the pH of the medium, but the powder using L100 showed enteric-soluble characteristics, indicating that CF is well incorporated in L100.     

α-常春藤皂苷丙烯酸树脂L100-55纳米粒的制备及体外评价

目的：采用肠溶材料丙烯酸树脂L100-55作为载体材料,制备α-常春藤皂苷丙烯酸树脂纳米粒（ SPD-L100-55-NPs）并进行体外评价。方法采用改良乳化溶剂扩散法制备SPD-L100-55-NPs,以粒径、包封率（ EE）和多分散指数（ P. I.）为综合指标,通过单因素实验和正交设计实验优化纳米粒的处方工艺,以红外光谱（ FT-IR）、X射线衍射（ XRD）、差示扫描量热分析（ DSC）等对制备的纳米粒进行评价,并考察其体外释放特性。结果制得的SPD-L100-55-NPs纳米粒外观圆整、分布均匀,平均粒径为（63.5±3.6）nm,包封率为98.91%±0.18%,P. I.为0.198±0.014。药物在纳米粒中被载体材料有效包裹,体外释放具有缓释特性和PH依赖性。结论所制得的纳米粒圆整均匀、包封率高,在体外具有良好的缓释特性和PH敏感性。     

Design of a colonic delivery system based on cationic polymethacrylate (Eudragit E100)-mesalamine complexes

In this work, the design and evaluation of a colonic drug delivery system containing mesalamine (M) is presented. The main goal was to enable M to reach the first part of the colon, where the drug could then be released. To facilitate this, a tablet core was coated with two thin layers. The first compounded by chitosan, which was responsible for core protection in the small intestine until it reached the colon. Once at the colon, microbiological enzymatic activity of the caecal content would degrade the Ch layer, thus triggering drug release. The second layer, the outer one, was compounded with Eudragit L100 (EL), with its function being to avoid the dissolution of the Ch-covered core along the gastro intestinal tract (GIT). In order to achieve a modulated drug release, carbomer P934 (1%) was also included. Dissolution studies showed that the formulation seemed to behave as predicted. The amount of M released from the coated tablet was less than 10% at pH?=?1.2 and 6.8. However, when the coated tablet was evaluated in a medium with a caecal content of pH?=?7.4, the M delivery was immediately triggered owing to enzymatic activity of the microflora. In this medium, ～ 60% of M was released in a period of 3?h. Although these results are promising, further studies are still necessary to evaluate the possible in vitro/in vivo correlations.     

Formulation optimization of double emulsification method for preparation of enzyme-loaded Eudragit S100 microspheres

The present study aimed to develop an oral sustained release microparticulate system for acid labile enzyme-Serratiopeptidase. A 3² full factorial experiment was designed to study the effects of the external aqueous phase volume and stabilizer (Tween® 80) concentration on the entrapment and size of Eudragit S100 microspheres prepared by a modified double emulsion solvent evaporation technique. The results of analysis of variance tests for both effects indicated that the test is significant. The effect of external aqueous phase volume was found to be higher on the entrapment efficiency of microspheres (SSY₁ = 1362.63; SSY₂ = 250.13), whereas Tween® 80 produced a significant effect on size of microspheres (SSY₁ = 944.01; SSY₂ = 737.26). Scanning electron microscopy of microspheres demonstrated smooth surface spherical particles. The effect of formulation variables on the integrity of enzyme was confirmed by in vitro proteolytic activity. Microspheres having maximum drug encapsulation (81.32 ± 3.97) released 4–5% enzyme at pH 1.2 in 2 h. The release of enzyme from microspheres followed Higuchi kinetics (R² = 0.987). In phosphate buffer, microspheres showed an initial burst release of 25.65 ± 2.35% in 1 h with an additional 62.96 ± 4.09% release in the next 5 h. Thus, formulation optimization represents an economical approach for successful preparation of Eudragit S100 microspheres involving fewest numbers of experiments.     

Microcapsules formulated in the enteric coating copolymer Eudragit L100 as delivery systems for oral vaccination against infections by gastrointestinal nematode parasites

Microcapsules using the copolymer of methacrylic acid (Eudragit L100) were formulated for oral delivery of vaccines against the enteral/parenteral nematode parasite Trichinella spiralis. Antigenic preparations from first stage larvae (L1) of T. spiralis were microencapsulated in Eudragit L100. The microcapsules prepared by the spray drying method were resistant to acid pH, although the antigen was rapidly released under neutral and basic environmental conditions. The native protein conformation and biological activity was preserved in the microcapsules, as assessed by SDS-PAGE and ELISA. When administered to NIH mice, the antigen loaded microcapsules protected against infection by T. spiralis at both the intestinal and muscular levels, the worm burden diminishing by 45.58 and 53.33%, respectively. Furthermore, following administration of the microparticles an increase of the serum IgG1 response, a marker for the Th2 type response, was evident. These results indicate that microcapsules formulated with anionic biocompatible polymers such as Eudragit may be useful for oral vaccination against nematode infections.     

Ionic Strength Dependence of Dissolution for Eudragit S-100 Coated Pellets

Pharmaceutical Research -     

Effect of pH on diclofenac release from Eudragit RS100 microparticles. A kinetic study by DSC

The present work is aimed at investigating the release of Diclofenac (DCF) from Eudragit RS100T^® (RS) microparticles to a biological model membrane consisting of dimyristoylphosphatidylcholine (DMPC) multilamellar vesicles (MLV). The microparticles were prepared by the Quasi-Emulsion Solvent Diffusion method (QESD). The drug release was monitored by Differential Scanning Calorimetry (DSC) technique, following the effects exerted by DCF on the thermotropic behaviour of DMPC multilamellar vesicles at different temperatures. DCF affects the transition temperature (T_m) of phospholipid vesicles, causing a m shift towards lower values, which is modulated by the drug fraction entering into the lipid bilayer. Calorimetric measurements were performed at two different pH (4.0 and 7.4) on suspensions of blank liposomes added to weighed amounts of unloaded and DCF-loaded microspheres, as well as to the powdered free drug, after incubation at 37°C. The T_m shifts, caused by the drug released from the polymeric system or by the free drug during incubation cycles, were compared to those caused by a chosen molar fractions of the free drug dispersed directly in the membrane. This in vitro study suggests as the kinetic process involved in drug release is influenced by the amount of drug loaded in the microspheres as well as by the pH value, acting on drug solubility and membrane disorder.     

Development and characterization of itraconazole-loaded solid lipid nanoparticles for ocular delivery

Abstract

The purpose of this study was to investigate the feasibility of entrapping water-insoluble drug itraconazole into solid lipid nanoparticles (SLNs) for topical ocular delivery. The drug-loaded SLNs were prepared from stearic acid and palmitic acid using different concentrations of polyvinyl alcohol employed as emulsifier. SLNs were prepared by the melt-emulsion sonication and low temperature-solidification method and characterized for particle size, zeta potential, drug loading and drug entrapment efficiency. The mean particle size of SLNs prepared with stearic acid ranged from 139 to 199?nm, while the SLNs prepared with palmitic acid had particle size in the range of 126–160?nm. The SLNs were spherical in shape. Stearic acid-SLNs showed higher entrapment of drug compared with palmitic acid-SLNs. Differential scanning calorimetry (DSC) and X-ray diffraction measurements showed decrease in crystallinity of drug in the SLN formulations. The modified Franz-diffusion cell and freshly excised goat corneas were used to test drug corneal permeability. Permeation of itraconazole from stearic acid-SLNs was higher than that obtained with palmitic acid-SLNs. The SLNs showed clear zone of inhibition against Aspergillus flavus indicating antimicrobial efficacy of formulations.     

The Preparation and Evaluation of Sustained Release Suppositories Containing Ketoprofen and Eudragit RL 100 by Using Factorial Design

The preparation of ketoprofen (KP) sustained release (SR) suppositories was designed according to the 3² × 2¹ factorial design as three different KP:Eudragit RL 100 ratios (1:0.5, 1:1, 1:2), three particle sizes of prepared granules (250–500, 500–710, and 710–1000 μm) and two different PEG 400:PEG 6000 ratios (40:60, 50:50). The conventional KP suppositories were also prepared by using Witepsol H 15, Massa Estarinum B, Cremao and the mixture of PEG 400:PEG 6000. The dissolution studies of suppositories prepared were carried out according to the USP XXIII basket method in the phosphate buffer (pH = 7.2) at 50 rpm, and it was shown that the dissolution time was sustained up to 8 hours. According to the results of the factorial design, the most important independent variable on t₅₀ and t₈₀ was drug:polymer ratios. The log of partition coefficient of KP was determined as 1.46, showing the high affinity to the oily phase. n exponent and kinetic studies were conducted to explain diffusion mechanism, and it is understood that if the inert KP:Eudragit RL 100 ratio is increased in the particles, the Fickian difusion dominates and the best kinetic turns to Higuchi from the Hixson-Crowell. There is neither crystalline form of KP nor degradation product in the suppositories detected with the differential scanning calorimetry (DSC) studies. In addition to these studies, antiinflammatory activity of SR suppositories also determined that it was significantly extended according to the conventional suppositories.     

Design of Eudragit RL 100 nanoparticles by nanoprecipitation method for ocular drug delivery

The objective of the current study was to prepare positively charged amphotericin-B–loaded nanoparticles providing a controlled release formulation. The particles were prepared by solvent displacement or nanoprecipitation method. The non-biodegradable positively charged polymer Eudragit RL 100 was used to prepare the different formulations with varying ratios of drug and polymer. The formulations were evaluated in terms of particle size, zeta potential, and differential scanning calorimetry measurements. Drug entrapment and release properties were examined also. The antimicrobial activity against Fusarium solani was determined. In vivo eye irritation study was carried out by a modified Draize test. All the formulations remained within a size range of 130 to 300 nm in fresh preparation as well as after 2 months. The zeta potential was positive (+22 to +42 mV) for all the formulations and was suitable for ophthalmic application. A prolonged drug release was shown by all the formulations. The formulation possesses a good antifungal activity against Fusarium solani when tested by disk diffusion method, and no eye irritation on in vivo testing was found.From the Clinical EditorThe objective of the current study was to prepare positively charged amphotericin-B -loaded nanoparticles providing a controlled release formulation. The described formulation displayed good antifungal activity against Fusarium solani when tested by disk diffusion method, and no eye irritation on in vivo testing was found.     

Development and characterization of HBsAg-loaded Eudragit nanoparticles for effective colonic immunization

The present study was undertaken with an aim to investigate the potential of targeting colonic mucosa following oral vaccine delivery to generate prophylactic humoral and mucosal immune response. In present study, response surface methodology (RSM) using the central composite design (CCD) was applied for optimization of process and composition to get uniform, stable reproducible eudragit nanoparticles suitable for targeting to colon. The optimized formulation had the composition of 173?μg HBsAg, 250?mg polymers concentration (4:1 combination of Eudragit S-100 and L-100) and 2% w/v Polyvinyl alcohol (PVA) along with adjuvant Monophosphoryl lipid A (MPLA). Mean particle size of optimized nanoparticles was found to be 730.4?nm, entrapment efficiency (58.38%) and polydispersity index of 0.185. Fluorescent spectroscopy, differential scanning calorimetry, and antigen integrity by SDS-PAGE established that antigen structure was preserved during and after formulation development. In-vitro release studies in different intestinal pH concluded antigen release at mild alkaline conditions. Real time fluorescence animal imaging confirmed the effective absorption and distribution of NPs at colon resulted in improved immune response. Present study concludes that Eudragit nanoparticles offers strong potential in colon targeting of vaccines through oral immunization.     

Doxycycline hyclate-loaded in situ forming gels composed from bleached shellac,Ethocel, and Eudragit RS for periodontal pocket delivery

Polymeric material plays an important role as a matrix former in the modulation of drug release of antimicrobial-loaded in situ forming gel (ISG) for efficient periodontitis treatment. This study was conducted to compare three polymers, namely bleached shellac (BS), Ethocel (EC) and Eudragit RS (ERS), as matrix formers of doxycycline hyclate (DH)-loaded solvent exchange-induced ISG. All prepared ISGs, except 25% EC ISG, exhibited the Newtonian flow behaviour. Transformation from solution into matrix-like was achieved rapidly within 5 min. Increasing the amount of these polymers extended the release of DH. DH-loaded EC and ERS ISG systems exhibited high antimicrobial activity, and all ISGs were effective in inhibiting the growth of Staphylococcus aureus, Escherichia coli, Streptococcus mutans, Porphyromonas gingivalis and Candida albicans. By comparison, the DH-loaded ERS ISG, through the solvent exchange mechanism, was found to be ease in injection with low viscosity and sustained the release with higher concentration, meanwhile, it also exhibited interesting in vitro degradability and antimicrobial activities. Therefore, the DH-loaded ERS ISG exhibited a potential use for localized periodontal drug delivery system for the treatment periodontitis.     

Development of gatifloxacin-loaded cationic polymeric nanoparticles for ocular drug delivery

The present investigation aimed at improving the ocular bioavailability of gatifloxacin by prolonging its residence time in the eye and reducing problems associated with the drug re-crystallization after application through incorporation into cationic polymeric nanoparticles. Gatifloxacin-loaded nanoparticles were prepared via the nanoprecipitation and double emulsion techniques. A 50:50 Eudragit® RL and RS mixture was used as cationic polymer with other formulation parameters varied. Prepared nanoparticles were evaluated for size, zeta potential, and drug loading. An optimized formulation was selected and further characterized for in vitro drug release, cytotoxicity, and antimicrobial activity. The double emulsion method produced larger nanoparticles than the nanoprecipitation method (410?nm and 68?nm, respectively). Surfactant choice also affected particle size and zeta potential with Tween 80 producing smaller-sized particles with higher zeta potential than PVA. However, the zeta potential was positive at all experimental conditions investigated. The optimal formulation produced by double emulsion technique and has achieved 46% drug loading. This formulation had optimal physicochemical properties with acceptable cytotoxicity results, and very prolonged release rate. The particles antimicrobial activities of the selected formulation have been tested against Escherichia coli, Pseudomonas aeruginosa, and Staphylococcus aureus and showed prolonged antimicrobial effect for gatifloxacin.     

Ranitidine Hydrochloride-loaded Ethyl Cellulose and Eudragit RS 100 Buoyant Microspheres: Effect of pH Modifiers

A floating type of dosage form of ranitidine hydrochloride in the form of microspheres capable of floating on simulated gastric fluid was prepared by solvent evaporation technique. Microspheres prepared with ethyl cellulose, Eudragit^® RS100 alone or in combination were evaluated for percent yield, drug entrapment, percent buoyancy and drug release and the results demonstrated satisfactory performance. Microspheres exhibited ranitidine hydrochloride release influenced by changing ranitidine hydrochloride-polymer and ranitidine hydrochloride-polymer-polymer ratio. Incorporation of a pH modifier has been the usual strategy employed to enhance the dissolution rate of weakly basic drug from floating microspheres. Further citric acid, fumaric acid, tartaric acid were employed as pH modifiers. Microspheres prepared with ethyl cellulose, Eudragit^® RS100 and their combination that showed highest release were utilized to study the effect of pH modifiers on ranitidine hydrochloride release from microspheres which is mainly affected due to modulation of microenvironmental pH. In vitro release of ranitidine hydrochloride from microspheres into simulated gastric fluid at 37° showed no significant burst effect. However the amount of release increased with time and significantly enhanced by pH modifiers. 15% w/w concentration of fumaric acid provide significant drug release from ranitidine hydrochloride microspheres prepared with ranitidine hydrochloride:ethyl cellulose (1:3), ranitidine hydrochloride:Eudragit^® RS100 (1:2) and ranitidine hydrochloride:ethyl cellulose:Eudragit^® RS100 (1:2:1) whereas citric acid, tartaric acid showed significant cumulative release at 20% w/w. In all this study suggest that ethyl celluose, Eudragit^® RS100 alone or in combination with added pH modifiers can be useful in floating microspheres which can be proved beneficial to enhance the bioavailability of ranitidine hydrochloride.     

Design,in vitro and in vivo evaluation of glipizide Eudragit microparticles

Glipizide microparticles made with Eudragit (RS 100 and RL 100), prepared by emulsion solvent evaporation technique were evaluated for various in-vitro properties viz. encapsulation efficiency, particle size and surface morphology, drug release pattern and in-vivo hypoglycaemic activity. The optimized formulation parameters were used to prepare smooth and spherical microparticles (2–32 µm) with higher entrapment efficiency (67–89%). Drug release patterns of glipizide microparticles of Eudragit RS 100 and Eudragit RL 100 with drug-to-polymer ratio of 1 : 4 (i.e. EGM14 and ELGM14) have shown gradual and extended release for 24 h with cumulative release of glipizide to the extent of 72.3% and 83.9%, respectively. However, EGM14 showed a significant in-vivo hypoglycaemic effect up to 12 h in rabbits while ELGM14 showed for 9 h. Hence, glipizide microparticles of Eudragit RS 100 (glipizide: polymer 1 : 4) is better suited for oral sustained release formulation.     

A Simple and Rapid Method for the Quantification of Eudragit RS100 and RL100 Poly(methacrylates) in Sustained-Release Dosage Forms

A colorimetric ion-pair complexation method has been developed which provides a simple and rapid way of quantifying Eudragit RS100 and RL100 in pharmaceutical dosage forms. The quaternary ammonium groupings in these polymers appear to form an ion-pair complex with the dye tropaeolin OOO. When extracted into an organic phase, the optical density at 484 nm is linearly related to polymer concentration. Control of pH is important, and it should be maintained within the range 4.5 to 9.0. A wide range of pharmaceutical excipients commonly used in tablet, pellet, and film-coating formulations did not interfere with formation of the complex, but certain drugs were found to significantly enhance or decrease the assay response. Good reproducibility, precision, and accuracy were demonstrated when the method was applied to a film-coated pellet formulation containing an interfering drug (promethazine hydrochloride). However, removal of interfering substances must be optimized. The method was sufficiently sensitive for the determination of polymer on a single dose unit of encapsulated beads.     

Design,statistical optimisation,characterisation and pharmacodynamic studies on Pioglitazone hydrochloride floating microparticles

Abstract

The purpose of this study was to develop floating microparticles containing Pioglitazone HCl, for controlled release and perform pharmacodynamic studies. The FTIR and DSC studies revealed that there is no interaction between drug and excipients used. The 2² factorial design was employed to evaluate the effect of drug: polymer (total) and Eudragit RS 100: Eudragit RL 100. The floating microparticles were prepared by solvent evaporation technique. The predicted and actual values of drug release at 1?h, 8?h and drug entrapment were 38.307%, 77.76%, 84.25% and 38.712%, 76.237% and 84.62%, respectively. XRD and SEM studies showed reduced crystallinity of drug and spherical microparticles. Buoyancy studies revealed good floating of particles for 12?h. Pharmacodynamic studies showed significant reduction in blood glucose levels in male New Zealand rabbits. The results demonstrate the feasibility of the factorial design in successfully developing floating microparticles of Pioglitazone HCl for controlled release.