Encapsulation of doxorubicin in magnetic‐polymer hybrid colloidal particles of Eudragit E100 and their hyperthermia and drug release studies

Water‐soluble magnetite Fe₃O₄ nanoparticles were synthesized by coprecipitation that exhibit spherical morphology and superparamagnetic behavior with a saturation magnetization of 46 emu/g. These nanoparticles were coated with amino methacrylate copolymer (Eudragit E100) along with encapsulation of Doxorubicin drug under the action of sonication via a double emulsion solvent evaporation method. The prepared magnetic colloids were evaluated for particle size, surface morphology, surface charge, drug loading capacity, and entrapment efficiency. The drug release studies indicated the sustained release of drug of 92% in 24 hours at physiological pH of 7.4 and drug release kinetics followed first order. The prepared nanoparticles and their colloids were also investigated for magnetic hyperthermia and specific absorption rate values were found to be 2.41, 2.71, and 4.28 W/g at 259, 327, and 518 kHz, respectively. The developed magnetic colloids have the potential to perform controlled hyperthermia and drug release to the target sites.     

Effect of preparation temperature in solvent evaporation process on Eudragit RS microsphere properties

Eudragit RS 100 microspheres containing ketoprofen as a model drug were prepared by the solvent evaporation method using an acetone/liquid paraffin solvent system. The influence of various preparation temperatures: 10, 25, 35, and 40 degrees C, on particle size and morphology, drug content and release kinetics, and drug crystal state was evaluated. With increasing temperature, microsphere average size was found to increase and particle size distribution to widen significantly. At 10 degrees C particles of irregular shape are formed, whereas higher temperatures gradually improve the sphericity of microspheres. As can be seen from SEM photographs, particle surface roughness decreases as preparation temperature increases. It was found that temperature had no effect either on ketoprofen microencapsulation efficiency or on its crystal state, but it does influence emulsion-stabilizer incorporation. Ketoprofen forms solid solution in Eudragit matrix and maintains amorphous state for significant period of time. Drug release rates from microspheres correlated with microspheres' surface roughness and to a lesser extent with particle size.     

Use of supercritical CO2‐aided and conventional melt extrusion for enhancing the dissolution rate of an active pharmaceutical ingredient

Dispersing at the molecular level a drug in a polymer matrix is a major challenge to be addressed by the pharmaceutical industry to enhance its bioavailability or to control its release. Melt extrusion and supercritical CO₂‐aided melt extrusion of solid pharmaceutical formulations were performed to enhance the dissolution rate of carvedilol, taken as a model of poorly soluble drug. The presence of the drug improved the processability of the polyacrylate matrix (Eudragit E) through its plasticizing effect. The supercritical method was found gentle compared with melt extrusion owing to the shorter residence time and lower processing temperature and melt viscosity. No traces of decomposition of the drug could be detected after the supercritical extrusion process based on capillary electrophoresis results. This extrusion process resulted in effective homogenization of the components and amorphization of the drug according to Raman mapping, Fourier transform infrared spectrometry, X‐ray diffraction, and polarized light microscopy. The kinetics of dissolution can be dramatically improved. Copyright © 2011 John Wiley & Sons, Ltd.     

Ethylcellulose, polycaprolactone, and eudragit matrices for controlled release of piroxicam from tablets and microspheres

The present paper provides details of the preparation of polymeric tablets and microspheres based on piroxicam as a therapeutic active agent and the drug release study from these formulations. Tablets composed of ethylcellulose, Eudragit? or mixtures of Eudragit? and synthesised poly(oxepan-2-one) were prepared and tested. The effect of the matrix on the drug release at 37°C was studied. The drug-loaded microparticles were prepared using solvent evaporation microencapsulation. These systems were characterised by SEM and FTIR spectroscopy and the size and size distribution were also determined. The results demonstrated that the drug release could be modified by means of these formulations. Finally, piroxicam dissolution rate constants were calculated from Higuchi??s release model.     

A new drug delivery system using plasma-irradiated pharmaceutical aids. VIII. Delayed-release of theophylline from double-compressed tablet composed of eudragit as wall material.

The rapid release from a double-compressed tablet containing theophylline as a core drug with the pH-dependent water-soluble polymers, Eudragit L100, S100 or L100-55 used as a wall material was suppressed by argon plasma-irradiation due to an effect of inter-segmental cross-link reactions on the decrease in the surface polymer solubility of outer layer. In addition, the rapid theophylline release from the double-compressed tablet of Eudragit L100-55 with a lower glass transition temperature (Tg) has converted into the delayed-release system under a set of plasma operational conditions due to an additional effect of plasma heat flux on softening of Eudragit L100-55 surface resulting in the formation of the film-like surface with a particle-particle interlinking of the outer layer.     

Effect of pore former on the properties of casted film prepared from blends of Eudragit NE 30 D and Eudragit L 30 D-55

The casted films of aqueous dispersions of Eudragit NE30 D and Eudragit L30 D-55 containing pore former were prepared. The study investigated the influence of pore former on basic model drug clarithromycin release, water uptake and water vapor permeability from casted film prepared from the blends of neutral polymer dispersion of Eudragit NE30 D and enteric polymer dispersion of Eudragit L30 D-55. This study was concluded that pore former hydroxypropyl methyl cellulose, lactose, polyethylene glycol (PEG) and polyvinyl pyrrolidon (PVP) was released at the beginning of the release process, the rate and extent of water uptake of the polymeric films were much higher in phosphate buffer pH 6.8 than in pH 5.0 and the concentration of pore former have a significant influence on the permeability to water vapour.     

pH-enzyme di-dependent chronotherapeutic drug delivery system of theophylline for nocturnal asthma

The purpose of this research work was to develop and evaluate a chronotherapeutic based colon-targeted drug delivery system of theophylline (THEO) exploiting pH-enzyme sensitive property for the prevention of episodic attack of asthma in early morning. Guar gum microspheres of theophylline were prepared by emulsification technique. Coating of microspheres was performed using solvent evaporation method with pH sensitive Eudragit(?) polymers. The particle size and surface morphology, entrapment efficiency and degree of swelling of microspheres were examined. The in vitro drug release studies were performed in pH progression medium and also in the presence of 2% rat caecal content. Theophylline was efficiently microencapsulated in guar gum microspheres at different polymer concentrations (1-4%). Fourier transform infrared (FT-IR)-spectroscopy confirmed the intermolecular interactions between guar gum and glutaraldehyde. Coating of guar gum microspheres by Eudragit led to decelerate the in vitro drug release of THEO. Moreover in vitro drug release studies also performed with 2% rat caecal content showed marked increment in drug release. The controlled release of THEO after a lag time was achieved with developed formulation for chronotherapeutic delivery. The pH dependent solubility behavior of Eudragit and gelling properties of guar gum are found to be responsible for delaying the release.     

Sodium alginate/HPMC/liquid paraffin emulsified (o/w) gel beads,by factorial design approach; and in vitro analysis

The present study involved development of a novel sodium alginate (SA)/HPMC/light liquid paraffin emulsified (o/w) gel beads containing Diclofenac sodium (DS) as an active pharmaceutical ingredient and its site specific delivery by using hard gelatin capsule fabricated by enteric coated Eudragit L-100 polymer. Emulsified gel beads were formulated by 3-level factorial design, ionic gelatin method. The obtained beads were characterized by Fourier transform infrared, X-ray diffraction and Field emission scanning electron microscope analysis. The variables such as SA (X₁), HPMC (X₂), were optimized for drug loading and in vitro drug release with the help of response surface methodology (RSM). The RSM analysis predicted that SA was significant for both drug loading (p = 0.0005) and drug release (p = 0.0041). HPMC was only significant for drug release (p = 0.0154). The cross-product contribution (2FI) and quadratic model were found to be adequate and statistically accurate with correlation value (R²) of 0.9054 and 0.9450 to predict the drug loading and drug release respectively. An increase in concentration of HPMC and SA decreases the drug loading as well as the drug release. The obtained optimum values of drug loading and DS released were 7.43 % and 85.54 % respectively, which were well in agreement with the predicted value by RSM.     

Development of extended release coevaporates and coprecipitates of promethazine HCl with acrylic polymers: formulation considerations

The present investigation studied a novel extended release system of promethazine hydrochloride (PHC) with acrylic polymers Eudragit RLPO and Eudragit RS100 in different weight ratios (1 : 1 and 1 : 5) using coevaporation and coprecipitation techniques. Solid dispersions were characterized by Fourier-transformed infrared spectroscopy (FT-IR), Differential scanning calorimetry (DSC), Powder X-ray diffractometry (PXRD), Nuclear magnetic resonance (NMR), Scanning electron microscopy (SEM) as well as solubility and in vitro dissolution studies in 0.1 n HCl (pH 1.2), double distilled water and phosphate buffer (pH 7.4). Adsorption test from drug solution to solid polymers were also performed. Selected solid dispersion system was subjected to direct compression and compressed tablets were evaluated for in vitro dissolution studies. The progressive disappearance of drug peaks in thermotropic profiles of coevaporates were related to increasing amount of polymers while SEM studies suggested homogenous dispersion of drug in polymer. Eudragit RLPO had a greater adsorptive capacity than Eudragit RS100 and thus its coevaporates in 1 : 5 ratio exhibited higher dissolution rate with 91.90% drug release for 12 h. Among different formulations, tablets prepared by Eudragit RLPO coevaporates (1 : 5) displayed extended release of drug for 12 h with 90.87% release followed by zero order kinetics (r(2)=0.9808).     

Characterization and release of triptolide-loaded poly (d,l-lactic acid) nanoparticles

Triptolide (TP), which has immunosuppressive effect, anti-neoplastic activity, anti-fertility function and severe toxicities on digestive, urogenital, blood circulatory system, was used as a model drug in this study. TP-loaded poly (d,l-lactic acid) (PLA) nanoparticles were prepared by the modified spontaneous emulsification solvent diffusion method (modified-SESD method). Dynamic light scattering system (DLS), transmission electron microscope (TEM), atomic force microscopy (AFM), differential scanning calorimetry (DSC), X-ray powder diffractometry and Fourier transform infra-red spectroscopy (FT-IR) were employed to characterize the nanoparticles fabricated for size and size distribution, surface morphology, the physical state of drug in nanoparticles, and the interaction between the drug and polymer. Encapsulation efficiency (EE) and the in vitro release of TP in nanoparticles were measured by the reverse phase high-performance liquid chromatography (RP-HPLC). The produced nanoparticles exhibited a narrow size distribution with a mean size of approximately 150 nm and polydispersity index of 0.088. The morphology of the nanoparticles exhibited a fine spherical shape with smooth surfaces without aggregation or adhesion. TP-entrapped in nanoparticles was found in the form of amorphous or semicrystalline. It was found that a weak interaction existed between the drug and polymer. In all experiments, more than 65% of EE were obtained. The in vitro release profile of TP from nanoparticles exhibited a typical biphasic release phenomenon, namely initial burst release and consequently sustained release. In this case, the particle size played an important role for the drug release. The modified-SESD method was a potential and advantage method to produce an ideal polymer nanoparticles for drug delivery system (DDS).     

Colon specific chitosan microspheres for chronotherapy of chronic stable angina

In the present work, chitosan microspheres with a mean diameter between 6.32 μm and 9.44 μm, were produced by emulsion cross-linking of chitosan, and tested for chronotherapy of chronic stable angina. Aiming at developing a suitable colon specific strategy, diltiazem hydrochloride (DTZ) was encapsulated in the microspheres, following Eudragit S-100 coating by solvent evaporation technique, exploiting the advantages of microbiological properties of chitosan and pH dependent solubility of Eudragit S-100. Different microsphere formulations were prepared varying the ratio DTZ:chitosan (1:2 to 1:10), stirring speed (1000-2000 rpm), and the concentration of emulsifier Span 80 (0.5-1.5% (w/v)). The effect of these variables on the particle size and encapsulation parameters (production yield (PY), loading capacity (LC), encapsulation efficiency (EE)) was evaluated to develop an optimized formulation. In vitro release study of non-coated chitosan microspheres in simulated gastrointestinal (GI) fluid exhibited a burst release pattern in the first hour, whereas Eudragit S-100 coating allowed producing systems of controlled release diffusion fitting to the Higuchi model, and thus suitable for colon-specific drug delivery. DSC analysis indicated that DTZ was dispersed within the microspheres matrix. Scanning electron microscopy revealed that the microspheres were spherical and had a smooth surface. Chitosan biodegradability was proven by the enhanced release rate of DTZ in presence of rat caecal contents.     

Coordination bonding based pH-responsive albumin nanoparticles for anticancer drug delivery

Zn-loaded bovine serum albumin nanoparticles (Zn-BSA nanoparticles) were prepared and used as carriers for pH-responsive anticancer drug delivery. Zinc was introduced into this system to increase the stability of the BSA nanoparticles and to load the anticancer drug based on the coordination bonding formation of Zn-BSA and Zn-drug molecules, respectively. The cleavage of either the "Zn-BSA" or the "Zn-drug" coordination bonding, in response to pH, would result in the release of the drug under designated pH conditions. The nanoparticles were spherical with diameters of 50-60 nm and narrow size distribution. Mitoxantrone (MX) was chosen as the model drug to study the release behavior and the inhibitory efficacy against tumor cells. In vitro release behavior of MX loaded Zn-BSA nanoparticles (MX-Zn-BSA nanoparticles) showed a fine pH-responsiveness. The release amount at pH 5.0 was close to 80%, while the cumulative release amount at pH 7.4 was less than 6% within 24 h. The blank Zn-BSA nanoparticles were of low cytotoxicity, while a high cytotoxic activity of MX-Zn-BSA nanoparticles against MCF-7 cells was demonstrated by in vitro cell assays.     

Characterization and release behaviors of porous PCL/Eudragit RS microcapsules containing tulobuterol

In this work, porous poly(ɛ-caprolactone) (PCL)/Eudragit RS 100 (ERS-100) microcapsules containing tulobuterol base as a model drug were prepared by a solvent evaporation method and the effect of the quaternary ammonium groups of ERS-100 on the release behaviors of the microcapsules was investigated. The microcapsules prepared with PCL alone showed a stable and smooth surface, whereas porous microcapsules were formed with the addition of ERS-100. Drug loading and encapsulation efficiency of the microcapsules were slightly decreased with an increase of ERS-100 content, resulting from an increase in the porosity of the microcapsules. In an acidic release medium, PCL microcapsules showed slow drug release, whereas PCL/ERS-100 microcapsules showed a faster release rate with an increasing ERS-100 content. These behaviors are likely due to an increase in the diffusion rate of the drugs stemming from an increased hydration of the microcapsules, which results from the interaction between the carboxyl group of the release medium and the quaternary ammonium group of ERS-100.     

Application of TPGS in polymeric nanoparticulate drug delivery system

d-alpha-Tocopheryl polyethylene glycol 1000 succinate (TPGS) has great potential in pharmacology and nanotechnology. The present work investigated the molecular behaviour of TPGS at the air-water interface, its effect on a model bio-membrane composed of dipalmitoylphosphatidylcholine (DPPC) lipid monolayer, and the interaction between the TPGS coated nanoparticles with the lipid model membrane. Paclitaxel loaded polymeric nanoparticles with TPGS as surfactant stabiliser were fabricated and characterised in terms of their drug incorporation capability and release kinetics. The result showed that TPGS exhibited notable effect on the surface properties of air-water interface as well as the lipid monolayer. The inter-particle force and the interaction between nanoparticles and lipid monolayer varied with the surface substance. The penetration of various nanoparticles into the model membrane indicated that an optimal balance between hydrophilicity and hydrophobicity on nanoparticle surface is needed to achieve an effective cellular uptake of nanoparticles. The results also demonstrate that the drug incorporation capability and the release characteristics of drug-loaded nanoparticles can be influenced by surfactant stabiliser.     

Floating and sustained-release characteristics of effervescent tablets prepared with a mixed matrix of Eudragit L-100-55 and Eudragit E PO

The aim of this study was to evaluate the influence of Na-bicarbonate as an effervescent agent on the floating and sustained-release characteristics in 0.1 M HCl of tablets made of Eudragit E PO (EE) and/or Eudragit L-100-55 (EL) as matrix formers at different EE:EL weight ratios: 0:100, 25:75, 50:50, 75:25, and 100:0. The tablets were made by direct compression utilizing metronidazole as a model drug. Effervescent tablets with 50EE/50EL (w/w) showed the best floating and sustained drug release properties in the dissolution medium. The corresponding noneffervescent tablets were nonfloating and showed significantly faster drug release. Effervescent tablets with single polymers showed an immediate drug release pattern. These results were explained by Fourier-transform infrared spectroscopy and elemental analysis, which showed strong evidence of interpolyelectrolyte complexation between EE and EL when they were exposed to 0.1 M HCl as an effervescent hybrid matrix, but not as a noneffervescent hybrid matrix. The role of Na-bicarbonate in allowing EE-EL complexation during dissolution was explained as due to raising the pH around EL particles for sufficient polymer ionization and ionic-interaction with the ionized EE.     

Functional delivery vehicle of organic nanoparticles in inorganic crystals

This work has developed a functional delivery vehicle of an organic-inorganic hybrid consisted of organic nanoparticles in inorganic crystals, which greatly improves the stability of the bioactive and implements a unique pH-triggered release.     

Eudragit as controlled release system for anti-inflammatory drugs: A comparison between DSC and dialysis experiments

A comparative study between the release of Ibuprofen (IBU) from Eudragit RS100^® (RS) and RL100^® (RL) nanosuspensions as well as the free drug to a biological model membrane, consisting of dimyristoylphosphatidylcholine (DMPC) multilamellar vesicles (MLV), was carried out by DSC technique. The aim was to assess the suitability of such calorimetric technique to determine the kinetics of drug release from a polymer system, compared with a classical release test by dialysis method. Nanosuspensions were prepared by a modification of the quasi-emulsion solvent diffusion technique (QESD), a particular approach to the general solvent-change method. This kind of system was planned for the ophthalmic release of non-steroidal anti-inflammatory drugs in ocular diseases associated with inflammatory processes (i.e. post-cataract surgery or uveitis). The drug release was monitored by differential scanning calorimetry (DSC), following the effects exerted by IBU on the thermotropic behaviour of DMPC multilamellar vesicles. IBU affects the main transition temperature (T_m) of phospholipid vesicles, causing a shift towards lower values, driven by the drug fraction entering the lipid bilayer. The obtained values have been used as a calibration curve. DSC was performed on suspensions of blank liposomes added to fixed amounts of unloaded and IBU-loaded Eudragit RS100^® and RL100^® nanosuspensions as well as to powdered free drug. The T_m shifts caused by the drug released from the polymer system or by the free drug, during incubation cycles at 37 °C, were compared to the calibration curve in order to obtain the fraction of drug released. The results were also compared with in vitro dialysis release experiments. The suitability of the two different techniques to follow the drug release as well as the differences between the RL and RS polymer systems was compared, confirming the efficacy of DSC for studying the release from polymer nanoparticulate systems. Explanation of the different rate of kinetic release could be due to void liposomes, which represent a better up-taking system than the aqueous solution phase in the dialysis experiments.     

The influence of chitosan on in vitro properties of Eudragit RS microspheres

Eudragit RS microspheres containing chitosan hydrochloride were prepared by the solvent evaporation method using acetone/liquid paraffin solvent system and their properties were compared with Eudragit RS microspheres without chitosan, prepared in our previous study. Different stirring rates were applied (400-1200 rpm) and drug content, Higuchi dissolution rate constant, surface and structure characteristics of the microspheres were determined for each size fraction. An increase in average particle size with a reduction of stirring rate appeared in limited interval in both series. The average particle size of microspheres without chitosan, prepared at the same stirring rate, was smaller. Pipemidic acid content increased with increasing fraction particle size, but not with increasing stirring rate as it was observed for microspheres without chitosan. We presume that high pipemidic acid content in larger microspheres is a consequence of cumulation of undissolved pipemidic acid particles in larger droplets during microspheres preparation procedure. Pipemidic acid release was faster from microspheres with chitosan and no correlation between Higuchi dissolution rate constant and stirring rate or fraction particle size was found, though it existed in the system without chitosan. Structure and surface characteristics of microspheres observed by scanning electron microscope (SEM) were not changed significantly by incorporation of chitosan. But in contrast with microspheres without chitosan, the surface of chitosan microspheres was more porous after three hours of dissolution. It is supposed that the influence of particle size fraction and stirring rate on release characteristics is expressed to a great extent through porosity and indirectly through total effective surface area, but the incorporation of highly soluble component i.e. chitosan salt hides these effects on drug release. In conclusion, changes in biopharmaceutical properties due to varying stirring rate and fraction particle size exhibited the same direction as those reported for the microspheres without chitosan, although they are less expressed because of increased experimental variability, likely caused by chitosan.     

Optimization of Water/Oil/Surfactant System for Preparation of Medium-Chain-Length Poly-3-Hydroxyalkanoates (mcl-PHA)-Incorporated Nanoparticles via Nanoemulsion Templating Technique

Polymeric nanoparticles gain a widespread interest in food and pharmaceutical industries as delivery systems that encapsulate, protect, and release lipophilic compounds such as omega-3 fatty acids, fat-soluble vitamins, carotenoids, carvedilol, cyclosporine, and ketoprofen. In this study, medium-chain-length poly-3-hydroxyalkanoate (mcl-PHA)-incorporated nanoparticle was developed via facile organic solvent-free nanoemulsion templating technique. The water content (W/surfactant-to-oil (S/O)), S/O, and Cremophor EL-to-Span 80 (Cremo/Sp80) ratios were first optimized using response surface methodology (RSM) to obtain nanoemulsion template prior to incorporation of mcl-PHA. Their effects on nanoemulsion formation were investigated. The mcl-PHA-incorporated nanoparticle system showed a good preservation capability of β-carotene and extended storage stability.     

Preparation and characterization of stearic acid nanostructured lipid carriers by solvent diffusion method in an aqueous system

Nanostuctured lipid carriers (NLC) based on mixture of solid lipids with spatially incompatible liquid lipids are a new type of lipid nanoparticles, which offer the advantage of improved drug loading capacity and release properties. In present study, stearic acid (SA) nanostuctured lipid carriers with various oleic acid (OA) content were successfully prepared by solvent diffusion method in an aqueous system. The size and surface morphology of nanoparticles were significantly influenced by OA content. As OA content increased up to 30 wt%, the obtained particles showed pronounced smaller size and more regular morphology in spherical shape with smooth surface. Compared with solid lipid nanoparticles (SLN), NLC exhibited improved drug loading capacity, and the drug loading capacity increased with increasing OA content. These results were explained by differential scanning calorimetry (DSC) investigations. The addition of OA to nanoparticles formulation resulted in massive crystal order disturbance and less ordered matrix of NLC, and hence, increased the drug loading capacity. The drug in vitro release behavior from NLC displayed biphasic drug release pattern with burst release at the initial stage and prolonged release afterwards, and the successful control of release rate at the initial stage can be achieved by controlling OA content.