Miscibility studies of indomethacin and Eudragit® E PO by thermal, rheological, and spectroscopic analysis

The objective of this study is to understand the underlying mechanisms responsible for the superior stability of indomethacin (INM)–Eudragit® E PO (E PO) system by exploring the miscibility and intermolecular interactions through the combination of thermal, rheological, and spectroscopic analysis. The zero shear rate viscosity drops monotonically with the increase of INM concentration at 145°C, suggesting that E PO and INM form a solution and the small molecular drug acts as a plasticizer. Flow activation energy was calculated from the viscosity data at different temperature. The glass transition temperature (T_g) of the mixture at different composition was determined using differential scanning calorimetry. The T_g and flow activation energy peak at the INM concentration around 60%–70%. Fourier transform infrared analysis provided direct evidence for the intermolecular ionic interactions, which may disrupt the dimer formation of amorphous INM. The study explained the superior stability of INM–E PO mixtures, and demonstrated that a combination of thermal, rheological, and spectroscopic technologies can help us to obtain a full picture of the drug–polymer interactions and to determine the formulation and processing conditions.     

Properties of theophylline tablets dry powder coated with Eudragit® E PO and Eudragit® L 100-55

The aim of the present study was to investigate the influence of Eudragit^® E PO on the drug release mechanism of Eudragit^® L 100-55 film coatings applied to theophylline tablets by a dry powder coating technique. The process was entirely liquid-free. Calculation of the Flory-Huggins interaction parameter based on solubility parameters suggested immiscibility of the two copolymers. MDSC thermograms were characterized by two glass transitions for the investigated Eudragit^® E PO/Eudragit^® L 100-55 ratios and confirmed incomplete miscibility of the copolymers at processing conditions. FT-IR analysis was employed to study binding interactions of the polymers. Due to the higher affinity of the plasticizer, triethyl citrate, for Eudragit^® E PO compared to Eudragit^® L 100-55, redistribution of the plasticizer was observed during the curing phase of the process. Plasticizer migration also affected the initial phase of drug release from powder-coated theophylline tablets that were stored for four weeks. Drug release from powder-coated tablets was dependent on the polymer blend ratio, coating thickness, and the pH of the dissolution medium. A broad range of pH dependent theophylline release profiles were obtained as a function of the polymer blend ratio. The particle size of the coating powder influenced the microstructure of the film coating.     

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.     

Physical characterization of carteolol: Eudragit® L binding interaction

Eudragit® L 30D was used as a carrier to prepare carteolol polymeric complexes in order to obtain controlled release dosage forms. The polyanionic form of the polymer, neutralized at different degrees, reacts readily with carteolol hydrochloride to give water-insoluble complexes. Carteolol complexes were characterized by differential scanning calorimetry, IR, ¹H- and ¹³C-NMR spectroscopy. In fact, results indicated that there were intermolecular associations between the polymer and the drug consisting in ammonium salt interactions. Maximum carteolol content was found to be 22% in the complexes.     

Salmon calcitonin-loaded Eudragit® and Eudragit®-PLGA nanoparticles: in vitro and in vivo evaluation

The main objective of this study was to prepare salmon calcitonin (sCT)-loaded Eudragit®RSPO, Eudragit®L100 and Eudragit®-poly(lactic-co-glycolic acid) blend nanoparticles for in vitro and in vivo evaluation as an oral drug delivery system. The prepared nanoparticles ranged in size from 179.7 to 308.9?nm with a polydispersity index between 0.051 and 2.75, and had surface charges ? ?11 to +6?mV. Efficient sCT encapsulation and release was observed with all the nanoparticle formulations. The polymer type was an important factor that influenced the release characteristics and the in vivo hypocalcemic effect. Nanoparticle formulations were also prepared with sodium taurodeoxycholate (NaTDC) and characterized. No statistically significant difference was noted between the hypocalcemic effect of any of the nanoparticle formulations with and without NaTDC (p?>?0.05). The use of Eudragit®RSPO nanoparticles appears to be a potential approach for the oral delivery of sCT.     

In situ amorphisation of indomethacin with Eudragit® E during dissolution

In this study, the possibility of utilising in situ crystalline-to-amorphous transformation for the delivery of poorly water soluble drugs was investigated. Compacts of physical mixtures of γ-indomethacin (IMC) and Eudragit® E in 3:1, 1:1 and 1:3 (w/w) ratios were subjected to dissolution testing at pH 6.8 at which IMC but not the polymer is soluble. Compacts changed their colour from white to yellow indicating amorphisation of IMC.X-ray powder diffractometry (XRPD) confirmed the amorphisation and only one glass transition temperature was observed (58.1 °C, 54.4 °C, and 50.1 °C for the 3:1, 1:1 and 1:3 (w/w) drug-to-polymer ratios, respectively). Furthermore, principal component analysis of infrared spectra resulted in clustering of in situ transformed samples together with quench cooled glass solutions for each respective ratio. Subsequent dissolution testing of in situ transformed samples at pH 4.1, at which the polymer is soluble but not IMC, led to a higher dissolution rate than for quench cooled glass solution at 3:1 and 1:1 ratios, but not for the 1:3 ratio.This study showed that crystalline drug can be transformed into amorphous material in situ in the presence of a polymer, leading to the possibility of administering drugs in the amorphous state without physical instability problems during storage.     

Fabrication and evaluation of Eudragit® polymeric films for transdermal delivery of piroxicam

The aims of this work were to develop and characterize the prolonged release piroxicam transdermal patch as a prototype to substitute oral formulations, to reduce side effects and improve patient compliance. The patches were composed of film formers (Eudragit^®) as a matrix backbone, with PVC as a backing membrane and PEG200 used as a plasticizer. Results from X-ray diffraction patterns and Fourier transform-infrared spectroscopy indicated that loading piroxicam into films changed the drug crystallinity from needle to an amorphous or dissolved form. Piroxicam films were prepared using Eudragit^® RL100 and Eudragit^® RS100 as film formers at various ratios from 1:0 to 1:3. Films prepared solely by Eudragit^® RL100 showed the toughest and softest film, while other formulations containing Eudragit^® RS100 were hard and brittle. Drug release kinetic data from the films fitted with the Higuchi model, and the piroxicam release mechanism was diffusion controlled. Among all formulation tested, Eudragit^® RL100 films showed the highest drug release rate and the highest drug permeation flux across human epidermal membrane. Increasing drug loading led to an increase in drug release rate. Eudragit^® can be used as a film former for the fabrication of piroxicam films.     

Salmon calcitonin-loaded Eudragit® and Eudragit®-PLGA nanoparticles: in vitro and in vivo evaluation

The main objective of this study was to prepare salmon calcitonin (sCT)-loaded Eudragit?RSPO, Eudragit?L100 and Eudragit?-poly(lactic-co-glycolic acid) blend nanoparticles for in vitro and in vivo evaluation as an oral drug delivery system. The prepared nanoparticles ranged in size from 179.7 to 308.9?nm with a polydispersity index between 0.051 and 2.75, and had surface charges ~ -11 to +6?mV. Efficient sCT encapsulation and release was observed with all the nanoparticle formulations. The polymer type was an important factor that influenced the release characteristics and the in vivo hypocalcemic effect. Nanoparticle formulations were also prepared with sodium taurodeoxycholate (NaTDC) and characterized. No statistically significant difference was noted between the hypocalcemic effect of any of the nanoparticle formulations with and without NaTDC (p?>?0.05). The use of Eudragit?RSPO nanoparticles appears to be a potential approach for the oral delivery of sCT.     

Eudragit® microparticles as a possible tool for ophthalmic administration of acyclovir

This paper describes the production and characterization of polyacrylic polymer (Eudragit® RL, RS and NE) microparticles by spray drying method. Microparticles were designed for ophthalmic administration of acyclovir. Microparticle morphology was characterized by optical and electron microscopy. The release kinetics of the drug from microspheres were determined by a dialysis method. The spray drying method described allows the production of microparticles with acceptable encapsulation efficiency and appropriate dimensional characteristics for ophthalmic administration. Release profile data indicate that acyclovir is released from microparticles in a controlled manner. In addition the release pattern of the drug is influenced by the type of Eudragit® used for microparticle production. Moreover the plaque reduction efficiency of acyclovir containing microparticles (except for RS/NE microspheres) is comparable to that displayed by the free drug. Finally our results suggest that acyclovir containing microparticles could represent an interesting system for the release of this antiviral drug at the eye site.     

Preparation and characterization of metformin hydrochloride loaded-Eudragit®RSPO and Eudragit®RSPO/PLGA nanoparticles

The aim of the present study was to develop and characterize metformin HCl-loaded nanoparticle formulations. Nanoparticles were prepared by the nanoprecipitation method using both a single polymer (Eudragit^®RSPO) and a polymer mixture (Eudragit/PLGA). The mean particle size ranged from 268.8 to 288?nm and the nanoparticle surface was positively charged (9.72 to 10.1 mV). The highest encapsulation efficiency was observed when Eudragit®RSPO was used. All formulations showed highly reproducible drug release profiles and the in vitro drug release in phosphate buffer (pH?=?6.8) ranged from 92 to 100% in 12?h. These results suggest that Eudragit^®RSPO or Eudragit/PLGA nanoparticles might represent a promising sustained-release oral formulation for metformin HCl, reducing the necessity of repeated administrations of high doses to maintain effective plasma concentrations, and thus, increasing patient compliance and reducing the incidence of side-effects.     

In vitro testing of controlled release theophylline preparations: Theolair ®, Theograd® and Theolin®

Three dissolution methods,i.e. a paddle type, theusp disintegration and a column method, were used to characterize the release from three controlled release theophylline preparations,i.e. Theolair Retard® 250, Theolin Retard® 300 and Theograd® 350. The release profiles proved to be dependent upon agitation intensity and pH or a combination of both, but the sensitivity towards these variables differed markedly between the products tested.     

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.     

Influence of plasticizers on the mechanical properties of pellets containing Eudragit® RS 30 D

The influence of plasticizers on the mechanical properties of single pellets containing the acrylic polymeric dispersion, Eudragit® RS 30 D, as a granulating binder was investigated. Microcrystalline cellulose and anhydrous lactose were used as the substrate powders for pellets prepared by the wet massing and extrusion/spheronization technique. The effects of hydrophilic and hydrophobic plasticizers on the mechanical properties of the pellets and thermal properties of free films were investigated. The mechanical properties, including tensile strength and Young's modulus, of individual pellets were determined by a diametral compression method with a Chatillon® tension/compression apparatus. The results demonstrated that both the tensile strength and Young's modulus of the pellets decreased as the plasticizer content increased in the pellet formulation, with the exception at low plasticizer levels. The influence of plasticization on the granulating polymer was reflected in the mechanical properties of pellets, indicating that the pellets underwent a cohesive fracture. The unexpected increase in the tensile strength and Young's modulus of the pellets containing low levels of plasticizers was ascribed to the antiplasticization of the polymer due to the immobilization of the polymer molecules by hydrogen bonding, van der Waal's forces and steric hindrance from the plasticizer molecules. Pellets containing low levels of plasticizers exhibited a brittle fracture behavior under compression while a ductile property was observed at higher plasticizer concentrations. The transition of the fracture behavior from a brittle to a ductile pattern was found to take place when plasticizer levels in the acrylic polymer were between 10 and 20% based on the weight of dry polymer. The transition was due to the shift of the polymeric binder from a glassy to a rubbery state, which was verified by the glass transition temperature values of the free films.     

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.     

Preparation and characterization of spray-dried valsartan-loaded Eudragit® E PO solid dispersion microparticles

The purpose of this study was to develop the immediate release stomach-specific spray-dried formulation of valsartan (VAL) using Eudragit^® E PO (EPO) as the carrier for enhancing dissolution rate in a gastric environment. Enhanced solubility and dissolution in gastric pH was achieved by formulating the solid dispersion using a spray drying technique. Different combinations of drug–polymer–surfactant were dissolved in 10% ethanol solution and spray-dried in order to obtain solid dispersion microparticles. Use of the VAL–EPO solid dispersion microparticles resulted in significant improvement of the dissolution rate of the drug at pH 1.2 and pH 4.0, compared to the free drug powder and the commercial product. A hard gelatin capsule was filled with the VAL–EPO solid dispersion powder prior to the dissolution test. The increased dissolution of VAL from solid dispersion microparticles in gastric pH was attributed to the effect of EPO and most importantly the transformation of crystalline drugs to amorphous solid dispersion powder, which was clearly shown by scanning electron microscopy (SEM), differential scanning calorimetry (DSC), and powder X-ray diffraction (P-XRD) studies. Thus, VAL, a potential antihypertensive drug in the form of a solid dispersion microparticulate powder, can be effectively delivered in the immediate release dosage form for stomach-specific drug delivery.     

Eudragit® S100 coated calcium pectinate microspheres of curcumin for colon targeting

Currently, colon-specific drug delivery systems have been investigated for drugs that can exert their bioactivities in the colon. In this study, Eudragit? S100 coated calcium pectinate microsphere, a pH-dependent and enzyme-dependent system, as colon-specific delivery carrier for curcumin was investigated. Curcumin-loaded calcium pectinate microspheres were prepared by emulsification-linkage method, and the preparation technology was optimised by uniform experimental design. The morphology of microspheres was observed under scanning electron microscopy. Interactions between drug and polymers were investigated with differential scanning calorimetry (DSC) and X-ray diffraction. In?vitro drug release studies were performed in simulated colonic fluid in the presence of Pectinex Ultra SP-L or 1% (w/v) rat caecal content, and the results indicated that the release of curcumin was significantly increased in the presence of 1% (w/v) rat caecal contents. It could be concluded that Eudragit? S100 coated calcium pectinate microsphere was a potential carrier for colon delivery of curcumin.     

Dry Powder Coating of Pellets with Micronized Eudragit® RS for Extended Drug Release

PURPOSE: To develop a novel powder coating technology for extended-release pellets based on the acrylic polymer, Eudragit RS. METHODS: A mixture of micronized Eudragit RS plus talc and a liquid feed (plasticizer plus binder solution) were sprayed separately onto propranolol hydrochloride-loaded pellets in a fluidized bed coater. The coated pellets were heat-cured under different conditions (40 degrees C to 60 degrees C, 2 h to 24 h). The coalescence (film formation) of the polymer particles was studied via the determination of the glass transition and the minimum polymer-softening temperatures (MST). The coated pellets were characterized with respect to their morphologic, release, and stability properties. RESULTS: The optimum plasticizer type and concentration and process temperatures could be identified by the determination of the MST. High concentrations of plasticizer (40% based on the polymer) and a thermal treatment were necessary to achieve complete film formation and extended drug release. Curing the pellets resulted in release profiles, which did not change during storage for 3 years. The coated pellets had a smooth, continuous surface and a dense film structure after curing. CONCLUSIONS: This novel coating technique avoids the use of organic polymer solutions or latex dispersions, has short processing times, and results in stable extended-release profiles.     

Identification of Phase Separation in Solid Dispersions of Itraconazole and Eudragit® E100 Using Microthermal Analysis

Purpose. To evaluate the phase separation in itraconazole/Eudragit® E100 solid dispersions prepared by hot-stage extrusion. Methods. Extrudates were prepared using a corotating twin-screw extruder at 180°C. Micro-TA was used to evaluate the phase separation, where the AFM mode is used to visualize the different phases and local thermal analysis (LTA) to characterize the different phases Results. Itraconazole formed a homogeneous mixture with Eudragit® E100 with drug concentrations up to approximately 20%. Above this concentration, phase separation was observed. MTDSC revealed two T_gs and the mesophase of free glassy itraconazole. Performing micro-TA on the surface of these dispersions indicated an increase in sample roughness in the z-axis piezo signal, which could be an indication of free glassy itraconazole. However, thermal conductivity did not reveal differences between separate phases. Performing LTA, where only a small area (20 × 20 m) is heated, showed two separate and mixed phases of itraconazole and Eudragit® E100. Tip penetration in itraconazole and Eudragit® E100 occurred at 332K and 383K respectively. The difference in tip penetration was explained in terms of the difference in fragility. Conclusion. Micro-TA makes it possible to characterize separate phases of itraconazole and Eudragit® E100, thereby confirming the MTDSC results on phase separation.