Control of prolonged drug release and compression properties of ibuprofen microspheres with acrylic polymer, eudragit RS, by changing their intraparticle porosity [corrected]

Prolonged-release spherical micro-matrices of ibuprofen with Eudragit RS were prepared using a novel emulsion-solvent diffusion method. Those particles were termed "microspheres" due to their characteristic sponge-like texture and unique dissolution and compression properties unlike conventional microcapsules or microspheres. The internal porosity of microspheres could be easily controlled by changing the concentration of the drug and the polymer in the emulsion droplet (ethanol). With lower concentration of ibuprofen in the ethanol, the resultant microspheres had a higher porosity, about 50%. The drug release rate from the microspheres was interpreted by the Higuchi model of spherical matrices, which depended only on their internal porosity of the microspheres when size distribution and drug content were the same. The tortuosities in the microspheres were found to be almost constant (3-4) irrespective of porosity, suggesting the same internal texture. Microsphere compressibility was much improved over the physical mixture of the drug and polymer owing to the plastic deformation of their sponge-like structure. The more porous microspheres produced stronger tablets [corrected].     

Application of eudragit RS to thermo-sensitive drug delivery systems. I. Thermo-sensitive drug release from acetaminophen matrix tablets consisting of eudragit RS/PEG 400 blend polymers

In order to develop the polymer materials having temperature-sensitive and high biological safety, Eudragit RS-PO and polyethylene glycol 400 (PEG 400) blend polymers (EPG) were prepared. The EPGs that have the glass transition temperature (Tg) at around the body temperature were prepared by the addition of 5--13% PEG 400 to Eudragit RS. As glassy polymers are not in thermodynamic equilibrium below their Tg, the effects of isothermal aging on the T(g)s of Eudragit RS and EPG containing 10% PEG 400 (10% EPG) were also studied at various aging temperatures. The Tg values of Eudragit RS increased with the aging time and after 30 d of aging, they apparently reached constant values which markedly differed depending on the aging temperatures. On the other hand, the Tg values of 10% EPG were almost independent of the aging temperature and reached around 33 degrees C at 30 d after aging. The ability as thermo-sensitive polymer of EPG was evaluated by the dissolution test of the acetaminophen (AAP) matrix tablets prepared with EPG. The AAP release rate from the EPG matrix tablets slightly changed below the Tg of tablets, and then, it markedly increased above the Tg. Considering high biological safety of Eudragit RS and PEG 400, EPG might be available to develop the novel thermo-sensitive drug delivery systems.     

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).     

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.     

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.     

Mechanism of pellet coat rupture and its effect on drug release.

In the formation of a coated controlled release preparation with functional coat layers, hydroxypropyl-methylcellulose was used to form a diffusion layer which swelled immediately upon wetting. Eudragit RS30D was used to form the outer retention layer. The rupture of pellet coat occurred when the Eudragit RS30D was unable to withstand the expansion in volume due to the influx of water and swelling of the hydroxypropylmethylcellulose diffusion layer. The sucrose core was able to contribute an osmotic effect. The hydrostatic pressure built up within the pellet can cause the pellet coat to rupture. Sodium chloride deposited in the diffusion coat was able to delay the bursting of the pellet coat. This was due to the competition for the imbibed water between sodium chloride and hydroxypropylmethylcellulose. The rupture of the pellet coat did not result in a total failure of the controlled drug delivery mechanism. Similar drug release rates were obtained irrespective whether there was a puncture in the pellet coat or not. Pressure built-up in the region away from the puncture pushed the core material towards the point of puncture and sealed the puncture point. In addition, the swelling of polymer around the point of rupture ensured continuity in the drug diffusion barrier.     

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.     

Modelling of drug diffusion through swellable polymeric systems

A drug diffusion model for the case of diffusion of an initially uniformly distributed drug through a polymeric matrix is presented and solved. Drug diffusion from a single surface is analyzed for the case of countercurrent diffusion of a solvent which is thermodynamically compatible with the polymer. Due to swelling, considerable volume expansion is observed leading to a moving-boundary diffusion problem. Drug concentration profiles within the polymer and drug release rates can be determined. The results are in agreement with experimental data obtained for the system of KCl distributed in hydrophilic hydroxypropyl methyl cellulose matrices, in the form of tablets.     

Formulation and Evaluation of 5-FU Loaded Eudragit Microspheres: Effect of Various Eudragit on Micromeretic Properties of Microspheres

The aim of the present study was to prepare and evaluate microspheres of Eudragit (RS, RL and RSPO) containing an anticancer drug 5-FU. Microspheres were prepared by O/O solvent evaporation method using a acetone/liquid paraffin system. Magnesium stearate was used as the droplet stabilizer and n-hexane was added to harden the microspheres. The prepared microspheres were characterized for their micromeretic properties and entrapment efficiency; as well by Fourier transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC), X-ray powder diffractometry (XRPD), thin layer chromatography (TLC) and scanning electron microscopy (SEM) revealed the crystalline nature of drug in a final state. The in vitro release studies were performed in a Phosphate Buffer Solution (PBS) pH 7.4. The best fit release kinetics was achieved with a Higuchi plot. The yields of preparation and entrapment efficiencies were very high with a larger particle size for all the formulations. Mean particle size, entrapment efficiency and production yield were highly influenced by the type of polymer and polymer concentration. It is concluded from the present investigation that various Eudragit are promising controlled release carriers for 5-FU.     

Influence of Crosslinking Agent on the Release of Drug from the Matrix Transdermal Patches of HPMC/Eudragit RL 100 Polymer Blends

The present work was designed to develop suitable transdermal matrix patches using the polymer blends of hydroxy propyl methyl cellulose (HPMC) and Eudragit RL100 (ERL) with triethyl citrate as a plasticizer in group A and in group B, other than HPMC and ERL, crosslinking agent, succinic acid was added. A 3² full factorial design was employed for both groups. The concentration of HPMC and ERL were used as independent variables, while percentage drug release was selected as dependent variable. Physical evaluation was performed such as moisture content, moisture uptake, tensile strength, flatness and folding endurance. In vitro diffusion studies were performed using cellulose acetate membrane (pore size 0.45 μ) in a Franz's diffusion cell. The concentration of diffused drug was measured using UV-visible spectrophotometer (V-530, Jasco) at λ _max 272 nm. The experimental results shows that the transdermal drug delivery system (TDDS) containing ERL in higher proportion gives sustained the release of drug and patches containing crosslinking agent shows more release than those do not contains succinic acid.     

Comparison of the fragility index of different eudragit polymers determined by activation enthalpies

The present study aimed to apply fragility index (m) of polymers in the determination of the optimal amount of plasticizer in polymer films. The fragility index of different Eudragit polymers (RS, RL, EPO) was assessed by differential scanning calorimerty (DSC), applying the Arrhenius connection (logq–1/T _g). The fragility of Eudragit EPO films proved to be the highest, while in the case of RS and RL, the increase of the alkyl-chain length caused the increase of fragility. Studying the effect of plasticizer (triethyl citrate, TEC) on the m value of Eudragit RL and RS films, a near linear reduction of the fragility index could be observed between 5–30% TEC concentration, but above 30%, this value leveled out to constant.     

Image analysis studies of dimensional changes in swellable hydrophilic polymer matrices

Studies of the fronts which are created by the process of swelling, their movement and the effect of drug solubility on release mechanisms, are presented. Tablets comprising solely of hydroxypropyl methylcellulose (HPMC) (Metolose 90 SH 100 000 SR), HPMC with sodium diclofenac (relatively soluble in the buffer solution used) and HPMC with furosemide (insoluble in the buffer solution used) were prepared. The tablets were made by direct compression in a manual hydraulic press and the matrix swelling was studied by an optical analysis technique. During the experimental procedure measurements were taken of the gel layer dimensions, the movement of the swelling, and the erosion and diffusion fronts at different time points. These measurements allowed the investigation of the possible mechanisms involved in the swelling/release process. The results showed that the rate and mechanism of drug release from swellable matrices depends on the following factors: the dissolution, the diffusion of the drug, the translocation of undissolved drug particles in the gel layer, and the solubility of the drugs used. This is supported by the following: (a) the diffusion layer thickness, which is observed as a result of the presence of undissolved drug in the gel layer, increases in the case of the water insoluble drug furosemide and as a result the diffusion front converges on the erosion front; (b) from the analysis of the dissolution data it appears that sodium diclofenac is released as a result of diffusion via the gel layer as well as due to polymer relaxation and/or matrix erosion. Conversely, the release of furosemide is only dependent on the polymer relaxation and/or matrix erosion. Copyright © 2004 John Wiley & Sons, Ltd.     

Effect of method of preparation and process variables on controlled release of insoluble drug from chitosan microspheres

An inexpensive and simple method was adopted for the preparation of chitosan microspheres, crosslinked with glutaraldehyde (GA), for the controlled release of an insoluble drug‐ibuprofen, which is a commonly used NSAID (non‐steroidal anti‐inflammatory drug). The chitosan microspheres were prepared by different methods and varying the process conditions such as rate of stirring, concentration of crosslinking agent, and drug:polymer ratio in order to optimize these process variables on microsphere size, size distribution, degree of swelling, drug entrapment efficiency, and release rates. The absence of any chemical interaction between drug, polymer, and the crosslinking agent was confirmed by Fourier transform infrared (FTIR) spectroscopy, differential scanning calorimetry (DSC), and thermogravimetric analyses (TGA) techniques. The microspheres were characterized by optical microscopy, which indicated that the particles were in the size range of 30–200 µm and scanning electron microscopy (SEM) studies revealed a smooth surface and spherical shape of microspheres. The microsphere size/size distributions were increased with the decreased stirring rates as well as GA concentration in the suspension medium. Decreasing the concentration of crosslinker increased the swelling ratio whereas extended crosslinking exhibited lowered entrapment efficiency. The in vitro drug release was controlled and extended up to 10 hr. Copyright © 2007 John Wiley & Sons, Ltd.     

The importance of the film structure during self-powered ibuprofen salicylate drug release from polypyrrole electrodeposited on AZ31 Mg

Therapeutic drugs uploaded into conjugated conductive polymer matrices deposited on active magnesium alloys serve as controlled-dose, self-powered drug-delivery systems. Preferentially, drugs are added into polymer films in the largest amount possible, mostly to prevent long-term treatments. However, added drugs can interact with the polymer matrix affecting either the structure or the final mechanical properties of the polymer film. In this work, polypyrrole films (PPy) electrodeposited on an AZ31 Mg alloy in ibuprofen and salicylate-containing solutions are investigated in terms of their uploading capacity, surface morphology and mechanical properties. The techniques used to investigate the uploaded PPy films include cyclic voltammetry (CV), scanning electron microscopy (SEM), EDS, and depth-sensing indentation (DSI). A maximum ibuprofen concentration of 440 ± 40 μg cm^?2 was obtained in PPy films in the presence of sodium salicylate. The release fraction of ibuprofen as a function of time is fitted to Avrami’s equation. The hardness and reduced modulus decreased by 54 and 40 %, respectively, when the PPy films are prepared in the presence of sodium ibuprofen compared with those prepared in sodium salicylate only, indicating a more plastic film with ibuprofen.     

A different diffusion mechanism for drug molecules in amorphous polymers

Polymer materials are widely used in controlled drug release, and the diffusion property of drug molecules in these materials is of great importance. In this work, the diffusion behavior of a model drug (aspirin) in different ratios of poly(lactic acid-co-ethylene glycol) (PLA-PEG) was investigated by molecular dynamics simulations. Two major factors, which influence the diffusion of aspirin in polymer matrix: the wriggling of the polymer chain and the free volume of the polymer matrix, are discussed. The wriggling of the polymer chain mainly controls the diffusion of aspirin molecules. Free volume becomes the secondary effect. For two different polymers having a similar degree of wriggling, the free volume controls the diffusion of the aspirin molecules. Comparing with the diffusion behavior of small gas molecules in polymer matrix, a different mechanism was proposed for the drug molecules. The drug molecules can only diffuse along with the wriggling of the polymer matrix.     

Preparation of functional composite particles of salbutamol sulfate using a 4-fluid nozzle spray-drying technique

A previous study on spray-drying demonstrated that it could promote the solubility of poorly water-soluble drugs using water-soluble polymers. Here, the preparation of composite particles of salbutamol sulfate (Sb) with water-insoluble polymers, such as Eudragit RS (RS) or Eudragit RL (RL) as a carrier, was examined. Despite the water insolubility of both polymers, the permeability of water was low in the former but high in the latter. We attempted to prepare controlled release composite particles by exploiting the characteristics of these carriers. The composite particles of the three components (Sb, RS, and RL) were prepared using a 4-fluid nozzle spray-dryer, and their physico-chemical and dissolution properties were compared with physical mixtures. Examination of particle morphology by scanning electron microscopy (SEM) revealed that the particles from the spray-drying process had atomized to several microns and were spherical. Analysis by X-ray diffraction and differential scanning calorimetry revealed that diffraction peaks and heat of fusion of Sb in the spray-dried samples decreased, indicating that the drug was amorphous and formed a solid dispersion. FT-IR analysis suggested that the amino group of Sb and a carbonyl group of the polymers formed a hydrogen bond. A dissolution test of Sb-RS-RL particles prepared using the 4-fluid nozzle spray-drying method showed that release rates were depressed significantly compared to the physical mixture at pH 1.2 and 6.8, and the depression was greater when RS was used instead of RL, presumably because of the permeability difference. The compression of these particles into tablets revealed that desirable controlled released dosage forms could be prepared. In addition, Sb was used to simulate an anti-asthmatic drug. For this an Andersen cascade impactor for dry powder inhalers was used to investigate delivery to the lungs.     

Thermoresponsive N-vinyl caprolactam grafted sodium alginate hydrogel beads for the controlled release of an anticancer drug

A series of thermoresponsive sodium alginate-g-poly(vinyl caprolactam) (NaAlg-g-PNVCL) beads were prepared as drug delivery matrices of 5-flurouracil (5-FU) crosslinked by glutaraldehyde (GA) in the hydrochloric acid catalyst. Graft copolymers of sodium alginate with vinyl caprolactam were synthesized using azobisisobutyronitrile as an initiator, and characterized by Fourier infrared spectroscopy, differential scanning calrimetry and X-ray diffraction for analysis of the amorphous nature drug in the beads, and by scanning electron microscopy for the spherical nature of the beads. Preparation condition of the beads was optimized by considering the percentage of encapsulation efficiency, swelling behavior of beads and their release data. Effects of variables such as GA concentration, drug/polymer ratio and catalyst concentration on the release of 5-FU were carried out at two different temperatures (25 and 37 °C) in simulated intestinal fluid for 12 h. It was observed that, drug release from the beads decreased with increasing drug/polymer (d/p) ratio, extent of crosslinking agent and catalyst concentration. The swelling degree of graft copolymer beads was found to be increased with decreasing of environmental temperature. In vitro release studies were performed at 25 and 37 °C for 12 h, and showed that thermoresponsive graft copolymer beads had higher drug release behavior at 25 °C than that at 37 °C, following Fickian diffusion transport mechanism with slight deviation.     

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.     

Dispersion polymerization of vinyl monomers in supercritical carbon dioxide in the presence of drug molecules: A one‐pot route for the preparation of controlled delivery systems

The polymerization of 1‐vinyl‐2‐pyrrolidone in supercritical carbon dioxide in the presence of ibuprofen as a model drug was investigated as a new one‐pot process for the preparation of polymer‐based drug delivery systems (DDSs). The composites were prepared at 65 °C and P = 31–42 MPa by changing the initial concentration of the drug and the concentration of a crosslinking agent and that of a hydrophobic comonomer. The effects of these parameters on the performances of the polymerization and on the in vitro release kinetics of ibuprofen were studied. In all the experiments, part of the drug was entrapped inside the polymer particles and dissolved more slowly with respect to the pure compound. Copolymerization with methyl methacrylate was the most effective route to obtain a DDS with sustained temporal release of the drug molecule. © 2008 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 46: 7429–7446, 2008     

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.