Prevent Drug Release Research Articles

Eudragit S-100 coated sodium alginate microspheres of naproxen sodium: Formulation, optimization and in vitro evaluation / Alginatne mikrosfere naproksen natrija obložene Eudragitom S-100: Priprava, optimizacija i in vitro vrednovanje

The aim of the study was to prepare site specific drug delivery of naproxen sodium using sodium alginate and Eudragit S-100 as a mucoadhesive and pH-sensitive polymer, respectively. Core microspheres of alginate were prepared by a modified emulsification method followed by cross-linking with CaCl2, which was further coated with the pH dependent polymer Eudragit S-100 (2.5 or 5 %) to prevent drug release in the upper gastrointestinal environment. Microspheres were characterized by FT-IR spectroscopy, X-ray diffraction, differential scanning calorimetry and evaluated by scanning electron microscopy, particle size analysis, drug loading efficiency, in vitro mucoadhesive time study and in vitro drug release study in different simulated gastric fluids. Stability studies of the optimized formulation were carried out for 6 months. SEM images revealed that the surface morphology was rough and smooth for core and coated microspheres, respectively. Core microspheres showed better mucoadhesion compared to coated microspheres when applied to the mucosal surface of freshly excised goat colon. The optimized batch of core microspheres and coated microspheres exhibited 98.42 ± 0.96 and 95.58 ± 0.74 % drug release, respectively. Drug release from all sodium alginate microsphere formulations followed Higuchi kinetics. Moreover, drug release from Eudragit S-100 coated microspheres followed the Korsmeyer-Peppas equation with a Fickian kinetics mechanism. Stability study suggested that the degradation rate constant of microspheres was minimal, indicating 2 years shelf life of the formulation.

In vitro estimation of drug loss during the implantation procedure of drug-eluting stents

Drug-eluting stents are drug/device combinatory products designed to physically re-establish the blood flow in arteriosclerotic blood vessels and deliver anti-proliferative drugs to the stented vessel section to prevent neointimal hyperplasia. Drug that is released during the implantation procedure is washed away with the blood flow. It was our aim to estimate this drug loss using stents coated with fluorescent model substances in an in vitro setup. Stents mounted on balloon catheters were introduced into a polymethacrylate coronary artery model (adapted from ASTM standard F 2394-07 intended for measurement of securement of stents on delivery systems) via a guiding catheter. The system was perfused by phosphate buffered saline pH 7.4 at a flow-rate adapted to the blood flow-rate in coronary arteries. The perfusate was collected in fractions and model substance content was determined fluorimetrically. The hydrophilic model substance fluorescein sodium was released very fast resulting in a loss of approximately 64 % of the drug load within the first minute and up to 82 % after 5 minutes. The hydrophobic model substance triamterene was released much slower from the coating. A total loss of 5 % was detected after 5 minutes. Furthermore, commercially available sirolimus-eluting Cypher Select + stents were tested. Release into the media was not detected. Obviously, the drug-free top coating effectively prevented drug release during the simulated passage to the site of implantation. An in vitro test system to estimate drug loss during the implantation procedure of drug-eluting stents was successfully established. First results using fluorescent model substances indicate that vast losses have to be expected when using fast releasing delivery systems. Therefore, the model may also prove valuable for the in vitro testing of drug-eluting balloons. Further adaptations, such as the inclusion of biorelevant media, may be suitable to further improve the predictability of in vivo performance.

Encapsulation of Liposomes within pH Responsive Microspheres for Oral Colonic Drug Delivery

A novel liposome-in-microsphere (LIM) formulation has been created comprising drug-loaded liposomes within pH responsive Eudragit S100 microspheres. The liposomes contained the model drug 5-ASA and were coated with chitosan in order to protect them during encapsulation within the microspheres and to improve site-specific release characteristics. In vitro drug release studies showed that LIMs prevented drug release within simulated stomach and small intestine conditions with subsequent drug release occurring in large intestine conditions. The formulation therefore has potential for oral colonic drug delivery.

Biocompatible and Bioactive Surface Modifications for Prolonged In Vivo Efficacy

Generally, medical implants, regardless of their construction materials, will become coated in a layer of non-specific proteins mere seconds after implantation. This adsorbed layer activates an irrevocable host defense mechanism, known as the foreign body reaction, which ultimately results in the production of a fibrous avascular capsule that isolates the device from its target tissues, clogs the pores of membranes and sensors, and prevents drug release from a delivery vehicle. Many devices eventually fail because of their inability to effectively communicate with the surrounding tissues. It is becoming apparent that sub-cellular interactions at the biological-material interface have macroscopic outcomes. The success of the next generation of implants depends on overcoming limitations in biological communication by selective modification of device surfaces. This review focuses on recent advances in increased implant efficacy through selective surface modifications. Several approaches co-opt solutions found in the natural world to create a surface that mimics the properties of the cell membrane, thereby imparting a pseudo-biological character to synthetic materials. We begin with a short description of the foreign body reaction and then examine the biocompatible and bioactive device surface modification advances from the past five years that hold the potential of increased in vivo effectiveness.

DESIGN AND DEVELOPMENT OF PACLITAXEL - LOADED MICROSPHERES FOR TARGETED DRUG DELIVERY TO THE COLON

The purpose of this investigation was to prepare and evaluate the colon-specific microspheres of Paclitaxel for the treatment of colon cancer. Core microspheres of alginate were prepared by the modified emulsification method in liquid paraffin and by cross-linking with calcium chloride. The core microspheres were coated with Eudragit S-100 by the solvent evaporation technique to prevent drug release in the stomach and small intestine. The microspheres were characterized by shape, size, surface morphology, size distribution, incorporation efficiency, and in vitro drug release studies. The outer surfaces of the core and coated microspheres, which were spherical in shape, were rough and smooth, respectively. The size of the core microspheres ranged from 20 to 52 µm, and the size of the coated microspheres ranged from 107 to 178 µm. The core microspheres sustained the drug release for 10 hours. The release studies of coated microspheres were performed in a pH progression medium mimicking the conditions of the gastrointestinal tract. Release was sustained for up to 20 hours in formulations with core microspheres to a Eudragit S-100 coat ratio of 1:7, and there were no changes in the size, shape, drug content, differential scanning calorimetry thermogram, and in vitro drug release after storage at 40°C/75% relative humidity for 6 months.

Polyethyleneimine-modified pectin beads for colon-specific drug delivery: In vitro and in vivo implications

Calcium-pectinate (Ca-pectinate) beads have shown immense potential as colon-specific drug carrier. However, Ca-pectinate itself is unable to prevent its swelling/degradation in the upper gastro-intestinal (GI) conditions. Hence, polyethyleneimine (PEI) was added in the cross-linking solution to strengthen the Ca-pectinate network. Resveratrol was used as a model drug due to its promising therapeutic activity towards several colonic diseases. Beads were prepared by varying cross-linking solution pH and other formulation variables. The effects of these formulation variables were investigated on the bead's characteristics. Furthermore, surface morphology, drug–polymer interaction, stability, and in vivo pharmacokinetic study of the optimized formulation were performed. The optimized PEI-modified beads prevented drug release in the upper GI conditions, while released the drug in simulated colonic fluid. Furthermore, in vivo pharmacokinetics studies in rats demonstrated delayed appearance of drug in blood after oral administration. The optimized Ca-pectinate beads demonstrated both in vitro and in vivo colon-specific drug release.

Assessment of the in-vivo drug release from pellets film-coated with a dispersion of high amylose starch and ethylcellulose for potential colon delivery

The aim of this study was to test the ability of a colon targeting system comprising pellets film-coated with a dispersion of high amylose starch (Hylon VII) and ethylcellulose (Surelease) (1 : 2 w/w) to deliver a model drug (5-aminosalicylic acid; 5-ASA) in vivo into the colon of rabbits. An uncoated pellet formulation was used as a control. Six New Zealand female rabbits, approximately 2 kg, were randomly divided into two groups. Pellet formulations containing 50 mg/kg of 5-ASA were filled into hard gelatin capsules size 4, and were administered orally using a cannula. The rabbits were fasted for 12 h before, and throughout, the study but had free access to water. Blood samples were collected, through a catheter inserted into the marginal vein of the ear, at pre-determined times and the plasma analysed by a validated HPLC method with fluorescence detection. Analysis of the 5-ASA plasma levels following administration of the uncoated pellets showed a C(max) of 2.38 +/- 0.49 microg/ml at 2 h post administration confirming that this system released the drug at an unspecific site, most likely in the rabbits' stomach and proximal small intestine. On the other hand, the coated formulation showed a delayed drug absorption (C(max) 0.22 +/- 0.19 microg/ml and t(max) of 8 h), suggesting that the coating is able to prevent drug release in the stomach and small intestine, but allowing drug release in the colon. The coated pellets were retrieved from the rabbits' faeces after the 24-h study. They had a drug content of < 40%, suggesting that the film-coating had been digested by the bacterial amylases of the colon and the drug was released specifically in the colon of the rabbits. Results from this study showed that the proposed drug delivery system has the potential to deliver drugs specifically into the colon.

Poly(ethylene glycol)-mesalazine conjugate for colon specific delivery

Chronic inflammatory bowel diseases (IBDs) are still waiting for improved and innovative therapeutic treatments, which can overcome the limits of the current approaches. Since IBDs affect mainly the lower tract of the intestine, a localized therapy in the colon tract will avoid most of the problems caused by systemic or poor selective therapies. Particularly promising are the advance drug delivery systems that can reach specific colon delivery, thus guaranteeing active agent release only at the site of action. This approach can meet two aims at the same time, first of all the drug will not affect healthy tissue and second a lower drug dose may be used because all the administered active agent will reach the target. To obtain a specific colon delivery we exploited the azoreductase enzymes, selectively present only in colon, by inserting an azo linker between a selected drug and a macromolecular carrier. The drug employed is mesalazine, a well know and used agent against IBDs. Poly(ethylene glycol) (PEG), of different molecular weights and structures, was used as carrier. Three different conjugates were synthesized and characterized, and the most promising one, with highest drug loading thanks to the use of diamino PEG of 4kDa, was further investigated in vitro on mouse colonic epithelial cells (CMT-9) and in vivo on model mice with induced colitis. The data presented here demonstrate that PEG conjugation of mesalazine prevents drug release and absorption in upper intestine, after oral administration of the conjugates, and that the azo linker ensures a good drug release in the colon tract. The results in vivo take into consideration mice bodyweight gain, tissue histology and interleukin-2β as an index of inflammation. These parameters, all together, demonstrated the conjugate effectiveness against the controls.

Characterization of calcium alginate beads of 5-fluorouracil for colon delivery

Amultiparticulate system combining pH-sensitive property and specific biodegradability for colon targeted delivery of 5-fluorouracil (5-FU) was examined. The purpose of this study was to prepare and evaluate the colon-specific alginate beads of 5-FU for the treatment of colon cancer. Calcium alginate beads were prepared by extruding 5-FU loaded alginate solution to calcium chloride solution, and gelled spheres were formed instantaneously by ionotropic gelation reaction using different ratios of FU and alginate, alginate and calcium chloride, stirring speeds (500-1500 rpm), and reaction time. The core beads were coated with Eudragit S-100 to prevent drug release in the stomach and provide controlled dissolution of enteric coat in the small intestine and maximum drug release in the colon. Morphology and surface characteristics of the formulation were determined by scanning electron microscopy. In vitro drug release studies were performed in conditions simulating stomach to colon transit. No significant release was observed at acidic pH, however, when it reached the pH where Eudragit S-100 starts to dissolve, drug release was observed. Also, release of drug was found to be higher in presence of rat caecal content.

Recent Approaches for Colon Drug Delivery

Colon delivery is especially required for drugs intended to act locally or for drugs that exhibit maximum systemic absorption from the colon. However, exposure to extreme pH conditions, gastric enzymes, bile salts and variation in gastric emptying makes the development of colon release dosage forms extremely challenging. The approaches generally used for formulating a colon release dosage form include use of pH dependent release polymers, time-release coatings, prodrugs and biodegradable polymers. Although, considerable choice exists while selecting a pH dependent release polymer, the drug release from these polymers is easily influenced by nature of diet and disease. In addition, while these polymers may prevent drug release in stomach (pH 1-3) and proximal small intestine (pH 6.5), the drug may be prematurely released in vivo in lower small intestine (pH 7.5). Similarly, variation in gastric transit time due to nature of diet and severity of disease often lead to reduced performance of time-release based colon delivery dosage forms. Therefore, new approaches are continuously being evaluated to ensure compliance with requirement of colon release and to reduce the variation in their performance. This article is aimed at studying the recent patents with a view to unveil new concepts being put into use for designing colon release dosage forms.

A comparative in vitro assessment of the drug release performance of pH-responsive polymers for ileo-colonic delivery

The aim of this study was to investigate the in vitro dissolution characteristics of pH-responsive polymers in a variety of simulated fluids. Prednisolone tablets were fabricated and coated with the following polymer systems: Eudragit S (organic solution), Eudragit S (aqueous dispersion), Eudragit FS (aqueous dispersion) and Eudragit P4135 (organic solution). Dissolution tests were conducted using a pH change method whereby tablets were transferred from acid to buffer. Three different buffer media were investigated: two compendial phosphate buffers (pH range 6.8–7.4) and a physiological buffer solution (Hanks buffer) with very similar ionic composition to intestinal fluid (pH 7.4). There was considerable drug release from tablets coated with Eudragit P4135 in acid, prompting discontinuation of further investigations of this polymer. Eudragit S (organic solution), Eudragit S (aqueous dispersion) and Eudragit FS on the other hand prevented drug release in acid, though subsequent drug release in the buffer media was found to be influenced by the duration of tablet exposure to acid. At pH 7.4 drug release rate from the polymer coated tablets was similar in the two compendial media, however in the physiological buffer, they were found to differ in the following order: Eudragit S (aqueous dispersion) > Eudragit FS > Eudragit S (organic solution). The results indicate that the tablets coated with the newer Eudragit FS polymer would be more appropriate for drug delivery to the ileo-colonic region in comparison to the more established Eudragit S. More importantly, however, dissolution in the physiological buffer was found to be markedly slower for all the coated tablets than in the two compendial buffers, a result akin to reported slower dissolution of enteric coated tablets in vivo. There is therefore the need to adequately simulate the ionic composition of the intestinal fluid in the dissolution media.

Interactions of ibuprofen with cationic polysaccharides in aqueous dispersions and hydrogels. Rheological and diffusional implications.

Non-steroidal antiinflammatory drugs, such as ibuprofen, are amphiphilic substances capable of self-association in aqueous solutions and able to be sorbed onto polymers through hydrophobic and electrostatic bonds. The aim of this work was to analyze the association processes of sodium ibuprofen with cationic celluloses (Celquat H-100 (PQ-4) and SC-230 M (PQ-10)) and cationic guar gums (Ecopol 261-S and 14-S) and their repercussions on the properties of the aqueous dispersions and cross-linked hydrogels. The interaction process was studied in aqueous dispersions through transmittance, surface tension, fluorescence, conductivity, viscosity and oscillatory rheometry measurements. Below cmc, the drug molecules weakly interact with the polymers through hydrophobic and ionic interactions. Around the cmc (4%), a notable decrease in the viscosity, and storage and loss moduli of the dispersions (even precipitation in PQ-10 systems) was observed. An additional increase in drug concentration induced the dispersions to recover their initial properties. Since ibuprofen/polymer cationic groups ratio were in all cases above 1, these observations indicate that drug self-association induces the polymer to coil around the micelles and, as the number of micelles increases (more drug concentration) the polymer chains interact with more of them, uncoiling again to some extent. Polymer (1%) dispersions containing 6% ibuprofen showed drug diffusion coefficients much lower than in water. When a surfactant, sodium dodecylsulfate, was added to these systems the diffusion coefficients decreased even more, suggesting the formation of new associative structures. Chemically cross-linked hydrogels made of these cationic polysaccharides absorb considerable amounts of ibuprofen (up to 15 g/g) and showed a pH-dependent release process. At acidic pH, drug-polymer affinity is maintained, preventing drug release. In contrast, at pH 8 the interactions are broken and the release process is sustained for more than 4h. In summary, ibuprofen interactions with cationic polysaccharides strongly determine the performance of their aqueous dispersions and hydrogels.

Multiparticulate chitosan-dispersed system for drug delivery.

A multiparticulate chitosan-dispersed system (CDS), which is composed of the drug reservoir and the drug release-regulating layer, was developed for drug delivery. The drug release-regulating layer is a mixture of water-insoluble polymer and chitosan powder. The drug is released from CDS pellets in all regions of the gastrointestinal tract (from the stomach to the colon). CDS pellets containing chitosan powder were designed to dissolve chitosan powder partly in the release-regulating layer in the stomach and release part of drug. After passing through the stomach, the drug is released from CDS pellets at a constant speed in the small intestine. In the large intestine, CDS pellets were designed to disintegrate the remaining chitosan powder at an accelerated speed and the remaining drug in CDS pellets is released. The drug release rate can be controlled with the thickness of the chitosan-dispersed water-insoluble layer. Furthermore, for colon-specific drug delivery, an additional outer enteric coating is necessary to prevent drug release from CDS pellets in the stomach, because the chitosan-dispersed water-insoluble layer dissolves gradually under acidic conditions. The resulting enteric-coated CDS (E-CDS) pellets were found to permit colon-specific drug delivery. In this study, the multiparticulate CDS was adopted not only for colon-specific drug delivery but also for sustained drug release.

Cationic cellulose hydrogels: kinetics of the cross-linking process and characterization as pH-/ion-sensitive drug delivery systems

The cross-linking process of two cationic hydroxyethylcelluloses of different hydroxyethyl and ammonium group contents, polyquaternium-4 (PQ-4) and polyquaternium-10 (PQ-10), with ethylenglycol diglycidylether (EGDE) was characterized and optimized through rheometric analysis of the forming network. The influence of NaOH concentration, temperature, and EGDE concentration on the cross-linking rate were studied. The evolution of the elastic ( G′) and viscous ( G″) moduli, recorded in time-sweep experiments carried out at a fixed angular frequency, showed that the cross-linker requires a minimum of 0.05 M NaOH and 30 °C to be active. The increase in G′ and G″ followed first order kinetics, the slopes of G′ being higher than those corresponding to G″. The gel time, i.e. the time at which the crossover of G′ and G″ occurs, decreases exponentially when temperature increases from 30 to 60 °C. Apparent activation energies, estimated from the gel times, ranged between 70 and 90 kJ/mol. The cross-linking rate was greater in PQ-4 than in PQ-10 owing to the initial lower viscosity and higher content in hydroxyethyl groups of the former. However, IR spectra of the final hydrogels suggest the formation of a similar number of cross-linking junctions in both polymer systems. The optimum conditions for hydrogel preparation were 60 °C in 0.10 M NaOH medium, and no depolymerization was observed. Such hydrogels were transparent, presented a smooth, continuous surface, and were superabsorbent in water. After drying in an oven, the degree of swelling was lower than that of freshly prepared hydrogels; the behavior of water uptake being Fickian. The hydrogels presented a significant loading capacity of diclofenac sodium, with which they interact through ionic and hydrophobic bonding. The affinity is kept at an acidic pH, preventing drug release. In contrast, at pH 8 the interactions are broken and the release process is sustained for more than 4 h. The results also indicate that the ionic strength as well as the initial pH of the medium, when the release was evaluated switching the pH from acidic to basic, are two critical factors which have to be considered to extract conclusions about the behavior of the hydrogels as site-specific delivery systems under in vivo conditions.

Tamoxifen decreases drug efflux from liposomes: relevance to its ability to reverse multidrug resistance in cancer cells?

Tamoxifen decreased the efflux of the fluorescent marker drug, chloroquine, from phosphatidylcholine liposomes. Tamoxifen is a known structural-mimic of cholesterol, which were both found to be similarly effective in preventing drug release from liposomes. This ability of tamoxifen and cholesterol to decrease drug efflux in a concentration-dependent manner is likely to arise from their known ability to decrease membrane fluidity both in liposomes and also in cancer cells. The possible importance of the ability of tamoxifen to inhibit drug efflux from liposomes in relation to its ability to reverse multidrug resistance in cancer patients caused by the efflux of cytotoxic therapeutic agents, is discussed.

Press-coated tablets for time-programmed release of drugs

A new dry-coated device for the release of drug after a programmable period of time is proposed. It is intended to be used mainly in the therapy of those diseases which depend on circadian rhythms. Some core formulations, characterized by different release rates and mechanisms (containing diltiazem hydrochloride or sodium diclofenac as model drugs), were coated by compression with different polymeric barrier layers (press-coated systems). The shell formulations tested contained either gellable or erodible polymers. The dissolution profiles of uncoated cores and press-coated devices were compared. The gellable and/or erodible characteristics (properties) of the barrier formulations were also examined by means of a penetrometer. The coatings prevent drug release from the core until the polymeric shell is completely eroded or swollen. This delay in release start is not influenced by the core composition and depends only on the shell formulation. Except for the time-lag, the release kinetics of the drug contained in the core are not significantly influenced by the presence of the erodible barrier, but can be widely modulated using a swellable polymeric shell.