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.     

Influence of Fumed Silicon Dioxide on the Stabilization of Eudragit® RS/RL 30 D Film-Coated Theophylline Pellets

The objective of this study was to investigate the influence of various grades of fumed silicon dioxide on the drug release rate and physical aging of theophylline pellets coated with Eudragit® RS 30 D and RL 30 D. Free films were assessed for both physicomechanical properties and water vapor permeability with respect to time and storage conditions. The release rate of theophylline was influenced by the physical properties of the silicon dioxide employed. As the particle size of the silica dioxide decreased, there was an increase in dispersion viscosity, as well as a decrease in the theophylline release rate from the coated pellets. Films prepared from formulas containing Aeroperl® 300 had twice the water vapor transmission rate of films prepared from formulas containing Aerosil® 200 VV and Cab-O-Sil® M-5P and showed consistent moisture permeability values during storage for up to 1 month at 25°C/0% relative humidity (RH). Scanning electron microscopy (SEM) imaging of pellets coated with a formulation containing Aerosil® 200 VV or Cab-O-Sil® M-5P demonstrated film structures that were homogenous, while those coated with a formulation containing Aeroperl® 300 produced heterogeneous films with large particles of the excipient present within the polymeric matrix of the film. Stability in the drug release rate exhibited by pellets coated with a formulation containing Eudragit® RS 30 D, 15% triethyl citrate (TEC), and 30% Aeroperl® 300 was attributed to the stabilization of the moisture vapor transmission rate of the acrylic films. Increasing the concentration of Aeroperl® 300 in the coating formulation increased the theophylline release rate from coated pellets.     

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.     

Novel microparticle drug delivery systems based on chitosan and Eudragit®RSPM to enhance diltiazem hydrochloride release property

The aim of this study was to enhance the release properties of diltiazem hydrochloride (diltiazem HCl) by using microparticle system. For this reason, microparticle drug delivery systems based on chitosan and Eudragit^®RSPM were developed. The microparticles were prepared by using double-emulsion solvent extraction method and the mean sizes of microparticles were less than 120?µm. The in vitro drug release from microparticles was studied in simulated gastric (pH 1.2) and intestinal media (pH 7.4) than the results were evaluated by kinetically. In vitro diltiazem HCl release from microparticles showed good zero order kinetic. For the microparticles with chitosan, the release of diltiazem HCl at pH 1.2 could be effectively sustained, while the release of diltiazem HCl increased at pH 7.4 when compared to Eudragit^®RSPM microparticles. The highest release percent obtained was 1:1 ratio of drug: polymer at pH 1.2 and 7.4. All results clearly suggest that the release properties of diltiazem HCl were improved by using microparticle systems especially which contain chitosan.     

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.     

Interaction between Eudragit® E100 and anionic drugs: addition of anionic polyelectrolytes and their influence on drug release performance

In this work, we report results concerning the study of solid complexes compounded by a cationic polymethacrylate (Eudragit® E100, Eu) and mesalazine (M) (Eu–M_x complex). The influence of an anionic polyacrylic acid polymer (carbomer, C) on dissolution behavior of M from the complex was evaluated (Eu–M_xC_y complex). The dissolution profiles and solvent front movements of solid matrices in different media (water, buffer pH 7.4, 0.9% NaCl) were investigated and ionic interactions among Eu, M, and C were determined through Fourier transform infrared (FT‐IR) spectroscopy. For Eu–M_x complexes, the affinity between M and Eu modulated the delivery of free M in solution, with the dissolution media affecting the delivery rate mainly due to an ionic interchange process between M and anionic electrolytes (i.e., Cl^?). FTIR spectroscopy allowed the ionic interaction between Eu and M to be verified. The addition of C (Eu–M_xC_y) influenced the dissolution behavior of these matrices. As the amount of C was increased, the release mechanism changed from diffusion (Eu–M₅₀) or anomalous (Eu–M₁₀₀) to zero order (Eu–M_xC₅₀). This variation in rate delivery was also affected by the dissolution media, as occurred with Eu–M_x complexes. The formation of the gel layer during the dissolution process, as consequence of Eu–M_xC_y matrices hydration, was influenced by C amount and dissolution media. © 2011 Wiley‐Liss, Inc. and the American Pharmacists Association J Pharm Sci 100:4664–4673, 2011     

Influence of plasticizer type and level on the properties of Eudragit® S100 matrix pellets prepared by hot-melt extrusion

Matrix-type pellets with controlled-release properties may be prepared by hot-melt extrusion applying a single-step, continuous process. However, the manufacture of gastric-resistant pellets is challenging due to the high glass transition temperature of most enteric polymers and an unacceptably high, diffusion-controlled drug release from the matrix during the acidic phase. The objective was to investigate the influence of three plasticizers (triethyl citrate, methylparaben and polyethylene glycol 8000) at two levels (10% or 20%) on the properties of hot-melt extruded Eudragit® S100 matrix pellets. Extrusion experiments showed that all plasticizers produced similar reductions in polymer melt viscosity. Differential scanning calorimetry and powder X-ray diffraction demonstrated that the solid state plasticizers were present in the amorphous state. The drug release in acidic medium was influenced by the aqueous solubility of the plasticizer. Less than 10% drug was released after 2 h at pH 1.2 when triethyl citrate or methylparaben was used, independent of the plasticizer level. Drug release at pH 7.4 resulted from polymer dissolution and was not influenced by low levels of plasticizer, but increased significantly at the 20% level. Mechanical testing by diametral compression demonstrated the high tensile strength of the hot-melt extruded pellets that decreased when plasticizers were present.     

A Study of the Effects of Curing and Storage Conditions on Controlled Release Diphenhydramine HCl Pellets Coated with Eudragit® NE30D

The objective of this study was to investigate the possible impacts of curing and storage conditions on dissolution of controlled release diphenhydramine HCl pellets coated with EUDRAGIT® NE30D. The accumulative percentage of dissolved active drug was used as the response in three statistical experimental design studies: 3² full factorial, Box–Behnken and 2³ designs. By only considering curing temperature and curing time, both factors were found to significantly affect the dissolution rate, but curing temperature had greater impact than curing time. When considering polymer coating level, curing temperature and curing time together, polymer coating level and curing temperature had important effects on dissolution rate, but curing time became insignificant among these three factors. The addition of the water-soluble additives hydroxypropyl methyl cellulose and mannitol made coating films less sensitive to curing, and there was little or no difference in their effect in the model studied. Lower levels of a water-insoluble additive (kaolin) had little impact on dissolution; however, when the level of water-insoluble additive increased, the coating film became more sensitive to curing, especially at the lower curing temperature of 30°C.     

Influence of polymers ratio on insulin-loaded nanoparticles based on poly-ε-caprolactone and Eudragit® RS for oral administration

Nanoparticles loaded with two different commercial insulins (Actrapid^®, Novorapid^®) and based on different blends of a biodegradable polyester (poly-ε-caprolactone) and a polycationic non-biodegradable acrylic polymer (Eudragit^® RS) were characterized in vitro. The zeta potential was positive whenever Eudragit^® RS was part of the nanoparticles matrix. The encapsulation efficiency was ~ 96% except for Novorapid^®-loaded particles of poly-ε-caprolactone (only 35%). In vitro release studies revealed a burst release from nanoparticles, which may be of interest for oral delivery. Novorapid-loaded nanoparticles were orally administered to diabetic rats and allowed the glycemia to be decreased when compared with free nanoparticles.     

A pH/enzyme-responsive polymer film consisting of Eudragit® FS 30 D and arabinoxylane as a potential material formulation for colon-specific drug delivery system

Polymer film based on pH-dependent Eudragit^® FS 30 D acrylic polymer in association with arabinoxylane, a polysaccharide issued from gum psyllium, was produced by way of solvent casting. Physical-chemical characterization of the polymer film samples was performed by means of thermogravimetry (TGA), differential scanning calorimetry (DSC), and scanning electron microscopy (SEM). Furthermore, water-equilibrium swelling index (I_s) and weight loss of the films in KCl buffer solution of pH 1.2, in KH₂PO₄ buffer solution of pH 5.0, or in KH₂PO₄ buffer solution of pH 5.0 consisting of 4% enzyme Pectinex^® 3X-L (w/v) were also carried out for the film characterization. No chemical interactions between the Eudragit^® FS 30 D and the arabinoxylane polymer chains were evidenced, thus suggesting that the film-forming polymer structure was obtained from a physical mixture of both polymers. The arabinoxylane-loader films showed a more pronounced weight loss after their immersion in buffer solution containing enzyme Pectinex^® 3X-L. The introduction of the arabinoxylane makes the film more susceptible to undergo an enzymatic degradation. This meant that the enzyme-dependent propriety issued from the arabinoxylane has been imprinted into the film formulation. This type of polymer film is an interesting system for applications in colon-specific drug delivery system.     

Effect of formulation variables on in vitro release of a water-soluble drug from chitosan–sodium alginate matrix tablets

The objective of this study is to investigate the feasibility of using chitosan–sodium alginate (CS–SA) based matrix tablets for extended-release of highly water-soluble drugs by changing formulation variables. Using trimetazidine hydrochloride (TH) as a water-soluble model drug, influence of dissolution medium, the amount of CS–SA, the CS:SA ratio, the type of SA, the type and amount of diluents, on in vitro drug release from CS–SA based matrix tablets were studied. Drug release kinetics and release mechanisms were elucidated. In vitro release experiments were conducted in simulated gastric fluid (SGF) followed by simulated intestinal fluid (SIF). Drug release rate decreased with the increase of CS–SA amount. CS:SA ratio had only slight effect on drug release and no influence of SA type on drug release was found. On the other hand, a large amount of water-soluble diluents could modify drug release profiles. It was found that drug release kinetics showed the best fit to Higuchi equation with Fickian diffusion as the main release mechanism. In conclusion, this study demonstrated that it is possible to design extended-release tablets of water-soluble drugs using CS–SA as the matrix by optimizing formulation components, and provide better understanding about drug release from CS–SA matrix tablets.     

Synthesis and characterization of a new carrier based on Eudragit® EPO/S100 interpolyelectrolyte complex for controlled colon-specific drug delivery

With a view to the development of peroral controlled drug delivery systems, a new interpolyelectrolyte complex (IPEC) between oppositely charged types of Eudragit?, EPO and S100, has been synthesized and investigated at neutral pH values. According to data of turbidimetry, capillary viscometry, gravimetry, and elemental analysis, the obtained IPEC has a composition of Z = [EPO]/[S100] = 1.26. Structural features of the IPEC samples have been evaluated by FTIR spectroscopy and modulated-temperature differential scanning calorimetry. The results confirmed that the IPEC is stabilized by cooperative intermacromolecular ionic bonds, is chemically homogeneous, and is characterized by a single glass transition temperature. The observed features of the carrier swelling and diclofenac sodium release from the matrix system confirm that the proposed IPEC has great potential to be used as a carrier for controlled colon-specific drug delivery.     

Effect of cations on the microstructure and in-vitro drug release of κ- and ι-carrageenan liquid and semi-solid aqueous dispersions

Objectives The main objective of this study was to determine the effect of potassium and calcium ions on the microstructure and release dynamics of kappa (κ) and iota (ι) carrageenan. Methods The microstructure of the dispersions was imaged using a cryogenic scanning electron microscope. Franz‐cell diffusion apparatus was used to determine the release kinetics of a model hydrophilic drug, sodium fluorescein, incorporated in selected polymer dispersions. Release profiles were analysed using Higuchi, Korsmeyer‐Peppas and dual first‐order models. Key Findings Cryogenic scanning electron microscope images showed that κ‐carrageenan forms hexagonal structures, whereas ι‐carrageenan forms rectangular pores at low cation concentrations. In‐vitro release studies showed sustained release profiles for all carrageenan systems; however the model drug, fluorescein, diffusion from ι‐carrageenan with 0.06% w/v calcium was significantly higher than other ι‐carrageenan systems. This may be attributed to improved tortuosity of this system. However further increase in cation concentration led to a reduction in fluorescein release from the matrices. The dual first‐order release model illustrated two distinct release rates, an initial rapid release followed by a slow diffusion of fluorescein from the carrageenan matrices. Conclusions The observed microstructural differences may account for the well known variation in mechanical properties of κ‐ and ι‐carrageenan gels. The dual first order release model adds a new tool in the elucidation of release mechanisms from polymer matrices, where parallel processes contribute to drug release.     

Effect of solid lipid’s structure on nanostructured lipid carriers encapsulated with sun filter: characterisation,photo-stability and in vitro release

Three series of solid lipid are formulated in nanostructured lipid carriers (NLC) system, which encapsulated with sun filter to evaluate the effect on the physicochemical properties of the nanocarriers. Production is performed by ultrasonication–homogenisation, analysis by particle size, zeta potential (ZP), transmission electron microscope, Fourier transform infrared spectroscopy, differential scanning calorimetry (DSC), X-ray diffraction (XRD). Moreover, the encapsulation efficiency, ultraviolet performance and in vitro release are also investigated. The particle sizes of NLCs are between 185 and 225?nm and the polydispersity index is lower than 0.4, ZP from ?56.4 to ?78.6?mV, and the particles are spherical and in homogenous shading. All prepared NCLs encapsulated the sun filter and the EE are higher than 73%. DSC analysis revealed α- to β-polymorphic modification existed in the system of fatty alcohol and fatty acid. However, α, β and β′-polymorphic modifications are exist in the system of cetyl palmitate (PC). Compared with conventional emulsion, all NLCs displayed perfect photo-protective property, especially for the alcohol system. The photo-stability studies showed that the all NLCs have the ability to improve the photo-stability of sunscreens. The in vitro release study suggested all three NLCs displayed sustained release profile and they were fit well with Higuchi equation.     

Effect of chronic treatment with the GABA transaminase inhibitors γ-vinyl GABA and ethanolamine O-sulphate on the in vitro GABA release from rat hippocampus

1. The effects of 2, 8 and 21 day oral treatment with the specific γ-aminobutyric acid transaminase (GABA-T) inhibitors γ-vinyl GABA (GVG) and ethanolamine O-sulphate (EOS) on brain GABA levels, GABA-T activity, and basal and stimulated GABA release from rat cross-chopped brain hippocampal slices was investigated.
2. Treatment with GABA-T inhibitors lead to a reduction in brain GABA-T activity by 65–80% compared with control values, with a concomitant increase in brain GABA content of 40–100%.
3. Basal hippocampal GABA release was increased to 250–450% of control levels following inhibition of GABA-T activity. No Ca²⁺ dependence was observed in either control or treated tissues.
4. GVG and EOS administration led to a significant elevation in the potassium stimulated release of GABA from cross-chopped hippocampal slices compared with that of controls. Although stimulated GABA release from control tissues was decreased in the presence of a low Ca²⁺ medium, GVG and EOS treatment abolished this Ca²⁺ dependency.
5. GABA compartmentalization, Na⁺ and Cl⁻ coupled GABA uptake carriers and glial release may provide explanations for the loss of the Ca²⁺ dependency of stimulated GABA release observed following GVG and EOS treatment.
6. Administration of GABA-T inhibitors led to increases in both basal and stimulated hippocampal GABA release. However, it is not clear which is the most important factor in the anticonvulsant activity of these drugs, the increased GABA content ‘leaking'' out of neurones and glia leading to widespread inhibition, or the increase in stimulated GABA release which may occur following depolarization caused by an epileptic discharge.

     

Effect of gliclazide modified release on adiponectin,interleukin‐6, and tumor necrosis factor‐α plasma levels in individuals with type 2 diabetes mellitus

ABSTRACT

Objective: The aim of the study was to evaluate the effect of gliclazide modified release (MR) treatment on adiponectin, interleukin 6 (IL-6), and tumor necrosis factor-α (TNF‐α) plasma concentrations in type 2 diabetic patients.

Research design and methods: 24 randomly selected type 2 diabetic patients, aged 61.2 ± 15.4 years, with poorly controlled glucose level (mean glycated hemoglobin [HbA_1c] 7.6 ± 1.1%) despite treatment with diet and/or oral hypoglycemic agents, were included in the study. All of the patients, after a 2‐week run-in period, were given gliclazide MR for 12 weeks. At baseline, and after gliclazide MR treatment, HbA_1c and plasma concentrations of IL‐6, TNF‐α, and adiponectin were measured.

Results: Gliclazide MR treatment produced significant reductions in fasting plasma glucose (from 7.6 ± 1.4 to 6.6 ± 1.2?mmol/L, p < 0.01), HbA_1c (from 7.6 ± 1.1 to 6.9 ± 0.8%, p < 0.01), and plasma IL‐6 concentrations (from 2.5 ± 1.8 to 1.8 ± 1.2?pg/mL, p < 0.05). A significant increase in plasma adiponectin level was noted (from 6.4 ± 3.3 to 7.6 ± 4.4?µg/mL, p < 0.05). Plasma TNF‐α concentrations and homeostasis model assessment of insulin resistance (HOMA‐IR) decreased after treatment, but these changes did not reach statistical significance.

Conclusions: Gliclazide MR improves glycemic control and, in addition, has a positive influence on the plasma level of some inflammatory markers and adiponectin. Increased plasma adiponectin and decreased plasma IL‐6, and TNF‐α levels may explain, at least in part, the anti-atherogenic action of this drug reported elsewhere.     

Synthesis of 2α-Heteroarylalkyl Active Vitamin D3 with Therapeutic Effect on Enhancing Bone Mineral Density in Vivo

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