Cationic Polymethacrylate Research Articles

An Imidazolium-Based Ionic Liquid as a Model to Study Plasticization Effects on Cationic Polymethacrylate Films.

Ionic liquids (ILs) have been touted as effective and environmentally friendly agents, which has driven their application in the biomedical field. The study compares the effectiveness of an IL agent, 1-hexyl-3-methyl imidazolium chloride ([HMIM]Cl), to current industry standards for plasticizing a methacrylate polymer. Industrial standards glycerol, dioctyl phthalate (DOP) and the combination of [HMIM]Cl with a standard plasticizer was also evaluated. Plasticized samples were evaluated for stress-strain, long-term degradation, thermophysical characterizations, and molecular vibrational changes within the structure, and molecular mechanics simulations were performed. Physico-mechanical studies showed that [HMIM]Cl was a comparatively good plasticizer than current standards reaching effectiveness at 20-30% w/w, whereas plasticizing of standards such as glycerol was still inferior to [HMIM]Cl even at concentrations up to 50% w/w. Degradation studies show HMIM-polymer combinations remained plasticized for longer than other test samples, >14 days, compared to glycerol <5 days, while remaining more pliable. The combination of [HMIM]Cl-DOP was effective at concentrations >30% w/w, demonstrating remarkable plasticizing capability and long-term stability. ILs used as singular agents or in tandem with other standards provided equivalent or better plasticizing activity than the comparative free standards.

Preparation and characterization of colon-targeted pH/Time-dependent nanoparticles using anionic and cationic polymethacrylate polymers

Inflammatory bowel disease (IBD), which is a chronic inflammatory disease of the gastrointestinal system, has two subtypes: Ulcerative Colitis (UC) and Crohn's Disease (CD). Only pH-sensitive drug delivery systems are commonly utilized for the treatment of IBD, but their effectiveness is frequently obstructed by the change in intestinal pH. To overcome the inadequacy of only pH-dependent delivery systems, we developed in vitro evaluated both pH- and time-dependent nanoparticles loaded budesonide (BUD) for the treatment of IBD in this study. Anionic polymethacrylate was utilized as a pH-dependent polymer whereas cationic polymethacrylate was utilized as a time-dependent sustained release polymer. Nanoparticles were prepared through a single oil-in-water emulsion/solvent evaporation method. The encapsulation efficiency, mean particle size, zeta potential, polydispersity index (PDI), drug release profiles, drug release kinetics, and stability of these nanoparticles were investigated. In all formulations, mean particle sizes were below 250 nm and PDI values were between 0.1 and 0.3. Nanoparticles containing 90% anionic-10% cationic polymethacrylate polymers inhibited burst BUD release under acidic conditions and exhibited sustained drug release at neutral pH. Consequently, in the medication of IBD, BUD-loaded pH and time-dependent nanoparticles may be a promising choice as a drug delivery system.

Fabrication and characterization of budesonide loaded colon-specific nanofiber drug delivery systems using anionic and cationic polymethacrylate polymers

Inflammatory bowel disease (IBD) is a chronic disease characterized by the inflammation of the gastrointestinal system (GIS). Electrospun nanofibers are commonly used in pharmaceutical technology due to many advantages such as high porosity, loading efficiency, large surface area, and stability. Budesonide is the first choice drug in the treatment of IBD and is used as a model drug. In this study, it was aimed to obtain controlled release nanofibers for colon targeting by using anionic, pH-sensitive Eudragit S100 (ES100) and cationic, time-dependent Eudragit RL100 (ERL100) polymers. The conductivity, surface tension, and viscosity of the polymer solutions were analysed before electrospinning process. After production, the surface morphology, drug release kinetics, water contact angle, swelling index, and mucoadhesion studies of nanofibers were evaluated. Drug release studies were carried out at pH 1.2, 6.8, and 7.4. The formulation containing ES100:ERL100 (95:5) showed the most suitable drug release as a colon-specific drug delivery system with a minor release at pH 1.2, 6.8, and major release at pH 7.4. As a result, electrospun nanofibers obtained by mixing anionic and cationic polymethacrylate polymers may be a promising alternative as a drug delivery system in the treatment of IBD and other intestinal diseases.

Cationic Polymethacrylate-Modified Liposomes Significantly Enhanced Doxorubicin Delivery and Antitumor Activity

Liposome (LP) encapsulation of doxorubicin (DOX) is a clinically validated method for cancer drug delivery, but its cellular uptake is actually lower than the free DOX. Therefore, we modified DOX-LP with a cationic polymer (Eudragit RL100; ER) to improve its cellular uptake and antitumor activity. The resulting DOX-ERLP was a 190 nm nanoparticle that was absorbed efficiently and caused cancer cell death in 5 hrs. Growth as measured by the MTT assay or microscopic imaging demonstrated that DOX-ERLP has at least a two-fold greater potency than the free DOX in inhibiting the growth of a DOX resistant (MCF7/adr) cell and an aggressive liver cancer H22 cell. Further, its in vivo efficacy was tested in H22-bearing mice, where four injections of DOX-ERLP reduced the tumor growth by more than 60% and caused an average of 60% tumor necrosis, which was significantly better than the DOX and DOX-LP treated groups. Our work represents the first use of polymethacrylate derivatives for DOX liposomal delivery, demonstrating the great potential of cationic polymethacrylate modified liposomes for improving cancer drug delivery.

Buccal delivery of low molecular weight heparin by cationic polymethacrylate nanoparticles

Buccal delivery seems to be a very promising administration route for macromolecular drugs. Here, we explored the potential of cationic polymethacrylate nanoparticles (NPs) as a carrier system for the buccal delivery of low molecular weight heparin (LMWH). LMWH-loaded NPs were prepared by emulsification solvent diffusion method and the NPs were analyzed for their physiochemical properties, rheological evaluations and ex vivo transport studies across buccal mucosa. The prepared LMWH-loaded NPs showed a mean diameter between 400 and 500nm with unimodal size distribution with negative surface charge. Viscosity measurements revealed a positive rheological synergism between the prepared NPs and mucin when mixed under physiological conditions. After 4h, about 6.3±0.9% of LMWH was released in case of using Eudragit® RS (ERS); while Eudragit® RL (ERL) NPs released only 3.0±0.3 % of its LMWH content and this incomplete release was slightly ameliorated in the presence of mucin reaching to 7.2±0.3 % and 4.8±0.3 % for ERS and ERL, respectively. The ex-vivo permeability of heparin through the buccal mucosa was significantly increased after using polymetharylate NPs while no heparin permeation was detected from free heparin solution. Confocal laser scanning microscopy (CLSM) imaging indicated the mucoadhesive properties of the polymetharylate NPs where the drug-free NPs were detected in the superficial layers of buccal mucosa. LMWH-loaded NPs had less mucoadhesive properties showing significant deeper penetration of the mucosa. The results indicated that mucoadhesive cationic polymethacrylate NPs offer a possible approach for the buccal delivery of heparin.

Microstructural investigation using synchrotron radiation X-ray microtomography reveals taste-masking mechanism of acetaminophen microspheres

The structure of solid drug delivery systems has considerable influence on drug release behaviors from particles and granules and also impacts other properties relevant to release characteristics such as taste. In this study, lipid-based microspheres of acetaminophen were prepared to mask the undesirable taste of drug and therefore to identify the optimal formulation for drug release. Synchrotron radiation X-ray computed microtomography (SR-μCT) was used to investigate the fine structural architectures of microspheres non-destructively at different sampling times during drug release test, which were simultaneously determined to quantitatively correlate the structural data with drug release behaviors. The results demonstrated that the polymeric formulation component, namely, cationic polymethacrylate (Eudragit E100), was the key factor to mask the bitter taste of acetaminophen by inhibiting immediate drug release thereby reducing the interaction intensity of the bitter material with the oral cavity taste buds. The structure and morphology of the microspheres were found to be influenced by the shape and particle size of the drug, which was also an important factor for taste-masking performance. The quantitative analysis generated detailed structural information which was correlated well with drug release behaviors. Thus, SR-μCT has been proved as a powerful tool to investigate the fine microstructure of particles and provides a new approach in the design of particles for taste masking.

New mucoadhesive polymeric film for ophthalmic administration of acetazolamide.

This article reports the results concerning the design and manufacture of a novel polymeric film for ocular administration of acetazolamide (AZM), and a patent document presented to INPI- National Institute of Industrial/Intelectual Property. The system was designed using mucoadhesive polymers, such as carbomer (CB974P) and sodium carboxymethylcellulose (NaCMC), combined with the poloxamer (POL407) which behaves as a swelling modulator, surfactant and slightly plasticizer. The maximum amount of AZM to be incorporated without loss of homogeneity or precipitation of the drug, was 0.04 mg AZM/mg of the film. The addition of a polymeric coating based on Eudragit RSPO (cationic permeable polymethacrylate polymer) allowed optimizing drug release. The coating in a proportion of 10% (determined as percentage of total weight of the film) seemed to be the most adequate, since 80% of controlled drug release was achieved along 240 minutes. This coating membrane did not affect the mucoadhesive properties of the swellable polymers. Thus, the system obtained, showed good efficiency and the intra ocular pressure (IOP) decreased according to the results derived from in vivo studies performed on normotensive rabbits. Finally, irritation scored studies demonstrated that these systems were not irritant for rabbit´s ocular mucosa.

Films loaded with insulin-coated nanoparticles (ICNP) as potential platforms for peptide buccal delivery

The goal of this investigation was to develop films containing insulin-coated nanoparticles and evaluate their performance in vitro as potential peptide delivery systems. To incorporate insulin into the films, a new antisolvent co-precipitation fabrication process was adapted to obtain insulin-coated nanoparticles (ICNPs). The ICNPs were embedded in polymeric films containing a cationic polymethacrylate derivative (ERL) or a combination of ERL with hydroxypropyl methylcellulose (HPMC). ICNP-loaded films were characterized for morphology, mucoadhesion, and insulin release. Furthermore, in vitro insulin permeation was evaluated using a cultured tridimensional human buccal mucosa model. The antisolvent co-precipitation method was successfully adapted to obtain ICNPs with 40% (w/w) insulin load, achieving 323±8nm particles with a high zeta potential of 32.4±0.8mV, indicating good stability. High yields were obtained after manufacture and the insulin content did not decrease after one month storage. ICNP-embedded films using ERL as the polymer matrix presented excellent mucoadhesive and insulin release properties. A high permeation enhancement effect was observed for ICNP-loaded ERL films in comparison with ICNP-loaded ERL–HPMC films and a control insulin solution. ICNP-loaded ERL formulations were found to be more effective in terms of film performance and insulin permeation through the human buccal mucosa model, and thus are a promising delivery system for buccal administration of a peptide such as insulin.

Enhanced intestinal permeability and oral bioavailability of enalapril maleate upon complexation with the cationic polymethacrylate Eudragit E100

The low bioavailability of enalapril maleate associated to its instability in solid state motivated the development of a polyelectrolyte-drug complex between enalapril maleate and the cationic polymethacrylate Eudragit E100. The solid complexes were characterized by DSC–TG, FT-IR and X-ray diffraction. Their aqueous dispersions were evaluated for drug delivery in bicompartimental Franz cells and electrokinetic potentials. Stability in solid state was also evaluated using an HPLC–UV stability indicating method. Absorption of enalapril maleate was assessed thorough the rat everted gut sac model. In addition, urinary recovery after oral administration in rats was used as an indicator of systemic exposition. The solid materials are stable amorphous solids in which both moieties of enalapril maleate are ionically bonded to the polymer. Their aqueous dispersions exhibited controlled release over more than 7h in physiologic saline solution, being ionic exchange the fundamental mechanism that modified the extent and rate of drug release. Intestinal permeation of enalapril maleate was 1.7 times higher in the presence of the cationic polymer. This increase can be related with the capacity to adhere the mucosa due to the positive zeta potential of the complexes. As a consequence bioavailability was significantly improved (1.39 times) after oral administration of the complexes. In addition, no signs of chemical decomposition were observed after a 14months period. The results indicated that the products are new chemical entities that improve unfavorable properties of a useful drug.

Nanoparticle-based clodronate delivery mitigates murine experimental colitis

In inflammatory bowel disease (IBD) the disruption of the intestinal barrier function and the strong presence of immune-related cells like macrophages in inflamed tissue allow the selective accumulation of particulate carrier systems at the site of action. We developed clodronate loaded nanoparticles (ClNP) based on a cationic polymethacrylate (Eudragit RL) using a modified solvent displacement method. Particle diameter of ClNP was around 120nm and dissolution experiments showed that ionic interactions with either the dissolution medium or mucin have to take place to enable complete drug release. In murine experimental colitis in-vivo, myeloperoxidase activity decreased significantly in 2,4,6-trinitrobenzenesulfonic acid (TNBS)-colitis and oxazolone (OXA)-colitis models after treatment with ClNP while free clodronate did not show a mitigating effect. Similarly, alkaline phosphatase could be lowered significantly from 12.5±1.9 to 6.8±2.2ng/mg tissue in TNBS-colitis and from 16.6±6.2 to 11.8±2.7ng/mg tissue in OXA-colitis. In cultured RAW 264.7 cells, only ClNP but not clodronate alone led to a decrease in tumor necrosis factor-alpha and interleukin-6 secretion of the activated macrophages. The therapeutic benefit of ClNP was confirmed in-vivo although it is limited compared to data with other drugs. Cell culture experiments indicated that intracellular delivery of clodronate was necessary to obtain an anti-inflammatory effect.

Equilibrium and Release Properties of Aqueous Dispersions of Non Steroidal Antiinflammatory Drugs Complexed with Polyelectrolyte Eudragit E 100

Equilibria and release properties of aqueous systems consisting of a set of five non-steroidal anti-inflammatory drugs (AH) complexed with the cationic polymethacrylate Eudragit E 100 (EU) are reported in this study. The composition (EU(AH)50 (HCl)50) having fifty mole percent of each counterion (A− and Cl−) produces clear, stable aqueous dispersions in which a remarkably high proportion of AH (higher than 98%) is condensed with the PE under the form of ion pairs. This property expands the interval of pH in which AH are aqueous soluble. The set of AH contains members with and without an alpha methyl group (-(CH3)CH-COOH: Flurbiprofen, Naproxen, Ketoprofen) and (-CH2-COOH: Diclofenac, Indomethacin). The proportion of ion pairs in the complexes was lower in the former group. Release of AH from the complexes toward a saline (NaCl 0.9%) solution was assayed in Franz cells. The five complexes behaved as drug carriers that exhibited a slow drug release with a remarkable zero order. In line with the percentages of counterionic condensation observed, release rates from -(CH3)CH-COOH complexes were clearly higher than those of -CH2-COOH ones.

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–Mx complex). The influence of an anionic polyacrylic acid polymer (carbomer, C) on dissolution behavior of M from the complex was evaluated (Eu–MxCy 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–Mx 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–MxCy) 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–MxC50). This variation in rate delivery was also affected by the dissolution media, as occurred with Eu–Mx complexes. The formation of the gel layer during the dissolution process, as consequence of Eu–MxCy 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

Design of a colonic delivery system based on cationic polymethacrylate (Eudragit E100)-mesalamine complexes

In this work, the design and evaluation of a colonic drug delivery system containing mesalamine (M) is presented. The main goal was to enable M to reach the first part of the colon, where the drug could then be released. To facilitate this, a tablet core was coated with two thin layers. The first compounded by chitosan, which was responsible for core protection in the small intestine until it reached the colon. Once at the colon, microbiological enzymatic activity of the caecal content would degrade the Ch layer, thus triggering drug release. The second layer, the outer one, was compounded with Eudragit L100 (EL), with its function being to avoid the dissolution of the Ch-covered core along the gastro intestinal tract (GIT). In order to achieve a modulated drug release, carbomer P934 (1%) was also included. Dissolution studies showed that the formulation seemed to behave as predicted. The amount of M released from the coated tablet was less than 10% at pH = 1.2 and 6.8. However, when the coated tablet was evaluated in a medium with a caecal content of pH = 7.4, the M delivery was immediately triggered owing to enzymatic activity of the microflora. In this medium, ∼ 60% of M was released in a period of 3 h. Although these results are promising, further studies are still necessary to evaluate the possible in vitro/in vivo correlations.

Molecular dynamics simulations for drug dosage form development: thermal and solubility characteristics for hot-melt extrusion

Properties of pharmaceutical drug polymer mixtures like miscibility, stability and drug release are determined by the interactions of active pharmaceutical ingredients (APIs) and excipients (e.g. plasticisers) with functional polymers. Molecular dynamics (MD) simulations (Materials Studio®, COMPASS force field) are used to predict the principal behaviour of such drug products, especially miscibility and glass transition temperature (T g). Different mixtures containing APIs (theophylline or ibuprofen (IBU)) and water-soluble (triethyl citrate, (TEC)) or water-insoluble plasticiser (acetyl tributyl citrate (ATBC) or dibutyl sebacate (DBS)) dissolved/dispersed in a cationic polymethacrylate (EUDRAGIT® RS) were studied. Force field-based calculations of the cohesive energy densities of single constituents led to a qualitative approach according to Hanson describing the solid state of the mixture, while further calculations on the basis of the theory of free energy of mixing facilitated a semi-quantitative prediction. In the case of miscibility also calculation of T g was possible via modelling specific volumes of amorphous cells at various temperatures. The simulated data correlated well with the experimental data obtained from differential scanning calorimetry (DSC) of drug products processed via hot-melt extrusion. Accordingly, the described method facilitates a good estimate of pharmaceutical polymer drug mixtures, thus decreasing product development time, as well as the consumption of active ingredients.

Novel Combination of Anionic and Cationic Polymethacrylate Polymers for Sustained Release Tablet Preparation

The objectives of this study were to prepare and evaluate a novel sustained release tablet formulation using a binary mixture of polymethacrylate polymers: Eudragit E-100 (EE) and Eudragit L-100 (EL) in their salt forms. Tablets prepared using EE-citrate and EL-Na showed the highest degree of swelling among other combinations of EE and EL. The drug release rates were independent of the pH of the dissolution medium as the release profiles exhibited a continuous release pattern with no burst effect when changing the pH of the medium. These results, along with other test results, indicated the presence of an ionic interaction between both polymers when combined in the salt forms.

Interaction between a cationic polymethacrylate (Eudragit E100) and anionic drugs

The interaction between a cationic polymethacrylate (Eudragit ® E, EU) and a set of 7 drugs having acid groups (AH) was studied. Two series of complexes were prepared (EU–AH 50 and EU–AH 50Cl 50), in both 50% of the basic groups of EU were neutralized with AH but in the second, the remaining groups were further neutralized with HCl. These products were stable solid ionic complexes that were characterized through infrared spectroscopy and X-ray power diffraction. All EU–AH 50Cl 50 at 5–10 mg/ml produced clear optically isotropic aqueous dispersions. This result was in line with the increase of the apparent solubility of the low solubility AH assayed. The species distribution, as determined on the complex of diclofenac, showed a degree of counterion condensation as high as 97.9%. The reversibility of the counterion condensation, as well as the affinity between EU and AH, was evaluated through the proton withdrawing effect produced by the ionic exchange generated by titration with NaCl. Besides, drug delivery in bicompartimental Franz cells towards water as receptor medium was very slow. However, it was increased as water was replaced by NaCl solution that upon diffusion generates ionic exchange. Therefore, the EU–AH system behaves as a reservoir of drug able to deliver it in simulated biological fluid.

Preparation of polysaccharide–polymethacrylate hybrid materials by radical polymerization of cationic methacrylate monomer in the presence of anionic polysaccharide

AbstractThis article describes preparation of polysaccharide–polymethacrylate hybrid materials by means of free‐radical polymerization of a cationic methacrylate monomer in the presence of anionic polysaccharides. In particular, synthesis of the hybrid material composed of carboxymethyl cellulose (CMC) and a cationic polymethacrylate, i.e. poly(2‐aminoethyl methacrylate) is disclosed. The formation of the materials was achieved by radical polymerization of 2‐aminoethyl methacrylate hydrochloride (AEMA‐HCl) in aqueous solution of CMC. The insoluble material was formed and the structure was determined by the IR spectra and elemental analysis to be composed of CMC and polymethacrylate. Thermal analyses such as thermal gravimetric analysis (TGA) and differential scanning calorimetry (DSC) were performed to confirm the network structure of the material. The dehydrative amidation occurred by heating the material at 200°C, giving rise to the new hybrid material hybridized by the amide linkages. Copyright © 2007 John Wiley &amp; Sons, Ltd.

The Influence of Surfactants and Additives on Drug Release from a Cationic Eudragit Coated Multiparticulate Diltiazem Formulation

A cationic polymethacrylate coated multiparticulate diltiazem formulation exhibited sigmoidal drug release. Lag time prior to drug release was influenced by dissolution media, coat thickness, and by the nature of additives included in the formulation. Incorporation of up to 5% w/w sodium lauryl sulfate (SLS) in the coating membrane resulted in substantial increases in lag times in acidic and neutral media. The extent of drug release in acid was 100%, whereas in phosphate buffer, the extent of release was dependent on the level of SLS. Substituting SLS for various compounds was used to assess the functionality of the SLS molecule responsible for these behaviors. The ability to ion-pair with the polymer and the presence of a hydrophobic moiety were both important functionalities.

Glass transition temperature of a cationic polymethacrylate dependent on the plasticizer content – Simulation vs. experiment

Atomistic molecular dynamics simulations ( NPT ensemble) are performed to compute the specific volume as a function of temperature of cationic polymethacrylate (Eudragit ® RS) with varying plasticizer (triethylcitrate) content ranging from pure polymer to a plasticizer weight proportion of 7.70%. The simulated glass transition temperature of these polymer–plasticizer blends is determined as the temperature marking the kink in the slope of specific volume vs. temperature plots. A linear dependence of the glass transition temperature on the plasticizer content is found. The computational findings are supported by differential scanning calorimetry experiments showing the same trend thus validating the applied computational method.

Poly(3-guanidinopropyl methacrylate): A Novel Cationic Polymer for Gene Delivery

A cationic polymethacrylate with a guanidinium side group was designed in order to create a polymer with cell membrane-penetrating properties such as Tat or other arginine-rich peptides. The polymer, poly(3-guanidinopropyl methacrylate), abbreviated as pGuaMA, was synthesized by free radical polymerization. The DNA-condensing properties of pGuaMA (Mw 180 kDa) were investigated via dynamic light scattering and zeta potential measurements, and small, positively charged particles (110 nm, +37 mV) were found. It was shown that polyplexes based on pGuaMA were able to transfect COS-7 cells efficiently in the absence of serum, while under the same conditions poly(arginine) (pArg) polyplexes did not show detectable transfection levels. Addition of a membrane-disrupting peptide, INF 7, derived from the influenza virus, to preformed pGuaMA polyplexes did result in approximately 2 times increased transfection levels. DLS, zeta potential measurements, gel electrophoresis, and ethidium bromide displacement measurements indicated that serum induced aggregation of the polyplexes at high polymer/plasmid ratios, while at low polymer/plasmid ratios the polarity of the polyplexes reversed likely due to adsorption of negatively charged proteins on their surface. Likely, the unfavorable interactions of pGuaMA polyplexes with serum proteins is the reason for the absent transfection activity of these polyplexes in the presence of serum. Confocal laser scanning microscopy indicated cellular internalization via endocytosis of both polyplexes and free polymer. Thus, pGuaMA polyplexes enter cells, as reported for other polyplexes, by endocytosis and not, as hypothesized, via direct membrane passage.