Effect of lipid and cellulose based matrix former on the release of highly soluble drug from extruded/spheronized, sintered and compacted pellets.

BACKGROUND: The study was to develop an extended release (ER) encapsulated and compacted pellets of Atenolol using hydrophobic (wax based and polymeric based) and high viscosity grade hydrophilic matrix formers to control the release of this highly water soluble drug by extrusion/spheronization (ES). Atenolol is used for cardiovascular diseases and available as an immediate release (IR) tablet dosage form. The lipids, Carnauba wax (CW), Glyceryl monostearate (GMS) and cellulose based i.e. Hydroxypropyl methylcellulose (HPMC) and Ethyl cellulose (EC) were used in preparing Atenolol ER pellets. Thermal sintering and compaction techniques were also applied to control the burst release of Atenolol. METHOD: For this purpose, thirty-six trial formulations (F1-F36) were designed by Response Surface Methodology (RSM), using Design-Expert 10 software, keeping (HPMC K4M, K15 M & K100 M), (EC 7FP, 10FP & 100FP), waxes (GMS, & CW), their combinations, sintering temperature and duration, as input variables. Dissolution studies were performed in pH, 1.2, 4.5 and 6.8 dissolution media. Drug release kinetics using different models such as zero order, first order, Korsmeyer-Peppas, Hixon Crowell, Baker-Lonsdale and Higuchi kinetics were studied with the help of DDsolver, an excel based add-in program. RESULTS: The formulations F35 and F36 showed compliance with Korsmeyer-Peppas Super case II transport model (R2 = 0.975-0.971) in dissolution medium pH 4.5. No drug excipient interaction observed by FTIR. Stereomicroscopy showed that sintered combination pellets, (F35), were highly spherical (AR = 1.061, and sphericity = 0.943). The cross-sectional SEM magnification (at 7000X) of F34 and F35 showed dense cross-linking. The results revealed that the optimized formulations were F35 (sintered pellets) and F36 (compacted pellets) effectively controlling the drug release for 12 h. CONCLUSION: Extended-release encapsulated, and compacted pellets were successfully prepared after the combination of lipids CW (10%) and GMS (20%) with EC (10FP 20% & 100FP 20%). Sintering and compaction, in addition, stabilized the system and controlled the initial burst release of the drug. Extended release (ER) Atenolol is an effective alternative of IR tablets in controlling hypertension and treating other cardiovascular diseases.

Improved Enantioselectivity for Atenolol Employing Pivot Based Molecular Imprinting.

In the last few decades, molecular imprinting technology went through a spectacular evolution becoming a well-established tool for the synthesis of highly selective biomimetic molecular recognition platforms. Nevertheless, there is still room for advancement in the molecular imprinting of highly polar chiral compounds. The aim of the present work was to investigate the favorable kosmotropic effect of a ternary complex involving a polar chiral template (eutomer of atenolol) and a functional monomer, bridged by a central metal ion through well-defined, spatially directional coordinate bonds. The efficiency of the chiral molecular recognition was systematically assessed on polymers obtained both by non-covalent and metal-mediated molecular imprinting. The influence on the chromatographic retention and enantioselectivity of different experimental variables (functional monomers, cross-linkers, chaotropic agents, metal ions, porogenic systems, etc.) were studied on both slurry packed and monolithic HPLC columns. Deliberate changes in the imprinting and rebinding (chromatographic) processes, along with additional thermodynamic studies shed light on the particularities of the molecular recognition mechanism. The best performing polymer in terms of enantioselectivity (α = 1.60) was achieved using 4-vinyl pyridine as functional monomer and secondary ligand for the Co(II)-mediated imprinting of S-atenolol in the presence of EDMA as cross-linker in a porogenic mixture of [BMIM][BF4]:DMF:DMSO = 10:1:5, v/v/v.

Influence of Peroxide Impurities in Povidone on the Stability of Selected ß-Blockers with the Help of HPLC.

A present study was conducted to investigate compatibility of ß-blocker drugs( like atenolol, labetalol hydrochloride, bisoprolol fumarate, metoprolol succinate, carvedilol and propranolol hydrochloride) with the pharmaceutical excipient povidone. To check the influence of peroxide impurity present in povidone on the stability of ß-blockers, a binary mixture technique has been adopted. The binary mixtures (1:1) of ß-blockers with povidone excipient were stored for the duration of 6 months at accelerated conditions (40°C and 75% RH) and analyzed with the technique of high-performance liquid chromatography (HPLC). On analysis, HPLC results shows that, the percentage of total impurity for atenolol-2.15%, bisoprolol fumarate-3.55%, carvedilol-2.19%, and labetalol hydrochloride-1.89%, with respect to povidone. To verify the interaction of H2O2 present in povidone as an impurity, oxidative degradation of selected active pharmaceutical ingredients were performed and degradation profile were compared with that of degradation impurities generated in drug-excipient mixture at accelerated conditions. The relative retention time (RRT) of impurities generated in accelerated stability study samples resembles the RRT of degradation products generated by oxidative degradation of pure drugs. Thus, it confirms that degradation of ß-blockers with povidone was mediated by organic peroxides present as an impurity in povidone.

Interaction of PEGylated anti-hypertensive drugs, amlodipine, atenolol and lisinopril with lipid bilayer membrane: A molecular dynamics simulation study.

The interaction of PEGylated anti-hypertensive drugs, amlodipine, atenolol and lisinopril with lipid bilayer membrane dimyristoylphosphatidylcholine (DMPC) has been studied in nine different simulation systems consisting of 128 lipid molecules and appropriate number of water molecules by molecular dynamics method and by utilizing GROMACS software. The influences of PEGylation on the mentioned drugs and the differences in application of two types of spacer molecules on the performance of drugs and DMPC membrane have been evaluated and mass density of the components in the simulation box, mean square displacement (MSD), electrostatic potential, hydrogen bonding, radial distribution function (RDF), area per lipid, order parameter, and angle distribution of the component molecules including drug, DMPC and PEG has been investigated. Furthermore, umbrella sampling analysis indicated that, PEGylation of the drugs made amlodipine to behave more hydrophilic, whereas in case of lisinopril and atenolol, PEGylation made these drugs to behave more hydrophobic. In almost all of the simulated systems, PEGylation increased the diffusion coefficient of the drugs.

Simultaneous enantiospecific recognition of several ß-blocker enantiomers using molecularly imprinted polymer-based electrochemical sensor.

The development of a chiral electrochemical sensor using an electrogenerated molecularly imprinted polymer (MIP)-based ultrathin film using R(+)-atenolol (ATNL) as a template was reported. The proposed sensor exhibited distinctive enantiospecific oxidation peaks toward the R-antipodes of four ß-blocker representatives and additional oxidation peaks common to both enantiomers of each studied ß-blocker, allowing thus the simultaneous analysis of all of their enantiomers in a single analysis. The specific preconditioning of the polymer by alternative exposure to aqueous and nonaqueous medium was proven to be essential for the chiral recognition ability of the obtained sensor. The rebinding property of the MIP film was studied by using a well-known redox probe, a change in the morphology and diffusive permeability of the thin polymeric layer in the presence of its template being observed. The applicability of the optimized analytical procedure was demonstrated by the analysis of ATNL's enantiomers in the range of 1.88 × 10(-7)-1.88 × 10(-5) mol/L. The developed polymeric interface is the first reported transductor of a chiral electrochemical sensor able to exhibit simultaneous enantiospecificity toward several ß-blocker representatives extensively used in the pharmaceutical and biomedical fields, offering good prospects in the simple, cost-effective, and fast assessment of their enantiomeric ratio and total concentration.

Formulation and in vitro evaluation of prolonged release floating microspheres of atenolol using multicompartment dissolution apparatus.

The aim of the present work was to prepare floating microspheres of atenolol as prolonged release multiparticulate system and evaluate it using novel multi-compartment dissolution apparatus. Atenolol loaded floating microspheres were prepared by emulsion solvent evaporation method using 3² full factorial design. Formulations F1 to F9 were prepared using two independent variables (polymer ratio and % polyvinyl alcohol) and evaluated for dependent variables (particle size, percentage drug entrapment efficiency and percentage buoyancy). The formulation(F8) with particle size of 329 ± 2.69 µm, percentage entrapment efficiency of 61.33% and percentage buoyancy of 96.33% for 12 h was the of optimized formulation (F8). The results of factorial design revealed that the independent variables significantly affected the particle size, percentage drug entrapment efficiency and percentage buoyancy of the microspheres. In vitro drug release study revealed zero order release from F8 (98.33% in 12 h). SEM revealed the hollow cavity and smooth surface of the hollow microspheres.

Chromatographic comparison of atenolol separation in reaction media on cellulose tris-(3,5-dimethylphenylcarbamate) chiral stationary phase using ultra fast liquid chromatography.

Because chiral liquid chromatography (LC) could become a powerful tool to estimate racemic atenolol quantity, excellent enantiomeric separation should be produced during data acquisition for satisfactory observation of atenolol concentrations throughout the racemic resolution processes. Selection of chiral LC column and analytical protocol that fulfill demands of the ultra fast LC analysis is essential. This article describes the characteristics of atenolol chromatographic separation that resulted from different resolution media and analytical protocols with the use of a Chiralcel® OD column. The chromatograms showed quite different characteristics of the separation process. The single enantiomer and racemic atenolol could be recognized by the Chiralcel® OD column in less than 20 min. Symmetrical peaks were obtained; however, several protocols produced peaks with wide bases and slanted baselines. Observations showed that efficient enantioresolution of racemic atenolol was obtained at slow mobile phase flow rate, decreased concentration of amine-type modifier but increased alcohol content in mobile phase and highest ultraviolet detection wavelength were required. The optimal ultra fast LC protocol enables to reduce and eliminate the peaks of either the atenolol solvent or the buffers and provided the highest peak intensities of both atenolol enantiomers.

Study of the influence of alkalizing components on matrix pellets prepared by extrusion/spheronization.

The aim of this study was to investigate the effects of alkalizing components and the nature of the wetting liquid on the properties of matrix pellets prepared by extrusion and spheronization. Atenolol was used as an active pharmaceutical ingredient, ethylcellulose as a matrix former, microcrystalline cellulose as a filler and disodium phosphate anhydrous and trisodium phosphate dodecahydrate as alkalizing materials. Water and a water-ethanol mixture served as granulation liquids. Pellet formation was evaluated via mechanical, dissolution and morphological studies. In order to enhance the dissolution of Atenolol from the pellets, alkalizing components were used and the influence of these components on the pH was tested. Investigations of the breaking hardness, the morphology and the dissolution revealed that the pellets containing trisodium phosphate dodecahydrate and prepared with a higher amount of water as binding liquid displayed the best physico-chemical parameters and uniform dissolution. In in vitro experiments, the dissolution release complied with the texture of the pellets and the effect of pH. The pellets have suitable shape and very good hardness for the coating process and are appropriate for subsequent in vivo experiments.

Mucoadhesive liposomal delivery systems: the choice of coating material.

OBJECTIVE: Development of liposomal mucoadhesive drug delivery system, which is able to improve the bioavailability of poorly absorbed oral drugs by prolonging their gastric and intestinal residence time, through facilitating the intimate contact of the delivery system with the absorption membrane. MATERIALS AND METHODS: Liposomes containing model drug atenolol were prepared by the modified ethanol injection method. Liposomes containing atenolol were coated by different mucoadhesive polymers, for example, chitosan, Carbopol 974P, Eudragit L100, and Eudragit S100, to optimize the choice of coating material. The delivery systems were tested for their in vitro mucoadhesiveness. RESULTS: Liposomes prepared by the ethanol injection method were of satisfactory size (around 100 nm, before coating). Through the coating of liposomes in the presence of unentrapped material, the entrapment efficiency for drug was increased. In vitro mucoadhesive test confirmed the mucoadhesive properties of the coated layer for all tested polymers; however, Eudragit S100-coated liposomes were superior to other coating materials. DISCUSSION: Eudragit coating appeared to be an optimal polymer choice. These preliminary data indicate that polymer-coated mucoadhesive liposomes are able to carry sufficient amount of drug and to remain attached to the intestinal mucosa for a sufficient period of time to enable prolonged absorption of entrapped drug. CONCLUSION: While keeping in mind that the in vivo conditions may vary with the in vitro ones, we may recommend the system described in our work for possible oral delivery of peptides and phytochemicals.

Fixed dose combinations for cardiovascular treatment via coaxial electrospraying: Coated amorphous solid dispersion particles.

As a result of an aging population, the need for fixed dose combinations in the treatment of cardiovascular diseases, that are easy to swallow and administer, has been growing remarkably. In this work, the feasibility of coaxial electrospraying (CES) was investigated to manufacture in one single step, a powder of individually coated particles containing atenolol (ATE), lovastatin (LOV) and acetylsalicylic acid (ASA). To improve the dissolution rate of the poorly water soluble LOV, an amorphous solid dispersion (ASD) of LOV with Soluplus® (SOL) was formulated and Eudragit S100®, an enteric copolymer that only dissolves above pH 7, was applied as coating to avoid LOV hydrolysis in acidic medium. Furthermore, ATE was added to the inner ASD compartment and the acidic ASA was embedded in the coating layer. With regard to the uncoated ASD particles, which were prepared with single nozzle electrospraying, the rate and extent of the LOV dissolution was increased, even to an extent of 100% for the 1/1/6 (ATE/LOV/SOL) ratio. Hence, this ratio was selected and coated particles with proper release of the three APIs could be successfully produced via CES. However, a peculiar behaviour of the coating performance was observed. Regarding LOV, the enteric layer of the particles performed as expected in acidic medium and supersaturation was obtained after the switch to a neutral pH, but in contrast, over 50% of ATE was released after 90 min in acidic medium. Nonetheless, hardly any ATE was released under acidic circumstances from ATE tablets that were, as a benchmark, manually dip-coated with Eudragit S100®. Two different model APIs, namely paracetamol (well soluble) and fenofibrate (poorly soluble) were tested as well, revealing similar discrepancy in the coating performance. The coating layer formed during CES is most likely less dense as compared to the layer produced with tablet coating and consequently, more permeable for highly soluble APIs, but not for the poorly soluble compounds.

Preparation and evaluation of propranolol molecularly imprinted solid-phase microextraction fiber for trace analysis of beta-blockers in urine and plasma samples.

An improved multiple co-polymerization technique was developed to prepare a novel molecularly imprinted polymer (MIP)-coated solid-phase microextraction (SPME) fiber with propranolol as template. Investigation was performed for the characteristics and application of the fibers. The MIP coating was highly crosslinked and porous with the average thickness of only 25.0 microm. Consequently, the adsorption and desorption of beta-blockers within the MIP coating could be achieved quickly. The specific selectivity was discovered with the MIP-coated fibers to propranolol and its structural analogues such as atenolol, pindolol, and alprenolol. In contrast, only non-specific adsorption could be shown with the non-imprinted polymer (NIP)-coated fibers, and the extraction efficiencies of propranolol and pindolol with the MIP-coated fibers were higher markedly than that with the commercial SPME fibers. A MIP-coated SPME coupled with high-performance liquid chromatography (HPLC) method for propranolol and pindolol determination was developed under the optimized extraction conditions. Linear ranges for propranolol and pindolol were 20-1000 microg L(-1) and detection limits were 3.8 and 6.9 microg L(-1), respectively. Propranolol and pindolol in the spiked human urine and plasma samples, extracted with organic solvent firstly, could be simultaneous monitored with satisfactory recoveries through this method.

New insight into transdermal drug delivery with supersaturated formulation based on co-amorphous system.

The objective of this study was to prepare a supersaturated formulation based on formation of a co-amorphous system of a drug and a coformer in order to enhance skin permeation. Atenolol (ATE) and urea (URE) were used as the model drug and the coformer, respectively. Thermal analysis of physical mixtures of ATE and URE showed decreases in the melting points and the formation of a co-amorphous system which was in a supercooled liquid state because of a low glass transition temperature. Supersaturated solutions of ATE and URE at different molar ratios in polyethylene glycol 400 (PEG400) were prepared. The precipitations were observed under storage at 25 °C for all formulations except for ATE-URE at 1:8 molar ratio which remained in the supersaturated state for 2 months. 1H NMR analysis confirmed the interactions between ATE and URE in PEG400. The ATE-URE supersaturated formulation showed higher permeability for mice skin than that of ATE saturated formulation, which was superior to the expected permeability from the degree of supersaturation. We concluded that co-amorphous based supersaturated formulation offers much promise for transdermal drug delivery.

Ion-pair approach coupled with nanoparticle formation to increase bioavailability of a low permeability charged drug.

Atenolol is a drug widely used for the treatment of hypertension. However, the great drawback it presents is a low bioavailability after oral administration. To obtain formulations that allow to improve the bioavailability of this drug is a challenge for the pharmaceutical technology. The objective of this work was to increase the rate and extent of intestinal absorption of atenolol as model of a low permeability drug, developing a double technology strategy. To increase atenolol permeability an ion pair with brilliant blue was designed and the sustained release achieved through encapsulation in polymeric nanoparticles (NPs). The in vitro release studies showed a pH-dependent release from NPs, (particle size 437.30 ±â€¯8.92) with a suitable release profile of drug (atenolol) and counter ion (brilliant blue) under intestinal conditions. Moreover, with the in vivo assays, a significant increase (2-fold) of atenolol bioavailability after administering the ion-pair NPs by oral route was observed. In conclusion, the combination of ion-pair plus polymeric NPs have proved to be a simple and very useful approach to achieve a controlled release and to increase the bioavailability of a low permeability charged drugs.

Facile fabrication and characterization of a novel oral pH-sensitive drug delivery system based on CMC hydrogel and HNT-AT nanohybrid.

The main aim of the present study was to design pH-sensitive bionanocomposite hydrogel beads based on CMC and HNT-AT nanohybrid and evaluate whether prepared bionanocomposite beads have the potential to be used in drug delivery applications. Atenolol (AT), as a model drug, was incorporated into the lumen of HA nanotubes via the co-precipitation technique. HNT/AT nanohybrid and CMC/HNT-AT beads were characterized via XRD, SEM, TGA, and FT-IR techniques. Drug loading and encapsulation efficiency was found to be high for CMC/HNT3 beads. Moreover, the swelling and drug release properties of the prepared CMC/HA-AT beads were investigated, and showed a pH sensitive swelling behavior with maximum its content at pH 6.8. Also, it was found that the swelling ratio of CMC/HNT beads was lower than that of pristine CMC beads. Drug release behavior of CMC/HNT-AT bionanocomposite hydrogel beads were investigated. A more sustained and controlled drug releases were observed for CMC/HNT-AT beads.

Preparation of monolithic osmotic pump system by coating the indented core tablet.

A method for the preparation of monolithic osmotic pump tablet was obtained by coating the indented core tablet compressed by the punch with a needle. Atenolol was used as the model drug, sodium chloride as osmotic agent and polyethylene oxide as suspending agent. Ethyl cellulose was employed as semipermeable membrane containing polyethylene glycol 400 as plasticizer for controlling membrane permeability. The formulation of atenolol osmotic pump tablet was optimized by orthogonal design and evaluated by similarity factor (f2). The optimal formulation was evaluated in various release media and agitation rates. Indentation size of core tablet hardly affected drug release in the range of (1.00-1.14) mm. The optimal osmotic tablet was found to be able to deliver atenolol at an approximately constant rate up to 24h, independent of both release media and agitation rate. The method that is simplified by coating the indented core tablet with the elimination of laser drilling may be promising in the field of the preparation of osmotic pump tablet.

[Preparation of atenolol monolithic osmotic pump tablets].

AIM: The simplified preparative method and formulation for atenolol monolithic osmotic pump tablets were investigated. METHODS: The core tablets with an indentation were compressed by the punch with a needle. Osmotic pump tablets were prepared by coating the indented tablets. Similarity factor was used to evaluate formulation of osmotic pump tablets. RESULTS: The formulation of core tablets and the composition and thickness of coating membrane showed marked effects on drug release. Orifice size of core tablets in the range of 1.00 - 1.14 mm scarcely affected drug release. CONCLUSION: The preparation of osmotic pump tablets was simplified with the exempting of laser drilling. The atenolol monolithic osmotic pump tablets could deliver drug constantly for 24 h.

The influence of non-ionisable excipients on precipitation parameters measured using the CheqSol method.

OBJECTIVES: The aim of this study was to determine the influence of non-ionisable excipients hydroxypropyl-ß-cyclodextrin (HPßCD) and poloxamers 407 and 188 on the supersaturation and precipitation kinetics of ibuprofen, gliclazide, propranolol and atenolol induced through solution pH shifts using the CheqSol method. METHODS: The drug's kinetic and intrinsic aqueous solubilities were measured in the presence of increasing excipient concentrations using the CheqSol method. Experimental data rate of change of pH with time was also examined to determine excipient-induced parachute effects and influence on precipitation rates. KEY FINDINGS: The measured kinetic and intrinsic solubilities provide a determination of the influence of each excipient on supersaturation index, and the area under the CheqSol curve can measure the parachute capability of excipients. The excipients influence on precipitation kinetics can be measured with novel parameters; for example, the precipitation pH or percentage ionised drug at the precipitation point, which provide further information on the excipient-induced changes in precipitation performance. CONCLUSION: This method can therefore be employed to measure the influence of non-ionisable excipients on the kinetic solubility behaviour of supersaturated solutions of ionisable drugs and to provide data, which discriminates between excipient systems during precipitation.

Influence of cholesterol on liposome stability and on in vitro drug release.

Cholesterol plays a strategic role in liposome composition; however, the quantity used to achieve an appropriate formulation has not been yet clarified. Therefore, by screening arrangement of lipids and cholesterol ratio, the main aim of this study is to investigate the most suitable amount of cholesterol in lipids in order to prepare stable and controlled drug release vehicles. For the preparation of liposomes, DMPC, DPPC and DSPC phospholipids were used and combined with different molar ratios of cholesterol (e.g. 100, 80-20, 70-30, 60-40 and 50-50%). Stability studies were conducted by storing the formulations at 37 and 50 °C for 30 days and by analysing them by AFM, DLS and FT-IR. By detecting the two most stable formulations from the stability results, drug encapsulation and in vitro release studies in PBS were performed by encapsulating atenolol and quinine. The release results were validated using a simulation model to ensure the reliability and suitable interpretation of the data. The generated model showed a good correlation between the prediction and the in vitro obtained results. By using 70:30% ratio (known in literature as 2:1), it is possible to reach the most stable formulation to guarantee a controlled and reproducible release for drugs with different physicochemical characteristics and pharmaceutical applications.

Drug release from a porous ion-exchange membrane in vitro.

The effect of environmental ionic strength on the rate of drug release from a cation exchange membrane was evaluated. Cationic propranolol-HCl, timolol, sotalol-HCl, atenolol and dexmedetomidine-HCl and neutral diazepam were adsorbed onto a porous poly(vinylidene fluoride) (PVDF) membrane that was grafted with bioadhesive poly(acrylic acid) chains (PAA-PVDF). Despite its porosity, the PAA-PVDF membrane acted as a cation exchange membrane. The release of adsorbed drug from the PAA-PVDF membrane was investigated by using a USP rotating basket apparatus. Adsorption of cationic drugs onto the PAA-PVDF membrane tended to increase with increasing lipophilicity of the drug. A decrease in the ionic strength of the adsorption medium increased the amount of the cationic drugs adsorbed onto the membrane, but had no effect on diazepam adsorption. The release of cationic drugs from the PAA-PVDF membrane was greatly affected by the ionic strength of both the adsorption medium and the dissolution medium, while ionic strengths did not affect diazepam release. Our results suggest that the ionic strength of both the adsorption and dissolution media substantially affects the release rate of a drug that has been adsorbed onto the ion exchange membrane, primarily via electrostatic interactions, while ionic strength has no effect on the release of a drug which has been adsorbed onto the membrane via non-electrostatic forces.

Stabilized lipid film based biosensor for atenolol.

This work reports a technique for the stabilization after storage in air of a lipid film based biosensor for atenolol. Microporous filters composed of glass fibers (nominal pore sizes 0.7 and 1.0 microm) were used as supports for the formation and stabilization of these devices. The lipid film is formed on the filter by polymerization prior to its use. Methacrylic acid was the functional monomer, ethylene glycol dimethacrylate was the crosslinker and 2,2'-azobis-(2-methylpropionitrile) was the initiator. The method for preparation of stabilized lipid film biosensor is studied throughout this work. The response towards atenolol of these stabilized lipid membrane biosensor, for repetitive use, composed of phosphatidylcholine was compared with planar freely suspended bilayer lipid membranes (BLMs). The stabilized lipid membranes provided similar artificial ion gating events as BLMs in the form of transient signals and can function for repetitive uses after storage in air. This will allow the practical use of the techniques for chemical sensing based on lipid films and commercialization of these devices.