Ionic Drugs Research Articles

Hybrid Anion Exchange Hollow Fiber Membrane for Delivery of Ionic Drugs

Hybrid anion exchange hollow fiber membranes (HAEHFMs) based on bromomethylated poly(2,6-dimethyl-1,4-phenylene oxide) (BPPO) are proposed as potential drug carriers for four anionic model drugs, including the sodium salts of benzoate (NaBS), salicylate (NaSA), meta-amino salicylate (NaMAS), and loxoprofen (NaLS). The results of the static loading and release experiments suggest that electrostatic interaction, hydrogen bonding, and hydrophobic interaction are the main interaction patterns between the membrane and the drugs. And they are directly influenced by the external phase conditions and the drug physicochemical characteristics, such as structure, molecular weight, dissociation (pKa), and hydrogen bonding capability. Among the four different drugs, NaSA and NaMAS appear to be the most suitable for controlled release by the HAEHFM due to their excellent adsorption/release behaviors.

New Insights into the Mechanisms of the Interactions Between Doxorubicin and the Ion-Exchange Hydrogel DC Bead™ for Use in Transarterial Chemoembolization (TACE)

Ion-exchange microspheres (IEMs) are widely employed in controlled drug delivery of ionic drugs due to their high loading capacity and the possibility to obtain the controlled release of the loaded drug(s) at a specific site. Among IEMs, DC Bead™ are embolic microdevices (100–300 μm diameter) designed for transarterial chemoembolization (TACE) and composed of cross-linked poly(vinyl alcohol) (PVA) hydrogel, bearing anionic sulfonate moieties on the cross-links, and able to bind cationic drugs such as doxorubicin hydrochloride (Dox). Even if DC Bead™ were studied for their release and bulk characteristics, a thorough characterization of these devices is still lacking. In particular, the aim of this work was the determination of bound and free water, Dox distribution within the microdevices and drug–DC Bead™ interactions, in terms of transport features within the device. Compared with previous results, different Dox radial distributions in DC Bead™ were found, and related to bead microsctructure and ion exchange mechanism. Artifacts due to the self-quenching of Dox at high concentration were prevented and the diffusion coefficients of drug-polymer (Dox-ionic sites) evaluated in different sections of the microspheres. Furthermore, DSC results indicated that in the hydrogel either free (bulk) or bound (non-freezable) water could be found, and that no freezing-bound water was present.

Investigation of Furosemide Dialysis Rate in the Presence of Anionic Polymers

The aim of the present study was to determine the in vitro dialysis of furosemide, an anionic drug, in the presence of anionic macromolecules. The polymers (sodium carboxymethylcellulose, sodium alginate, and methylcellulose) were used at different concentrations, and the drug concentration in the dialysis bag was 250 µg/mL. The entire process was performed in a receptor chamber in which a dialysis bag was placed as a donor medium. The samples were collected at different times up to 4 h at 37 °C. Finally, the samples were analyzed by UV spectrophotometry at 277.5 nm. Methylcellulose was used as a neutral macromolecule to show the influence of polymer viscosity in the dialysis process. The dialysis rate increased with increasing macromolecule concentration up to a certain limit. This effect could be explained by Donnan equilibrium. Polyelectrolytes (e.g., sodium alginate and sodium carboxymethylcellulose) enhance the transport rate of ionic drugs with the same electrical charge. However, the increased medium viscosity in the dialysis process limits the Donnan effect. It is concluded that anionic macromolecules in specific concentrations could be used as transport-enhancer excipients for anionic drugs such as furosemide.

Predicting hydrophilic drug encapsulation inside unilamellar liposomes

A mathematical model has been developed to predict the encapsulation efficiency of hydrophilic drugs in unilamellar liposomes, and will be useful in formulation development to rapidly achieve optimized formulations. This model can also be used to compare drug encapsulation efficiencies of liposomes prepared via different methods, and will assist in the development of suitable process analytical technologies to achieve real-time monitoring and control of drug encapsulation during liposome manufacturing for hydrophilic molecules. Liposome particle size as well as size distribution, lipid concentration, lipid molecular surface area, and bilayer thickness were used in constructing the model. Most notably, a Log-Normal probability function was utilized to account for sample particle size distribution. This is important to avoid significant estimation error. The model-generated predictions were validated using experimental results as well as literature data, and excellent correlations were obtained in both cases. A Langmuir balance study provided insight regarding the effect of media on the liposome drug encapsulation process. The results revealed an inverse correlation between media ionic strength and lipid average molecular area, which helps to explain the phenomenon of inverse correlation between media ionic strength and drug encapsulation efficiency. Finally, a web application has been written to facilitate use of the model allowing calculations to be easily performed. This model will be useful in formulation development to rapidly achieve optimized formulation.

Ionic and Polyampholyte N-Isopropylacrylamide-Based Hydrogels Prepared in the Presence of Imprinting Ligands: Stimuli-Responsiveness and Adsorption/Release Properties

The conformation of the imprinted pockets in stimulus-responsive networks can be notably altered when the stimulus causes a volume phase transition. Such a tunable affinity for the template molecule finds interesting applications in the biomedical and drug delivery fields. Nevertheless, the effect that the binding of the template causes on the stimuli-responsiveness of the network has barely been evaluated. In this work, the effect of two ionic drugs used as templates, namely propranolol hydrochloride and ibuprofen sodium, on the responsiveness of N-isopropylacrylamide-based hydrogels copolymerized with acrylic acid (AAc) and N-(3-aminopropyl) methacrylamide (APMA) and on their ability to rebind and to control the release of the template was evaluated. The degree of swelling and, in some cases, energetics (HS-DSC) of the transitions were monitored as a function of temperature, pH, and concentration of drug. Marked decrease in the transition temperature of the hydrogels, accompanied by notable changes in the transition width, was observed in physiological NaCl solutions and after the binding of the drug molecules, which reveals relevant changes in the domain structure of the hydrogels as the charged groups are shielded. The ability of the hydrogels to rebind propranolol or ibuprofen was quantified at both 4 and 37 °C and at two different drug concentrations, in the range of those that cause major changes in the network structure. Noticeable differences between hydrogels bearing AAc or APMA and between imprinted and non-imprinted networks were also observed during the release tests in NaCl solutions of various concentrations. Overall, the results obtained evidence the remarkable effect of the template molecules on the responsiveness of intelligent imprinted hydrogels.

Iontophoresis: A Potential Emergence of a Transdermal Drug Delivery System

The delivery of drugs into systemic circulation via skin has generated much attention during the last decade. Transdermal therapeutic systems propound controlled release of active ingredients through the skin and into the systemic circulation in a predictive manner. Drugs administered through these systems escape first-pass metabolism and maintain a steady state scenario similar to a continuous intravenous infusion for up to several days. However, the excellent impervious nature of the skin offers the greatest challenge for successful delivery of drug molecules by utilizing the concepts of iontophoresis. The present review deals with the principles and the recent innovations in the field of iontophoretic drug delivery system together with factors affecting the system. This delivery system utilizes electric current as a driving force for permeation of ionic and non-ionic medications. The rationale behind using this technique is to reversibly alter the barrier properties of skin, which could possibly improve the penetration of drugs such as proteins, peptides and other macromolecules to increase the systemic delivery of high molecular weight compounds with controlled input kinetics and minimum inter-subject variability. Although iontophoresis seems to be an ideal candidate to overcome the limitations associated with the delivery of ionic drugs, further extrapolation of this technique is imperative for translational utility and mass human application.

Ion-paired Drug Delivery: An Avenue for Bioavailability Improvement

Ion-pairing is reported to improve the lipophilicity and subsequently the transport rate of polar drugs across lipid membranes. Lipophilisation of ionic drugs with high aqueous solubilities by ion-pair formation with appropriate counter-ion have proven to be promising for several applications. The aim of this review is to present the usefulness of ion-pair for improving the poor bioavailability of ionic drugs through various routes. The review covers an update on the applications of this strategy to improve drug delivery through various routes of administration including ocular, oral, parenteral and transdermal. It is discussed how ion-pair complexes assist in introducing functionality that would allow formation of a neutral molecule which can be subsequently encapsulated into delivery systems to be distributed by various routes of administration. Keywords: Bioavailability, Counter-ion, Drug- delivery, Hydrophobic molecule, Ion-pair formation

Electromembrane Extraction from Biological Fluids

Electro-assisted extraction of ionic drugs from biological fluids through a supported liquid membrane (SLM) and into an aqueous acceptor solution was recently introduced as a new sample preparation technique termed electromembrane extraction (EME). The applied electrical potential across the SLM has typically been in the range of 1-300 V. Successful extractions have been demonstrated even with common batteries (9 V) instead of a power supply. The chemical composition of the SLM has been crucial for the selectivity and for the recoveries of the extraction. Compared to other liquid-phase microextraction techniques (LPME), extraction times have been reduced by a factor of 6-17, and successful extractions have been obtained at extraction times of 1-5 min, and even down to a few seconds with online microfluidic EME devices. The technique has provided very efficient sample clean-up and has been found well suited for the extraction of sample sizes in the low µL range. Extractions have been performed with both rod-shaped hydrophobic porous fibers and with flat hydrophobic porous sheets as SLM support. The technique has been successfully downscaled into the micro-chip format. The nature of the SLM has been tuned for extraction of drugs with different polarity allowing extractions to be tailored for specific applications depending on the analyte of interest. The technique has been found to be compatible with a wide range of biological fluids and extraction of drugs directly from untreated human plasma and whole blood has been demonstrated. EME selectively extracts the compounds from the complex biological sample matrix as well as allowing concentration of the drugs. With home-built equipment fully acceptable validation results have been obtained.

Preparation and characterization of chitosan nanopores membranes for the transport of drugs

In this paper, a novel chitosan nanopores membrane was developed by selective dissolution of its composition. Polyethylene glycol (PEG) as the porogen was selected to generate the nanopores structure of chitosan membrane. As the observation with scanning electron microscopy (SEM), we could find that the PEG content was greatly influenced on the structure of chitosan membrane. As the PEG content was larger than 50%, the chitosan nanopores membrane could successfully developed. Differential scanning calorimeter (DSC) measurement revealed that the PEG component could not be completely dissolved from the membrane and there was presence the possible interaction (hydrogen bond) between two components. Water adsorption test suggested that the obtained membranes have the great capacity of water adsorption ranging from 162.4 ± 22.5% to 321.5 ± 6.5%. In vitro degradation experiment showed that the obtained chitosan membranes have good biodegradability in the lysozyme solution. The permeability test was performed with two model drugs: vitamin B12 (non-ionic water-soluble drug) and sodium sulfamerazine (ionic water-soluble drug). And the results showed that these two drugs have significant differences in the permeability, indicating that chitosan nanopores membranes can potentially be used to the transport of drugs with controlled diffusion manner.

Cross-Linked Nanoassemblies from Poly(ethylene glycol)-poly(aspartate) Block Copolymers as Stable Supramolecular Templates for Particulate Drug Delivery

Block copolymer cross-linked nanoassemblies (CNAs) were developed as stable supramolecular templates for particulate drug delivery. Poly(ethylene glycol)-poly(aspartate) [PEG-p(Asp)] block copolymers, consisting of PEG (5 or 12 kDa) and Asp (5, 14, 25, 33, and 37 repeating units), were used as scaffolds and grafts in combination to prepare a nanoassembly library of grafted nanoassemblies (GNAs) and CNAs. Four synthesis routes were tested to maximize the number of drug-binding Asp units per nanoassembly. Grafting-onto-scaffold and grafting-from-scaffold methods were used for GNA synthesis. Either partially or completely deprotected PEG-p(Asp) was cross-linked with diamine compounds to prepare CNAs. (1)H NMR and GPC measurements showed that GNAs and CNAs contained the maximum 183 and 253 Asp units, respectively. Initial screening of the nanoassemblies revealed that GNAs would be impractical for further development as drug carriers due to variable grafting efficiency and low product yields. CNAs were obtained in high yields and identified as a promising supramolecular template that can entrap and release ionizable drugs (doxorubicin), enhancing the particle stability of nanoassemblies in the pharmaceutically relevant pH ranges between 4 and 9. Light scattering measurements demonstrated that the particle size of CNAs remained uniform before and after drug entrapment, causing neither aggregation nor dissociation (<5 mg/mL).

Modelling of pH dependent n-octanol/water partition coefficients of ionizable pharmaceuticals

The lipophilicity of a compound is generally described by its n-octanol/water partition coefficient. Lipophilicity is an important descriptor, e.g. to correlate the toxic effect of substances or adsorption and transport properties of drug molecules in the human body. Often drug molecules contain one or more ionizable groups, hence the lipophilicity is strongly pH-dependent. The thermodynamic model COSMO-RS is a widely accepted method to predict partition coefficients of neutral compounds between neutral solvents and ionic liquids, thus COSMO-RS is principally able to handle molecules containing ionizable groups. In this work the model COSMO-RS was used to predict lipophilicity profiles of ionizable pharmaceuticals containing one acidic group. Under consideration of ion paring the partition of ionizable drugs can be calculated. The predicted pH dependent lipophilicities are in good agreement with literature data and own measurements.

Effect of lipophilicity of ionisable drugs on deviations from expected pH-partition behaviour [proceedings

Effect of lipophilicity of ionisable drugs on deviations from expected pH-partition behaviour [proceedings

Microcalorimetric Study for the Binding of Ionic Drugs to Human Erythrocytes and the Ghost Membranes

The binding of phenothiazine derivatives (as cationic drugs) and non-steroidal anti-inflammatory drugs (as anionic drugs) to human erythrocytes and ghost membranes has been compared with respect to their thermodynamic characteristics, by flow microcalorimetry at pH 7.4 and 37 C. From enthalpyentropy correlation, it was shown that anionic and cationic drugs are bound to different binding sites on the membranes. Phenothiazines bind to a single common site of the erythrocyte membranes with relatively high binding affinities (K = 10(4)-10(5) M-1). The binding is entropy-driven and characterized by a small negative enthalpy (delta H) and a positive entropy change (delta S), reflecting hydrophobic interactions. However, the binding reaction for the intact erythrocytes shows large negative values for both delta H and delta S. The values of K for the membranes and delta H for the intact erythrocytes increased with the increase of the hydrophobic character of the substituent group at the C-2 position of the phenothiazine nucleus (H less than Cl less than CF3). The results indicate that phenothiazines bind and or penetrate to the inner membranes of the erythrocytes and react with intracellular components such as haemoglobin, while anti-inflammatory drugs bind to the surface protein on the membranes with a lower affinity (K = 10(3) M-1) than phenothiazines, reflecting the small negative delta H and positive delta S for the interaction with intact erythrocytes.

Factors affecting drug encapsulation and stability of lipid–polymer hybrid nanoparticles

Lipid-polymer hybrid nanoparticles are polymeric nanoparticles enveloped by lipid layers that combine the highly biocompatible nature of lipids with the structural integrity afforded by polymeric nanoparticles. Recognizing them as attractive drug delivery vehicles, antibiotics are encapsulated in the present work into hybrid nanoparticles intended for lung biofilm infection therapy. Modified emulsification-solvent-evaporation methods using lipid as surfactant are employed to prepare the hybrid nanoparticles. Biodegradable poly (lactic-co-glycolic acid) and phosphatidylcholine are used as the polymer and lipid models, respectively. Three fluoroquinolone antibiotics (i.e. levofloxacin, ciprofloxacin, and ofloxacin), which vary in their ionicity, lipophilicity, and aqueous solubility, are used. The hybrid nanoparticles are examined in terms of their drug encapsulation efficiency, drug loading, stability, and in vitro drug release profile. Compared to polymeric nanoparticles prepared using non-lipid surfactants, hybrid nanoparticles in general are larger and exhibit higher drug loading, except for the ciprofloxacin-encapsulated nanoparticles. Hybrid nanoparticles, however, are unstable in salt solutions, but the stability can be conferred by adding TPGS into the formulation. Drug-lipid ionic interactions and drug lipophilicity play important roles in the hybrid nanoparticle preparation. First, interactions between oppositely charged lipid and antibiotic (i.e. ciprofloxacin) during preparation cause failed nanoparticle formation. Charge reversal of the lipid facilitated by adding counterionic surfactants (e.g. stearylamine) must be performed before drug encapsulation can take place. Second, drug loading and the release profile are strongly influenced by drug lipophilicity, where more lipophilic drug (i.e. levofloxacin) exhibit a higher drug loading and a sustained release profile attributed to the interaction with the lipid coat.

The Corrected Traditional Equations for Calculation of Hepatic Clearance that Account for the Difference in Drug Ionization in Extracellular and Intracellular Tissue Water and the Corresponding Corrected PBPK Equation

The estimation of hepatic clearance, Clh, using in vitro data on metabolic stability of compound, its protein binding and blood–plasma equilibrium concentration ratio is commonly performed using well-stirred, parallel tube or dispersion models. It appears that for ionizable drugs there is a difference of the steady-state concentrations in extracelluar and intracellular water (at hepatocytes), where metabolism takes place. This occurs due to the different pH of extra- and intracellular water (7.4 and 7.0, respectively). The account of this fact leads to the novel equations for Clh . These equations include the additional parameter named ionization factor, FI, which is the ratio of the unionized drug fractions in plasma and intracellular tissue water (or the ratio of the unbound drug concentrations in intracellular tissue water and plasma at equilibrium). For neutral drugs FI = 1 and the novel equations coincide with the traditional ones. It is shown that the account of this factor may yield the calculated Clh up to 6.3-fold greater than that obtained by the traditional equations for the strong diprotic basic compounds, and up to 6.3-fold smaller for the strong diprotic acidic compounds. For triprotic acids and bases the difference could be as much as 15-fold. The account of pH difference between extra- and intracellular water also results in the change of the term commonly used to describe drug metabolic elimination rate in physiologically based pharmacokinetic (PBPK) equation. This consequently may lead to a noticeable change of drug concentration-time profiles in plasma and tissues. The effect of ionization factor is especially pronounced for the low-extraction ratio drugs. The examples of significant improvement in the prediction of hepatic clearance due to the account of ionization factor are provided. A more general equation for hepatic clearance, which accounts for ionization factor and possible drug uptake and efflux, is obtained.

Emerging antiarrhythmic agents: a personal view from the Far East

Introduction: Arrhythmia treatments today take three different approaches. One uses electronic devices, such as electronic pacemakers or defibrillators, and this is regarded as life-saving in cases of bradyarrhythmias and ventricular fibrillation. Another is the ablation technique which eliminates abnormal pacemakers and/or conductive pathways by applying thermal or cryo-injury to pathological portions of the heart. The most classical one is the antiarrhythmic drugs, but are they effective and safe?Areas covered: Recent development of the understanding of arrhythmias, cardiac ionic channels and antiarrhythmic drugs covered by papers mostly published after 2000 are discussed.Expert opinion: The market size of the antiarrhythmic drugs is small, but various multichannel acting drugs may become candidates as antiarrhythmic drugs. As the cardiac ionic channels have become recognized as proteins, the molecular target for antiarrhythmic drugs has become apparent, but at the same time accurate data on clinical effectiveness and safety are required for drug approval; thus, few atrium selective drugs, such as IKur, IKACh and IKAde blocking drugs and amiodarone-like multichannel acting drugs are being developed.

Physico-chemical characterization and in vitro/ in vivo evaluation of loratadine:dimethyl-β-cyclodextrin inclusion complexes

A tricyclic, piperidine derivative of antihistamines, loratadine, which belongs in class II of the Biopharmaceutical Classification System, was investigated. It is an ionizable drug, whose solubility depends on the gastrointestinal pH, and the bioavailability is therefore very variable. Inclusion complexes were prepared by kneading method, containing loratadine (LOR) and dimethyl-β-cyclodextrin (DIMEB) in two different molar ratios in an attempt to achieve better dissolution and therefore the better bioavailability of loratadine. The formation and physicochemical properties of the inclusion complexes were investigated by means of dissolution tests, pH-dependent solubility studies, electrospray ionization mass spectrometry and diffusion-ordered 1H NMR spectroscopy. The in vivo efficiency of the complexes was examined in rat animal experiments to confirm the better in vitro dissolution. The instrumental examinations proved the presence of total complexes in 1:1 ratio in both compositions. However, the in vitro pH-dependent solubility results, the in vivo blood levels and the greater pharmacological effect prove that excess DIMEB is needed to achieve the pH-independent and complete solubility of LOR, and therefore better and more consistent bioavailability.

Dissolution-Enhancing Mechanism of Alkalizers in Poloxamer-Based Solid Dispersions and Physical Mixtures Containing Poorly Water-Soluble Valsartan

The purpose of this study was to investigate the effects of alkalizers in dissolution rate and crystal structure of valsartan (VAL) in Poloxamer 407 (POX)-based solid dispersions (SD). VAL, a poorly-water soluble drug was selected as a model drug because of its low solubility at low pH. The POX-based SDs containing alkalizers (Na₂CO₃, MgO, meglumine and arginine) were prepared by melting method. The dissolution tests were performed using the United States Pharmacopeia (USP) paddle II method in enzyme-free simulated gastric fluid (pH 1.2) for 2 h. Microenvironmental pH (pH(M)) was examined potentiometrically by using a surface pH electrode. Dissolution rate of SD incorporating Na₂CO₃ was drastically increased. The differential scanning calorimetry (DSC) and powder X-ray diffraction (PXRD) data indicated that crystalline structure of VAL in SD was transformed to amorphous form by the addition of alkalizers but could not explain the differences in the dissolution rates. The molecular interaction between VAL and Na₂CO₃ was observed in the Fourier transform infrared spectroscopy (FT-IR) spectra by the shift of C=O band from 1732 to 1719 cm⁻¹ and the disappearance of carbonyl group at 1598 cm⁻¹. Furthermore, Na₂CO₃ efficiently modulated pH(M) by providing a favorable microenvironment for drug dissolution. A combination of SD method and use of alkalizer is a promising approach to modulate release rate of poorly water-soluble and ionizable drug with an aid of changes of drug crystallinity, molecular interaction and pH(M).

Ionic Liquids: Future Solvents and Reagents for Pharmaceuticals

The pharmaceutical industries are undoubtedly experiencing a series of challenges. One of these is the administration of solid form of many drugs due to many well known drawbacks including low solubility, polymorphic conversion and low bioavailability. Such problems are further aggravated when drug molecules or starting materials for synthesis of drugs are insoluble or sparingly soluble in aqueous media and most of pharmaceutical acceptable organic solvents. To overcome these problems, some times, highly polar organic solvents including pyridine, dimethylformamide (DMF) and N-methylpyrrolidone (NMP) which are not considered as environmental benign solvents have been used. These restrictions demand superior solvent systems and/or new drug forms that can be used as reaction media to avoid volatile organic solvents and/or as new forms of drugs. Much effort is being invested in such approaches to find new delivery technologies or development of new controlled-release dosage forms. In recent years, ionic liquids (ILs) that are salts of low melting point and consist only of ions have been increasingly exploited as solvents and/or (co)solvents and/or reagents in a wide range of pharmaceutical applications due to their tailor-made chemical, physical and biological properties. Studies have shown that ionic liquid-assisted drug carrier or active pharmaceutical ingredients (APIs) synthesized as IL form or many drug compounds produced using ILs as reaction media provide many unique and attractive properties compared to conventional counterparts. Furthermore, ILs could be employed as potential antimicrobial agents for various microorganisms. The aim of this article is to summarize the efforts placed on using ionic liquids in pharmaceutical applications.

The use of nanocrystalline cellulose for the binding and controlled release of drugs

The objective of this work was to investigate the use of nanocrystalline cellulose (NCC) as a drug delivery excipient. NCC crystallites, prepared by an acid hydrolysis method, were shown to have nanoscopic dimensions and exhibit a high degree of crystallinity. These crystallites bound significant quantities of the water soluble, ionizable drugs tetratcycline and doxorubicin, which were released rapidly over a 1-day period. Cetyl trimethylammonium bromide (CTAB) was bound to the surface of NCC and increased the zeta potential in a concentration-dependent manner from −55 to 0 mV. NCC crystallites with CTAB-modified surfaces bound significant quantities of the hydrophobic anticancer drugs docetaxel, paclitaxel, and etoposide. These drugs were released in a controlled manner over a 2-day period. The NCC-CTAB complexes were found to bind to KU-7 cells, and evidence of cellular uptake was observed.