Suitability of Smopex-102 cation-exchange fiber for analytical purposes and drug monitoring.

The present study aimed to evaluate the suitability of Smopex-102 cation-exchange fiber for the separation of acidic and basic model drugs from biological fluids (e.g. serum) prior to chromatographic analysis. In addition, the interactions of the drugs with the fiber were studied. The study found that basic antidepressant model drugs bound to a considerably greater extent than acidic drugs to poly(acrylic acid) (PAA) grafted Smopex-102 cation-exchange fiber from 25 mM HEPES buffer (pH 7.0) and spiked serum. Drug binding from serum decreased except for acidic drugs due to drug distribution between serum proteins and cation-exchange fiber. Electrostatic interactions were possibly the most important factors affecting drug binding to the fiber. Basic drugs were released most effectively from the fiber by using acetic acid (mean released amount 123.7 +/- 36.3% and mean absolute recovery 95.4 +/- 23.8%). Results demonstrated that the cation-exchange fiber evaluated might be a potential material for separating basic drugs from protein-free and proteinaceous (e.g. serum) liquid solutions for subsequent monitoring and evaluation. However, the drug release solution and release time must be optimized more precisely in order to validate described sample preparation method for each basic drug.

Ion-exchange fibers and drugs: a novel device for the screening of iontophoretic systems.

The objective of this study was to theoretically model and experimentally measure the extent of drug release from ion-exchange fibers. The release was measured as a function of current density and NaCl concentration using a novel iontophoretic cell. The fibers tested contained weak carboxylate (-COOH) ion-exchange groups. The cationic model drugs tacrine and metoprolol were chosen on the basis of previous research, where tacrine had the lowest release rate and metoprolol the highest release rate. An in-house designed three compartment test cell was developed to test the suitability of drugs for iontophoretic drug delivery. In this cell, the anode and the drug containing ion-exchange fiber compartments were separated with a Nafion ion-selective membrane, while the fiber and the return electrode compartments were separated with a porous membrane. Tacrine proved to be a good drug candidate for this system as the release of the tacrine from the device was controllable with salt concentration and current density. Metoprolol release from the device was, however, not controllable.

Ion-exchange fibers and drugs: a transient study.

The objective of this study was to theoretically model and experimentally measure the kinetics and extent of drug release from different ion-exchange materials using an in-house-designed flow-cell. Ion-exchange fibers (staple fibers and fiber cloth) were compared with commercially available ion-exchange materials (resins and gels). The functional ion-exchange groups in all the materials were weak -COOH or strong -SO3H groups. The rate and extent of drug release from the fibers (staple fiber>fiber cloth) was much higher than that from the resin or the gel. An increase in the hydrophilicity of the model drugs resulted in markedly higher rates of drug release from the fibers (nadolol>metoprolol>propranolol>tacrine). Theoretical modelling of the kinetics of ion exchange provided satisfactory explanations for the experimental observations: firstly, a change in the equilibrium constant of the ion-exchange reaction depending on the drug and the ion-exchange material and, secondly, a decrease in the Peclet number (Pe) with decreasing flow-rate of the drug-releasing salt solution.

Ion-exchange fibers and drugs: an equilibrium study.

The purpose of this study was to investigate the mechanisms of drug binding into and drug release from cation-exchange fibers in vitro under equilibrium conditions. Ion-exchange groups of the fibers were weakly drug binding carboxylic acid groups (-COOH), strongly drug binding sulphonic acid groups (-SO(3)H), or combinations thereof. Parameters determining the drug absorption and drug release properties of the fibers were: (i) the lipophilicity of the drug (tacrine and propranolol are lipophilic compounds, nadolol is a relatively hydrophilic molecule), (ii) the ion-exchange capacity of the fibers, which was increased by activating the cation-exchange groups with NaOH, (iii) the ionic strength of the extracting salt (NaCl), which was studied in a range of 1.5 mM to 1.5 M, and finally (iv) the effect of divalent calcium ions (CaCl(2)) on the release of the model drugs, which was tested and compared to monovalent sodium ions (NaCl), and combinations thereof. It was found that the lipophilic drugs, tacrine and propranolol, were retained in the fibers more strongly and for longer than the more hydrophilic nadolol. The more hydrophilic nadolol was released to a greater extent from the fibers containing strong ion-exchange groups (-SO(3)H), whereas the lipophilic drugs were attached more strongly to strong ion-exchange groups and released more easily from the weak (-COOH) ion-exchange groups. The salt concentration and the choice of the salt also had an effect: at lower NaCl concentrations more drug was released as a result of the influence of both electrostatic and volume effects (equimolar drug:salt ratio). Incorporation of CaCl(2) in the bathing solution increased drug release considerably as compared to NaCl alone. The equilibrium distribution of the drug species between the fiber and external solution phases was also simulated and it was found that the theoretical modelling proposed describes adequately the basic trends of the behavior of these systems.

Electron transfer reactions at gold nanoparticles.

It is demonstrated that scanning electrochemical microscopy can be used to investigate the kinetics of electron transfer reactions catalysed by metal nanoparticles supported on an insulating substrate.

Controlled transdermal iontophoresis by ion-exchange fiber.

The objective of this study was to assess the transdermal delivery of drugs using iontophoresis with cation- and anion-exchange fibers as controlled drug delivery vehicles. Complexation of charged model drugs with the ion-exchange fibers was studied as a method to achieve controlled transdermal drug delivery. Drug release from the cation-exchange fiber into a physiological saline was dependent on the lipophilicity of the drug. The release rates of lipophilic tacrine and propranolol were significantly slower than that of hydrophilic nadolol. Permeation of tacrine across the skin was directly related to the iontophoretic current density and drug concentration used. Anion-exchange fiber was tested with anionic sodium salicylate. The iontophoretic flux enhancement of sodium salicylate from the fiber was substantial. As the drug has to be released from the ion-exchange fiber before permeating across the skin, a clear reduction in the drug fluxes from the cationic and anionic fibers were observed compared to the respective fluxes of the drugs in solution. Overall, the ion-exchange fibers act as a drug reservoir, controlling the release and iontophoretic transdermal delivery of the drug.

Influence of ionic strength on drug adsorption onto and release from a poly(acrylic acid) grafted poly(vinylidene fluoride) membrane.

Ion exchange resins have several applications in pharmacy for controlled or sustained release of drugs. In the present study, effects of the ionic strengths of adsorption medium and dissolution medium on drug adsorption onto and release from a acrylic acid grafted poly(vinylidene fluoride) (PAA-PVDF) were studied. Despite their porosity, PAA-PVDF membranes act reasonable well as cation exchange membranes. It was observed, that ionic strength of adsorption medium, degree of grafting and concentration of propranolol-HCl in adsorption medium affect propranolol-HCl adsorption onto the membrane. The fluxes of smaller molecules (MW < 500) across the membrane decreased with ionic strength of buffer solution, whereas the fluxes of the large molecules (FITC-dextran, MW 4400) increased with ionic strength. Release rate of adsorbed propranolol-HCl from the membrane into phosphate buffer was greatly affected by ionic strength of adsorption medium. These results can be explained by a cation exchange process between membrane and cations present in the buffer solution and swelling behavior of the grafted PAA chains.

Effect of diffusion potential, osmosis and ion-exchange on transdermal drug delivery: theory and experiments.

Equations expressing the effect of the diffusion potential on the trace ion transfer across a porous charged membrane have been derived. These equations have been tested with experiments with human cadaver skin. The transfer of sotalol and salicylate was measured varying the salt (NaCl) concentration in the donor and receiver compartments. It appears that osmotic pressure and ion-exchange make a significant contribution to the flux enhancement by the diffusion potential.

Experimental verification of the mechanistic model for transdermal transport including iontophoresis.

An experimental verification of the previously introduced model for transdermal transport (Kontturi and Murtomäki, J. Control. Release, 41 (1996) 177) is presented. The model comprises two penetration routes: an aqueous and a lipoidal pathway. Lipophilicity of the drug determines which route the drug uses. Constant potential iontophoresis can be used to evaluate the relative proportions of the two competing pathways. beta-blockers sotalol, timolol and propranolol, whose water-octanol partition coefficients span three orders of magnitude, are used as model compounds. Experiments reinforce the predictions of the model in that iontophoresis enhances the flux of the most hydrophilic drug, sotalol, the most whereas the flux of the least hydrophilic drug, propranolol, is enhanced the least. The effect of electroosmosis has now been included in the model.

Transport of drugs across porous ion exchange membranes.

Porous ion exchange membranes have potential applications for drug delivery systems. Permeability of these membranes can be controlled by environmental factors like pH and ionic strength but also the drug properties have an important role in the permeation process. In this paper the influence of the drug charge, lipophilicity and molecular weight on the diffusional drug flux is demonstrated. The membranes under study were poly(acrylic acid) (PAA) grafted porous poly(vinylidene fluoride) (PVDF) membranes which are cation selective due to the partial ionization of carboxyl groups in grafted PAA chains. At low pH the membrane pores are open and the drugs can diffuse through the membrane quite easily. However, at pH 7 the grafted chains partially block the pores and the diffusional flux of bigger drug molecules (Mw9400) decreases five orders of magnitude and also the flux of smaller molecules is clearly reduced. When the influence of the drug charge on the diffusion of the drugs across the membranes was studied, it turned out that the PAA-PVDF membranes facilitate the transport of cationic drugs and repel anionic ones. The presented mathematical model, based on Donnan drugs equilibrium and measured transport number data, predicted the observed trends reasonably well.

Characterization of paracellular and aqueous penetration routes in cornea, conjunctiva, and sclera.

PURPOSE: To characterize quantitatively the paracellular permeation routes in rabbit cornea, conjunctiva, and sclera using polyethylene glycol (PEG) oligomers. METHODS: Corneal, conjunctival, and scleral tissues from New Zealand white rabbits were tested individually in a modified two-chamber Ussing apparatus with the mixture of PEGs with mean molecular weights 200, 400, 600, and 1000 in glutathione bicarbonated Ringer's solution buffer on the donor side of the chamber. The samples and standards were analyzed with high-performance liquid chromatography-thermospray mass spectrometry method. The pore sizes and the pore densities of the corneal and conjunctival epithelia were calculated using an effusion-like approach. RESULTS: The conjunctival and scleral tissues were 15 to 25 times more permeable than the cornea and the molecular size affected the conjunctival permeability less than that of the cornea. The palpebral and bulbar conjunctivas had equal permeabilities. The scleral permeability was approximately half of that in the conjunctiva and approximately 10 times more than in the cornea. The conjunctival epithelia had 2 times larger pores and 16 times higher pore density than the cornea. The total paracellular space in the conjunctiva was estimated to be 230 times greater than that in the cornea. CONCLUSIONS: The conjunctival epithelium, due to its higher membrane permeability and larger absorptive and intercellular space surface areas, is the most viable route for ocular delivery of peptides and oligonucleotides.

Separation of proteins of nearly the same size but having different isoelectric points by convective electrophoresis.

A method for separating proteins of nearly the same size but having different isoelectric points is presented. The method used is convective electrophoresis, which is based on the simultaneous effects of diffusion, electrical migration and opposing convective flow on the transport of proteins through a porous membrane. The pairs of model proteins used in this study were cytochrome c-lysozyme and human serum albumin-haemoglobin. The obtained results show that with a careful adjustment of pH these proteins can be separated by a continuous manner, and no coupling of protein fluxes could be detected in either case.

Electrochemical characterization of human skin by impedance spectroscopy: the effect of penetration enhancers.

The electrochemical properties of human cadaver skin were studied in a diffusion cell with impedance spectroscopy as a function of time in the absence and presence of penetration enhancers dodecyl N,N-dimethylamino acetate and Azone. An improved electrochemical model of skin is presented, and combining the novel model with modern fractal mathematics, the effect of enhancers on the surface of skin is demonstrated. The enhancers appeared to open new penetration routes and increase the ohmic resistance, capacitive properties, and fractal dimension of skin, which means a rougher or more heterogeneous surface.

Electrochemical determination of partition coefficients of drugs.

An electrochemical method for the determination of partition coefficients of drugs that can exist as ions in aqueous solutions is presented. The method involves cyclic voltammetry at the polarizable interface between two immiscible electrolyte solutions. Because n-octanol is an unsuitable solvent for electrochemical purposes, 1,2-dichloroethane, which has electronic properties similar to those of n-octanol, was used in the measurements. The values obtained could be correlated with the values for n-octanol-water partition taken from the literature by an approach based on the linear solvation relationship: log P1 = a log P2 + b; in this relationship, a and b are constants and P1 and P2 correspond to the two different organic and aqueous phase partition equilibria. Furthermore, aqueous diffusion coefficients of drugs were determined from voltammograms.

The effective charge number and diffusion coefficient of cationic cytochrome c in aqueous solution.

The diffusion coefficient and the effective charge number of cytochrome c as a function of ionic strength, temperature and pH have been measured. The measurements were carried out using a method based on a convective diffusion process across a porous membrane. The effect of ionic strength was studied in an NaCl solution the concentration of which varied from 0.001 to 1.0 M. The temperature range studied was 10-50 degrees C, and the pH values studied were 4.0, 6.5 and 8.25. The diffusion coefficient is fairly constant as a function of ionic strength and pH, and Walden's rule is valid in the temperature range studied. The effective charge number is practically constant (ca. 2) in the concentration range studied, except in 0.001 M solution, where it is the same as the titrated value. The charge number decreases slightly in the temperature range 10-30 degrees C, but seems to drop suddenly to zero at ca. 40 degrees C. Measurements using heavy water (D2O) as a solvent instead of water did not give zero charge at 40 degrees C for cytochrome c.

Transport properties of a cation exchange membrane with sodium and potassium as counterions.

The measured transport properties for the cation exchange membrane Ionics 61AZL389 in the Na+ + K+ mixed counterion states are presented. The transport numbers of counterions and of water as well as the specific conductivity of the membrane showed approximately linear behaviour as a function of ionic fraction in the membrane. It is therefore concluded that it is possible to estimate the transport numbers of counterions from known selectivity coefficients and concentrations in the external solution. The transport number of water and the specific conductivity of the membrane can also be evaluated reasonably accurately using data for membranes in pure homoionic states. The separation ratio was found to be constant over a wide range of concentration ratios under the hydrodynamic conditions used experimentally.