Anders Axelsson

The mechanisms of drug release in poly(lactic-co-glycolic acid)-based drug delivery systems-A review.

Poly(D,L-lactic-co-glycolic acid) (PLGA) is the most frequently used biodegradable polymer in the controlled release of encapsulated drugs. Understanding the release mechanisms, as well as which factors that affect drug release, is important in order to be able to modify drug release. Drug release from PLGA-based drug delivery systems is however complex. This review focuses on release mechanisms, and provides a survey and analysis of the processes determining the release rate, which may be helpful in elucidating this complex picture. The term release mechanism and the various techniques that have been used to study release mechanisms are discussed. The physico-chemical processes that influence the rate of drug release and the various mechanisms of drug release that have been reported in the literature are analyzed in this review, and practical examples are given. The complexity of drug release from PLGA-based drug delivery systems can make the generalization of results and predictions of drug release difficult. However, this complexity also provides many possible ways of solving problems and modifying drug release. Basic, generally applicable and mechanistic research provides pieces of the puzzle, which is useful in the development of controlled-release pharmaceuticals.

Diffusion measurement in gels

Methods for measuring diffusion coefficients in gels are reviewed, and their capacities, limitations and requirements are briefly discussed. With four of these methods, i.e., the diaphragm cell, uptake/release from beads, holographic laser interferometry and nuclear magnetic resonance (FT-PGSE), a comparison is made with regard to accuracy and precision. The comparison is based on a number of studies in which the diffusion coefficient of ethanol in agarose gel has been measured. It is concluded that the diaphragm cell and nuclear magnetic resonance (FT-PGSE) are very accurate and precise.

Mechanistic modelling of drug release from polymer-coated and swelling and dissolving polymer matrix systems

The time required for the design of a new delivery device can be sensibly reduced if the release mechanism is understood and an appropriate mathematical model is used to characterize the system. Once all the model parameters are obtained, in silico experiments can be performed, to provide estimates of the release from devices with different geometries and compositions. In this review coated and matrix systems are considered. For coated formulations, models describing the diffusional drug release, the osmotic pumping drug release, and the lag phase of pellets undergoing cracking in the coating due to the build-up of a hydrostatic pressure are reviewed. For matrix systems, models describing pure polymer dissolution, diffusion in the polymer and drug release from swelling and eroding polymer matrix formulations are reviewed. Importantly, the experiments used to characterize the processes occurring during the release and to validate the models are presented and discussed.

Determination of effective diffusion coefficients in calcium alginate gel plates with varying yeast cell content

Effective diffusion coefficients (De) have been determined for lactose, glucose, galactose, and ethanol in calcium alginate gel with varying yeast cell concentration. The measurements have been performed in a diffusion cell, and the results evaluated with the quasisteady-state method. An ultrasonic meter was used for gel thickness determination with an accuracy of 1.5% and a new method for the reproducible preparation of gel plates was developed. It was found thatDe in pure alginate gel decreased to about 90% of the diffusivity in water and did not vary with alginate concentration.De decreased considerably with increasing yeast cell concentration. For the solutes studied, the effective diffusion coefficient can be estimated according to the equationDe =Deo (1 - ϕ)/[1+(ϕ/2)], whereDeo is the effective diffusivity in pure gel and ϕ is the volume fraction of yeast cells.

Simulation and parametric study of a film-coated controlled-release pharmaceutical

Pharmaceutical formulations can be designed as Multiple Unit Systems, such as Roxiam CR, studied in this work. The dose is administrated as a capsule, which contains about 100 individual pellets, which in turn contain the active drug remoxipride. Experimental data for a large number of single pellets can be obtained by studying the release using microtitre plates. This makes it possible to study the release of the individual subunits making up the total dose. A mathematical model for simulating the release of remoxipride from single film-coated pellets is presented including internal and external mass transfer hindrance apart from the most important film resistance. The model can successfully simulate the release of remoxipride from single film-coated pellets if the lag phase of the experimental data is ignored. This was shown to have a minor influence on the release rate. The use of the present model is demonstrated by a parametric study showing that the release process is film-controlled, i.e. is limited by the mass transport through the polymer coating. The model was used to fit the film thickness and the drug loading to the experimental release data. The variation in the fitted values was similar to that obtained in the experiments.

Diffusion of lysozyme in gels and liquids - A general approach for the determination of diffusion coefficients using holographic laser interferometry

A study on diffusion measurements of the protein lysozyme in liquids and agarose gels, at different pH and ionic strengths, has been performed using holographic laser interferometry. The measurements showed that the diffusive flux was very dependent on pH and ionic strength when the protein was not at its isoelectric point or when the charge of the lysozyme molecules was not screened by ions in the solution. Evaluation of the experimental data with Ficks law, resulted in diffusion coefficients for lysozyme that are strongly dependent on pH and ionic strength. Evaluation of the experimental data using a more general transport model, based on chemical potential gradients instead of concentration gradients resulted in lysozyme diffusion coefficients that are independent of pH and ionic strength. The chemical potential was estimated by using the Poisson-Boltzmann equation.

Coated formulations: New insights into the release mechanism and changes in the film properties with a novel release cell.

The effect of the blend ratio of water-insoluble ethyl cellulose (EC) and water-soluble hydroxypropyl cellulose (HPC-LF), on the properties of sprayed films and on the drug release mechanism of formulations coated with the material was investigated. When the original HPC-LF content exceeded 22%, both the amount of HPC-LF leached out and the water permeability of the films increased drastically when they were immersed in a phosphate buffer solution. The release mechanism of potassium nitrate through EC/HPC-LF films containing 20, 24 and 30% HPC-LF was elucidated in a new release cell equipped with a manometer to measure the pressure build-up inside the cell. A lag phase in the release accompanied by a pressure build-up was observable in all the experiments showing that all the films were initially semi-permeable to KNO3. However, pressure data revealed that films with 30% HPC-LF became permeable to KNO3 during the release process due to HPC-LF leaching. Importantly, the blend ratio influenced not only the release rate (which increased as the amount of HPC-LF increased), and the lag time (which increased as the amount of HPC-LF decreased), but also the release mechanism, which changed from osmotic pumping to diffusion as the amount of HPC-LF increased.

Simulation of chromatographic processes applied to separation of proteins

The advantages of using a detailed mathematical model for fixed bed chromatography is demonstrated by the personal computer program SIMCHROM. The chromatography model includes axial dispersion in the bulk liquid, external and internal mass transfer resistances and an instationary non-linear adsorption model. Frontal and pulse chromatography can be studied for single and multicomponent systems. The simulation program can easily be used to make parametric evaluations to study the influence of variations in physical, kinetical and operating parameters. The special features of the present intrinsic model is demonstrated by comparing the SIMCHROM results With simulations using simplified lumped models. Experimental data describing affinity chromatography of lysozyme on Cibacron Blue Sepharose CL-6B is used as a model system. The intrinsic model is able to describe variations in the physical, kinetic and operating parameters better than the simplified models. This results in a more reliable prediction of the performance of the chromatography process as well as a better understanding of che underlying mechanisms responsible for the separation

Swelling kinetics of poly(N-isopropylacrylamide) gel

In many gel applications the swelling and shrinking kinetics are very important, e.g. in controlled/slow release, where the kinetics determined the rate of out-diffusion of the active component, and in gel extraction where the gel is swollen and shrunk several times. In this study swelling kinetics of poly(N-isopropylacrylamide) gel (NiPAAm gel) was determined by monitoring the swelling process using a stereo microscope and a video camera. The swelling of spherical gel bodies could conveniently be studied after a temperature change. The results obtained were treated according to the approach of Tanaka and Fillmore, in which the swelling and shrinking of a gel is described as a motion of the gel network according to the diffusion equation. This was shown to be valid when the temperature changes are kept below the critical point of the gel. However, the model fails to describe the shrinking process when passing from below to above the critical temperature. The collective diffusion coefficient (D), defined as the osmotic bulk modulus divided by the friction factor, was determined by fitting to the experimental data. D was found to increase with temperature according to the Wilke-Chang relation D = 2.0.10(-11) + 7.6.10(-17).T/mu. The results were used to simulate the swelling/shrinking process. The simulations show the importance of having sufficiently small gel bodies to achieve a short swelling time.

Direct measurements of convective fluid velocities in superporous agarose beads

Superporous agarose beads contain two sets of pores, diffusion pores and so-called superpores or flow pores, in which the chromatographic flow can transport substances to the interior of each individual bead [Gustavsson and Larsson, J. Chromatogr. A 734 (1996) 231]. The existence of pore flow may be proven indirectly by the chromatographic performance of beads but it has never been directly demonstrated in a chromatographic bed. In this report, pore flow was directly measured by following the movement of micro-particles (dyed yeast cells) in a packed bed. The passage of the micro-particles through the superpores and through the interstitial pores was followed by a microscope/video camera focused on beads which were situated four layers from the glass wall. The video recordings were subsequently used to determine the convective fluid velocities in both the superpores and the interstitial pores. Experiments were carried out with three different bead size ranges, all of which contained superporous beads having an average superpore diameter of 30 microns. The superpore fluid velocity as % of interstitial fluid velocity was determined to be 2-5% for columns packed with 300-500-micron beads (3% average value), 6-12% for columns packed with 180-300-micron beads (7% average value) and 11-24% for columns packed with 106-180-micron beads (17% average value). These data were compared to and found to agree with theoretically calculated values based on the Kozeny-Carman equation. In order to observe and accurately measure fluid velocities within a chromatographic bed, special techniques were adopted. Also, precautions were made to ensure that the experimental conditions used were representative of normal chromatography runs.