Underlying Release Mechanisms Research Articles

Measurement of Protein Diffusion Through Poly(d,l-Lactide-Co-Glycolide)

A novel method was developed for studying the diffusion of proteins through poly(d,l-lactide-co-glycolide) (PLG), using a diffusion cell. To develop improved formulations for the controlled release of encapsulated drugs it is important to understand the underlying release mechanisms. When using low-molecular-weight PLG as the release-controlling polymer, diffusion through the pores is often proposed as the main release mechanism. The experimental set-up and method of determining the diffusion coefficient were thoroughly evaluated with regard to the reliability and the influence of the stirring rate. A procedure for spraying thin films of PLG onto a filter, which could be placed in the diffusion cell, was optimized. The method was then applied to the determination of the diffusion coefficient of human growth hormone (hGH) through a PLG film. The results show that the method enables measurements of the diffusion coefficient through the polymer film. Neither the stirring rate nor the concentration of hGH influenced the diffusion coefficient. The diffusion coefficient of hGH through degraded PLG films was 5.0 · 10− 13 m2/s, which is in the range that could be expected, i.e., several orders of magnitude smaller than its the diffusivity in pure water. The reproducibility was good, considering the dynamic properties of PLG, i.e., the difference in diffusion coefficients, at, for example, different stages of degradation and for different compositions of PLG, is expected to be much higher. The variation is probably also present in PLG films used for controlled-release formulations. Although the PLG film contains a large amount of water, a considerable time elapsed before pores of sufficient size formed and diffusion through the film started. In two-component diffusion experiments, the difference in diffusion rate did not correspond to the difference in molecular weight of the solutes, indicating a size exclusion effect. This method can be used to study the effect of changes in the formulation specification. By studying the change in the diffusion coefficient through the degradation process of PLG, or similar polymers, a better understanding of diffusion and, thus, also release mechanisms can be obtained.

Inhibitory Effects of Platelet-rich Plasma on Osteoclast Differentiation in RAW264.7 Cells

Platelet-rich plasma (PRP) is an autologous source of platelet-derived growth factors, and has been used successfully in oral surgery repair and in the placement of osseointegrated implants. However, little is known about the underlying release mechanisms of these factors or the manner in which inhibition of osteoclastic cells is regulated. The present study investigated the efficacy of PRP as an inhibitor of receptor activator of NF-kappaB ligand (RANKL)-induced TRAP-positive multinucleated cell formation in RAW264.7 cells. RANKL-induced formation of osteoclasts was significantly inhibited by treatment with PRP, while washed platelet treatment was more effective in inhibiting osteoclast formation. These results suggest that PRP and washed platelets are potent inhibitors of osteoclast differentiation.

PLGA-based microparticles: elucidation of mechanisms and a new, simple mathematical model quantifying drug release

The two major aims of this study were: (i) to elucidate the underlying release mechanisms from drug-loaded, erodible microparticles based on poly(lactic-co-glycolic acid) (PLGA) showing biphasic drug release behavior: an initial ‘burst’ effect, followed by a zero order release phase; and (ii) to develop a new, simple mathematical model that allows the quantitative description of the observed in vitro drug release patterns from this type of delivery system. PLGA-based microparticles offer various advantages, such as the possibility to control the resulting drug release rate accurately over prolonged periods of time, easiness of administration (e.g., by stereotaxic injection), good biocompatibility and complete erosion (avoiding the removal of empty remnants). Consequently, the practical importance of these advanced drug delivery systems is remarkably increasing. However, only little knowledge is yet available concerning the processes controlling the release rate of the drug out of these devices. Various chemical and physical phenomena are involved, rendering the identification of the crucial mechanisms and the mathematical description of the resulting drug release kinetics difficult. In the present study, different physicochemical characterization methods (e.g., DSC, SEM, SEC, particle size analysis) were used to monitor the changes occurring within anticancer drug-loaded PLGA microparticles upon exposure to phosphate buffer pH 7.4. Based on these experimental findings, the most important underlying drug release rate controlling mechanisms were identified and a new mathematical model was developed that allows the quantitative description of the resulting release patterns.

Bimodal drug release achieved with multi-layer matrix tablets: transport mechanisms and device design

The aim of this study was to develop new multi-layer matrix tablets to achieve bimodal drug release profiles (fast release/slow release/fast release). Hydroxypropyl methylcellulose acetate succinate (HPMCAS, type MF) was chosen as a matrix former, because it is water-insoluble at low, and water-soluble at high pH values. Studies focused on the elucidation of the drug release mechanisms from HPMCAS-MF:drug tablets. In 0.1 N HCl the resulting release kinetics can be described using Fick’s second law of diffusion, taking into account axial and radial mass transfer in cylindrical geometry. As the diffusion coefficients are found to be constant and the boundary conditions to be stationary, these systems are purely drug diffusion-controlled. In contrast, the dominating mass transport phenomena in phosphate buffer pH 7.4 are more complex. Due to polymer dissolution the resulting matrix structure is time-variant, leading to increasing drug diffusion coefficients and decreasing tablet dimensions, and thus moving boundary conditions. Drug release is affected by water imbibition, drug diffusion and polymer dissolution and is faster compared to 0.1 N HCl. With knowledge of these underlying release mechanisms, multi-layer matrix tablets were developed to achieve bimodal drug release. HPMCAS-MF:drug mixtures were used as tablet cores. As expected, changing the release medium from 0.1 N HCl to phosphate buffer pH 7.4 after 2 h, lead to a significant increase in drug release. The abruptness of this rate change could be enhanced by adding two drug-free HPMCAS-MF barrier layers (one on each side) to the system. The addition of a fourth, drug-containing and fast disintegrating initial dose layer yielded the desired bimodal drug release patterns. The process and formulation parameters affecting the resulting release rates were investigated using theophylline and acetaminophen as model drugs.

Chemical erosion behavior of graphite due to energetic oxygen impact

Pyrolytic graphite, fine grain graphite and amorphous a-C:H films were irradiated with energetic oxygen in the energy range 1–5 keV between room temperature and 1800 K. CO and CO 2 molecules released during implantation were analyzed by residual and line-of-sight mass spectroscopy and their velocity distributions were determined by time-of-flight measurements. The retained oxygen was determined by thermal desorption spectroscopy after irradiation. The impact of energetic oxygen ( E > 1 keV) on these materials results in the formation of CO and CO 2 with an erosion yield close to unity. The observed CO release behavior can be described by a local saturation model. Special experiments indicate that the underlying release mechanism is driven by ion-induced collision processes at the end of the ion trajectory of the impinging oxygen. Time-of-flight measurements have shown that released CO molecules have two different energy distributions with a thermal component corresponding to the target temperature and an overthermal component at a maximum energy of about 0.12 eV, whereas the CO 2 molecules are exclusively released with thermal energies.

A new in vitro technique for the evaluation of drug release profile from colloidal carriers - ultrafiltration technique at low pressure

A new in vitro technique, ultrafiltration at low pressure, is proposed for the evaluation of drug release profile from colloidal carriers such as submicron emulsions and nanoparticles. A thorough description is given after having reviewed the various available techniques for drug release evaluation from colloidal carriers. The results yielded by the new technique clearly show that miconazole release from either the submicron emulsion or a marketed micellar aqueous solution was very rapid under perfect sink conditions. This fact raised doubts and practically rules out the possibility of using submicron emulsions as a controlled-release drug delivery system for i.v. administration. The in vitro indomethacin release profile from PLA or PLGA nanoparticles was found to be biphasic with an immediate release of 40–80% of the initial drug concentration, followed by a slower exponential release which lasted a few hours. It was deduced from the overall kinetic results that the ultrafiltration method at low pressure was versatile, sensitive and capable of distinguishing between different kinetic behaviors. The technique offers the possibility of identifying the underlying release mechanism of drug from colloidal carriers.

Temperature Stress Causes Host Cell Detachment in Symbiotic Cnidarians: Implications for Coral Bleaching.

During the past decade, acute and chronic bleaching of tropical reef corals has occurred with increasing frequency and scale. Bleaching, i.e., the loss of pigment and the decrease in population density of symbiotic dinoflagellates (zooxanthellae), is often correlated with an increase or decrease in sea surface temperature. Because little is known of the cellular events concomitant with thermal bleaching, we have investigated the mechanism of release of zooxanthellae by the tropical sea anemone Aiptasia pulchella and the reef coral Pocillopora damicornis in response to cold and heat stress. Both species released intact host endoderm cells containing zooxanthellae. The majority of the released host cells were viable, but they soon disintegrated in the seawater leaving behind isolated zooxanthellae. The detachment and release of intact host cells suggests that thermal stress causes host cell adhesion dysfunction in these cnidarians. Knowledge of the cellular entity released by the host during bleaching provides insight into both the underlying release mechanism and the way in which natural environmental stresses evoke a bleaching response.

Fundamentals of release mechanism interpretation in multiparticulate systems: determination of substrate release from single microcapsules and relation between individual and ensemble release kinetics

For assessing theories underlying release kinetics of contents from ensembles of microparticles in multiparticle dispersions, population release studies are incapable of revealing the operative physicochemical mechanism, in spite of attempts by many authors to interpret such cumulative data. The present study pioneers techniques for determining release kinetics from single microparticles, using microcapsules as model systems with microconductimetric or spectrophotometric measurement of contents released into the external medium. In four systems giving overall first-order release from populations, the individuals all released their contents at constant rates almost to total payload. A statistical model relating the sum of individual release to cumulative release was applied to the data. It was based on the distribution of two fundamental parameters of the individuals, m ∞ the payload and t ∞ the time to complete release. Statistical analysis of the experimental data validated the proposed relation in the four systems. The conditions required to obtain first-order cumulative kinetics from summated single constant rate data are either: (1) gamma-distribution with shape parameter = 2 of t ∞ and independence of m ∞ and t ∞; or (2) exponential distribution of t ∞ and correlation betw m ∞ and t ∞. Cumulative kinetics and rate constants based on an approximation to a standard release equation are useful for characterization of batch release properties (e.g. in checking repeatability, effects of production variables, sustained release character under controlled conditions) but do not reveal the underlying release mechanism or the actual distribution of parameters, which require studies on individuals. Cumulative kinetics may in fact be altered if the distribution profile of the population undergoes accidental or pre-determined change.

Different Kinds of Acetylcholine Release From The Motor Nerve

Publisher Summary Studies of transmitter release at the neuromuscular junction have revealed the presence of several distinct types of acetylcholine (ACh) secretion. This chapter describes these processes and discusses the underlying release mechanisms and the possible physiological significance of the various kinds of transmitter action. Transmitter release from the motor nerve may be divided into those involving intermittent, quantal, or nonquantal release of ACh as well as those characterized by a continuous leakage of ACh. Intermittent secretion of ACh involves either a Ca 2+ –sensitive(I) or a Ca 2+ – insensitive (II) type of transmitter release process. The former characterizes phasic, nerve impulse evoked or spontaneous quantal ACh release and the latter the spontaneous intermittent, nonquantal secretion of ACh giving rise postsynaptically to so-called giant and slow-rising miniature end-plate potentials. Molecular leakage of ACh is a continuous process originating not only from the presynaptic nerve (III) but also from the postsynaptic muscle cell.