34 research outputs found
An adaptable model for growth and/or shrinkage of droplets in the respiratory tract during inhalation of aqueous particles
AbstractThe site of deposition of pulmonary delivered aerosols is dependent on the aerosol׳s droplet size distribution, which may change during inhalation. The aim of this study was to develop a freely accessible and adaptable model that describes the growth (due to condensation) and shrinkage (due to evaporation) of inhaled droplets as a function of the distance from the airway wall during various inhalation conditions, for a laminar flow scenario. This was achieved by developing a model with which the evaporation of water from a droplet surface or condensation of water onto the droplet surface can be calculated. This model was then applied to a second model that describes the heat and mass transfer from the airway wall to the inhaled aerosol. The latter was based on the Weibel model. It was found that the growth and shrinkage of inhaled droplets markedly differs, depending on the distance from the airway wall. Droplets near the wall start to grow immediately due to fast water vapor transfer from the wall to the cold inhaled air. This growth continues until the air reaches body temperature and is fully saturated. However, droplets in the center of the airway first evaporate partly, due to a delay in water vapor transfer from the airway wall, before they start to grow. Depending on the conditions during inhalation, the droplet size distribution can widen considerably, which may affect the lung deposition and thereby the efficacy of the inhalation therapy. In conclusion, the model was able to show the effect of the conditions in the respiratory tract on the growth and shrinkage of inhaled droplets during standard inhalation conditions. Future developments can be aimed at expanding the model to include turbulent flow and hygroscopic growth, to improve the accuracy of the model and make it applicable to both droplets of solutions and dry particles
Model to predict inhomogeneous protein-sugar distribution in powders prepared by spray drying
AbstractA protein can be stabilized by spray drying an aqueous solution of the protein and a sugar, thereby incorporating the protein into a glassy sugar matrix. For optimal stability, the protein should be homogeneously distributed inside the sugar matrix. The aim of this study was to develop a model that can predict the distribution of protein and sugar in an evaporating droplet using bovine serum albumin (BSA) and trehalose as model protein and sugar, respectively. This was achieved by expanding a previously developed model that was able to predict the growth or shrinkage of inhaled droplets in the airways (Grasmeijer, Frijlink & Hinrichs, 2016). The droplet was considered to consist of a finite number of concentric spherical shells in which the change in concentration of components was calculated in time, enabling the prediction of concentration gradients inside the droplet. It was found that during evaporation of the droplet, an inhomogeneous protein–sugar distribution was formed even when surface active properties were not considered. The relatively large protein molecule was predicted to accumulate much faster at the surface of the droplet than the sugar due to slower diffusion, resulting in a lower sugar/protein ratio at the surface of the particle than in the center. For a mixture of BSA and trehalose, not considering surface active properties, it was predicted that 60% of protein was incorporated in the powder at a lower sugar/protein ratio than when protein and sugar would have been homogeneously distributed, which may hamper efficient protein stabilization. These predictions can be used to more accurately adapt the initial composition of the solution to ensure proper stabilization of the protein, for example by simply increasing the amount of sugar to increase the sugar/protein ratio at the surface. Or, if this is limited by the desired loading, changing the drying conditions to slow down the drying rate
Efficient production of solid dispersions by spray drying solutions of high solid content using a 3-fluid nozzle
To evaluate the feasibility of producing solid dispersions with 3-fluid nozzle spray drying to improve the dissolution behavior of lipophilic drugs, 60 experiments were performed based on a Design of Experiment. Solid dispersions with mannitol as a hydrophilic matrix and diazepam as a model drug with a drug load of 20 wt-% were produced. The variables of the experiments were the water/organic solvent ratio, liquid feed flow, total solid content, atomizing airflow and type of organic solvent (ethanol or ethyl acetate). The responses measured were dissolution rate, yield, actual drug load, particle size and crystallinity of diazepam and mannitol. Increasing water/organic solvent ratio was found to be the main factor for enhancing the dissolution rate. The total solid content of the solutions to be spray dried did not affect any of the responses, which means that processing solutions of high concentrations is possible. The choice of organic solvent did not affect the responses as well, i.e. both the fully water miscible solvent ethanol and the poorly water miscible solvent ethyl acetate could be used which makes this production method highly versatile
Identifying critical process steps to protein stability during spray drying using a vibrating mesh or a two-fluid nozzle
The aim of this study was to identify critical steps to protein stability during spray drying using two different nozzle types: a vibrating mesh nozzle and a standard two-fluid nozzle in a Buchi B-90 spray dryer. L-Lactic dehydrogenase was used as a model protein as it is a heat and shear stress sensitive protein. Trehalose was used as excipient because of its excellent stabilizing capacities. The entire spray drying process was split up into smaller steps and after each step the enzymatic activity of the protein was measured. With the vibrating mesh nozzle in total 78% of activity was lost About 68% was due to atomizing and healing and 10% was caused by dehydration and circulation of the liquid. With the two-fluid nozzle the total activity loss was only 23%, to which atomization, dehydration, and circulation contributed almost equally. Healing was not an issue, as the two-fluid nozzle could be cooled with water. In conclusion, the type and the configuration of the nozzle used for spray drying are important determinants for maintaining protein stability, as atomizing, healing, ultra-sonication, and recirculation of the feed solution negatively influence it The possibility to cool the two-fluid nozzle offers an important advantage to the vibrating mesh nozzle in the spray drying process of proteins. In this study, we show that, next to the optimization of the formulation, optimization of the spray drying process should be taken into account to maintain protein stability
Ovalbumin-containing core-shell implants suitable to obtain a delayed IgG1 antibody response in support of a biphasic pulsatile release profile in mice
A single-injection vaccine formulation that provides for both a prime and a boost immunization would have various advantages over a multiple-injection regime. For such a vaccine formulation, it is essential that the booster dose is released after a certain, preferably adjustable, lag time. In this study we investigated whether a core-shell based implant, containing ovalbumin as core material and poly(DL-lactic-co-glycolic acid) of various monomer ratios as shell material can be used to obtain such a booster release. An in vitro release study showed that the lag time after which the ovalbumin was released from the core-shell implant increased with increasing lactic to glycolic acid ratio of the polymer and ranged from 3-6 weeks. Fluorescence spectroscopy showed minimal differences between native ovalbumin and ovalbumin from core-shell implants that were incubated until just before the observed in vitro release. In addition, mice immunized with a subcutaneous inserted core-shell implant containing ovalbumin showed an ovalbumin-specific IgG1 antibody response after a lag time of 4 or 6-8 weeks. Moreover, delayed release of ovalbumin caused higher IgG1 antibody titers than conventional subcutaneous vaccination with ovalbumin dissolved in PBS. Collectively, these findings could contribute to the further development of a single-injection vaccine, making multiple injections of the vaccine superfluous
The mechanism behind the biphasic pulsatile drug release from physically mixed poly(DL-lactic(-co-glycolic) acid)-based compacts
Successful immunization often requires a primer, and after a certain lag time, a booster administration of the antigen. To improve the vaccinees' comfort and compliance, a single-injection vaccine formulation with a biphasic pulsatile release would be preferable. Previous work has shown that such a release profile can be obtained with compacts prepared from physical mixtures of various poly(DL-lactic(-co-glycolic) acid) types (Murakami et al., 2000). However, the mechanism behind this release profile is not fully understood. In the present study, the mechanism that leads to this biphasic pulsatile release was investigated by studying the effect of the glass transition temperature (Tg) of the polymer, the temperature of compaction, the compression force, the temperature of the release medium, and the molecular weight of the incorporated drug on the release behavior. Compaction resulted in a porous compact. Once immersed into release medium with a temperature above the Tg of the polymer, the drug was released by diffusion through the pores. Simultaneously, the polymer underwent a transition from the glassy state into the rubbery state. The pores were gradually closed by viscous flow of the polymer and further release was inhibited. After a certain period of time, the polymer matrix ruptured, possibly due to a build-up in osmotic pressure, resulting in a pulsatile release of the remaining amount of drug. The compression force and the molecular weight of the incorporated drug did not influence the release profile. Understanding this mechanism could contribute to further develop single-injection vaccines
Improving protein stabilization by spray drying: formulation and process development
There is an increasing interest for dried protein formulations in pharmacy. They may offer several advantages over aqueous formulations, such as ease of storage, longer shelf life, and use for solid dosage forms. However, the mechanisms underlying stabilization in the solid state are not yet fully understood. Proteins in their solid state can be stabilized by incorporating them into a matrix of sugar molecules. The sugar is believed to act as a replacement for water or to keep the protein vitrified. Although usually only one of the mechanisms is considered, in this study both were found to play a role. The importance of either mechanism depends on the storage temperature and ambient humidity, which should therefore be taken into account when developing dry stabilized protein formulations. Furthermore, the drying technique should also be considered during the development. For example, because spray drying can be stressful to the protein, the process conditions can largely affect the quality of the product. Therefore, also the drying process should be tailored to the specific protein to be formulated. Therefore, a mathematical model was developed to predict optimal process conditions. It is believed that more detailed models can further help with the formulation and process development by understanding better what happens at a more microscopic level. For protein formulations, predicting the behavior of drying droplets showed and quantified the separation of the stabilizing sugar and the protein on a molecular level inside the droplet. With this knowledge a better approach can be chosen to obtain optimal protein stability
Recent advances in the fundamental understanding of adhesive mixtures for inhalation
Adhesive mixtures for inhalation are the most widely used type of formulation in dry powder inhalation products. Although they have been the subject of active research, the relationships between properties of the starting materials, the mixing and dispersion processes, and the dispersion performance of this type of formulation are generally poorly understood. Interactions between relevant variables have been mentioned as an important cause. By reviewing the effects on mixture dispersion performance of the most widely studied formulation variables we try to find out whether or not the understanding of adhesive mixtures has improved in recent years. We furthermore propose an approach that may potentially accelerate the process of understanding. General conclusions concerning the effects of the variables considered cannot be drawn, because inconsistent findings are reported throughout the literature for all of them. These inconsistencies are indeed largely the result of interactions between variables of the formulation and dispersion processes. Mechanisms for most of the observed effects and interactions have been proposed, but they often remain unproven and, therefore, speculative. We have attempted to condense the knowledge from the literature into a theoretical framework that is intended to help explain the interplay between variables. According to this framework, only few mixture properties are key to understanding the effects of and interactions between formulation variables. Therefore, we suggest that the development or optimisation of techniques to accurately characterise these mixture properties could be an effective approach to further the fundamental understanding of adhesive mixtures for inhalation and enable their rational engineering