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

Inhaled vaccine delivery in the combat against respiratory viruses:A 2021 overview of recent developments and implications for COVID-19

Introduction: As underlined by the late 2019 outbreak of severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2), vaccination remains the cornerstone of global health-care. Although vaccines for SARS-CoV-2 are being developed at a record-breaking pace, the majority of those that are licensed or currently registered in clinical trials are formulated as an injectable product, requiring a tightly regulated cold-chain infrastructure, and primarily inducing systemic immune responses.Areas covered: Here, we shed light on the status of inhaled vaccines against viral pathogens, providing background to the role of the mucosal immune system and elucidating what factors determine an inhalable vaccine's efficacy. We also discuss whether the development of an inhalable powder vaccine formulation against SARS-CoV-2 could be feasible. The review was conducted using relevant studies from PubMed, Web of Science and Google Scholar.Expert opinion: We believe that the scope of vaccine research should be broadened toward inhalable dry powder formulations since dry vaccines bear several advantages. Firstly, their dry state can tremendously increase vaccine stability and shelf-life. Secondly, they can be inhaled using disposable inhalers, omitting the need for trained health-care personnel and, therefore, facilitating mass-vaccination campaigns. Thirdly, inhalable vaccines may provide improved protection since they can induce an IgA-mediated mucosal immune response

Bottom-Up Preparation Techniques for Nanocrystals of Lipophilic Drugs

# The Author(s) 2010. This article is published with open access at Springerlink.com KEY WORDS bottom-up. large-scale production. nanocrystal. solubilit

Inhomogeneous Distribution of Components in Solid Protein Pharmaceuticals:Origins, Consequences, Analysis, and Resolutions

Successful development of stable solid protein formulations usually requires the addition of one or several excipients to achieve optimal stability. In these products, there is a potential risk of an inhomogeneous distribution of the various ingredients, specifically the ratio of protein and stabilizer may vary. Such inhomogeneity can be detrimental for stability but is mostly neglected in literature. In the past, it was challenging to analyze inhomogeneous component distribution, but recent advances in analytical techniques have revealed new options to investigate this phenomenon. This paper aims to review fundamental aspects of the inhomogeneous distribution of components of freeze-dried and spray-dried protein formulations. Four key topics will be presented and discussed, including the sources of component inhomogeneity, its consequences on protein stability, the analytical methods to reveal component inhomogeneity, and possible solutions to prevent or mitigate inhomogeneity

Natural and bioinspired excipients for dry powder inhalation formulations

Pulmonary drug delivery can have several advantages over other administration routes, in particular when using dry powder formulations. Such dry powder inhalation formulations generally include natural and bio-inspired excipients, which, among other purposes, are used to improve dosing reproducibility and aerosolization performance. Amino acids can enhance powder dispersibility and provide protection against moisture uptake. Sugars are used as drug-carrying diluents, stabilizers for biopharmaceuticals, and surface enrichers. Lipids and lipid-like excipients can reduce interparticle adhesive forces and are also used as constituents of liposomal drug delivery systems. Finally, biodegradable polymers are used to facilitate sustained release and targeted drug delivery. Despite their promise, pulmonary toxicity of many of the discussed excipients remains largely unknown and requires attention in future research

Oxytocin formulations and uses thereof

The present invention relates to the field of preventive and therapeutic medicine, in particular to peptide formulations. Provided is a p H-buffered aqueous formulation comprising oxytocin, vasopressin or an analogue thereof and at least one non-toxic source of divalent metal ions in a concentration of at least 2 m M, and the use of the formulation for the manufacture of a medicament for therapeutic and/or prophylactic treatments. Also provided is a method for treating or preventing haemorrhage in a subject in need thereof, comprising administering to said subject an effective dosage amount of an oxytocin formulation according to the invention. Further provided is a method for treating or preventing diabetes insipidus or vasodilatory shock in a subject in need thereof, comprising administering to said subject an effective dosage amount of a vasopressin formulation according to the invention

Peptide formulations and uses thereof

The present invention relates to the field of preventive and therapeutic medicine, in particular to peptide formulations. Provided is a p H-buffered aqueous formulation comprising oxytocin, vasopressin or an analogue thereof and at least one non-toxic source of divalent metal ions in a concentration of at least 2 m M, and the use of the formulation for the manufacture of a medicament for therapeutic and/or prophylactic treatments. Also provided is a method for treating or preventing haemorrhage in a subject in need thereof, comprising administering to said subject an effective dosage amount of an oxytocin formulation according to the invention. Further provided is a method for treating or preventing diabetes insipidus or vasodilatory shock in a subject in need thereof, comprising administering to said subject an effective dosage amount of a vasopressin formulation according to the invention