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

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

Are inhaled mRNA vaccines safe and effective? A review of preclinical studies

Introduction: Injected mRNA vaccines have been proven effective and safe in the SARS-CoV-2 pandemic. Using the machinery of the cell, mRNA vaccines translate into an antigen, which triggers an adaptive immune response. The effectiveness of intramuscular administered mRNA vaccines wanes in the months post-vaccination, which makes frequent booster administrations necessary. To make booster administration easier and increase efficacy, pulmonary administration could be investigated. The aim of this literature study was therefore to review the published preclinical (animal) studies on the safety and efficacy of pulmonary administered mRNA vaccines. Areas covered: We first provide background information on mRNA vaccines and immunological mechanisms of vaccination. Thereafter, we provide an evaluation of published animal studies, in which mRNA vaccines (or mRNA containing nanoparticles) were delivered into the lungs. We covered the following areas: biodistribution, cellular uptake, immune response, protection, and safety. All relevant papers were found using PubMed/MEDLINE database. Expert opinion: In our opinion, head-to-head comparison studies examining the safety and efficacy of intramuscular injected and pulmonary administered liquid mRNA vaccines should be performed first. When pulmonary delivered mRNA vaccines are shown to be effective and safe, inhalable dry powder formulations should be engineered. Finally, the tolerability of patients with respiratory diseases should be considered

Stability of Lysozyme in Aqueous Extremolyte Solutions during Heat Shock and Accelerated Thermal Conditions

The purpose of this study was to investigate the stability of lysozyme in aqueous solutions in the presence of various extremolytes (betaine, hydroxyectoine, trehalose, ectoine, and firoin) under different stress conditions. The stability of lysozyme was determined by Nile red Fluorescence Spectroscopy and a bioactivity assay. During heat shock (10 min at 70uC), betaine, trehalose, ectoin and firoin protected lysozyme against inactivation while hydroxyectoine, did not have a significant effect. During accelerated thermal conditions (4 weeks at 55uC), firoin also acted as a stabilizer. In contrast, betaine, hydroxyectoine, trehalose and ectoine destabilized lysozyme under this condition. These findings surprisingly indicate that some extremolytes can stabilize a protein under certain stress conditions but destabilize the same protein under other stress conditions. Therefore it is suggested that for the screening extremolytes to be used for protein stabilization, an appropriate storage conditions should also be taken into account

Inulin, a flexible oligosaccharide. II:Review of its pharmaceutical applications

AbstractInulin is a flexible oligosaccharide which has been used primarily in food for decades. Recently new applications in the pharmaceutical arena were described. In a previous review (Mensink et al. (2015). Carbohydrate Polymers, 130, 405) we described the physicochemical characteristics of inulin, characteristics which make inulin a highly versatile substance. Here, we review its pharmaceutical applications. Applications of inulin that are addressed are stabilization of proteins, modified drug delivery (dissolution rate enhancement and drug targeting), and lastly physiological and disease-modifying effects of inulin. Further uses of inulin include colon specific drug administration and stabilizing and adjuvating vaccine formulations. Overall, the uses of inulin in the pharmaceutical area are very diverse and research is still continuing, particularly with chemically modified inulins. It is therefore likely that even more applications will be found for this flexible oligosaccharide

A New Strategy to Stabilize Oxytocin in Aqueous Solutions: I. The Effects of Divalent Metal Ions and Citrate Buffer

In the current study, the effect of metal ions in combination with buffers (citrate, acetate, pH 4.5) on the stability of aqueous solutions of oxytocin was investigated. and divalent metal ions (Ca2+, Mg2+, and Zn2+) were tested all as chloride salts. The effect of combinations of buffers and metal ions on the stability of aqueous oxytocin solutions was determined by RP-HPLC and HP-SEC after 4 weeks of storage at either 4°C or 55°C. Addition of sodium or potassium ions to acetate- or citrate-buffered solutions did not increase stability, nor did the addition of divalent metal ions to acetate buffer. However, the stability of aqueous oxytocin in aqueous formulations was improved in the presence of 5 and 10 mM citrate buffer in combination with at least 2 mM CaCl2, MgCl2, or ZnCl2 and depended on the divalent metal ion concentration. Isothermal titration calorimetric measurements were predictive for the stabilization effects observed during the stability study. Formulations in citrate buffer that had an improved stability displayed a strong interaction between oxytocin and Ca2+, Mg2+, or Zn2+, while formulations in acetate buffer did not. In conclusion, our study shows that divalent metal ions in combination with citrate buffer strongly improved the stability of oxytocin in aqueous solutions

pH-dependent ileocolonic drug delivery, part I:in vitro and clinical evaluation of novel systems

After the pH dependency of novel pH-dependent ileocolonic drug delivery systems is confirmed in vitro, their performance should be evaluated in human volunteers