Zinc oxide in formulation for respiratory vaccination
Active immunisation is the best option to prevent infectious diseases. Intramuscular application is the most commonly used administration route, because of systemic immune response and exact dosing possibilities. Due to its low cost and good effect, aluminium salts are the most frequently used adjuvants in adsorbate vaccines to enhance the immune response of an attenuated antigen or antigen components. While intramuscular administration requires the use of a needle and a sterile dosage form, mucosal immunisation is one opportunity of non-invasive administration. The respiratory tract comprises numerous immune competent cells as part of the MALT and thereby represents an excellent possibility to induce both local and systemic immune response. Since aluminium salts are ineffective as adjuvant on the mucosa, this work focussed on zinc oxide in formulations for respiratory vaccination. Zinc oxide is well characterised in a number of clinical studies and has many different uses. An immunomodulating effect of zinc oxide based on an increasing proliferation of T cells and high expression of MHC-II molecules is described in a number of papers. A special form of zinc oxide are the zinc oxide tetrapods. They have a three-dimensional tetrapodial structure and the potential uses are manifold due to their properties. Worth mentioning is the potential application as a prophylactic, preventive and/or adjuvant formulation for viral infection as they have among other things the ability to bind antigens. Viruses bound to zinc oxide tetrapods can therefore be absorbed by antigen-presenting cells in the mucosa and then presented to activate the immune system. In adsorption studies the adsorption capacity of zinc oxide, zinc oxide tetrapods, short milled and long milled zinc oxide tetrapods with five different proteins with varying isoelectric points and different molecular weights were investigated. While the zinc oxide tetrapods were able to adsorb mainly positively charged proteins due to their negatively charged surface, there was no discernible difference in the case of zinc oxide. All materials showed higher adsorption capacities towards the proteins with smaller molecular weights. Formulations for the delivery to the respiratory tract with zinc oxide were spray dried for nasal and pulmonary administration. Six different formulations with various amounts of zinc oxide were produced for each application route. Mannitol and hyaluronic acid were used as additional excipient and ovalbumin served as model antigen. Since spray drying with acetic acid (2 %) for the nasal formulations led to numerous difficulties in characterisation and undesired properties, the pulmonary formulations were spray dried with water as suspension medium. After spray drying, all six formulations were white powders with an x50 smaller than 5 µm and almost 100 % of the ovalbumin used was recovered. The composition of the formulation and thus the zinc oxide concentration had an influence on almost all experiments. Finally, cell activation experiments were performed to investigate whether zinc oxide presented its adjuvant effect when formulated as dry powder. Since formulation 2 showed the best aerodynamic properties for in-vivo studies, it was therefore used as example. The expression of CD80, CD86 and MHC-II indicated an activation of the used murine bone marrow-derived dendritic cells. The use of zinc oxide as an adjuvant thus appeared to be possible but needs to be further elucidated in in-vivo studies.
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