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Biologics are a rapidly emerging class of therapeutics that have succeeded clinically and commercially due to their specificity and efficacy against various diseases including cancer, inflammatory, and autoimmune diseases. Even though most biologics are administered parenterally, nasal and pulmonary delivery would be beneficial due to numerous advantages such as being patient-friendly, noninvasive, cost-effective, and less toxic. While there are currently a few nasal and inhaled biologics on the market, for example, Suprefact®, Minirin®, Miacalcin®, most of them are designed to treat ailments related to prostate carcinoma, diabetes, osteoporosis but not for respiratory diseases. Moreover, there are some marketed nasally delivered vaccines such as Flumist® and Nasovac-S® against influenza virus, inhaled vaccines that did not make it to market. Given the rise of respiratory infections such as MERS, SARS, and SARS-CoV-2, a great deal of interest exists in developing nasal and pulmonary-delivered biologics and vaccines for respiratory diseases. The objective of this chapter is to describe the potential for pulmonary and nasal delivery of biologics. Each section delves into introducing biologics and vaccines, followed by a portrayal of recent updates on nasal and pulmonary delivery of biologics and vaccines. The most promising formulation strategies for enhancing the stability and therapeutic efficacy of biologics as a part of research and development will be discussed.

Background/aim: Vaccines are often lyophilized in order to retain their stability and efficacy for a longer period of time. However, the same lyophilization process may also cause a major degradation of the vaccine, especially during early phases of manufacturing, leading to a loss of potency of the product. Many viral diseases, such as rabies, are acute and fatal unless the vaccine is administered prior to exposure or the onset of symptoms in the case of postexposure treatment. Materials and methods: We investigated the effect of lyophilization on the stability of the virus structure during rabies vaccine manufacturing using dynamic light scattering and transmission electron microscopy. Results: Our results indicate that some viruses lose their stability and efficacy in the course of lyophilization if the pH of the cell culture medium is controlled by solvated CO2 because the structure of the rabies virus is very sensitive to the solution pH: the virus either aggregates or its shape is deformed at low solution pH, whereas at high pH empty capsid shells are formed. Conclusion: Based on our findings, we developed a new formulation for the rabies vaccine that is stable in different buffers owing to the prevention of pH upshift upon lyophilization.

Detailed and generalized protocols are presented for the synthesis and subsequent purification of four palladium N-heterocyclic carbene complexes from benzimidazolium salts. Detailed and generalized protocols are also presented for testing the catalytic activity of such complexes in arylation and Suzuki-Miyaura cross-coupling reactions. Representative results are shown for the catalytic activity of the four complexes in arylation and Suzuki-Miyaura type reactions. For each of the reactions investigated, at least one of the four complexes successfully catalyzed the reaction, qualifying them as promising candidates for catalysis of many carbon-carbon bond-forming reactions. The protocols presented are general enough to be adapted for the synthesis, purification and catalytic activity testing of new palladium N-heterocyclic carbene complexes.

Protein-carbohydrate interactions are important for glycoprotein structure and function. Antibodies of the IgG class, with increasing significance as therapeutics, are glycosylated at a conserved site in the constant Fc region. We hypothesized that disruption of protein-carbohydrate interactions in the glycosylated domain of antibodies leads to the exposure of aggregation-prone motifs. Aggregation is one of the main problems in protein-based therapeutics because of immunogenicity concerns and decreased efficacy. To explore the significance of intramolecular interactions between aromatic amino acids and carbohydrates in the IgG glycosylated domain, we utilized computer simulations, fluorescence analysis, and site-directed mutagenesis. We find that the surface exposure of one aromatic amino acid increases due to dynamic fluctuations. Moreover, protein-carbohydrate interactions decrease upon stress, while protein-protein and carbohydrate-carbohydrate interactions increase. Substitution of the carbohydrate-interacting aromatic amino acids with non-aromatic residues leads to a significantly lower stability than wild type, and to compromised binding to Fc receptors. Our results support a mechanism for antibody aggregation via decreased protein-carbohydrate interactions, leading to the exposure of aggregation-prone regions, and to aggregation., Novartis Pharma AG