Chitosan is a promising drug delivery system for pulmonary applications and is therefore of particular interest for vaccine development in the Corona Pandemic. The biodegradable and biocompatible polymer's mucoadhesive, permeation-increasing and site-/cell-specific properties are useful in this context. Nanocarriers based on various microencapsulation and micro-nano mixing systems have already been developed. The aerodynamic character is important to enable efficient pulmonary aerosol formation and inhalation. In this article we present research on chitosan as pulmonary particulate anti-infective drug carrier.
A review on chitosan and its development as pulmonary particulate anti-infective and anti-cancer drug carriers
Ruhisy Mohd Rasul, M. Tamilarasi Muniandy, Zabliza Zakaria, Kifayatullah Shah, Chin Fei Chee, Ali Dabbagh, Noorsaadah Abd Rahman, and Tin Wui Wong. Carbohydr Polym. 2020 Dec 15; 250: 116800. Published online 2020 Aug 18. doi: 10.1016/j.carbpol.2020.116800
By inhalation it is possible to administer therapeutics in a non-invasive, organ-specific way directly into the lung. By equipping the drug delivery system with special ligands, certain cell types can be specifically addressed. Since the lung, in contrast to the gastrointestinal tract, has only limited enzymes for drug metabolism, the use of protein- and gene-based therapeutics is possible. A major challenge in pulmonary drug administration is the high degree of airway branching with different lengths and diameters.
The following inhalation devices are currently in use in pulmonary medicine:
- Pressure Dosing Inhalers
- Powder Inhalers
Lots of research about chitosan-based drug delivery systems is conducted for the treatment of tuberculosis. Tuberculosis is a chronic, bacterial infection caused by M. tuberculosis and transmitted via air. The disease mainly affects the lungs and treatment is complicated by restrictions in drug dosage, side effects and poor penetration of the active ingredients to the site of infection. Various chitosan-based nano- and micro-release systems have been investigated for the pulmonary administration of tuberculosis drugs (see table below). Nanoparticles are produced by the solvent evaporation-emulsification technique or by ionic gelation of oppositely charged materials in the liquid state, with subsequent freeze-drying or spray-drying. Alternatively, the systems are produced directly by spray drying with variation of the parameters. Fillers/dispersants such as lactose, mannitol or maltodextrin are used to prevent aggregation of the nanoparticles. It was found that when chitosan nanoparticles are mixed with lactose microparticles, the size, shape and specific surface area of the nanoparticles have a strong influence on the inhalation efficiency of the nanoparticles (Alhajj et al., 2020).
Table: Examples of investigated pulmonary chitosan-based transport systems for the treatment of infectious diseases.
|Formulation and preparation||Testing||Source|
|Chitosan nanoparticles loaded with "Prothionamide" (active ingredient for tuberculosis), ionic cross-linking and freeze-drying, powder formulation||In vivo: Prolongation of the availability of active ingredients through the nanoparticles||Debnath et al., 2018|
|Isoniazid and Rifampin loaded genipine-crosslinked carboxymethyl-chitosan nanogels||In vivo: Successful transport into the lungs, in vitro: strong antibacterial effect||Wu et al.,
|Rifampicin loaded octanoyl-chitosan nanoparticles, solvent evaporation and freeze drying, with 1 %w/v trehalose dehydrate as freeze protection||In vitro: no cell toxicity||Petkar et al.,
|Isoniazid and rifampicin loaded chitosan nanoparticles, ionic gelation and spray drying||In vitro: Treatment of M. tuberculosis infected mice with nebulized nanoparticles for 28 days, after treatment no detectable mycobacterial colony forming unit in lung and spleen homogenates||Garg et al.,
Conclusion: Chitosan and its derivatives are excellent carriers for pulmonary drug delivery for the treatment of respiratory infections. In the future, they could be a suitable alternative to lactose, which is currently often used as the main drug carrier. The use of chitosan and derivatives requires in-depth analysis including aerodynamic in vitro characterization and in vivo study of the pharmacokinetics and functionality of these particles to evaluate their therapeutic performance.
Alhajj, N., Zakaria, Z., Naharudin, I., Ahsan, F., Li, W., & Wong, T. W. (2020). Critical physicochemical attributes of chitosan nanoparticles admixed lactose-PEG 3000 microparticles in pulmonary inhalation. Asian Journal of Pharmaceutical Sciences, 15(3), 374–384.
Garg, T., Rath, G., & Goyal, A. K. (2015). Inhalable chitosan nanoparticles as antitubercular drug carriers for an effective treatment of tuberculosis. Artificial Cells, Nanomedicine, and Biotechnology, 44(3), 1–5.
Petkar, K. C., Chavhan, S., Kunda, N., Saleem, I., Somavarapu, S., Taylor, K. M. G., & Sawant, K. K. (2018). Development of novel octanoyl chitosan nanoparticles for improved rifampicin pulmonary delivery: Optimization by factorial design. AAPS PharmSciTech, 19(4), 1758–1772.
Wu, T., Liao, W., Wang, W., Zhou, J., Tan, W., Xiang, W., & Cai, X. (2018). Genipincrosslinked carboxymethyl chitosan nanogel for lung-targeted delivery of isoniazid and rifampin. Carbohydrate Polymers, 197, 403–413.
Debnath, S. K., Saisivam, S., Debanth, M., & Omri, A. (2018). Development and evaluation of chitosan nanoparticles based dry powder inhalation formulations of prothionamide. PloS One, 13(1), Article e0190976.