Abstract
Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis, which mainly affects the lungs. The current treatment by the oral or/and parenteral route of administration requires very high doses of the anti-TB drugs as only a small fraction of the administered dose reaches the lungs. Hence, there has been increasing interest in the inhalation of anti-TB drugs for direct delivery to the lungs for improved treatment. However, the rapid dissolution and subsequent absorption of drugs from the alveolar region of the lungs minimizes the local therapeutic action of an inhaled anti-TB drug. Therefore, the primary objective of this thesis was to develop slowly dissolving inhalable dry powders of anti-TB drugs and evaluate their dissolution behaviour in a small volume of dissolution medium that simulates the dissolution in the lung.
A dissolution apparatus that uses a small volume of stationary medium (25 μL) has been custom made for in vitro dissolution testing of respirable drug particles. The design of the apparatus is similar to DissolvIt® system. A simulation model was constructed for the prediction of dissolution of anti-TB drugs from the respirable size particles at small volume of mucus simulant under well-stirred or unstirred conditions. The simulated permeation profiles of moxifloxacin from solution (only diffusion) and respirable sized particles (dissolution followed by the diffusion through the membrane) were similar, indicating fast dissolution of the particles. However, the simulated permeation profile of ethionamide from respirable size particles showed slower permeation compared to the solution indicating the slow dissolution of the respirable size particles of ethionamide. Similar to the simulation profiles, the experimental dissolution study using the dissolution apparatus with a small volume of mucus simulant also showed rapid disappearance of the moxifloxacin particles followed by faster permeation (<30 min) compared to the ethionamide particles.
Phospholipid-based spray dried (SD) microparticles of pyrazinamide were prepared using 1,2-dipalmitoyl-sn-glycero-3-phosphatidylcholine (DPPC, 5, 15 and 25% w/w), 1,2-distearoyl-sn-glycero-3-phospho ethanolamine N-(carbonyl-methoxy polyethylene glycol-2000) (5% w/w) and L-leucine (20% w/w). The SD powder with 25% w/w DPPC exhibited the best aerosolization with a fine particle fraction of ~75% and reduced dissolution compared to the SD powder without excipients.
Further, the mechanism by which DPPC and L-leucine improve the aerosolization behaviour of two anti-TB drugs, pyrazinamide and moxifloxacin was investigated by conducting surface morphology and composition analysis. Addition of L-leucine and DPPC produced inhalable size (<5 µm), uneven surfaced spherical dry powder particles which were suitable for deep lung delivery. X-ray photoelectron spectroscopy and time-of-flight secondary ion mass spectrometry revealed the migration of surface active L-leucine and DPPC onto the surface of the particles during the spray drying process which decreases the particle cohesiveness and improves their aerosolization behaviour.
Following a pharmaceutical cocrystallization approach, a cocrystal powder of the moxifloxacin was prepared using trans-cinnamic acid as a coformer at 1:1 molar ratio (MCA1:1) to reduce the drug solubility and dissolution rate. The solubility (mg mL-1) of the cocrystal powder (6.10 ± 0.05) in phosphate buffered saline, pH 7.4 was three times lower compared to that of free moxifloxacin (17.68 ± 0.85). The respirable cocrystal particles also showed a lower dissolution (microscopic observation) and permeation compared to the supplied moxifloxacin.
The developed phospholipid and cocrystal particles of anti-TB drugs with reduced dissolution might improve the residence time in the lungs. However, further evaluation of the developed powders is necessary to determine their therapeutic potential for treating pulmonary tuberculosis.