Encapsulation of clofazimine in mesoporous silica as a potential dry powder formulation for treating tuberculosis
Jesús Enrique Campos Pacheco 1,2 Azra Riaz1,2, Peter Falkman1,2, Adam Feiler3,4*, Mikael Ekström5, Georgia Pilkington3 & Sabrina Valetti1,2
1 Biomedical Science, Faculty of Health and Society, Malmö University, 205 06 Malmö, Sweden
2Biofilms – Research Center for Biointerfaces (BRCB), Malmö University, 205 06 Malmö, Sweden
3Nanologica AB (publ), Forskargatan 20G, 151 36 Södertälje, Sweden
4Surface and Corrosion Science, KTH Royal Institute of Technology, SE-100 44 Stockholm, Sweden
5Iconovo AB, Ideongatan 3A-B, 223 70 Lund, Sweden
*Current affiliation Interrobang AB. Sweden.
Summary
Over the past two decades, mesoporous silica particles (MSPs) have generated significant interest for the delivery of poorly soluble drugs for oral administration. However, only more recently has their use for drug delivery via inhalation been considered, harnessing the particles’ free flowing and aerodynamic properties towards delivery to the airways. The present study demonstrates the formulation of a dry powder composed of micron-sized MSPs loaded with clofazimine (CLZ), a drug that has been shown to be effective for the treatment of multidrug-resistant tuberculosis. Solid state analysis indicated that the drug was fully amorphous when confined in the nanometre pores (9-10 nm) of the mesoporous structure, with a drug loading content around 8-10% w/w. Under simulated lung fluid conditions, 50% of the encapsulated dose of CLZ was released in 2.5 h. The concentration of drug released from CLZ loaded MSPs was greater than the measured solubility of the crystalline drug. This observation was attributed to the increased solubility of CLZ in its amorphous form. The Aerodynamic Particle Size Distribution (APSD) of the CLZ loaded particles actuated from an ICOone® inhaler at 4 kPa showed a Fine Particle Fraction (<5 µm) of 48%. In vitro permeation studies of CLZ released from MSP were performed using a Calu-3 monolayer. The results revealed that the encapsulated CLZ can permeate across epithelium cells, whilst retention in the cell monolayer was observed. The present study indicates that CLZ-MSPs could have value as a potential inhaled formulation for pulmonary treatment of TB and warrants further investigation.
Key Message
Micron sized mesoporous silica particles have great potential as an inhalation carrier platform for clofazimine. The amorphization of encapsulated clofazimine enhances the drug release, whilst the uniform size and shape of the MSPs facilitates deposition in the airways. In addition, permeation across an epithelium cell monolayer was demonstrated in vitro.