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Riaz, Azra
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Campos Pacheco, J. E., Yalovenko, T., Riaz, A., Kotov, N., Davids, C., Persson, A., . . . Valetti, S. (2024). Inhalable porous particles as dual micro-nano carriers demonstrating efficient lung drug delivery for treatment of tuberculosis. Journal of Controlled Release, 369, 231-250, Article ID S0168-3659(24)00165-2.
Öppna denna publikation i ny flik eller fönster >>Inhalable porous particles as dual micro-nano carriers demonstrating efficient lung drug delivery for treatment of tuberculosis
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2024 (Engelska)Ingår i: Journal of Controlled Release, ISSN 0168-3659, E-ISSN 1873-4995, Vol. 369, s. 231-250, artikel-id S0168-3659(24)00165-2Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Inhalation therapy treating severe infectious disease is among the more complex and emerging topics in controlled drug release. Micron-sized carriers are needed to deposit drugs into the lower airways, while nano-sized carriers are of preference for cell targeting. Here, we present a novel and versatile strategy using micron-sized spherical particles with an excellent aerodynamic profile that dissolve in the lung fluid to ultimately generate nanoparticles enabling to enhance both extra- and intra-cellular drug delivery (i.e., dual micro-nano inhalation strategy). The spherical particles are synthesised through the condensation of nano-sized amorphous silicon dioxide resulting in high surface area, disordered mesoporous silica particles (MSPs) with monodispersed size of 2.43 μm. Clofazimine (CLZ), a drug shown to be effective against multidrug-resistant tuberculosis, was encapsulated in the MSPs obtaining a dry powder formulation with high respirable fraction (F.P.F. <5 μm of 50%) without the need of additional excipients. DSC, XRPD, and Nitrogen adsorption-desorption indicate that the drug was fully amorphous when confined in the nano-sized pores (9-10 nm) of the MSPs (shelf-life of 20 months at 4 °C). Once deposited in the lung, the CLZ-MSPs exhibited a dual action. Firstly, the nanoconfinement within the MSPs enabled a drastic dissolution enhancement of CLZ in simulated lung fluid (i.e., 16-fold higher than the free drug), increasing mycobacterial killing than CLZ alone (p = 0.0262) and reaching concentrations above the minimum bactericidal concentration (MBC) against biofilms of M. tuberculosis (i.e., targeting extracellular bacteria). The released CLZ permeated but was highly retained in a Calu-3 respiratory epithelium model, suggesting a high local drug concentration within the lung tissue minimizing risk for systemic side effects. Secondly, the micron-sized drug carriers spontaneously dissolve in simulated lung fluid into nano-sized drug carriers (shown by Nano-FTIR), delivering high CLZ cargo inside macrophages and drastically decreasing the mycobacterial burden inside macrophages (i.e., targeting intracellular bacteria). Safety studies showed neither measurable toxicity on macrophages nor Calu-3 cells, nor impaired epithelial integrity. The dissolved MSPs also did not show haemolytic effect on human erythrocytes. In a nutshell, this study presents a low-cost, stable and non-invasive dried powder formulation based on a dual micro-nano carrier to efficiently deliver drug to the lungs overcoming technological and practical challenges for global healthcare.

Ort, förlag, år, upplaga, sidor
Elsevier, 2024
Nyckelord
Clofazimine, Disordered mesoporous silica particles, Dissolution enhancement, Dried powder formulation, Dual micro-nano carrier, Lung drug delivery, Soluble carrier
Nationell ämneskategori
Farmaceutiska vetenskaper
Identifikatorer
urn:nbn:se:mau:diva-66943 (URN)10.1016/j.jconrel.2024.03.013 (DOI)001219489000001 ()38479444 (PubMedID)2-s2.0-85189001903 (Scopus ID)
Tillgänglig från: 2024-04-26 Skapad: 2024-04-26 Senast uppdaterad: 2024-05-23Bibliografiskt granskad
Campos Pacheco, J. E., Riaz, A., Falkman, P., Feiler, A., Ekström, M., Pilkington, G. & Valetti, S. (2023). Encapsulation of clofazimine in mesoporous silica as a potential dry powder formulation for treating tuberculosis. Journal of Aerosol Medicine, 36(6), A13-A13, Article ID A13.
Öppna denna publikation i ny flik eller fönster >>Encapsulation of clofazimine in mesoporous silica as a potential dry powder formulation for treating tuberculosis
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2023 (Engelska)Ingår i: Journal of Aerosol Medicine, ISSN 1941-2711, E-ISSN 1941-2703, Vol. 36, nr 6, s. A13-A13, artikel-id A13Artikel i tidskrift, Meeting abstract (Övrigt vetenskapligt) Published
Nationell ämneskategori
Biomedicinsk laboratorievetenskap/teknologi
Identifikatorer
urn:nbn:se:mau:diva-66242 (URN)001126390700043 ()
Tillgänglig från: 2024-03-07 Skapad: 2024-03-07 Senast uppdaterad: 2024-06-18Bibliografiskt granskad
Riaz, A., Gidvall, S., Prgomet, Z., Hernandez, A. R., Ruzgas, T., Nilsson, E. J., . . . Valetti, S. (2023). Three-Dimensional Oral Mucosal Equivalents as Models for Transmucosal Drug Permeation Studies. Pharmaceutics, 15(5), 1513-1513
Öppna denna publikation i ny flik eller fönster >>Three-Dimensional Oral Mucosal Equivalents as Models for Transmucosal Drug Permeation Studies
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2023 (Engelska)Ingår i: Pharmaceutics, E-ISSN 1999-4923, Vol. 15, nr 5, s. 1513-1513Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Oral transmucosal administration, where drugs are absorbed directly through the non-keratinized, lining mucosa of the mouth, represents a solution to drug delivery with several advantages. Oral mucosal equivalents (OME) developed as 3D in vitro models are of great interest since they express the correct cell differentiation and tissue architecture, simulating the in vivo conditions better than monolayer cultures or animal tissues. The aim of this work was to develop OME to be used as a membrane for drug permeation studies. We developed both full-thickness (i.e., connective plus epithelial tissue) and split-thickness (i.e., only epithelial tissue) OME using non-tumor-derived human keratinocytes OKF6 TERT-2 obtained from the floor of the mouth. All the OME developed here presented similar transepithelial electrical resistance (TEER) values, comparable to the commercial EpiOral™. Using eletriptan hydrobromide as a model drug, we found that the full-thickness OME had similar drug flux to EpiOral™ (28.8 vs. 29.6 µg/cm2/h), suggesting that the model had the same permeation barrier properties. Furthermore, full-thickness OME showed an increase in ceramide content together with a decrease in phospholipids in comparison to the monolayer culture, indicating that lipid differentiation occurred due to the tissue-engineering protocols. The split-thickness mucosal model resulted in 4–5 cell layers with basal cells still undergoing mitosis. The optimum period at the air–liquid interface for this model was twenty-one days; after longer times, signs of apoptosis appeared. Following the 3R principles, we found that the addition of Ca2+, retinoic acid, linoleic acid, epidermal growth factor and bovine pituitary extract was important but not sufficient to fully replace the fetal bovine serum. Finally, the OME models presented here offer a longer shelf-life than the pre-existing models, which paves the way for the further investigation of broader pharmaceutical applications (i.e., long-term drug exposure, effect on the keratinocytes’ differentiation and inflammatory conditions, etc.).

Ort, förlag, år, upplaga, sidor
MDPI, 2023
Nyckelord
oral transmucosal delivery, oral mucosal equivalents, drug permeation, 3R principles, 3D in vitro models
Nationell ämneskategori
Farmaceutiska vetenskaper
Identifikatorer
urn:nbn:se:mau:diva-61046 (URN)10.3390/pharmaceutics15051513 (DOI)000997495400001 ()37242755 (PubMedID)2-s2.0-85160448981 (Scopus ID)
Forskningsfinansiär
Crafoordska stiftelsen, 20210937KK-stiftelsen, 20190010
Tillgänglig från: 2023-06-19 Skapad: 2023-06-19 Senast uppdaterad: 2024-07-04Bibliografiskt granskad
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