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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.
Open this publication in new window or tab >>Inhalable porous particles as dual micro-nano carriers demonstrating efficient lung drug delivery for treatment of tuberculosis
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2024 (English)In: Journal of Controlled Release, ISSN 0168-3659, E-ISSN 1873-4995, Vol. 369, p. 231-250, article id S0168-3659(24)00165-2Article in journal (Refereed) 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.

Place, publisher, year, edition, pages
Elsevier, 2024
Keywords
Clofazimine, Disordered mesoporous silica particles, Dissolution enhancement, Dried powder formulation, Dual micro-nano carrier, Lung drug delivery, Soluble carrier
National Category
Pharmaceutical Sciences
Identifiers
urn:nbn:se:mau:diva-66943 (URN)10.1016/j.jconrel.2024.03.013 (DOI)001219489000001 ()38479444 (PubMedID)2-s2.0-85189001903 (Scopus ID)
Available from: 2024-04-26 Created: 2024-04-26 Last updated: 2024-05-23Bibliographically approved
Yalovenko, T., Campos Pacheco, J. E., Schousboe, E., Gustafsson, A., Pilkington, G. & Valetti, S. (2023). Cell viability and inflammatory responses of amorphous mesoporous silica particles on different macrophage cells. Journal of Aerosol Medicine, 36(6), A37-A38
Open this publication in new window or tab >>Cell viability and inflammatory responses of amorphous mesoporous silica particles on different macrophage cells
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2023 (English)In: Journal of Aerosol Medicine, ISSN 1941-2711, E-ISSN 1941-2703, Vol. 36, no 6, p. A37-A38Article in journal, Meeting abstract (Other academic) Published
National Category
Biomedical Laboratory Science/Technology
Identifiers
urn:nbn:se:mau:diva-66243 (URN)001126390700129 ()
Available from: 2024-03-07 Created: 2024-03-07 Last updated: 2024-03-07Bibliographically approved
Hernandez, A. R., Bogdanova, E., Campos Pacheco, J. E., Kocherbitov, V., Feiler, A., Pilkington, G., . . . Valetti, S. (2023). Disordered mesoporous silica particles as emerging platform to deliver biologic molecules to the lungs. Journal of Aerosol Medicine, 36(6), Article ID A32.
Open this publication in new window or tab >>Disordered mesoporous silica particles as emerging platform to deliver biologic molecules to the lungs
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2023 (English)In: Journal of Aerosol Medicine, ISSN 1941-2711, E-ISSN 1941-2703, Vol. 36, no 6, article id A32Article in journal, Meeting abstract (Other academic) Published
Place, publisher, year, edition, pages
Mary Ann Liebert, 2023
National Category
Biomedical Laboratory Science/Technology
Identifiers
urn:nbn:se:mau:diva-66241 (URN)001126390700109 ()
Available from: 2024-03-07 Created: 2024-03-07 Last updated: 2024-03-07Bibliographically approved
Campos Pacheco, J. E., Riaz, A., Falkman, P., Feiler, A., Ekstrom, 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.
Open this publication in new window or tab >>Encapsulation of clofazimine in mesoporous silica as a potential dry powder formulation for treating tuberculosis
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2023 (English)In: Journal of Aerosol Medicine, ISSN 1941-2711, E-ISSN 1941-2703, Vol. 36, no 6, p. A13-A13, article id A13Article in journal, Meeting abstract (Other academic) Published
National Category
Biomedical Laboratory Science/Technology
Identifiers
urn:nbn:se:mau:diva-66242 (URN)001126390700043 ()
Available from: 2024-03-07 Created: 2024-03-07 Last updated: 2024-03-07Bibliographically approved
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
Open this publication in new window or tab >>Three-Dimensional Oral Mucosal Equivalents as Models for Transmucosal Drug Permeation Studies
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2023 (English)In: Pharmaceutics, ISSN 1999-4923, E-ISSN 1999-4923, Vol. 15, no 5, p. 1513-1513Article in journal (Refereed) 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.).

Place, publisher, year, edition, pages
MDPI, 2023
Keywords
oral transmucosal delivery, oral mucosal equivalents, drug permeation, 3R principles, 3D in vitro models
National Category
Pharmaceutical Sciences
Identifiers
urn:nbn:se:mau:diva-61046 (URN)10.3390/pharmaceutics15051513 (DOI)000997495400001 ()37242755 (PubMedID)2-s2.0-85160448981 (Scopus ID)
Funder
The Crafoord Foundation, 20210937Knowledge Foundation, 20190010
Available from: 2023-06-19 Created: 2023-06-19 Last updated: 2023-08-15Bibliographically approved
Valetti, S., Riaz, A., Doko, A., Sultana, K., Eskandari, M., Prgomet, Z., . . . Björklund, S. (2022). Oral transmucosal delivery of eletriptan for neurological diseases.. International Journal of Pharmaceutics, 627, Article ID 122222.
Open this publication in new window or tab >>Oral transmucosal delivery of eletriptan for neurological diseases.
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2022 (English)In: International Journal of Pharmaceutics, ISSN 0378-5173, E-ISSN 1873-3476, Vol. 627, article id 122222Article in journal (Refereed) Published
Abstract [en]

Migraine is a highly prevalent neurological disease affecting circa 1 billion patients worldwide with severe incapacitating symptoms, which significantly diminishes the quality of life. As self-medication practice, oral administration of triptans is the most common option, despite its relatively slow therapeutic onset and low drug bioavailability. To overcome these issues, here we present, to the best of our knowledge, the first study on the possibility of oral transmucosal delivery of one of the safest triptans, namely eletriptan hydrobromide (EB). Based on a comprehensive set of in vitro and ex vivo experiments, we highlight the conditions required for oral transmucosal delivery, potentially giving rise to similar, or even higher, drug plasma concentrations expected from conventional oral administration. With histology and tissue integrity studies, we conclude that EB neither induces morphological changes nor impairs the integrity of the mucosal barrier following 4 h of exposure. On a cellular level, EB is internalized in human oral keratinocytes within the first 5 min without inducing toxicity at the relevant concentrations for transmucosal delivery. Considering that the pKa of EB falls within the physiologically range, we systematically investigated the effect of pH on both solubility and transmucosal permeation. When the pH is increased from 6.8 to 10.4, the drug solubility decreases drastically from 14.7 to 0.07 mg/mL. At pH 6.8, EB gave rise to the highest drug flux and total permeated amount across mucosa, while at pH 10.4 EB shows greater permeability coefficient and thus higher ratio of permeated drug versus applied drug. Permeation experiments with model membranes confirmed the pH dependent permeation profile of EB. The distribution of EB in different cellular compartments of keratinocytes is pH dependent. In brief, high drug ionization leads to higher association with the cell membrane, suggesting ionic interactions between EB and the phospholipid head groups. Moreover, we show that the chemical permeation enhancer DMSO can be used to enhance the drug permeation significantly (i.e., 12 to 36-fold increase). Taken together, this study presents important findings on transmucosal delivery of eletriptan via the oral cavity and paves the way for clinical investigations for a fast and safe migraine treatment.

Place, publisher, year, edition, pages
Elsevier, 2022
Keywords
Caffeine, Cell uptake, Digitonin, Dissolution, Eletriptan hydrobromide, Enhancer, FITC-labeled dextran, Oral transmucosal delivery, Permeation pathway, Tissue integrity, Triptans
National Category
Pharmaceutical Sciences
Identifiers
urn:nbn:se:mau:diva-56096 (URN)10.1016/j.ijpharm.2022.122222 (DOI)000886537500005 ()36155795 (PubMedID)2-s2.0-85139046757 (Scopus ID)
Available from: 2022-11-17 Created: 2022-11-17 Last updated: 2024-02-05Bibliographically approved
Gidvall, S., Björklund, S., Feiler, A., Dahlström, B., Rönn, R., Engblom, J. & Valetti, S. (2021). A novel versatile flow-donor chamber as biorelevant ex-vivo test assessing oral mucoadhesive formulations. European Journal of Pharmaceutical Sciences, 166, Article ID 105983.
Open this publication in new window or tab >>A novel versatile flow-donor chamber as biorelevant ex-vivo test assessing oral mucoadhesive formulations
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2021 (English)In: European Journal of Pharmaceutical Sciences, ISSN 0928-0987, E-ISSN 1879-0720, Vol. 166, article id 105983Article in journal (Refereed) Published
Abstract [en]

Oral transmucosal drug delivery is a non-invasive administration route for rapid therapeutic onset and greater bioavailability avoiding the first-pass metabolism. Mucoadhesive formulations are advantageous as they may retain the drug at the administration site. Proper equipment to assess mucoadhesive properties and corresponding drug absorption is fundamental for the development of novel drug delivery systems. Here we developed a new flow-through donor chamber for well-established diffusion cells, and we tested the effects on drug and formulation retention in situ of adding mucoadhesive polymers or mesoporous silica particles to a reference formulation. Mesoporous silica particles are of particular interest as they may be used to encapsulate and retain drug molecules. Compared to other ex-vivo methods described in literature for assessing mucoadhesive performance and transmucosal drug delivery, this new donor chamber provides several advantages: i) it reflects physiological conditions better as a realistic saliva flow can be provided over the administration site, ii) it is versatile since it can be mounted on any kind of vertical diffusion cell allowing simultaneous detection of drug retention at the administration site and drug permeation through the tissue, and iii) it enables optical quantification of formulations residence time aided by image processing. This new flow-through donor diffusion cell set-up proved sensitive to differentiate a reference formulation from one where 20 %(w/w) Carbomer was added (to further improve the mucoadhesive properties), with respect to both drug and formulation residence times. We also found that mesoporous silica particles, investigated as particles only and mixed together with the reference formulation, gave very similar drug and formulation retention to what we observed with the mucoadhesive Carbomer. However, after some time (>30 min) it became obvious that the tablet excipients in the reference formulation promote particle retention on the mucosa. This work provides a new simple and versatile biorelevant test for the evaluation of oral mucoadhesive formulations and paves the way for further studies on mesoporous silica particles as valuable excipients for enhancing oral mucoadhesion.

Place, publisher, year, edition, pages
Elsevier, 2021
Keywords
Ex-vivo release-permeation systems, Flow through diffusion cells, Intraoral drug delivery, Mesoporous silica particles, Mucoadhesion, Oral transmucosal delivery
National Category
Pharmaceutical Sciences
Identifiers
urn:nbn:se:mau:diva-45899 (URN)10.1016/j.ejps.2021.105983 (DOI)000704269600004 ()34461276 (PubMedID)2-s2.0-85114373054 (Scopus ID)
Available from: 2021-09-15 Created: 2021-09-15 Last updated: 2024-02-05Bibliographically approved
Valetti, S., Thomsen, H., Wankar, J., Falkman, P., Manet, I., Feiler, A., . . . Engblom, J. (2021). Can mesoporous nanoparticles promote bioavailability of topical pharmaceutics?. International Journal of Pharmaceutics, 602, Article ID 120609.
Open this publication in new window or tab >>Can mesoporous nanoparticles promote bioavailability of topical pharmaceutics?
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2021 (English)In: International Journal of Pharmaceutics, ISSN 0378-5173, E-ISSN 1873-3476, Vol. 602, article id 120609Article in journal (Refereed) Published
Abstract [en]

When applied to skin, particulate matter has been shown to accumulate in hair follicles. In addition to follicles, the skin topography also incorporates trench-like furrows where particles potentially can accumulate; however, the furrows have not been as thoroughly investigated in a drug delivery perspective. Depending on body site, the combined follicle orifices cover up to 10% of the skin surface, while furrows can easily cover 20%, reaching depths exceeding 25 µm. Hence, porous particles of appropriate size and porosity could serve as carriers for drugs to be released in the follicles prior to local or systemic absorption. In this paper, we combine multiphoton microscopy, scanning electron microscopy, and Franz cell diffusion technology to investigate ex-vivo skin accumulation of mesoporous silica particles (average size of 400-600 nm, 2, and 7 µm, respectively), and the potential of which as vehicles for topical drug delivery of the broad-spectrum antibiotic metronidazole. We detected smaller particles (400-600 nm) in furrows at depths of about 25 µm, also after rinsing, while larger particles (7 µm) where located more superficially on the skin. This implies that appropriately sized porous particles may serve as valuable excipients in optimizing bioavailability of topical formulations. This work highlights the potential of skin furrows for topical drug delivery.

Place, publisher, year, edition, pages
Elsevier, 2021
Keywords
dermal drug delivery, multiphoton microscopy, nanoparticles, skin topography, targeted delivery
National Category
Pharmaceutical Sciences
Identifiers
urn:nbn:se:mau:diva-42122 (URN)10.1016/j.ijpharm.2021.120609 (DOI)000657606400004 ()33901597 (PubMedID)2-s2.0-85105266815 (Scopus ID)
Available from: 2021-05-07 Created: 2021-05-07 Last updated: 2024-02-05Bibliographically approved
Angiolini, L., Valetti, S., Cohen, B., Feiler, A. & Douhal, A. (2018). Fluorescence imaging of antibiotic clofazimine encapsulated within mesoporous silica particle carriers: relevance to drug delivery and the effect on its release kinetics (ed.). Physical Chemistry, Chemical Physics - PCCP, 20(17), 11899-11911
Open this publication in new window or tab >>Fluorescence imaging of antibiotic clofazimine encapsulated within mesoporous silica particle carriers: relevance to drug delivery and the effect on its release kinetics
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2018 (English)In: Physical Chemistry, Chemical Physics - PCCP, ISSN 1463-9076, E-ISSN 1463-9084, Vol. 20, no 17, p. 11899-11911Article in journal (Refereed)
Abstract [en]

We report on the encapsulation of the antibiotic clofazimine (CLZ) within the pores of mesoporous silica particles having hydrophilic (CBET value of 137) and more hydrophobic (CBET value of 94 after calcination at 600 °C) surfaces. We studied the effect of pH on the released amount of CLZ in aqueous solutions and observed a maximum at pH 4.1 in correlation with the solubility of the drug. Less release of the drug was observed from the more hydrophobic particles which was attributed to a difference in the affinity of the drug to the carrier particles. Fluorescence lifetime imaging microscopy, emission spectra, and fluorescence lifetimes of single drug loaded particles provided detailed understanding and new knowledge of the physical form of the encapsulated drug and the distribution within the particles. The distribution of CLZ within the particles was independent of the surface chemistry of the particles. The confirmation of CLZ molecules as monomers or aggregates was revealed by controlled removal of the drug with solvent. Additionally, the observed optical "halo effect" in the fluorescent images was interpreted in terms of specific quenching of high concentration of molecules. The emission lifetime experiments suggest stronger interaction of CLZ with the more hydrophobic particles, which is relevant to its release. The results reported in this work demonstrate that tuning the hydrophilicity/hydrophobicity of mesoporous silica particles can be used as a tool to control the release without impacting their loading ability.

Place, publisher, year, edition, pages
Royal Society of Chemistry, 2018
Keywords
drug delivery, mesoporous silica particle, clofazimine, fluorescence imaging, Clofazimine, Drug Carriers, Drug Delivery Systems, Drug Liberation, Fluorescence, Kinetics, Silicon Dioxide
National Category
Engineering and Technology
Identifiers
urn:nbn:se:mau:diva-5574 (URN)10.1039/c7cp08328a (DOI)000431824000044 ()29666860 (PubMedID)2-s2.0-85046692379 (Scopus ID)26776 (Local ID)26776 (Archive number)26776 (OAI)
Available from: 2020-02-28 Created: 2020-02-28 Last updated: 2024-02-05Bibliographically approved
Valetti, S., Feiler, A. & Martin, T. (2017). Bare and Effective Charge of Mesoporous Silica Particles (ed.). Langmuir, 33, 7343-7351
Open this publication in new window or tab >>Bare and Effective Charge of Mesoporous Silica Particles
2017 (English)In: Langmuir, ISSN 0743-7463, E-ISSN 1520-5827, Vol. 33, p. 7343-7351Article in journal (Refereed)
Abstract [en]

We develop and combine a novel numerical model, within the Poisson−Boltzmann framework, with classical experimental titration techniques for mesoporous silica particles to study the charging behavior as both pH and the amount of monovalent salt are varied. One key finding is that these particles can be considered to have an effectively or apparent electroneutral inner core with an effectively charged rim. As a consequence, the total apparent charge of the particle is several orders of magnitude smaller than that of the bare silica charge, which accounts only for the charged silanol groups of the mesoporous silica particles and which has its major contribution from the interior. Hence, the interior dictates the mesoporous silicas’ bare charge while the rim its effective charge. We furthermore report density, charge, and accumulated charge profiles across the particle’s interface.

Place, publisher, year, edition, pages
American Chemical Society (ACS), 2017
National Category
Natural Sciences
Identifiers
urn:nbn:se:mau:diva-4290 (URN)10.1021/acs.langmuir.7b01135 (DOI)000406573400016 ()28635290 (PubMedID)2-s2.0-85025841212 (Scopus ID)24197 (Local ID)24197 (Archive number)24197 (OAI)
Available from: 2020-02-28 Created: 2020-02-28 Last updated: 2024-02-05Bibliographically approved
Projects
Pickering emulsions on skin: Effects of ethanol prior to, during and after application at different ambient conditions; Malmö UniversityNanoporous silica particles for pharmaceutical formulations; Malmö University
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0002-2535-7108

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