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Encapsulation of Anti-Tuberculosis Drugs within Mesoporous Silica and Intracellular Antibacterial Activities
Stockholm University, Faculty of Science, Department of Materials and Environmental Chemistry (MMK). Nanologica AB, Sweden.
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2014 (English)In: Nanomaterials, ISSN 2079-4991, Vol. 4, no 3, 813-826 p.Article in journal (Refereed) Published
Abstract [en]

Tuberculosis is a major problem in public health. While new effective treatments to combat the disease are currently under development, they tend suffer from poor solubility often resulting in low and/or inconsistent oral bioavailability. Mesoporous materials are here investigated in an in vitro intracellular assay, for the effective delivery of compound PA-824; a poorly soluble bactericidal agent being developed against Tuberculosis (TB). Mesoporous materials enhance the solubility of PA-824; however, this is not translated into a higher antibacterial activity in TB-infected macrophages after 5 days of incubation, where similar values are obtained. The lack of improved activity may be due to insufficient release of the drug from the mesopores in the context of the cellular environment. However, these results show promising data for the use of mesoporous particles in the context of oral delivery with expected improvements in bioavailability.

Place, publisher, year, edition, pages
2014. Vol. 4, no 3, 813-826 p.
Keyword [en]
tuberculosis, mesoporous materials, solubility, intracellular, formulation, nanomedicine
National Category
Inorganic Chemistry
Research subject
Inorganic Chemistry
Identifiers
URN: urn:nbn:se:su:diva-108543DOI: 10.3390/nano4030813ISI: 000342202400016OAI: oai:DiVA.org:su-108543DiVA: diva2:764648
Note

AuthorCount:9;

Available from: 2014-11-19 Created: 2014-10-29 Last updated: 2015-10-27Bibliographically approved
In thesis
1. Dissolving the Rocks: Solubility Enhancement of Active Pharmaceutical Ingredients using Mesoporous Silica
Open this publication in new window or tab >>Dissolving the Rocks: Solubility Enhancement of Active Pharmaceutical Ingredients using Mesoporous Silica
2014 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Poor aqueous solubility is one of the greatest barriers for new drug candidates to enter toxicology studies, let alone clinical trials. This thesis focuses on contributing to solving this problem, evaluating the oral toxicity of mesoporous silica particles, and enhancing the apparent solubility and bioavailability of active pharmaceutical ingredients in vitro and in vivo using mesoporous silica particles.

Toxicological studies in rats showed that two types of mesoporous silica particles given by oral administration were well tolerated without showing clinical signs of toxicity. Solubility enhancement, including in vivo bioavailability and in vitro intracellular activity, has been evaluated for selected drug compounds. Mesoporous silica was shown to effectively increase drug solubility by stabilizing the amorphous state of APIs, such as itraconazole (anti-fungal), dasatinib (anti-cancer), atazanavir (anti-HIV) and PA-824 (anti-tuberculosis). Itraconazole was successfully loaded into a variety of porous silica materials showing a distinct improvement in the dissolution properties in comparison to non-porous silica materials (and the free drug). Microporosity in SBA-15 particles has advantages in stabilizing the supersaturation state of dasatinib. Small pore sizes show better confinement of atazanavir, contributing to a higher dissolution of the drug compound. In the in vivo animal studies, NFM-1 loaded with atazanavir shows a four-fold increase in bioavailability compared to free crystalline atazanavir. PA-824 has a higher dissolution rate and solubility after loading into AMS-6 mesoporous particles. The loaded particles show similar antibacterial activity as the free PA-824.

This thesis aims at highlighting some of the important factors enabling the selection of adequate mesoporous structures to enhance the pharmacokinetic profile of poorly water-soluble compounds, and preparing the scientific framework for uncovering the effects of drug confinement within mesopores of varying structural properties.

Place, publisher, year, edition, pages
Stockholm: Department of Materials and Environmental Chemistry (MMK), Stockholm University, 2014. 77 p.
Keyword
mesoporous silica, drug delivery, solubility enhancement, active pharmaceutical ingredients, oral toxicity, confinement, crystallization, pharmaceutical excipients, bioavailability
National Category
Inorganic Chemistry
Research subject
Inorganic Chemistry
Identifiers
urn:nbn:se:su:diva-103190 (URN)978-91-7447-924-9 (ISBN)
Public defence
2014-06-18, Magnélisalen, Kemiska övningslaboratoriet, Svante Arrhenius väg 16 B, Stockholm, 13:00 (English)
Opponent
Supervisors
Note

At the time of the doctoral defense, the following papers were unpublished and had a status as follows: Paper 2: Submitted. Paper 3: Submitted. Paper 5: Submitted.

Available from: 2014-05-22 Created: 2014-05-08 Last updated: 2015-10-27Bibliographically approved

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