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Dissolving the Rocks: Solubility Enhancement of Active Pharmaceutical Ingredients using Mesoporous Silica
Stockholm University, Faculty of Science, Department of Materials and Environmental Chemistry (MMK).
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 [en]
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: urn:nbn:se:su:diva-103190ISBN: 978-91-7447-924-9 (print)OAI: oai:DiVA.org:su-103190DiVA: diva2:716217
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
List of papers
1. In vivo oral toxicological evaluation of mesoporous silica particles
Open this publication in new window or tab >>In vivo oral toxicological evaluation of mesoporous silica particles
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2013 (English)In: Nanomedicine, ISSN 1743-5889, E-ISSN 1748-6963, Vol. 8, no 1, 57-64 p.Article in journal (Refereed) Published
Abstract [en]

Background: Mesoporous silica particles are highly promising nanomaterials for biomedical applications. They can be used to improve bioavailability, solubility and drug stability and to protect drugs from the acidic conditions of the stomach, leading to increased drug effectiveness. Their biocompatibility in vivo has recieved little attention, in particular regarding oral administration. Aim: To study the oral tolerance of micron-sized nanoporous folic acid-templated material-1 (cylindrical, 2D hexagonal pore structure) and nanometer-sized anionic-surfactant-templated mesoporous silica material-6 (cylindrical, 3D cubic pore structure) mesoporous silica particles in Sprague Dawley rats. Materials & methods: A dose stepwise procedure or range finding test was followed by a consequent confirmatory test. The confirmatory test included daily administrations of 2000 and 1200 mg/kg doses for nanoporous folic acid-templated material-1 and anionic-surfactant-templated mesoporous silica material-6, respectively. Results: The maximum tolerated dose for anionic-surfactant-templated mesoporous silica material-6 was not reached. Similar results were observed for nanometer-sized anionic-surfactant-templated mesoporous silica material-1 in most of the animals, although adverse effects were observed in some animals that are most probably due to the administration by oral gavage of the formulated particles. Conclusion: The results are promising for the use of mesoporous silica materials as drug-delivery systems in oral administration.

Keyword
biovailability, mesoporous, oral administration, silica particle, toxicity
National Category
Other Environmental Biotechnology Microbiology Nano Technology
Identifiers
urn:nbn:se:su:diva-88753 (URN)10.2217/NNM.12.77 (DOI)000314577800014 ()
Funder
Swedish Research CouncilEU, European Research Council, 261378
Note

AuthorCount:6;

Available from: 2013-03-26 Created: 2013-03-26 Last updated: 2017-12-06Bibliographically approved
2. Systematic study of itraconazole in solubility enhancement and solid dispersion state using 3 different nanoporous silica particles
Open this publication in new window or tab >>Systematic study of itraconazole in solubility enhancement and solid dispersion state using 3 different nanoporous silica particles
(English)Article in journal (Refereed) Submitted
National Category
Inorganic Chemistry
Identifiers
urn:nbn:se:su:diva-103187 (URN)
Available from: 2014-05-08 Created: 2014-05-08 Last updated: 2014-05-08Bibliographically approved
3. Influence of microporosity in SBA-15 on the release properties of anticancer drug dasatinib
Open this publication in new window or tab >>Influence of microporosity in SBA-15 on the release properties of anticancer drug dasatinib
2014 (English)In: Journal of materials chemistry. B, ISSN 2050-750X, E-ISSN 2050-7518, Vol. 2, no 32, 5265-5271 p.Article in journal (Refereed) Published
Abstract [en]

The release of the hydrophobic cancer drug dasatinib from two mesoporous silica materials as drug delivery vehicles has been studied. One material is a reference 2D-hexagonal SBA-15 with the typical bimodal pore system with ordered primary mesopores and disordered intrawatI pores. The other material is a modified version of the same material where the intrawall porosity in the micropore regime has been selectively removed. Material characterization shows that, with the exception of the difference in intrawall porosity, the materials have identical properties. The drug dasatinib, a tyrosine kinase inhibitor, has been loaded, to the same extent, into the pores of both materials. The two materials give rise to very different release profiles of the drug. The presence of micropores leads to desired release properties: a high initial release of the drug, which is maintained over time. The lack of micropores also leads to a high initial release but followed by a rapid drop in the concentration of released drug, a consequence of its low solubility and hence crystallisation. We suggest that the presence of micropores in the carrier material, and the resultant kinetic release profile, leads to a stabilization of dasatinib in solution and to a sustained supersaturated level of the released drug. Our findings suggest that by controlling the mesoporous host with small variation in the textural properties, the kinetic release and crystallization behaviour of a drug can be altered. It is thus potentially possible to influence the drug post-release and thereby its bioavailability.

National Category
Inorganic Chemistry
Research subject
Inorganic Chemistry
Identifiers
urn:nbn:se:su:diva-107098 (URN)10.1039/c4tb00418c (DOI)000340076100015 ()
Note

AuthorCount:4;

Available from: 2014-09-05 Created: 2014-09-03 Last updated: 2017-12-05Bibliographically approved
4. In vivo Enhancement in Bioavailability of Atazanavir in the Presence of Proton-Pump Inhibitors using Mesoporous Materials
Open this publication in new window or tab >>In vivo Enhancement in Bioavailability of Atazanavir in the Presence of Proton-Pump Inhibitors using Mesoporous Materials
2012 (English)In: ChemMedChem, ISSN 1860-7179, E-ISSN 1860-7187, Vol. 7, 43-48 p.Article in journal (Refereed) Published
Place, publisher, year, edition, pages
Wiley-VCH Verlagsgesellschaft, 2012
National Category
Chemical Sciences
Identifiers
urn:nbn:se:su:diva-103166 (URN)10.1002/cmdc.201100500 (DOI)
Available from: 2014-05-07 Created: 2014-05-07 Last updated: 2017-12-05Bibliographically approved
5. Encapsulation of Anti-Tuberculosis Drugs within Mesoporous Silica and Intracellular Antibacterial Activities
Open this publication in new window or tab >>Encapsulation of Anti-Tuberculosis Drugs within Mesoporous Silica and Intracellular Antibacterial Activities
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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.

Keyword
tuberculosis, mesoporous materials, solubility, intracellular, formulation, nanomedicine
National Category
Inorganic Chemistry
Research subject
Inorganic Chemistry
Identifiers
urn:nbn:se:su:diva-108543 (URN)10.3390/nano4030813 (DOI)000342202400016 ()
Note

AuthorCount:9;

Available from: 2014-11-19 Created: 2014-10-29 Last updated: 2015-10-27Bibliographically approved

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