Change search
ReferencesLink to record
Permanent link

Direct link
Mesoporous magnesium carbonate as a drug delivery vehicle for stabilising amorphous drugs and regulating their release rate
Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Nanotechnology and Functional Materials.ORCID iD: 0000-0002-3845-6279
2016 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

In today’s drug discovery, the number of candidate drugs based on new molecular entities with poor aqueous solubility is increasing. Since poor aqueous solubility of an active pharmaceutical ingredients (APIs) is associated with low bioavailability and thus limite their therapeutic effect, this is often a great challenge in the development of new drugs when oral administration is the preferred route of administration. A number of different strategies have been developed to circumvent this problem where salt formulations of an API is the most widely employed method. However, new strategies are needed since there is no one solution that solves this issue for all substances. In recent time, the concept of stabilizing poorly soluble APIs in their amorphous form has gained a lot of attention since amorphous compounds exhibit a higher apparent solubility compared to their crystalline counterparts. Amorphous substances are prone to crystallize if left in a non-constricted environment and thus need to be stabilized if the amorphous state is to be conserved until administration. Inorganic mesoporous materials have been proposed as an interesting type of excipients that can conserve the amorphous state of APIs.

In this work, the focus was to investigate the possibilities of using a mesoporous type of magnesium carbonate to stabilize the amorphous state of different APIs. Due to the nanometer sized pores in the material, complete conservation of amorphous APIs was obtained. This resulted in both an increase in in vitro release rate and a higher solubility of the substances which may translate to both a faster onset of action and an improved therapeutic effect of the APIs in a clinical situation. The long term stability of formulations was also investigated showing promising results.

The results presented in this work show that mesoporous magnesium carbonate represents an interesting type of excipient for oral formulations of APIs with poor aqueous solubility.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2016. , 68 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1651-6214 ; 1452
Keyword [en]
mesoporous, magnesium carbonate, drug delivery, solubility enhancement, bioavailability, pharmacokinetics, diffusion release, controlled release
National Category
Engineering and Technology
Research subject
Engineering Science with specialization in Nanotechnology and Functional Materials
Identifiers
URN: urn:nbn:se:uu:diva-303832ISBN: 978-91-554-9752-1OAI: oai:DiVA.org:uu-303832DiVA: diva2:974151
Public defence
2016-11-11, Ång/2001, Ångströmlaboratoriet, Lägerhyddsvägen 1, Uppsala, 09:30 (English)
Opponent
Supervisors
Note

Felaktigt ISBN 978-91-554-9702-6 i tryck version.

Available from: 2016-10-20 Created: 2016-09-25 Last updated: 2016-11-18
List of papers
1. Stabilisation of amorphous ibuprofen in Upsalite, a mesoporous magnesium carbonate, as an approach to increasing the aqueous solubility of poorly soluble drugs
Open this publication in new window or tab >>Stabilisation of amorphous ibuprofen in Upsalite, a mesoporous magnesium carbonate, as an approach to increasing the aqueous solubility of poorly soluble drugs
2014 (English)In: International Journal of Pharmaceutics, ISSN 0378-5173, E-ISSN 1873-3476, Vol. 472, no 1-2, 185-191 p.Article in journal (Refereed) Published
Abstract [en]

One attractive approach to increase the aqueous solubility and thus the bioavailability of poorly soluble drugs is to formulate them in their amorphous state since amorphous compounds generally exhibit higher apparent solubilities than their crystalline counterparts. In the current work, mesoporous magnesium carbonate was used to stabilise the amorphous state of the model substance ibuprofen. Crystallisation of the drug was completely supressed in the formulation, resulting in both a higher apparent solubility and a three times faster dissolution rate of the drug where the drug release was shown to be diffusion controlled. It was also shown that the formulation is stable for at least three months when stored at 75% relative humidity. The simple synthesis together with a high loading capacity and narrow pore size distribution of the mesoporous magnesium carbonate is foreseen to offer great advantages in formulations of poorly soluble drugs.

National Category
Nano Technology
Research subject
Engineering Science with specialization in Nanotechnology and Functional Materials
Identifiers
urn:nbn:se:uu:diva-228395 (URN)10.1016/j.ijpharm.2014.06.025 (DOI)000340328400022 ()24950364 (PubMedID)
Available from: 2014-07-11 Created: 2014-07-11 Last updated: 2016-11-30Bibliographically approved
2. Diffusion-Controlled Drug Release from the Mesoporous Magnesium Carbonate Upsalite®
Open this publication in new window or tab >>Diffusion-Controlled Drug Release from the Mesoporous Magnesium Carbonate Upsalite®
Show others...
2016 (English)In: Journal of Pharmaceutical Sciences, ISSN 0022-3549, E-ISSN 1520-6017, Vol. 105, no 2, 657-663 p.Article in journal (Refereed) Published
Abstract [en]

In vitro drug release from well-defined particle-size fractions of the mesoporous magnesium carbonate material Upsalite® was investigated in detail using ibuprofen, a biopharmaceutics classification system class II drug, as the model compound. The weight of loaded drug corresponded to 30% of the weight of the carrier and the pores were filled to approximately 80%. The incorporated ibuprofen was found to be in an amorphous state and was physisorbed, rather than chemisorbed, to the surfaces of the pore walls. In contrast to ibuprofen in mesoporous silica, there was no detectable drug on the outer surface of the carrier particles. Two ibuprofen doses were loaded into Upsalite® particles with size fractions ranging from 25 μm to more than 200 μm. The initial release rate was controlled by the particle size; the dissolution rate of the loaded ibuprofen during this period was more than four times faster than that of the crystalline drug. An extended-release period of about 24 h followed the initial rapid-release period. The features of this extended-release period were dependent on the total drug concentration in the release medium. Detailed analysis of the diffusion of ibuprofen in Upsalite® provided the ibuprofen diffusion coefficient (9.8 × 10−8 cm2/s), the constrictivity of the diffusion process (0.47) and the tortuosity of the carrier (15). This relatively high tortuosity value indicates that Upsalite® can be used not only to enhance the dissolution rate of poorly soluble drugs but also as a carrier in sustained-release applications by using larger particle sizes or even pellets of the material.

Keyword
mesoporous material, Upsalite®, poorly soluble drugs, diffusion, constrictivity, tortuosity, controlled release, ibuprofen, magnesium carbonate
National Category
Nano Technology
Research subject
Engineering Science with specialization in Nanotechnology and Functional Materials
Identifiers
urn:nbn:se:uu:diva-255928 (URN)10.1002/jps.24553 (DOI)000381768500029 ()26087956 (PubMedID)
Funder
VINNOVAEU, European Research CouncilSwedish Research Council
Available from: 2015-06-19 Created: 2015-06-19 Last updated: 2016-11-30Bibliographically approved
3. Nanostructure and pore size control of template-free synthesised mesoporous magnesium carbonate
Open this publication in new window or tab >>Nanostructure and pore size control of template-free synthesised mesoporous magnesium carbonate
Show others...
2016 (English)In: RSC Advances, Vol. 6, no 78, 74241-74249 p.Article in journal (Refereed) Published
Abstract [en]

The structure of mesoporous magnesium carbonate (MMC) first presented in 2013 is investigated using a bottom-up approach. MMC is found to be built from the aggregation of nanoparticles of amorphous MgCO3 and MgO with a coating of amorphous MgCO3. The nanoparticles have dimensions of approximately 2-5 nm as observed using transmission electron microscopy and the aggregation of the particles creates the pore structure of MMC. We further show that the average pore diameter of MMC can be controlled by varying the temperature during the powder formation process and demonstrate that altering the pore size opens the possibility to tune the amorphous phase stabilisation properties that MMC exerts on poorly soluble drug compounds. Specifically, we show the loading and release of the antifungal drug itraconazole using MMC as a drug carrier.

National Category
Nano Technology
Research subject
Engineering Science with specialization in Nanotechnology and Functional Materials
Identifiers
urn:nbn:se:uu:diva-300220 (URN)10.1039/C6RA14171D (DOI)000381513600033 ()
Funder
Swedish Research Council, 2014-3929Swedish Energy Agency, P38273-1Knut and Alice Wallenberg Foundation
Available from: 2016-08-05 Created: 2016-08-05 Last updated: 2016-11-30Bibliographically approved
4. Supersaturation of poorly soluble drugs induced by mesoporous magnesium carbonate
Open this publication in new window or tab >>Supersaturation of poorly soluble drugs induced by mesoporous magnesium carbonate
Show others...
2016 (English)In: European Journal of Pharmaceutical Sciences, ISSN 0928-0987, E-ISSN 1879-0720, Vol. 93, 468-474 p.Article in journal (Refereed) Published
Abstract [en]

Abstract This work investigates whether the solubility of poorly soluble compounds can be improved by using mesoporous magnesium carbonate (MMC) as the drug delivery system. A solvent evaporation method was used to load structurally diverse model drugs (celecoxib, cinnarizine and griseofulvin) into the pores of MMC. The drug-loaded carrier system was then characterized in terms of porosity, crystallinity, and release profiles by a variety of experimental techniques, including X-ray diffraction, nitrogen adsorption analysis, differential scanning calorimetry, infrared spectroscopy, UV absorption spectroscopy, and thermogravimetric analysis. All three drugs were in a non-crystalline state after loading into the pores of MMC. The concentrations of the drugs in solution over time (a measure of the release rates from loaded MMC) were higher than the corresponding concentrations (dissolution rates) of equal amounts of the crystalline drugs. The release rates were five (celecoxib), three (cinnarizine) and two times (griseofulvin) higher than the dissolution rates of their crystalline counterparts. Supersaturation release profiles were also observed; the areas under the concentration-time curves (0–240 min) were 25- (celecoxib), 5- (cinnarizine) and 2-fold (griseofulvin) greater than those of the crystalline drugs. Hence, MMC shows promise as a general drug delivery vehicle for increasing the bioavailability of compounds with dissolution rate- or solubility-limited absorption.

Keyword
Mesoporous, Crystallinity suppression, Drug release, Kinetics, Magnesium carbonate, Supersaturation
National Category
Nano Technology
Research subject
Engineering Science with specialization in Nanotechnology and Functional Materials
Identifiers
urn:nbn:se:uu:diva-302846 (URN)10.1016/j.ejps.2016.08.059 (DOI)000384853200050 ()27590126 (PubMedID)
Funder
Swedish Research Council, 621-2014-3929VINNOVA
Available from: 2016-09-11 Created: 2016-09-11 Last updated: 2016-11-30Bibliographically approved
5. Amine Modification of Mesoporous Magnesium Carbonate and the Effects on Controlled Drug Release
Open this publication in new window or tab >>Amine Modification of Mesoporous Magnesium Carbonate and the Effects on Controlled Drug Release
Show others...
(English)Manuscript (preprint) (Other academic)
National Category
Engineering and Technology
Identifiers
urn:nbn:se:uu:diva-303795 (URN)
Available from: 2016-09-23 Created: 2016-09-23 Last updated: 2016-11-30

Open Access in DiVA

fulltext(3331 kB)65 downloads
File information
File name FULLTEXT01.pdfFile size 3331 kBChecksum SHA-512
9778296841e0be0cef98bed119dffa193a6e461bb22ed62ce591a1fe6fbb8e2c4f7571664bc0eb2c8e8ca475a30cb0594ecbd28fcdfc6864ee7e2d890a447447
Type fulltextMimetype application/pdf
Buy this publication >>

Search in DiVA

By author/editor
Zhang, Peng
By organisation
Nanotechnology and Functional Materials
Engineering and Technology

Search outside of DiVA

GoogleGoogle Scholar
Total: 65 downloads
The number of downloads is the sum of all downloads of full texts. It may include eg previous versions that are now no longer available

Total: 328 hits
ReferencesLink to record
Permanent link

Direct link