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Ceramic Materials for Administration of Potent Drugs
Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Applied Materials Sciences. (Material in Medicine)
2015 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

This thesis aimed to investigate and document the potential of applying ceramics in two specific drug delivery applications: tamper-resistant opioid formulations and transdermal enhancement protrusions.

Geopolymers were developed into the matrix for a tamper-resistant formulation, aiming to protect drug substances from non-medical abuse. The synthesis conditions and excipients composition of the geopolymer-based formulation were modified in this work to facilitate a stable and extended drug delivery. Results showed that 37ºC 100% humidity for 48 hours were applicable conditions to obtain geopolymer with suitable mechanical strength and porosity. Moreover, it was found that the integration of poly(methyl acrylate) into the geopolymer-based formulation could reduce the drug release at low pH and, meanwhile, maintain the mechanical strength. Therefore, the geopolymer-based drug formulations concluded from these studies were applied in oral and transdermal delivery systems. Evidence of the tamper-resistance of geopolymer-based oral and transdermal formulations was documented and compared to the corresponding commercial opioid formulations. The results provided experimental support for the positive effects of geopolymers as drug carriers for the tamper-resistance of oral and transdermal delivery systems.

Self-setting bioceramics, calcium phosphate and calcium sulfate were fabricated into transdermal enhancement protrusions in this work for the first time. Results showed that, under mild conditions, both bioceramics could form pyramid-shaped needles in the micron size. The drug release from these needles could be controlled by the bulk surface area, porosity and degradation of the bioceramics. An in vitro insertion test showed that the bioceramic microneedles had enough mechanical strength to insert into skin. Further optimization on the geometry of needles and the substrate material was also performed. The higher aspect-ratio needles with a flexible and self-swellable substrate could release most of the drug content within 4 hours and could penetrate through the stratum corneum by manual insertion. This study explored the potential application of bioceramics in transdermal enhancement protrusions and showed promising indication of their future developments.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2015. , 65 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1651-6214 ; 1235
Keyword [en]
Tamper-resistance, Oral formulation, Transdermal formulation, Biomaterials, Microneedles
National Category
Biomaterials Science Ceramics
Identifiers
URN: urn:nbn:se:uu:diva-245031ISBN: 978-91-554-9188-8 (print)OAI: oai:DiVA.org:uu-245031DiVA: diva2:793450
Public defence
2015-04-28, Polhemssalen, Lägerhyddsvägen 2, Uppsala, 10:00 (English)
Opponent
Supervisors
Available from: 2015-04-07 Created: 2015-02-24 Last updated: 2015-04-17
List of papers
1. The effect of curing conditions on compression strength and porosity of metakaolin-based geopolymers
Open this publication in new window or tab >>The effect of curing conditions on compression strength and porosity of metakaolin-based geopolymers
2013 (English)In: Developments in Strategic Materials and Computational Design IV, John Wiley & Sons, 2013Conference paper, Published paper (Refereed)
Abstract [en]

Geopolymers have been suggested to use as construction, waste treatment and fire proof materials and even drug delivery material due to its excellent mechanical strength, chemical stability and flame resistance. The aim of this study was to investigate the influence of temperature, time and humidity during curing on mechanical strength and porosity of geopolymers.

The geopolymer precursor paste was obtained by mixing metakaolin, waterglass and de-ionized water. The paste was molded into cylindrical rubber moulds (6  12 mm) and cured under different conditions: i.e. temperatures (ambient temperature, 37°C and 90°C), humidity and time (24, 48 and 96 hours). The compressive strength was determined using a universal testing machine. Helium pycnometer was used to measure the porosity. Via x-ray diffraction the phase composition of the cured samples was determined.

Elongated curing slightly decreased the total porosity of the tested geopolymers. Higher curing temperature increased the compressive strength after 24 hour but did not affect strength for longer curing times. In general, the samples cured in moisture had higher mechanical strength than those cured in air. But low compression strength of samples cured under high temperature and long time showed that some water content in geopolymer was essential to retaining its microstructure.

Place, publisher, year, edition, pages
John Wiley & Sons, 2013
Series
Ceramic Engineering and Science Proceedings
National Category
Medical Materials
Identifiers
urn:nbn:se:uu:diva-219258 (URN)10.1002/9781118807743.ch5 (DOI)
Conference
37th International Conference and Expo on Advanced Ceramics and Composites; 27 Jan - 1 Feb 2013; Daytona Beach, Fia., USA
Funder
Swedish Research Council
Available from: 2014-02-25 Created: 2014-02-25 Last updated: 2015-04-17Bibliographically approved
2. Polymer excipients enable sustained drug release in low pH from mechanically strong inorganic geopolymers
Open this publication in new window or tab >>Polymer excipients enable sustained drug release in low pH from mechanically strong inorganic geopolymers
Show others...
2012 (English)In: Results in Pharma Sciences, ISSN 2211-2863, Vol. 2, 23-28 p.Article in journal (Refereed) Published
Place, publisher, year, edition, pages
Elsevier, 2012
National Category
Pharmaceutical Sciences Engineering and Technology
Identifiers
urn:nbn:se:uu:diva-161811 (URN)10.1016/j.rinphs.2012.02.001 (DOI)
Available from: 2011-11-17 Created: 2011-11-17 Last updated: 2016-11-30
3. Evaluation of the resistance of a geopolymer-based drug delivery system to tampering
Open this publication in new window or tab >>Evaluation of the resistance of a geopolymer-based drug delivery system to tampering
2014 (English)In: International Journal of Pharmaceutics, ISSN 0378-5173, E-ISSN 1873-3476, Vol. 465, no 1-2, 169-174 p.Article in journal (Refereed) Published
Abstract [en]

Tamper-resistance is an important property of controlled-release formulations of opioid drugs. Tamper-resistant formulations aim to increase the degree of effort required to override the controlled release of the drug molecules from extended-release formulations for the purpose of non-medical use. In this study, the resistance of a geopolymer-based formulation to tampering was evaluated by comparing it with a commercial controlled-release tablet using several methods commonly used by drug abusers. Because of its high compressive strength and resistance to heat, much more effort and time was required to extract the drug from the geopolymer-based formulation. Moreover, in the drug-release test, the geopolymer-based formulation maintained its controlled-release characteristics after milling, while the drug was released immediately from the milled commercial tablets, potentially resulting in dose dumping. Although the tampering methods used in this study does not cover all methods that abuser could access, the results obtained by the described methods showed that the geopolymer matrix increased the degree of effort required to override the controlled release of the drug, suggesting that the formulation has improved resistance to some common drug-abuse tampering methods. The geopolymer matrix has the potential to make the opioid product less accessible and attractive to non-medical users.

National Category
Medical Materials
Research subject
Engineering Science with specialization in Materials Science
Identifiers
urn:nbn:se:uu:diva-219255 (URN)10.1016/j.ijpharm.2014.02.029 (DOI)000333675100022 ()
Funder
Swedish Research Council
Available from: 2014-02-25 Created: 2014-02-25 Last updated: 2017-12-05Bibliographically approved
4. Development and evaluation of a tampering resistant transdermal fentanyl patch
Open this publication in new window or tab >>Development and evaluation of a tampering resistant transdermal fentanyl patch
2015 (English)In: International Journal of Pharmaceutics, ISSN 0378-5173, E-ISSN 1873-3476, Vol. 488, no 1-2, 102-107 p.Article in journal (Refereed) Published
Keyword
Transdermal patch, Tamper-resistance, Geopolymer, Fentanyl, Abuse, Drug delivery
National Category
Ceramics Substance Abuse
Identifiers
urn:nbn:se:uu:diva-245029 (URN)10.1016/j.ijpharm.2015.04.061 (DOI)000355887100013 ()25913120 (PubMedID)
Available from: 2015-02-24 Created: 2015-02-24 Last updated: 2017-12-04Bibliographically approved
5. Self-setting bioceramic microscopic protrusions for transdermal drug delivery
Open this publication in new window or tab >>Self-setting bioceramic microscopic protrusions for transdermal drug delivery
2014 (English)In: Journal of materials chemistry. B, ISSN 2050-750X, E-ISSN 2050-7518, Vol. 2, no 36, 5992-5998 p.Article in journal (Refereed) Published
Abstract [en]

Microneedle (MN) technology offers both an efficient and a minimally invasive transdermal drug delivery strategy. The current MNs, made of silicon and metal, have poor biocompatibility and low drug loading, while the polymer MNs have some constraints related to mechanical strength and storage conditions. In this study, self-setting bioceramics were explored as substitutes for the current MN materials for the first time. Self-setting bioceramic microneedles were fabricated using a master mold by a procedure under mild conditions, which could minimize the drug degradation during fabrication and also facilitates a higher drug loading capability than the other current ceramic microneedles. The drug release and mechanical strength were correlated with the microstructure and porosity of the needles. As observed by SEM and microCT, the ceramic paste could fully fill the geometry of the mould and was cured into an array of micro-sized needles. The drug release study showed that the release rate from this type of MN array could be controlled by the bulk surface area, porosity and resorption rate of the ceramic needles. Applying the MNs to porcine skin indicated that the needles were able to pierce the stratum corneum of the skin. We successfully prepared the bioceramic needles that have high mechanical strength and are resorbable, which can promote safe, efficient and successful transdermal drug delivery.

National Category
Bio Materials Engineering and Technology
Research subject
Engineering Science with specialization in Materials Science
Identifiers
urn:nbn:se:uu:diva-233125 (URN)10.1039/c4tb00764f (DOI)000341300300007 ()
Conference
microneedles 2014, Baltimore, May 19-21, 2014
Available from: 2014-09-29 Created: 2014-09-29 Last updated: 2017-12-05
6. Bioceramic microneedles with flexible and self-swelling substrate
Open this publication in new window or tab >>Bioceramic microneedles with flexible and self-swelling substrate
(English)Article in journal (Other academic) Submitted
Keyword
Microneedles; Bioceramics; Controlled-release; Skin penetration; Clonidine
National Category
Biomaterials Science Ceramics
Identifiers
urn:nbn:se:uu:diva-246404 (URN)
Available from: 2015-03-06 Created: 2015-03-06 Last updated: 2015-04-17

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