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Diffusion Controlled Drug Release from Slurry Formed, Porous, Organic and Clay-derived Pellets
2012 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Coronary artery disease and chronic pain are serious health issues that cause severe discomfort and suffering in society today. Antithrombotic agents and highly potent analgesics play a critical role in improving the recovery process for patients being treated for these diseases. This thesis focuses on the design and study of pellet-based drug dosage forms which allow diffusion-controlled delivery of drugs with the aim of achieving optimal therapeutic outcomes.

A wet slurry process was used to mix the drug and the polymer and/or clay precursor excipients into a paste. The pellets were then shaped via ionotropic gelation (alginate hydrogel beads/pellets), extrusion/spheronization (halloysite clay pellets) or geopolymerization.

The decrease in the drug diffusion rate in the alginate beads was affected by the drug's molecular size and charge and the characteristics (such as concentration and chemical structure) of the surrounding alginate gel.

The halloysite clay pellets provided sustained release of the highly potent drug fentanyl at both gastric pH 1 and intestinal pH 6.8. As expected, crushing the pellets reduced the diffusion barrier, resulting in more rapid release (dose dumping).

The use of mechanically strong geopolymer gels was investigated as a potential means of preventing dose dumping as a result of crushing of the dosage form. Variations in the synthesis composition resulted in drastic changes in the microstructure morphology, the porosity, the mechanical stability and the drug release rate. Pore network modeling and finite element simulations were employed to theoretically evaluate the effects of porosity and drug solubility in the geopolymer structure on the drug release process. Fitting the model parameters to experimental data showed that increased average pore connectivity, a greater pore size distribution, and increased drug solubility in the pellet resulted in an increased drug release rate. Furthermore, incorporation of pH-sensitive organic polymers in the geopolymer structure reduced the high drug release rate from the pellets at gastric pH. These results indicate that geopolymers have potential for use in pellet form; both the release rate of the drug and the mechanical stability of the pellets can be optimized to prevent dose dumping.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis , 2012. , 80 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1651-6214 ; 884
Keyword [en]
Diffusion, Drug delivery, Antithrombotic drugs, Highly potent opioids, Modeling, Clays, Polymers, Pellets, Beads
National Category
Pharmaceutical Sciences
Research subject
Materials Science
Identifiers
URN: urn:nbn:se:uu:diva-161812ISBN: 978-91-554-8229-9 (print)OAI: oai:DiVA.org:uu-161812DiVA: diva2:457470
Public defence
2012-01-20, Häggsalen, Ångströmslaboratoriet, Lägerhyddsvägen 1, Uppsala, 13:00 (English)
Opponent
Supervisors
Available from: 2011-12-21 Created: 2011-11-17 Last updated: 2013-07-22
List of papers
1. Release of antithrombotic drugs from alginate gel beads
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2010 (English)In: Current drug delivery, ISSN 1875-5704, Vol. 7, no 4, 297-302 p.Article in journal (Refereed) Published
Abstract [en]

The aim of the present work was to evaluate alginate hydrogels in the form of spherical beads as carrier for antithrombotic drugs for future use in artificial grafts. The ionotropic gelation technique was employed to prepare beads from the L. hyperborea stipe of alginate with two different alginate concentrations and two different guluronic to manuronic acid ratios. The beads were loaded, via soaking, with three different types of low molecular weight model molecules representing drugs with antithrombotic action and their release characteristics were subsequently evaluated. The entire release process of the negatively charged model drugs under study (Salicylic acid and Hirudin), was found to be governed by diffusion, while additional electrostatic interactions between drug molecule and alginate matrix was indicated to influence the release rate of the analyzed positively charged drug molecule (Dipyridamole). It was found that the alginate hydrogel matrix imposed a decrease of the drug diffusion rate on the molecules under study as compared to the corresponding diffusion rates in water. All diffusion coefficients decreased slightly with increasing concentration of alginate and with increasing guluronic to manuronic acid ratio. The results show on the potential use of alginate gel beads when developing vehicles for release of low molecular weight antithrombotic drugs.

National Category
Engineering and Technology
Identifiers
urn:nbn:se:uu:diva-130060 (URN)20695840 (PubMedID)
Available from: 2010-08-30 Created: 2010-08-30 Last updated: 2016-11-30Bibliographically approved
2. A ceramic drug delivery vehicle for oral administration of highly potent opioids
Open this publication in new window or tab >>A ceramic drug delivery vehicle for oral administration of highly potent opioids
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2010 (English)In: Journal of Pharmaceutical Sciences, ISSN 0022-3549, E-ISSN 1520-6017, Vol. 99, no 1, 219-226 p.Article in journal (Refereed) Published
Abstract [en]

Pellets composed of the ceramic material Halloysite and microcrystalline cellulose were synthesized with the aim of producing a drug delivery vehicle for sustained release of the opioid Fentanyl with low risk for dose dumping at oral intake of the highly potent drug. Drug release profiles of intact and crushed pellets, to simulate swallowing without or with chewing, in pH 6.8, pH 1, and in 48% ethanol were recorded in order to replicate the conditions in the small intestines, in the stomach, as well as cointake of the drug with alcohol. The drug release was analyzed by employing the Weibull equation, which showed that the release profiles were either governed by fickian diffusion (intact pellets in pH 6.8 and in ethanol) or by diffusion in a fractal or disordered pore network (intact pellets in pH 1 and crushed pellets in all solutions). A sustained release for approximately 3-4 h was obtained in all studied solutions from intact pellets, whereas crushed pellets released the drug content during approximately 2-3 h. The finding that a sustained release profile could be obtained both in alcohol and after crushing of the pellets, shows that the ceramic carrier under investigation, at least to some extent, hampers dose dumping, and may thus be a promising material in future developments of new opioid containing oral dosage forms.

National Category
Other Materials Engineering
Research subject
Engineering Science with specialization in Nanotechnology and Functional Materials
Identifiers
urn:nbn:se:uu:diva-111786 (URN)10.1002/jps.21814 (DOI)000273151500016 ()19492338 (PubMedID)
Available from: 2009-12-21 Created: 2009-12-21 Last updated: 2017-12-12Bibliographically approved
3. Mechanically strong geopolymers offer new possibilities in treatment of chronic pain
Open this publication in new window or tab >>Mechanically strong geopolymers offer new possibilities in treatment of chronic pain
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2010 (English)In: Journal of Controlled Release, ISSN 0168-3659, E-ISSN 1873-4995, Vol. 146, no 3, 370-377 p.Article in journal (Refereed) Published
Abstract [en]

We propose that a clay derived class of materials, known as geopolymers, may solve the problem of finding materials for controlled release with the right combination of properties necessary for a safe and sustained oral delivery of highly potent opioids. We show that the opioid Fentanyl, and its structurally similar sedative Zolpidem, can be embedded into metakaolin based geopolymer pellets to provide prolonged release dosage forms with mechanical strengths of the same order of magnitude as that of human teeth. The results presented in the current work may open up new opportunities for future development of drug delivery for high potency drugs employing high-strength and variable-pore-structure geopolymers and materials alike.

National Category
Engineering and Technology
Identifiers
urn:nbn:se:uu:diva-131243 (URN)10.1016/j.jconrel.2010.05.029 (DOI)000282398100014 ()20685295 (PubMedID)
Available from: 2010-09-28 Created: 2010-09-28 Last updated: 2017-12-12Bibliographically approved
4. Modeling structure-function relationships for diffusive drug transport in inert porous geopolymer matrices
Open this publication in new window or tab >>Modeling structure-function relationships for diffusive drug transport in inert porous geopolymer matrices
2011 (English)In: Journal of Pharmaceutical Sciences, ISSN 0022-3549, E-ISSN 1520-6017, Vol. 100, no 10, 4338-4348 p.Article in journal (Refereed) Published
Abstract [en]

A unique structure-function relationship investigation of mechanically strong geopolymer drug delivery vehicles for sustained release of potent substances is presented. The effect of in-synthesis water content on geopolymer pore structure and diffusive drug transport is investigated. Scanning electron microscopy, N(2) gas adsorption, mercury intrusion porosimetry, compression strength test, drug permeation, and release experiments are performed. Effective diffusion coefficients are measured and compared with corresponding theoretical values as derived from pore size distribution and connectivity via pore-network modeling. By solely varying the in-synthesis water content, mesoporous and mechanically strong geopolymers with porosities of 8%-45% are obtained. Effective diffusion coefficients of the model drugs Saccharin and Zolpidem are observed to span two orders of magnitude (∼1.6-120 × 10(-8) cm(2) /s), comparing very well to theoretical estimations. The ability to predict drug permeation and release from geopolymers, and materials alike, allows future formulations to be tailored on a structural and chemical level for specific applications such as controlled drug delivery of highly potent substances.

National Category
Pharmaceutical Sciences Engineering and Technology
Identifiers
urn:nbn:se:uu:diva-158928 (URN)10.1002/jps.22636 (DOI)000295733800024 ()21656516 (PubMedID)
Available from: 2011-09-22 Created: 2011-09-19 Last updated: 2017-12-08Bibliographically approved
5. Influence of drug distribution and solubility on release from geopolymer pellets: A finite element method study
Open this publication in new window or tab >>Influence of drug distribution and solubility on release from geopolymer pellets: A finite element method study
2012 (English)In: Journal of Pharmaceutical Sciences, ISSN 0022-3549, E-ISSN 1520-6017, Vol. 101, no 5, 1803-1810 p.Article in journal (Refereed) Published
Abstract [en]

This study investigates the influence of drug solubility and distribution on its release from inert geopolymer pellets of three different sizes (1.5 × 1.5, 3 × 6, and 6 × 6 mm), having the same geopolymer composition and containing highly potent opioid fentanyl, sumatriptan, theophylline, or saccharin. Scanning electron microscopy, nitrogen sorption, drug solubility, permeation, and release experiments were performed, and estimates of the drug diffusion coefficients and solubilities in the geopolymer matrix were derived with the aid of finite element method (FEM). FEM was further employed to investigate the effect of a nonuniform drug distribution on the drug release profile. When inspecting the release profiles for each drug, it was observed that their solubilities in the geopolymer matrix imposed a much greater influence on the drug release rate than their diffusion coefficients. Concentrating the initial drug load in FEM into nonuniformly distributed drug regions inside the matrix created drug release profiles that more closely resembled experimental data than an FEM-simulated uniform drug distribution did. The presented FEM simulations and visualization of drug release from geopolymers under varying initial and dynamic conditions should open up for more systematic studies of additional factors that influence the drug release profile from porous delivery vehicles.

Keyword
controlled release, solubility, diffusion, dissolution, materials science, oral drug delivery
National Category
Nano Technology
Research subject
Engineering Science with specialization in Nanotechnology and Functional Materials; Engineering Science with specialization in Materials Science
Identifiers
urn:nbn:se:uu:diva-161810 (URN)10.1002/jps.23071 (DOI)000302800100016 ()
Available from: 2011-11-17 Created: 2011-11-17 Last updated: 2017-12-08Bibliographically approved
6. 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
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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

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