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Single bead investigation of a clinical drug delivery system – a novel release mechanism
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.ORCID iD: 0000-0002-8700-1369
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.ORCID iD: 0000-0003-4318-6039
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
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2018 (English)In: Journal of Controlled Release, ISSN 0168-3659, E-ISSN 1873-4995, Vol. 292, p. 235-247Article in journal (Refereed) Published
Abstract [en]

Microgels, such as polymeric hydrogels, are currently used as drug delivery devices (DDSs) for chemotherapeutics and/or unstable drugs. The clinical DDS DC bead® was studied with respect to loading and release, measured as relative bead-volume, of six amphiphilic molecules in a micropipette-assisted microscopy method. Theoretical models for loading and release was used to increase the mechanistic understanding of the DDS.

It was shown that equilibrium loading was independent of amphiphile concentration. The loading model showed that the rate-determining step was diffusion of the molecule from the bulk to the bead surface (‘film control’). Calculations with the developed and applied release model on the release kinetics were consistent with the observations, as the amphiphiles distribute unevenly in the bead. The rate determining step of the release was the diffusion of the amphiphile molecule through the developed amphiphile-free depletion layer. The release rate is determined by the diffusivity and the tendency for aggregation of the amphiphile where a weak tendency for aggregation (i.e. a large cacb) lead to faster release. Salt was necessary for the release to happen, but at physiological concentrations the entry of salt was not rate-determining. This study provides valuable insights into the loading to and release from the DDS. Also, a novel release mechanism of the clinically used DDS is suggested.

Place, publisher, year, edition, pages
2018. Vol. 292, p. 235-247
Keywords [en]
Microgel, Drug delivery, Release mechanism
National Category
Pharmaceutical Sciences
Identifiers
URN: urn:nbn:se:uu:diva-360988DOI: 10.1016/j.jconrel.2018.11.011ISI: 000452348100019PubMedID: 30419268OAI: oai:DiVA.org:uu-360988DiVA, id: diva2:1249765
Funder
Swedish Research Council, 521-2011-373Available from: 2018-09-20 Created: 2018-09-20 Last updated: 2022-04-18Bibliographically approved
In thesis
1. In vitro evaluation of formulations used in the treatment of hepatocellular carcinoma
Open this publication in new window or tab >>In vitro evaluation of formulations used in the treatment of hepatocellular carcinoma
2018 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Hepatocellular carcinoma (HCC) causes ~ 600,000 deaths annually, making it the second most deadly cancer form. HCC is classified into five stages and for the intermediate HCC treatment, the two most commonly used drug delivery systems (DDSs) are lipiodol-based emulsions and drug-eluting beads. The aims of this thesis were to develop in vitro methods suitable for studying these DDSs. It is important to investigate the release mechanisms and release rates with relevant in vitro methods, as this can improve the understanding of the in vivo performance. Miniaturized in vitro methods with sample reservoirs separated from the release medium by a diffusion barrier were developed and shown to be suitable for studying drug release from particle DDSs (Paper I). In Paper II these methods were further developed and used to study the release of doxorubicin (DOX) from the clinically used drug-eluting beads. DOX release rates were affected by the method set-up and the characteristics of the release medium. The choice of method and volume of release medium could improve the in vivo-likeness of the in vitro release profiles. Applied theoretical models suggested a film-controlled type of DOX release mechanism from the beads when self-aggregation, DOX-bead interaction, and DOX deprotonation were taken into account.

A micropipette-assisted microscopy method was used to further improve the understanding of the release mechanism of amphiphilic molecules from the beads (Paper III). A detailed analysis suggested an internal depletion-layer model dependent on molecular self-aggregation for the release. It was further suggested that a simple ion-exchange mechanism is unrealistic in physiological conditions.

The important pharmaceutical factors for the emulsion-based formulations were investigated in Paper IV. DOX solubility, lipid phase distribution, and emulsion stability increased when the contrast agent iohexol was added. Also, an increase in release half-life (h) was observed from emulsions with iohexol.

The in vitro methods and theoretical models presented in this thesis can be used during development and optimization of future DDSs.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2018. p. 61
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 261
Keywords
Drug delivery system, Doxorubicin, Microgel, Emulsion, Hepatocellular carcinoma
National Category
Pharmaceutical Sciences
Research subject
Biopharmaceutics
Identifiers
urn:nbn:se:uu:diva-361017 (URN)978-91-513-0498-4 (ISBN)
Public defence
2018-12-20, A1:111a, BMC, Husargatan 3, Uppsala, 09:15 (English)
Opponent
Supervisors
Available from: 2018-11-27 Created: 2018-10-30 Last updated: 2018-12-27
2. Microgels as drug delivery vehicles: loading and release of amphiphilic drugs
Open this publication in new window or tab >>Microgels as drug delivery vehicles: loading and release of amphiphilic drugs
2022 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Polyelectrolyte microgels are used as delivery vehicles for amphiphilic drugs in, e.g., treatments of liver cancer by a method called trans-arterial chemoembolization. The thesis deals with fundamental properties of such delivery systems related to the self-assembling properties of the drug molecules and their interaction with the charged polymer network of the microgel. The main objective was to establish mechanistic models describing the loading and release of drugs under relevant conditions. For that purpose experimental techniques providing thermodynamic, compositional and microstructural information were used to elucidate how the kinetics depend on the stability of the drug self-assemblies and the volume response of the microgels. Micromanipulator-assisted microscopy studies showed that negatively charged microgels phase separated during loading and release of cationic amphiphilic drugs. At intermediate loading levels the drug aggregates and part of the network formed a collapsed phase coexisting with a swollen, drug-lean phase. In particular, during release in a medium of physiological ionic strength, the drug-lean phase formed a depletion layer (shell) surrounding a drug-rich core. Investigations of a series of drugs with different molecular architectures showed that the drug release rate was determined mainly by the stability of the drug aggregates in the core and the diffusive mass transport of drug molecules through the shell. Detailed studies of polyacrylate microgels interacting with amitriptyline hydrochloride showed that swelling of the shell network greatly influenced the release rate. Furthermore, experiments with a specially constructed microscopy cell was used to establish that the collapsed and swollen phases could coexist in equilibrium, and that the swelling of the network in the swollen phase depended on the proportion between them when present in the same microgel. The latter effect was related to the elastic coupling between the phases. Confocal Raman microscopy was employed to demonstrate, for the first time, the related elastic effect, that the concentration of amitriptyline in the swollen phase decreased with increasing proportion of the collapsed phase. Small-angle X-ray scattering showed that the collapsed phase had a disordered microstructure of drug micelles with ellipsoidal shape. The aggregation number increased with increasing concentration of drug in the microgel, most likely by incorporating the uncharged base form. By providing detailed information about thermodynamic properties and microstructures, the results of the thesis provide a basis for rational design of microgel drug delivery systems.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2022. p. 61
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 312
Keywords
microgel, amphiphilic drug, phase separation, micropipette, Raman microscopy, controlled release, drug delivery, SAXS
National Category
Pharmaceutical Sciences
Research subject
Pharmaceutical Physical Chemistry
Identifiers
urn:nbn:se:uu:diva-472818 (URN)978-91-513-1502-7 (ISBN)
Public defence
2022-06-14, Room A1:111a, BMC, Husargatan 3, Uppsala, 09:15 (English)
Opponent
Supervisors
Available from: 2022-05-17 Created: 2022-04-18 Last updated: 2022-06-15

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Ahnfelt, EmelieAl-Tikriti, YassirSjögren, ErikLennernäs, HansHansson, Per

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