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In vitro evaluation of formulations used in the treatment of hepatocellular carcinoma
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.ORCID-id: 0000-0002-8700-1369
2018 (engelsk)Doktoravhandling, med artikler (Annet vitenskapelig)
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.

sted, utgiver, år, opplag, sider
Uppsala: Acta Universitatis Upsaliensis, 2018. , s. 61
Serie
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 261
Emneord [en]
Drug delivery system, Doxorubicin, Microgel, Emulsion, Hepatocellular carcinoma
HSV kategori
Forskningsprogram
Biofarmaci
Identifikatorer
URN: urn:nbn:se:uu:diva-361017ISBN: 978-91-513-0498-4 (tryckt)OAI: oai:DiVA.org:uu-361017DiVA, id: diva2:1259692
Disputas
2018-12-20, A1:111a, BMC, Husargatan 3, Uppsala, 09:15 (engelsk)
Opponent
Veileder
Tilgjengelig fra: 2018-11-27 Laget: 2018-10-30 Sist oppdatert: 2018-12-27
Delarbeid
1. A miniaturized in vitro release method for investigating drug-release mechanisms
Åpne denne publikasjonen i ny fane eller vindu >>A miniaturized in vitro release method for investigating drug-release mechanisms
2015 (engelsk)Inngår i: International Journal of Pharmaceutics, ISSN 0378-5173, E-ISSN 1873-3476, Vol. 486, nr 1-2, s. 339-349Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

We have evaluated a miniaturized in vitro method, based on the mDISS Profiler (TM) technique that enables on-line monitoring of drug release from a 21 mu l sample with 10 ml of release medium. Four model drugs in eight clinically used formulations, including both solid and non-solid drug delivery systems, were investigated. The acquired data were compared with historical in vitro release data from the same formulations. Use of the Weibull function to describe the in vitro drug-release profiles allowed discrimination between the selected formulations with respect to the drug-release mechanisms. Comparison of the release data from the same formulation in different in vitro set-ups showed that the methodology used can affect the mechanism of in vitro release. We also evaluated the ability of the in vitro methods to predict in vivo activity by comparing simulated plasma concentration-time profiles acquired from the application of the biopharmaceutical software GI-Sim to the in vitro observations. In summary, the simulations based on the miniaturized-method release data predicted the plasma profiles as well as or more accurately than simulations based on the historical release data in 71% of the cases and this miniaturized in vitro method appears to be applicable for both solid and non-solid formulations.

Emneord
In vitro release methods, Release mechanisms, Weibull function, GI-Sim, In vivo prediction
HSV kategori
Identifikatorer
urn:nbn:se:uu:diva-255064 (URN)10.1016/j.ijpharm.2015.03.076 (DOI)000353999100037 ()25843760 (PubMedID)
Tilgjengelig fra: 2015-06-22 Laget: 2015-06-12 Sist oppdatert: 2018-10-30bibliografisk kontrollert
2. In Vitro Release Mechanisms of Doxorubicin From a Clinical Bead Drug-Delivery System
Åpne denne publikasjonen i ny fane eller vindu >>In Vitro Release Mechanisms of Doxorubicin From a Clinical Bead Drug-Delivery System
2016 (engelsk)Inngår i: Journal of Pharmaceutical Sciences, ISSN 0022-3549, E-ISSN 1520-6017, Vol. 105, nr 11, s. 3387-3398Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

The release rate of doxorubicin (DOX) from the drug-delivery system (DDS), DC Bead, was studied by 2 miniaturized in vitro methods: free-flowing and sample reservoir. The dependencies of the release mechanisms on in vitro system conditions were investigated experimentally and by theoretical modeling. An inverse relationship was found between release rates and bead size, most likely due to the greater total surface area. The release rates correlated positively with temperature, release medium volume, and buffer strength, although the release medium volume had larger effect than the buffer strength. The sample reservoir method generated slower release rates, which described the in vivo release profile more accurately than the free-flowing method. There was no difference between a pH of 6.3 or 7.4 on the release rate, implying that the slightly acidic tumor microenvironment is less importance for drug release. A positive correlation between stirring rate and release rate for all DDS sizes was observed, which suggests film controlled release. Theoretical modeling highlighted the influence of local equilibrium of protonation, self-aggregation, and bead material interactions of DOX. The theoretical release model might describe the observed larger sensitivity of the release rate to the volume of the release medium compared to buffer strength. A combination of miniaturized in vitro methods and theoretical modeling are useful to identify the important parameters and processes for DOX release from a micro gel-based DDS.

Emneord
controlled release, diffusion, dissolution, dissolution rate, drug-delivery systems, in vitro models, mathematical model, microspheres
HSV kategori
Identifikatorer
urn:nbn:se:uu:diva-311211 (URN)10.1016/j.xphs.2016.08.011 (DOI)000388268200018 ()27663384 (PubMedID)
Forskningsfinansiär
Swedish Research Council, 521-2011-373
Tilgjengelig fra: 2016-12-22 Laget: 2016-12-22 Sist oppdatert: 2018-10-30bibliografisk kontrollert
3. Single bead investigation of a clinical drug delivery system – a novel release mechanism
Åpne denne publikasjonen i ny fane eller vindu >>Single bead investigation of a clinical drug delivery system – a novel release mechanism
Vise andre…
2018 (engelsk)Inngår i: Journal of Controlled Release, ISSN 0168-3659, E-ISSN 1873-4995, Vol. 292, s. 235-247Artikkel i tidsskrift (Fagfellevurdert) 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.

Emneord
Microgel, Drug delivery, Release mechanism
HSV kategori
Identifikatorer
urn:nbn:se:uu:diva-360988 (URN)10.1016/j.jconrel.2018.11.011 (DOI)000452348100019 ()30419268 (PubMedID)
Forskningsfinansiär
Swedish Research Council, 521-2011-373
Tilgjengelig fra: 2018-09-20 Laget: 2018-09-20 Sist oppdatert: 2019-01-21bibliografisk kontrollert
4. In vitro evaluation of lipiodol-based emulsions in clinical use
Åpne denne publikasjonen i ny fane eller vindu >>In vitro evaluation of lipiodol-based emulsions in clinical use
Vise andre…
(engelsk)Manuskript (preprint) (Annet vitenskapelig)
HSV kategori
Identifikatorer
urn:nbn:se:uu:diva-360987 (URN)
Tilgjengelig fra: 2018-09-20 Laget: 2018-09-20 Sist oppdatert: 2018-10-30

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