| 1. |
- Ahnfelt, Emelie
(författare)
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In vitro evaluation of formulations used in the treatment of hepatocellular carcinoma
- 2018
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- 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.
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| 4. |
- Carlsson, Per, 1969-
(författare)
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Surface Engineering in Sheet Metal Forming
- 2005
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- In recent years, surface engineering techniques have been developed in order to improve the tribological performance in many industrial applications. In sheet metal forming processes, the usage of liquid lubricants can be decreased by using self lubricated tribo surfaces which will result in more environmentally friendly workshops. In the present work two different concepts, i.e. the deposition of thin organic coatings on the steel sheet and PVD coatings on the tool, have been evaluated. The sheet materials investigated include Zn and 55%Al-Zn metal coated steel sheet, which in general are difficult materials to form under dry conditions since they are sticky and thus have a high tendency to adhere to the tool surface. The PVD coatings include CrN, TiN and various DLC coatings. The work comprises tribo testing and post test characterisation using surface analytical techniques in order to evaluate the tribological properties of the tribo surfaces. The tribological tests of different tribo couples were conducted by using modified scratch testing and ball-on-disc testing. From these test results different friction and wear mechanisms have been identified. The deposition of thin organic coatings on the steel sheet metal has been found to be promising in order to control the friction and to avoid metal-metal contact resulting in galling. However, it has been found that the tribological characteristics of organic coated steel sheet are strongly influenced by coating chemical composition, the substrate surface topography and the coating thickness distribution. The performance of the PVD coatings depends mainly on the chemical composition and topography of the coated surface. By choosing PVD coatings such as diamond like carbon (DLC) low and stable friction coefficients can be obtained in sliding contact against Zn. Surface irregularities such as droplet-like asperities may cause an initial high friction coefficient. However, after a running in process or by polishing the PVD coating low friction coefficients can be obtained resulting in a stable sliding contact. The combination of imaging (optical profilometry, LOM, SEM) and chemical analytical techniques (EDS, AES, ToF-SIMS) gave valuable information concerning the friction and wear properties of the tribo surfaces investigated.
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| 5. |
- Dubbelboer, Ilse R, et al.
(författare)
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Treatment of intermediate stage hepatocellular carcinoma : a review of intrahepatic doxorubicin drug-delivery systems
- 2014
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Ingår i: Therapeutic delivery. - : Future Science Ltd. - 2041-5990 .- 2041-6008. ; 5:4, s. 447-466
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Tidskriftsartikel (refereegranskat)abstract
- The biopharmaceutical properties of doxorubicin delivered via two drug-delivery systems (DDSs) for the palliative treatment of unresectable hepatocellular carcinoma were reviewed with relation to the associated liver and tumor (patho)physiology. These two DDSs, doxorubicin emulsified with Lipiodol(®) and doxorubicin loaded into DC Bead(®) are different regarding tumor delivery, release rate, local bioavailability, if and how they can be given repeatedly, biodegradability, length of embolization and safety profile. There have been few direct head-to-head comparisons of these DDSs, and in-depth investigations into their in vitro and in vivo performance is warranted.
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| 8. |
- Grudén, Stefan, et al.
(författare)
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Antitumoral effect and reduced systemic toxicity in mice after intra-tumoral injection of an in vivo solidifying calcium sulfate formulation with docetaxel
- 2017
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Ingår i: European journal of pharmaceutics and biopharmaceutics. - : Elsevier BV. - 0939-6411 .- 1873-3441. ; 114, s. 186-193
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundDocetaxel is a cytostatic agent approved for treatment of non-small cell lung cancer as well as other cancers. Although docetaxel is an effective cytostatic agent, its effectiveness in clinical practice is associated with a variety of acute and long term side-effects. To overcome systemic side-effects, a slow release formulation based on calcium sulfate with docetaxel for intra-tumoral administration was developed.MethodsTwo formulations with the calcium sulfate NanoZolid technology were generated with a twofold difference in docetaxel drug load. The formulations were injected intra-tumorally as a paste which solidified within the tumor. The effects of the two intra-tumoral injection formulations were tested in female mice (n = 60) inoculated with subcutaneous Lewis lung carcinoma cells. The two formulations were compared to systemic intraperitoneal injection of docetaxel and a placebo formulation without docetaxel. Tumor volumes were measured and systemic side-effects were evaluated using body weight and cell counts from whole blood as well as plasma concentrations.ResultsBoth docetaxel formulations showed a significantly higher antitumor efficacy compared to placebo, which was comparable to that of systemic administration of docetaxel. Moreover, the intra-tumoral formulations with docetaxel showed reduced systemic toxicity compared to systemic treatment, including less weight loss and no decrease in blood cell counts.ConclusionsThe results suggest that intra-tumoral slow release calcium sulfate based formulations with docetaxel can be an alternative strategy as an efficient local antitumoral treatment with reduced systemic toxicity.
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| 9. |
- Lilienberg, Elsa, 1984-
(författare)
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Biopharmaceutical Evaluation of Intra-arterial Drug-Delivery Systems for Liver Cancer : Investigations in healthy pigs and liver cancer patients
- 2015
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- There are currently two types of intra-arterial drug-delivery system (DDS) in clinical use in the palliative treatment of primary liver cancer. The chemotherapeutic drug doxorubicin (DOX) can be formulated into a drug-in-lipiodol emulsion (LIPDOX) or a microparticulate drug-eluting bead system (DEBDOX). To facilitate development of future DDSs, we need to understand the release and local distribution of drug from these DDSs into the complex, in vivo, pathological environment.The overall aim of this project was to assess and improve understanding of the in vivo release of DOX from LIPDOX and DEBDOX and its local disposition in the liver. These processes were investigated in detail in a multisampling-site, healthy pig model and in human patients with liver cancer. The mechanisms involved in DOX disposition were studied by examining potential interactions between DOX and lipiodol and/or cyclosporine A (CsA) in pigs. In this project, the main elimination pathway for DOX and its primary metabolite doxorubicinol (DOXol) was via bile; their extensive canalicular carrier-mediated transport (e.g. ATP-binding cassette transporters ABCB1, ABCC1, ABCC2 and ABCG2) was inhibited by CsA. CsA had no effect on the carbonyl and aldo-keto reductases responsible for the metabolism of DOX into DOXol. LIPDOX released DOX more rapidly and to a greater extent into the circulation than DEBDOX, which had only released 15% of the dose in patients after 24 hrs. The systemic exposure to DOX was lower for DEBDOX than for LIPDOX. Greater fractions of DOXol were formed in blood and bile with LIPDOX than with DEBDOX. This may have been because DOX was more widely distributed into regions with increased metabolic capacity or because of increased intracellular uptake when DOX was delivered in LIPDOX. The excipient lipiodol in the LIPDOX formulation did not interact with transporters, enzymes or membranes that would explain the increased cellular uptake of DOX.In conclusion, the release of DOX from DEBDOX is more controlled in vivo than that from LIPDOX, indicating that DEBDOX is a more robust pharmaceutical product. The formulations for future optimized DDSs should therefore be more similar to DEBDOX than to LIPDOX.
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| 10. |
- Lilienberg, Elsa, et al.
(författare)
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Investigation of Hepatobiliary Disposition of Doxorubicin Following Intrahepatic Delivery of Different Dosage Forms
- 2014
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Ingår i: Molecular Pharmaceutics. - : American Chemical Society (ACS). - 1543-8384 .- 1543-8392. ; 11:1, s. 131-144
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Tidskriftsartikel (refereegranskat)abstract
- Unresectable, intermediate stage hepatocellular carcinoma (HCC) is often treated palliatively in humans by doxorubicin (DOX). The drug is administered either as a drug-emulsified-in-Lipiodol (DLIP) or as drug loaded into drug eluting beads (DEB), and both formulations are administered intrahepatically. However, several aspects of their in vivo performance in the liver are still not well-understood. In this study, DLIP and DEB were investigated regarding the local and systemic pharmacokinetics (PK) of DOX and its primary metabolite doxorubicinol (DOXol). An advanced PK-multisampling site acute in vivo pig model was used for simultaneous sampling in the portal, hepatic, and femoral veins and the bile duct. The study had a randomized, parallel design with four treatment groups (TI–TIV). TI (n = 4) was used as control and received an intravenous (i.v.) infusion of DOX as a solution. TII and TIII were given a local injection in the hepatic artery with DLIP (n = 4) or DEB (n = 4), respectively. TIV (n = 2) received local injections of DLIP in the hepatic artery and bile duct simultaneously. All samples were analyzed for concentrations of DOX and DOXol with UPLC-MS/MS. Compared to DLIP, the systemic exposure for DOX with DEB was reduced (p < 0.05), in agreement with a slower in vivo release. The approximated intracellular bioavailability of DOX during 6 h appeared to be lower for DEB than DLIP. Following i.v. infusion (55 min), DOX had a liver extraction of 41 (28–53)%, and the fraction of the dose eliminated in bile of DOX and DOXol was 20 (15–22)% and 4.2 (3.2–5.2)%, respectively. The AUCbile/AUCVP for DOX and DOXol was 640 (580–660) and 5000 (3900–5400), respectively. In conclusion, DLIP might initially deliver a higher hepatocellular concentration of DOX than DEB as a consequence of its higher in vivo release rate. Thus, DLIP delivery results in higher intracellular peak concentrations that might correlate with better anticancer effects, but also higher systemic drug exposure and safety issues.
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| 11. |
- Sjögren, Erik, et al.
(författare)
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Pharmacokinetics of an injectable modified-release 2-hydroxyflutamide formulation in the human prostate gland using a semiphysiologically based biopharmaceutical model.
- 2014
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Ingår i: Molecular pharmaceutics. - : American Chemical Society (ACS). - 1543-8392 .- 1543-8384. ; 11:9, s. 3097-111
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Tidskriftsartikel (refereegranskat)abstract
- The local distribution of 2-hydroxyflutamide (2-HOF) in prostate tissue after a single intraprostatic injection of a novel parenteral modified-release (MR) formulation in patients with localized prostate cancer was estimated using a semiphysiologically based biopharmaceutical model. Plasma concentration-time profiles for 2-HOF were acquired from a phase II study in 24 patients and the dissolution of the MR formulation was investigated in vitro. Human physiological values and the specific physicochemical properties of 2-HOF were obtained from the literature or calculated via established algorithms. A compartmental modeling approach was adopted for tissue and blood in the prostate gland, where the compartments were modeled as a series of concentric spherical shells contouring the centrally positioned depot formulation. Discrete fluid connections between the blood compartments were described by the representative flow of blood, whereas the mass transport of drug from tissue to tissue and tissue to blood was described by a one-dimensional diffusion approximation. An empirical dissolution approach was adopted for the release of 2-HOF from the formulation. The model adequately described the plasma concentration-time profiles of 2-HOF. Predictive simulations indicated that the local tissue concentration of 2-HOF within a distance of 5 mm from the depot formulation was approximately 40 times higher than that of unbound 2-HOF in plasma. The simulations also indicated that spreading the formulation throughout the prostate gland would expose more of the gland and increase the overall release rate of 2-HOF from the given dose. The increased release rate would initially increase the tissue and plasma concentrations but would also reduce the terminal half-life of 2-HOF in plasma. Finally, an in vitro-in vivo correlation of the release of 2-HOF from the parenteral MR formulation was established. This study shows that intraprostatic 2-HOF concentrations are significantly higher than systemic plasma concentrations and that increased distribution of 2-HOF throughout the gland, using strategic imaging-guided administration, is possible. This novel parenteral MR formulation, thus, facilitates good pharmacological effect while minimizing the risk of side effects.
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| 12. |
- Zheng, Jie, et al.
(författare)
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Carbide-metal phase interpenetrated double skeleton microstructures
- 2000
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Ingår i: 24th Annual Conference on Composites, Advanced Ceramics, Materials, and Structures. - Hoboken, NJ : John Wiley & Sons. - 9780470375686
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Konferensbidrag (refereegranskat)abstract
- Carbide-metal composites, such as Cr3C2-Cu, Cr3C2-bronze and TiC-Cu, were prepared by infiltrating liquid metal into carbide skeletons with open micro-porosity at high temperatures. X-ray diffraction and scanning electron microscopy equipped with energy dispersive spectrometry were used to characterize these materials. The resulting microstructures consisted of two interpenetrating three-dimensional skeletons. There is no sign of porosity at the interface indicating good wetting between the metal and ceramic. The combination of a ceramic and a metal in the composites resulted in unique combinations of mechanical and electrical properties. Abrasion and friction tests showed that the composite materials had better abrasion resistance than that of ceramics such as Al2O3 and SiC as well as lower friction coefficients than that of SiC. Tests in electrical contacts have revealed a contact resistance similar to copper. The composites are well suited for special applications, such as sliding electrical contacts, arc resistant switches, friction components and bearing/seal components.
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