| 1. |
- Boyd, Ben J., et al.
(författare)
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Successful oral delivery of poorly water-soluble drugs both depends on the intraluminal behavior of drugs and of appropriate advanced drug delivery systems
- 2019
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Ingår i: European Journal of Pharmaceutical Sciences. - : ELSEVIER. - 0928-0987 .- 1879-0720. ; 137
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Tidskriftsartikel (refereegranskat)abstract
- Poorly water-soluble drugs continue to be a problematic, yet important class of pharmaceutical compounds for treatment of a wide range of diseases. Their prevalence in discovery is still high, and their development is usually limited by our lack of a complete understanding of how the complex chemical, physiological and biochemical processes that occur between administration and absorption individually and together impact on bioavailability. This review defines the challenge presented by these drugs, outlines contemporary strategies to solve this challenge, and consequent in silico and in vitro evaluation of the delivery technologies for poorly water-soluble drugs. The next steps and unmet needs are proposed to present a roadmap for future studies for the field to consider enabling progress in delivery of poorly water-soluble compounds.
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| 2. |
- Bader, Erik, et al.
(författare)
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Identification of proliferative and mature beta-cells in the islets of Langerhans
- 2016
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 535:7612, s. 430-
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Tidskriftsartikel (refereegranskat)abstract
- Insulin-dependent diabetes is a complex multifactorial disorder characterized by loss or dysfunction of beta-cells. Pancreatic beta-cells differ in size, glucose responsiveness, insulin secretion and precursor cell potential(1-5); understanding the mechanisms that underlie this functional heterogeneity might make it possible to develop new regenerative approaches. Here we show that Fltp (also known as Flattop and Cfap126), a Wnt/planar cell polarity (PCP) effector and reporter gene(6), acts as a marker gene that subdivides endocrine cells into two subpopulations and distinguishes proliferation-competent from mature beta-cells with distinct molecular, physiological and ultrastructural features. Genetic lineage tracing revealed that endocrine subpopulations from Fltp-negative and -positive lineages react differently to physiological and pathological changes. The expression of Fltp increases when endocrine cells cluster together to form polarized and mature 3D islet mini-organs(7-9). We show that 3D architecture and Wnt/PCP ligands are sufficient to trigger beta-cell maturation. By contrast, the Wnt/PCP effector Fltp is not necessary for beta-cell development, proliferation or maturation. We conclude that 3D architecture and Wnt/PCP signalling underlie functional beta-cell heterogeneity and induce beta-cell maturation. The identification of Fltp as a marker for endocrine subpopulations sheds light on the molecular underpinnings of islet cell heterogeneity and plasticity and might enable targeting of endocrine subpopulations for the regeneration of functional beta-cell mass in diabetic patients.
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| 3. |
- Eriksen, Jonas Borregaard, et al.
(författare)
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'Stirred not Shaken!' Comparing Agitation Methods for Permeability Studies Using a Novel Type of 96-Well Sandwich-Plates
- 2022
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Ingår i: Journal of Pharmaceutical Sciences. - : Elsevier. - 0022-3549 .- 1520-6017. ; 111:1, s. 32-40
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Tidskriftsartikel (refereegranskat)abstract
- In order to achieve a high sample throughput, permeation experiments are often carried out using 96-well sandwich plates. Even though agitation is regarded as important, permeation studies in 96-well format are often carried out without agitation since orbital shaking, the most common agitation method for 96-well plates, has been reported to create difficulties (e.g., well-to-well cross-talk), and high cost and low availability limits the use of other agitation techniques (e.g., magnetic stirring). This study investigates how orbital shaking and magnetic stirring affect the apparent permeability of model compounds with different water-solubilities (methylene blue, carbamazepine, and albendazole) using a novel 96-well sandwich plate comprising a cellulose-hydrate membrane (PermeaPlain (R) plate). Orbital shaking was found less efficient than magnetic stirring in terms of homogeneously distributing a small volume of dye within the donor compartment. Furthermore, in terms of achieving maximum trans-barrier flux, magnetic stirring was found a more effective agitation method than orbital shaking. Obviously, with orbital shaking the medium in the bottom compartment of the sandwich plates never was mixed in-phase. The impact of insufficient mixing on permeation was found strongest with the most lipophilic compound, which correlates with literature reports that the contribution of the unstirred water layer towards the overall resistance of the barrier is most expressed in case of lipophilic drugs. Finally, it was tested how different liquid volumes in the bottom compartment of the plates affect the well-to-well cross-talk during permeation experiments under orbital shaking. This study revealed that 250-300 mu L should be used in the bottom compartment of the sandwich plates to reduce well-to-well cross-talk when using orbital shaking for agitation. (C) 2021 Published by Elsevier Inc. on behalf of American Pharmacists Association.
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| 4. |
- Settele, Josef, et al.
(författare)
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Rice ecosystem services in South-east Asia
- 2018
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Ingår i: Paddy and Water Environment. - : Springer. - 1611-2490 .- 1611-2504. ; 16:2, s. 211-224
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)
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| 5. |
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| 6. |
- Flaten, Gøril Eide, et al.
(författare)
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Drug permeability across a phospholipid vesicle-based barrier 2. Characterization of barrier structure, storage stability and stability towards pH changes.
- 2006
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Ingår i: European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences. - : Elsevier BV. - 0928-0987. ; 28:4, s. 336-43
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Tidskriftsartikel (refereegranskat)abstract
- Recently we reported on the development of a phospholipid vesicle-based barrier as a medium throughput method for screening of drug permeability. The aim of this present study is to characterize the barrier structure, including an estimation of the amount of phospholipid within it, its storage stability and its stability over various pH ranges found in different parts of the gastrointestinal tract. The amount of lipid in the barrier was quantified using a colorimetric phospholipase D-based assay. The total amount averaged 3.30mg phospholipid per barrier. The preparation process comprises the consecutive deposition of two types of liposomes on a filter support. We estimated that the smallest liposomes, with a mean diameter of 298nm, would fill the pore volume of the filter when tightly packed. The volume of the bigger liposomes, deposited on top of the filter, was calculated to generate a 0.1mm thick layer. Visualisation of fluorescently labelled liposomes by confocal laser-scanning microscopy confirmed that the pores of the filter were completely filled with liposomes and that there was a liposome layer on top. Small angle X-ray scattering (SAXS) analysis was used to study the lamellarity of the liposomes. The liposomes contained oligo- and/or multilamellar structures before and after deposition. The functionality of the barriers during storage at three different temperatures was examined for a period of up to 4 weeks by measuring the permeability of the hydrophilic marker calcein across them. The conclusion was that the phospholipid vesicle-based barriers could be stored at -80 degrees Celsius for up to 2 weeks without significant changes. The stability of the barriers in a pH range from 2.0 to 8.0 was investigated by performing permeation studies with fluorescein at different pH values. It was found that the phospholipid vesicle-based barrier did not lose its integrity within this range. Thus, the barriers appear suitable for further studies to provide insight into segmental absorption in the human gastrointestinal tract. Furthermore, because the phospholipid vesicle-based barrier can be stored, larger batches can be produced. This makes the phospholipid vesicle-based barrier more appropriate for high throughput screening.
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| 7. |
- Flaten, Goril Eide, et al.
(författare)
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Drug permeability across a phospholipid vesicle-based barrier: 4. The effect of tensides, co-solvents and pH changes on barrier integrity and on drug permeability
- 2008
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Ingår i: European Journal of Pharmaceutical Sciences. - : Elsevier BV. - 0928-0987. ; 34:2-3, s. 173-180
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Tidskriftsartikel (refereegranskat)abstract
- In this study the integrity of the recently developed phospholipid vesicle-based permeability barrier in the presence of a variety of co-solvents and tensides has been investigated. Also included are studies of the influence of these additives on drug permeation and the effect of pH changes on the permeability of ionogenic drug compounds. Permeability experiments using the hydrophilic model compound calcein together with polysorbate 80 (Tween 80), polyoxyl 35 castor oil (Cremophor EL), macrogol lauryl ether (Brij 35), sorbitan monolaurate (Span 20), polyethylene glycol 400 (PEG 400), ethanol and dimethylsulphoxide (DMSO) were performed to determine whether the barriers were affected by the presence of these additives in the donor compartment. It was found that the integrity of the phospholipid vesicle-based barriers did not seem to be influenced by Span 20 up to a concentration of 5 mg/ml, PEG 400 up to a concentration of 40 mg/ml and ethanol and DMSO up to a concentration of 20 mg/ml, respectively. Brij 35, Tween 80 and Cremophor EL were however found to be incompatible with the model at all concentrations as the barriers became leaky. Appearance of phospholipid in the donor chamber in presence of these three tensides indicated that the loss of integrity was due to partial dissolution of the phospholipid vesicles from the barrier. The permeability of testosterone was not significantly improved by the presence of the different co-solvents, except for 40 mg/ml PEG 400 and 20 mg/ml DMSO where the permeability was increased.
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| 8. |
- Flaten, Gøril Eide, et al.
(författare)
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Drug permeability across a phospholipid vesicle based barrier: a novel approach for studying passive diffusion.
- 2006
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Ingår i: European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences. - : Elsevier BV. - 0928-0987. ; 27:1, s. 80-90
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Tidskriftsartikel (refereegranskat)abstract
- The aim of this study was to develop a novel predictive medium-throughput screening method for drug permeability, with use of a tight barrier of liposomes on a filter support. To our knowledge no one has succeeded in depositing membrane barriers without the use of an inert solvent such as hexadecane. The first part of the study involved development of a protocol for preparation of these barriers, which were made of liposomes from egg phosphatidylcholin in phosphate buffer pH 7.4 with 10 % (v/v) ethanol. The liposomes were deposited into the pores and onto the surface of a filter support (mixed cellulose ester) by use of centrifugation. Solvent evaporation and freeze-thaw cycling were then used to promote fusion of liposomes. A tight barrier could thus be obtained as shown with calcein permeability and electrical resistance. In the second part of the study the model was validated using 21 drug compounds, which cover a wide range of physicochemical properties and absorption (F(a)) in humans (13-100%). The drug permeation studies were carried out at room temperature with phosphate buffer (pH 7.4) in both acceptor and donor chambers. The apparent permeability coefficients obtained from the phospholipid vesicle based model correlated well with literature data on human absorption in vivo, which suggests that its performance is adequate and that the method is suitable for rapid screening of passive transport of new chemical entities. The results obtained from our model were compared with polar surface area (PSA) and experimental logD and with results obtained by established permeability screening methods such as immobilized liposome chromatography (ILC), the PAMPA models and the Caco-2 model. Our approach seems to model the in vivo absorption better than PSA, experimental logD, the ILC and PAMPA models, when similar conditions are used as in our assay, and equally well as the Caco-2 model and the Double Sink PAMPA (DS-PAMPA) model.
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| 9. |
- Flaten, Gøril Eide, et al.
(författare)
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The Phospholipid Vesicle-Based Drug Permeability Assay: 5. Development Toward an Automated Procedure for High-Throughput Permeability Screening
- 2009
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Ingår i: Journal of the Association for Laboratory Automation. - : SAGE Publications. - 1535-5535. ; 14, s. 12-21
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Tidskriftsartikel (refereegranskat)abstract
- In vitro screening for oral absorption has become an essential part of drug discovery and development. Recently, a new phospholipid vesicle-based permeation assay was developed which has shown to satisfyingly predict passive absorption of drugs in humans. The purpose of the current study was to investigate whether the assay may be further developed into a high-throughput tool by automating its most time-consuming steps. The following challenges were addressed: (1) to design, build, and test a heat-sealing machine for mounting of the desired type of filter support onto both single wells and 24-well titer plate inserts and (2) to transfer the permeability assay to a robotic workstation with attached ultraviolet (UV) reader. The workstation is able to pipette and transport both plates and filter inserts and perform on-line photometric quantification of the amount of drug permeated. To enable the robot to move single (Standard Transwell; Corning Inc, Lowell, MA) filter inserts, an extension of the gripping arm was designed, built, and tested. Furthermore, in an alternative approach 24-well filter plates (Millicell; Millipore, Billerica, MA) were used instead of single filter inserts. The latter turned out to be more suitable in terms of error-free high-throughput robotic handling. The permeability values of drugs gained by the two automated procedures were compared with those measured by manual handling of the assay. Only neglectable differences in permeability values were seen. In conclusion, the most time-consuming steps of the assay were shown to be eligible for automation. This represents an interesting addition to the toolbox of in vitro permeability screening assays running in a medium- to high-throughput format due to its easiness, its transferability to other laboratories, and its good correlation with in vivo data on fraction absorbed of drugs in humans.
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