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- Alvebratt, Caroline, et al.
(författare)
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A Modified In Situ Method to Determine Release from a Complex Drug Carrier in Particle-Rich Suspensions
- 2018
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Ingår i: AAPS PharmSciTech. - : Springer Science and Business Media LLC. - 1530-9932. ; 19:7, s. 2859-2865
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Tidskriftsartikel (refereegranskat)abstract
- Effective and compound-sparing methods to evaluate promising drug delivery systems are a prerequisite for successful selection of formulations in early development stages. The aim of the study was to develop a small-scale in situ method to determine drug release and supersaturation in highly concentrated suspensions of enabling formulations. Mesoporous magnesium carbonate (MMC), which delivers the drug in an amorphous form, was selected as a drug carrier. Five model compounds were loaded into the MMC at a 1:10 ratio using a solvent evaporation technique. The μDiss Profiler was used to study the drug release from MMC in fasted-state simulated intestinal fluid. To avoid extensive light scattering previously seen in particle-rich suspensions in the μDiss Profiler, an in-house-designed protective nylon filter was placed on the in situ UV probes. Three types of release experiments were conducted for each compound: micronized crystalline drug with MMC present, drug-loaded MMC, and drug-loaded MMC with 0.01% w/w hydroxypropyl methyl cellulose. The nylon filters effectively diminished interference with the UV absorption; however, the release profiles obtained were heavily compound dependent. For one of the compounds, changes in the UV spectra were detected during the release from the MMC, and these were consistent with degradation of the compound. To conclude, the addition of protective nylon filters to the probes of the μDiss Profiler is a useful contribution to the method, making evaluations of particle-rich suspensions feasible. The method is a valuable addition to the current ones, allowing for fast and effective evaluation of advanced drug delivery systems.
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| 5. |
- Alvebratt, Caroline
(författare)
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Advanced Methods for Evaluation of the Performance of Complex Drug Delivery System
- 2021
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Low oral bioavailability of drugs originating from poor aqueous solubility is a common issue in drug development. Various enabling formulations have been presented to circumvent this limitation, many making use of supersaturation. In these, the drug is delivered to the gastro-intestinal lumen in a high energy state e.g. in amorphous form or a liquid lipid vehicle. Concentrations surpassing the equilibrium solubility of the crystalline drug are achieved, which facilitate increased absorption for dissolution-rate limited compounds. Meanwhile the use of the enabling formulation can be beneficial to increase the bioavailability of poorly water-soluble drugs, in vitro evaluation of these systems remain challenging. Limited methods have also evaluated several different types of enabling formulation in the same experimental setup. The overall aim of this thesis was therefore to develop assays to study the performance of various complex drug delivery systems. In the first part, a small scale dissolution apparatus, the µDiss Profiler, was used to study drug release from drug-loaded mesoporous magnesium carbonate (MMC). A protective filter was developed to minimize particle interference on the UV-measurements, enabling studies of supersaturation from the amorphous carrier. In the second paper, lipids were adsorbed onto the MMC. A modified in vitro lipolysis setup was established and the samples were analyzed with nuclear magnetic resonance spectroscopy. A stability study of the lipid-loaded MMC was also performed. The methods developed in the first two projects provided an insight to events occurring in the intestinal lumen. The intestinal absorption has however been shown to be a complex interplay between dissolution-digestion and permeation. In the final two projects, two devices comprising of a donor (luminal) chamber and a receiver (serosal) chamber were studied (the µFLUX and the enabling absorption, ENA, device). The two chambers were separated by a semipermeable membrane (cell-based and/or phospholipid-based). A wide range of enabling formulations were evaluated in the two assays. As the exposure in the donor correlated poorly with the exposure in the receiver compartment, this emphasizes the importance of in vitro methods taking both the dissolution-digestion and permeation into account. The ENA results also predicted the in vivo performance in rats well. To conclude, several models have been established in the thesis to study the in vitro performance of enabling formulations, which will be valuable for screening of appropriate drug delivery systems.
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| 6. |
- Alvebratt, Caroline, et al.
(författare)
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An in vitro dissolution–digestion–permeation assay for the study of advanced drug delivery systems
- 2020
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Ingår i: European journal of pharmaceutics and biopharmaceutics. - : Elsevier BV. - 0939-6411 .- 1873-3441. ; 149, s. 21-29
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Tidskriftsartikel (refereegranskat)abstract
- Advanced drug delivery systems (ADDS) are widely explored to overcome poor aqueous solubility of orally administered drugs. However, the prediction of their in vivo performance is challenging, as in vitro models typically do not capture the interplay between processes occurring in the gut. In additions, different models are used to evaluate the different systems. We therefore present a method that allows monitoring of luminal processing (dissolution, digestion) and its interplay with permeation to better inform on the absorption of felodipine formulated as ADDS. Experiments were performed in a µFLUX-apparatus, consisting of two chambers, representing the intestinal and serosal compartment, separated by Caco-2 monolayers. During dissolution–digestion–permeation experiments, ADDS were added to the donor compartment containing simulated intestinal fluid and immobilized lipase. Dissolution and permeation in both compartments were monitored using in situ UV-probes or, when turbidity interfered the measurements, with HPLC analysis.The method showed that all ADDS increased donor and receiver concentrations compared to the condition using crystalline felodipine. A poor correlation between the compartments indicated the need for an serosal compartment to evaluate drug absorption from ADDS. The method enables medium-throughput assessment of: (i) dynamic processes occurring in the small intestine, and (ii) drug concentrations in real-time.
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| 8. |
- Alvebratt, Caroline, et al.
(författare)
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In Vitro Performance and Chemical Stability of Lipid-Based Formulations Encapsulated in a Mesoporous Magnesium Carbonate Carrier
- 2020
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Ingår i: Pharmaceutics. - : MDPI AG. - 1999-4923 .- 1999-4923. ; 12:5
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Tidskriftsartikel (refereegranskat)abstract
- Lipid-based formulations can circumvent the low aqueous solubility of problematic drug compounds and increase their oral absorption. As these formulations are often physically unstable and costly to manufacture, solidification has been suggested as a way to minimize these issues. This study evaluated the physicochemical stability and in vitro performance of lipid-loaded mesoporous magnesium carbonate (MMC) particles with an average pore size of 20 nm. A medium chain lipid was loaded onto the MMC carrier via physical adsorption. A modified in vitro lipolysis setup was then used to study lipid release and digestion with 1H nuclear magnetic resonance spectroscopy. The lipid loading efficiency with different solidification techniques was also evaluated. The MMC, unlike more commonly used porous silicate carriers, dissolved during the lipolysis assay, providing a rapid release of encapsulated lipids into solution. The digestion of the dispersed lipid-loaded MMC therefore resembled that of a coarse dispersion of the lipid. The stability data demonstrated minor degradation of the lipid within the pores of the MMC particles, but storage for three months did not reveal extensive degradation. To conclude, lipids can be adsorbed onto MMC, creating a solid powder from which the lipid is readily released into the solution during in vitro digestion. The chemical stability of the formulation does however merit further attention.
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- Andersson, Sara B. E., et al.
(författare)
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Controlled Suspensions Enable Rapid Determinations of Intrinsic Dissolution Rate and Apparent Solubility of Poorly Water-Soluble Compounds
- 2017
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Ingår i: Pharmaceutical research. - : Springer Science and Business Media LLC. - 0724-8741 .- 1573-904X. ; 34:9, s. 1805-1816
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: To develop a small-scale set-up to rapidly and accurately determine the intrinsic dissolution rate (IDR) and apparent solubility of poorly water-soluble compounds.Methods: The IDR and apparent solubility (S-app) were measured in fasted state simulated intestinal fluid (FaSSIF) for six model compounds using wet-milled controlled suspensions (1.0% (w/w) PVP and 0.2% (w/w) SDS) and the mu DISS Profiler. Particle size distribution was measured using a Zetasizer and the total surface area was calculated making use of the density of the compound. Powder and disc dissolution were performed and compared to the IDR of the controlled suspensions.Results: The IDR values obtained from the controlled suspensions were in excellent agreement with IDR from disc measurements. The method used low amount of compound (mu g-scale) and the experiments were completed within a few minutes. The IDR values ranged from 0.2-70.6 mu g/min/cm(2) and the IDR/S-app ratio ranged from 0.015 to 0.23. This ratio was used to indicate particle size sensitivity on intestinal concentrations reached for poorly water-soluble compounds.Conclusions: The established method is a new, desirable tool that provides the means for rapid and highly accurate measurements of the IDR and apparent solubility in biorelevant dissolution media. The IDR/S-app is proposed as a measure of particle size sensitivity when significant solubilization may occur.
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