| 1. |
- Lafitte, Géraldine, et al.
(author)
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Diffusion of nutrients molecules and model drug carriers through mucin layer investigated by magnetic resonance imaging with chemical shift resolution
- 2007
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In: Journal of Pharmaceutical Sciences. - : Elsevier BV. - 0022-3549. ; 96:2, s. 258-263
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Journal article (peer-reviewed)abstract
- Magnetic resonance imaging (MRI) with chemical shift resolution is a recent extension of MRI and it provides information about species resolved molecular transport on the macroscopic scale in complex systems. In this contribution, we show that by using this novel method, one can predict the behavior of drug and food molecules when they are in contact with the mucosal layer in the gastrointestinal tract. For the first time, the transport properties of a mixture of nutrients (i.e., a solution of ethanol and glucose) and of a model drug carrier (i.e., an equimolar solution of cationic and nonionic surfactants) through a mucin gel have been investigated. This study shows that transport properties of the diffusing molecules through a mucin gel are dependent on their size and physicochemical properties. In addition, we show that mucin gel acts as an efficient selective barrier. It favors the disintegration of mixed micelles of nonionic and cationic surfactants by stopping the diffusion of cationic surfactants with slightly affecting the diffusion of the nonionic surfactants. (c) 2006 Wiley-Liss, Inc.
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| 2. |
- Lafitte, Géraldine, et al.
(author)
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Mixtures of mucin and oppositely charged surfactant aggregates with varying charge density. Phase behavior, association, and dynamics
- 2005
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In: Langmuir. - : American Chemical Society (ACS). - 0743-7463 .- 1520-5827. ; 21:16, s. 7097-7104
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Journal article (peer-reviewed)abstract
- The nonionic surfactant Tween80 is a commonly used excipient in drug formulations containing an active substance with low aqueous solubility. Model drug vehicles with varying charge density were obtained by mixing Tween80 (PS-80) with the cationic surfactant Tetradecyltrimethylammonium chloride (TTAC), thus forming mixed micelles. The micelles were mixed with the negatively charged polyelectrolyte mucin, which is a component in the protective mucus layer covering epithelial cell linings. Depending on the composition of the mixture, complex-formation could be followed by precipitation. Using X-ray diffraction, it was found that the precipitate contained a lamellar phase with properties sensitive to the proportion of PS-80. Higher amounts of PS-80 were found to oppose phase separation. Further analysis in the one-phase region, or alternatively of the supernatant of two-phase samples, by H-1 NMR, HPLC, and diffusion measurements with PGSE-NMR led to the conclusions that at low proportion of PS-80 aggregates composed of mixed (PS-80 and TTAC) micelles and mucin were formed, whereas increased concentrations of PS-80 favored the dissolution of the precipitate and limited the interactions between mixed micelles and the polymer.
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| 3. |
- Lafitte, Géraldine
(author)
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Molecular associations and transport properties of amphiphiles and gastrointestinal mucin in aqueous solution
- 2007
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Doctoral thesis (other academic/artistic)abstract
- An effective uptake/absorption of drug formulations involve many processes; one being the transport of the active molecule through the mucus layer. The mucus layer is a complex mixture of biological molecules. Among them, mucin is the molecule that mainly provides the gel properties of the layer. Thus, the in-vivo physico-chemical properties of the mucus can to a first approximation be mimicked by an in-vitro mucin gel. Since most of the active molecules contained in drug formulations are hydrophobic, the aqueous environment in the gastrointestinal tract frequently requires solubilization in appropriate drug delivery carriers. Surfactants are one of the most common excipient used to form these carriers. Recently, studies have shown that inclusion of cationic amphiphiles may improve the bioavailability of active molecules. Therefore, in this work, the molecular associations between nonionic/cationic model drug carriers and mucin are studied by Pulse field gradient nuclear magnetic resonance (PFG-NMR). The drug carriers investigated are formed by Polysorbate 80 (PS-80), which is a common excipient, and quaternary ammonium chloride molecule, or dodecylbetaine ester which is a cleavable surfactant. These molecules are able to formed mixed micelles in solution. It appears that the binding of the micelles with mucin is highly dependent on the charge density. Indeed, strong binding with mucin molecules are observed for highly charged micelles. However, the interactions of nonionic model drug carriers are limited due to strong steric hindrance from the mucin molecules and the nonionic surfactant. The structure of a mucin gel also shows strong pH-dependence. Indeed, a loose network of expanded fully charged mucin molecules with considerable mobility is formed pH 7.4. At intermediate pH (pH 4), a three-dimensional expanded network is favoured. At pH 1, the predominant hydrophobic associations lead to the formation of clusters concentrated in the mucin molecules separated by water-rich domains. These structures are due to an equilibrium between electrostatic repulsions and hydrophobic associations between the mucin molecules. These different structures may explain why the transport properties of cationic drug vehicle is dependent on the pH as observed by magnetic resonance imaging with chemical shift resolution (MRI-CS). The transport properties of nonionic/cationic micelles are also dependent on the length of the aliphatic chain of the cationic molecules. The results obtained by MRI-CS lead to the conclusion that the bioavailability of drug carriers may be improved by the use of cationic surfactants. Therefore, the formulation of such carriers requires that the charge density of the carrier, the choice of the surfactant as well as the site of adsorption be taken into account.
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| 4. |
- Lafitte, Géraldine, et al.
(author)
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PFG-NMR diffusometry: A tool for investigating the structure and dynamics of noncommercial purified pig gastric mucin in a wide range of concentrations
- 2007
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In: Biopolymers. - : Wiley. - 0006-3525 .- 1097-0282. ; 86:2, s. 165-175
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Journal article (peer-reviewed)abstract
- For the first time, Pulsed Field Gradient-Nuclear Magnetic Resonance, a powerful noninvasive tool for studying the dynamics and structure of complex-gels, has been used to measure diffusion of probe molecules in aqueous solutions/gels of noncommercial purified pig gastric mucin (PGM), in a concentration range up to 5 wt%. Complementary data were obtained from rheology measurements. The combination of techniques revealed a strong pH dependency of the structure of the PGM samples while changes in concentration, ionic strength, and temperature appeared to induce less pronounced alterations. Viscosity was found to vary in a nonmonotonous way with pH, with the more viscous solutions found at intermediate pH. We propose that this finding is due to a reduced charge density at lower pH, which is expected to continuously increase the relative importance of hydrophobic associations. The results suggest a loose network of expanded fully charged PGM molecules woth considerable mobility at neutral pH (pH 7.4). At intermediate pH (pH 4), a three-dimensional expanded network is favored. At pH 1, the charge density is low and microphase seperation occurs since hydrophobic associations prevail. This leads to the formation of clusters concentrated in PGM molecules seperated by regions depleted in PGM. The results obtained increase our knowledge about the gastric mucosal layer, which in vivo contains mucin in the same concentration range as that of the samples investigated here. (c) 2007 Wiley Periodicals, Inc.
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| 5. |
- Lafitte, Géraldine, et al.
(author)
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Transport properties and aggregation phenomena of polyoxyethylene sorbitane monooleate (polysorbate 80) in pig gastrointestinal mucin and mucus
- 2007
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In: Langmuir. - : American Chemical Society (ACS). - 1520-5827 .- 0743-7463. ; 23:22, s. 10933-10939
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Journal article (peer-reviewed)abstract
- The aqueous environment in the gastrointestinal tract frequently requires solubilization of hydrophobic drug molecules in appropriate drug delivery vehicles. An effective uptake/absorption and systemic exposure of a drug molecule entails many processes, one being transport properties of the vehicles through the mucus layer. The mucus layer is a complex mixture of biological molecules. Among them, mucin is responsible of the gel properties of this layer. In this study, we have investigated the diffusion of polyoxyethylene sorbitane monooleate (polysorbate 80), a commonly used nonionic surfactant, in aqueous solution, in mucin solutions at 0.25 and 5 wt %, and in mucus. These measurements were done by using the pulsed field gradient spin echo nuclear magnetic resonance (PGSE-NMR) technique. We conclude that polysorbate 80 is a mixture of non-surface-active molecules that can diffuse freely through all the systems investigated and of surface-active molecules that form micellar structures with transport properties strongly dependent on the environment. Polysorbate 80 micelles do not interact with mucin even though their diffusion is hindered by obstruction of the large mucin molecules. On the other hand, the transport is slowed down in mucus due to interactions with other components such as lipids depots. In the last part of this study, a hydrophobic NMR probe molecule has been included in the systems to mimic a hydrophobic drug molecule. The measurements done in aqueous solution revealed that the probe molecules were transported in a closely similar way as the polysorbate 80 micelles, indicating that they were dissolved in the micellar core. The situation was more complex in mucus. The probe molecules seem to dissolve in the lipid depots at low concentrations of polysorbate 80, which slows down their transport. At increasing concentration of polysorbate 80, the diffusion of the probe molecules increases indicating a continuous dissolution of hexamethyldisilane in the core of polysorbate 80 micelles.
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| 6. |
- Lundberg, Dan, 1975, et al.
(author)
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Studies on the Interactions Between Mucin and Surfactant Aggregates Containing the Cationic Surfactant Dodecyl Betainate
- 2009
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In: Journal of Dispersion Science and Technology. - : Informa UK Limited. - 1532-2351 .- 0193-2691. ; 30:6, s. 920-928
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Journal article (peer-reviewed)abstract
- The interactions of surfactant aggregates containing the cationic, cleavable surfactant dodecyl betainate (DB) with mucin are investigated. The aggregates were either mixed micelles of DB and the nonionic surfactant PS-80 in different ratios or a dispersion of the commercial self-emulsifying drug-delivery formulation Sandimmun Neoral charged with DB. It is found that for the surfactant aggregates to show any notable interactions with mucin these must have a high positive charge density. Also presented are results from Ussing chamber experiments, which suggest that DB has a limited impact on the integrity and the barrier function of the intestinal epithelium.
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| 7. |
- Maleki, Atoosa, et al.
(author)
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Effect of pH on the association behavior in aqueous solutions of pig gastric mucin
- 2008
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In: Carbohydrate Research. - : Elsevier BV. - 1873-426X .- 0008-6215. ; 343:2, s. 328-340
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Journal article (peer-reviewed)abstract
- In this study, dynamic light scattering (DLS), turbidity, and rheo-small angle light scattering (rheo-SALS) methods have been utilized to examine the impact of pH (1 <= pH <= 7) on aqueous solutions of noncommercial purified pig gastric mucin. The asymmetric flow field-flow fractionation (AFFFF) measurements established that the mucin sample has a high molecular weight and is polydisperse. DLS measurements on dilute solutions of mucin disclosed large interchain aggregates at pH 2, where the polymer has a low charge density or is uncharged. At lower or higher values of pH, mucin is charged and the tendency of forming interpolymer complexes is affected. In the semidilute concentration regime, pronounced junction zones (`lumps' of polymer) are evolved and a heterogeneous connected network is formed at pH 2, whereas the association structures are disintegrated (smaller `lumps') at lower or higher pH values due to electrostatic repulsive interactions, and a more homogeneous network is evolved. The DLS and viscosity results at pH 1 indicate the development of a fragmented network, composed of contracted chains that are decorated by some positive charges. The effect of shear flow on the structure of semidilute solutions of mucin was investigated with the aid of rheo-SALS methods. The scattered intensity revealed a strong upturn at low values of the wave vector (q) for mucin solutions at pH 2 and pH 4, which suggests the evolution of large association domains. At these pH values, a flow-induced anisotropy in the 2D SALS patterns in the form of elliptical shapes was observed at high shear rates.
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