Bile Salt Micelles and Phospholipid Vesicles Present in Simulated and Human Intestinal Fluids: Structural Analysis by Flow Field–Flow Fractionation/Multiangle Laser Light Scattering

Elvang, Philipp A.; Hinna, Askell; Brouwers, Joachim; Hens, Bart; Augustijns, Patrick; Brandl, Martin

doi:10.1016/j.xphs.2016.03.005

Cited by 38 publications

(19 citation statements)

References 31 publications

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“…A significant interaction between pH and either oleate or bile salt is therefore to be expected since their ionisation will vary in the DoE pH range and the results indicate that this influences solubilisation. Based on literature results this is probably also linked to changes in the systems phase behaviour ( Elvang et al, 2016 ) however it is interesting that the DoE does not register a significant interaction between bile salt and oleate for the acidic drugs. No other factor combinations produced a statistically significant average value but for individual drugs statistically significant events are present.…”

Section: Resultsmentioning

confidence: 97%

Statistical investigation of simulated fed intestinal media composition on the equilibrium solubility of oral drugs

Zhou

Dunn

Khadra

et al. 2017

European Journal of Pharmaceutical Sciences

113

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Gastrointestinal fluid is a complex milieu and it is recognised that gut drug solubility is different to that observed in simple aqueous buffers. Simulated gastrointestinal media have been developed covering fasted and fed states to facilitate in vitro prediction of gut solubility and product dissolution. However, the combination of bile salts, phospholipids, fatty acids and proteins in an aqueous buffered system creates multiple phases and drug solubility is therefore a complex interaction between these components, which may create unique environments for each API. The impact on solubility can be assessed through a statistical design of experiment (DoE) approach, to determine the influence and relationships between factors. In this paper DoE has been applied to fed simulated gastrointestinal media consisting of eight components (pH, bile salt, lecithin, sodium oleate, monoglyceride, buffer, salt and pancreatin) using a two level D-optimal design with forty-four duplicate measurements and four centre points. The equilibrium solubility of a range of poorly soluble acidic (indomethacin, ibuprofen, phenytoin, valsartan, zafirlukast), basic (aprepitant, carvedilol, tadalafil, bromocriptine) and neutral (fenofibrate, felodipine, probucol, itraconazole) drugs was investigated. Results indicate that the DoE provides equilibrium solubility values that are comparable to literature results for other simulated fed gastrointestinal media systems or human intestinal fluid samples. For acidic drugs the influence of pH predominates but other significant factors related to oleate and bile salt or interactions between them are present. For basic drugs pH, oleate and bile salt have equal significance along with interactions between pH and oleate and lecithin and oleate. Neutral drugs show diverse effects of the media components particularly with regard to oleate, bile salt, pH and lecithin but the presence of monoglyceride, pancreatin and buffer have significant but smaller effects on solubility. There are fourteen significant interactions between factors mainly related to the surfactant components and pH, indicating that the solubility of neutral drugs in fed simulated media is complex. The results also indicate that the equilibrium solubility of each drug can exhibit individualistic behaviour associated with the drug's chemical structure, physicochemical properties and interaction with media components. The utility of DoE for fed simulated media has been demonstrated providing equilibrium solubility values comparable with similar in vitro systems whilst also providing greater information on the influence of media factors and their interactions. The determination of a drug's gastrointestinal solubility envelope provides useful limits that can potentially be applied to in silico modelling and in vivo experiments.

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Section: Resultsmentioning

confidence: 97%

Statistical investigation of simulated fed intestinal media composition on the equilibrium solubility of oral drugs

Zhou

Dunn

Khadra

et al. 2017

European Journal of Pharmaceutical Sciences

113

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“…The kinetics for ganglioside transfer from micelles to bilayers, starting from nonequilibrium conditions, has been investigated and seems to occur on time scales of minutes to hours [70]. Similar behavior of micelle-vesicles co-existence is also highly relevant for, e.g., mixtures of bile salts and phospholipids and cholesterol [71,72].…”

Section: Discussionmentioning

confidence: 99%

Self-Assembly in Ganglioside‒Phospholipid Systems: The Co-Existence of Vesicles, Micelles, and Discs

Mojumdar

Grey

Sparr

2019

IJMS

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Ganglioside lipids have been associated with several physiological processes, including cell signaling. They have also been associated with amyloid aggregation in Parkinson’s and Alzheimer’s disease. In biological systems, gangliosides are present in a mix with other lipid species, and the structure and properties of these mixtures strongly depend on the proportions of the different components. Here, we study self-assembly in model mixtures composed of ganglioside GM1 and a zwitterionic phospholipid, 1,2-Dioleoyl-sn-glycero-3-phosphocholine (DOPC). We characterize the structure and molecular dynamics using a range of complementary techniques, including cryo-TEM, polarization transfer solid state NMR, diffusion NMR, small-angle X-ray scattering (SAXS), dynamic light scattering (DLS), and calorimetry. The main findings are: (1) The lipid acyl chains are more rigid in mixtures containing both lipid species compared to systems that only contain one of the lipids. (2) The system containing DOPC with 10 mol % GM1 contains both vesicles and micelles. (3) At higher GM1 concentrations, the sample is more heterogenous and also contains small disc-like or rod-like structures. Such a co-existence of structures can have a strong impact on the overall properties of the lipid system, including transport, solubilization, and partitioning, which can be crucial to the understanding of the role of gangliosides in biological systems.

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“…Therefore, the increase in CXB permeation seen here must only be caused by CXB's amorphous solid state leading to true supersaturation of CXB. However, the presence of FaSSIF, which mainly forms mixed micelles upon dispersion (Elvang et al, 2016), seems to stabilize the supersaturated state leading to a further increase in CXB permeation.…”

Section: Accepted Manuscriptmentioning

confidence: 98%

A dynamic in vitro permeation study on solid mono- and diacyl-phospholipid dispersions of celecoxib

Jacobsen

Elvang

Bauer‐Brandl

et al. 2019

European Journal of Pharmaceutical Sciences

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Bile Salt Micelles and Phospholipid Vesicles Present in Simulated and Human Intestinal Fluids: Structural Analysis by Flow Field–Flow Fractionation/Multiangle Laser Light Scattering

Cited by 38 publications

References 31 publications

Statistical investigation of simulated fed intestinal media composition on the equilibrium solubility of oral drugs

Statistical investigation of simulated fed intestinal media composition on the equilibrium solubility of oral drugs

Self-Assembly in Ganglioside‒Phospholipid Systems: The Co-Existence of Vesicles, Micelles, and Discs

A dynamic in vitro permeation study on solid mono- and diacyl-phospholipid dispersions of celecoxib

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