Structural properties of so-called NSAID–phospholipid-complexes

Hüsch, Jan; Dutagaci, Bercem; Glaubitz, Clemens; Geppert, Tim; Schneider, Gisbert; Harms, Meike; Müller‐Goymann, Christel C.; Fink, Lothar; Schmidt, Martin; Setzer, Constanze; Zirkel, Jürgen; Rebmann, Herbert; Schubert‐Zsilavecz, Manfred; Abdel‐Tawab, Mona

doi:10.1016/j.ejps.2011.06.010

Cited by 38 publications

(15 citation statements)

References 35 publications

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“…This pH-dependence is completely consistent with previous studies in animal models as well as clinical studies [22, 29, 67–69]. Similar experimental (NMR and IR) associations between NSAIDs and DPPC have recently been reported by Husch et al [70], although this group questioned the physiological significance of these “so-called complexes in physiologically relevant aqueous media.” In the present study, detailed MD simulations demonstrated the same pattern on the theoretical basis. In the MD simulations, anionic NSAIDs (pH > pKa) partition most favorably into the headgroup region of the phospholipid bilayer, due to electrostatic interactions with the positively-charged quarternary ammonium component of choline.…”

Section: Discussionsupporting

confidence: 90%

Insight into NSAID-induced membrane alterations, pathogenesis and therapeutics: Characterization of interaction of NSAIDs with phosphatidylcholine

Lichtenberger

Zhou

Jayaraman

et al. 2012

Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biolog

108

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Nonsteroidal anti-inflammatory drugs (NSAIDs) are one of the most widely consumed pharmaceuticals, yet both the mechanisms involved in their therapeutic actions and side-effects, notably gastrointestinal (GI) ulceration/bleeding, have not been clearly defined. In this study, we have used a number of biochemical, structural, computational and biological systems including; Fourier Transform InfraRed (FTIR). Nuclear Magnetic Resonance (NMR) and Surface Plasmon Resonance (SPR) spectroscopy, and cell culture using a specific fluorescent membrane probe, to demonstrate that NSAIDs have a strong affinity to form ionic and hydrophobic associations with zwitterionic phospholipids, and specifically phosphatidylcholine (PC), that are reversible and non-covalent in nature. We propose that the pH-dependent partition of these potent anti-inflammatory drugs into the phospholipid bilayer, and possibly extracellular mono/multilayers present on the luminal interface of the mucus gel layer, may result in profound changes in the hydrophobicity, fluidity, permeability, biomechanical properties and stability of these membranes and barriers. These changes may not only provide an explanation of how NSAIDs induce surface injury to the GI mucosa as a component in the pathogenic mechanism leading to peptic ulceration and bleeding, but potentially an explanation for a number of (COX-independent) biological actions of this family of pharmaceuticals. This insight also has proven useful in the design and development of a novel class of PC-associated NSAIDs that have reduced GI toxicity while maintaining their essential therapeutic efficacy to inhibit pain and inflammation.

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Section: Discussionsupporting

confidence: 90%

Insight into NSAID-induced membrane alterations, pathogenesis and therapeutics: Characterization of interaction of NSAIDs with phosphatidylcholine

Lichtenberger

Zhou

Jayaraman

et al. 2012

Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biolog

108

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“…Phospholipid-based systems have been developed to increase solubility and enhance dissolution rate and bioavailability of water-insoluble drugs, especially phytopharmaceuticals (17)(18)(19)(20). Furthermore, they have been investigated to reduce NSAID-induced gastrointestinal toxicity and hepatotoxicity (21).…”

Section: Introductionmentioning

confidence: 99%

In Vitro-In Vivo Evaluation of Novel Co-spray Dried Rifampicin Phospholipid Lipospheres for Oral Delivery

Singh¹,

Koduri²,

Bhatt³

et al. 2016

AAPS PharmSciTech

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Abstract. The objective of this study comprises of developing novel co-spray dried rifampicin phospholipid lipospheres (SDRPL) to investigate its influence on rifampicin solubility and oral bioavailability. Solid-state techniques were employed to characterize the liposphere formulation. SDRPL solubility was determined in distilled water. BACTEC 460TB System was employed to evaluate SDRPL antimycobacterial activity. The oral bioavailability of the lipospheres was evaluated in Sprague Dawley rats. Lipospheres exhibited amorphous, smooth spherical morphology with a significant increase (p < 0.001) in solubility of SDRPL (2:1), 350.9 ± 23 versus 105.1 ± 12 μg/ml and SDRPL (1:1) 306.4 ± 20 versus 105.1 ± 12 μg/ml in comparison to rifampicin (RMP). SDRPL exhibited enhanced activity against Mycobacterium tuberculosis, H37Rv strain, with over twofolds less minimum inhibitory concentration (MIC) than the free drug. Lipospheres exhibited higher peak plasma concentration (109.92 ± 25 versus 54.31 ± 18 μg/ml), faster T max (two versus four hours), and enhanced area under the curve (AUC 0-∞ ) (406.92 ± 18 versus 147.72 ± 15 μg h/L) in comparison to pure RMP. Thus, SDRPL represents a promising carrier system exhibiting enhanced antimycobacterial activity and oral bioavailability of rifampicin.

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“…Phospholipid complexation has been studied for many years and is currently applied either to reduce the gastrointestinal toxicity caused by non-steroidal antiinflammatory drugs (NSAIDs) or to increase the solubility and consequent therapeutic efficacy by improving the bioavailability of drugs with poor absorbability following oral administration. [11][12][13][14] Current research has shown the beneficial role of phospholipids in changing the polarity and enhancing the therapeutic efficacy of some molecules with poor oral bioavailability. [15][16][17][18] In this study, a phospholipid complex was developed to increase the solubility and oral bioavailability of pranlukast.…”

Section: Introductionmentioning

confidence: 99%

Enhancement of Solubility, Transport Across Madin-Darby Canine Kidney Monolayers and Oral Absorption of Pranlukast Through Preparation of a Pranlukast-Phospholipid Complex

Hao¹,

Wang²,

Li³

et al. 2015

j biomed nanotechnol

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This study aimed to enhance the solubility of a poorly water-soluble drug, pranlukast, as well as its transport across MadinDarby canine kidney (MDCK) monolayers, thus increasing its oral bioavailability. To accomplish this aim, we prepared a pranlukast-phospholipid complex (PPC). The PPC was prepared by solvent-evaporation and characterized by transmission electron microscopy (TEM), X-ray diffraction (XRD), infrared (IR) spectroscopy, and solubilization studies. The solubility of pranlukast in the PPC was increased from 1.03 ± 0.32 g/ml to 160.63 ± 2.72 g/ml with a yield of 96.39 ± 1.20% when the PPC was prepared under optimal conditions. TEM images showed that the PPC particles had a spherical shape. XRD data indicated that pranlukast in the PPC was either in an amorphous form or in a dispersed molecular distribution. IR analysis confirmed the interaction between pranlukast and the phospholipids. The transport mechanism of the PPC and non-complexed pranlukast across MDCK cells was measured and was observed to be significantly greater for the former than for the latter. The in vivo bioavailability of the PPC in rats hastened the onset of pranlukast-induced therapeutic effects, with C max and AUC increases of 21.88-and 28.64-fold, respectively, compared with raw crystals. In addition, an in vivo imaging method was used to corroborate that the PPC exhibited rapid circulatory distribution and gastrointestinal tract accumulation. These results indicate that PPC appears to be a promising drug delivery system for pranlukast, improving drug absorption and decreasing side effects by reducing the required oral dose.

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Structural properties of so-called NSAID–phospholipid-complexes

Cited by 38 publications

References 35 publications

Insight into NSAID-induced membrane alterations, pathogenesis and therapeutics: Characterization of interaction of NSAIDs with phosphatidylcholine

Insight into NSAID-induced membrane alterations, pathogenesis and therapeutics: Characterization of interaction of NSAIDs with phosphatidylcholine

In Vitro-In Vivo Evaluation of Novel Co-spray Dried Rifampicin Phospholipid Lipospheres for Oral Delivery

Enhancement of Solubility, Transport Across Madin-Darby Canine Kidney Monolayers and Oral Absorption of Pranlukast Through Preparation of a Pranlukast-Phospholipid Complex

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