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Kanji Takada - One of the best experts on this subject based on the ideXlab platform.
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Enhancing mechanism of Labrasol on intestinal membrane permeability of the hydrophilic drug gentamicin sulfate
European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V, 2006Co-Authors: Kenjiro Koga, Yoichi Kusawake, Yukako Ito, Nobuyuki Sugioka, Nobuhito Shibata, Kanji TakadaAbstract:The aim of this study was to clarify the mechanism by which caprylocaproyl macrogol-8 glyceride (Labrasol) enhances the intestinal absorption of gentamicin sulfate (GM), a drug that has poor permeability but relatively high solubility. We studied the following characteristics: (i) the phase behavior of Labrasol in aqueous solution, (ii) the affinity of GM to Labrasol micelles, and (iii) the interaction between Labrasol and membrane lipids. We measured the critical micelle concentration of Labrasol in aqueous solution to be approximately 0.01%. The average diameters of Labrasol micelles in 2% and 25% solutions were approximately 10 nm and 20 nm, respectively, indicating that micelles increase in size with increasing Labrasol concentration. Although GM dissolved in 5% Labrasol solution was dialyzable, GM dissolved in either 25% or 50% Labrasol solutions was not, suggesting that GM exists in the hydrophilic region of the Labrasol micelle or in the high affinity region of the micelle surface where GM is retained. In membrane permeability experiments and electrophysiological studies conducted with rat ileum, only 25% Labrasol solution enhanced GM permeability, but did not remarkably affect membrane resistance. Furthermore, Labrasol increased membrane lipid fluidity as determined by fluorescence anisotropy in porcine intestinal brush border membrane liposomes. These results suggest that high concentrations of Labrasol solution enhance membrane permeability of GM via a transcellular rather than a paracellular route. We propose the following mechanism: Labrasol micelles grow when the concentration of Labrasol exceeds 20%, at which point GM shows high affinity for the hydrophilic region of the micelles. Since Labrasol micelles increase membrane lipid fluidity, the membrane permeability of GM is concomitantly enhanced.
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research paper enhancing mechanism of Labrasol on intestinal membrane permeability of the hydrophilic drug gentamicin sulfate
2006Co-Authors: Kenjiro Koga, Yoichi Kusawake, Yukako Ito, Nobuyuki Sugioka, Nobuhito Shibata, Kanji TakadaAbstract:The aim of this study was to clarify the mechanism by which caprylocaproyl macrogol-8 glyceride (Labrasol) enhances the intestinal absorption of gentamicin sulfate (GM), a drug that has poor permeability but relatively high solubility. We studied the following characteristics: (i) the phase behavior of Labrasol in aqueous solution, (ii) the affinity of GM to Labrasol micelles, and (iii) the interaction between Labrasol and membrane lipids. We measured the critical micelle concentration of Labrasol in aqueous solution to be approximately 0.01%. The average diameters of Labrasol micelles in 2% and 25% solutions were approximately 10 nm and 20 nm, respectively, indicating that micelles increase in size with increasing Labrasol concentration. Although GM dissolved in 5% Labrasol solution was dialyzable, GM dissolved in either 25% or 50% Labrasol solutions was not, suggesting that GM exists in the hydrophilic region of the Labrasol micelle or in the high affinity region of the micelle surface where GM is retained. In membrane permeability experiments and electrophysiological studies conducted with rat ileum, only 25% Labrasol solution enhanced GM permeability, but did not remarkably affect membrane resistance. Furthermore, Labrasol increased membrane lipid fluidity as determined by fluorescence anisotropy in porcine intestinal brush border membrane liposomes. These results suggest that high concentrations of Labrasol solution enhance membrane permeability of GM via a transcellular rather than a paracellular route. We propose the following mechanism: Labrasol micelles grow when the concentration of Labrasol exceeds 20%, at which point GM shows high affinity for the hydrophilic region of the micelles. Since Labrasol micelles increase membrane lipid fluidity, the membrane permeability of GM is concomitantly enhanced. � 2006 Elsevier B.V. All rights reserved.
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liquid filled nanoparticles as a drug delivery tool for protein therapeutics
Biomaterials, 2005Co-Authors: Natarajan Venkatesan, Yukako Ito, Nobuhito Shibata, Junichiro Yoshimitsu, Kanji TakadaAbstract:Abstract In the present study, an attempt was made to study the feasibility of nanoparticulate adsorbents in the presence of an absorption enhancer, as a drug delivery tool for the administration of erythropoietin (EPO) to the small intestine. Liquid filled nano- and micro-particles (LFNPS/LFMPS) were prepared using solid adsorbents such as porous silicon dioxide (Sylysia 550), carbon nanotubes (CNTs), carbon nanohorns, fullerene, charcoal and bamboo charcoal. Surfactants such as a saturated polyglycolysed C8–C18 glyceride (Gelucire 44/14), PEG-8 capryl/caprylic acid glycerides (Labrasol) and polyoxyethylene hydrogenated castor oil derivative (HCO-60) were used as an absorption enhancer at 50 mg/kg along with casein/lactoferrin as enzyme inhibitors. The absorption of EPO was studied by measuring serum EPO levels by an ELISA method after small intestinal administration of EPO-LFNPS preparation to rats at the EPO dose level of 100 IU/kg. Among the adsorbents studied, CNTs showed the highest serum EPO level of 62.7±11.6 mIU/ml. In addition, with the use of casein, EPO absorption was improved, C max 143.1±15.2 mIU/ml. Labrasol showed the highest absorption enhancing effect after intra-jejunum administration than Gelucire 44/14 and HCO-60, 25.6±3.2 and 22.2±3.6 mIU/ml, respectively. Jejunum was found to be the best absorption site for the absorption of EPO from LFNPS. The use of CNTs as LFNPS, improved the bioavailability of EPO to 11.5% following intra-small intestinal administration.
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in situ intestinal absorption studies on low molecular weight heparin in rats using Labrasol as absorption enhancer
International Journal of Pharmaceutics, 2004Co-Authors: Y Rama V Prasad, Nobuhito Shibata, Takashi Minamimoto, Yukako Yoshikawa, Saori Mori, Akihiro Matsuura, Kanji TakadaAbstract:Abstract Oral absorption of low molecular weight heparin (LMWH) is limited by its molecular size and negative charge. Development of its oral formulations would allow outpatient treatment with LMWH and decrease the hospital expenses. Studies were aimed at evaluating Labrasol for improving intestinal absorption of LMWH. Formulations containing LMWH and Labrasol were administered to duodenum, jejunum, and ileum of the fasted rats. The doses of LMWH and Labrasol were 200 IU/kg and 50 mg/kg, respectively. Reversibility of absorption enhancing effect of Labrasol was assessed by administering LMWH to jejunum after 0.5 and 1 h of administration of Labrasol. The effect of different doses of Labrasol on LMWH absorption was studied by administering Labrasol at 50, 100, and 200 mg/kg doses. Administration of LMWH formulation to jejunum resulted in the highest plasma anti-Xa activity (0.50±0.03 IU/ml) compared to duodenum (0.19±0.03 IU/ml), and ileum (0.29±0.06 IU/ml) and the anti-Xa levels were maintained above the therapeutic level for about 160 min. The absorption of LMWH was negligible when LMWH was administered at 0.5 and 1 h post-Labrasol administration. Increasing the dose of Labrasol has decreased the absorption of LMWH from jejunum. Labrasol increased the intestinal absorption of LMWH, and jejunum was found to be the best site of absorption. Intestinal membrane permeability changes induced by Labrasol were transient and reversible. Maintaining high drug concentration gradient across intestinal wall is important to obtain increased intestinal LMWH absorption.
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evaluation of oral formulations of gentamicin containing Labrasol in beagle dogs
International Journal of Pharmaceutics, 2003Co-Authors: Y Rama V Prasad, Yoichi Kusawake, Nobuhito Shibata, Yukako Yoshikawa, Riichi Tawa, Makoto Ishida, Sudarat Eaimtrakarn, Kanji TakadaAbstract:Gentamicin (GM) is a polarized water-soluble compound having very poor intestinal membrane permeability resulting in low oral bioavailability. Labrasol was found to improve the intestinal absorption of GM in rats. In the present study, GM formulations containing Labrasol were evaluated in beagle dogs after filling into hydroxypropylmethyl cellulose (HPMC) capsules wrapped with Eudragit L100 (Eud L) and Eudragit S100 (Eud S) films. The results of the in vitro drug release studies could not differentiate between two kinds of enteric capsules and among the three kinds of GM formulations. Oral administration of GM solution at a dose of 50.0 mg per dog of GM and 0.60 ml per dog of Labrasol has resulted in Cmax values of 2.38 +/- 0.50 microg/ml and 2.30 +/- 0.42 microg/ml with Eud L and Eud S capsules, respectively. The AUC values obtained were also higher at 4.35 +/- 1.31 microg h/ml and 5.34 +/- 0.95 microg h/ml with Eud L and Eud S capsules, respectively. Formulation of GM as a suspension in Labrasol has resulted in the decrease of Cmax values by two to four times and AUC values by > 2.5 times compared to the solution formulation. The above results indicate that solution formulation was better over the suspension. An absorbent, synthetic sponge was used to absorb GM solution formulation and encapsulated with Eud L and Eud S capsules. The Cmax and AUC values obtained with sponge formulation were higher than those of suspension formulations but were lower than solution formulations. There was no significant difference in the extent of GM absorption between Eud L and Eud S capsules used for encapsulating GM formulations.
Vincent Jannin - One of the best experts on this subject based on the ideXlab platform.
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Labrasol is an efficacious intestinal permeation enhancer across rat intestine ex vivo and in vivo rat studies
Journal of Controlled Release, 2019Co-Authors: Fiona Mccartney, Vincent Jannin, Nicolas Ritter, Frederic Demarne, Stephanie Chevrier, Hakime Boulghobra, Delyan R Hristov, Cedric Miolane, Yann Chavant, David J BraydenAbstract:Abstract Labrasol® ALF (Labrasol®), is a non-ionic surfactant excipient primarily used as a solubilising agent. It was investigated here as an intestinal permeation enhancer in isolated rat colonic mucosae in Ussing chamber and in rat in situ intestinal instillations. Labrasol® comprises mono-, di- and triglycerides and mono- and di- fatty acid esters of polyethylene glycol (PEG)-8 and free PEG-8, with caprylic (C8)- and capric acid (C10) as the main fatty acids. Source components of Labrasol® as well as Labrasol® modified with either C8 or C10 as the sole fatty acid components were also tested to determine which element of Labrasol® was responsible for its permeability-enhancing properties. Labrasol® (4, 8 mg/mL) enhanced the transport of the paracellular markers, [14C] mannitol, FITC-dextran 4000, and FITC-insulin across colonic mucosae. The enhancement was non-damaging, transient, and molecular weight-dependent. The PEG ester fraction of Labrasol® also had enhancing properties. When insulin was administered with Labrasol® in instillations, it had a relative bioavailability of 7% in jejunum and 12% in colon. C8– and C10 versions of Labrasol® and the PEG ester fraction also induced similar bioavailability values in jejunal instillations: 6, 5 and 7% respectively. Inhibition of lipases in instillations did not reduce the efficacy of Labrasol®, suggesting that its mechanism as a PE is not simply due to liberated medium chain fatty acids. Labrasol® acts as an efficacious intestinal permeation enhancer and has potential for use in oral formulations of macromolecules and BCS Class III molecules.
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modulation of transepithelial electric resistance teer in reconstructed human epidermis by excipients known to permeate intestinal tight junctions
Experimental Dermatology, 2015Co-Authors: Rawad Abdayem, Vincent Jannin, Frederic Demarne, Sylvie Callejon, Pascal Portes, Plamen Kirilov, Fabrice Pirot, Marek HaftekAbstract:Several excipients are commonly used to enhance the drug absorption through simple epithelia of the digestive tract. They permeate the paracellular barrier constituted by tight junctions (TJs). We compared the effects of two excipients, sodium caprate (C10) and a self-emulsifying excipient Labrasol composed of a mixture of caprylocaproyl polyoxyl-8 glycerides, both applied to emerged reconstructed human epidermis either 'systemically', that is by addition to the culture medium, or topically. During the 'systemic' application, which produced cytoplasmic translocation of occludin and leakage of the biotin marker into the lower stratum corneum, the decrease in the trans-epithelial electrical resistance (TEER) was less abrupt with Labrasol when compared with C10, even though both excipients produced comparable final effects over time. With topical Labrasol, a significant TEER decrease was obtained with 5 times the 'systemic' concentrations. Topical application of C10 also resulted in the loss of the barrier function measured with TEER but had dramatic deleterious effects on the tissue morphology observed with light and electron microscopy. Our study demonstrates the potential value of Labrasol as an enhancer of bioavailability of molecules applied through the transcutaneous route. Our results suggest modulation of the epidermal TJs by both compounds. Even though the C10 action was at least partly due to overall cell damage and despite the fact that the decrease in TEER after topical application was apparently related to the permeabilization of the primary barrier of the stratum corneum in the first place.
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in vitro digestion of the self emulsifying lipid excipient Labrasol by gastrointestinal lipases and influence of its colloidal structure on lipolysis rate
Pharmaceutical Research, 2013Co-Authors: Sylvie Fernandez, Vincent Jannin, Frederic Demarne, Stephanie Chevrier, Yann Chavant, Frederic CarriereAbstract:Purpose Labrasol® is a self-emulsifying excipient used to improve the oral bioavailability of poorly water-soluble drugs. It is a mixture of acylglycerols and PEG esters, these compounds being substrates for digestive lipases. The characterization of Labrasol® gastrointestinal lipolysis is essential for understanding its mode of action.
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in vitro gastrointestinal lipolysis of four formulations of piroxicam and cinnarizine with the self emulsifying excipients Labrasol and gelucire 44 14
Pharmaceutical Research, 2009Co-Authors: Sylvie Fernandez, Nicolas Ritter, Bruno Mahler, Frederic Demarne, Frederic Carriere, Stephanie Chevrier, Vincent JanninAbstract:Purpose Labrasol® and Gelucire® 44/14 are defined admixtures of acylglycerols and PEG esters which are substrates for digestive lipases.
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lipolysis of the semi solid self emulsifying excipient gelucire 44 14 by digestive lipases
Biochimica et Biophysica Acta, 2008Co-Authors: Sylvie Fernandez, Jeandavid Rodier, Nicolas Ritter, Bruno Mahler, Frederic Demarne, Frederic Carriere, Vincent JanninAbstract:Abstract Gelucire® 44/14 is a semi-solid self-emulsifying excipient used for the oral delivery of poorly water-soluble drugs. It is composed of C8-C18 acylglycerols and PEG-32 esters, all of which are potential substrates for digestive lipases. Here we studied the lipolysis of Gelucire® 44/14 by porcine pancreatic extracts, human pancreatic juice and several purified digestive lipases. Human pancreatic lipase (HPL), the main lipase involved in the digestion of triacylglycerols, did not show any significant activity on Gelucire® 44/14 or on either of its individual compounds, C8-C18 acylglycerols and PEG-32 esters. Other pancreatic lipases such as human pancreatic lipase-related protein 2 (HPLRP2) showed low activity on Gelucire® 44/14 although the highest activity of HPLRP2 was that observed on the C8-C18 acylglycerol fraction, which accounts for 20% (w/w) of Gelucire® 44/14. In addition, HPLRP2 showed low activities on the PEG-32 esters, whether these were tested individually or mixed together. Carboxyl ester hydrolase (CEH) showed high activity on Gelucire® 44/14, and the highest activities of CEH were those recorded on the total PEG-32 ester fraction and on each individual PEG-32 ester, except for PEG-32 monostearate. The highest activity of all the enzymes tested was that of dog gastric lipase (DGL) on Gelucire® 44/14, although DGL showed low activity on the PEG-32 ester fraction and on each individual PEG-32 ester. We compared the lipolysis of Gelucire® 44/14 with that of Labrasol®, another self-emulsifying excipient, which is liquid at room temperature. Human pancreatic juice showed similar rates of activity on both Gelucire® 44/14 and Labrasol®. This finding means that these excipients are hydrolyzed in vivo during pancreatic digestion, mainly by CEH in the case of Gelucire® 44/14 and by both HPLRP2 and CEH in that of Labrasol®, whereas HPL showed very low activities on each of these two excipients. This is the first time the effects of PEG and acyl chain length on the lipolytic activity of digestive lipases on PEG esters have been investigated.
Nobuhito Shibata - One of the best experts on this subject based on the ideXlab platform.
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Enhancing mechanism of Labrasol on intestinal membrane permeability of the hydrophilic drug gentamicin sulfate
European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V, 2006Co-Authors: Kenjiro Koga, Yoichi Kusawake, Yukako Ito, Nobuyuki Sugioka, Nobuhito Shibata, Kanji TakadaAbstract:The aim of this study was to clarify the mechanism by which caprylocaproyl macrogol-8 glyceride (Labrasol) enhances the intestinal absorption of gentamicin sulfate (GM), a drug that has poor permeability but relatively high solubility. We studied the following characteristics: (i) the phase behavior of Labrasol in aqueous solution, (ii) the affinity of GM to Labrasol micelles, and (iii) the interaction between Labrasol and membrane lipids. We measured the critical micelle concentration of Labrasol in aqueous solution to be approximately 0.01%. The average diameters of Labrasol micelles in 2% and 25% solutions were approximately 10 nm and 20 nm, respectively, indicating that micelles increase in size with increasing Labrasol concentration. Although GM dissolved in 5% Labrasol solution was dialyzable, GM dissolved in either 25% or 50% Labrasol solutions was not, suggesting that GM exists in the hydrophilic region of the Labrasol micelle or in the high affinity region of the micelle surface where GM is retained. In membrane permeability experiments and electrophysiological studies conducted with rat ileum, only 25% Labrasol solution enhanced GM permeability, but did not remarkably affect membrane resistance. Furthermore, Labrasol increased membrane lipid fluidity as determined by fluorescence anisotropy in porcine intestinal brush border membrane liposomes. These results suggest that high concentrations of Labrasol solution enhance membrane permeability of GM via a transcellular rather than a paracellular route. We propose the following mechanism: Labrasol micelles grow when the concentration of Labrasol exceeds 20%, at which point GM shows high affinity for the hydrophilic region of the micelles. Since Labrasol micelles increase membrane lipid fluidity, the membrane permeability of GM is concomitantly enhanced.
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research paper enhancing mechanism of Labrasol on intestinal membrane permeability of the hydrophilic drug gentamicin sulfate
2006Co-Authors: Kenjiro Koga, Yoichi Kusawake, Yukako Ito, Nobuyuki Sugioka, Nobuhito Shibata, Kanji TakadaAbstract:The aim of this study was to clarify the mechanism by which caprylocaproyl macrogol-8 glyceride (Labrasol) enhances the intestinal absorption of gentamicin sulfate (GM), a drug that has poor permeability but relatively high solubility. We studied the following characteristics: (i) the phase behavior of Labrasol in aqueous solution, (ii) the affinity of GM to Labrasol micelles, and (iii) the interaction between Labrasol and membrane lipids. We measured the critical micelle concentration of Labrasol in aqueous solution to be approximately 0.01%. The average diameters of Labrasol micelles in 2% and 25% solutions were approximately 10 nm and 20 nm, respectively, indicating that micelles increase in size with increasing Labrasol concentration. Although GM dissolved in 5% Labrasol solution was dialyzable, GM dissolved in either 25% or 50% Labrasol solutions was not, suggesting that GM exists in the hydrophilic region of the Labrasol micelle or in the high affinity region of the micelle surface where GM is retained. In membrane permeability experiments and electrophysiological studies conducted with rat ileum, only 25% Labrasol solution enhanced GM permeability, but did not remarkably affect membrane resistance. Furthermore, Labrasol increased membrane lipid fluidity as determined by fluorescence anisotropy in porcine intestinal brush border membrane liposomes. These results suggest that high concentrations of Labrasol solution enhance membrane permeability of GM via a transcellular rather than a paracellular route. We propose the following mechanism: Labrasol micelles grow when the concentration of Labrasol exceeds 20%, at which point GM shows high affinity for the hydrophilic region of the micelles. Since Labrasol micelles increase membrane lipid fluidity, the membrane permeability of GM is concomitantly enhanced. � 2006 Elsevier B.V. All rights reserved.
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liquid filled nanoparticles as a drug delivery tool for protein therapeutics
Biomaterials, 2005Co-Authors: Natarajan Venkatesan, Yukako Ito, Nobuhito Shibata, Junichiro Yoshimitsu, Kanji TakadaAbstract:Abstract In the present study, an attempt was made to study the feasibility of nanoparticulate adsorbents in the presence of an absorption enhancer, as a drug delivery tool for the administration of erythropoietin (EPO) to the small intestine. Liquid filled nano- and micro-particles (LFNPS/LFMPS) were prepared using solid adsorbents such as porous silicon dioxide (Sylysia 550), carbon nanotubes (CNTs), carbon nanohorns, fullerene, charcoal and bamboo charcoal. Surfactants such as a saturated polyglycolysed C8–C18 glyceride (Gelucire 44/14), PEG-8 capryl/caprylic acid glycerides (Labrasol) and polyoxyethylene hydrogenated castor oil derivative (HCO-60) were used as an absorption enhancer at 50 mg/kg along with casein/lactoferrin as enzyme inhibitors. The absorption of EPO was studied by measuring serum EPO levels by an ELISA method after small intestinal administration of EPO-LFNPS preparation to rats at the EPO dose level of 100 IU/kg. Among the adsorbents studied, CNTs showed the highest serum EPO level of 62.7±11.6 mIU/ml. In addition, with the use of casein, EPO absorption was improved, C max 143.1±15.2 mIU/ml. Labrasol showed the highest absorption enhancing effect after intra-jejunum administration than Gelucire 44/14 and HCO-60, 25.6±3.2 and 22.2±3.6 mIU/ml, respectively. Jejunum was found to be the best absorption site for the absorption of EPO from LFNPS. The use of CNTs as LFNPS, improved the bioavailability of EPO to 11.5% following intra-small intestinal administration.
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in situ intestinal absorption studies on low molecular weight heparin in rats using Labrasol as absorption enhancer
International Journal of Pharmaceutics, 2004Co-Authors: Y Rama V Prasad, Nobuhito Shibata, Takashi Minamimoto, Yukako Yoshikawa, Saori Mori, Akihiro Matsuura, Kanji TakadaAbstract:Abstract Oral absorption of low molecular weight heparin (LMWH) is limited by its molecular size and negative charge. Development of its oral formulations would allow outpatient treatment with LMWH and decrease the hospital expenses. Studies were aimed at evaluating Labrasol for improving intestinal absorption of LMWH. Formulations containing LMWH and Labrasol were administered to duodenum, jejunum, and ileum of the fasted rats. The doses of LMWH and Labrasol were 200 IU/kg and 50 mg/kg, respectively. Reversibility of absorption enhancing effect of Labrasol was assessed by administering LMWH to jejunum after 0.5 and 1 h of administration of Labrasol. The effect of different doses of Labrasol on LMWH absorption was studied by administering Labrasol at 50, 100, and 200 mg/kg doses. Administration of LMWH formulation to jejunum resulted in the highest plasma anti-Xa activity (0.50±0.03 IU/ml) compared to duodenum (0.19±0.03 IU/ml), and ileum (0.29±0.06 IU/ml) and the anti-Xa levels were maintained above the therapeutic level for about 160 min. The absorption of LMWH was negligible when LMWH was administered at 0.5 and 1 h post-Labrasol administration. Increasing the dose of Labrasol has decreased the absorption of LMWH from jejunum. Labrasol increased the intestinal absorption of LMWH, and jejunum was found to be the best site of absorption. Intestinal membrane permeability changes induced by Labrasol were transient and reversible. Maintaining high drug concentration gradient across intestinal wall is important to obtain increased intestinal LMWH absorption.
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evaluation of oral formulations of gentamicin containing Labrasol in beagle dogs
International Journal of Pharmaceutics, 2003Co-Authors: Y Rama V Prasad, Yoichi Kusawake, Nobuhito Shibata, Yukako Yoshikawa, Riichi Tawa, Makoto Ishida, Sudarat Eaimtrakarn, Kanji TakadaAbstract:Gentamicin (GM) is a polarized water-soluble compound having very poor intestinal membrane permeability resulting in low oral bioavailability. Labrasol was found to improve the intestinal absorption of GM in rats. In the present study, GM formulations containing Labrasol were evaluated in beagle dogs after filling into hydroxypropylmethyl cellulose (HPMC) capsules wrapped with Eudragit L100 (Eud L) and Eudragit S100 (Eud S) films. The results of the in vitro drug release studies could not differentiate between two kinds of enteric capsules and among the three kinds of GM formulations. Oral administration of GM solution at a dose of 50.0 mg per dog of GM and 0.60 ml per dog of Labrasol has resulted in Cmax values of 2.38 +/- 0.50 microg/ml and 2.30 +/- 0.42 microg/ml with Eud L and Eud S capsules, respectively. The AUC values obtained were also higher at 4.35 +/- 1.31 microg h/ml and 5.34 +/- 0.95 microg h/ml with Eud L and Eud S capsules, respectively. Formulation of GM as a suspension in Labrasol has resulted in the decrease of Cmax values by two to four times and AUC values by > 2.5 times compared to the solution formulation. The above results indicate that solution formulation was better over the suspension. An absorbent, synthetic sponge was used to absorb GM solution formulation and encapsulated with Eud L and Eud S capsules. The Cmax and AUC values obtained with sponge formulation were higher than those of suspension formulations but were lower than solution formulations. There was no significant difference in the extent of GM absorption between Eud L and Eud S capsules used for encapsulating GM formulations.
David J Brayden - One of the best experts on this subject based on the ideXlab platform.
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Labrasol is an efficacious intestinal permeation enhancer across rat intestine ex vivo and in vivo rat studies
Journal of Controlled Release, 2019Co-Authors: Fiona Mccartney, Vincent Jannin, Nicolas Ritter, Frederic Demarne, Stephanie Chevrier, Hakime Boulghobra, Delyan R Hristov, Cedric Miolane, Yann Chavant, David J BraydenAbstract:Abstract Labrasol® ALF (Labrasol®), is a non-ionic surfactant excipient primarily used as a solubilising agent. It was investigated here as an intestinal permeation enhancer in isolated rat colonic mucosae in Ussing chamber and in rat in situ intestinal instillations. Labrasol® comprises mono-, di- and triglycerides and mono- and di- fatty acid esters of polyethylene glycol (PEG)-8 and free PEG-8, with caprylic (C8)- and capric acid (C10) as the main fatty acids. Source components of Labrasol® as well as Labrasol® modified with either C8 or C10 as the sole fatty acid components were also tested to determine which element of Labrasol® was responsible for its permeability-enhancing properties. Labrasol® (4, 8 mg/mL) enhanced the transport of the paracellular markers, [14C] mannitol, FITC-dextran 4000, and FITC-insulin across colonic mucosae. The enhancement was non-damaging, transient, and molecular weight-dependent. The PEG ester fraction of Labrasol® also had enhancing properties. When insulin was administered with Labrasol® in instillations, it had a relative bioavailability of 7% in jejunum and 12% in colon. C8– and C10 versions of Labrasol® and the PEG ester fraction also induced similar bioavailability values in jejunal instillations: 6, 5 and 7% respectively. Inhibition of lipases in instillations did not reduce the efficacy of Labrasol®, suggesting that its mechanism as a PE is not simply due to liberated medium chain fatty acids. Labrasol® acts as an efficacious intestinal permeation enhancer and has potential for use in oral formulations of macromolecules and BCS Class III molecules.
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Labrasol and salts of medium chain fatty acids can be combined in low concentrations to increase the permeability of a macromolecule marker across isolated rat intestinal mucosae
Journal of Pharmaceutical Sciences, 2018Co-Authors: Joanne Heade, Sam Maher, Sinead B Bleiel, David J BraydenAbstract:In addition to their solubilizing properties, excipients used in lipid-based formulations can improve intestinal permeability of macromolecules. We determined whether admixing of medium-chain fatty acid (MCFA) permeation enhancers with a lipoidal excipient (Labrasol®) could potentiate transepithelial flux of a poorly permeable macromolecule (fluorescein isothiocyanate dextran 4 kDa [FD4]) across rat intestinal mucosae mounted in Ussing chambers. Low concentrations of sodium caprate (C10), sodium undecylenate (C11:1), or sodium laurate (C12) combined with Labrasol® increased the apparent permeability coefficient (Papp) of FD4 to values typically seen with higher concentrations of MCFAs or Labrasol® alone. For example, combination of C11:1 (0.5 mg/mL) with Labrasol® (1 mg/mL) increased the Papp of FD4 by 10- and 11-fold over the respective individual agents at the same concentrations where no enhancement was evident. The increased enhancement ratios seen with the combinations were associated with some perturbation in intestinal histology and with attenuation of an epithelial functional measure, carbachol-stimulated inward short-circuit current. In conclusion, combining three MCFAs separately with Labrasol® increased the Papp of FD4 to values greater than those seen for MCFAs or Labrasol® alone. Ultimately, this may permit lower concentrations of MCFA to be used in combination with other excipients in oral formulations of poorly permeable molecules.
Frederic Demarne - One of the best experts on this subject based on the ideXlab platform.
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Labrasol is an efficacious intestinal permeation enhancer across rat intestine ex vivo and in vivo rat studies
Journal of Controlled Release, 2019Co-Authors: Fiona Mccartney, Vincent Jannin, Nicolas Ritter, Frederic Demarne, Stephanie Chevrier, Hakime Boulghobra, Delyan R Hristov, Cedric Miolane, Yann Chavant, David J BraydenAbstract:Abstract Labrasol® ALF (Labrasol®), is a non-ionic surfactant excipient primarily used as a solubilising agent. It was investigated here as an intestinal permeation enhancer in isolated rat colonic mucosae in Ussing chamber and in rat in situ intestinal instillations. Labrasol® comprises mono-, di- and triglycerides and mono- and di- fatty acid esters of polyethylene glycol (PEG)-8 and free PEG-8, with caprylic (C8)- and capric acid (C10) as the main fatty acids. Source components of Labrasol® as well as Labrasol® modified with either C8 or C10 as the sole fatty acid components were also tested to determine which element of Labrasol® was responsible for its permeability-enhancing properties. Labrasol® (4, 8 mg/mL) enhanced the transport of the paracellular markers, [14C] mannitol, FITC-dextran 4000, and FITC-insulin across colonic mucosae. The enhancement was non-damaging, transient, and molecular weight-dependent. The PEG ester fraction of Labrasol® also had enhancing properties. When insulin was administered with Labrasol® in instillations, it had a relative bioavailability of 7% in jejunum and 12% in colon. C8– and C10 versions of Labrasol® and the PEG ester fraction also induced similar bioavailability values in jejunal instillations: 6, 5 and 7% respectively. Inhibition of lipases in instillations did not reduce the efficacy of Labrasol®, suggesting that its mechanism as a PE is not simply due to liberated medium chain fatty acids. Labrasol® acts as an efficacious intestinal permeation enhancer and has potential for use in oral formulations of macromolecules and BCS Class III molecules.
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modulation of transepithelial electric resistance teer in reconstructed human epidermis by excipients known to permeate intestinal tight junctions
Experimental Dermatology, 2015Co-Authors: Rawad Abdayem, Vincent Jannin, Frederic Demarne, Sylvie Callejon, Pascal Portes, Plamen Kirilov, Fabrice Pirot, Marek HaftekAbstract:Several excipients are commonly used to enhance the drug absorption through simple epithelia of the digestive tract. They permeate the paracellular barrier constituted by tight junctions (TJs). We compared the effects of two excipients, sodium caprate (C10) and a self-emulsifying excipient Labrasol composed of a mixture of caprylocaproyl polyoxyl-8 glycerides, both applied to emerged reconstructed human epidermis either 'systemically', that is by addition to the culture medium, or topically. During the 'systemic' application, which produced cytoplasmic translocation of occludin and leakage of the biotin marker into the lower stratum corneum, the decrease in the trans-epithelial electrical resistance (TEER) was less abrupt with Labrasol when compared with C10, even though both excipients produced comparable final effects over time. With topical Labrasol, a significant TEER decrease was obtained with 5 times the 'systemic' concentrations. Topical application of C10 also resulted in the loss of the barrier function measured with TEER but had dramatic deleterious effects on the tissue morphology observed with light and electron microscopy. Our study demonstrates the potential value of Labrasol as an enhancer of bioavailability of molecules applied through the transcutaneous route. Our results suggest modulation of the epidermal TJs by both compounds. Even though the C10 action was at least partly due to overall cell damage and despite the fact that the decrease in TEER after topical application was apparently related to the permeabilization of the primary barrier of the stratum corneum in the first place.
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in vitro digestion of the self emulsifying lipid excipient Labrasol by gastrointestinal lipases and influence of its colloidal structure on lipolysis rate
Pharmaceutical Research, 2013Co-Authors: Sylvie Fernandez, Vincent Jannin, Frederic Demarne, Stephanie Chevrier, Yann Chavant, Frederic CarriereAbstract:Purpose Labrasol® is a self-emulsifying excipient used to improve the oral bioavailability of poorly water-soluble drugs. It is a mixture of acylglycerols and PEG esters, these compounds being substrates for digestive lipases. The characterization of Labrasol® gastrointestinal lipolysis is essential for understanding its mode of action.
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in vitro gastrointestinal lipolysis of four formulations of piroxicam and cinnarizine with the self emulsifying excipients Labrasol and gelucire 44 14
Pharmaceutical Research, 2009Co-Authors: Sylvie Fernandez, Nicolas Ritter, Bruno Mahler, Frederic Demarne, Frederic Carriere, Stephanie Chevrier, Vincent JanninAbstract:Purpose Labrasol® and Gelucire® 44/14 are defined admixtures of acylglycerols and PEG esters which are substrates for digestive lipases.
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lipolysis of the semi solid self emulsifying excipient gelucire 44 14 by digestive lipases
Biochimica et Biophysica Acta, 2008Co-Authors: Sylvie Fernandez, Jeandavid Rodier, Nicolas Ritter, Bruno Mahler, Frederic Demarne, Frederic Carriere, Vincent JanninAbstract:Abstract Gelucire® 44/14 is a semi-solid self-emulsifying excipient used for the oral delivery of poorly water-soluble drugs. It is composed of C8-C18 acylglycerols and PEG-32 esters, all of which are potential substrates for digestive lipases. Here we studied the lipolysis of Gelucire® 44/14 by porcine pancreatic extracts, human pancreatic juice and several purified digestive lipases. Human pancreatic lipase (HPL), the main lipase involved in the digestion of triacylglycerols, did not show any significant activity on Gelucire® 44/14 or on either of its individual compounds, C8-C18 acylglycerols and PEG-32 esters. Other pancreatic lipases such as human pancreatic lipase-related protein 2 (HPLRP2) showed low activity on Gelucire® 44/14 although the highest activity of HPLRP2 was that observed on the C8-C18 acylglycerol fraction, which accounts for 20% (w/w) of Gelucire® 44/14. In addition, HPLRP2 showed low activities on the PEG-32 esters, whether these were tested individually or mixed together. Carboxyl ester hydrolase (CEH) showed high activity on Gelucire® 44/14, and the highest activities of CEH were those recorded on the total PEG-32 ester fraction and on each individual PEG-32 ester, except for PEG-32 monostearate. The highest activity of all the enzymes tested was that of dog gastric lipase (DGL) on Gelucire® 44/14, although DGL showed low activity on the PEG-32 ester fraction and on each individual PEG-32 ester. We compared the lipolysis of Gelucire® 44/14 with that of Labrasol®, another self-emulsifying excipient, which is liquid at room temperature. Human pancreatic juice showed similar rates of activity on both Gelucire® 44/14 and Labrasol®. This finding means that these excipients are hydrolyzed in vivo during pancreatic digestion, mainly by CEH in the case of Gelucire® 44/14 and by both HPLRP2 and CEH in that of Labrasol®, whereas HPL showed very low activities on each of these two excipients. This is the first time the effects of PEG and acyl chain length on the lipolytic activity of digestive lipases on PEG esters have been investigated.
