Comparative study on digestive lipase activities on the self emulsifying excipient Labrasol®, medium chain glycerides and PEG esters

Fernandez, Sylvie; Jannin, Vincent; Rodier, Jean-David; Ritter, Nicolas; Mahler, Bruno; Carrière, Frédéric

doi:10.1016/j.bbalip.2007.02.009

Cited by 105 publications

(96 citation statements)

References 45 publications

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“…When required, the final concentration of NaTDC was varied from 0 to 10 mM. When activities were assayed at pH values below 8.0, back titration experiments were performed following the protocol described by Fernandez et al (12).…”

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confidence: 99%

A Monoacylglycerol Lipase from Mycobacterium smegmatis Involved in Bacterial Cell Interaction

et al. 2010

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MSMEG_0220 from Mycobacterium smegmatis, the ortholog of the Rv0183 gene from M. tuberculosis, recently identified and characterized as encoding a monoacylglycerol lipase, was cloned and expressed in Escherichia coli. The recombinant protein (rMSMEG_0220), which exhibits 68% amino acid sequence identity with Rv0183, showed the same substrate specificity and similar patterns of pH-dependent activity and stability as the M. tuberculosis enzyme. rMSMEG_0220 was found to hydrolyze long-chain monoacylglycerol with a specific activity of 143 ؎ 6 U mg ؊1 . Like Rv0183 in M. tuberculosis, MSMEG_0220 was found to be located in the cell wall. To assess the in vivo role of the homologous proteins, an MSMEG_0220 disrupted mutant of M. smegmatis (Ms⌬0220) was produced. An intriguing change in the colony morphology and in the cell interaction, which were partly restored in the complemented mutant containing either an active (ComMs⌬0220) or an inactive (ComMs⌬0220S111A) enzyme, was observed. Growth studies performed in media supplemented with monoolein showed that the ability of both Ms⌬0220 and ComMs⌬0220S111A to grow in the presence of this lipid was impaired. Moreover, studies of the antimicrobial susceptibility of the Ms⌬0220 strain showed that this mutant is more sensitive to rifampin and more resistant to isoniazid than the wild-type strain, pointing to a critical structural role of this enzyme in mycobacterial physiology, in addition to its function in the hydrolysis of exogenous lipids.Tuberculosis, which is caused by Mycobacterium tuberculosis, is a major public health issue worldwide. Because of the emergence of multidrug-resistant (MDR) and extensively drug-resistant (XDR) strains and the high incidence of HIV and tuberculosis coinfection (16), it is becoming increasingly difficult to combat the spread of this disease, and the global health burden of tuberculosis is extremely heavy. The reasons for the persistence of the tubercle bacillus include not only its ability to enter into a state of dormancy in its host for decades, evading the immune system by forming structures called granulomas (17), but also its unique and complex cell wall composed of specific lipids (8). These characteristics are thought to be good focus points for drug development. In granulomas, during the nonreplicative stage, the bacteria have been found to accumulate lipids in the form of intracellular lipid inclusion bodies (LIBs) (13). These lipids are composed mainly of triacylglycerols (TAG) (9, 13) and may originate from the lipolysis of host lipids and/or fatty acid uptake. In fact, M. tuberculosis in the granuloma center can even accumulate lipids originating from the degradation of immune cells (20). In addition, it has been reported that M. tuberculosis internalized by foamy macrophages accumulated LIBs when it joined cell lipid droplets composed of neutral lipids (32). Lipid storage may provide the bacillus with energy via the ␤-oxidation pathway followed by the glyoxylate cycle, during the chronic phase and the reactivation step (3, 17...

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A Monoacylglycerol Lipase from Mycobacterium smegmatis Involved in Bacterial Cell Interaction

et al. 2010

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“…PPE were used as a model of human pancreatic juice. Indeed, we previously showed that human pancreatic juice and porcine pancreatic extracts presented similar lipolytic activities on both Labrasol ® and Gelucire ® 44/14 (Fernandez et al, 2007;Fernandez et al, 2008), although their enzyme compositions are slightly different. Moreover, the volume of pancreatic enzyme solution added was adapted to obtain a 1.7-fold dilution of the gastric phase which corresponds to the dilution of the chyme by biliary and pancreatic secretions that occurs in vivo (Carriere et al, 2000).…”

Section: Methodsmentioning

confidence: 99%

“…Thanks to the gastric emptying, the lipolysis continues in the duodenum where the chyme is mixed with bile and pancreatic juice which contains several lipolytic enzymes able to hydrolyze various natural substrates such as triacylglycerols, phospholipids, galactolipids, and vitamin esters (De Caro et al, 2004;Eydoux et al, 2007). We have already shown that in vitro, Labrasol ® and Gelucire ® 44/14 were hydrolyzed by several digestive lipases (Fernandez et al, 2007;Fernandez et al, 2008). These findings suppose that in vivo, these excipients are hydrolyzed by digestive lipases and their lipolytic products might play an important role in the transport of the drug from the formulation to the mixed micelles and/or the unstirred water layer next to the enterocytes.…”

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Gastrointestinal lipolysis of lipid-based excipients intended for the oral drug delivery of poorly water-soluble drugs

Fernandez¹,

Carrière²,

Jannin³

2010

OCL

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Labrasol ® and Gelucire ® 44/14 are lipid-based excipients used for the oral drug delivery of poorly water-soluble drugs. These macrogolglycerides are composed of acylglycerols and PEG esters, potential substrates of digestive lipases. We developed an in vitro method to simulate the gastrointestinal lipolysis of these excipients and to evaluate the impact of lipolysis in vivo. At the end of the gastric phase, the composition of both excipients was significantly modified underlining the importance of gastric lipolysis in vivo. We also studied the influence of excipients' lipolysis on the solubilization of a poorly water-soluble drug, cinnarizine, in aqueous phase. Gastrointestinal lipolysis of Labrasol ® was a prerequisite to maintain cinnarizine in aqueous solution, whereas the lipolysis of Gelucire ® 44/14 did not affect the cinnarizine solubilization.

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“…It has been recommended to increase the pH of the lipolysis medium after the actual lipolysis experiment to values above the pK a of the fatty acids (e.g. to pH 9) to titrate all the fatty acids liberated during in vitro lipolysis which might have been obscured at lower pH (67).…”

Section: In Vitro Lipolysismentioning

confidence: 99%

Characterising Lipid Lipolysis and Its Implication in Lipid-Based Formulation Development

Thomas

Holm

Rades

2012

AAPS J

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Abstract. Facing the increasing number of poorly water-soluble drugs, pharmaceutical scientists are required to break new grounds for the delivery of these pharmaceutically problematic drugs. Lipid-based drug delivery systems (LBDDS) have received increased interest as a novel drug delivery platform during the last decades and several successfully marketed products have shown the potential for LBDDS. However, there exists a discrepancy between the clear need for innovative delivery forms and their rational design. In the case of LBDDS, this can be attributed to the complexity of LBDDS after administration. Unlike conventional formulations, LBDDS are susceptible to digestion in the gastrointestinal tract, the interplay of delivery system, drug and physiology ultimately effecting drug disposition. In vitro lipolysis has become an important technique to mimic the enzymatic degradation. For the better understanding of how LBDDS promote drug delivery, in vitro lipolysis requires advanced characterisation methods. In this review, the physiological background of lipid digestion is followed by a thorough summary of the techniques that are currently used to characterise in vitro lipolysis. It would be desirable that the increasing knowledge about LBDDS will foster their rationale development thereby increasing their broader application.KEY WORDS: in vitro digestion; in vitro lipolysis models; lipid-based drug delivery systems; poorly soluble drugs; self-nanoemulsifying drug delivery systems (SNEDDS).

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Comparative study on digestive lipase activities on the self emulsifying excipient Labrasol®, medium chain glycerides and PEG esters

Cited by 105 publications

References 45 publications

A Monoacylglycerol Lipase from Mycobacterium smegmatis Involved in Bacterial Cell Interaction

A Monoacylglycerol Lipase from Mycobacterium smegmatis Involved in Bacterial Cell Interaction

Gastrointestinal lipolysis of lipid-based excipients intended for the oral drug delivery of poorly water-soluble drugs

Characterising Lipid Lipolysis and Its Implication in Lipid-Based Formulation Development

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