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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

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ABSTRACT

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.

Methods

Labrasol® lipolysis was investigated using either individual enzymes (gastric lipase, pancreatic lipase-related protein 2, pancreatic carboxyl ester hydrolase) or a combination of enzymes under in vitro conditions mimicking first the gastric phase of lipolysis and second the duodenal one. Specific methods for quantifying lipolysis products were established in order to determine which compounds in Labrasol® were preferentially hydrolyzed.

Results

Gastric lipase showed a preference for di- and triacylglycerols and the main acylglycerols remaining after gastric lipolysis were monoacylglycerols. PEG-8 diesters were also hydrolyzed to a large extent by gastric lipase. Most of the compounds initially present in Labrasol® were found to be totally hydrolyzed after the duodenal phase of lipolysis. The rate of Labrasol® hydrolysis by individual lipases was found to vary significantly with the dilution of the excipient in water and the resulting colloidal structures (translucent dispersion; opaque emulsion; transparent microemulsion), each lipase displaying a distinct pattern depending on the particle size.

Conclusions

The lipases with distinct substrate specificities used in this study were found to be sensitive probes of phase transitions occurring upon Labrasol® dilution. In addition to their use for developing in vitro digestion models, these enzymes are interesting tools for the characterization of self-emulsifying lipid-based formulations.

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Abbreviations

BSA:

Bovine serum albumin

CEH:

Carboxylester hydrolase

CMC:

Critical micellar concentration

DAG:

Diacylglycerol

FFA:

Free fatty acid

HPJ:

Human pancreatic juice

HPL:

Human pancreatic lipase

MAG:

Monoacylglycerol

NaTDC:

Sodium taurodeoxycholate

PCS:

Photon correlation spectroscopy

PPE:

Porcine pancreatic extracts

PPL:

porcine pancreatic lipase

PSD:

Particle size distribution

rDGL:

Recombinant dog gastric lipase

rHPLRP2:

Recombinant human pancreatic lipase-related protein 2

SEDDS:

Self Emulsifying Drug Delivery Systems

SMEDDS:

Self MicroEmulsifying Drug Delivery Systems

SNEDDS:

Self NanoEmulsifying Drug Delivery Systems

TAG:

Triacylglycerol

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ACKNOWLEDGMENTS AND DISCLOSURES

We are grateful to Dr. Sawsan Amara for her help with the production and purification of rHPLRP2. Sylvie Fernandez’s PhD research was supported by a CIFRE contract from Association Nationale de la Recherche Technique (ANRT, France). Sylvie Fernandez, Vincent Jannin, Stéphanie Chevrier, Yann Chavant and Frédéric Demarne were all employed by Gattefossé SAS manufacturing and selling Labrasol® at the time this study was performed.

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  1. CNRS - Aix-Marseille Université - Enzymologie Interfaciale et Physiologie de la Lipolyse, UMR 7282, 31 chemin Joseph Aiguier, 13402, Marseille cedex 20, France

    Sylvie Fernandez & Frédéric Carrière

  2. Gattefossé SAS, 36 chemin de Genas, 69804, Saint-Priest, France

    Sylvie Fernandez, Vincent Jannin, Stéphanie Chevrier, Yann Chavant & Frédéric Demarne

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  1. Sylvie Fernandez
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  2. Vincent Jannin
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  3. Stéphanie Chevrier
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  4. Yann Chavant
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  5. Frédéric Demarne
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  6. Frédéric Carrière
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Correspondence to Frédéric Carrière.

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Fernandez, S., Jannin, V., Chevrier, S. et al. In Vitro Digestion of the Self-Emulsifying Lipid Excipient Labrasol® by Gastrointestinal Lipases and Influence of its Colloidal Structure on Lipolysis Rate. Pharm Res 30, 3077–3087 (2013). https://doi.org/10.1007/s11095-013-1053-0

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