title: In vitro digestion of the self-emulsifying lipid excipient Labrasol(®) by gastrointestinal lipases and influence of its colloidal structure on lipolysis rate.
abstract: OBJECTIVE
  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.
authors: CNRS - Aix-Marseille Université - Enzymologie Interfaciale et Physiologie de la Lipolyse, UMR 7282, 31 chemin Joseph Aiguier, 13402, Marseille cedex 20, France.
authors: Sylvie
authors: S
authors: Fernandez
authors: Vincent
authors: V
authors: Jannin
authors: Stéphanie
authors: S
authors: Chevrier
authors: Yann
authors: Y
authors: Chavant
authors: Frédéric
authors: F
authors: Demarne
authors: Frédéric
authors: F
authors: Carrière
mesh_terms: D000818:Animals; D002417:Cattle; D003102:Colloids / Q000737:chemistry / Q000378:metabolism*; D004285:Dogs; D004655:Emulsions / Q000737:chemistry / Q000378:metabolism*; D005079:Excipients / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D008049:Lipase / Q000378:metabolism*; D008055:Lipids / Q000737:chemistry; D008066:Lipolysis; D010179:Pancreas / Q000201:enzymology; D011994:Recombinant Proteins / Q000378:metabolism; D013552:Swine
chemical_list: D003102:Colloids; D004655:Emulsions; D005079:Excipients; D008055:Lipids; D011994:Recombinant Proteins; D008049:Lipase; C075988:pancreatic lipase related protein 2
references: J Pharm Biomed Anal. 2001 Jun;25(3-4):651-61
references: 11377046
references: Int J Pharm. 2009 Jun 5;374(1-2):66-72
references: 19446761
references: Scand J Gastroenterol. 1993 May;28(5):443-54
references: 8511506
references: J Pharm Pharmacol. 2006 Jun;58(6):809-20
references: 16734982
references: Pharm Res. 2009 Aug;26(8):1901-10
references: 19452130
references: J Pharm Sci. 2008 Feb;97(2):995-1012
references: 18064698
references: J Pharm Sci. 2012 Sep;101(9):3360-80
references: 22644939
references: Int J Pharm. 2003 Jan 2;250(1):181-90
references: 12480284
references: Colloids Surf B Biointerfaces. 2012 Dec 1;100:50-61
references: 22766282
references: Drug Dev Ind Pharm. 2012 May;38(5):587-96
references: 21988221
references: Pharm Res. 2007 Apr;24(4):748-57
references: 17372700
references: J Biol Chem. 2002 Jan 18;277(3):2266-74
references: 11689574
references: J Drug Target. 2002 May;10(3):255-60
references: 12075827
references: Biomed Pharmacother. 2004 Apr;58(3):173-82
references: 15082340
references: Eur J Pharm Sci. 2007 Jun;31(2):85-94
references: 17418543
references: Drug Dev Ind Pharm. 2010 Jun;36(6):735-45
references: 20136493
references: Biochim Biophys Acta. 1965 Jul 29;105(1):121-36
references: 5849108
references: Pharm Res. 2007 Oct;24(10):1844-53
references: 17458683
references: Gastroenterology. 1993 Sep;105(3):876-88
references: 8359655
references: Anal Biochem. 1976 May 7;72:248-54
references: 942051
references: Am J Physiol Gastrointest Liver Physiol. 2001 Jul;281(1):G16-28
references: 11408251
references: J Biotechnol. 2008 Feb 1;133(3):343-50
references: 18068847
references: J Pharm Sci. 2004 May;93(5):1110-21
references: 15067688
references: Comp Biochem Physiol B Biochem Mol Biol. 2008 May;150(1):1-9
references: 18328758
references: J Microencapsul. 2012;29(4):323-30
references: 22233141
references: Biochim Biophys Acta. 2007 May;1771(5):633-40
references: 17418634
references: Eur J Pharm Biopharm. 2008 Oct;70(2):439-44
references: 18603415
references: Food Funct. 2012 May;3(5):537-46
references: 22349893
references: Drug Dev Ind Pharm. 2011 Dec;37(12):1415-21
references: 21623688
references: Int J Pharm. 2005 Jul 25;298(2):328-32
references: 15979260
references: J Pharm Pharmacol. 2004 Mar;56(3):307-16
references: 15025855
references: Cancer Chemother Pharmacol. 2011 May;67(5):995-1006
references: 20623225
references: Life Sci. 2001 Nov 2;69(24):2899-910
references: 11720093
references: J Pharm Pharmacol. 2010 Feb;62(2):173-80
references: 20487196
references: Nat Rev Drug Discov. 2007 Mar;6(3):231-48
references: 17330072
references: Eur J Pharm Biopharm. 2009 Aug;72(3):539-45
references: 19298857
references: J Pharm Pharmacol. 2002 Jan;54(1):29-41
references: 11833493
references: Int J Pharm. 2004 Mar 1;271(1-2):225-32
references: 15129989
references: Eur J Pharm Sci. 2003 Sep;20(1):91-7
references: 13678797
references: Mol Pharm. 2012 Nov 5;9(11):3286-300
references: 23030411
references: Ther Deliv. 2012 Jan;3(1):105-24
references: 22833936
references: Biochim Biophys Acta. 2009 Oct;1791(10):983-90
references: 19447192
references: Biochim Biophys Acta. 2008 Aug;1781(8):367-75
references: 18571509
references: Gastroenterology. 2000 Oct;119(4):949-60
references: 11040182
references: Gastroenterology. 1992 May;102(5):1535-45
references: 1568562
references: Eur J Pharm Sci. 2000 Oct;11 Suppl 2:S93-8
references: 11033431
references: Eur J Pharm Sci. 2006 Nov;29(3-4):278-87
references: 16815001
references: Pharm Res. 1992 Jan;9(1):87-93
references: 1589415
references: Anal Biochem. 2008 Dec 15;383(2):289-95
references: 18814836
references: Int J Pharm. 2012 May 10;427(2):452-9
references: 22387278
references: J Pharm Sci. 1997 Mar;86(3):269-82
references: 9050793
references: J Lipid Res. 2007 Jul;48(7):1539-49
references: 17401110
references: Biochemistry. 2006 Jan 24;45(3):993-1001
references: 16411775
references: Int J Pharm. 2002 Mar 20;235(1-2):247-65
references: 11879759
references: Biochim Biophys Acta. 1986 Dec 5;879(3):419-23
references: 3778930
references: Biol Pharm Bull. 2011;34(8):1179-86
references: 21804203
references: Eur J Biochem. 1991 Nov 15;202(1):75-83
references: 1935982