In vitro gastrointestinal lipolysis of four formulations of piroxicam and cinnarizine with the self emulsifying excipients Labrasol and Gelucire 44/14.
OBJECTIVE
Labrasol and Gelucire 44/14 are defined admixtures of acylglycerols and PEG esters which are substrates for digestive lipases.


METHODS
We investigated their in vitro gastrointestinal lipolysis to understand which compounds are, after digestion, responsible for keeping poorly water-soluble drugs in solution. The precipitation of piroxicam and cinnarizine formulated in these excipients during the gastrointestinal lipolysis was also studied.


RESULTS
Monoacylglycerols and PEG monoesters are the largest compounds present at the end of gastric phase whereas PEG-monoesters are the largest compounds after the duodenal phase. The precipitation of piroxicam is mainly due to the gastric lipolysis. In the control experiments performed without digestive lipases, cinnarizine formulated in Labrasol was found to precipitate upon dilution of the gastric medium to form the solution mimicking the duodenal medium. In the presence of gastric lipase, Labrasol was hydrolyzed and the precipitation of cinnarizine was not observed in this case. When the cinnarizine was formulated with Gelucire 44/14 the precipitation was only due to the dilution of the gastric medium.


CONCLUSIONS
Our study highlights the importance of the gastrointestinal lipolysis and the associated phenomena such as the dilution of chyme by biliary and pancreatic secretions in vivo, on the solubilisation of poorly water-soluble drugs formulated with lipid-based excipients.
Fernandez
Sylvie
S
Laboratoire d'Enzymologie Interfaciale et de Physiologie de la Lipolyse, CNRS UPR 9025, 31 chemin Joseph Aiguier, 13402, Marseille cedex 20, France.
Chevrier
Stéphanie
S
Ritter
Nicolas
N
Mahler
Bruno
B
Demarne
Frédéric
F
Carrière
Frédéric
F
Jannin
Vincent
V
D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry / Q000378:metabolism*; D002936:Cinnarizine / Q000737:chemistry / Q000378:metabolism*; D005079:Excipients / Q000737:chemistry*; D041981:Gastrointestinal Tract / Q000378:metabolism*; D005989:Glycerides; D006634:Histamine H1 Antagonists / Q000737:chemistry / Q000378:metabolism*; D066298:In Vitro Techniques; D008066:Lipolysis; D009930:Organic Chemicals / Q000737:chemistry; D010894:Piroxicam / Q000737:chemistry / Q000378:metabolism*; D011092:Polyethylene Glycols / Q000737:chemistry*; D012995:Solubility
D000894:Anti-Inflammatory Agents, Non-Steroidal; D005079:Excipients; D005989:Glycerides; D006634:Histamine H1 Antagonists; D009930:Organic Chemicals; C440220:Labrasol; C104509:gelucire 44-14; D010894:Piroxicam; D002936:Cinnarizine; D011092:Polyethylene Glycols