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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.

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. [ABSTRACT FROM AUTHOR]

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. [Copyright &y& Elsevier]