Lipolysis of the semi-solid self-emulsifying excipient Gelucire® 44/14 by digestive lipases

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

doi:10.1016/j.bbalip.2008.05.006

Cited by 80 publications

(84 citation statements)

References 48 publications

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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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confidence: 99%

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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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Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

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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“…Specific activities were expressed as U per mg of pure enzyme. Table 1 presents the specific activities of four lipases on Gelucire ® 44/14 and its components: acylglycerol fraction and PEG fraction [7]. Human Pancreatic Lipase (HPL), the main lipase involved in the digestion of dietary triacylglycerols, does not show any significant activity on Gelucire ® 44/14 (2 ± 2 U/mg) nor on either of its fractions.…”

Section: Lipolysismentioning

confidence: 99%

“…It is composed of a defined admixture of C8-C18 mono-, di-and triacylglycerols (20% w/w), PEG-32 mono-and diesters and free PEG-32 (80% w/w). The main fatty acid present is lauric acid which accounts for 45% on average of the total fatty acids [5][6][7]. Gelucire ® 44/14 has been widely used and characterized during the last five years in order to increase the solubility and bioavailability of many drugs: carbamazepine [8], glibenclamide [9], antiviral agent PG301026 [10], piroxicam [11,12], propranolol [13,14], flurbiprofen [15], aceclofenac [16], carvedilol [17], griseofulvin [18], spironolactone [19], and cinnarizine [11].…”

Section: Introductionmentioning

confidence: 99%

Lauroyl polyoxylglycerides, functionalized coconut oil, enhancing the bioavailability of poorly soluble active substances

Jannin¹

2009

OCL

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Gelucire ® 44/14, a lauroyl polyoxylglycerides obtained by polyglycolysis of hydrogenated coconut oil with PEG-32, is used to increase the oral bioavailability of poorly-water soluble drugs. It is a solid dispersion composed of a PEG ester fraction under a lamellar phase of 120 Å with a helical conformation and an acylglycerol fraction under a hexagonal packing. This excipient spontaneously evolves to its most stable phase of 120 Å after storage at 25°C for 21 hours leading to physically stable formulations. Gelucire ® 44/14 is a hydrophilic system that hydrates and swells in contact with water and forms cubic mesophases before complete erosion/emulsification. It is also lipolyzed by various enzymes such as gastric lipase or carboxyl ester hydrolase. After an in vitro gastrointestinal lipolysis simulation, the main components remaining are mono and diesters of PEG-32. These amphiphilic metabolites can explain the beneficial role of Gelucire ® 44/14 on the solubility of poorly-water soluble drugs such as cinnarizine even after partial lipolysis of the lipid-based system. Finally that excipient can also increase the bioavailability of active substances by interacting with enterocyte-based proteins like P-glycoprotein or cytochromes P450.

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“…The increase only accounted for ionized liberated FFAs, titrated at pH 6.5 (21,22). FFAs are known to have a higher apparent pK a in micellar solutions than a typical carboxylic acid in water (e.g., acetic acid, pK a 4.75) and are therefore not fully deprotonated at pH 6.5 (21,(25)(26)(27). Thus, in order to quantify all liberated FFAs, it was necessary to perform a backtitration to pH 9 at the end of the lipolysis assay, as explained in previous publications, to also detect the FFAs that are unionized at pH 6.5 (10,11,(21)(22)(23)(24)).…”

Section: In Vitro Lipolysis: Effect Of Varying Pancreatin Levelsmentioning

confidence: 99%

Toward the Establishment of Standardized In Vitro Tests for Lipid-Based Formulations, Part 6: Effects of Varying Pancreatin and Calcium Levels

Sassene

Kleberg

Williams³

et al. 2014

AAPS J

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Abstract. The impact of pancreatin and calcium addition on a wide array of lipid-based formulations (LBFs) during in vitro lipolysis, with regard to digestion rates and distribution of the model drug danazol, was investigated. Pancreatin primarily affected the extent of digestion, leaving drug distribution somewhat unaffected. Calcium only affected the extent of digestion slightly but had a major influence on drug distribution, with more drug precipitating at higher calcium levels. This is likely to be caused by a combination of removal of lipolysis products from solution by the formation of calcium soaps and calcium precipitating with bile acids, events known to reduce the solubilizing capacity of LBFs dispersed in biorelevant media. Further, during the digestion of hydrophilic LBFs, like IIIA-LC, the un-ionizedionized ratio of free fatty acids (FFA) remained unchanged at physiological calcium levels. This makes the titration curves at pH 6.5 representable for digestion. However, caution should be taken when interpreting lipolysis curves of lipophilic LBFs, like I-LC, at pH 6.5, at physiological levels of calcium (1.4 mM); un-ionized-ionized ratio of FFA might change during digestion, rendering the lipolysis curve at pH 6.5 non-representable for the total digestion. The ratio of un-ionized-ionized FFAs can be maintained during digestion by applying non-physiological levels of calcium, resulting in a modified drug distribution with increased drug precipitation. However, as the main objective of the in vitro digestion model is to evaluate drug distribution, which is believed to have an impact on bioavailability in vivo, a physiological level (1.4 mM) of calcium is preferred.

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Lipolysis of the semi-solid self-emulsifying excipient Gelucire® 44/14 by digestive lipases

Cited by 80 publications

References 48 publications

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

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

Lauroyl polyoxylglycerides, functionalized coconut oil, enhancing the bioavailability of poorly soluble active substances

Toward the Establishment of Standardized In Vitro Tests for Lipid-Based Formulations, Part 6: Effects of Varying Pancreatin and Calcium Levels

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