Evaluation of the Impact of Surfactant Digestion on the Bioavailability of Danazol after Oral Administration of Lipidic Self-Emulsifying Formulations to Dogs

Cuiné, Jean; McEvoy, Claire Louise; Charman, William N.; Pouton, Colin W.; Edwards, Glenn A.; Benameur, Hassan; Porter, Christopher John

doi:10.1002/jps.21246

Cited by 159 publications

(132 citation statements)

References 39 publications

(51 reference statements)

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“…In recent years, in vitro lipolysis model for lipid digestion have been increasingly used as tools to assist in the design of self-emulsifying lipid-based formulations to enhance the oral bioavailability of poorly water-soluble drugs (16)(17)(18). During in vitro lipolysis studies, the data generated from the pH-stat can be used to quantify the rate and extent of lipolysis, and more importantly, the products of lipolysis can be examined after completion of the reaction, to determine the fate of the drug; whether it is solubilized or precipitated (12).…”

Section: Dynamic In Vitro Lipolysis Test For Lipid Digestionmentioning

confidence: 99%

Design of Lipid-Based Formulations for Oral Administration of Poorly Water-Soluble Drug Fenofibrate: Effects of Digestion

Kazi

2012

AAPS PharmSciTech

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Abstract. Lipid-based drug carriers are likely to have influence on bioavailability through enhanced solubilization of the drug in the gastrointestinal tract. The study was designed to investigate the lipid formulation digestibility in the simulated gastro intestinal media. Fenofibrate was formulated in representative Type II, IIIA, IIIB and IV selfemulsifying/microemulsifying lipid delivery systems (SEDDS and SMEDDS designed for oral administration) using various medium-chain glyceride components, non-ionic surfactants and cosolvents as excipients. Soybean oil was used only as an example of long-chain triglycerides to compare the effects of formulation with their counterparts. The formulations were subjected to in vitro digestion specifically to predict the fate of the drug in the gastro intestinal tract after exposure of the formulation to pancreatic enzymes and bile. In vitro digestion experiments were carried out using a pH-stat maintained at pH 7.5 for 30 min using intestinal fluids simulating the fed and fasted states. The digestion rate was faster and almost completed in Type II and IIIA systems. Most of the surfactants used in the studies are digestible. However, the high concentration of surfactant and/or cosolvent used in Type IIIB or IV systems lowered the rate of digestion. The digestion of medium-chain triglycerides was faster than long-chain triglycerides, but kept comparatively less drug in the post digestion products. Medium-chain mixed glycerides are good solvents for fenofibrate as rapidly digested but to improve fenofibrate concentration in post digestion products the use of long-chain mixed glycerides are suggested for further investigations.KEY WORDS: fenofibrate; in vitro lipolysis; lipid formulation classification system; self-emulsifying/ microemulsifying drug delivery systems (SEDDS, SMEDDS).

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Section: Dynamic In Vitro Lipolysis Test For Lipid Digestionmentioning

confidence: 99%

Design of Lipid-Based Formulations for Oral Administration of Poorly Water-Soluble Drug Fenofibrate: Effects of Digestion

Kazi

2012

AAPS PharmSciTech

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“…It is assumed that the drug solubilised in the aqueous phase is the fraction available for absorption, whereas precipitated drug has been considered undesirable since the solid drug requires a dissolution step potentially reducing bioavailability (2,57).…”

Section: Methods For the Characterisation Of The Drugmentioning

confidence: 99%

“…In order to compensate for this 'background lipolysis', blank experiments are carried out that involve the 'digestion' of pure (i.e. formulation free) lipolysis medium and subsequent subtraction of the recorded NaOH volumes from the formulation-containing lipolysis experiments (55,57).…”

Section: In Vitro Lipolysismentioning

confidence: 99%

“…While the concentration of bile is similar (5-30 mM) throughout the employed lipolysis models, some groups utilise pure taurocholic acid (51,52,71) or taurodeoxycholic acid (57,58,72), whereas others employ a crude (porcine) bile extract (47,73,56). The utilisation of pure bile acids renders the composition of the lipolysis medium more reproducible compared with the more variable crude extract, but lacks the complex composition of human bile (63).…”

Section: In Vitro Lipolysismentioning

confidence: 99%

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Characterising Lipid Lipolysis and Its Implication in Lipid-Based Formulation Development

Thomas

Holm

Rades

2012

AAPS J

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Abstract. Facing the increasing number of poorly water-soluble drugs, pharmaceutical scientists are required to break new grounds for the delivery of these pharmaceutically problematic drugs. Lipid-based drug delivery systems (LBDDS) have received increased interest as a novel drug delivery platform during the last decades and several successfully marketed products have shown the potential for LBDDS. However, there exists a discrepancy between the clear need for innovative delivery forms and their rational design. In the case of LBDDS, this can be attributed to the complexity of LBDDS after administration. Unlike conventional formulations, LBDDS are susceptible to digestion in the gastrointestinal tract, the interplay of delivery system, drug and physiology ultimately effecting drug disposition. In vitro lipolysis has become an important technique to mimic the enzymatic degradation. For the better understanding of how LBDDS promote drug delivery, in vitro lipolysis requires advanced characterisation methods. In this review, the physiological background of lipid digestion is followed by a thorough summary of the techniques that are currently used to characterise in vitro lipolysis. It would be desirable that the increasing knowledge about LBDDS will foster their rationale development thereby increasing their broader application.KEY WORDS: in vitro digestion; in vitro lipolysis models; lipid-based drug delivery systems; poorly soluble drugs; self-nanoemulsifying drug delivery systems (SNEDDS).

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“…No fast initial lipolysis was observed, and the extent of lipolysis was very limited (approximately 0.028 mmol FFA was titrated at standard conditions). No triacylglyceride (TAG) is present in this formulation, and the only digestible excipient is Cremophor EL, which during digestion only released 0.36 mmol per gram of surfactant (28). Thus, the presence of additional pancreatin had negligible effect on lipolysis rate especially at activity levels 150 to 600 USPU/ml.…”

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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Evaluation of the Impact of Surfactant Digestion on the Bioavailability of Danazol after Oral Administration of Lipidic Self-Emulsifying Formulations to Dogs

Cited by 159 publications

References 39 publications

Design of Lipid-Based Formulations for Oral Administration of Poorly Water-Soluble Drug Fenofibrate: Effects of Digestion

Design of Lipid-Based Formulations for Oral Administration of Poorly Water-Soluble Drug Fenofibrate: Effects of Digestion

Characterising Lipid Lipolysis and Its Implication in Lipid-Based Formulation Development

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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