Increasing the Proportional Content of Surfactant (Cremophor EL) Relative to Lipid in Self-emulsifying Lipid-based Formulations of Danazol Reduces Oral Bioavailability in Beagle Dogs

Cuiné, Jean; Charman, William N.; Pouton, Colin W.; Edwards, Glenn A.; Porter, Christopher John

doi:10.1007/s11095-006-9194-z

Cited by 139 publications

(148 citation statements)

References 47 publications

(33 reference statements)

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“…In this study, the medium-chain lipids were mostly used except only soybean oil, which was explored as an example of the long-chain lipid to compare their performance under the same experimental conditions. Sample obtained from each of the separated phases was analysed for drug content by HPLC as described previously (24).…”

Section: Analysis Of Post Lipolysis Productsmentioning

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: Analysis Of Post Lipolysis Productsmentioning

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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“…Cremophor EL has been successfully used in several SMEDDSs as a surfactant because it has an excellent solubilizing capacity for poorly water-soluble drugs, and high self-microemulsifying efficiency. 1,3,8) Cremophor EL was therefore used as the surfactant, and determined the feasibility (by phase diagram) and characterization of the SMEDDS. Transcutol P provided higher drug solubility than polyethylene glycol-400 (PEG-400).…”

Section: Resultsmentioning

confidence: 99%

“…7) A correlation between the solubilization behavior of the formulation during in vitro lipolysis and oral bioavailability was noted. 8) In vitro lipolysis may therefore be an appropriate indicator of performance, and models of in vitro lipid digestion have recently been developed to assist in the design of lipid-based formulations. 7,9,10) Based on these findings, solubilization capacity under a digestion condition was established as a valuable response instead of in situ intestinal absorption in this study.…”

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confidence: 99%

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An Improved Formulation Screening and Optimization Method Applied to the Development of a Self-Microemulsifying Drug Delivery System

Liu

Chen

Zhang

et al. 2010

CHEMICAL & PHARMACEUTICAL BULLETIN

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This study focused on the development of an improved formulation screening and optimization method for a self-microemulsifying drug delivery system (SMEDDS). Solubility study and construction of a ternary phase diagram were carried out to determine the primary formulation components. Experimental design combined with a desirability study was employed to obtain the optimal formulation composition. The obtained bufalin SMEDDS formulation was Maisine 35-1 and Miglyol 812N (1 : 1, w/w) of 29.5%, Cremophor EL of 39.5%, and Transcutol P of 30.5%. It showed desired properties with droplet size of 33.9 nm; polydispersity index of 0.126; equilibrium solubility of 12.6 mg/ml, and 73.6% of soluble drug post-digestion. A rapid release of up to 21% occurred in the first 10 min. A bufalin SMEDDS was well absorbed at all intestinal segments. The absorption of bufalin from a SMEDDS was 2.38-fold higher than that of bufalin suspension in terms of relative bioavailability. The studies on solubility and ternary phase diagrams combined with experimental design may offer a valuable and efficient strategy for developing and optimizing a SMEDDS to obtain optimal formulations with desired characteristics.Key words self-microemulsifying drug delivery system; bufalin; in vitro digestion; in situ intestinal absorption Chem.

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“…Furthermore, amounts and proportions of these components are critical for SEDDS formulations stability and performance. Lipid composition and/or amount of surfactants may inversely affect the drug solubilization and in vivo performance (15,22).…”

Section: Introductionmentioning

confidence: 99%

Nonlinear Absorption Kinetics of Self-Emulsifying Drug Delivery Systems (SEDDS) Containing Tocotrienols as Lipophilic Molecules: In Vivo and In Vitro Studies

Alqahtani

Alayoubi

Nazzal

et al. 2013

AAPS J

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Abstract. Self-emulsifying drug delivery systems (SEDDS) have been broadly used to promote the oral absorption of poorly water-soluble drugs. The purpose of the current study was to evaluate the in vivo oral bioavailability of vitamin E isoforms, δ-tocotrienol (δ-T3) and γ-tocotrienol (γ-T3) administered as SEDDS, as compared to commercially available UNIQUE E® Tocotrienols capsules. Results from studies in rats showed that low dose treatment with δ-T3 (90%) and γ-T3 (10%) formulated SEDDS showed bioavailability of 31.5% and 332%, respectively. However, bioavailability showed a progressive decrease with increased treatment dose that displayed nonlinear absorption kinetics. Additional in vitro studies examining cellular uptake studies in Caco 2 cells revealed that the SEDDS formulation increased passive permeability of δ-T3 and γ-T3 by threefold as compared to the commercial capsule formulation. These studies also showed that free surfactants decreased δ-T3 and γ-T3 absorption. Specifically, combined treatment cremophor EL or labrasol with tocotrienols caused a 60-85% reduction in the cellular uptake of δ-T3 and γ-T3 and these effects appear to result from surfactant-induced inhibition of the δ-T3 and γ-T3 transport protein Niemann-Pick C1-like 1 (NPC1L1). In summary, results showed that SEDDS formulation significantly increases the absorption and bioavailability δ-T3 and γ-T3. However, this effect is self-limiting because treatment with increasing doses of SEDDS appears to be associated with a corresponding increase in free surfactants levels that directly and negatively impact tocotrienol transport protein function and results in nonlinear absorption kinetics and a progressive decrease in δ-T3 and γ-T3 absorption and bioavailability.

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Increasing the Proportional Content of Surfactant (Cremophor EL) Relative to Lipid in Self-emulsifying Lipid-based Formulations of Danazol Reduces Oral Bioavailability in Beagle Dogs

Cited by 139 publications

References 47 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

An Improved Formulation Screening and Optimization Method Applied to the Development of a Self-Microemulsifying Drug Delivery System

Nonlinear Absorption Kinetics of Self-Emulsifying Drug Delivery Systems (SEDDS) Containing Tocotrienols as Lipophilic Molecules: In Vivo and In Vitro Studies

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