(68a) Emulsion Function in a Simulated Gastric Environment. A Quantitative Study of Digestion Kinetics and Intestinal Permeability Enhancement

The oral route is the most preferred method of administration of drugs. Unfortunately, this route is not possible for 50% of currently marketed drug compounds due to their low solubility in water and low oral bioavailability. Lipid-based drug delivery systems are commonly studied for the enhancement of oral bioavailability of hydrophobic drugs. However, these systems are not being commonly utilized commercially, partially due to the lack of guidance for formulation and lack of knowledge of how these systems function to enhance bioavailability [1, 2]. Self-emulsifying drug delivery systems (SEDDS) are oil-in-water emulsions, typically consisting of oil and one or more surfactants, that spontaneously emulsify under the gentle mixing conditions in the gastrointestinal environment. These systems, in particular, have shown great promise for enhancing oral bioavailability of low-solubility compounds as well as offering the advantages of minimal processing and inherent stability.

To gain a greater understanding of the dependence of emulsion function in the gastrointestinal (GI) tract on formulation design, a quantitative study of processes central to emulsion function, digestion and intestinal permeability enhancement, was undertaken. A broad range of formulations was studied: Oils from three different structural classes (long chain triglyceride (Soybean oil), medium chain trigylcerides (Neobee M5), and propylene glycol dicaprylate/dicaprate (Captex 200)) and surfactants varying in hydrophilic-lipophilic balance (HLB) value from 10-15 (Cremophor EL, Tween 80, a mixture of Capmul MCM and Labrasol) were combined at three different ratios. Naproxen was included to test the influence of drug on emulsion properties. The dependence of emulsion formation and emulsion characteristics on physicochemical emulsion formulation properties was investigated. An HLB value of 10 or higher was required for spontaneous emulsification; emulsions formed had particle sizes ranging from 60-500 nm. MTT assay results showed that only oil-surfactant mixtures that did not spontaneously form emulsions were toxic. Changes in transcellular permeability were assessed by measuring drug transport across epithelial layers, and epithelial tight junction integrity was assessed by measuring transepithelial electric resistance. Formulations composed of high levels of high HLB surfactant (Tween 80) significantly reduced epithelial tight junction integrity. Digestion kinetics were studied by monitoring the change in particle size and by quantitative analysis of digestion products by HPLC upon exposure of emulsions to digestive enzymes. Ultimately, the relation of emulsion formulation physical and chemical properties to relative kinetics of processes occurring in the GI tract (permeation enhancement, digestion, drug release) will be utilized to aid in rational design of emulsions and fulfillment of the tremendous potential of this technology for oral bioavailablility enhancement.

References

[1] Neslihan Gursoy, et al. Biomedicine Pharmacotherapy, 58; 173 (2004).

[2] Charman, William N., et al. Journal of Pharmaceutical Sciences,89; 967 (2000).