Lipid-Based Delivery Systems for Improving the Bioavailability and Lymphatic Transport of a Poorly Water-Soluble LTB4 Inhibitor

Abstract

Ontazolast is a potent inhibitor (IC50 = 1 nm) of calcium ionophore A23187-stimulated leukotriene B4 (LTB4) biosynthesis in human peripheral blood leukocytes. The compound is practically insoluble in water (0.14 microgram/mL) and previous studies in animals have demonstrated extensive presystemic drug clearance through hepatic first-pass metabolism. Bioavailability of a suspension formulation in rats was less than 1%, but increased to approximately 9% when administered as a 20% soybean oil-in-water emulsion. The emulsion formulation and three additional lipid-based formulations were administered by gavage to conscious, minimally restrained rats in a novel, double-cannulated model to determine the effects of formulation on systemic blood absorption and mesenteric lymph transport of ontazolast. The bioavailability of ontazolast was significantly and substantially enhanced by all of the lipid-based formulations. While these formulations also significantly increased the amount of ontazolast transported by the lymph, the total amounts transported were insufficient to account for the improvement in bioavailability, which may be due to the elimination or reduction of the barriers of poor aqueous solubility and slow dissolution to absorption of ontazolast from the gastrointestinal tract, or the effects of lipid on the gastrointestinal membrane permeability, transit time, or metabolism of ontazolast. Semisolid SEDDS formulations, composed of Peceol and Gelucire 44/14, produced bioavailability similar to the emulsion formulation. The total amount of ontazolast transported by the lymph varied directly with the amount of concurrent triglyceride transport and appeared to be favored by formulations that prolong gastric emptying time or promote rapid absorption of ontazolast from the gastrointestinal tract.

Novel gastroretentive sustained-release tablet of tacrolimus based on self-microemulsifying mixture: in vitro evaluation and in vivo bioavailability test

“…The higher bioavailability of hydrophobic drugs incorporated in a SMEDDS has been reported elsewhere [35][36][37] . The contribution of the GRDF approach extended the length of the absorption phase in comparison with the non-gastroretentive dosage form.…”

Commentary: Liquid-filled Formulations

“…For this type of formulation, high surfactant levels in the formulation are required to achieve a microemulsion state as the formulation comes into contact with the GI fluids. Thus, it is possible that this type of formulation may reduce the positive food effect since high levels of surfactant are already present in the drug product and the bile acid effect on micelle formation may become less significant [11][12]. The design of SEEDS and SNEEDS systems are more complex than the co-solvent or lipid-based systems previously discussed.Special attention needs to be paid to choice of surfactant as this will govern the propensity for emulsification and the particle size of the emulsion droplets formed.…”

Untitled

“…[5] A variety of mechanisms is believed to be involved in the improvement of the bioavailability of hydrophobic drugs by lipid based formulations. Inhibition of P-glycoprotein-mediated drug efflux, [6] promotion of lymphatic transport, which delivers the drug directly to the systemic circulation while avoiding hepatic firstpass metabolism [7][8][9] and increasing gastrointestinal (GI) membrane permeability [10] are some of the important mechanisms of bioavailability enhancement. In addition to these mechanisms, an important advantage of SEDDS is the availability of prodigious surface area of the oil globules.…”