Abstract
A novel supersaturable self-emulsifying drug delivery system (S-SEDDS) of cyclosporine A (CyA)—a poorly water-soluble immunosuppressant—was constructed in order to attain an apparent concentration–time profile comparable to that of conventional SEDDS with reduced use of oil, surfactant, and cosolvent. Several hydrophilic polymers, including polyvinylpyrrolidone (PVP), were employed as precipitation inhibitors in the conventional SEDDS, which consists of corn oil-mono-di-triglycerides, polyoxyl 40 hydrogenated castor oil, ethanol, and propylene glycol. PVP-incorporated pre-concentrate (CyA:vehicle ingredients:PVP = 1:4.5:0.3 w/v/w) spontaneously formed spherical droplets less than 120 nm within 7 min of being diluted with water. In an in vitro dialysis test in a biorelevant medium such as simulated fed and/or fasted state intestinal and/or gastric fluids, PVP-based S-SEDDS exhibited a higher apparent drug concentration profile compared to cellulose derivative-incorporated S-SEDDS, even displaying an equivalent concentration profile with that of conventional SEDDS prepared with two times more vehicle (CyA:vehicle ingredients = 1:9 w/v). The supersaturable formulation was physicochemically stable under an accelerated condition (40 °C/75% RH) over 6 months. Therefore, the novel formulation is expected to be a substitute for conventional SEDDS, offering a supersaturated state of the poorly water-soluble calcinurin inhibitor with a reduced use of vehicle ingredients.
Highlights
Cyclosporine A (CyA) is a potent cyclic polypeptide which has been prescribed to prevent organ rejection in cases of allogeneic liver, heart, and kidney transplantation [1,2]
To increase intestinal absorption while lessening the pharmacokinetic variations of the immunosuppressant, the manufacturer formulated a self-emulsifying drug delivery system (SEDDS), which mainly consists of oil, surfactant
transmission electron microscope (TEM) observation revealed that all SEDDS and
Summary
Cyclosporine A (CyA) is a potent cyclic polypeptide which has been prescribed to prevent organ rejection in cases of allogeneic liver, heart, and kidney transplantation [1,2]. The bioavailability (BA) of the calcinurin inhibitor following oral administration is low and variable, owing to its low solubility (6.6 μg/mL in water at 37 ◦ C) in the gastrointestinal (GI) tract and pre-systemic metabolism [3,4]. 40 hydrogenated castor oil), and cosolvent (ethanol and propylene glycol) [5]. The pre-concentrate forms oil-in-water droplets upon contact with gastric fluids, placing the hydrophobic compound in a fine droplet in an aqueous environment, with no precipitation. This leads to a more profound dissolution profile, providing a large interfacial area for drug diffusion [6,7].
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