Abstract
Hot-melt extrusion (HME) has great advantages for the preparation of solid dispersion (SD), for instance, it does not require any organic solvents. Nevertheless, its application to high-melting-point and thermosensitive drugs has been rarely reported. In this study, thermally unstable curcumin (Cur) was used as a drug model. The HME process was systematically studied by adjusting the gradient temperature mode and residence time, with the content, crystallinity and dissolution of Cur as the investigated factors. The effects of barrel temperature, screw speed and cooling rate on HME were also examined. Solubility parameters and the Flory–Huggins method were used to evaluate the miscibility between Cur and carriers. Differential scanning calorimetry, X-ray diffraction, Fourier transform infrared spectroscopy, equilibrium solubility and in vitro and in vivo experiments were used to characterize and evaluate the results. An amorphous Cur SD was successfully obtained, increasing the solubility and release of Cur. In the optimal process, the mass ratio of Cur to Eudragit® E PO (EPO) was 1:4 and the barrel temperature was set at a gradient heating mode (130 °C–135 °C–140 °C–145 °C–150 °C–155 °C–160 °C) at 100 rpm. Related pharmacokinetic test results also showed the improved bioavailability of the drug in rats. In a pharmacodynamic analysis of Sprague–Dawley rats, the Cmax and the bioavailability of the Cur-EPO SD were 2.6 and 1.5 times higher than those of Cur, respectively. The preparation of the amorphous SD not only provided more solubility but also improved the bioavailability of Cur, which provides an effective way to improve the bioavailability of BCS II drugs.
Highlights
Curcumin (Cur) is a natural polyphenol, isolated from Curcuma longa, with a wide range of pharmacological effects, such as anti-inflammatory, anti-oxidant, anti-cancer and anti-microbial effects [1,2], and it has produced relatively low levels of adverse reactions during clinical applications [3,4]
The dissolution rate and bioavailability were significantly improved compared to the raw drug
Knowledge of the the thermodynamic properties of drugs is essential for the preparation of Solid dispersion (SD) through Hot-melt extrusion (HME) [30]
Summary
Curcumin (Cur) is a natural polyphenol, isolated from Curcuma longa, with a wide range of pharmacological effects, such as anti-inflammatory, anti-oxidant, anti-cancer and anti-microbial effects [1,2], and it has produced relatively low levels of adverse reactions during clinical applications [3,4]. Cur is a thermosensitive compound that degrades without reaching its melting point (Tm). Its therapeutic efficacy is limited because of its poor solubility [5]. Several methods, such as the preparation of liposomes and nanoparticles [6,7] and self-microemulsion, have been used to increase the solubility and dissolution rate of insoluble drugs [8,9,10,11]. Solid dispersion (SD) can efficiently increase the dissolution rate and solubility of insoluble drugs by changing the size and dispersion within the carrier. Solvent evaporation has been applied to prepare thermosensitive Cur SDs [5,14,15,16]
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