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Comparison of solubility enhancement by solid dispersion and micronized butein and its correlation with in vivo study

Journal of Pharmaceutical Investigation 2021년 51권 1호 p.53 ~ 60
김남아, 오희경, 이재철, 최영희, 정성훈,
소속 상세정보
김남아 ( Kim Nam-Ah ) - Dongguk University College of Pharmacy
오희경 ( Oh Hee-Kyung ) - Dongguk University College of Pharmacy
이재철 ( Lee Jae-Chul ) - Dongguk University College of Pharmacy
최영희 ( Choi Young-Hee ) - Dongguk University College of Pharmacy
정성훈 ( Jeong Seong-Hoon ) - Dongguk University College of Pharmacy

Abstract


Purpose: Even though butein can be a promising candidate for anti-inflammatory and anti-diabetic activities, it is poorly soluble limiting its availability for product development. Size reduction and solid dispersion (SD) were adopted independently to evaluate their feasibility for enhancement in solubility as well as bioavailability.

Methods: To reduce the particle size, milling method was carried out under dry and wet conditions. For solid dispersion preparation, simple solvent evaporation method was used with hydrophilic excipients including PVP K-30 and Poloxamer 407. Physicochemical properties such as crystallinity, size, and kinetic solubility of prepared formulations were assessed using dynamic light scattering, X-ray powder diffraction, differential scanning calorimetry, and solubility. In vivo pharmacokinetic study was also conducted with selected samples.

Results: Butein is weakly basic with its pKa 6.76 and log P 3.81 based on the Henderson-Hasselbalch equation. High temperature and basic pH were degradative stresses as significant color change in solution. Milling decreased the size distribution down to 4.2 μm without dramatic change in the solubility. However, the solubility of solid dispersion increased from 3.15 up to 114.57 μg/mL, suggesting amorphous state increased solubility significantly. Its amorphous state was confirmed by DSC and PXRD. In addition, oral absorption of SD in vivo confirmed its enhanced pharmacokinetic parameters; faster Tmax, higher Cmax and AUC.

Conclusions: Solid dispersion exhibited enhancement in pharmacokinetic parameters compared to size reduction, suggesting its feasibility for solid dispersion formulation.

키워드

Butein; Milling; Solid dispersion; Amorphous; Solubility; Absorption

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