Department of Sustainable Biomaterials, Virginia Tech, Blacksburg, VA 24061, USA.
Carbohydr Polym. 2013 Feb 15;92(2):1443-50. doi: 10.1016/j.carbpol.2012.10.051. Epub 2012 Oct 29.
Structurally varied, carboxyl-containing cellulose derivatives were evaluated for their ability to form amorphous solid dispersions (ASD) with ellagic acid (EA), in order to improve the solubility of this high-melting, poorly bioavailable, but highly bioactive natural flavonoid compound. ASDs of EA with carboxymethylcellulose acetate butyrate (CMCAB), cellulose acetate adipate propionate (CAAdP), and hydroxypropylmethylcellulose acetate succinate (HPMCAS) were prepared, and EA dissolution from these ASDs was compared with that from pure crystalline EA and from EA/poly(vinylpyrrolidinone) (PVP) solid dispersions (SD). Polymer/drug mixtures were characterized by powder X-ray diffraction (XRPD), modulated differential scanning calorimetry (MDSC), nuclear magnetic resonance (NMR) and Fourier transform infrared spectroscopy (FT-IR). The XRPD and FT-IR results indicated that EA was amorphous in solid dispersions with EA concentration up to 25 wt%. The stability against crystallization and solution concentrations of EA from these solid dispersions were significantly higher than those observed for physical mixtures and pure crystalline EA. HPMCAS stabilized EA most effectively, among the polymers tested, against both chemical degradation and recrystallization. The relative ability to solubilize EA from ASDs at pH 6.8 was PVP>>HPMCAS>>CMCAB. EA dissolves from ASD in PVP quickly and completely (maximum 92%) at pH 6.8, but EA is also released from PVP at pH 1.2, and then crystallizes rapidly. Therefore PVP is not a practical candidate for EA ASD. In contrast, the cellulose derivative ASDs show very slow EA release at pH 1.2 (<4%) and faster but still incomplete drug release at pH 6.8 (maximum 35% for HPMCAS SD). The pH-triggered drug release from HPMCAS ASD makes HPMCAS a practical choice for EA solubility enhancement.
结构多样、含羧基的纤维素衍生物被评估为与鞣花酸（EA）形成无定形固体分散体（ASD）的能力，以提高这种高熔点、生物利用度差但具有高度生物活性的天然类黄酮化合物的溶解度。制备了 EA 与羧甲基纤维素醋酸丁酸酯（CMCAB）、醋酸纤维素己二酸丙酯（CAAdP）和羟丙基甲基纤维素醋酸琥珀酸酯（HPMCAS）的 ASD，并比较了这些 ASD 中 EA 的溶解情况与纯结晶 EA 和 EA/聚乙烯吡咯烷酮（PVP）固体分散体（SD）中的溶解情况。聚合物/药物混合物通过粉末 X 射线衍射（XRPD）、调制差示扫描量热法（MDSC）、核磁共振（NMR）和傅里叶变换红外光谱（FT-IR）进行了表征。XRPD 和 FT-IR 结果表明，在 EA 浓度高达 25wt%的固体分散体中，EA 为无定形。与物理混合物和纯结晶 EA 相比，这些固体分散体中 EA 的结晶稳定性和溶液浓度显著提高。在所测试的聚合物中，HPMCAS 最有效地稳定 EA，防止其化学降解和重结晶。在 pH 6.8 下从 ASD 中溶解 EA 的相对能力为 PVP>HPMCAS>CMCAB。在 pH 6.8 下，PVP 能快速、完全地（最高 92%）从 ASD 中溶解 EA，但在 pH 1.2 下，EA 也从 PVP 中释放出来，然后迅速结晶。因此，PVP 不是 EA ASD 的实际候选物。相比之下，纤维素衍生物 ASD 在 pH 1.2 下释放 EA 的速度非常慢（<4%），在 pH 6.8 下药物释放速度较快但仍不完全（HPMCAS SD 最高 35%）。HPMCAS ASD 中的 pH 触发药物释放使得 HPMCAS 成为提高 EA 溶解度的实用选择。
