3',4'-二甲氧基黄酮醇-3-O-β-D-吡喃葡萄糖苷一水合物的多晶型和渗透性

doi:10.5246/jcps.2022.08.053

摘要/Abstract

摘要：

3',4'-二甲氧基黄酮醇-3-O-β-D-吡喃葡萄糖苷一水合物(GDH)可以显著降低血脂、主动脉粥样硬化病变和肝损伤, 但其口服生物利用度较差。本研究的目的是制备和表征GDH多晶型(II、III、IV、V和VI)和GDH的无定型态(GDH-AM)。通过扫描电子显微镜(SEM)、差示扫描量热法(DSC)、热重分析(TGA)、X射线粉末衍射(XRPD)和傅里叶变换红外光谱(FTIR)对GDH多晶型和GDH-AM进行了表征, 随后进行了溶出试验、物理稳定性、多晶型转化和渗透性研究。结果表明, 与GDH-I相比, GDH-II和GDH-IV溶出达到了更高的浓度, GDH-AM表现出明显的高溶解速率和长时间的过饱和状态。GDH-I和GDH-AM在储存3个月后没有发现相变, 而GDH-II、GDH-III、GDH-IV、GDH-V和GDH-VI则很容易转化为GDH-I。单向肠灌注实验表明, GDH在高浓度表现出低渗透性。十二烷基硫酸钠和牛胆盐作为有潜力的吸收促进剂用来改善GDH的渗透性, 可用于GDH剂型的进一步开发。

关键词: 多晶型, 无定形, 溶解度, 稳定性, 渗透性

Abstract:

3',4'-Dimethoxy-flavonol-3-O-β-D-glucopyranoside monohydrate (GDH), which can significantly reduce blood lipids, atherosclerotic aortic lesions, and liver injury, has poor oral bioavailability. In the present study, we aimed to prepare and characterize five new polymorphs of GDH (II, III, IV, V, and VI) and the amorphous form of GDH (GDH-AM). The GDH polymorphs and GDH-AM were characterized by scanning electron microscopy (SEM), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), X-ray powder diffraction (XRPD), and Fourier transform infrared spectroscopy (FTIR). Dissolution tests, physical stability, polymorphic transformation, and permeability studies were subsequently investigated. Dissolution of GDH-II and GDH-IV reached higher concentrations compared with GDH-I. GDH-AM exhibited a significantly high dissolution rate and prolonged supersaturation during dissolution. No phase transition was found for GDH-I and GDH-AM after 3 months of storage, while GDH-II, GDH-III, GDH-IV, GDH-V, and GDH-VI were readily converted to GDH-I. In situ single-pass intestinal perfusion experiments showed that the high concentration of GDH exhibited low permeability. Sodium dodecyl sulfate and bovine bile salts were used as absorption enhancers to improve the permeability of GDH. The results showed that sodium dodecyl sulfate and taurocholate were good absorption enhancers for further formulation development of GDH.

Key words: Polymorph, Amorphous, Solubility, Stability, Permeability

Supporting:

周锋, 孙丹玲, 王一茹, 张莹, 邓月义. 3',4'-二甲氧基黄酮醇-3-O-β-D-吡喃葡萄糖苷一水合物的多晶型和渗透性[J]. 中国药学(英文版), 2022, 31(8): 634-645.

Feng Zhou, Danling Sun, Yiru Wang, Ying Zhang, Yueyi Deng. Polymorphs and permeability of 3',4'-dimethoxy flavonol-3-O-β-D-glucopyranoside monohydrate[J]. Journal of Chinese Pharmaceutical Sciences, 2022, 31(8): 634-645.

图/表 11

Figure 1. Chemical structure of GDH.

Figure 2. SEM graphs of (a) GDH-I, (b) GDH-II, (c) GDH-III, (d) GDH-IV, (e) GDH-AM, (f) GDH-V, and (g) GDH-VI.

Figure 3. XRPD patterns for GDH polymorphs (I, II, III, IV, V, VI, and AM).

Figure 4. DSC thermograms of GDH polymorphs (I, II, III, IV, V, VI, and AM).

Figure 5. TGA curves of GDH polymorphs (I, II, III, IV, V, VI, and AM).

Figure 6. FT-IR spectra of GDH polymorphs (I, II, III, IV, V, VI, and AM).

Figure 7. Solubility of GDH polymorphs (I, II, III, IV, V, VI, and AM).

Figure 8. In vitro dissolution Curves of GDH polymorphs (I, II, III, IV, V, VI, and AM).

Figure 9. XRPD patterns of GDH (I, II, III, IV, V, VI, and AM) stored at 25 °C/2% RH for 3 months.

Figure 10. Effect of different concentrations on Peff of GDH. *P < 0.01 versus 100 μg/mL GDH solution. Average ± SD; n = 4.

Figure 11. Effect of small intestinal molecular promoting absorbent on Peff. The error barsrepresent the SD for each substance (*P < 0.01 compared with 100 μg/mL GDH solution).

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