Stabilized Carriers of Erlotinib Amorphous Solid Dispersions
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摘要: 固体分散体（SDs）作为提高难溶性药物溶出度的主要技术之一，其能保持长期物理稳定性的关键是选择合适的载体。采用溶剂挥发法，选用六种聚合物为载体，制备厄洛替尼（ERL）SDs。通过Flory-Huggins相互作用参数χ与反溶剂显微观察评估了聚合物与ERL的相容性及对ERL结晶的影响，聚焦光束反射测量仪（FBRM）在线分析聚合物对结晶的过程调控作用机制。对不同比例SDs的固态性质进行表征，并测定了加速稳定性试验样品的无定型状态。结果表明，优选出的羟丙甲基纤维素能长期保持SDs中药物的无定型态，三种方法联合应用有助于快速选择最适载体。Abstract: Solid dispersions (SDs) is one of the main technologies to improve the dissolution of poorly soluble drugs in drug research and development. However, supersaturated high-energy amorphous state drug in SDs are often associated with a tendency to recrystallized during long term storage. The carrier of SDs plays a key role in maintaining the amorphous state of the drug. Traditionally, the screening of the carrier in the development process is a time-consuming process. The effect of polymer carriers on the long-term physical stability of the amorphous state of Erlotinib (ERL) in SDs were studied. ERL SDs were prepared with different ratios of HPMC, HPMCAS, PVP, PVP/VA, Eudragit, and Soluplus by solvent evaporation method. Through the Flory-Huggins interaction parameter χ and anti-solvent microscopic observations, the compatibility of the polymer with ERL and polymer's influence on the crystallization of ERL were predicted. Focused Beam Reflectance Measurement (FBRM) system was used to analyzed morphologically the regulating effect of the polymer on the crystallization process. Then the amorphous state formed by different proportions of SDs were characterized by Powder X-Ray Diffraction (PXRD), Differential Scanning Calorimetry (DSC) and Fourier Transform Infrared Spectroscopy(FT-IR). The physical stability of amorphous state of SDs in accelerated test condition were determined by PXRD. The results showed that HPMC is a suitable carrier for the preparation of ERL amorphous SDs. The combination of the interaction parameter χ, anti-solvent microscopic observation and FBRM analysis is an effective way to select suitable carrier for amorphous SDs. A full understanding of the impact of polymers on amorphous SDs is of positive significance for the rapid development of poorly soluble drugs.
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Key words:
- Erlotinib /
- Solid dispersions /
- Carrier /
- Stability /
- HPMC
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图 1 不同聚合物溶液中析出ERL晶体的显微照片（×100）
Figure 1. Microscope images (100×) of ERL in water without or with different polymers
图 2 ERL峰面积对浓度线性回归的标准曲线
Figure 2. Standard curve of linear regression between peak area and concentration
图 3 ERL在水中和聚合物溶液中粒子弦长随时间的变化曲线图
Figure 3. The variation curve of chord length of ERL microparticles in water and polymer aqueous solution
图 5 不同质量比例ERL固体分散体的DSC图 (a) ERL:聚合物=1:1; (b) ERL:聚合物=1:3.
Figure 5. DSC patterns of ERL SDs at different ratio (w/w) (a) ERL:Polymers=1:1; (b) ERL:Polymers=1:3.
图 6 ERL-HPMC固体分散体红外光谱图(a) 4000~2000 cm−1和 (b) 2000~1000 cm−1.
Figure 6. FT-IR spectra of ERL-HPMC SDs (a) from 4000 to 2000 cm−1 and (b) 2000 to 1000 cm−1.
图 7 ERL固体分散体在pH 6.8的PBS中的溶出曲线（n=6）
Figure 7. Dissolution profiles of ERL SDs in pH 6.8 phosphates buffer (n=6)
图 8 ERL固体分散体稳定性试验典型PXRD图 (a) ERL-Soluplus; (b) ERL-羟丙甲基纤维素.
Figure 8. Typical PXRD patterns of ERL SDs stability test. (a) ERL- Soluplus; (b) ERL-HPMC.
表 1 熔点降低法计算Flory-Huggins相互作用参数(χ)
Table 1. The Flory-Huggins interaction parameter (χ) calculated by melting point depression method
ERL-Polymer χ ERL-Eud −0.175 ERL-HPMCAS −0.249 ERL-K30 −0.756 ERL-S630 −0.853 ERL-Soluplus −0.921 ERL-HPMC −1.072 
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表 2 室温下ERL在聚合物溶液中的溶解度（n=3）
Table 2. The solubility of ERL in polymer solutions at room temperature (n=3)
Solubility/(μg·mL−1) Standard deviation Water 0.36 0.03 HPMCAS 0.55 0.05 Eud 0.43 0.04 HPMC 0.48 0.04 S630 0.56 0.03 K30 0.53 0.07 Soluplus 21.76 0.18
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表 3 加速稳定性试验样品中ERL的状态
Table 3. State of ERL in accelerated stability test sample
ERL:Polymer Time(mon) Eud HPMCAS K30 S630 Soluplus HPMC 3:1 1 C C A C C A 2 C C C C C C 3 C C C C C C 6 C C C C C C 1:1 1 C A A A C A 2 C A A A C A 3 C A A A C A 6 C A C C C A 1:3 1 A A A A A A 2 A A A A C A 3 A A A A C A 6 A A A A C A *C: crystal; A: Amorphous
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