Drug Dynamics Institute, The University of Texas at Austin, Austin, TX, USA.
Drug Dev Ind Pharm. 2012 Feb;38(2):180-9. doi: 10.3109/03639045.2011.595415. Epub 2011 Jul 21.
The development of amorphous solid dispersions containing poorly soluble drug substances has been well-documented; however, little attention has been given to the development of the finished dosage form. The objective of this study was to investigate the use of Ceolus(™) microcrystalline cellulose, a highly compressible excipient, for the production of rapidly disintegrating tablets containing a hydrophilic solid dispersion of a poorly soluble drug, indomethacin. Solid dispersions of indomethacin and Kollidon(®) VA64 were prepared by hot melt extrusion and characterized for amorphous nature. Milled dispersion particles at 500 mg/g drug loading were shown to be amorphous by differential scanning calorimetry and provided rapid dissolution in sink conditions. Physical characterization of the milled extrudate showed that the particle size of the intermediate was comparable with Ceolus(™) PH-102 and larger than the high compressibility grades of microcrystalline cellulose selected for the trial (Ceolus(™) KG-802, Ceolus(™) UF-711). Preliminary tableting trials showed that dissolution performance was significantly reduced for formulations at dispersion loadings in excess of 50%. Using a mixture design of experiments (DOE), the levels of PH-102, KG-802, UF-711, and PH-301 were optimized. Trials revealed a synergistic relationship between conventional grades (PH-102 and PH-301) and highly compressible grades (KG-802 and UF-711) leading to improved compression characteristics and more rapid dissolution rates. The formulation and resulting compressibility were also shown to have an impact on in vitro supersaturation indicating tablet formulation could impact oral bioavailability. Through the use of highly compressible microcrystalline cellulose grades such as Ceolus(™) KG-802 and UF-711, it may be possible to maximize the bioavailability benefit of amorphous solid dispersions administered as tablet dosage forms.
含有难溶性药物的无定形固体分散体的开发已有大量文献记载；然而，对于成品剂型的开发却关注甚少。本研究旨在考察高度可压缩赋形剂 Celox(™)微晶纤维素在制备含有亲水性难溶性药物吲哚美辛的速崩片方面的应用。通过热熔挤出法制备吲哚美辛和 Kollidon(®) VA64 的固体分散体，并对其无定形性质进行了表征。在 500mg/g 药物载药量下研磨的分散体颗粒通过差示扫描量热法显示为无定形，在溶出度测定条件下能迅速溶解。研磨挤出物的物理特性表明，中间产物的粒径与 Celox(™) PH-102 相当，大于所选用于试验的高可压缩微晶纤维素的等级（Celox(™) KG-802、Celox(™) UF-711）。初步压片试验表明，当分散体载药量超过 50%时，溶出性能显著降低。采用实验设计（DOE）的混合物设计，优化了 PH-102、KG-802、UF-711 和 PH-301 的水平。试验结果表明，常规等级（PH-102 和 PH-301）与高可压缩等级（KG-802 和 UF-711）之间存在协同关系，从而改善了压缩特性并提高了溶解速率。配方及其可压缩性也对体外过饱和度有影响，这表明片剂配方可能会影响口服生物利用度。通过使用高度可压缩的微晶纤维素等级，如 Celox(™) KG-802 和 UF-711，可能最大限度地提高作为片剂剂型给药的无定形固体分散体的生物利用度效益。
