Pharmaceutics and Drug Delivery, Amgen, Inc., One Amgen Center, Drive Thousand Oaks, California 93120, USA.
Pharm Res. 2004 Mar;21(3):500-6. doi: 10.1023/B:PHAM.0000019305.79599.a5.
The purpose of this work was to evaluate spray-freeze drying and spray drying processes for encapsulation of darbepoetin alfa (NESP, Aranesp).
Darbepoetin alfa was encapsulated in poly(lactide-co-glycolide) by spray-freeze drying and by spray drying. Integrity was evaluated by size-exclusion chromatography and Western blot. Physical properties and in vitro release kinetics were characterized. Pharmacokinetics and pharmacodynamics were evaluated in nude rats.
Microspheres produced by spray drying were larger than those produced by spray-freeze drying (69 microm vs. 29 microm). Postencapsulation integrity was excellent for both processes, with < 2% dimer by size-exclusion chromatography. In vitro release profiles were similar, with low burst (< 25%) and low cumulative protein recovery at 4 weeks (< or = 30%), after which time covalent dimer (< or = 6.5%) and high molecular weight aggregates (< or = 2.3%) were recovered by denaturing extraction. After a single injection, darbepoetin alfa was detected in serum through 4 weeks for all microsphere formulations tested in vivo, although relative bioavailability was higher for spray-freeze drying (28%) compared with spray drying (21%; p = 0.08) as were yields (73-82% vs. 34-57%, respectively). For both processes hemoglobin was elevated for 7 weeks, over twice as long as unencapsulated drug.
Spray drying, conducted at pilot scale with commercial equipment, is comparable to spray-freeze drying for encapsulation of darbepoetin alfa.
本研究旨在评估喷雾冷冻干燥和喷雾干燥工艺在达贝泊汀α（NESP，Aranesp）包封中的应用。
达贝泊汀α通过喷雾冷冻干燥和喷雾干燥包封于聚（乳酸-共-乙醇酸）中。完整性通过尺寸排阻色谱法和 Western blot 进行评估。物理性质和体外释放动力学进行了表征。在裸鼠中评估了药代动力学和药效动力学。
喷雾干燥法制备的微球比喷雾冷冻干燥法制备的微球大（69μm 比 29μm）。两种方法的包封后完整性均良好，尺寸排阻色谱法检测到的二聚体小于 2%。体外释放曲线相似，具有低突释（<25%）和低 4 周累积蛋白回收率（<或=30%），之后通过变性提取回收共价二聚体（<或=6.5%）和高分子量聚集物（<或=2.3%）。在体内试验中，所有微球制剂单次注射后，在 4 周内均可在血清中检测到达贝泊汀α，尽管喷雾冷冻干燥的相对生物利用度（28%）高于喷雾干燥（21%；p=0.08），产率也更高（73-82%比 34-57%）。两种方法的血红蛋白升高持续 7 周，是未包封药物的两倍以上。
采用商业设备进行的喷雾干燥，在包封达贝泊汀α方面与喷雾冷冻干燥相当。
