Sawicki E, Schellens J H M, Beijnen J H, Nuijen B
a Department of Pharmacy and Pharmacology , Antoni van Leeuwenhoek Hospital/MC Slotervaart , Amsterdam , The Netherlands.
b Department of Clinical Pharmacology , the Netherlands Cancer Institute , Amsterdam , the Netherlands.
Drug Dev Ind Pharm. 2017 Apr;43(4):584-594. doi: 10.1080/03639045.2016.1274901. Epub 2017 Jan 8.
A novel tablet formulation containing an amorphous solid dispersion (ASD) of elacridar hydrochloride was developed with the purpose to resolve the drug's low solubility in water and to conduct proof-of-concept clinical studies.
Elacridar is highly demanded for proof-of-concept clinical trials that study the drug's suitability to boost brain penetration and bioavailability of numerous anticancer agents. Previously, clinical trials with elacridar were performed with a tablet containing elacridar hydrochloride. However, this tablet formulation resulted in poor and unpredictable absorption which was caused by the low aqueous solubility of elacridar hydrochloride.
Twenty four different ASDs were produced and dissolution was compared to crystalline elacridar hydrochloride and a crystalline physical mixture. The formulation with highest dissolution was characterized for amorphicity. Subsequently, a tablet was developed and monitored for chemical/physical stability for 12 months at +15-25 °C, +2-8 °C and -20 °C.
The ASD powder was composed of freeze dried elacridar hydrochloride-povidone K30-sodium dodecyl sulfate (1:6:1, w/w/w), appeared fully amorphous and resulted in complete dissolution whereas crystalline elacridar hydrochloride resulted in only 1% dissolution. The ASD tablets contained 25 mg elacridar hydrochloride and were stable for at least 12 months at -20 °C.
The ASD tablet was considered feasible for proof-of-concept clinical studies and is now used as such.
开发一种含有盐酸艾拉司群无定形固体分散体（ASD）的新型片剂制剂，以解决该药物在水中的低溶解度问题，并开展概念验证性临床研究。
在研究该药物促进多种抗癌药物脑渗透和生物利用度的适用性的概念验证性临床试验中，对盐酸艾拉司群有很高的需求。此前，盐酸艾拉司群的临床试验使用的是含有盐酸艾拉司群的片剂。然而，这种片剂制剂由于盐酸艾拉司群的低水溶性导致吸收不佳且不可预测。
制备了24种不同的无定形固体分散体，并将其溶出度与结晶型盐酸艾拉司群和结晶物理混合物进行比较。对溶出度最高的制剂进行无定形特征表征。随后，开发了一种片剂，并在15 - 25°C、2 - 8°C和 - 20°C下监测其化学/物理稳定性12个月。
无定形固体分散体粉末由冻干的盐酸艾拉司群 - 聚维酮K30 - 十二烷基硫酸钠（1:6:1，w/w/w）组成，呈现完全无定形状态，溶出完全，而结晶型盐酸艾拉司群的溶出度仅为1%。无定形固体分散体片剂含有25mg盐酸艾拉司群，在 - 20°C下至少稳定12个月。
无定形固体分散体片剂被认为适用于概念验证性临床研究，目前正用于此类研究。
