Kurihara A, Shibayama Y, Yasuno A, Ikeda M, Hisaoka M
Analytical and Metabolic Research Laboratories, Sankyo Co Ltd., Tokyo, Japan.
Biopharm Drug Dispos. 1996 May;17(4):343-53. doi: 10.1002/(SICI)1099-081X(199605)17:4<343::AID-BDD958>3.0.CO;2-7.
Emulsion formulations of various particle sizes for the highly lipophilic antitumour agent, RS-1541 (13-O-palmitoylrhizoxin), were prepared using dioctanoyldecanoylglycerol (ODO) as lipids and polyoxyethylene-(60)-hydrogenated castor oil (HCO-60) as a surfactant. These emulsions were evaluated as injectable drug carriers and compared with a colloidal solution. Both in vitro and in vivo after i.v. administration, RS-1541 was distributed into lipoproteins from the colloidal solution. When applied as emulsions of various particle sizes (124-419 nm) in vitro, RS-1541 was retained and stabilized within the emulsions. In the in vivo study, however, retention of RS-1541 in the emulsions after i.v. injection depended on their size. The small-particle emulsions (94-112 nm) resulted in long retention, and the large-particle emulsions (415-474 nm) led to short retention. Lipolysis rates of emulsion particles by lipoprotein lipase also depended on their size, indicating rapid lipolysis for small-particle emulsions (133 nm). However, the lipolysis was not such an extensive one, showing 10-30% release of capric acid from ODO within 6 h. Blood dispositions of capric acids approximately paralleled those of RS-1541 after i.v. injection of various particle size emulsions (130-368 nm) to rats, although relatively rapid eliminations of capric acids compared with RS-1541 were observed for the small-particle size emulsions (130 nm). These results suggest that when injected as emulsion formulations, the highly lipophilic antitumour agent, RS-1541, has behaviour similar to that of the emulsion particles in the body, which is dependent on the size of the latter. Thus, by properly selecting the particle size, lipid emulsions consisting of ODO and HCO-60 are expected to be effective and useful DDS carriers for RS-1541.
以二辛酰癸酰甘油（ODO）为脂质、聚氧乙烯（60）氢化蓖麻油（HCO - 60）为表面活性剂，制备了用于高亲脂性抗肿瘤药物RS - 1541（13 - O - 棕榈酰根霉素）的各种粒径的乳剂配方。这些乳剂被评估为可注射药物载体，并与胶体溶液进行比较。静脉注射后，RS - 1541在体外和体内均从胶体溶液中分布到脂蛋白中。当在体外以各种粒径（124 - 419 nm）的乳剂形式应用时，RS - 1541保留并稳定在乳剂中。然而，在体内研究中，静脉注射后RS - 1541在乳剂中的保留情况取决于其粒径。小粒径乳剂（94 - 112 nm）导致长时间保留，大粒径乳剂（415 - 474 nm）导致短时间保留。脂蛋白脂肪酶对乳剂颗粒的脂解速率也取决于其粒径，表明小粒径乳剂（133 nm）的脂解迅速。然而，脂解并不广泛，在6小时内ODO中癸酸的释放率为10 - 30%。给大鼠静脉注射各种粒径乳剂（130 - 368 nm）后，癸酸的血液分布情况与RS - 1541大致平行，尽管对于小粒径乳剂（130 nm），观察到癸酸与RS - 1541相比消除相对较快。这些结果表明，当以乳剂配方注射时，高亲脂性抗肿瘤药物RS - 1541在体内的行为与乳剂颗粒相似，这取决于后者的粒径。因此，通过适当选择粒径，由ODO和HCO - 60组成的脂质乳剂有望成为RS - 1541有效且有用的药物递送系统载体。
