Department of Pharmaceutics, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, PR China.
Int J Pharm. 2012 May 10;427(2):410-6. doi: 10.1016/j.ijpharm.2012.01.054. Epub 2012 Feb 2.
The purpose of the study is to develop a new formulation for clinically used anti-cancer agent tacrolimus (FK506) to minimize the severe side effects. Toward this end, a new formulation method has been developed by complexation of FK506 with an hydrophilic cyclodextrin derivative, heptakis (2,6-di-O-methyl)-β-cyclodextrin (DM-β-CD) using ultrasonic means. The resulting complex displays dramatically enhanced solubility of FK506. Then bovine serum albumin (BSA) nanoparticles were prepared directly from the preformed FK506/DM-β-CD inclusion complex by the desolvation-chemical crosslinking method, with the size of 148.4-262.9 nm. Stable colloidal dispersions of the nanoparticles were formed with zeta potentials of the range of -24.9 to -38.4 mV. The entrapment efficiency of FK506 was increased as high as 1.57-fold. Moreover, notably FK506 was released from the nanoparticles in a sustained manner. As demonstrated, pharmacokinetic studies reveal that, as compared with FK506-loaded BSA nanoparticles, the FK506/DM-β-CD inclusion complex-loaded BSA nanoparticles have significant increase at T(max), t(1/2), MRT and decrease at C(max). In summary, these results suggest that the drug/DM-β-CD inclusion complex-loaded BSA nanoparticles display significantly improved delivery efficiency for poorly soluble FK506 or its derivatives.
本研究旨在开发一种新的制剂，用于临床应用的抗癌药物他克莫司（FK506），以最大限度地减少严重的副作用。为此，通过超声手段将 FK506 与亲水性环糊精衍生物七（2,6-二-O-甲基）-β-环糊精（DM-β-CD）络合，开发了一种新的制剂方法。所得的配合物显示 FK506 的溶解度显著提高。然后，通过去溶剂-化学交联法直接从预形成的 FK506/DM-β-CD 包合物制备牛血清白蛋白（BSA）纳米颗粒，其粒径为 148.4-262.9nm。纳米颗粒形成稳定的胶体分散体，zeta 电位范围为-24.9 至-38.4mV。FK506 的包封效率高达 1.57 倍。此外，值得注意的是，FK506 从纳米颗粒中以持续的方式释放。如所证明的，药代动力学研究表明，与载 FK506 的 BSA 纳米颗粒相比，载 FK506/DM-β-CD 包合物的 BSA 纳米颗粒在 T(max)、t(1/2)、MRT 方面显著增加，而在 C(max)方面则降低。综上所述，这些结果表明，药物/DM-β-CD 包合物负载的 BSA 纳米颗粒显著提高了难溶性 FK506 或其衍生物的递药效率。
