Preparation.docx

1、PreparationPreparation, characterization and pharmacokinetic studies of tacrolimus-dimethyl-cyclodextrin inclusion complex-loaded albumin nanoparticles Shanshan Gaob, Jun Sunb, Dongjun Fub, Hongli Zhaoa, Minbo Lana, Feng Gaoa, b, c, , a Shanghai Key Laboratory of Functional Materials Chemistry, East

2、 China University of Science and Technology, Shanghai 200237, PR China b Department of Pharmaceutics, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, PR China c Shanghai Key Laboratory of New Drug Design, East China University of Science and Technology, Shanghai

3、 200237, PR ChinaReceived 15 November 2011Revised 30 December 2011Accepted 24 January 2012Available online 2 February 2012 http:/dx.doi.org/10.1016/j.ijpharm.2012.01.054, How to Cite or Link Using DOI Permissions & ReprintsAbstractThe purpose of the study is to develop a new formulation for clinical

4、ly 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)-cyclodextrin (DM-CD) using ultrasonic means. The resulting c

5、omplex displays dramatically enhanced solubility of FK506. Then bovine serum albumin (BSA) nanoparticles were prepared directly from the preformed FK506/DM-CD inclusion complex by the desolvation-chemical crosslinking method, with the size of 148.4262.9nm. Stable colloidal dispersions of the nanopar

6、ticles were formed with zeta potentials of the range of 24.9 to 38.4mV. 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 FK5

7、06-loaded BSA nanoparticles, the FK506/DM-CD inclusion complex-loaded BSA nanoparticles have significant increase at Tmax, t1/2, MRT and decrease at Cmax. In summary, these results suggest that the drug/DM-CD inclusion complex-loaded BSA nanoparticles display significantly improved delivery efficien

8、cy for poorly soluble FK506 or its derivatives.Graphical abstractFigure options View in workspace Download full-size image Download high-quality image (145 K) Download as PowerPoint slideKeywords FK506/DM-CD inclusion complex; BSA nanoparticle; Sustained-release1. IntroductionTacrolimus (FK506, mole

9、cular weight of 822.05, water solubility of 1.3g/ml), a hydrophobic macrolide lactones natural product isolated from by Streptomyces tsukubaensis, exerts potent immunosuppressive effects and has been in clinical use as prophylaxis against organ rejection after liver and renal transplantation (Hideto

10、shi et al., 2001). Recently, it has been reported that FK506 can be widely distributed in the body with a high degree binding of red blood cells and plasma proteins. However, the distribution is significantly affected by individual differences, and the administration routes. For example, the gastroi

11、ntestinal tract has a narrow therapeutic window due to low bioavailability (Taher et al., 2009), and side effects. In addition, FK506 is known to exhibit low oral bioavailability and a wide range of variability in absorption, ranging from 4 to 89% in kidney and liver transplant recipients (Venkatara

12、manan et al., 1995). For the intravenous administration, because of its low solubility, some solubilizer or injection oil was used, thus inducing greater toxicity.-Cyclodextrin (-CD) and its derivatives, as distinct solubilizers, have received considerable attention, giving prominence to their low b

13、iotoxicity and high biocompatibility. As attractive materials for drug inclusion, -CD can be further chemically modified to improve its physicochemical properties ( Hassan and Asghar, 2009andSong et al., 2009). A number of studies have shown that adding -CD can improve the loading efficiency of nano

14、particles and slow down the release of drugs ( Alexander and Maria, 2007, Boudad et al., 2001andMaestrelli et al., 2006). Ferreira and collaborators prepared inclusion complexes with hydroxypropyl-cyclodextrin and the aqueous solubility of the drug increased linearly with the concentration of the cy

15、clodextrins (Denise et al., 2004). The cavity depth and surface activity of 2,6-di-O-methyl-cyclodextrin (DM-CD), a derivative of -CD, improved significantly, as well as the solubility increased as much as by 25 times (Gamal et al., 1986). Various -CD derivatives have been evaluated to probe their e

16、nhancing effect on solubility and stability of FK506 in rats. It was found that DM-CD had a dramatic improvement on solubilization and stabilization of FK506 (Hidetoshi et al., 2001).Modern nanotechnology is considered as an emerging and converging technology (Roco, 2008) and that is said to be one of the key technologies of the 21st century. Nanotechno