In vitro and in vivo evaluation of folate receptor-targeting amphiphilic copolymer-modified liposomes loaded with docetaxel

Xiang Li1, Xin Tian2, Jing Zhang3, Xu Zhao1, Xiaohui Chen1, Youhong Jiang2, Dongkai Wang1, Weisan Pan11Department of Pharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, Shenyang; 2The Second Laboratory of Cancer Research Institution, The First Hospital of China Medical University, Shenyang; 3Key Laboratory of Modern Preparation of TCM, Ministry of Education, Jiangxi University of Traditional Chinese Medicine, Nanchang, ChinaBackground: The purpose of this study was to develop folate-poly (PEG-cyanoacrylate-co-cholesteryl cyanoacrylate) (FA-PEG-PCHL)-modified freeze-dried liposomes for targeted chemotherapy using docetaxel as a model drug.Methods: FA-PEG-PCHL was synthesized and its cytotoxicity was evaluated by CCK-8 assay in L929. Docetaxel-loaded liposomes modified by FA-PEG-PCHL were prepared by an organic solvent injection method and lyophilized to obtain freeze-dried FA-PEG-PCHL-docetaxel liposomes (FA-PDCT-L). Two carcinoma cell lines (MCF-7 and A-549 cells) were cultured with docetaxel solution, conventional docetaxel-loaded liposomes, or FA-PDCT-L, and the cytotoxicity and apoptosis was evaluated for each preparation. The uptake of the docetaxel preparations into MCF-7 cells was studied by confocal laser scanning microscopy. Liquid chromatography-mass spectrometry was used to study the pharmacokinetics and tissue distribution characteristics of the preparations.Results: The existence of an enlarged fixed aqueous layer on the surface of the liposomes was affirmed by zeta potential analysis. The entrapment efficiency and particle size distribution were almost the same as those of docetaxel-loaded liposomes. The drug release profile showed that the release rate was faster at higher molecular weight of the polymer. Compared with docetaxel solution and docetaxel-loaded liposomes, FA-PDCT-L demonstrated the strongest cytotoxicity against two carcinoma cell lines, the greatest intracellular uptake especially in the nucleus, as well as the most powerful apoptotic efficacy. In pharmacokinetic studies, the area under the plasma concentration-time curve of FA-PDCT-L was increased 3.82 and 6.23 times in comparison with the values for the docetaxel-loaded liposomes and docetaxel solution, respectively. Meanwhile, a lower concentration of docetaxel was observed for FA-PDCT-L in the liver and spleen, and a significantly higher concentration of FA-PDCT-L in tumors suggested that the presence of FA-PEG-PCHL on the liposomes resulted in greater accumulation of the drug in tumor tissue.Conclusion: Liposomes modified by FA-PEG-PCHL could be one of the promising suspensions for the delivery of antitumor drugs in cancer.Keywords: folate-poly (PEG-cyanoacrylate-co-cholesteryl cyanoacrylate), docetaxel, freeze-dried liposomes, tumor targetin

Development and evaluation of orally disintegrating tablet containing mosapride resin complex

The purpose of this study was to prepare a mosapride citrate-resin (Amberlite® IRP 88) complex and orally fast-disintegrating tablets of the resin complex. The resinate complex of mosapride-Amberlite® IRP 88, weight ratio 2:1, was prepared in an ethanol-water solution. The effects of alcohol concentration, temperature, and pH of the solution on complex formation were evaluated. The complex physicochemical properties were characterized by differential scanning calorimetry, X-ray diffraction and scanning electron microscopy. Orally disintegrating tablets were prepared by direct compression and were optimized using the response surface method. Optimized orally fast-disintegrating tablets disintegrated within 18 s. The pH dependence of mosapride release from the tablet decreased drug dissolution in simulated saliva, whereas it promptly released in the pH 1.0 solution. The data reported herein clearly demonstrate that tablets containing the mosapride- Amberlite® IRP 88 complex for oral disintegration could be particularly useful for patients with swallowing difficulties

Solid dispersion in the development of a nimodipine delayed-release tablet formulation

Nimodipine (NMD) is a dihydropyridine calcium channel blocker with selectivity for cerebral blood vessels and the major therapeutic indication of NMD is for the prevention and treatment of delayed ischemic neurological disorders and other cerebrovascular disorders, such as stroke which is associated with biological rhythm. This study was mainly designed to solve the drawback of conventional NMD solid dosage form, low bioavailability and limited clinical efficacy, by preparing enteric solid dispersion (SD) and the SD was prepared via melting method. The physical state of the dispersed NMD in the polymer matrix was characterized by differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD) and dissolution studies. Compared with pure drug and physical mixture, the dissolution of NMD-SD was enhanced dramatically (about 80%). Furthermore, in consideration of the biological rhythm of stroke, we first obtained a delayed-release tablet containing NMD-SD by a direct powder compression method. As shown in the dissolution studies, the tablet released less than 10% in the artificial gastric acid in the initial 2 h and released 32.1%, 75%, more than 90% at 4, 10 and 14 h respectively in the artificial intestinal fluid. This investigation has solved the problems of oral solid dosage forms of NMD, and it has the good industry prospect