Bekerman Tania, Golenser Jacob, Domb Abraham
Department of Medicinal Chemistry and Natural Products, School of Pharmacy, The Hebrew University of Jerusalem, Jerusalem 91120, Israel.
J Pharm Sci. 2004 May;93(5):1264-70. doi: 10.1002/jps.20057.
Cyclosporin is a first line immunosuppressive drug used to prevent transplant rejection and to treat autoimmune diseases. It is a hydrophobic cyclic peptide built from nonmammalian amino acids with low oral bioavailability. The aim of this study was to develop an oral delivery system for cyclosporin A (CyA) and investigate the effect of composition and particle size of the CyA lipid nanoparticles (lipospheres) on the oral bioavailability of this drug. Dispersible concentrated oil formulations that upon mixing in water spontaneously form a nanodispersion were developed. The concentrated oil formulations were clear solutions composed of the drug, a solid triglyceride, a water miscible organic solvent, and a mixture of surfactants and emulsifiers. The activity of the formulated cyclosporin was determined in vitro following the effect on the proliferation of T cells. The oral bioavailability was determined on humans following the cyclosporin blood levels after oral intake of formulated cyclosporin. Cyclosporin dispersion systems resulting in particle size of 25 to 400 nm were prepared from acceptable pharmceutical components. The composition of the surfactants and emulsifiers, the lipid core component, and the amount and type of the water miscible organic solvent N-methylpyrrolidone (NMP) and alcohols had a strong effect on the particle size of the dispersions. All formulations were reproducible and stable at room temperature for at least 6 months, with full activity of cyclosporin retained. Human oral bioavaiability study indicated a correlation between the AUC and C(max) and the particle size of the dispersion. A C(max) of approximately 1300 ng/mL was found after 2 h of oral intake of four capsules, each loaded with 50 mg cyclosporin.
环孢素是一种一线免疫抑制药物，用于预防移植排斥反应和治疗自身免疫性疾病。它是一种由非哺乳动物氨基酸构成的疏水性环肽，口服生物利用度低。本研究的目的是开发一种环孢素A（CyA）的口服给药系统，并研究CyA脂质纳米颗粒（脂质球）的组成和粒径对该药物口服生物利用度的影响。开发了一种可分散的浓缩油制剂，其在与水混合时会自发形成纳米分散体。浓缩油制剂是由药物、固体甘油三酯、与水混溶的有机溶剂以及表面活性剂和乳化剂的混合物组成的澄清溶液。在体外测定配制的环孢素对T细胞增殖的影响后确定其活性。在口服摄入配制的环孢素后，根据人体中环孢素的血药浓度确定口服生物利用度。由可接受的药物成分制备了粒径为25至400nm的环孢素分散系统。表面活性剂和乳化剂的组成、脂质核心成分以及与水混溶的有机溶剂N-甲基吡咯烷酮（NMP）和醇的量及类型对分散体的粒径有很大影响。所有制剂在室温下至少6个月可重现且稳定，环孢素的活性得以保留。人体口服生物利用度研究表明，AUC和C(max)与分散体的粒径之间存在相关性。口服四粒每粒含50mg环孢素的胶囊2小时后，C(max)约为1300ng/mL。
