Nagai Noriaki, Nakazawa Yosuke, Ito Yoshimasa, Kanai Kazutaka, Okamoto Norio, Shimomura Yoshikazu
Faculty of Pharmacy, Kindai University.
Faculty of Pharmacy, Keio University.
Biol Pharm Bull. 2017;40(7):1055-1062. doi: 10.1248/bpb.b17-00137.
We designed ophthalmic formulations containing dexamethasone-loaded solid nanoparticles (DEX dispersion), and investigated corneal permeability and toxicity. 0.1% dexamethasone (DEX) powder (DEX microparticles), 0.026% methyl p-hydroxybenzoate (MP), 0.014% propyl p-hydroxybenzoate (PP), and 0.5% methylcellulose were used, and the DEX dispersion was prepared by the bead mill method. The mean particle size of DEX dispersion was 78 nm. Antimicrobial activity of the DEX dispersion were measured by using Escherichia coli, and the corneal epithelium-debrided rat model and HCE-T cells (immortalized human corneal epithelial cell line) were used to estimate the corneal toxicity. The transcorneal penetration of the DEX dispersion were evaluated in the corneas of rabbit. The DEX dispersion was found to be highly stable until 14 d after its preparation. Although DEX itself did not exhibit antimicrobial activity, the DEX dispersion containing parabens (MP and PP) showed high antimicrobial activity, approximately equal to that of the solution containing parabens without DEX. The corneal penetration rate (J) and mean residence time (MRT) of DEX from the DEX dispersion were approximately 5.1- and 1.3-fold higher, respectively, than those of a dispersion containing DEX microparticles (mean particle size, 11.3 µm). In addition, no significant difference was found in corneal stimulation between the vehicle and DEX dispersion. In conclusion, we successfully prepared high quality dispersion containing DEX solid nanoparticles, and the nanoparticle-based ophthalmic formulation of DEX enhanced the corneal permeability and residence time of the drug. It is possible that DEX dispersion will show increased effectiveness in treating ocular inflammation.
我们设计了含有载地塞米松固体纳米颗粒的眼科制剂（地塞米松分散体），并研究了其角膜渗透性和毒性。使用了0.1%地塞米松（DEX）粉末（DEX微粒）、0.026%对羟基苯甲酸甲酯（MP）、0.014%对羟基苯甲酸丙酯（PP）和0.5%甲基纤维素，通过珠磨法制备地塞米松分散体。地塞米松分散体的平均粒径为78nm。用地塞米松分散体对大肠杆菌进行抗菌活性测定，并使用角膜上皮刮除大鼠模型和HCE-T细胞（永生化人角膜上皮细胞系）评估角膜毒性。在兔角膜中评估地塞米松分散体的角膜透过性。发现地塞米松分散体在制备后14天内高度稳定。虽然地塞米松本身不具有抗菌活性，但含有对羟基苯甲酸酯（MP和PP）的地塞米松分散体显示出高抗菌活性，约等于不含地塞米松的含对羟基苯甲酸酯溶液的抗菌活性。地塞米松分散体中地塞米松的角膜渗透速率（J）和平均驻留时间（MRT）分别比含有地塞米松微粒（平均粒径11.3μm）的分散体高约5.1倍和1.3倍。此外，赋形剂和地塞米松分散体之间在角膜刺激性方面未发现显著差异。总之，我们成功制备了含有地塞米松固体纳米颗粒的高质量分散体，基于纳米颗粒的地塞米松眼科制剂提高了药物的角膜渗透性和驻留时间。地塞米松分散体在治疗眼部炎症方面可能会显示出更高的疗效。
