Department of Pharmaceutical Sciences, University of Michigan, 428 Church St., Ann Arbor, Michigan, USA.
Pharm Res. 2011 Oct;28(10):2599-609. doi: 10.1007/s11095-011-0489-3. Epub 2011 Jun 15.
To develop fenretinide oral mucoadhesive patch formulations and evaluate their in vitro and in vivo release performance for future site-specific chemoprevention of oral cancer.
Solubilization of fenretinide in simulated saliva (SS) was studied by incorporating nonionic surfactants (Tween® 20 and 80, and Brij® 35 and 98), bile salts (sodium salt of cholic, taurocholic, glycocholic, and deoxycholic acids), phospholipid (lecithin), and novel polymeric solubilizer (Souplus®). Adhesive (polycarbophil: hydroxypropyl methylcellulose 4KM) and drug release (Fenretinide/Eudragit® RL PO with or without solubilizers) layers were prepared by solvent casting. Oral mucoadhesive patches were formed by attaching drug and adhesive layers onto backing layer (Tegaderm™ film). Physical state of drug in Eudragit® films was examined by X-ray diffraction (XRD). Evaluation of in vitro and in vivo fenretinide release from the patch was conducted in SS containing 5%w/v sodium deoxycholate and rabbits, respectively. Fenretinide was quantified by HPLC.
Tween® 20 and 80, Brij® 98, and sodium deoxycholate exhibited the highest fenretinide solubilization potential among the solubilizers. Drug loading efficiency in Eudragit® films was 90%-97%. XRD suggested fenretinide was amorphous in solubilizer-free and solubilizer-loaded films. Solubilizer-free patch exhibited poor in vitro and in vivo controlled drug release behavior. Increases in drug loading (5-10 wt%) or changes in polymeric matrix permeability did not provide continuous drug release. Co-incorporation of either single or mixed solubilizers in fenretinide/Eudragit® patches, (20 wt% Tween® 20, Tween® 80 and sodium deoxycholate or 20 wt% Tween® 80 + 40 wt% sodium deoxycholate solubilizers) led to significantly improved continuous in vitro/in vivo fenretinide release.
Fenretinide/Eudragit® RL PO patches with 20 wt% Tween® 80 + 40 wt% sodium deoxycholate solubilizers exhibit excellent release behavior for further preclinical and/or clinical evaluation in oral cancer chemoprevention.
开发芬维 A 口服黏膜黏附贴片制剂，并评估其体外和体内释放性能，以期用于口腔癌的局部化学预防。
通过加入非离子表面活性剂（吐温® 20 和 80 以及 Brij® 35 和 98）、胆汁盐（胆酸钠、牛磺胆酸钠、甘胆酸钠和脱氧胆酸钠）、磷脂（卵磷酯）和新型聚合物增溶剂（Souplus®）研究芬维 A 在模拟唾液（SS）中的溶解情况。通过溶剂浇铸法制备黏附（聚卡波非：羟丙甲纤维素 4KM）和药物释放（含或不含增溶剂的芬维 A/Eudragit® RL PO）层。将药物和黏附层黏附到背衬层（Tegaderm™ 膜）上形成口腔黏膜黏附贴片。通过 X 射线衍射（XRD）检查 Eudragit® 薄膜中药物的物理状态。分别在含有 5%w/v 脱氧胆酸钠的 SS 和兔子体内进行体外和体内芬维 A 释放评估。通过 HPLC 定量芬维 A。
吐温® 20 和 80、Brij® 98 和脱氧胆酸钠在增溶剂中显示出最高的芬维 A 溶解能力。Eudragit® 薄膜中的药物载药量为 90%-97%。XRD 表明，无增溶剂和含增溶剂的薄膜中芬维 A 为无定形。无增溶剂贴片表现出较差的体外和体内控释药物释放行为。增加药物载药量（5-10wt%）或改变聚合物基质通透性并不能提供持续的药物释放。在芬维 A/Eudragit® 贴片中共加入单一或混合增溶剂（20wt%吐温® 20、吐温® 80 和脱氧胆酸钠或 20wt%吐温® 80+40wt%脱氧胆酸钠增溶剂）可显著改善体外/体内芬维 A 的持续释放。
含 20wt%吐温® 80+40wt%脱氧胆酸钠增溶剂的芬维 A/Eudragit® RL PO 贴片具有优异的释放性能，可进一步在口腔癌化学预防的临床前和/或临床评估中进行研究。
