Ozgüney Işık, Kardhiqi Anita, Yıldız Gülbeyaz, Ertan Gökhan
Department of Pharmaceutical Technology, Faculty of Pharmacy, Ege University, 35100, Bornova, Izmir, Turkey,
Eur J Drug Metab Pharmacokinet. 2014 Dec;39(4):283-91. doi: 10.1007/s13318-013-0157-6. Epub 2013 Oct 6.
The main objective of this study was to investigate the release and pharmacokinetic profiles of ketoprofen (KP) from developed thermosensitive and mucoadhesive liquid suppositories. Thermosensitive liquid suppositories were prepared using KP, poloxamer 407 (P 407), poloxamer 188 (P 188) and various amounts of different mucoadhesive polymers. In vitro release studies was monitored by the USP XXVI paddle method. The results thus obtained were evaluated kinetically and mechanism of release was analyzed. Identification of poloxamer gel localization in vivo was conducted using white male rabbits by adding 1 % methylene blue. For in vivo studies, twenty-four white male rabbits were randomly divided into three groups. The rabbits in each group were administered with liquid suppository F1 [P407/P188/KP (4/20/2.5 %)], F5 [P407/P188/KP/C (4/20/2.5/0.8 %)] or conventional suppository (F-C) into the rectum. The plasma concentration of KP was analyzed by high performance liquid chromatography (HPLC). C max, AUC, MRT and T max were evaluated. The release of KP was variously affected by the mucoadhesive polymers. In vitro release studies showed that Carbopol 934 P(C) has significant effect on release rate among the mucoadhesive polymers. When the formulations were evaluated kinetically, different kinetic models were obtained. Formulation F6 [P407/P188/KP/C (4/20/2.5/1.6 %)] which contains the highest C concentration and very high viscosity, shows a significantly better fit with Higuchi kinetic model. n value of this formulation was also found approximately 0.5. n exponent results of the other formulations showed that KP might be released from the suppositories by non-Fickian diffusion. Identification of poloxamer gel localization in vivo showed that the suppositories remain in the rectum without leakage after administration. With regard to the results of in vivo studies, the AUC6→14 values of KP in liquid suppository containing C are significantly higher than those in liquid suppository without C. MRT0→24 and MRT0→∞ values of liquid suppository containing C are significantly higher than those in liquid suppository without C and conventional suppository. Conventional suppository and liquid suppository without C significantly gave faster time to reach the maximum plasma concentrations of KP. With regard to the in vitro and in vivo experiments, liquid suppository formulation F5 might be a promising formulation for the development of an effective rectal dosage form.
本研究的主要目的是考察酮洛芬（KP）在研制的热敏性和黏膜黏附性液体栓剂中的释放情况及药代动力学特征。采用KP、泊洛沙姆407（P 407）、泊洛沙姆188（P 188）和不同量的不同黏膜黏附聚合物制备热敏性液体栓剂。体外释放研究采用美国药典XXVI桨法进行监测。对所得结果进行动力学评估并分析释放机制。通过添加1%的亚甲蓝，利用雄性白兔对泊洛沙姆凝胶在体内的定位进行鉴定。对于体内研究，将24只雄性白兔随机分为三组。给每组兔子直肠给药液体栓剂F1 [P407/P188/KP（4/20/2.5%）]、F5 [P407/P188/KP/C（4/20/2.5/0.8%）]或传统栓剂（F-C）。采用高效液相色谱法（HPLC）分析KP的血浆浓度。评估C max、AUC、MRT和T max。KP的释放受到黏膜黏附聚合物的不同影响。体外释放研究表明，在黏膜黏附聚合物中，卡波姆934 P（C）对释放速率有显著影响。对制剂进行动力学评估时，得到了不同的动力学模型。含有最高C浓度和非常高黏度的制剂F6 [P407/P188/KP/C（4/20/2.5/1.6%）]与Higuchi动力学模型拟合度显著更好。该制剂的n值也约为0.5。其他制剂的n指数结果表明，KP可能通过非菲克扩散从栓剂中释放。泊洛沙姆凝胶在体内的定位鉴定表明，给药后栓剂保留在直肠中无泄漏。关于体内研究结果，含C的液体栓剂中KP的AUC6→14值显著高于不含C的液体栓剂。含C的液体栓剂的MRT0→24和MRT0→∞值显著高于不含C的液体栓剂和传统栓剂。传统栓剂和不含C的液体栓剂达到KP最大血浆浓度的时间明显更快。关于体外和体内实验，液体栓剂制剂F5可能是开发有效直肠剂型的一种有前景的制剂。
