Li Xin, Du Lina, Chen Xu, Ge Pingju, Wang Yu, Fu Yangmu, Sun Haiyan, Jiang Qingwei, Jin Yiguang
Chinese PLA General Hospital, Beijing 100853, China.
Department of Pharmaceutical Sciences, Beijing Institute of Radiation Medicine, Beijing 100850, China.
Int J Pharm. 2015 Jul 15;489(1-2):252-60. doi: 10.1016/j.ijpharm.2015.05.009. Epub 2015 May 6.
Ketorolac tromethamine (KT) was potent to treat moderate to moderately severe pains. However, KT solutions for nasal delivery lost quickly from the nasal route. Thermo- and ion-sensitive in-situ hydrogels (ISGs) are appropriate for nasal drug delivery because the intranasal temperature maintains ∼37 °C and nasal fluids consist of plentiful cations. In this study, a novel nasal thermo- and ion-sensitive ISG of KT was prepared with thermo-sensitive poloxamer 407 (P407) and ion-sensitive deacetylated gellan gum (DGG). The optimal formulation of the KT ISG consisted of 3% (w/v) DGG and 18% (w/v) P407 and its viscosity was up to 7.63 Pas at 37 °C. Furthermore, penetration enhancers and bacterial inhibitors were added and their fractions in the ISG were optimized based on transmucosal efficiencies and toxicity on toad pili. Sulfobutyl ether-β-cyclodextrin of 2.5% (w/v) and chlorobutanol of 0.5% (w/v) were chosen as the penetration enhancer and the bacterial inhibitor, respectively. The Fick's diffusion and dissolution of KT could drive it continuous release from the dually sensitive ISG according to the in vitro investigation. Two methods, writhing frequencies induced by acetic acid and latency time of tails retracting from hot water, were used to evaluate the pharmacodynamics of the KT ISG on the mouse models. The writhing frequencies significantly decreased and the latency time of tail retracting was obviously prolonged (p<0.05) for the KT ISG compared to the control. The thermo- and ion-sensitive KT ISG had appropriate gelation temperature, sustained drug release, improved intranasal absorption, obvious pharmacodynamic effect, and negligible nasal ciliotoxicity. It is a promising intranasal analgesic formulation.
酮咯酸氨丁三醇（KT）对治疗中度至中度重度疼痛有效。然而，用于鼻腔给药的KT溶液会迅速从鼻腔途径流失。热敏和离子敏感原位水凝胶（ISG）适用于鼻腔给药，因为鼻腔内温度维持在约37°C，且鼻液中含有大量阳离子。在本研究中，用热敏性泊洛沙姆407（P407）和离子敏感性脱乙酰结冷胶（DGG）制备了一种新型的KT鼻腔热敏和离子敏感ISG。KT ISG的最佳配方由3%（w/v）DGG和18%（w/v）P407组成，其在37°C时的粘度高达7.63 Pas。此外，添加了渗透促进剂和细菌抑制剂，并根据透粘膜效率和对蟾蜍皮肤的毒性对它们在ISG中的比例进行了优化。分别选择2.5%（w/v）的磺丁基醚-β-环糊精和0.5%（w/v）的三氯叔丁醇作为渗透促进剂和细菌抑制剂。根据体外研究，KT的菲克扩散和溶解可促使其从双重敏感ISG中持续释放。采用乙酸诱导的扭体频率和尾巴从热水中缩回的潜伏时间这两种方法来评估KT ISG对小鼠模型的药效学。与对照组相比，KT ISG的扭体频率显著降低，尾巴缩回的潜伏时间明显延长（p<0.05）。热敏和离子敏感的KT ISG具有合适的胶凝温度、持续的药物释放、改善的鼻腔吸收、明显的药效学作用以及可忽略不计的鼻纤毛毒性。它是一种有前景的鼻腔镇痛制剂。
