乙酰甲喹掩味纳米前药的制备及体外释放

Preparation and in vitro controlled release of mequindox taste-masked nanoprodrug

乙酰甲喹作为治疗畜禽肠道感染的首选药物在兽医临床上被广泛应用,然而,由于味苦、代谢快而影响了其对养殖动物腹泻的治疗效果。本试验以氨基功能化的MCM-41型介孔纳米材料MSN-NH2为载体,通过酸敏感的席夫碱共价键将乙酰甲喹固定于介孔纳米材料的孔道内制得乙酰甲喹纳米前药MEQ@MSN-NH2,以实现掩味的目的。分别通过扫描电镜、透射电镜、氮气吸附-脱附试验、傅里叶红外光谱等手段对载药前后纳米粒子的结构进行比较研究。结果乙酰甲喹成功载入到介孔二氧化硅的孔洞中,并形成平均直径约为100 nm的分散球状粒子。体外释放试验结果表明,该纳米药物在模拟唾液中5 min内的释放率仅为3.9%,可见其掩味性能良好;在人工胃液中迅速释放,30 min内可释放总载药量的64.5%,24 h内基本释放完毕,表明其优异的药物运载和缓释性能。该乙酰甲喹纳米前药MEQ@MSN-NH2通过酸敏感的席夫碱有效实现了药物的控制释放,可以有效避免乙酰甲喹在口腔与味蕾接触所造成的养殖动物拒食等问题。结果表明,该pH-响应型乙酰甲喹纳米前药的掩味控释系统将会具有良好的应用前景。

Mequindox(MEQ)has been widely used in treatment of animal dysentery as medicinal additives to improve growth and ameliorate bacterial enteritis.However,the bitterness of mequindox is a serious problem affecting the adherence of infected animals to the medication.Therefore,taste-masking of mequindox is designed for patient-oriented multiparticulate dosage forms which are available to be orally administered via water or feed for ease of inability or reluctance of individual animal or even group animals.We herein report a simple and efficient approach to masking the taste of mequindox MEQ@MSN-NH2 for oral drug delivery system(DDS),which regulate release of bitter taste mequindox upon the stimulation of physiological environment with changing of pH values in alimentary canal.The mequindox taste-masked nanoprodrug MEQ@MSN-NH2 were prepared with synthesized MCM-41 type mesoporous silica nanoparticular(MSN)which had characteristics of high surface area,total pore volume and uniform mesoporous structure.Bothstructures of MSN and MEQ@MSN-NH2 were characterized by scanning electron microscopy(SEM),transmission electron microscopy(TEM),nitrogen adsorption-desorption and Fourier transform infrared spectra.Mequindox was successfully loaded into the pores of mesoporous silica,and the formed the dispersed spherical particles with an average diameter of about 100 nm.In this system,the Schiff’s base between mequindox and aminated-modified mesoporous silica nanoparticles(MSN-NH2)could effectively prevent the releasing of mequindox during swallowing drug.Therefore,there is only 3.9%of mequindox released from MEQ@MSN-NH2 drug delivery system(DDS)under artificial saliva environment(pH 6.6)within 5 min,which indicates the outstanding taste-masking efficiency of mequindox nanoprodrug MEQ@MSN-NH2 in oral cavity(pH 6.6).On the other hand,the artificial gastric fluid(pH 1.0)could break the Schiff’s base when the drug moves to stomach,resulting in immediate releasing of mequindox from the MSN-NH2.The pH-responsive release behaviour of MEQ@MSN-NH2 was then studied in artificial gastric fluid(pH1.0).Notably,64.5%of MEQ was favourably released when the MEQ@MSN-NH2 was exposed to mimicking gastric fluid(pH 1.0)at 37℃over 30 min,and almost all the MEQ molecules could be released before 24 h.This result shows that the MEQ@MSN-NH2 is a good drug delivery system.The pH-responsive mequindox nanoprodrug MEQ@MSN-NH2 is expected as a dosage forms which are orally administered for treating of sick aquaculture animal.We strongly believe that the simple and efficient taste-masking technology for mequindox will be of great benefit to future clinical applications in animal.