扎来普隆舌下喷雾剂的研制

【作者】 郭艳芳；

【导师】 胡文祥； 高永良；

【作者基本信息】 首都师范大学 ， 分析化学， 2008， 硕士

【摘要】 扎来普隆(Zaleplon)为非苯二氮卓类镇静催眠药。该药在临床上主要用于治疗失眠症,其可显著缩短失眠患者的入睡时间,疗效确切,副作用小。目前国内外临床上所用扎来普隆的剂型主要为片剂和胶囊剂等口服制剂。这些口服剂型不仅吸收较慢,而且由于肝脏首过效应严重,生物利用度只有大约30%。本研究根据扎来普隆的理化性质和舌下给药的特点,研制了扎来普隆舌下喷雾剂,旨在提高该药的用药水平和病人使用的顺应性,增加该药的新剂型。本研究首先进行了扎来普隆舌下喷雾剂的制剂学研究,该部分工作是本研究的关键。分别通过规格确定、溶剂的选择、矫味剂的选择及给药装置的选择确定处方,确定了制备工艺,并制备出一系列样品供质量标准研究和稳定性研究。结果表明该剂型的处方合理、工艺简单、重现性和稳定性好。为控制扎来普隆舌下喷雾剂的质量,建立了HPLC含量测定方法及稳定性分析方法,该方法准确、灵敏,辅料及降解产物不干扰主药测定。进而对扎来普隆舌下喷雾剂稳定性进行了考察。影响因素试验、加速试验、长期试验的结果显示该制剂外观、pH、药物含量、有关物质等指标在试验过程中没有明显变化,证明该制剂稳定性良好,为其包装选择和质量标准制订提供了依据。并在此基础上制定了扎来普隆舌下喷雾剂的质量标准草案,其能较好地控制该制剂的质量。扎来普隆舌下喷雾剂在6条比格犬体内的药代动力学和生物利用度研究表明:其体内药代动力学过程均符合一房室模型,扎来普隆舌下喷雾剂吸收速度比片剂约快1倍,Cmax比片剂约高1倍,对片剂的相对生物利用度为157.6%,经统计学检验具有生物等效性。关于扎来普隆舌下喷雾剂笔者未见国内外文献的相关报道,具有一定的新颖性和临床应用价值。本研究基本完成了国家二类新药的临床前资料,并已申报国家发明专利,专利申请号:200710175243.9更多还原

【Abstract】 Zaleplon is a kind of non-benzodiazepine sedative hypnotic drugs. It is used clinically for the treatment of insomnia. It can markedly shorten the time of falling asleep with good curative effect and few side effect. The dosage forms of Zaleplon mainly used on domestic and aboard clinical practice is tablet and capsule. Because of a serious liver first-pass effect, the absolute bioavailability of the oral administration was only 30%. At the same time , oral administration takes on action slowly. In order to provide an alternative administration of Zaleplon for systemic drug delivery to increase its absorption and improve patient compliance, considering the physiochemical properties of Zaleplon and the characteristics of sublingual administration, we planed to study on the sublingual spray of Zaleplon.The optimization of the formulation was the key work in our study. After selection of dosage, solvent, correctant and administration instrument, the formulation of the dosage form was detemined. A series of samples were prepared for quality criterion study, stability study. The result showed that the formulation of the dosage form was reasonable, simple and convenient to prepare, with good reproductivity.In order to control the quality of the preparation, a reliable HPLC method of determination of Zaleplon and its relative substances was established. Under the condition of test, the pharmaceutical aids and the decomposition products could be well separated from Zaleplon. The stability study on Zaleplon sublingual spray indicated that it was stable, nearly without any changes during the stability study. On base of formulation study and stability study, quality criterion studies were put forward. It was proved that the draft of quality criterion for the dosage form could well control the quality of products.The pharmacokinetics and bioavailability study of the sublingual spray of Zaleplon was carried out on 6 Beagle dogs in a randomized crossover manner. The result indicated that the concentration- time curves conformed to 1–compartment model with first-order absorption. The new dosage form took on action faster than oral administration. It was absorbed about 1 times faster than tablet, Tmax was 37.5min and Cmax was 415.5ng/mL, about 1 times higher than tablet. The bioavailability of it was 157.6% and it was bioequivalent to tablet.No report about Zaleplon sublingual spray was found. This study has its innovation and appli- cation value in clinics. The preclinical study of it as 2nd category new drug of China have been finished basically. Patent of it has been applied in process, filed No.was 200710175243.9更多还原