【作者】 彭亮；

【导师】 唐星；

【作者基本信息】 沈阳药科大学 ， 药剂学， 2006， 硕士

【摘要】 多索茶碱(doxofylline DOX)是一种新型平喘镇咳药，国外已广泛用于哮喘及慢支炎的治疗。国内1993年开始研究，并改进其工艺。现已开发出原料、片剂、针剂、输液等四种剂型。本品可松弛平滑肌，具有平喘作用，临床上用于治疗支气管哮喘和慢性阻塞性肺病等引起的喘息症状，与传统药物茶碱和氨茶碱相比，疗效高且毒性低，治疗效果是氨茶碱的10—15倍。但由于哮喘病的发作节律性，且本品和氨茶碱一样也存在着与血药浓度相关的副作用，因此作者将其制备成1日服1次的缓释微丸，其缓释作用既可有效预防多发于凌晨的哮喘发作，又能减少服药次数，降低多索茶碱与血药浓度相关的副作用，提高患者顺应性。同时本文还以多索茶碱普通片为参比制剂，对多索茶碱缓释胶囊在家犬体内的药动学和相对生物利用度进行了研究。处方前研究表明：多索茶碱在水中及各种生理范围内的介质中溶解度较好均为40mg／ml左右，油水分配系数为0.4左右。采用UV法进行微丸中药物含量和释放度进行测定。用离心造粒法制备多索茶碱微丸，采用粉末层积法进行试验。经处方筛选和工艺考察，结果24-32目的微丸收率90％以上，药物含量约为70％左右，微丸收率和主药含量均达到预期的效果。用流化床包衣法对多索茶碱微丸进行缓释包衣。单因素考察建立了包衣工艺；在单因素考察的基础上建立了三种Eudragit包衣液处方。研究了三个处方的释药机制。建立了多索茶碱体内血药浓度测定方法，并以市售普通片为对参比制剂，对两种缓释微丸F1和F3进行了家犬体内药物动力学研究，结果显示，F1的Cmax=15.16mg／L，Tmax=3.17h，MRT=7.56h，相对生物利用度Fr(F1)=101.25±13.89％：F3的Cmax=11.41mg／L，Tmax=5.00h，MRT=9.33h，相对生物利用度Fr(F3)=105.35±14.15％。体内外相关性良好。更多还原

【Abstract】 Doxofylline (DOX) is a new type of medicine for the treatment of cough and asthma.It is widely used to treat chronic bronchitis and asthma in foreign country.The domestic researchers have been to study it from 1993 and they have reformed the technics.Nowdays there are raw material tablet injection and infusion in the market. This drug can loose smooth muscle and process anti - asthmatic effect.It is used to cure the symptorm evocable by chronic asthmatic bronchitis and chronic obstructive pulmonary disease in clinic. Compare to traditional medicine theophylline and aminophyllin, it has a high curative effect and the low toxicity. The curative effect of doxofylline is 10—15 times to that of aminophyllin.On account of the rhythmicity of outbreak of asthma and the side-effect interrelated to blood drug concentration as aminophylline, the writer prepare the sustained release pellets of it which is taked one time every day.The advantages sustained release effect consist of proper therapeutic value,the prevention asthma which is evocable more common in wee hours, a stable drug concentration in plasma and least side effect .At the same time ,the writer study the Pharmacokinetics and relative bioavailability of the sustained release pellets compare to commercial tablet as a reference formulation.The preliminary study shows dissolvability of doxofylline is about 30mg/ml in different pH mediums, the octanol/waterpartition coefficient is about 0.4 .And the writer determinate the accumulative dissolution and content of DOX pellets byUltraviolet spetrophotometry (UV) method.Doxofylline pellets were prepared by means of powder layering with the centrifugan granulation equipment. After selecting the best sormulation and craft, yield of pellets between 24 and 32 mesh is about 90%,content of the main medicine is 70% .The purpose is perfect.A fluid-bed spray processor was adopted for the coating of the buffer pellets.The pellets were coated with Eudragit as coating material in a fluid bed coater. Based on the single factors design experiment, we set up 3 kinds of coating prescription coated by Eudragit and study the release mechanism of them.At last The HPLC method was performed to detect the concentration of DOX in plasma of dogs. The pharmacokinetic parmateters and relative bioavailability of the formulations F1 and F3 were studied with the commercial tablet as a reference formulation.The result shows: F1: Cmax=15.16 mg/L, Tmax=3.17h, MRT= 7.56h, relative bioavailability Fr (F1)=101.25±13.89%; F3的Cmax= 11.41mg/L, Tmax=5.00h, MRT=9.33h, relative bioavailability Fr (F3) =105.35±14.15%. It was appropriate of the correlation between absorption in vivo and release in vitro.The results indicated this dosage form had an improved pharmaceutical quality, which might enhance its therapeutic profile.更多还原