复方盐酸二甲双胍—格列齐特渗透泵胶囊的研究

发布时间：2019-01-26 10:55

【摘要】：糖尿病是一种需要终生治疗的慢性疾病,在目前医学水平下无法实现对其进行根治,给患者和全社会带来了日益沉重的经济和医疗负担。因此研发治疗糖尿病的药物,不仅可以满足广大糖尿病患者治疗的需要,而且具有很好的市场前景。格列齐特与盐酸二甲双胍组成的复方制剂,二者作用机理互补,联合应用可加强降糖效果。盐酸二甲双胍格列齐特复合制剂避免了餐前餐后服药的麻烦,患者顺应性更强。近年来缓控释给药系统由于其可改善患者用药的安全性和顺应性在药物研发中占重要地位。渗透泵制剂是以渗透压为释药动力,零级释放为动力学特征的一种制剂。与渗透泵片剂相比,渗透泵控释胶囊剂优势明显:制备工艺相对简单,生产效率高;囊壳和内容物可分别制备,便于工业化生产。目的:研究盐酸二甲双胍格列齐特渗透泵胶囊的处方和制备工艺,制备质量稳定的盐酸二甲双胍格列齐特渗透泵胶囊。方法:建立同时测定盐酸二甲双胍与格列齐特HPLC体外定量分析方法,同时测定盐酸二甲双胍与格列齐特。采用蘸胶法制备渗透泵胶囊壳,以相似因子f2为指标,对囊芯处方的盐酸二甲双胍含药层、格列齐特含药层、助推层,渗透泵胶囊壳组成及蘸胶次数进行进行单因素考察;根据单因素考察结果采用正交设计法进行处方优化,对最优处方进行处方验证。考察体外释放条件对释放影响,并对释药机理进行考察。参照中国药典附录要求对渗透泵胶囊壳进行质量评价计初步稳定性考察;分别建立盐酸二甲双胍与格列齐特HPLC体内定量分析方法,对复方盐酸二甲双胍—格列齐特渗透泵胶囊进行Beagle犬体内的药动学研究。结果:(1)建立了盐酸二甲双胍与格列齐特HPLC体外定量分析方法,在所选定的色谱条件下,盐酸二甲双胍和格列齐特能达到良好分离且峰形良好,本方法能够更准确、有效、简便地测定盐酸二甲双胍及格列齐特的含量。(2)经单因素考察及正交优化囊芯最优处方为:PVP—K90用量为25mg,PEO wsr N-80用量为55mg,助推层PEOwsr-303用量为70mg,Na Cl的用量为35mg;渗透泵胶囊壳的处方和制备工艺为:CA浓度为8%(W/V),PEG6000为35%(w/w,占醋酸纤维素比重),TEC为2%(w/w,占醋酸纤维素比重),蘸胶三次,自然干燥。(3)所制备的渗透泵胶囊壳外观整洁,无粘连、变形或破裂现象,色泽均匀,无斑点,无异臭,松紧度、脆碎度、干燥失重等均符合中国药典要求。所制备渗透泵胶囊壳高温及光照下外观及柔韧性仍较好,但在高湿条件下胶囊壳会变为白色不透明状。(4)在Beagle犬体内的药动学研究中,自制渗透泵制剂中盐酸二甲双胍及格列齐特血药浓度较市售普通片剂平稳,Cmax低于普通制剂,Tmax增长,t1/2延长,MRT延长,体内滞留时间延长,表明渗透泵制剂与市售普通片剂相比具有缓释特性,可延长作用时间。结论:盐酸二甲双胍—格列齐特渗透泵胶囊的处方及工艺可行,胶囊壳质量符合中国药典要求,渗透泵胶囊稳定性较好,盐酸二甲双胍—格列齐特渗透泵胶囊与市售普通片剂相比具有延长作用时间,有一定的缓释作用,显著提高了生物利用度。
[Abstract]:Diabetes is a chronic disease that requires life-long treatment, which can not be radically cured at present, and has brought an increasingly heavy economic and medical burden to both the patient and the whole society. therefore, the medicine for treating diabetes can not only meet the needs of the treatment of the patients with diabetes, but also has a good market prospect. The compound preparation, which is composed of gliclazide and dimethyldihydrochloride, is complementary to the mechanism of action, and the combined application can enhance the blood sugar-lowering effect. The compound preparation of the disibutalin hydrochloride avoids the trouble of taking the medicine after the pre-meal meal, and the patient has stronger compliance. In recent years, the slow-release drug delivery system has an important role in drug research and development because of its improved safety and compliance. the osmotic pump preparation is a preparation with the osmotic pressure as the drug release power and the zero order release as the kinetic characteristic. Compared with the osmotic pump tablet, the osmotic pump controlled-release capsule has the advantages of relatively simple preparation process and high production efficiency, and the capsule shell and the contents can be respectively prepared and are convenient for industrial production. Objective: To study the formulation and the preparation process of the capsules of the disibutrazil hydrochloride and the preparation of the capsules with stable quality. Methods: The quantitative method for the in vitro quantitative analysis was established for the simultaneous determination of dicyandiamide hydrochloride and glinzi by HPLC. The capsule shell of the osmotic pump was prepared by the dipping method, and the composition of the drug-containing layer, the drug-containing layer, the boosting layer, the capsule shell of the osmotic pump and the number of dipping glue were investigated by using the similar factor f2 as the index. According to the single factor, the orthogonal design method was used to optimize the prescription, and the prescription was verified by the prescription. The effect of in vitro release condition on the release was investigated, and the mechanism of drug release was investigated. The initial stability of the osmotic pump capsule shell was studied with reference to the appendix of the Chinese pharmacopoeia. The method of quantitative analysis was established in the method of the in-vivo quantitative analysis of the disimethine hydrochloride and the gatzitt HPLC, and the pharmacokinetics in Beagle dogs were studied. Results: (1) The method of in-vitro quantitative analysis was established for the method of the in-vitro quantitative analysis of dimethoxy-dicyandiamide hydrochloride and glinzitt. Under the selected chromatographic conditions, the dimethoxy-dicyandiamide hydrochloride and the gliclazide can be well separated and the peak-shape is good, and the method can be more accurate and effective, and the content of the dimethyl double-pass and the passing column of the hydrochloric acid is simply determined. (2) The optimal prescription of the single factor investigation and the orthogonal optimized capsule core is as follows: the dosage of PVP-K90 is 25mg, the dosage of PEO wsr N-80 is 55mg, the dosage of the boosting layer PEOwsr-303 is 70mg, the dosage of the Na Cl is 35mg, the prescription and the preparation process of the osmotic pump capsule shell are as follows: the CA concentration is 8% (W/ V) and the PEG6000 is 35% (w/ w, (the specific gravity of cellulose acetate), the TEC is 2% (w/ w, the specific gravity of cellulose acetate), the dipping glue is dipped for three times and is naturally dried. (3) The prepared osmotic pump capsule shell has the advantages of neat appearance, no adhesion, deformation or rupture, uniform color, no spot, no abnormal smell, tightness, friability, loss of drying, and the like, and meets the requirements of the Chinese pharmacopoeia. The prepared osmotic pump capsule shell has good appearance and flexibility under high temperature and light, but the capsule shell becomes white and opaque under the condition of high wet condition. (4) In the study of the pharmacokinetics of the Beagle dog, the concentration of the disimethin hydrochloride in the self-made osmotic pump preparation is stable, the Cmax is lower than that of the common preparation, the Tmax is increased, the t1/ 2 is prolonged, the MRT is prolonged, the retention time in the body is prolonged, It is shown that the osmotic pump preparation has a sustained-release characteristic compared with the conventional tablet sold in the market, and the working time can be prolonged. Conclusion: The formulation and process of the capsule of the disibutalin hydrochloride are in accordance with the requirements of the Chinese pharmacopoeia, the stability of the osmotic pump capsule is good, and the two-and-one-and-one-step osmotic pump capsules have an extended working time as compared with the conventional tablets sold in the market. has certain sustained-release effect, and the bioavailability is obviously improved.
【学位授予单位】：安徽中医药大学
【学位级别】：硕士
【学位授予年份】：2016
【分类号】：R943

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