液相沉淀法制备长春西汀纳微复合颗粒及其性能研究

发布时间：2018-07-30 07:58

【摘要】：长春西汀(VIN)是一种脑血管扩张剂,能维持或恢复脑血管的生理性扩张,增加缺血区的正常脑血流量,改善缺氧脑组织的代谢。但是由于其在水中微溶,目前的口服制剂溶出释放很差,导致它在消化道内溶解和吸收较差、生物利用度低。采用纳米技术把药物颗粒加工成纳米颗粒,可以提高水难溶药物的生物利用度,并且与常规药物制剂相比,纳米药物具有颗粒小、活性中心多、吸附能力强等优点,在保证药效的前提下可减少药用量,减轻或消除毒副作用,因而受到广大科技工作者和商业领域的青睐。鉴于此,本课题将包括反应沉淀法和反溶剂沉淀法在内的液相沉淀技术,应用于长春西汀复合药物微粉的制备,同时,适时地将液相沉淀法与高压均质法耦合使用,以达到将长春西汀药物微粉化的目的。本文结合反应沉淀法与喷雾干燥技术成功制备粒径较小、颗粒均匀的长春西汀复合颗粒。制备过程中,考察了表面活性剂、酸碱体积比、反应温度以及搅拌强度等因素对颗粒粒径与形貌的影响,并对产品性能进行了分析表征。结果表明,采用反应沉淀法时,在盐酸-氢氧化钠体系下HPMC为适宜的稳定剂,随着HPMC浓度的增加,颗粒粒径呈现减小的趋势并且粒度分布逐渐变窄,HPMC含量为0.2 %wt时最优；随着药物浓度的增加和搅拌时间的延长,颗粒粒径有增大的趋势。降低酸碱体积比和反应温度或增大搅拌强度可使颗粒粒径减小,但是当酸碱体积比小于1：10,搅拌速率达到10000 rpm后,粒径趋于稳定。在药物浓度为10mg/ml,HPMC含量为0.2%wt,酸碱体积比为1：10,反应温度为5℃,搅拌时间5 min,搅拌速率10000 rpm的最优实验条件下,可在浆料中制得粒径约130 nm且形貌规则、粒度分布窄的长春西汀纳米颗粒。通过喷雾干燥方法制得的VIN复合颗粒经XRD、FT-IR、BET和DSC分析表明,VIN复合颗粒与原料药具有相同的晶型但是比表面积提高显著,达7.4m2/g；溶出实验表明,复合颗粒具有远高达原料药的溶出速率,复合颗粒60 min时的累积溶出率约为原料药的9.5倍。本文还探索了结合反溶剂重结晶技术与高压均质技术制备长春西汀微粉的方法。考察了溶剂-反溶剂体系、表面活性剂、搅拌时间、高压均质操作参数等因素对颗粒粒径与形貌的影响。通过对不同溶剂-反溶剂体系的筛选,发现采用候选的单一溶剂以及水组合成不同体系制备长春西汀颗粒,所得粒子较大且不均匀；而采用混合比例为5：1的四氢呋喃-异丙醇共溶剂和水体系制备的长春西汀颗粒较小且成细长棒状,适于与高压均质法耦合以得到更小、更均匀的药物粒子。考察不同稳定剂对反溶剂重结晶颗粒的影响,发现PVP为适宜的稳定剂。在长春西汀溶液浓度为10mg/ml,体系温度为20℃,磁力搅拌速度为1000 rpm,溶剂／反溶剂体积比为1/10,PVP溶液浓度为0.2 wt%及搅拌时间5 min的实验条件下,对制得的长春西汀颗粒在均质压力700 bar下进行高压均质,结果表明经过高压均质后,颗粒破碎为椭圆形且颗粒粒径逐渐减小,当均质循环次数达到15次时颗粒粒径约1μm,此后继续增加循环次数,颗粒粒径变化不明显。实验进一步利用XRD、FT-IR对原料药及产品进行表征,结果表明：经喷雾干燥制得的长春西汀微粉与原料药的晶形相同,均为结晶型且长春西汀微粉的化学组成也与原料药保持一致。长春西汀微粉的溶出实验表明：溶出45 min时,药物微粉的溶出度即可达到约60%,而同一时间原料药溶出度仅为7.2%。
[Abstract]:VIN (VIN) is a kind of cerebral vasodilator, which can maintain or restore the physiological expansion of the cerebral vessels, increase the normal cerebral blood flow in the ischemic area and improve the metabolism of the hypoxic brain tissue. However, because of its solubility in the water, the dissolution and release of the oral preparation is poor, which leads to its poor dissolution and absorption in the digestive tract, and low bioavailability. Using nano technology to process the drug particles into nanoparticles can improve the bioavailability of the water-soluble drugs. Compared with the conventional drug preparation, the nanometers have the advantages of small particles, many active centers and strong adsorption ability. It can reduce the medicinal quantity, reduce or eliminate the side effects on the premise of ensuring the efficacy of the drug. Therefore, it is subject to a wide range of science and technology. In view of this, this topic will include the liquid phase precipitation technology, including the reaction precipitation method and the anti solvent precipitation method, which is applied to the preparation of the compound drug micropowder of Changchun West cement. At the same time, the liquid phase precipitation method is coupled with the high pressure homogenization method in time to achieve the purpose of micropowder of Changchun Westin medicine.
In this paper, the effect of surface active agent, volume ratio of acid base, reaction temperature and agitation strength on particle size and morphology were investigated in the preparation process of Changchun Xi Ting composite particles with smaller particle size and uniform particle size. When the reaction precipitation method is used, HPMC is a suitable stabilizer under the system of hydrochloric acid sodium hydroxide. With the increase of HPMC concentration, the particle size shows a decreasing trend and the particle size distribution becomes narrower and the HPMC content is 0.2%wt. With the increase of drug concentration and agitation time, the particle size has a tendency to increase. The particle size can be reduced by product ratio and reaction temperature or agitation strength, but when the ratio of acid and alkali volume is less than 1:10 and stirring rate reaches 10000 rpm, the particle size tends to be stable. The optimal experiment is that the concentration is 10mg/ml, the content of HPMC is 0.2%wt, the ratio of acid base volume is 1:10, the reaction temperature is 5, the stirring time is 5 min, and the stirring rate is 10000 rpm. Under the conditions, the size distribution of Changchun Xi Ting nanoparticles with a size of 130 nm and a narrow particle size distribution can be made in the slurry. The VIN composite particles obtained by the spray drying method are analyzed by XRD, FT-IR, BET and DSC. The results show that the VIN composite particles have the same crystalline form as the raw material, but the specific surface area is significantly higher than that of 7.4m2/g, and the dissolution experiment shows that The dissolution rate of the composite particles is far higher than that of the bulk drug, and the cumulative dissolution rate of the composite particles is 60 min, which is 9.5 times higher than that of the raw material.
This paper also explored the method of preparation of Changchun Westin micropowder with anti solvent recrystallization and high pressure homogenization technology. The effects of solvent anti solvent system, surfactant, stirring time and high pressure homogenization parameters on particle size and morphology were investigated. The candidates were found by screening different solutions and anti solvent systems. The single solvent and water group were prepared for the preparation of Changchun Xi Ting granules in different systems. The particles were large and uneven, and the Changchun oxetine particles, prepared by the tetrahydrofuran isopropanol co solvent and water system with mixed proportion of 5:1, were smaller and slender rods, suitable for coupling with high pressure homogenization to get smaller, more uniform drug particles. The effect of different stabilizers on recrystallized recrystallized particles was investigated. It was found that PVP was a suitable stabilizer. Under the conditions of 10mg/ml in Changchun, the system temperature was 20, the velocity of magnetic stirring was 1000 rpm, the volume ratio of solvent / anti solvent was 1/10, the concentration of PVP solution was 0.2 wt% and the mixing time was 5 min. The grain size was homogenized under the homogeneous pressure of 700 bar. The results showed that after high pressure homogenization, the particles were broken into ellipse and the particle size decreased gradually. When the number of homogeneous cycles reached 15 times, the particle size was about 1 mu m, and then the cycle times were increased and the particle size changes were not obvious. The experiment further used XRD and FT-IR for the drug and the particle size. The product was characterized. The results showed that the crystalline form of Changchun West cement powder made by spray drying was the same as that of the raw material, and the chemical composition of Changchun Xi Ting micropowder was also consistent with that of the raw material. The dissolution test of Changchun cement powder in Changchun showed that the dissolution rate of the drug powder could reach about 60% when the dissolution of 45 min, and the same time. The dissolution rate of the API was only 7.2%.
【学位授予单位】：北京化工大学
【学位级别】：硕士
【学位授予年份】：2011
【分类号】：R943

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