液相沉淀法制備長春西汀納微復合顆粒及其性能研究
發(fā)布時間：2018-07-30 07:58
【摘要】：長春西汀(VIN)是一種腦血管擴張劑,能維持或恢復腦血管的生理性擴張,增加缺血區(qū)的正常腦血流量,改善缺氧腦組織的代謝。但是由于其在水中微溶,目前的口服制劑溶出釋放很差,導致它在消化道內(nèi)溶解和吸收較差、生物利用度低。采用納米技術把藥物顆粒加工成納米顆粒,可以提高水難溶藥物的生物利用度,并且與常規(guī)藥物制劑相比,納米藥物具有顆粒小、活性中心多、吸附能力強等優(yōu)點,在保證藥效的前提下可減少藥用量,減輕或消除毒副作用,因而受到廣大科技工作者和商業(yè)領域的青睞。鑒于此,本課題將包括反應沉淀法和反溶劑沉淀法在內(nèi)的液相沉淀技術,應用于長春西汀復合藥物微粉的制備,同時,適時地將液相沉淀法與高壓均質(zhì)法耦合使用,以達到將長春西汀藥物微粉化的目的。 本文結合反應沉淀法與噴霧干燥技術成功制備粒徑較小、顆粒均勻的長春西汀復合顆粒。制備過程中,考察了表面活性劑、酸堿體積比、反應溫度以及攪拌強度等因素對顆粒粒徑與形貌的影響,并對產(chǎn)品性能進行了分析表征。結果表明,采用反應沉淀法時,在鹽酸-氫氧化鈉體系下HPMC為適宜的穩(wěn)定劑,隨著HPMC濃度的增加,顆粒粒徑呈現(xiàn)減小的趨勢并且粒度分布逐漸變窄,HPMC含量為0.2 %wt時最優(yōu)；隨著藥物濃度的增加和攪拌時間的延長,顆粒粒徑有增大的趨勢。降低酸堿體積比和反應溫度或增大攪拌強度可使顆粒粒徑減小,但是當酸堿體積比小于1：10,攪拌速率達到10000 rpm后,粒徑趨于穩(wěn)定。在藥物濃度為10mg/ml,HPMC含量為0.2%wt,酸堿體積比為1：10,反應溫度為5℃,攪拌時間5 min,攪拌速率10000 rpm的最優(yōu)實驗條件下,可在漿料中制得粒徑約130 nm且形貌規(guī)則、粒度分布窄的長春西汀納米顆粒。通過噴霧干燥方法制得的VIN復合顆粒經(jīng)XRD、FT-IR、BET和DSC分析表明,VIN復合顆粒與原料藥具有相同的晶型但是比表面積提高顯著,達7.4m2/g；溶出實驗表明,復合顆粒具有遠高達原料藥的溶出速率,復合顆粒60 min時的累積溶出率約為原料藥的9.5倍。 本文還探索了結合反溶劑重結晶技術與高壓均質(zhì)技術制備長春西汀微粉的方法。考察了溶劑-反溶劑體系、表面活性劑、攪拌時間、高壓均質(zhì)操作參數(shù)等因素對顆粒粒徑與形貌的影響。通過對不同溶劑-反溶劑體系的篩選,發(fā)現(xiàn)采用候選的單一溶劑以及水組合成不同體系制備長春西汀顆粒,所得粒子較大且不均勻；而采用混合比例為5：1的四氫呋喃-異丙醇共溶劑和水體系制備的長春西汀顆粒較小且成細長棒狀,適于與高壓均質(zhì)法耦合以得到更小、更均勻的藥物粒子�？疾觳煌�(wěn)定劑對反溶劑重結晶顆粒的影響,發(fā)現(xiàn)PVP為適宜的穩(wěn)定劑。在長春西汀溶液濃度為10mg/ml,體系溫度為20℃,磁力攪拌速度為1000 rpm,溶劑／反溶劑體積比為1/10,PVP溶液濃度為0.2 wt%及攪拌時間5 min的實驗條件下,對制得的長春西汀顆粒在均質(zhì)壓力700 bar下進行高壓均質(zhì),結果表明經(jīng)過高壓均質(zhì)后,顆粒破碎為橢圓形且顆粒粒徑逐漸減小,當均質(zhì)循環(huán)次數(shù)達到15次時顆粒粒徑約1μm,此后繼續(xù)增加循環(huán)次數(shù),顆粒粒徑變化不明顯。實驗進一步利用XRD、FT-IR對原料藥及產(chǎn)品進行表征,結果表明：經(jīng)噴霧干燥制得的長春西汀微粉與原料藥的晶形相同,均為結晶型且長春西汀微粉的化學組成也與原料藥保持一致。長春西汀微粉的溶出實驗表明：溶出45 min時,藥物微粉的溶出度即可達到約60%,而同一時間原料藥溶出度僅為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%.
【學位授予單位】：北京化工大學
【學位級別】：碩士
【學位授予年份】：2011
【分類號】：R943
本文編號：2154349
[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%.
【學位授予單位】：北京化工大學
【學位級別】：碩士
【學位授予年份】：2011
【分類號】：R943
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