微流控法制備納微結(jié)構(gòu)藥物顆粒的研究
發(fā)布時間：2018-12-21 21:41
【摘要】：納米藥物顆粒尺寸小、生物利用率高,具有傳統(tǒng)藥物制劑無法比擬的獨特優(yōu)勢。藥劑學(xué)中的納米顆�？梢苑殖杉{米藥物和納米載體,通過納米化技術(shù)將藥物加工成納米顆�；蚣{米分散體的成型和組裝加工技術(shù)具有重大的應(yīng)用前景、醫(yī)學(xué)學(xué)術(shù)價值和實用價值,是當前政府、學(xué)術(shù)界和工業(yè)界倍受青睞的前沿研究熱點課題。微通道反應(yīng)器具有強的微觀混合、傳質(zhì)和傳熱性能,已被廣泛應(yīng)用于多種無機納米顆粒的制備,但較少用于有機納米顆粒,特別是藥物納微顆粒的制備。鑒于此,本論文首先基于典型的Y型和線型微通道反應(yīng)器,分別選取口服型水難溶性藥物(保肝藥水飛薊賓)、吸入性藥物(糖皮質(zhì)激素類抗哮喘藥丙酸倍氯米松),以及藥物載體(聚乳酸-羥基乙酸共聚物(PLGA))為模型體系,進行微流控法藥物納微顆粒的可控制備研究；進一步,通過自制的高通量金屬套管式微通道進行抗生素藥頭孢呋辛酯納米顆粒的宏量制備研究。全文的主要內(nèi)容和創(chuàng)新點如下：1.基于Y型和線型微通道,采用反溶劑沉淀法結(jié)合噴霧干燥技術(shù)制備得到了在水中可再分散的水飛薊賓納米復(fù)合粉體及其水相透明分散體�？疾炝巳芤簼舛取⑷軇┝髁�、反溶劑流量、總流量、注入相和沉淀溫度等因素對顆粒粒徑的影響,研究發(fā)現(xiàn)：在實驗范圍內(nèi),注入相、液體流量和藥物濃度等對顆粒粒徑及粒度分布有重要影響。隨著溫度與溶劑流量的減小,顆粒粒徑迅速減小；隨著反溶劑流量、總流量與藥物濃度增加,顆粒粒徑先減小后增大；在線型微通道內(nèi),當溶劑為注入相時,所得顆粒粒徑更小。優(yōu)化制備條件后,所得產(chǎn)品的平均粒徑為30 nm。溶出性能研究表明：10分鐘內(nèi),水飛薊賓復(fù)合粉體的溶出速率可達97%以上,明顯優(yōu)于物理混合粉體的22%和原料藥的5%。2.進一步采用微流控反溶劑沉淀法,并結(jié)合高壓均質(zhì)和噴霧干燥技術(shù)制備丙酸倍氯米松納微顆粒�？疾炝吮砻婊钚詣�、溶劑和反溶劑流量、藥物濃度、高壓均質(zhì)和噴霧干燥條件等對顆粒粒徑和形貌的影響。結(jié)果表明：以甲醇和水為溶劑和反溶劑,不添加表面活性劑HPMC時,顆粒為細棒狀；添加HPMC后,顆粒為球形,其平均粒度為200～260 nm。此外,顆粒粒徑隨著溶劑流量的降低、反溶劑流量的增大、沉淀溫度的降低而減��；隨著藥物濃度的增大先減小后增加。進一步結(jié)合高壓均質(zhì)—噴霧干燥技術(shù),在不添加表面活性劑的條件下,可制備得到丙酸倍氯米松多孔微球。提高進料速度和干燥溫度、減小漿料中顆粒粒徑,可得到1～3μm丙酸倍氯米松多孔微球；肺部沉積性能研究表明,所得的丙酸倍氯米松多孔微球產(chǎn)品的FPFemitted為68.39%,真空干燥產(chǎn)品和原料藥分別僅為47.25%和24.76%。3.采用微流控反溶劑沉淀法制備藥物載體PLGA及載藥PLGA納米顆粒分散體。論文選取丙酮-水為溶劑-反溶劑體系,采用泊洛沙姆188為表面活性劑,制備PLGA納米顆粒分散體。考察了反應(yīng)溶液濃度、表面活性劑用量、流量以及注入相和反應(yīng)溫度對顆粒制備的影響,研究發(fā)現(xiàn),在Y型微通道內(nèi),隨著溫度和溶劑流量的降低,顆粒粒徑減��；隨著溶液濃度、反溶劑流量及總流量的增大,顆粒粒徑先減小后增大。在線型微通道內(nèi),當反溶劑為注入相時,所得顆粒粒徑更�。活w粒粒徑隨著溶劑流量的降低、反溶劑流量及總流量的增大而減小。優(yōu)化制備條件后,所得產(chǎn)品的平均粒徑為60-70nm。在Y型微通道內(nèi),進一步選擇伏立康唑為模型藥物,制備得到了PLGA載藥納米顆粒。研究發(fā)現(xiàn),PLGA載藥納米顆粒的粒徑隨著伏立康唑濃度的提高而增加；載藥PLGA納米顆粒的溶出明顯延長。4.基于上述研究,進一步采用自行設(shè)計和研制的高通量金屬套管式微通道反應(yīng)器(其處理量較典型Y型或線型微通道提高2個數(shù)量級),進行頭孢呋辛酯納米顆粒的宏量制備研究。重點考察了溶劑/反溶劑體積比、藥物濃度、流量、微孔孔徑、套管環(huán)隙尺寸等對顆粒粒徑和分布的影響規(guī)律。結(jié)果表明,顆粒粒徑隨兩相總流量的增大而減小；隨反應(yīng)器微孔孔徑和套管環(huán)隙尺寸的減小而減小。優(yōu)化條件后,可制備得到平均粒徑大約為300 nm的頭孢呋辛酯顆粒,與Y型或線型微通道反應(yīng)器結(jié)果一致。可見,此高通量微通道反應(yīng)器將可望滿足實際應(yīng)用的需求。上述研究結(jié)果表明,微通道反應(yīng)器在有機藥物納微顆粒的制備方面展現(xiàn)了良好的應(yīng)用前景。
[Abstract]:The nano medicine has the advantages of small size, high bioavailability, and can not be compared with the traditional medicinal preparation. the nano-particles in the pharmacy can be divided into a nano medicine and a nano carrier, and the forming and assembling and processing technology for processing the medicine into the nano-particles or the nano-dispersion by the nano-technology has a great application prospect, The academia and industry are in favor of leading research hot topics. The micro-channel reactor has strong micro-mixing, mass transfer and heat transfer performance, has been widely used in the preparation of various inorganic nano-particles, but is less used for the preparation of organic nano-particles, in particular drug nano-particles. In view of this, the present paper is based on the typical Y-type and linear micro-channel reactor, and selects the oral-type water-insoluble medicine (the liver-protecting liquid medicine fly-in-bin) and the inhalant medicine (the anti-asthma medicine propionate-betamethasone). and the drug carrier (polylactic acid-glycolic acid copolymer (PLGA)) is a model system, and the controllable preparation of the micro-flow control method drug nano-particles is carried out; further, A self-made high-flux metal sleeve type micro-channel is used for preparing the macro-amount preparation of the antibiotic-drug ceftriocine-ester nano-particles. The main content and innovation points of the full text are as follows: 1. Based on the Y-type and linear micro-channels, the water-free and water-phase transparent dispersion which can be re-dispersed in water is prepared by adopting an anti-solvent precipitation method and a spray drying technology. The effects of solution concentration, solvent flow, anti-solvent flow, total flow, injection phase and precipitation temperature on the particle size were investigated. With the decrease of the temperature and the flow of the solvent, the particle size of the particles is decreased rapidly; with the increase of the flux of the anti-solvent, the total flow and the drug concentration, the particle size of the particles is reduced, and the particle size of the particle is smaller in the linear micro-channel, and the particle size of the obtained particles is smaller when the solvent is the injection phase. After the preparation conditions were optimized, the average particle diameter of the obtained product was 30 nm. The study of the dissolution performance shows that the dissolution rate of the composite powder of the water-flying gabion can reach more than 97% in 10 minutes, which is obviously better than that of the physical mixed powder and 5% of the drug substance. the micro-flow-controlled anti-solvent precipitation method is further adopted, and the propionate micro-particles are prepared by combining the high-pressure homogenization and the spray drying technology. The effects of surfactant, solvent and anti-solvent flow, drug concentration, high pressure homogenization and spray-drying conditions on the particle size and morphology were investigated. The results show that the particle is fine rod when the methanol and water are used as the solvent and the anti-solvent and the surface active agent HPMC is not added; after the HPMC is added, the particles are spherical, and the average particle size is 200-260nm. in addition, that particle size of the particle decrease with the decrease of the flow of the solvent, the increase in the flow of the anti-solvent, and the decrease of the precipitation temperature; and as the increase of the drug concentration is first decrease, the increase is increased. and further combining the high-pressure homogeneous spray-drying technology, and under the condition of not adding a surfactant, the propionate porous microspheres can be prepared. The feed rate and the drying temperature were increased, the particle size of the slurry was reduced, and the porous microspheres of 1-3. m and the drug carrier PLGA and the drug-loaded PLGA nano-particle dispersion are prepared by adopting a micro-flow-controlled anti-solvent precipitation method. In this paper, acetone-water is selected as the solvent-antisolvent system, and poloxamer 188 is used as the surface active agent to prepare the PLGA nano-particle dispersion. The effects of the concentration of the reaction solution, the amount of the surfactant, the flow rate and the injection phase and the reaction temperature on the preparation of the particles were investigated. The flow of the anti-solvent and the total flow rate are increased, and the particle size of the particles is firstly reduced. In the linear micro-channel, when the anti-solvent is the injection phase, the particle size of the obtained particles is smaller, and the particle size of the particles decreases with the decrease of the solvent flow rate, the anti-solvent flow rate and the total flow. After the preparation conditions are optimized, the average particle size of the obtained product is 60-70nm. In the Y-type micro-channel, the V-Liankang-type drug is further selected as a model drug, and the PLGA-loaded nano-particles are prepared. The results showed that the particle size of the PLGA nano-particles increased with the increase of the concentration of V-Likang, and the solubility of the drug-loaded PLGA nano-particles was significantly prolonged. Based on the above research, a high-flux metal-casing micro-channel reactor designed and developed (with a treatment capacity of 2 orders of magnitude higher than that of a typical Y-type or linear microchannel) was further studied. The influence of solvent/ antisolvent volume ratio, drug concentration, flow rate, pore size and casing annulus size on the particle size and distribution was investigated. The results show that the particle size decreases with the increase of the total flow of the two phases, and decreases with the decrease of the pore size of the reactor and the size of the annulus. After the optimization conditions, the ceftriocine ester particles having an average particle size of about 300 nm can be prepared in accordance with the results of the Y-or linear microchannel reactor. It can be seen that this high-throughput microchannel reactor will be expected to meet the needs of the actual application. The results show that the micro-channel reactor has a good application prospect in the preparation of the organic nano-particles.
【學(xué)位授予單位】：北京化工大學(xué)
【學(xué)位級別】：博士
【學(xué)位授予年份】：2015
【分類號】：TQ460.1;TB383.1
本文編號：2389503
[Abstract]:The nano medicine has the advantages of small size, high bioavailability, and can not be compared with the traditional medicinal preparation. the nano-particles in the pharmacy can be divided into a nano medicine and a nano carrier, and the forming and assembling and processing technology for processing the medicine into the nano-particles or the nano-dispersion by the nano-technology has a great application prospect, The academia and industry are in favor of leading research hot topics. The micro-channel reactor has strong micro-mixing, mass transfer and heat transfer performance, has been widely used in the preparation of various inorganic nano-particles, but is less used for the preparation of organic nano-particles, in particular drug nano-particles. In view of this, the present paper is based on the typical Y-type and linear micro-channel reactor, and selects the oral-type water-insoluble medicine (the liver-protecting liquid medicine fly-in-bin) and the inhalant medicine (the anti-asthma medicine propionate-betamethasone). and the drug carrier (polylactic acid-glycolic acid copolymer (PLGA)) is a model system, and the controllable preparation of the micro-flow control method drug nano-particles is carried out; further, A self-made high-flux metal sleeve type micro-channel is used for preparing the macro-amount preparation of the antibiotic-drug ceftriocine-ester nano-particles. The main content and innovation points of the full text are as follows: 1. Based on the Y-type and linear micro-channels, the water-free and water-phase transparent dispersion which can be re-dispersed in water is prepared by adopting an anti-solvent precipitation method and a spray drying technology. The effects of solution concentration, solvent flow, anti-solvent flow, total flow, injection phase and precipitation temperature on the particle size were investigated. With the decrease of the temperature and the flow of the solvent, the particle size of the particles is decreased rapidly; with the increase of the flux of the anti-solvent, the total flow and the drug concentration, the particle size of the particles is reduced, and the particle size of the particle is smaller in the linear micro-channel, and the particle size of the obtained particles is smaller when the solvent is the injection phase. After the preparation conditions were optimized, the average particle diameter of the obtained product was 30 nm. The study of the dissolution performance shows that the dissolution rate of the composite powder of the water-flying gabion can reach more than 97% in 10 minutes, which is obviously better than that of the physical mixed powder and 5% of the drug substance. the micro-flow-controlled anti-solvent precipitation method is further adopted, and the propionate micro-particles are prepared by combining the high-pressure homogenization and the spray drying technology. The effects of surfactant, solvent and anti-solvent flow, drug concentration, high pressure homogenization and spray-drying conditions on the particle size and morphology were investigated. The results show that the particle is fine rod when the methanol and water are used as the solvent and the anti-solvent and the surface active agent HPMC is not added; after the HPMC is added, the particles are spherical, and the average particle size is 200-260nm. in addition, that particle size of the particle decrease with the decrease of the flow of the solvent, the increase in the flow of the anti-solvent, and the decrease of the precipitation temperature; and as the increase of the drug concentration is first decrease, the increase is increased. and further combining the high-pressure homogeneous spray-drying technology, and under the condition of not adding a surfactant, the propionate porous microspheres can be prepared. The feed rate and the drying temperature were increased, the particle size of the slurry was reduced, and the porous microspheres of 1-3. m and the drug carrier PLGA and the drug-loaded PLGA nano-particle dispersion are prepared by adopting a micro-flow-controlled anti-solvent precipitation method. In this paper, acetone-water is selected as the solvent-antisolvent system, and poloxamer 188 is used as the surface active agent to prepare the PLGA nano-particle dispersion. The effects of the concentration of the reaction solution, the amount of the surfactant, the flow rate and the injection phase and the reaction temperature on the preparation of the particles were investigated. The flow of the anti-solvent and the total flow rate are increased, and the particle size of the particles is firstly reduced. In the linear micro-channel, when the anti-solvent is the injection phase, the particle size of the obtained particles is smaller, and the particle size of the particles decreases with the decrease of the solvent flow rate, the anti-solvent flow rate and the total flow. After the preparation conditions are optimized, the average particle size of the obtained product is 60-70nm. In the Y-type micro-channel, the V-Liankang-type drug is further selected as a model drug, and the PLGA-loaded nano-particles are prepared. The results showed that the particle size of the PLGA nano-particles increased with the increase of the concentration of V-Likang, and the solubility of the drug-loaded PLGA nano-particles was significantly prolonged. Based on the above research, a high-flux metal-casing micro-channel reactor designed and developed (with a treatment capacity of 2 orders of magnitude higher than that of a typical Y-type or linear microchannel) was further studied. The influence of solvent/ antisolvent volume ratio, drug concentration, flow rate, pore size and casing annulus size on the particle size and distribution was investigated. The results show that the particle size decreases with the increase of the total flow of the two phases, and decreases with the decrease of the pore size of the reactor and the size of the annulus. After the optimization conditions, the ceftriocine ester particles having an average particle size of about 300 nm can be prepared in accordance with the results of the Y-or linear microchannel reactor. It can be seen that this high-throughput microchannel reactor will be expected to meet the needs of the actual application. The results show that the micro-channel reactor has a good application prospect in the preparation of the organic nano-particles.
【學(xué)位授予單位】：北京化工大學(xué)
【學(xué)位級別】：博士
【學(xué)位授予年份】：2015
【分類號】：TQ460.1;TB383.1
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