微流控法制备纳微结构药物颗粒的研究

发布时间：2018-12-21 21:41

【摘要】：纳米药物颗粒尺寸小、生物利用率高,具有传统药物制剂无法比拟的独特优势。药剂学中的纳米颗粒可以分成纳米药物和纳米载体,通过纳米化技术将药物加工成纳米颗粒或纳米分散体的成型和组装加工技术具有重大的应用前景、医学学术价值和实用价值,是当前政府、学术界和工业界倍受青睐的前沿研究热点课题。微通道反应器具有强的微观混合、传质和传热性能,已被广泛应用于多种无机纳米颗粒的制备,但较少用于有机纳米颗粒,特别是药物纳微颗粒的制备。鉴于此,本论文首先基于典型的Y型和线型微通道反应器,分别选取口服型水难溶性药物(保肝药水飞蓟宾)、吸入性药物(糖皮质激素类抗哮喘药丙酸倍氯米松),以及药物载体(聚乳酸-羟基乙酸共聚物(PLGA))为模型体系,进行微流控法药物纳微颗粒的可控制备研究；进一步,通过自制的高通量金属套管式微通道进行抗生素药头孢呋辛酯纳米颗粒的宏量制备研究。全文的主要内容和创新点如下：1.基于Y型和线型微通道,采用反溶剂沉淀法结合喷雾干燥技术制备得到了在水中可再分散的水飞蓟宾纳米复合粉体及其水相透明分散体。考察了溶液浓度、溶剂流量、反溶剂流量、总流量、注入相和沉淀温度等因素对颗粒粒径的影响,研究发现：在实验范围内,注入相、液体流量和药物浓度等对颗粒粒径及粒度分布有重要影响。随着温度与溶剂流量的减小,颗粒粒径迅速减小；随着反溶剂流量、总流量与药物浓度增加,颗粒粒径先减小后增大；在线型微通道内,当溶剂为注入相时,所得颗粒粒径更小。优化制备条件后,所得产品的平均粒径为30 nm。溶出性能研究表明：10分钟内,水飞蓟宾复合粉体的溶出速率可达97%以上,明显优于物理混合粉体的22%和原料药的5%。2.进一步采用微流控反溶剂沉淀法,并结合高压均质和喷雾干燥技术制备丙酸倍氯米松纳微颗粒。考察了表面活性剂、溶剂和反溶剂流量、药物浓度、高压均质和喷雾干燥条件等对颗粒粒径和形貌的影响。结果表明：以甲醇和水为溶剂和反溶剂,不添加表面活性剂HPMC时,颗粒为细棒状；添加HPMC后,颗粒为球形,其平均粒度为200～260 nm。此外,颗粒粒径随着溶剂流量的降低、反溶剂流量的增大、沉淀温度的降低而减小；随着药物浓度的增大先减小后增加。进一步结合高压均质—喷雾干燥技术,在不添加表面活性剂的条件下,可制备得到丙酸倍氯米松多孔微球。提高进料速度和干燥温度、减小浆料中颗粒粒径,可得到1～3μm丙酸倍氯米松多孔微球；肺部沉积性能研究表明,所得的丙酸倍氯米松多孔微球产品的FPFemitted为68.39%,真空干燥产品和原料药分别仅为47.25%和24.76%。3.采用微流控反溶剂沉淀法制备药物载体PLGA及载药PLGA纳米颗粒分散体。论文选取丙酮-水为溶剂-反溶剂体系,采用泊洛沙姆188为表面活性剂,制备PLGA纳米颗粒分散体。考察了反应溶液浓度、表面活性剂用量、流量以及注入相和反应温度对颗粒制备的影响,研究发现,在Y型微通道内,随着温度和溶剂流量的降低,颗粒粒径减小；随着溶液浓度、反溶剂流量及总流量的增大,颗粒粒径先减小后增大。在线型微通道内,当反溶剂为注入相时,所得颗粒粒径更小；颗粒粒径随着溶剂流量的降低、反溶剂流量及总流量的增大而减小。优化制备条件后,所得产品的平均粒径为60-70nm。在Y型微通道内,进一步选择伏立康唑为模型药物,制备得到了PLGA载药纳米颗粒。研究发现,PLGA载药纳米颗粒的粒径随着伏立康唑浓度的提高而增加；载药PLGA纳米颗粒的溶出明显延长。4.基于上述研究,进一步采用自行设计和研制的高通量金属套管式微通道反应器(其处理量较典型Y型或线型微通道提高2个数量级),进行头孢呋辛酯纳米颗粒的宏量制备研究。重点考察了溶剂/反溶剂体积比、药物浓度、流量、微孔孔径、套管环隙尺寸等对颗粒粒径和分布的影响规律。结果表明,颗粒粒径随两相总流量的增大而减小；随反应器微孔孔径和套管环隙尺寸的减小而减小。优化条件后,可制备得到平均粒径大约为300 nm的头孢呋辛酯颗粒,与Y型或线型微通道反应器结果一致。可见,此高通量微通道反应器将可望满足实际应用的需求。上述研究结果表明,微通道反应器在有机药物纳微颗粒的制备方面展现了良好的应用前景。
[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.
【学位授予单位】：北京化工大学
【学位级别】：博士
【学位授予年份】：2015
【分类号】：TQ460.1;TB383.1

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