超临界溶液浸渍法制备缓控释给药系统
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摘要
超临界溶液浸溃法(supercritical solution impregnation, SSI)是一种利用超临界C02将活性物质负载到聚合物中的过程技术。目前,该技术主要用于纤维的染色和聚合物的共混等过程,在缓控释药物领域中的应用还较少涉及。本文将SSI过程与单分散聚合物微球制备技术相结合,开发了一种缓控释给药系统制备方法。全文内容主要分为三部分：SSI过程原理研究,粒径均一聚合物微球制备,利用SSI法将药物负载到微球中实现缓控释给药。
首先,对SSI过程原理进行了研究。选取罗红霉素(roxithromycin)为模型药物,左旋聚乳酸(poly(l-lactic acid), PLLA)膜为聚合物载体,考察了罗红霉素、PLLA和超临界C02三者之间的相互作用：
(1)使用静态法测定了罗红霉素在超临界C02中的溶解度。所测数据范围为温度40-60-C和压力10-30MPa之间,测得的溶解度y2最小值为1.47×10-5mol/mol,最大值为1.84x10-4mol/mol。随着压力的升高,溶解度相应增大。而温度对溶解度的影响较为复杂。选用了五种经验模型、三种溶解度参数模型拟合和关联了溶解度数据。其中,SS模型、SP-RM模型和SP-3模型的拟合效果明显优于其它模型,平均相对偏差(AARD)为6.36-6.83%。
(2)使用重量变化法研究了超临界CO2在PLLA膜中的吸附及扩散行为。所测数据范围为温度40-60℃和压力10.0-20.0MPa。CO2在PLLA膜中的平衡吸附量Ms,∞随着压力的升高而增大,相反随着温度的升高而降低。脱附过程扩散系数Dd与平衡吸附量Ms,∞密切相关。当Ms,∞从8.3%增大到16.9%时,Dd从0.25x10-11m2/s增加到2.57x10-11m2/s,增大了约10倍。吸附过程扩散系数Ds与Dd处于同一数量级。选用溶胀模型、SP-4模型拟合和关联了实验数据。溶胀模型的AARD小于1%。SP-4模型的AARD也仅为1.94%。
(3)研究了超临界C02条件下罗红霉素在PLLA膜中的吸附行为,考察了浸渍时间(0.5-4.0h)、浸渍压力(8.0-30.0MPa)、浸渍温度(40-70℃)等操作条件对载药量的影响。当浸渍时间为2h,载药量已达到平衡值。载药量随浸渍压力升高而增加。浸渍温度对载药量的影响较为复杂。扫描电镜(SEM)照片显示SSI过程没有引起PLLA膜表面和截面的形貌变化,差示扫描量热(DSC)数据和X射线衍射(XRD)谱图表明以罗红霉素以无定形态均匀分散在PLLA基质中,可能为分子级分散。顶空气相色谱数据显示SSI过程能有效去除溶剂残留。体外缓释实验表明载药PLLA膜具有长期缓慢释放药物的性能。最后,计算了罗红霉素在聚合物相和超临界相之间的分配系数K。
其次,采用改进的锐孔法制备出粒径均一的PLLA微球。考察了油相流速、搅拌器转速、PLLA浓度和锐孔内径大小等因素对微球平均粒径(d)和变异系数(CV)的影响。通过减小锐孔内径能有效降低CV值。用内径50μm玻璃毛细管针头取代#4.5金属针头,成功使CV值从26.13%降低到17.59%。所得微球的球形度好,粒径可控且分布窄。
最后,使用SSI法将罗红霉素负载到四种不同粒径大小的PLLA微球中,考察了浸渍时间、微球粒径、浸渍压力、浸渍温度等因素对微球的总载药量、表面载药量及其内部载药量的影响。当浸渍时间达到3h以上,微球的内部载药量达到平衡值。随着微球粒径的减小,内部载药量呈下降趋势,而表面载药量呈增大趋势。微球粒径越小,经SSI处理后粘连越严重。总载药量、表面载药量和内部载药量随浸渍压力升高而增加。浸渍温度对载药量的影响较为复杂。SEM照片显示当微球粒径小于5μm时,极易粘连成块状。DSC数据显示罗红霉素主要以无定形态分布于微球中。四种微球的体外缓释实验表明SSI方法制备的载药微球具有良好的缓释性能。
此外,本文还对SSI法负载药物制备缓控释给药系统的适用范围进行了探讨。选取了三种药物包括胆固醇、阿司匹林、罗红霉素和三种聚合物如聚乙烯、聚苯乙烯、聚乙烯醇,考察了聚合物与药物溶解度参数之差(Δδ)的绝对值与载药量的关系。结果表明SSI法适用的药物较广,可选择的聚合物范围较宽；对于给定的药物,可将其与聚合物的Aδ作为选取合适载体材料的依据。
SSI法具有过程效率高、载体形式灵活、可去除有机溶剂残留等优点。本文成功地将SSI法与粒径均一聚合物微球制备技术相结合,为缓控释药物微球的制备提供了一条新的途径。
Supercritical solution impregnation (SSI) is a process technology to load active compounds onto/into polymer matrices using supercritical carbon dioxide (SCCO2). At present, it is mainly utilized in fabric dyeing, polymer blending, etc., and its application in the preparation of sustained-/controlled-release drug delivery system (SCRDDS) is rarely reported. This work combines the SSI technology with preparation of monodisperse polymer microparticles to develop a process of SCRDDS formulation. The contents of the thesis consist of three main parts:principle of SSI process, preparation of monodisperse polymer microparticles, and loading of drug into microparticles with SSI method.
Firstly, the principle of SSI process was studied in detail, in which roxithromycin and poly (l-lactic acid)(PLLA) were selected as model drug and polymer matrix respectively. The interactions among CO2, roxithromycin and PLLA were examined as follows:
(1) Solubility of roxithromycin in SCCO2was measured with the static method at temperature range from40to60℃, and pressure from10to30MPa. The minimum of solubility, y2, was determined at1.47×10-5mol/mol, and the maximum was1.84×10-4mol/mol. With the pressure elevating, solubility data increased correspondingly. The effect of temperature on solubility was more complex. Five empirical models and three solubility parameter models were chosen to fit and correlate the obtained solubility data. Among them, correlations of SS model, SP-RM model and SP-3model were better than that of other models, and the average absolute relative deviation (AARD) ranged from6.36%to6.83%.
(2) Sorption and diffusion behavior of CO2in PLLA film was examined with the weight variation method at temperature of40-60℃and pressure of10-30MPa. Equilibrium sorption amount, Ms,∞, increased with the elevation of pressure, while increased with the descending of temperature. Desorption diffusion coefficient, Dd, was greatly influenced by Ms,∞. Along with Ms,∞increasing from8.3%to16.9%, Dd expanded approximately10times from0.25x10-11m2/s to2.57x10-11m2/s. Sorption diffusion coefficient, Ds, was in the same order of magnitude as Dd at supercritical conditions. The swelling model and SP-4model were selected to correlate the sorption data. AARD of swelling model was below1%, and AARD of SP-4was only1.94%.
(3) Sorption of roxithromycin into PLLA film at SCCO2was determined. The effect of impregnation time (0.5-4.0h), impregnation pressure (8-30MPa), and impregnation temperature (40-70℃) on drug loading capacity(DLC) was investigated. With the time prolonging, DLC approached up to an equilibrium value. At a certain temperature, DLC increased with the elevating of impregnation pressure. The relationship between impregnation temperature and DLC was more complicated. SEM photos showed that no obvious change was observed for the surface and cross-over morphologies of PLLA film. DSC data and XRD spectra implied that roxithromycin could be molecularly dispersed into PLLA film, and headspace gas chromatography data demonstrated that SSI process could remove solvent residual effectively. In vitro release data indicated that drug-loaded PLLA film could slowly release drug for a long period. Besides, partition coefficient (K) of roxithromycin between polymer phase and supercritical phase was calculated.
Secondly, an improved orifice method was developed to prepare monodisperse PLLA microparticles. The effects of oil phase flow rate, stirring rate, PLLA concentration, and inner diameter of orifice on average diameter (d) and coefficient of variation (CV) were investigated. Decreasing orifice inner diameter was a valid way to reduce the CV value.Using glass capillary instead of#4.5metal needle, the CV droped greatly from26.13%to17.59%. The microparticles prepared with the improved orifice method presented perfectly spherical shape and narrow size distribution.
Finally, roxithromycin was loaded into PLLA microparticles with four different size distributions using SSI method. The effects of impregnation time, microparticles size, impregnation pressure and temperature on total drug loading capacity (TDLC), surface drug loading capacity (SDLC), and interior drug loading capacity (IDLC) were investigated. When impregnation time was above3h, IDLC of microparticles achieved an equilibrium value. With reducing of microparticles size, IDLC decreased while SDLC increased. The smaller micropartciles were prone to adhere to each other. With rising of impregnation pressure, TDLC, SDLC and IDLC increased. The effects of impregnation temperature on TDLC, IDLC and SDLC were more complex. SEM photos indicated that microparticles with diameter below5μm were aggregated badly to form a block. DSC data implied that roxithromycin was dispersed into PLLA microparticles mainly in an amorphous state. In vitro release curves showed that all of drug-loaded microparticles with different size distribution could release slowly for a long period.
Furthermore, the application of SSI technology in SCRDDS field was discussed. Three drugs (cholesterol, aspirin and roxithromycin) and three polymers (polyethylene, polystyrene and polyvinyl alcohol) were selected to investigate the effects of solubility parameter difference (△δ) between drug and polymer on DLC. The results demonstrate that SSI process is available for most of drugs using polymers in a wide range. For a certain SCRDDS,△δ between the drug and a polymer could be a criterion to choose a proper polymer matrix.
The advantages of SSI method include the high production efficiency, the shape diversity of polymer matrix, and the removal of solvent residual. This work successfully combines SSI technology with monodisperse polymer microparticles preparation to provide a new process to produce SCRDDS formulation.
首先,对SSI过程原理进行了研究。选取罗红霉素(roxithromycin)为模型药物,左旋聚乳酸(poly(l-lactic acid), PLLA)膜为聚合物载体,考察了罗红霉素、PLLA和超临界C02三者之间的相互作用：
(1)使用静态法测定了罗红霉素在超临界C02中的溶解度。所测数据范围为温度40-60-C和压力10-30MPa之间,测得的溶解度y2最小值为1.47×10-5mol/mol,最大值为1.84x10-4mol/mol。随着压力的升高,溶解度相应增大。而温度对溶解度的影响较为复杂。选用了五种经验模型、三种溶解度参数模型拟合和关联了溶解度数据。其中,SS模型、SP-RM模型和SP-3模型的拟合效果明显优于其它模型,平均相对偏差(AARD)为6.36-6.83%。
(2)使用重量变化法研究了超临界CO2在PLLA膜中的吸附及扩散行为。所测数据范围为温度40-60℃和压力10.0-20.0MPa。CO2在PLLA膜中的平衡吸附量Ms,∞随着压力的升高而增大,相反随着温度的升高而降低。脱附过程扩散系数Dd与平衡吸附量Ms,∞密切相关。当Ms,∞从8.3%增大到16.9%时,Dd从0.25x10-11m2/s增加到2.57x10-11m2/s,增大了约10倍。吸附过程扩散系数Ds与Dd处于同一数量级。选用溶胀模型、SP-4模型拟合和关联了实验数据。溶胀模型的AARD小于1%。SP-4模型的AARD也仅为1.94%。
(3)研究了超临界C02条件下罗红霉素在PLLA膜中的吸附行为,考察了浸渍时间(0.5-4.0h)、浸渍压力(8.0-30.0MPa)、浸渍温度(40-70℃)等操作条件对载药量的影响。当浸渍时间为2h,载药量已达到平衡值。载药量随浸渍压力升高而增加。浸渍温度对载药量的影响较为复杂。扫描电镜(SEM)照片显示SSI过程没有引起PLLA膜表面和截面的形貌变化,差示扫描量热(DSC)数据和X射线衍射(XRD)谱图表明以罗红霉素以无定形态均匀分散在PLLA基质中,可能为分子级分散。顶空气相色谱数据显示SSI过程能有效去除溶剂残留。体外缓释实验表明载药PLLA膜具有长期缓慢释放药物的性能。最后,计算了罗红霉素在聚合物相和超临界相之间的分配系数K。
其次,采用改进的锐孔法制备出粒径均一的PLLA微球。考察了油相流速、搅拌器转速、PLLA浓度和锐孔内径大小等因素对微球平均粒径(d)和变异系数(CV)的影响。通过减小锐孔内径能有效降低CV值。用内径50μm玻璃毛细管针头取代#4.5金属针头,成功使CV值从26.13%降低到17.59%。所得微球的球形度好,粒径可控且分布窄。
最后,使用SSI法将罗红霉素负载到四种不同粒径大小的PLLA微球中,考察了浸渍时间、微球粒径、浸渍压力、浸渍温度等因素对微球的总载药量、表面载药量及其内部载药量的影响。当浸渍时间达到3h以上,微球的内部载药量达到平衡值。随着微球粒径的减小,内部载药量呈下降趋势,而表面载药量呈增大趋势。微球粒径越小,经SSI处理后粘连越严重。总载药量、表面载药量和内部载药量随浸渍压力升高而增加。浸渍温度对载药量的影响较为复杂。SEM照片显示当微球粒径小于5μm时,极易粘连成块状。DSC数据显示罗红霉素主要以无定形态分布于微球中。四种微球的体外缓释实验表明SSI方法制备的载药微球具有良好的缓释性能。
此外,本文还对SSI法负载药物制备缓控释给药系统的适用范围进行了探讨。选取了三种药物包括胆固醇、阿司匹林、罗红霉素和三种聚合物如聚乙烯、聚苯乙烯、聚乙烯醇,考察了聚合物与药物溶解度参数之差(Δδ)的绝对值与载药量的关系。结果表明SSI法适用的药物较广,可选择的聚合物范围较宽；对于给定的药物,可将其与聚合物的Aδ作为选取合适载体材料的依据。
SSI法具有过程效率高、载体形式灵活、可去除有机溶剂残留等优点。本文成功地将SSI法与粒径均一聚合物微球制备技术相结合,为缓控释药物微球的制备提供了一条新的途径。
Supercritical solution impregnation (SSI) is a process technology to load active compounds onto/into polymer matrices using supercritical carbon dioxide (SCCO2). At present, it is mainly utilized in fabric dyeing, polymer blending, etc., and its application in the preparation of sustained-/controlled-release drug delivery system (SCRDDS) is rarely reported. This work combines the SSI technology with preparation of monodisperse polymer microparticles to develop a process of SCRDDS formulation. The contents of the thesis consist of three main parts:principle of SSI process, preparation of monodisperse polymer microparticles, and loading of drug into microparticles with SSI method.
Firstly, the principle of SSI process was studied in detail, in which roxithromycin and poly (l-lactic acid)(PLLA) were selected as model drug and polymer matrix respectively. The interactions among CO2, roxithromycin and PLLA were examined as follows:
(1) Solubility of roxithromycin in SCCO2was measured with the static method at temperature range from40to60℃, and pressure from10to30MPa. The minimum of solubility, y2, was determined at1.47×10-5mol/mol, and the maximum was1.84×10-4mol/mol. With the pressure elevating, solubility data increased correspondingly. The effect of temperature on solubility was more complex. Five empirical models and three solubility parameter models were chosen to fit and correlate the obtained solubility data. Among them, correlations of SS model, SP-RM model and SP-3model were better than that of other models, and the average absolute relative deviation (AARD) ranged from6.36%to6.83%.
(2) Sorption and diffusion behavior of CO2in PLLA film was examined with the weight variation method at temperature of40-60℃and pressure of10-30MPa. Equilibrium sorption amount, Ms,∞, increased with the elevation of pressure, while increased with the descending of temperature. Desorption diffusion coefficient, Dd, was greatly influenced by Ms,∞. Along with Ms,∞increasing from8.3%to16.9%, Dd expanded approximately10times from0.25x10-11m2/s to2.57x10-11m2/s. Sorption diffusion coefficient, Ds, was in the same order of magnitude as Dd at supercritical conditions. The swelling model and SP-4model were selected to correlate the sorption data. AARD of swelling model was below1%, and AARD of SP-4was only1.94%.
(3) Sorption of roxithromycin into PLLA film at SCCO2was determined. The effect of impregnation time (0.5-4.0h), impregnation pressure (8-30MPa), and impregnation temperature (40-70℃) on drug loading capacity(DLC) was investigated. With the time prolonging, DLC approached up to an equilibrium value. At a certain temperature, DLC increased with the elevating of impregnation pressure. The relationship between impregnation temperature and DLC was more complicated. SEM photos showed that no obvious change was observed for the surface and cross-over morphologies of PLLA film. DSC data and XRD spectra implied that roxithromycin could be molecularly dispersed into PLLA film, and headspace gas chromatography data demonstrated that SSI process could remove solvent residual effectively. In vitro release data indicated that drug-loaded PLLA film could slowly release drug for a long period. Besides, partition coefficient (K) of roxithromycin between polymer phase and supercritical phase was calculated.
Secondly, an improved orifice method was developed to prepare monodisperse PLLA microparticles. The effects of oil phase flow rate, stirring rate, PLLA concentration, and inner diameter of orifice on average diameter (d) and coefficient of variation (CV) were investigated. Decreasing orifice inner diameter was a valid way to reduce the CV value.Using glass capillary instead of#4.5metal needle, the CV droped greatly from26.13%to17.59%. The microparticles prepared with the improved orifice method presented perfectly spherical shape and narrow size distribution.
Finally, roxithromycin was loaded into PLLA microparticles with four different size distributions using SSI method. The effects of impregnation time, microparticles size, impregnation pressure and temperature on total drug loading capacity (TDLC), surface drug loading capacity (SDLC), and interior drug loading capacity (IDLC) were investigated. When impregnation time was above3h, IDLC of microparticles achieved an equilibrium value. With reducing of microparticles size, IDLC decreased while SDLC increased. The smaller micropartciles were prone to adhere to each other. With rising of impregnation pressure, TDLC, SDLC and IDLC increased. The effects of impregnation temperature on TDLC, IDLC and SDLC were more complex. SEM photos indicated that microparticles with diameter below5μm were aggregated badly to form a block. DSC data implied that roxithromycin was dispersed into PLLA microparticles mainly in an amorphous state. In vitro release curves showed that all of drug-loaded microparticles with different size distribution could release slowly for a long period.
Furthermore, the application of SSI technology in SCRDDS field was discussed. Three drugs (cholesterol, aspirin and roxithromycin) and three polymers (polyethylene, polystyrene and polyvinyl alcohol) were selected to investigate the effects of solubility parameter difference (△δ) between drug and polymer on DLC. The results demonstrate that SSI process is available for most of drugs using polymers in a wide range. For a certain SCRDDS,△δ between the drug and a polymer could be a criterion to choose a proper polymer matrix.
The advantages of SSI method include the high production efficiency, the shape diversity of polymer matrix, and the removal of solvent residual. This work successfully combines SSI technology with monodisperse polymer microparticles preparation to provide a new process to produce SCRDDS formulation.
引文
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