基于三维打印技术的植入式给药系统研究
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摘要
植入式给药系统是直接在病灶部位释药的创新制剂,植入部位药物浓度高,而进入血液的药物浓度很低。三维打印技术依据“逐层打印,层层叠加”的概念来制备具有特殊外型或复杂内部结构的物体,具有传统制造业上从未有过的高度灵活、精确可控、制备工艺自动化高的特点。在本研究中,我们考虑用三维打印技术制备植入式给药系统,分别探讨了三维打印技术用于植入式给药系统的打印液选择、操作工艺参数;设计了合理的植入式给药系统结构,提供可作为骨科病灶内植入给药的缓控体系,并进行了其体外和植入家兔体内释药行为研究。完成的研究工作包括以下几个方面:
(1)分别对聚乳酸粉末颗粒大小、打印液选择以及打印参数进行了研究。结果表明当聚乳酸粉末颗粒较小时,得到的植入剂比较致密精细,而当聚乳酸粉末颗粒较大时,植入剂就显得松脆。聚乳酸颗粒合适的尺寸应控制在Φ150μm～175μm范围内。三维打印打印液选择方面,以丙酮为主的混合溶剂最佳的成分配比是:丙酮100ml,乙醇20ml,水5ml,甘油0.4ml,SLS 0.2g。对三维打印工艺参数进行了优化,比较合适的参数值分别为:打印液流速1.4g/min,喷头移动速度150cm/s,粉末铺层厚度200μm,线间距100μm。
(2)对植入式给药系统的传统工艺方法和三维打印方法进行了比较研究,结果表明采用两种方法制备的制剂都有明显分布的空隙,三维打印法制备的植入剂,其整个截面微孔均匀分布;而传统工艺制备的植入剂截面的微孔集聚一起,而且大小不匀,有个别较大的微孔存在。其体外释放行为表明采用两种方法制备的制剂体外释药都有爆发释放量,三维打印技术制备的庆大霉素植入剂的初始爆发释放浓度相对较低,而传统工艺制备的庆大霉素植入剂在2天时获得68μg/ml的爆发释放,使得药物成分在初始阶段出现大量释放。
(3)利用三维打印技术制备了庆大霉素植入剂,①骨架结构植入剂:聚乳酸相对分子质量越大,释药就越慢;载有大剂量药物的植入剂在初始阶段就易于释放出来;通过PCL或HA与载体聚乳酸共混可以达到调控释放的作用。药物释放是载体材料的降解和药物溶解扩散的综合机制。②三明治结构植入剂:三明治结构能起到降低药物的释放表面积的作用,可以明显抑制爆发释放,相对于传统制备工艺,三维打印技术可以在一定程度上方便控制剂型的空间结构。
(4)利用三维打印技术制备了左氟沙星植入剂,①滞后释放植入剂:药物成分被包裹在制剂的囊心中,从而导致药物滞后释放;药物释放受囊心外的壳部性质影响较大,要获得比较长时间的滞后释药,包围囊心部分的壳厚度就要越大。②分阶段释放植入剂:左氟沙星释放分三个阶段,第一阶段开始阶段出现一定的爆发释放,然后释放慢慢减缓,第二阶段维持平稳浓度释放,第三阶段出现增大的趋势,最大浓度之后就不断降低。植入剂具有长效缓释和控制释放的特性,出现分阶段的释放行为主要由植入剂的几何结构决定。
(5)利用三维打印技术制备了含多种药物的植入式给药系统,①简单结构多药物植入剂(左氟沙星和利福平混合药物的骨架结构植入剂A和左氟沙星和利福平分别位于双层结构中一个骨架层的植入剂B)体外释放行为研究表明,左氟沙星更容易释放出来,而利福平释放速度比较慢;左氟沙星从制剂A比B中更易于释放出来;而利福平在制剂B比在A中释放速度稍快些,基本相当。②复杂结构多药物植入剂(左氟沙星位于囊心结构层囊心,利福平位于骨架层的植入剂C和利福平位于囊心结构层囊心,左氟沙星位于骨架层的植入剂D)体外释放行为研究表明,可以实现利福平先释放,20天后左氟沙星开始释放;或左氟沙星先释放,35天左右利福平开始释放,获得两种药物分阶段释放。
(6)研究了多药物植入式药剂体外抑菌行为,结果表明在整个实验时间(40天)内都可起到一定的抑菌作用,对大肠杆菌的抑菌作用出现双峰现象,而对金黄色葡萄球菌来说,植入剂的抑菌能力就呈现一直缓慢减小的趋势。
(7)研究了多药物植入式给药系统植入家兔体内的释放行为,结果表明多药物植入式药剂植入兔股骨后,左氟沙星和利福平先后分阶段释放出来,两者的局部骨组织能够达到有效的药物浓度并且持续时间长,而血药浓度也是先后出现,但始终保持较低水平。说明这种植入式给药系统可以实现双药物分阶段控制释放。家兔经植入多药物制剂后的骨组织初步观察研究发现,局部无软组织感染或骨质破坏,无明显死骨形成。植入式给药系统植入切口愈合好,未见分泌物和淤血,由此显示植入式药剂具有良好生物相容性。
Implantable drug delivery system (IDDS) is a novel drug delivery forms by which the drug liberates directly in disease focus. Three-dimensional printing (3DP) is a solid freeform fabrication technique, which employs powder processing in the construction of parts in a layer-wise manner. It is capable of fabricating parts such as special exterior shapes, complex inner structures and so on. In the present study, the 3DP technology was introduced to fabricate the IDDS. The polymer material, the selection of binder and the process for 3DP were investigated, respectively. And the IDDS have special designed and fabricated by 3DP to furnish the desired drug rlease profiles. The IDDS was also implanted in rabbit for in vivo investigation. The resulted IDDS have been evaluated. The main results are as follows:
(1) The polymer material, the selection of binder and the process for 3DP were investigated, respectively. The optical particles size of biodegradable polymer PLAs for 3DP wasΦ150μm～175μm. The binder was solutions with acetone 100ml,ethanal 20ml,water 5ml,glycerol 0.4ml,SLS 0.2g. The general optimal processes are: powder layer height (200μm), binder line spacing (100μm), binder printed speed (1.4g/min), binder flow rate (150cm/s). The results demonstrated that 3DP had superior preparing flexibility.
(2) Compared with the IDDS made by conventional process method, 3DP impalnt showed more uniform inner structure. The implant made by conventional compress process appears to have fewer pores while the implant made by 3D printing was more porous and uniform.With gentamicin as a model drug, the implants made by conventional and 3DP process showed the burst release in vitro. However there is some different in which the burst release can be lower concentration from implant by 3DP than that by conventional process, thus will relatively prolong the whole release. The gentamicin gained 68μg/ml at 2nd day, which means that a lot of gentamicin was released at first.
(3) Study on the single gentamicin IDDS preparation by 3DP and in vitro release was investigated.①Study of the IDDS with matrix structure reveal that the burst release was much smaller for lower loading implant. The burst release was due to the dissolution or diffusion of drug particles attached or near the surface. The mixture of PCL or HA and PLA affected the drug release easily. The mechanism of release was combination with degradation of PLA and drug diffusion.②The IDDS with sandwich structure loading gentamicin could sharply decrease the initial burst release.
(4) Study on the single levofloxacin (LVFX) IDDS preparation by 3DP and in vitro release was investigated.①IDDS with a delay release time showed that more complicated structure implant with LVFX as drug by 3DP was achived to release with a delay time. To gain longer lag time, a thicker shell of the IDDS was needed.②A sort of implant with multi-phase release was developed: the first was with a burst release; the second at constant concentration; the third with a small increscent release before falling. Since the 3D printing technique can give the implant the desired internal macroscopic architecture, the implants could be created with many regions of the same implant.
(5) The multi-drug IDDS with different kinds of structure were fabricated by 3DP technology and their in vitro dissolution tests were investigated:①The release characteristics of IDDS with simple structure (marked as IDDS A and IDDS B) illustrated that LVFX could be released easily from IDDS A and B.②The in vitro release characteristics of IDDS with simple structure (marked as C and D) illustrated that two drugs were released from these devices discontinuously. With LVFX and rifampicin (RFP) as model drugs in core structure IDDS, 20 days and 35 days delay time were achieved respectively. The release of core drug had two phases: a lag time delay and then a low speed release period. In a control experiment, the core and mantle were loaded with the opposite type of drug. One was liberated after the other with the delay, which indicated 3D printing having unambiguous advantages over the conventional technology in term of accurate dosage; reproduciblility; easiness and automation of the fabricating process.
(6) The activity of the antibiotic from multi-durg IDDS showed the implant had kept strong activity in vitro for more than 40 days. It had great and lasting bacteriostasis to common pathogens of orthopaedic infections, such as staphylococcus aureus, colibacillus.
(7) The implantation of IDDS in rabbit revealed that the drug concentration of bone, musucle near the implantation spot and serum in different time. The results showed that two drugs released from the implant successively and the local drug concentration was arrived at the effecitive content in bone and its near muscle for antibiotic action. But the level in serum was low all the time. In the first day the LVFX released with higher level following a little decrease. Four days later RFP began liberation which met the initial design of drug release one after another. The observation activity of the antibiotic suggested that IDDS had kept strong activity in vitro for more than 6 weeks. There was no obvious bone destroying or other parenchyma changes near the bone implantation spot. According to unaided eye, the operation spot seem better palingenetic and the outer thighbone too, which indicated that the IDDS had the good biocompatibility.
(1)分别对聚乳酸粉末颗粒大小、打印液选择以及打印参数进行了研究。结果表明当聚乳酸粉末颗粒较小时,得到的植入剂比较致密精细,而当聚乳酸粉末颗粒较大时,植入剂就显得松脆。聚乳酸颗粒合适的尺寸应控制在Φ150μm～175μm范围内。三维打印打印液选择方面,以丙酮为主的混合溶剂最佳的成分配比是:丙酮100ml,乙醇20ml,水5ml,甘油0.4ml,SLS 0.2g。对三维打印工艺参数进行了优化,比较合适的参数值分别为:打印液流速1.4g/min,喷头移动速度150cm/s,粉末铺层厚度200μm,线间距100μm。
(2)对植入式给药系统的传统工艺方法和三维打印方法进行了比较研究,结果表明采用两种方法制备的制剂都有明显分布的空隙,三维打印法制备的植入剂,其整个截面微孔均匀分布;而传统工艺制备的植入剂截面的微孔集聚一起,而且大小不匀,有个别较大的微孔存在。其体外释放行为表明采用两种方法制备的制剂体外释药都有爆发释放量,三维打印技术制备的庆大霉素植入剂的初始爆发释放浓度相对较低,而传统工艺制备的庆大霉素植入剂在2天时获得68μg/ml的爆发释放,使得药物成分在初始阶段出现大量释放。
(3)利用三维打印技术制备了庆大霉素植入剂,①骨架结构植入剂:聚乳酸相对分子质量越大,释药就越慢;载有大剂量药物的植入剂在初始阶段就易于释放出来;通过PCL或HA与载体聚乳酸共混可以达到调控释放的作用。药物释放是载体材料的降解和药物溶解扩散的综合机制。②三明治结构植入剂:三明治结构能起到降低药物的释放表面积的作用,可以明显抑制爆发释放,相对于传统制备工艺,三维打印技术可以在一定程度上方便控制剂型的空间结构。
(4)利用三维打印技术制备了左氟沙星植入剂,①滞后释放植入剂:药物成分被包裹在制剂的囊心中,从而导致药物滞后释放;药物释放受囊心外的壳部性质影响较大,要获得比较长时间的滞后释药,包围囊心部分的壳厚度就要越大。②分阶段释放植入剂:左氟沙星释放分三个阶段,第一阶段开始阶段出现一定的爆发释放,然后释放慢慢减缓,第二阶段维持平稳浓度释放,第三阶段出现增大的趋势,最大浓度之后就不断降低。植入剂具有长效缓释和控制释放的特性,出现分阶段的释放行为主要由植入剂的几何结构决定。
(5)利用三维打印技术制备了含多种药物的植入式给药系统,①简单结构多药物植入剂(左氟沙星和利福平混合药物的骨架结构植入剂A和左氟沙星和利福平分别位于双层结构中一个骨架层的植入剂B)体外释放行为研究表明,左氟沙星更容易释放出来,而利福平释放速度比较慢;左氟沙星从制剂A比B中更易于释放出来;而利福平在制剂B比在A中释放速度稍快些,基本相当。②复杂结构多药物植入剂(左氟沙星位于囊心结构层囊心,利福平位于骨架层的植入剂C和利福平位于囊心结构层囊心,左氟沙星位于骨架层的植入剂D)体外释放行为研究表明,可以实现利福平先释放,20天后左氟沙星开始释放;或左氟沙星先释放,35天左右利福平开始释放,获得两种药物分阶段释放。
(6)研究了多药物植入式药剂体外抑菌行为,结果表明在整个实验时间(40天)内都可起到一定的抑菌作用,对大肠杆菌的抑菌作用出现双峰现象,而对金黄色葡萄球菌来说,植入剂的抑菌能力就呈现一直缓慢减小的趋势。
(7)研究了多药物植入式给药系统植入家兔体内的释放行为,结果表明多药物植入式药剂植入兔股骨后,左氟沙星和利福平先后分阶段释放出来,两者的局部骨组织能够达到有效的药物浓度并且持续时间长,而血药浓度也是先后出现,但始终保持较低水平。说明这种植入式给药系统可以实现双药物分阶段控制释放。家兔经植入多药物制剂后的骨组织初步观察研究发现,局部无软组织感染或骨质破坏,无明显死骨形成。植入式给药系统植入切口愈合好,未见分泌物和淤血,由此显示植入式药剂具有良好生物相容性。
Implantable drug delivery system (IDDS) is a novel drug delivery forms by which the drug liberates directly in disease focus. Three-dimensional printing (3DP) is a solid freeform fabrication technique, which employs powder processing in the construction of parts in a layer-wise manner. It is capable of fabricating parts such as special exterior shapes, complex inner structures and so on. In the present study, the 3DP technology was introduced to fabricate the IDDS. The polymer material, the selection of binder and the process for 3DP were investigated, respectively. And the IDDS have special designed and fabricated by 3DP to furnish the desired drug rlease profiles. The IDDS was also implanted in rabbit for in vivo investigation. The resulted IDDS have been evaluated. The main results are as follows:
(1) The polymer material, the selection of binder and the process for 3DP were investigated, respectively. The optical particles size of biodegradable polymer PLAs for 3DP wasΦ150μm～175μm. The binder was solutions with acetone 100ml,ethanal 20ml,water 5ml,glycerol 0.4ml,SLS 0.2g. The general optimal processes are: powder layer height (200μm), binder line spacing (100μm), binder printed speed (1.4g/min), binder flow rate (150cm/s). The results demonstrated that 3DP had superior preparing flexibility.
(2) Compared with the IDDS made by conventional process method, 3DP impalnt showed more uniform inner structure. The implant made by conventional compress process appears to have fewer pores while the implant made by 3D printing was more porous and uniform.With gentamicin as a model drug, the implants made by conventional and 3DP process showed the burst release in vitro. However there is some different in which the burst release can be lower concentration from implant by 3DP than that by conventional process, thus will relatively prolong the whole release. The gentamicin gained 68μg/ml at 2nd day, which means that a lot of gentamicin was released at first.
(3) Study on the single gentamicin IDDS preparation by 3DP and in vitro release was investigated.①Study of the IDDS with matrix structure reveal that the burst release was much smaller for lower loading implant. The burst release was due to the dissolution or diffusion of drug particles attached or near the surface. The mixture of PCL or HA and PLA affected the drug release easily. The mechanism of release was combination with degradation of PLA and drug diffusion.②The IDDS with sandwich structure loading gentamicin could sharply decrease the initial burst release.
(4) Study on the single levofloxacin (LVFX) IDDS preparation by 3DP and in vitro release was investigated.①IDDS with a delay release time showed that more complicated structure implant with LVFX as drug by 3DP was achived to release with a delay time. To gain longer lag time, a thicker shell of the IDDS was needed.②A sort of implant with multi-phase release was developed: the first was with a burst release; the second at constant concentration; the third with a small increscent release before falling. Since the 3D printing technique can give the implant the desired internal macroscopic architecture, the implants could be created with many regions of the same implant.
(5) The multi-drug IDDS with different kinds of structure were fabricated by 3DP technology and their in vitro dissolution tests were investigated:①The release characteristics of IDDS with simple structure (marked as IDDS A and IDDS B) illustrated that LVFX could be released easily from IDDS A and B.②The in vitro release characteristics of IDDS with simple structure (marked as C and D) illustrated that two drugs were released from these devices discontinuously. With LVFX and rifampicin (RFP) as model drugs in core structure IDDS, 20 days and 35 days delay time were achieved respectively. The release of core drug had two phases: a lag time delay and then a low speed release period. In a control experiment, the core and mantle were loaded with the opposite type of drug. One was liberated after the other with the delay, which indicated 3D printing having unambiguous advantages over the conventional technology in term of accurate dosage; reproduciblility; easiness and automation of the fabricating process.
(6) The activity of the antibiotic from multi-durg IDDS showed the implant had kept strong activity in vitro for more than 40 days. It had great and lasting bacteriostasis to common pathogens of orthopaedic infections, such as staphylococcus aureus, colibacillus.
(7) The implantation of IDDS in rabbit revealed that the drug concentration of bone, musucle near the implantation spot and serum in different time. The results showed that two drugs released from the implant successively and the local drug concentration was arrived at the effecitive content in bone and its near muscle for antibiotic action. But the level in serum was low all the time. In the first day the LVFX released with higher level following a little decrease. Four days later RFP began liberation which met the initial design of drug release one after another. The observation activity of the antibiotic suggested that IDDS had kept strong activity in vitro for more than 6 weeks. There was no obvious bone destroying or other parenchyma changes near the bone implantation spot. According to unaided eye, the operation spot seem better palingenetic and the outer thighbone too, which indicated that the IDDS had the good biocompatibility.
引文
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