摘要
随着科学技术的快速发展,3D打印技术在个性化药物制造的应用日益成熟。与传统药物制造技术相比,3D打印技术可以轻松定制具有特定尺寸、形状及释放行为的药物,实现个性化用药。本文总结了几种常用于药物制造的3D打印技术原理,列举了3D打印技术用于药物制剂的特有优势及应用实例,并分析了全球药物3D打印行业的研究现状、发展动向,总结了目前存在的问题及挑战,为从事药物3D打印制剂的研究人员提供指导。
3D打印技术(three-dimensional printing,3DP),也称为增材制造技术(additive manufacturing),起源于19世纪末美国的照相雕塑和地貌成型技
美国材料与试验协会(American Society for Testing and Materials, ASTM)和国际标准组织F42增材制造技术委员会将3D打印技术分为7
黏结剂喷射技术是近年来广泛应用于药物制剂的研究,该技术与湿法制粒技术相似:粉末与粉末之间、颗粒与颗粒之间基于黏结剂形成固体桥或通过溶解和重结晶来形成颗粒。由于与传统制剂生产中使用的制粒技术有诸多相似之处,黏结剂喷射技术有广泛可选的原辅料种类并且在药物制剂中的应用前景广
黏结剂喷射型3D打印制剂的原理如

Figure 1 Diagram of the principle of binder-jet 3D printing technolog
材料挤出成型技术在打印过程中材料从机器喷嘴挤出,并且可以在任何基板上进行打印,是全球应用最广泛的3D打印技
以FDM技术为例,其成型机制如

Figure 2 Diagram of the principle of fused deposition modeling technolog
SSE技术与FDM相比,最大不同之处在于SSE使用的是在室温下以半固体形式存在的打印材料,且SSE的打印温度为室温或几十度,原料药的可选择范围更广,且可直接通过更换一次性注射筒来更换耗材,更适合于医院的使用场景。MED技术是将进料,混料以及材料输送模块和挤出式打印机直接相连,从原料,辅料直接一步法生产制剂,大大提高了生产效率。
光固化成型技术利用液态光敏树脂在紫外激光束照射下会快速固化的特性进行3D打印产品的制备,如

Figure 3 Diagram of the principle of stereo lithography appearance technolog
该技术将喷射成形和光固化成形的优点结合到一起,提高了药物成形的精度,并降低了打印成
儿童或老人等特殊人群的安全用药问题一直被广泛关注。不同年龄段儿童的生理、病理、免疫等方面都差别较大,而目前儿科用药的品种少、剂型少及规格少;老年人身体的各项功能下降,且往往多病共存,同时使用的药物品种多,时间长,容易发生不良反应。3D打印技术可以通过调整药片的尺寸、形状等参数打印出精准剂量的药片,确保特殊群体的用药准确。3D打印技术的个性化制药优势也为个性化医疗提供了一种技术支持,例如英国FabRx公司为患有枫糖尿病的儿童制备个性化药物,已在西班牙一家医院的药房放置了SSE打印机,并且开展了4例患者的临床试
与普通片剂相比,控释制剂不仅能保持血液中的药物浓度以避免不良反应,同时还能显著延长药物作用时间,提高药效,减少用药频率。传统的药物制备工艺不具备精确控制微观制造及空间精准调控的能力,在控释制剂的研发及生产上具有较大挑战。而3D打印技术具有高度的灵活性,同时具备一体化制造的优点,在复杂制剂的研发及生产都具备成本和效率的巨大优势。
南京三迭纪公司在2021年获美国食品药品监督管理局(Food and Drug Administration,FDA)新药临床试验申请(Investigational New Drug,IND)批准的3D打印制剂——T19产品,就是通过其独创的特殊三维结构设计,从而达到对药物组合释放的精准控制。类风湿性关节炎具有昼夜节律性,关节疼痛、关节僵硬及功能障碍等症状在早晨最严重,患者在睡前服用T19,血液中的药物浓度在早晨达峰,并能够维持其日间血药浓度,从而取得最佳的药物治疗效
口服速释制剂是指口服后能快速崩解或溶解的固体制剂,其优点包括易于给药、快速药物吸收和高生物利用率,特别适用于需要快速起效的药物。黏结剂喷射型3D打印技术在制备快速释放制剂时有着明显的优势,2015年上市的3D打印药物左乙拉西坦速溶片Sprita
近年来,有关3D打印速释制剂的研究也集中于黏结剂喷射型3D打印技术,如

Figure 4 Images of immediate release tablets prepared by 3D printing technology
A: Picture of personalized levetiracetam cartoon dispersible tablet
由于儿童特殊的心理生理特征,亟需开发适合于儿童患者的个性化儿童制剂,3D打印技术不仅可以准确灵活地调控药物剂量,制备适合儿童服用的制剂,还能通过外观的设计,制备对儿童患者更具吸引力的片剂。黏结剂喷射型技术在个性化儿童制剂的生产上有着快速分散及可制备彩色制剂的优势,例如上述提到的Wang
目前最常用于儿童制剂制备的是半固体挤出技术,可设计并制备无需吞服、通过咀嚼和吞咽即可服用的类似糖果的具有卡通外观的咀嚼片。2019年,Goyanes
缓控释制剂具有药物释放稳定、药效延长和不良反应小的优点。传统的片剂制备技术难以制备复杂结构的制剂,而3D打印技术可以轻松巧妙地完成复杂结构制剂的设计与制备。目前应用于缓控释制剂研究的3D打印技术主要为黏结剂喷射型3D打印技术,以及挤出式3D打印技术。
2007年,Yu

Figure 5 Release behavior of controlled release tablets
A: Formulations containing different concentrations of controlled release material; B: Formulations containing different concentrations of drug (a: blocking layer; b: drug-containing zone; c: number of sprays of controlled release material-containing print ink from outside to inside from 4 to 1, d: number of sprays of drug-containing print ink from outside to inside from 1 to 4)
三迭纪公司通过MED技术开发了多种具有不同释药行为的模
3D打印技术可以根据用药需求将多种药物组合用于制备复杂制剂,从而实现个性化给药。将药物放在不同隔室可解决药物不相容的问题,降低每天服药次数,防止患者漏服,提高患者服药的依从性,也为复方制剂的制备提供了一种新思路。可制备复方制剂的3D技术仍集中于黏结剂喷射型及挤出式3D打印技术。
2015年,Khaled

Figure 6 Model diagrams of compounded tablets prepared by 3D printing technology
A: 3D printed compounded preparation containing 5 drugs with both immediate-release and slow-release layer
3D打印技术不仅可以制备个性化的口服制剂,其在医疗器械如植入剂、贴片、假肢、组织工程器械、微针等领域也得到一定应用。医疗器械的制备主要受材料及精度的影响。光固化3D打印技术和其他3D打印技术相比,精度可达微米级,且能用于光固化的口服材料较少,因此,该技术主要用于制备各种类型的微针。Yadav
药物3D打印已走过20多年的发展历程,也逐渐出现了一些研发3D打印药物的公司,朝着各自不同的发展方向进行3D打印药物的开发。部分3D打印药物公司应用的3D打印技术及应用领域见
Company | Start time | Country | 3D printing technology | Fields of application |
---|---|---|---|---|
Aprecia Pharmaceuticals | 2003 | United States | Zipdose | Development of new immediate-release drugs |
FabRx | 2014 | United Kingdom | FDM, SLS, SLA | 3D printed drug device |
Triastek | 2015 | China | MED | Programmed release drugs |
Multiply Labs | 2016 | United States | FDM | Personalized capsule robots |
Laxxon Medical | 2017 | United States | Screen printing innovational drug technology (SPID) | Oral pills |
Merck KGaA | 2017 | Germany | SLS | New drug and equipment development |
TNO | 2017 | Netherlands | FDM, SLS, PB | Oral preparations |
DiHeSys | 2018 | Germany | FDM | 3D printed pharmaceutical equipment |
Craft Health | 2019 | Singapore | SSE | Healthcare products, 3D printing equipment |
除了Aprecia公司和三迭纪公司之外,德国默克公司和美国默沙东公司也开始布局和尝试使用3D打印技术开发可商业化的药物产品,目前两家公司都处于使用3D打印技术加速药物产品早期开发的阶段。默克公司于2020年2月宣布,计划使用粉末床熔融3D打印技术开发和生产药物用于临床试验,并与全球最大的SLS 3D打印设备制造商——德国EOS旗下的AMCM公司签订了合作协议,开发规模化药用3D打印设备用于商业化生产。默沙东公司选择使用FDM技术作为一种工具来加速具有药物释放需求的新药产品早期开发。他们通过FDM和灌注打印结合的方式,快速制备小批量的不同释药特征的药物剂型,由早期临床试验筛选出具有理想药时曲线的药物剂型原型,但到临床中后期和商业化生产阶段时,默沙东仍然沿用传统制药技术进行生产。
3D打印技术在药物制剂方面的应用前景良好,但目前很大一部分处于实验阶段,目前全球仅有1种药物通过了FDA的注册申请,国内外均未形成3D打印药物研究的政策法规,无法明确指导3D打印药物制剂的研发。3D打印技术在药物制剂方面的应用还有很长的路要走,要将这一技术实际应用起来,仍面临很多挑战。
3D打印用材料、打印速度和质量控制是阻碍其发展的主要因素,能用于药物3D打印的材料的开发程度远远不够,且必须深入而全面地研究3D打印加工过程对原料药的稳定性和相容性的影响。此外,设计3D模型的相关软件仍停留在CAD等传统软件,打印机喷头、打印材料核心辅料、打印工艺流程、打印精度控制等核心技术或专利仍被国外公司垄断,制约国内研发部门在该领域的发展。
药物3D打印技术在未来通过3D打印机的发展、专业软件的开发、基础材料的多样性、模型库的建立等,使制备的制剂能够精准地控制药物释放、科学地进行复方联合用药;也为人们实现个性化医疗提供了一种技术支持,更好地解决复杂的给药方案及特殊患者群体的用药需求。虽然该技术仍面临制备技术、材料选择、知识产权及药品监管等方面的诸多挑战,但Sprita
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