药学学报

Excipient	Chemical structure	Type	Function
Polyvinyl pyrrolidone (PVP)		Synthetic polymer materials	Carrier matrix
Polyvinyl alcohol (PVA)		Synthetic polymer materials	Vehicle
Polyethylene glycol (PEG)		Synthetic polymer materials	Plasticizer, vehicle
Poly lactic acid (PLA)		Synthetic polymer materials	Carrier matrix
Polycaprolactone (PCL)		Synthetic polymer materials	Carrier matrix
Tween	No fixed structure	Synthetic polymer materials	Plasticizer
Kollidon^® VA 64		Synthetic polymer materials	Carrier matrix
Soluplus^®		Synthetic polymer materials	Carrier matrix, solubilizer
Hydroxy propyl methyl cellulose (HPMC)		Natural polymers and their derivatives	Adhesive
Hydroxy propyl cellulose (HPC)		Natural polymers and their derivatives	Sustained-release matrix, controlled-release matrix, adhesive, film forming agent
Hydroxy propyl methyl cellulose acetate succinate (HPMCAS)		Natural polymers and their derivatives	Plasticizer
Glycerin		Small molecule excipients	Plasticizer, edulcorant
Mannitol		Small molecule excipients	Plasticizer, edulcorant
Triethyl citrate (TEC)		Small molecule excipients	Plasticizer
Magnesium stearate (MS)		Small molecule excipients	Fluidics

Excipient	Chemical structure	Type	Function
Polyvinyl pyrrolidone (PVP)		Synthetic polymer materials	Carrier matrix
Polyvinyl alcohol (PVA)		Synthetic polymer materials	Vehicle
Polyethylene glycol (PEG)		Synthetic polymer materials	Plasticizer, vehicle
Poly lactic acid (PLA)		Synthetic polymer materials	Carrier matrix
Polycaprolactone (PCL)		Synthetic polymer materials	Carrier matrix
Tween	No fixed structure	Synthetic polymer materials	Plasticizer
Kollidon^® VA 64		Synthetic polymer materials	Carrier matrix
Soluplus^®		Synthetic polymer materials	Carrier matrix, solubilizer
Hydroxy propyl methyl cellulose (HPMC)		Natural polymers and their derivatives	Adhesive
Hydroxy propyl cellulose (HPC)		Natural polymers and their derivatives	Sustained-release matrix, controlled-release matrix, adhesive, film forming agent
Hydroxy propyl methyl cellulose acetate succinate (HPMCAS)		Natural polymers and their derivatives	Plasticizer
Glycerin		Small molecule excipients	Plasticizer, edulcorant
Mannitol		Small molecule excipients	Plasticizer, edulcorant
Triethyl citrate (TEC)		Small molecule excipients	Plasticizer
Magnesium stearate (MS)		Small molecule excipients	Fluidics

3D打印挤出成型技术的药学研究进展

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张珂 ¹ , 郑道一 ¹ , 李安然 ² , 刘思远 ¹ , 王治钧 ² , 陈钰 ² , 俞嘉黎 ¹ , 高缘 ² , 张建军 ¹^,^*

药学学报 | 综述 2023,58(9): 2640-2655

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药学学报 |综述 2023 , 58 (9) : 2640 -2655

3D打印挤出成型技术的药学研究进展

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张珂¹, 郑道一¹, 李安然², 刘思远¹, 王治钧², 陈钰², 俞嘉黎¹, 高缘², 张建军¹^,^*

作者信息

1.中国药科大学药学院, 江苏南京 210009

2.中国药科大学中药学院, 江苏南京 210009

通讯作者:

*张建军, Tel / Fax: 86-25-83379418, E-mail: amicute@163.com

Recent advances of pharmaceutical 3D printing extrusion molding technology

Ke ZHANG¹, Dao-yi ZHENG¹, An-ran LI², Si-yuan LIU¹, Zhi-jun WANG², Yu CHEN², Jia-li YU¹, Yuan GAO², Jian-jun ZHANG¹^,^*

Affiliations

1. School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China

2. School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 210009, China

出版时间: 2023-09-12 doi: 10.16438/j.0513-4870.2023-0112

文章导航

摘要

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3D打印是借助数字化控制的一种增材制造技术, 自2015年FDA批准第一个3D打印药物以来, 其在药学领域的研究热度日渐高涨。在打印技术中, 熔融沉积成型(FDM)和半固体挤出(SSE)是应用最广的两种挤出成型技术。本文从挤出成型的机制、设备、辅料、设计、应用及产业化前景六个方面综述3D打印挤出成型技术的药学研究进展。

关键词

3D打印 / 熔融沉积成型技术 / 半固体挤出技术 / 设备原理 / 药用辅料

Abstract

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3D printing is an additive manufacturing technology with the help of digital control. Since FDA approved the first 3D printing drug in 2015, its research enthusiasm in the pharmaceutical field has been increasing year by year. In printing technology, fused deposition molding (FDM) and semi-solid extrusion (SSE) are the two most widely used extrusion molding technologies. In this review, recent advances of pharmaceutical 3D printing extrusion molding technology are reviewed from six aspects: mechanism, equipment, pharmaceutical excipients, applications, design and industrialization prospects of extrusion molding technology.

Key words

3D printing / fused deposition molding technology / semi-solid extrusion technology / equipment principle / pharmaceutical excipient

引用本文

张珂, 郑道一, 李安然, 刘思远, 王治钧, 陈钰, 俞嘉黎, 高缘, 张建军. 3D打印挤出成型技术的药学研究进展. 药学学报, 2023 , 58 (9) : 2640 -2655 . DOI: 10.16438/j.0513-4870.2023-0112

Ke ZHANG, Dao-yi ZHENG, An-ran LI, Si-yuan LIU, Zhi-jun WANG, Yu CHEN, Jia-li YU, Yuan GAO, Jian-jun ZHANG. Recent advances of pharmaceutical 3D printing extrusion molding technology[J]. Acta Pharmaceutica Sinica, 2023 , 58 (9) : 2640 -2655 . DOI: 10.16438/j.0513-4870.2023-0112

正文

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1 3D打印技术简介

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1.1 发展历史

3D打印是借助计算机软件设计出具有特殊结构的模型并逐层打印成型的技术^[1], 又可称为“快速成型” (rapid forming)、“固体自由成型” (solid free forming) 或“增材制造” (additive manufacturing)^[2]。由于3D打印技术的高度灵活性, 其在产品的个性化设计方面有着极大的优势, 同时其应用范围十分广泛, 在建筑、医疗器械、药物、电子、航天等方面均占有一席之地。1978年3D打印技术开始映入大众眼帘, 其经典技术有: 立体平版印刷(stereo lithography apparatus, SLA)、选择性激光烧结(selective laser sintering, SLS)、分层实体制造(laminated object manufacturing, LOM)、熔融沉积成型(fused deposition modeling, FDM)、黏合剂喷射(binder jetting, BJ)、数字光处理(digital light processing, DLP)、选择性激光熔化(selective laser melting, SLM)、半固体挤出(semi-solid extrusion, SSE) 等^[3]。

3D打印技术的发展历史可以追溯到20世纪80年代, 从SLA技术专利的申请开始。SLA是利用紫外光辐射光敏树脂进行固化而后按照模型信息快速成型的一项技术, 最早由Charles于1986年申请了该技术的专利。同年美国Helisys公司的Michael发明了LOM技术, 即利用热压辊将涂有热熔胶的两层材料碾压使之相互黏结, 而后通过激光束根据每层的轮廓信息进行切割, 直至完全成型, 这一技术在1990年实现商业化^[3]。1988年, Deckard和Beaman^[4]获得了SLS技术的专利, 这种技术利用激光照射聚合物使之熔化并包裹在金属颗粒表面, 冷凝后金属颗粒之间相互黏接而后快速成型。紧接着一种最常用的技术——FDM技术登上了历史的舞台, 该技术的原理是热塑性物质熔融后通过一定直径的喷嘴喷出沉积使之固化成型。1989年Scott^[5]发明了该项技术, 并在1992年获得了该技术的授权专利^[4]。

与此同时, Sachs等^[6]推出了BJ技术, 这种技术是根据设定好的模型信息将黏合剂从喷嘴中喷出并选择性地黏结粉末而后成型。到1996年, Nakamoto和Yamaguchi^[7]提出了DLP技术, 即使用数字光处理器投影仪固化液态光聚合物而后逐层成型。同年, 德国的夫劳恩霍夫激光技术研究所开发出了SLM技术, 属于SLS技术的衍生技术, 区别在于粉末床全熔化, 且会使用更高能量密度的激光源, 同时不需要二次使用低熔点黏结剂^[5]。

综上, 不难看出3D打印技术的发展速度非常之快。在药学领域, 该技术也可弥补一些传统制药技术的不足之处, 以下对3D打印技术在药学领域的应用进行概述。

1.2 药学领域的应用

3D打印技术在药学领域尚处于起步阶段, 1996年首次报道了有关药物的3D打印^[8], 同时实现了对药物内部结构的数字控制, 即以亚甲基蓝和茜黄素两种染料为模型药物, 以聚氧乙烯和聚己内酯为基质材料, 通过3D打印技术来控制局部结构和微观构造, 从而控制释放时间和释放量^[9]。2015年8月, 美国食品药品监督管理局(FDA) 批准上市了第一个3D打印药物——左乙拉西坦片^[10], 至此开启了3D打印药物的新篇章。

目前, 3D打印技术在口腔崩解片、控释制剂、植入剂、胃漂浮制剂、栓剂、透皮微针贴片、咀嚼片及生物支架等方面均有相关的文献^[11]报道。BJ、FDM、SSE、SLS、DLP、SLA等技术已成功应用于制药领域^[12], 图 1A展示了近五年发表在科学刊物上有关3D打印的文章, 其中以FDM和SSE技术为代表的挤出成型技术应用最为广泛, 约占所有技术的70%, 图 1B展示出科学工作者对于挤出成型技术日益增长的兴趣。本文将重点讨论挤出成型技术在药学领域的研究进展。

2 挤出成型技术及机制

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FDM技术和SSE技术是目前在药学领域应用最广的两种挤出成型技术。FDM是将热塑性物质熔融后通过一定直径的喷嘴喷出沉积使之固化成型的一种技术, 其工艺简单、成本较低, 且可实现多种材料的打印, 受到广大研究者的喜爱。SSE是在注射器中通过气动、机械或电磁系统等方式将半固体状态的凝胶或膏体挤出成型的技术, 又名压力辅助微型注射器(pressure assisted microsyringe, PAM) 打印或直接墨水书写(direct ink writing, DW) 等。SSE技术具有成本低, 载药量高的优势, 可打印热敏性药物、生物油墨等, 应用范围广。

3D打印挤出成型的过程(图 2) 为: 首先, 原辅料混合物在升温塑化(FDM中) 或溶剂塑化(SSE中) 作用下形成非牛顿流体, 在喷嘴处剪切稀化并挤出成丝; 紧接着挤出的细丝与热床黏合, 并按照计算机建模路线逐层沉积; 然后, 在降温固结和脱溶剂固化作用下形成具有理想结构的固体^[13]。在挤出成型的过程中, 挤出、沉积和固化的原理对于整个FDM及SSE打印过程非常重要。

2.1 挤出机制

3D打印挤出成型技术成功的首要前提是物料可从喷嘴中顺利挤出, 其原理在于非牛顿流体的剪切稀化作用^[14]。具体而言, FDM和SSE技术制备的非牛顿流体物料在压力和喷嘴剪切作用力下实现剪切稀化, 使之具有合适的塑性和流动性^[15]。其中, FDM是通过加热聚合物载体材料至玻璃化转变温度(T_g) 或熔点(T_m) 以上使之具有非牛顿流体的流变学特性^[16], 而SSE常将可凝胶化材料加水溶胀制备成水凝胶, 使之具有非牛顿流体的流变学特性^[17]。

载药线材的制备是FDM技术实施的关键步骤, 其制备方法分为浸渍载药法^[18]和热熔挤出法^[19]。浸渍载药法可使用市售的聚合物长丝, 具有良好的机械性质, 但是此方法依靠长丝表面吸附药物, 载药量较低^[20]; 热熔挤出法载药量较高, 且可制备无定形固体分散体改善难溶性药物的溶出^[21], 然而载药长丝的可打印性通常较差, 需要进行大量的处方和工艺优化获得具有良好可打印性的载药长丝^[20]。可打印性差具体表现为: 线材脆性较高, 易在输送时受力折断, 无法连续打印; 线材硬度较低, 易在齿轮处发生形变而无法向前输送; 线材表面粗糙, 不利于齿轮输送, 且在直径较细处易断裂^[22]。目前解决载药线材可打印性差的主要思路包括: ①更换或加入聚乙烯醇、羟丙甲纤维素等可打印性较好的聚合物可改善线材的可打印性, 此外, 聚合物的相对分子质量较高时, 分子间相互缠绕可提高分子间相互作用力, 从而改善线材的机械性质; ②可加入聚乙二醇、柠檬酸三乙酯或小分子药物作为增塑剂, 改善载药线材的机械性质; ③聚合物与药物的混溶性更好, 可使载药线材的表面更光滑; ④由远程挤出系统改为近程挤出系统, 由齿轮送料改为活塞送料^[23]。

2.2 沉积机制

沉积过程是按照切片软件设置的走线路径, 将上述挤出细丝层层沉积为特定结构的过程, 是区别于传统制剂成型技术的关键。该过程主要包括两个部分: ①挤出细丝与热床之间的黏连; ②挤出细丝层与层之间的黏连^[24]。两个过程的机制类似, 即在重力作用下, 挤出细丝沉积至指定位置并与下层(热床或物料层) 通过分子间相互作用力(范德华力、毛细管作用力或静电力) 结合, 并且该结合力应大于喷嘴机械位移对细丝的横向拉力^[25]。若材料和热床的结合力小于横向拉力, 则会出现不黏热床或“错层” (pushing dislocation) 的故障, 通过提高材料和热床的分子间相互作用力可有效解决该故障, 例如更换热床的材料以获取更大的结合强度、修饰热床表面粗糙度以获取更大的结合面积。此外, 挤出温度、热床温度、喷嘴与热床的距离均可能对沉积过程的分子间作用力产生较大影响, 也是调节不黏热床或错层等故障的常用参数^[26]。

2.3 固化机制

沉积后的固体虽具有理想的结构, 但材料在未固化前结构稳定性较差, 易受外力影响^[27]。固化是指将沉积后的固体通过降温、脱水等操作, 使之具有一定硬度, 便于包装、储存和运输等过程。固化通常可理解为挤出的逆过程, 挤出是将原辅料制备成非牛顿流体状态, 而固化是将流体状态重构为固体状态^[28]。反向思考可知, FDM的固化是将热塑性聚合物材料降温至T_g以下, 使之进入具有一定硬度的玻璃态^[24]; SSE的固化是脱去半固体中的自由水, 使之固化成型^[12]。固化之后的制剂具有理想的刚性结构, 为制剂功能多样性提供了结构基础。

综上, 3D打印挤出技术的机制主要是挤出、沉积和固化三部分, 简而言之是固体-半固体(非牛顿流体)-固体的转变过程, 挤出过程提供了3D打印的可能性, 沉积过程赋予了3D打印的创造性, 固化过程实现了3D打印的稳定性。深入理解三个过程的流变学、界面科学等原理, 为3D打印挤出成型技术的发展奠定了理论基础。

3 挤出成型设备

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3.1 硬件

3.1.1 硬件分类

地质学家Blanther在1892年提出了使用层叠成型方法制作地形图的构想, 这是3D打印切片技术的前身。百年之后, 3D打印逐渐由概念发展为实体^[29], 1988年Scott发明了熔融沉积成型技术, 该方法利用高温把材料熔化后再挤出重新凝固成型, 可轻松地制造复杂形状的零件, 具有快速、多功能、低成本的优势^[30], 成为了大多数桌面打印机所依赖的制造工艺。按照运动原理分类, FDM和SSE 3D打印机结构主要包括笛卡尔式、极坐标式、并联臂式, 以及近几年新兴的机械臂^[31]。

笛卡尔式(图 3A、B) 是目前最普及的结构, 其原理是基于笛卡尔坐标系, 将机械运动的方向处理为3个相互垂直的轴, 分别记为X、Y、Z轴, 三个轴上的电机带动喷嘴做轴向运动, 在空间形成三维结构^[32]。其优点在于各独立轴不会互相影响, 计算量小, 打印精度高。笛卡尔式包括龙门架式(图 3A) 与箱体式结构(图 3B), 龙门架结构的打印床在Y轴移动, 垂直方向的两个立柱架起双Z轴, 携带打印头的X轴两端安装在Z轴上。箱体式结构的热床在Z轴上下移动, 打印头在XY平面内运动, 根据XY平面内运动方式和传动设计的不同, 又分为Maker bot串联结构和Ultimaker、CoreXY等并联结构^[33]。

极坐标结构(图 3C) 也有三个轴向, 分别为θ、ρ、Z轴, θ和ρ轴控制底盘平面的运动, 但该结构的底盘平面运动方式为360°转动, 因此其坐标轴的计算方式和笛卡尔结构不同, 为在平面内由极点、极轴和极径组成的坐标系, 轴的运动量可以降低至半径的长度, 与基于笛卡尔坐标系的3D打印机相比运动幅度减小了一半, 因此机器的空间利用率高, 但极坐标结构对XY底盘的转动结构设计要求较高, 平台大时晃动越严重, 同时平台的转动惯量在反转时可能会导致失步, 影响打印质量^[34]。

并联臂结构(图 3D) 为三个竖直轴向的滑块与三个并联臂铰接, 并联臂的接合处安装打印头, 通过铰接轴产生的自由轨迹移动, 而打印床保持静态。其基本数学原理为笛卡尔坐标系, 但通过三角函数将X、Y坐标映射到三条和平台垂直的轴上。该结构打印速度快, 适合打印具有一定高度的物体, 但机器调试复杂, 整机体积较大^[35]。

机械臂结构(图 3E) 是通过将3D打印头与多轴机械臂相结合, 创造出比传统三轴(X、Y、Z) 机器更灵活的3D打印机, 通过专门的多轴工具路径编辑工具, 能够从任何角度进行打印, 实现极其复杂的几何形状, 且打印的部件通常不需要支撑, 但打印质量也取决于机器人的运动控制系统^[36]。

3.1.2 硬件组成

3D打印机的硬件部分主要由几大模块构成, 分别为: 程控模块、运动模块、熔融冷却模块、挤出模块、热床模块^[30], 其中FDM和SSE技术均搭载相同的运动模块和程控模块, 而其他的三个模块有所区别, 因此两种机器可在一定条件下相互改装。

3.1.2.1 FDM搭载模块

FDM技术需要将制备的载药线材进行再次熔融挤出, 因此需要喷嘴上方搭载有精确控温功能的熔融加热块, 使线材在较短的时间内熔融成非牛顿流体状态, 进而从喷嘴挤出^[37]。冷却风扇用于挤压线材的快速凝固, 热熔材料的边缘经常快速冷却, 收缩导致边缘翘曲, 而热床模块的作用是减缓冷却过程, 从而使打印片更好地黏接在印刷基板上, 避免了由于振动造成的打印失败^[38]。

FDM的挤出模块为输送线材至熔融模块的结构, 有近程挤出(direct drive)和远程挤出(bowden drive)两种(图 4A), 均由内部的齿轮啮合线材进行输送, 区别在于挤出模块与喷嘴的距离^[39]。远程挤出模块安装在离挤出头较远的位置, 模块和挤出头之间采用铁氟龙管相连接, 控制线材的走向。远程挤出减少了喷嘴部位的重量, 使打印速度更快, 但打印过程中无法换料, 若遇到含药线材断裂的情况, 则只能停止打印。而近程挤出模块和挤出头直接连接, 对送料量的控制比远程挤出更精确, 且换料方便, 更适合弹性较低的线材打印, 但近程挤出增加了喷嘴的重量, 对X轴的压力更大, 易造成X轴变形^[40]。

3.1.2.2 SSE搭载模块

SSE和FDM搭载模块大体相似, 主要区别有以下两点: ① SSE不必要搭载熔融冷却模块和热床模块。SSE与FDM之间的主要区别在于所使用的原料材, FDM打印原材料是载药长丝, 而SSE打印的原材料是半固体, 其过程为将配制好的含药半固体紧密地填充于料筒内, 利用机动或气动的方式, 将半固体从“墨盒”中挤压而出, 同时配合运动模块的空间运动, 实现挤出丝的逐层堆积^[12], 过程中不需要再次熔融, 因此大多不需要熔融冷却模块和热床模块。但在挤出明胶等对环境要求较为苛刻的材料时, 也可以通过加入控温模块和热床模块达到更好的打印效果^[41]。② SSE需额外搭载挤出动力模块(图 4B)。SSE技术应用的挤出动力模块主要依赖两种原理, 一种基于气动系统, 另一种基于机械力^[12]。基于气动的挤出装置为空压泵直接连接到带有活塞和喷嘴的注射器筒(图 4B左), 常用于打印黏度较高的材料, 如水凝胶、羟丙基甲基纤维素等。由于注射器筒可以瞬间加压, 气动挤出通常具有较高的精度^[42]。

基于机械力的挤出装置有活塞和螺杆两种驱动方式(图 4B右), 但两种方式均为螺杆提供挤压动力, 无需空气压缩机配合, 比气动系统更简单、经济。基于活塞系统的螺杆与活塞相连, 螺杆的前进推动活塞下压, 挤出物的受力和气动挤出类似, 对流体的控制较精确, 而基于螺杆的挤出系统螺杆与材料直接接触, 材料通过螺杆的旋转挤出, 能够挤出比活塞系统更高黏度的材料^[43]。

3.2 软件

FDM和SSE技术均通过计算机辅助设计软件构建所需的3D模型结构, 常用的建模软件有Auto CAD、SketchUp、Rhinoceros、SolidWorks、Cinema 4D等。建模软件将构建好的模型转换为标准镶嵌语言(standard tessellation language, STL) 格式文件, 该文件格式由3D Systems公司于1988年研发, 将模型进行三角化处理, 记录了物体表面的几何位置信息, 是CAD/CAM系统接口文件格式的工业标准之一^[44]。

但是3D打印机无法直接识别STL格式文件, 需要切片软件将数字3D模型转换为3D打印机可识别的打印代码, 从而让3D打印机开始执行打印命令。切片软件首先将STL等格式的模型进行水平切割, 从而得到每一层的平面图, 并计算打印机需要消耗多少耗材及时间, 而后将这些信息统一存入3D打印机可识别的G-Code文件中^[45]。常用的切片软件有Ultimaker Cura、Simplify3D、Makerbot print、Repetier等^[46], 在切片设置中, 层高、外壳厚度、填充密度、回抽、打印速度、温度等是关键因素, 决定了最终的打印效果^[38]。

4 挤出成型的辅料

收起

由于药物分子自身难以满足挤出成型的需要, 在使用挤出成型技术制备药物或者支架时, 通常需要选择合适的挤出成型辅料作为载体。挤出成型辅料在药物中可以作为黏合剂、赋形剂、成膜剂、载体基质、释放调节剂等, 选择合适的辅料不仅可以避免喷嘴堵头等问题, 还可以调控药物的释放曲线, 达到诸如速释、缓释、控释或迟释等目的^[28]。挤出成型技术常用的辅料已在表 1中列出, 本部分主要综述常用辅料的性质及其功能特性, 同时简述其在挤出成型技术中的作用和相关注意事项。

4.1 合成类聚合物材料

4.1.1 聚乙烯吡咯烷酮

聚乙烯吡咯烷酮(polyvinyl pyrrolidone, PVP) 是由1-乙烯-2-吡咯烷酮基的重复单元构成的线性非离子型聚合物, 其相对分子质量在2 500~3 000 000之间^[47], 是一种高极性的两亲性聚合物, 可溶于水和其他极性溶剂^[28]。PVP具有较强的引湿性, 与吡啶酮结构中的羰基的电负性基团能与水形成氢键有关^[48]。PVP的相对分子质量越小, T_g越低^[49], 因此使用低相对分子质量的PVP在较低温度下通过FDM技术制备固体制剂, 可避免热不稳定药物的降解^[50]。但是PVP载药长丝脆性过高, 在送料时易发生断裂, 无法直接用于FDM打印, Kimura等^[50]在处方中加入了大量的羟丙甲纤维素, 可降低载药长丝的脆性; Kempin等^[51]在处方中添加柠檬酸三乙酯作为增塑剂, 也成功改善了载药长丝的可打印性。此外PVP具有一定黏性, K30和K90型号可用作SSE技术的黏合剂, 并具有延长药物释放的作用^[52]。

4.1.2 聚乙烯醇

聚乙烯醇(polyvinyl alcohol, PVA) 是一种通过聚乙酸乙烯酯水解生成的具有生物相容性、可膨胀的水溶性聚合物^[14], 相对分子质量范围约为20 000~200 000^[47]。PVA的T_g约为85 ℃, T_m在180 ℃ (部分醇解) 到228℃ (完全醇解) 之间^[14]。PVA被认为是一种安全的药用辅料, 目前用作FDM 3D打印的高分子载体材料的研究较多^[28], 用于SSE技术的研究较少。PVA可通过浸渍法^[53]和热熔挤出法^[54]制备载药长丝, 也可先使用商用长丝(如AtlasSupport^TM, Sigma-Aldrich) 打印制剂外壳, 如片剂外壳^[55]、胶囊壳^[56]、栓剂壳^[57]等, 后将活性药物成分填充于壳中。PVA制备的载药长丝具有适宜的机械强度, 可直接作为药物载体使用, 无需添加增塑剂, Gioumouxouzis等^[58]使用PVA作为药物载体, 结合热熔挤出工艺和FDM技术, 制备了格列美脲的3D打印片剂, 结果表明载药长丝和片剂的药学性质均符合预期, 证明了PVA优良的可打印性。

4.1.3 聚乙二醇

聚乙二醇(polyethylene glycol, PEG) 又称为聚氧化乙烯或聚环氧乙烷(polyethylene oxide, PEO), 具体取决于其相对分子质量。相对分子质量 < 100 000的聚合物通常被称为PEG, 而相对分子质量较高的聚合物则被归类为PEO^[14]。由于其具有良好的生物相容性、水溶性和两亲性, PEG在SSE技术中可用于生物支架的制备^{[59, 60]}, 可起到触发药物释放和增加难溶性药物溶解度的作用^[59-61]。热熔挤出生产的纯PEG的长丝易断裂, 无法直接作为FDM 3D打印的载体^[61], 但可利用其增塑作用^[62]与其他聚合物联用, 可降低热熔挤出的加工温度, 调节长丝的热塑性^[63], 促进挤出, 也可用作致孔剂调节药物的释放^[64]。

PEO具有FDM技术所需的流变学和机械性能, 可直接用作FDM技术的载体^[65]。此外, 在FDM处方中加入PEO能提高长丝的机械柔韧性, 从而改善可打印性, 例如Gultekin等^[66]在Eudragit载体中加入PEO成功解决了Eudragit的可打印性难题, 使载药长丝具有适宜的机械性质, 成功制备了普拉克索缓释片。

4.1.4 聚乳酸

聚乳酸(poly lactic acid, PLA) 是脂肪族聚酯, 具有四种手性形式, 其中聚左旋乳酸(poly-l-lactic acid, PLLA) 和外消旋聚乳酸(poly-DL-lactic acid, PDLLA) 的机械强度较高、T_g较低, Gioumouxouzis等^[58]将之加入二甲双胍的缓释处方中, 用于增加Eudragit^® RL PO载药长丝的机械性质, 提高可打印性。PLA具有生物降解性、安全无毒等特点而被广泛用于生物支架和植入剂^[14]。此外, PLA的水溶性较差, 在酸中可以维持3 h不被溶解^[14], 因此可用于制备不溶性外壳或多层片的“隔间”^[67], Zhao等^[68]使用PLA打印带有气室和释药窗口的不溶性片剂外壳, 实现了片剂的胃漂浮行为, 并且根据释药窗口的大小设计了不同的释药速率。

4.1.5 聚己内酯

聚己内酯(polycaprolactone, PCL) 是一种半结晶疏水聚合物, 其结晶度随相对分子质量的减小而增大, 熔点在59~64 ℃之间, T_g约为-60 ℃^{[14, 69]}。PCL的抗张强度低(~0.023 GPa), 断裂伸长率高(4 700%), 是一种良好的弹性生物材料^[14]。PCL与多类药物具有良好的相容性^[14], 且具有低熔点、热塑性^[70]等优势, 这使其更适用于FDM 3D打印技术。此外, PCL具有良好的生物相容性, 且在体内的降解时间较PLA更长, 因此多运用FDM技术将其制备成植入装置^[69], 如骨支架^[71]、宫内节育器(ISU)^[72]、肿瘤术后治疗植入物^[73]等。

4.1.6 吐温

吐温(Tween) 又称聚氧乙烯山梨聚糖脂肪酸酯(聚山梨醇酯), 含有20个氧乙烯单元, 是亲水性非离子表面活性剂^[47], 在SSE和FDM 3D打印中均有所使用, 既能对水溶性差的药物起到良好的增溶作用, 又能改善3D打印结构的外部和内部表面的润湿性, 便于水的引入, 改善药物的释放^[61]。在FDM技术中, Tween 80还用作增塑剂, 将加工温度降低到安全温度, 克服药物降解问题; 同时也能提高载药长丝的韧性, 使FDM打印机的送料更容易^[74]。

4.1.7 Kollidon^® VA64

Kollidon^® VA64为乙烯基吡咯烷酮与醋酸乙烯酯按3∶2的质量比共聚获得的嵌段共聚物, 相对分子质量为45 000~70 000^[47]。Kollidon^® VA64是一种高水溶性聚合物, 是热熔挤出工艺和FDM技术的常用载体材料, 常用于制备速释制剂^[75], 可起到分散、增溶和加速药物释放的作用^[76]。Kollidon^® VA64制备的载药长丝脆性较高, 在输送过程中易断裂导致打印中断, 因此无法直接用于FDM 3D打印, 可通过与聚合物如羟丙甲纤维素^[75]、羟丙基纤维素^[77]等共同挤出改善载药长丝的韧性和脆性, 提供更优的可打印性。此外, Kollidon^® VA64的T_g较高, 挤出和打印温度通常较高, 可加入PEG、甘露醇等增塑剂以降低打印温度^[75]。

4.1.8 Soluplus^®

Soluplus^®是聚乙二醇、聚醋酸乙烯酯和聚己内酰胺(13∶30∶57) 组成的接枝共聚物^[14], 因其具有两亲性, 临界胶束浓度低(约7.6 mg·L^-1), 常被用作药物溶出的调节剂^{[14, 28]}。Soluplus^®具有低T_g (约70 ℃)、低吸湿性、优良的热稳定性, 适合作为热熔挤出工艺的载体^{[14, 28, 78]}, 但纯Soluplus^®热熔挤出长丝因脆性过高不能直接用于FDM打印^[78], 需与其他聚合物如羟丙甲纤维素、羟丙基纤维素联用以增强可打印性^[79]。

4.2 天然高分子及其衍生物

4.2.1 羟丙基甲基纤维素

羟丙基甲基纤维素(hydroxy propyl methyl cellulose, HPMC) 是相对分子质量在10 000~150 000之间的可膨胀水溶性聚合物, 具有热凝胶性质和一定的吸湿性, T_g较高约为170~180 ℃^[47]。HPMC在3D打印药物制剂领域的研究中的使用频率较高, 广泛用于FDM技术和SSE技术。在FDM打印中, 高相对分子质量的HPMC (如K15M) 因具有较高熔体黏度, 在热熔挤出机中无法单独挤出且长丝通常脆性较高^[80], 需要加入增塑剂增加熔体的流动性并降低细丝的脆性^[65]。低相对分子质量的HPMC (如AFFINISOL^TM) 具有低熔体黏度和适宜的韧性, 可直接打印^[20]。SSE打印中, 高相对分子质量的HPMC (如K100LV和K15M) 可用于制备缓释制剂^[81], 低相对分子质量的HPMC (如E5) 具有更低的黏度和更快的溶解速率, 可用于制备速释制剂^[82], 也可用作成膜材料^[82]。

4.2.2 羟丙基纤维素

羟丙基纤维素(hydroxy propyl cellulose, HPC) 是连续葡萄糖单元中一些羟基被羟丙基化时形成的一种相对分子质量在50 000~1 250 000之间的水溶性聚合物^[14]。HPC的引湿性较强, T_g在-25~0 ℃之间, T_m约为170~200 ℃^[83], 其制备的热熔挤出长丝通常具有优良的机械性质, 并在不添加任何增塑剂的情况下使用FDM技术成功打印^[84]。HPC具有较高的热稳定性, 广泛适用于高温打印的FDM技术, Nashed等^[85]使用JF和EF两个型号的HPC, 分别制备缓释和速释的茶碱3D打印制剂, 并与传统压片工艺进行对比, 结果表明3D打印片的释放与预期一致, 且密度更低、硬度更高。HPC有非常宽的黏度范围, 在SSE技术中可用作成膜剂^[86]、黏合剂^[87]和释放调节剂^[88]等, Cui等^[87]使用HPC制备了96%高载药量的左乙拉西坦3D打印片剂, 且该片剂具有和市售3D打印制剂相似的溶出行为。

4.2.3 醋酸羟丙甲纤维素琥珀酸酯

醋酸羟丙甲纤维素琥珀酸酯(hydroxy propyl methyl cellulose acetate succinate, HPMCAS) 是HPMC的醋酸、琥珀酸混合酯, 具有两亲性, 通过凝胶渗透色谱法测定的相对分子质量约为55 000~93 000, 是肠溶性聚合物, 有吸湿性, T_g约为120 ℃^[47]。HPMCAS在253 ℃前是热稳定的, 但其高黏度不利于FDM打印, 常添加热稳定性强的增塑剂(如PEG) 降低其T_g和熔体黏度, 增加长丝的塑性^[89]。HPMCAS具有pH敏感性特征^[20], 是良好的延迟释放聚合物载体^{[62, 90]}, Tabriz等^[62]将之作为利福平的肠溶载体, 制备了3D打印片剂, 该片剂在碱性条件释放, 避免了利福平在酸性介质中的降解。

4.3 小分子辅料

在3D打印挤出成型的过程中, 选用的辅料除去合成聚合物材料、天然高分子及其衍生物, 还会采用小分子辅料, 常作为增塑剂、润滑剂、甜味剂。

4.3.1 甘油

甘油是水溶性小分子脂肪醇, 具有吸湿性, 有甜味, 在FDM、SSE技术中都有应用。在FDM中, 甘油常作为增塑剂, 用于制备缓释制剂^[19]、胃漂浮制剂^[91]等, 但甘油加入过多会降低线材的硬度, 导致线材过于柔软, 不适合打印, 而适量甘油能使线材具有足够的黏度、均匀的直径和适当的抗拉伸强度, 增强可打印性^[92]。在SSE中也可作为增塑剂制备黏膜黏附薄膜类速释制剂^[82], 还可作为甜味剂用于制备儿童制剂^[93]。

4.3.2 甘露醇

甘露醇是一种高水溶性的糖醇(六己醇), 吸湿性低, 生物安全性高, 在FDA非活性物质数据库中口服单日最大剂量超过2 g。甘露醇在FDM技术中应用较多, 常作为增塑剂增加熔体的流动性和塑性^[94], 也可作为致孔剂调整3D打印药物的释放速率^[95]。在SSE技术中, 甘露醇在制备口腔薄膜制剂时作为甜味剂使用^[96], 还可通过加入比例调节水凝胶黏度进而改善半固体基质的流动性, 调节半固体从喷嘴的挤出行为^[97]。

4.3.3 柠檬酸三乙酯

柠檬酸三乙酯(triethyl citrate, TEC) 又称枸橼酸三乙酯, 是一种低毒低刺激性的辅料, 常用于口服固体制剂, 亦可作为食用性香精, 在食品中的用量可达200 mg·kg^-1。它可溶于大多数有机溶剂, 与大多数纤维素、乙烯基类热塑性树脂有良好的相容性。在熔体中加入TEC可降低聚合物基质的T_g^[98], 从而降低挤出和打印的温度, 改善打印长丝的塑性, 因此常用作热熔挤出和FDM工艺的增塑剂^{[51, 68]}。

4.3.4 硬脂酸镁

硬脂酸镁(magnesium stearate, MS) 是镁的多种固态有机醛的疏水性小分子化合物, 是黏性粉末, 附着力大, 通常硬脂酸镁用作传统固体制剂的润滑剂和助流剂, 可以改善压片过程的黏冲行为, 提高混合均匀性。在3D打印领域中, 硬脂酸镁主要用于FDM技术, 常用作助流剂提高原辅料混合物的流动性, 增加载体聚合物的挤出能力, 以促进热熔挤出过程^[65]。

5 挤出成型制剂的结构设计

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传统固体制剂常通过制粒或压片的方法成型, 形状固定且孔隙较少, 而挤出成型技术具有层层沉积的特点, 可通过三维建模软件设计模型, 通过切片软件控制每层打印的形状, 具有更高的结构设计性。

5.1 模型设计

5.1.1 形状结构

挤出成型技术可灵活制备不同形状结构的制剂, 通常包括圆柱体、球体、立方体、金字塔形、圆环形等(图 5A~E)。Goyanes等^[99]研究了系列形状结构的片剂的溶出行为, 结果表明, 在各形状片剂的表面积一致时, 比表面积更高的金字塔形片剂具有更高的溶出速率。此外, 有研究^[100]使用同型号的淀粉作为基质, 制备了两种不同形状的布洛芬片剂, 溶出试验同样表明, 具有较大比表面积的锥形片剂释放速率高于圆柱状的片剂, 证明了通过设计形状来调控溶出的可行性。同时, 3D打印技术由于其逐层打印的增材制造特性, 具有灵活设计的特点, 可以制备多种形状的植入剂。以宫内节育器为例, 不同患者的子宫内膜腔在形状和大小上具有高度特异性, 用传统方法制备此种装置时非常困难, 而3D打印技术则可以针对不同患者设计形状吻合的植入剂, 避免形状不合适的装置在体内发生移位^{[101, 102]}。

5.1.2 通道结构

通道结构(图 5F) 是指模型中存在贯穿模型的通道的结构, 常可用来增大表面积, 加速药物释放。Sadia等^[103]以Eudragit^® E作为成型材料, 制备了一种具有通道结构的胶囊形片剂, 可改善BCS Ⅳ类药物氢氯噻嗪的溶出行为。当通道直径为0.2~0.4 mm时, 药物溶出速率改善不显著, 但当通道直径增加到0.8、1.0或1.2 mm时, 药物溶出速率显著增加。另一项研究中, Arafat等^[104]设计了一个具有16个通道的胶囊形片剂, 当通道直径较小时, 由于聚合物基质的膨胀和凝胶层的形成, 通道被堵塞, 导致药物释放缓慢。当通道变大时, 溶出介质可以更好地进入孔隙并且促使片剂解体, 实现药物的快速释放。

5.1.3 多层结构

多层结构(图 5G) 常用于复方制剂, 根据药物的特点, 可设计不同层的释药行为, 例如速释层和缓释层组合, 胃溶层和肠溶层的组合等。Gioumouxouzis等^[58]开发了一种FDM 3D打印双层片, 分别将格列美脲和二甲双胍载入PVA速释层和Eudradit^® RL缓释层中, 结果表明双层片的溶出行为符合预期(格列美脲在2 h内快速释放, 二甲双胍在8 h内延迟释放)^[58]。另一项研究中, Sadia等^[105]将马来酸依那普利和氢氯噻嗪分别加入Eudradit^® EPO基质中, 构建了双层结构片剂, 实现了两种不同溶解度的药物的同步溶出。

5.1.4 核壳结构

核壳结构(图 5H) 可以根据药物释放的要求灵活设计外壳的厚度, 以达到迟释或肠溶等特点。Li等^[63]以HPMC E10为主要聚合物基质制备了对乙酰氨基酚的载药长丝, 通过FDM 3D打印制备成具有核壳结构的控释片剂。片剂的外壳呈现致密的层状结构, 而内芯呈现多孔结构。致密的壳结构为药物从内核释放提供了屏障, 因此壳越厚, 释放越慢。结果表明, 壳厚大于1.6 mm时, 药物释放符合零阶释放规律, 实现了控释给药预期目标。

5.2 切片设计

填充密度是切片设计中最常用的参数且和药物溶出息息相关, Goyanes等^[106]选择不同的填充密度来制造4-氨基水杨酸片剂, 发现填充密度较高时药物释放速率较慢。其中, 填充密度为10%的药物在4 h内完全释放, 而50%和90%的片剂释放较慢。Zhang等^[107]使用FDM技术制备了对乙酰氨基酚片, 结果表明100%填充密度的片剂表面积较小, 药物释放速度最慢。填充密度为80%和20%的片剂表现出多孔结构, 表面积较大, 药物释放更快^[107]。但填充密度在一定范围内可能对溶出影响较小, Đuranović等^[108]以PVA为骨架聚合物制备了对乙酰氨基酚FDM片剂, 70%和20%填充密度的片剂的溶出度无显著差异。这可能由于PVA具有高溶胀性, 在介质中明显膨胀, 导致孔隙闭合。

6 挤出成型3D打印在药物制剂中的应用

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随着3D打印技术的发展, 国内外越来越多的研究者将3D打印技术应用于药学领域, 已成功制备了速释制剂、缓释制剂和植入剂等产品, 本部分将综述挤出成型技术在药学领域的主要应用。

6.1 速释制剂

速释制剂中的活性药物成分能迅速地释放出来, 促进机体的吸收, 在短时间内产生疗效。与传统制剂技术相比, 挤出成型技术应用于制备高载药量的速释制剂时有着突出的优势, 如Cui等^{[87, 109]}使用SSE技术成功制备了载药量为93%和96%的硬度、脆碎度、含量等指标均满足USP标准的左乙拉西坦片剂, 在考察不同的填充密度和片剂形状时发现, 填充密度为50%的环形片2 min溶出度即可达到97.5%。此外, 挤出成型技术可通过控制制剂的精细结构, 使溶出介质更容易渗透到制剂内部, 提高溶出速率, 例如, Sadia等^[103]使用FDM技术制备了具有通道结构的氢氯噻嗪片剂, 在30 min时溶出度可以达到93.4%, 显著快于无通道片剂(30 min溶出度为60%); Fanous等^[77]通过降低填充密度制备了蜂窝状的多孔咖啡因片剂, 与市售制剂的溶出速率相似。

6.2 缓释制剂

缓释制剂在用药后能长时间释放药物, 降低患者服药频率, 提高患者的依从性。和传统缓释制剂的分类相似, 挤出成型技术也可将药物分散在缓释材料中直接打印成型, 类似于缓释骨架片, 或建立具有缓释外壳的核壳结构模型达到缓释效果, 类似于缓释包衣片。例如Cheng等^[110]将HPMC K4M和HPMC E4M作为缓释基质, 制备了茶碱凝胶缓释骨架片, 可释放持续12 h以上; Zhao等^[68]将PLA作为不溶性外壳, HPMC作为载药片芯, 设计了具有气仓和释药窗口的胃漂浮缓释制剂, 可根据释药窗口的大小调节释药速度。同时, 挤出成型技术制备缓释制剂的方法具有更高的灵活性, 如Cui等^[111]在不改变药物处方的条件下, 仅改变3D打印片剂轮廓和填充密度, 得到了12种具有不同药物释放曲线的格列吡嗪片剂。

6.3 控释制剂

控释制剂能够在设定的时间内按照设定的速度自动释放药物, 保持血药浓度稳定。Than等^[112]和Fang等^[88]分别使用FDM和SSE技术制备了多批次的制剂, 发现药物释放动力学均与零阶模型相匹配, 证明了挤出成型技术制备控释制剂的可行性。相较于传统方法, 挤出成型技术可以通过在片剂结构层面调整药物的填充密度和每层中药物的比例, 制备出符合预期药物释放曲线的制剂。Thakkar等^[90]制备了具有不同填充密度的布洛芬3D打印片剂, 发现调节填充密度可在不改变处方的情况下改变药物释放曲线。同时, 传统方法制备载有两种药物的双层制剂时, 两种药物可能会发生相互作用产生降解, 失去原有疗效, 而Tabriz等^[62]设计了具有隔间的3D打印双层片剂, 能够使异烟肼和利福平在不同pH条件下释放, 避免药物相互作用和降解。

6.4 迟释制剂

迟释制剂指在给药后不立即释放药物的制剂, 根据释药部位不同可分为肠溶制剂和结肠定位制剂等。Goyanes等^[113]将热熔挤出与FDM技术相结合, 制备了具有可控释放的布地奈德肠溶片, 为炎症性肠病的治疗提出了解决思路。传统制备肠溶片剂的方法, 需先制备载药片芯, 再使用包衣机进行肠溶包衣^[114]。相较于传统技术, 使用3D打印技术制备肠溶片剂时可选用搭载双挤出头的设备一体成型, 即第一个挤出头打印药物, 第二个打印肠溶外壳, 在一台3D打印机中即可完成肠溶片剂的制备。使用搭载双挤出头的设备时, 可以在聚合物中添加具有高沸点的润滑油(蓖麻油、油酸或PEG 400), 避免喷嘴的“堵头”问题^[115]。

6.5 胃滞留漂浮制剂

胃滞留漂浮片是定位释放制剂的一种, 能够在胃液中长时间漂浮, 可以增加胃部感染疾病的疗效, 提高胃部吸收药物的生物利用度, 增加弱碱性药物的吸收。Falcone等^[116]制备的胃滞留漂浮片漂浮时间长达14 h, 并将近80%的药物释放到模拟胃液中, 证明了挤出成型技术在制备定位释放制剂方面的可行性。值得一提的是, Chai等^[117]通过的研究发现, 与市售参比片剂相比, 3D打印的多潘立酮胃滞留漂浮剂能够在胃中停留更长时间, 延缓过饱和溶液的形成, 并防止在小肠中沉淀, 因此具有更高的相对生物利用度, 约为222.49% ± 62.85%。

6.6 植入剂

挤出成型技术还可打印除口服固体制剂以外其他的剂型, 如植入剂。相比于片剂和注射剂, 它的优势在于可以局部给药, 减少全身的药物暴露以减少不必要的不良反应, 以最低的药物浓度获得最佳疗效的长效制剂^[118]。

FDM和SSE技术制备的植入剂与传统方法制备的植入剂相比, 可以缓解药物最初的突释, 并能达到长期的缓释行为。Cui等^[119]在使用环丙沙星治疗骨损伤时发现, 传统方法制备的植入剂在第7天迅速达到176.85 μg·mL^-1的最大浓度, 此后药物浓度急速下降, 从第56天到第98天保持在100 μg·mL^-1以下, 而FDM和SSE技术制备的植入剂解决了传统制剂的快速突释, 药物浓度在到达峰值后降低速率缓慢, 且环丙沙星的浓度维持在100 μg·mL^-1以上。与传统制备方法相比, 3D打印技术制备植入剂时通常先将辅料通过热熔挤出制得长丝, 后将长丝浸泡在含有API的水溶液中, 以浸泡法装载药物, 此法能够有效避免因热熔挤出过程升温产生的药物降解^[120]。Qamar等^[121]通过将聚丙烯和聚乙烯醇长丝置于含有盐酸环丙沙星的水溶液中, 得到了载药长丝, 并发现药物在3D打印的过程中保持稳定, 没有降解发生。

7 挤出成型3D打印产业化面临的挑战

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3D打印技术作为一项迅速发展的新兴技术, 相较于传统药物制剂技术, 3D打印可构建相对复杂的几何结构和内部三维结构, 其中挤出成型技术的多功能性、研发快速及个性化定制的潜力为精准治疗、高端制剂及结构制剂提供了新的可能性^[122], 是制药行业的一次新突破。然而, 在其广泛应用于医药之前, 仍有一些产业化技术挑战和监管问题需要克服, 本部分将就此展开综述。

7.1 打印设备

理想的药品3D打印机需要具有合规性以符合药品生产规范(good manufacture process, GMP) 的需求, 耐用性以节约维修维护成本, 紧凑性以节约生产空间, 高效性以提高生产效率, 安全性以保障生产活动的正常进行。开展3D打印的专用设备的整机设计和制造, 是发展挤出成型3D打印产业化的首要目标。为了实现这一目标, 已有公司专注于开发符合GMP要求的制药3D打印机。例如, 专门从事3D打印药品制造的FabRx Ltd.最近开发了具有多个喷头的3D打印机(型号: M3DIMAKER^TM), 旨在用于医院药房或小规模生产。南京三迭纪科技有限公司设计了热熔挤出沉积技术, 可实现熔融物料的多喷头打印, 一次可生产64片, 日产量约3万片, 为挤出成型技术后续的产业化发展提供参考价值。

7.2 机械性能

挤出成型3D打印的载药长丝和片剂均面临机械性能不足的挑战。由于药品生产安全性和生物相容性的需求, 适用于药物3D打印的材料较少, 通常通过热熔挤出制备的载药长丝的机械性能较差, 在打印过程中断裂或变形, 无法实现连续生产, 该问题也是制约FDM技术产业化发展的重要问题。加入增塑剂是解决该问题的常规思路, Gioumouxouzis等^[58]通过实验发现, 在处方中加入5%的PEG 400可以增加载药长丝的机械性能, 在通过3D打印机的齿轮时不容易断裂; 此外, 还可采用无需制备载药长丝的挤出成型技术, 例如热熔挤出沉积技术是将原料药、聚合物载体以及辅料直接投入连续化进料和混匀装置中, 通过加热熔融将物料制备为含量均匀且具有流动性的熔融液体, 通过特殊的挤出机构将挤出的丝材打印成目标结构的制剂, 成功规避了载药长丝机械性能不足的难题。

3D打印片剂由于层层沉积的原因, 孔隙率较大, 层间的结合面积较低, 容易出现层间缝隙, 机械性能相对不足^[122]。基于Paul等^[123]的研究, 这一缺陷可以通过更换矩形喷嘴缓解, 因为矩形喷嘴相较于圆柱形喷嘴产生的空隙更少, 有利于层与层之间的紧密结合。

7.3 监管

3D打印技术在药学领域的应用和潜力吸引了监管机构的关注, 但是目前尚无关于3D打印药物的法规或指南。Alhnan等^[122]指出, 3D打印技术在药学领域的监管仍有很大空白需要弥补, FDA需要彻底改革其传统法规以适应3D打印的监管要求。

相较于传统制剂, 3D打印由于其制备的便捷性更容易非法仿制, 为药物防伪与溯源带来阻碍。针对此问题, 油墨打印和植入水印技术有望成为3D打印盗版行为的解决方案^[124]。Trenfield等^[125]使用防伪油墨将二维码打印至药片上, 以提供有关药品、患者和处方的定制信息, 有利于制剂的防伪与追溯。同时, 3D打印技术在制备适用于特定患者的个性化药物时, 需要制造商存储有关患者的相关信息, 因此数据的安全性也需要被保护^[126]。

幸运的是, 越来越多的专业人士正在推进有关3D打印技术相关法律法规的研究, 随着相关监管法律法规的完善, 3D打印技术的发展可以从理论探索向着解决实际问题实现质的飞跃^[127]。

8 总结和展望

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挤出成型技术具有灵活的结构设计功能, 较高的生物安全性, 较多的可供选择的辅料和初步的产业化前景, 是3D打印在药学领域应用的重要技术。在未来, 个性化给药和精准给药是临床用药的发展趋势, 而挤出成型技术由于其独特的灵活性将是改变传统制药工业统一剂量、统一模型的重要技术。例如, 可以利用挤出成型技术将具有多种疗效的不同药物组合打印在一片片剂之中^[128], 减少服药次数, 有效提高患者用药的依从性; 还可通过建立模型的尺寸精确控制给药剂量, 提高患者用药安全性和有效性。此外, 3D打印可以制备特殊结构和形状的体内植入制剂, 如阴道环和宫内节育器, 可以根据患者的需求设计植入剂的结构特征, 实现精准给药, 提高患者的依从性^[126]。

但是目前该技术还基本停留在实验室阶段, 想要该技术用于药品的大规模生产, 真正造福于社会和人类, 还需在以下方向继续投入: ①专用3D打印药物设备的整机设计和制造; ②为制药工艺和药物剂型设计所进行的辅料研究; ③为研究药物3D打印制剂的释放机制进行体内外研究和验证; ④ 3D打印技术的规模化生产; ⑤通过技术企业和法规部门合作, 共同制定新技术的法规和指南。

因此, 该技术的进一步发展需要工程学、材料学和药学等诸多专业学科人才的通力合作。并且, 这几个学科真正可以借鉴的前期研究成果都很有限, 需要从头开始搭建科学的研究体系, 进行系统的研究工作和技术开发, 期待通过学科间的协作和每个学科取得的阶段性研究成果, 来相互影响和推进3D打印技术的进步和成熟。

作者贡献: 张珂、郑道一、李安然、刘思远、王治钧负责文献检索、分析及文稿撰写; 陈钰、俞嘉黎负责修改文章; 高缘、张建军负责文章选题、指导写作、修改及校对文章。

利益冲突: 所有作者均声明不存在任何利益冲突。

基金

收起

国家自然科学基金资助项目(82074029)
国家自然科学基金资助项目(82104401)
国家自然科学基金资助项目(82274217)
国家自然科学基金资助项目(82204636)
中国药科大学“双一流”建设资助项目(CPU2018GY11)
中国药科大学“双一流”建设资助项目(CPU2018GY27)
中国药科大学“双一流”建设资助项目(3342100010)
中国药科大学“双一流”建设资助项目(2632021ZD15)
大学生创新创业训练计划项目(202210316013Z)

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2023年第58卷第9期

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doi: 10.16438/j.0513-4870.2023-0112

接收时间：2023-02-06
首发时间：2025-11-21
出版时间：2023-09-12

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收稿日期：2023-02-06
修回日期：2023-05-08

基金

国家自然科学基金资助项目(82074029)

国家自然科学基金资助项目(82104401)

国家自然科学基金资助项目(82274217)

国家自然科学基金资助项目(82204636)

中国药科大学“双一流”建设资助项目(CPU2018GY11)

中国药科大学“双一流”建设资助项目(CPU2018GY27)

中国药科大学“双一流”建设资助项目(3342100010)

中国药科大学“双一流”建设资助项目(2632021ZD15)

大学生创新创业训练计划项目(202210316013Z)

作者信息

1.中国药科大学药学院, 江苏南京 210009

2.中国药科大学中药学院, 江苏南京 210009

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*张建军, Tel / Fax: 86-25-83379418, E-mail: amicute@163.com

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2种不同金属材料的力学参数

科 Family	属数 Number of genus	种数 Number of species	占总种数比例 Percentage of total species (%)	属 Genus	种数 Number of species	占总种数比例 Percentage of total species (%)
鹅膏菌科Amanitaceae	2	11	5.26	鹅膏菌属 Amanita	10	4.78
小菇科 Mycenaceae	2	12	5.74	丝盖伞属 Inocybe	5	2.39
多孔菌科 Polyporaceae	8	14	6.70	蜡蘑属 Laccaria	5	2.39
红菇科 Russulaceae	3	23	11.00	小皮伞属 Marasmius	6	2.87
				小菇属 Mycena	11	5.26
				光柄菇属 Pluteus	5	2.39
				红菇属 Russula	17	8.13
				栓菌属 Trametes	5	2.39

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