三维打印技术在制药领域中的应用

摘 要三维打印技术作为一种新型快速成型技术,广泛应用于各种领域,如工业设计、家居制造、建筑行业及军事领域等方面。随着三维打印技术研究的深入和发展,因其具有可用材料广泛、柔性高、成型速度快、技术高度集成、绿色节能等优点,逐渐渗入到医药领域。FDA于2015年7月批准首个由Aprecia制药公司采用三维打印技术制备的SPRITAM口崩片,并于2016年3月22日正式上市。这不仅标志着三维打印药物正式进入临床应用,而且证明了三维打印技术在制药领域中的重要价值。本文概述了三维打印技术在制药领域的应用,并讨论了影响药物三维打印的因素。     

3D打印在肺肿瘤应用实例分析

目的 探讨3D打印技术在肺肿瘤的应用价值.方法 选取2例肺脏肿瘤患者化疗或靶向治疗前后肺脏肿瘤的变化进行CT成像,并利用数字化三维重建技术构建实体瘤三维模型进行3D打印,对实体瘤进行直观评价.结果 成功构建了实体瘤数字化三维模型,并利用3D打印技术打印出完整的3D模型进行疗效分析.结论 3D打印模型具有立体性、直观性及个体化特点,能够丰富个体化治疗水准、方便医患沟通,为临床、科研及医学教学提供一种新的方法.     

口腔修复用三维打印金属材料性能评价研究介绍

三维打印技术的快速发展为解决口腔修复体等形态复杂、个性化特征强的医疗器械制备提供了新的手段.通过产学研医管等多方联合开展技术攻关,构建三维打印金属材料性能评价体系,推动了三维打印金属材料科研成果向临床的顺利转化.风险精准控制的性能评价体系和监管方式优化对医疗器械新材料等领域科研成果转化具有重要意义,应加强监管科学研究,...     

3D打印技术在骨科中的应用进展

骨科医生主要通过X线片、CT和MR等影像学资料进行病情分析和诊断治疗,往往依赖医生的经验,且缺乏立体的视触感。近年来,3D打印技术迅猛发展,其可将患者虚拟的影像迅速转换成三维实体物件,并且可实现材料结构的个性化定制以及与病变部位的解剖学匹配,已广泛应用于骨科疾病的诊断、治疗和康复。另外,三维组装细胞和材料的生物打印技术有望实现骨肌组织的再生修复,具有广阔的应用前景。本文旨在综述3D技术在骨科应用的前沿研究,总结存在的问题,展望未来。     

基于3D打印技术制备复方丹参缓控释制剂的研究

目的 使用3D打印技术制备复方丹参缓控释制剂,实现复方丹参制剂中特定组分在特定部位释放.方法 通过计算机辅助设计软件,设计多组分、双层级释放的药物三维数字模型,使用热熔挤出方式制备负载药物的打印丝材,使用熔融沉积3D打印方式制备复方丹参缓控释制剂,以及体外溶出试验初步测试制剂中药物释放情况.结果 使用3D打印技术成功制...     

3D打印技术在医学相关领域的应用现状及展望

本文就3D打印技术的概念、优势以及在临床实践、医护教学、医疗设备研发中的应用现状进行综述,阐述3D打印技术在医学相关领域应用中的优势及其局限性,为3D打印技术在医学相关领域的应用与研究提供参考.     

三维耳廓模型在小耳畸形二期再造术中的应用

目的 应用3D打印技术为小耳畸形患者患侧耳廓再造提供手术指导.方法 选取2015年11月-2016年2月小耳一期再造术后患者,应用软件对患者健患侧耳廓3D-CT数据进行分割、镜像、膨胀等处理,获得双侧耳廓及双耳差值的三维虚拟模型,将其导入3D打印机生产三维实体模型,并应用于小耳二期再造.结果 8例(8耳)小耳畸形二期患者耳支架测量高度1.9～2.7 em,平均2.3 cm术后随访观察,1例出现植皮区感染,软骨外露,其余7例(7耳)再造耳廓与健侧耳匹配,形状相似、逼真,颅耳角与健侧耳对称.结论 应用软件和3D打印技术制作的耳廓三维模型,能很好地指导术中精细雕刻耳廓软骨支架并调整二期再造术中耳后支架、颅耳角高度.     

3D打印技术在脊柱肿瘤手术中的应用

目的 探讨3D打印技术在辅助脊柱肿瘤手术中的应用.方法 对22例脊柱肿瘤患者术前行CT扫描,收集数据进行三维模型重建,使用3D打印机制作出与实体1:1大小的病灶区域的脊柱模型,参考打印模型,制定手术方案、模拟手术操作、预处理内置物,指导治疗.结果 22例均手术成功,症状均较术前有改善.术中参照打印模型,做到了精确、完整的切除病灶区域.术后X线复查,可见内置物位置良好,未见松动、移位.结论 使用3D打印技术能够直观、全面的显示脊柱病灶区域的解剖毗邻关系,术者能够提前熟悉病灶,术中可以精确、完整的切除肿瘤,避免重要血管、神经的损伤,预处理内置物材料,进而缩短手术时间,减少术中出血.     

CBCT与3D打印技术在口腔颌面外科的研究进展全文替换

锥束计算机断层扫描(CBCT)可创建感兴趣区域的立体模型,在外科和医学实践中提供直观的三维(3D)图像,产生了深远的影响。而3D打印被称为一种新颖,引人入胜的“未来建筑技术”。这项技术在医学领域,尤其是在口腔颌面外科领域的应用正在扩大,开启了口腔颌面部外科领域的新时代。该文介绍了近年来CBCT与3D打印方法及其在当代口腔颌面外科手术中的作用,并回顾了CBCT与3D打印辅助手术在口腔颌面部区域的不同应用和益处。而3D打印将改变传统的制造模式,并已成为数字医学发展过程中的重要环节。     

数字化导航模板在胫骨平台畸形愈合截骨矫形术中的应用

目的 探讨3D打印技术在胫骨平台畸形愈合截骨矫形术中的应用效果.方法 将l例胫骨平台畸形愈合患者右膝关节CT扫描得到的数据进行计算机三维建模、3D打印导板制作和术前预演.手术时利用建立的定位模板导孔进行截骨,根据对侧镜像测得的高度与旋转角度进行矫形固定.术后根据X线及CT扫描结果评价截骨矫形的准确性,并随访观察患者功能改善情况.结果 本例术区骨面能够与导板准确帖服并引导摆锯截骨成功,导航模板准确性佳,矫形后胫骨对位对线均恢复正常,导板在应用过程中未出现变形、断裂,手术时间明显缩短.截骨端顺利愈合,无感染发生,对位对线未出现再次移位.结论 3D打印技术具有能够实现术前个体化设计、进行手术预演、缩短手术时间、减少医源性损伤、提高手术效率等优点,给患者、医生乃至社会都带来了巨大的帮助.     

Three-dimensional printing in pharmaceutics: promises and problems

Three-dimensional printing (3DP) is a rapid prototyping (RP) technology. Prototyping involves constructing specific layers that uses powder processing and liquid binding materials. Reports in the literature have highlighted the many advantages of the 3DP system over other processes in enhancing pharmaceutical applications, these include new methods in design, development, manufacture, and commercialization of various types of solid dosage forms. For example, 3DP technology is flexible in that it can be used in applications linked to linear drug delivery systems (DDS), colon-targeted DDS, oral fast disintegrating DDS, floating DDS, time controlled, and pulse release DDS as well as dosage form with multiphase release properties and implantable DDS. In addition 3DP can also provide solutions for resolving difficulties relating to the delivery of poorly water-soluble drugs, peptides and proteins, preparation of DDS for high toxic and potent drugs and controlled-release of multidrugs in a single dosage forms. Due to its flexible and highly reproducible manufacturing process, 3DP has some advantages over conventional compressing and other RP technologies in fabricating solid DDS. This enables 3DP to be further developed for use in pharmaceutics applications. However, there are some problems that limit the further applications of the system, such as the selections of suitable excipients and the pharmacotechnical properties of 3DP products. Further developments are therefore needed to overcome these issues where 3DP systems can be successfully combined with conventional pharmaceutics. Here we present an overview and the potential 3DP in the development of new drug delivery systems.     

Recent technological advances in oral drug delivery - a review

Despite disadvantages, oral drug delivery remains the preferred route of drug delivery. Novel technologies with improved performance, patient compliance, and enhanced quality have emerged in the recent past. Oral fast-dispersing dosage forms, three-dimensional Printing (3DP) and electrostatic coating are a few examples of a few existing technologies with the potential to accommodate various physico-chemical, pharmacokinetic and pharmacodynamic characteristics of drugs. This article provides a comprehensive review of these three technologies.     

The use of prostaglandin D2 receptor antagonists to treat allergic rhinitis

Two applications describe 1-(heteroarylmethoxybenzoyl)-2-methylindolylacetic acid derivatives that are active as prostaglandin D₂ receptor (DP) antagonists. Both indol-3-ylacetic acid and indol-4-ylacetic acid derivatives have good affinity for the DP receptor. The use of these antagonists for the treatment of various inflammatory diseases is claimed but the preferred indication is allergic rhinitis, with the development compound by Ono Pharm., ONO4217Na, likely to be described in one of the applications.     

Three ‘D’s: Design approach,dimensional printing,and drug delivery systems as promising tools in healthcare applications

The development of pharmaceutical drug products is required for the treatment of disease, which has resulted in an increasing number of approvals by regulatory agencies across the globe. To establish a hassle-free manufacturing process, the systematic use of a quality-by-design (QbD) approach combined with process analytical technology (PAT) and printing techniques can revolutionize healthcare applications. Printing technology has been emerged in various dimensions, such as 3D, 4D, and 5D printing, with respect to their production capabilities, durability, and accuracy of pharmaceutical manufacturing, which can efficiently deliver novel patient-centric healthcare products with holistic characteristics. In this review, we provide current trends in pharmaceutical product development using a design approach and high-quality printing techniques.     

核磁共振化学位移计算在天然产物结构鉴定中的应用

随着计算机科学技术的发展,量子化学理论的不断完善,复杂天然产物的结构鉴定已经从传统的核磁共振技术及光谱技术演变成了量子化学计算与核磁共振技术相结合的方法,其中以量子计算¹H和¹³C化学位移尤为重要,无论在精度、可及性还是应用方面均有明显提高。同时,结果分析方法也从简单的统计学方法逐渐发展为基于更为复杂的统计学原理或人工神经网络的方法,如CP3、DP4、DP4+、DP4-AI、DU8+等。文章将重点对量子化学理论辅助计算¹H和¹³C化学位移在理论和实践应用2个方面作简要介绍,阐述其在天然产物结构鉴定中的优势。     

Targeting the prostaglandin D2 receptors DP and CRTH2 for treatment of inflammation

The involvement of prostaglandin D(2) (PGD(2)) in inflammatory diseases like allergy and asthma is well established, thus blocking the effect of this mediator represents a novel therapeutic approach for the treatment of such diseases. PGD(2) is now known to act through two seven-transmembrane (7TM) receptors, DP (DP(1)) and CRTH2 (DP(2)), which are also activated by several endogenous metabolites from the arachidonic acid cascade, making the regulatory system highly complex. There has recently been a considerable effort aimed at developing antagonists of the PGD(2) receptors for treatment of inflammatory conditions like asthma and rhinitis. Several potent DP antagonists are now known, and one of these is currently in clinical trials for treatment of asthma. CRTH2 has received much attention since its identification as the second high affinity PGD(2) receptor in 2001, and a number of potent and selective antagonists have recently become available. This review will briefly discuss the biological background and validation of DP and CRTH2 as targets for antiinflammatory drugs, and then highlight developments in medicinal chemistry which have appeared in journals and patent applications in the last few years, and which have brought us closer to therapeutic applications of PGD(2) receptor antagonists in various indications.     

Efficacy of d-penicillamine, a sequestering acetaldehyde agent, in the prevention of alcohol relapse-like drinking in rats

Rationale

Nowadays, very few approved anti-relapse treatments for alcoholism exist, and their overall efficacy can be considered moderate. An exciting rationale drug development opportunity for the treatment of chronic alcoholism is the use of acetaldehyde sequestering agents. Although these compounds are able to attenuate or prevent most of the behavioral and neurochemical effects of ethanol, the efficacy of acetaldehyde sequestration, by using agents such as d-penicillamine (DP), in relapse prevention has not been studied yet.

Objectives

The aim of this study was to analyze the effects of DP treatment on the alcohol deprivation effect (ADE) in long-term ethanol-experienced rats as a model of relapse behavior and measure drug plasma and brain levels during treatment.

Methods

Rats were subcutaneously implanted with mini-osmotic pumps delivering 0, 0.25, or 1 mg/h of DP during 1 week. The efficacy to prevent ADE was determined. DP plasma and brain levels achieved during its subcutaneous administration were measured. In a second experiment, animals received bilateral infusions of 0 or 1.5 μg/h of DP directly into pVTA, and the appearance of ADE was evaluated.

Results

One milligram per hour, but not 0.25 mg/h, DP infusion prevented ADE and reduced the total ethanol preference in animals. DP plasma concentrations associated with ADE suppression were around 3–4 μg/ml, and brain DP levels in these conditions were about 2–3 % of those found in plasma. Intra-pVTA DP administration also suppressed ADE.

Conclusion

DP is able to prevent alcohol-relapse-like drinking in rats suggesting that this drug may be a useful new tool in the management of relapse in alcohol-dependent patients.     

Evaluation of WO2012078210 – development process for the preparation of a DP2 receptor antagonist; Ironwood's first development DP2 antagonist

This application claims processes for the preparation of a series of pyrrole-based DP2 receptor antagonists, in particular 2-[3-cyano-2,5-dimethyl-4-[(2-pyrrolidin-1-ylsulfonylphenyl)methyl]pyrrol-1-yl]acetic acid. The nature of the filing points to this compound being a development compound and it may be IW-1221 which has previously been identified as a DP2 antagonist.     

Evaluation of WO2012078210 - development process for the preparation of a DP2 receptor antagonist; Ironwood's first development DP2 antagonist

This application claims processes for the preparation of a series of pyrrole-based DP2 receptor antagonists, in particular 2-[3-cyano-2,5-dimethyl-4-[(2-pyrrolidin-1-ylsulfonylphenyl)methyl]pyrrol-1-yl]acetic acid. The nature of the filing points to this compound being a development compound and it may be IW-1221 which has previously been identified as a DP2 antagonist.     

An Intercompany Perspective on Biopharmaceutical Drug Product Robustness Studies

The Biophorum Development Group (BPDG) is an industry-wide consortium enabling networking and sharing of best practices for the development of biopharmaceuticals. To gain a better understanding of current industry approaches for establishing biopharmaceutical drug product (DP) robustness, the BPDG-Formulation Point Share group conducted an intercompany collaboration exercise, which included a bench-marking survey and extensive group discussions around the scope, design, and execution of robustness studies. The results of this industry collaboration revealed several key common themes: (1) overall DP robustness is defined by both the formulation and the manufacturing process robustness; (2) robustness integrates the principles of quality by design (QbD); (3) DP robustness is an important factor in setting critical quality attribute control strategies and commercial specifications; (4) most companies employ robustness studies, along with prior knowledge, risk assessments, and statistics, to develop the DP design space; (5) studies are tailored to commercial development needs and the practices of each company. Three case studies further illustrate how a robustness study design for a biopharmaceutical DP balances experimental complexity, statistical power, scientific understanding, and risk assessment to provide the desired product and process knowledge. The BPDG-Formulation Point Share discusses identified industry challenges with regard to biopharmaceutical DP robustness and presents some recommendations for best practices.