3D打印技术用于市售华法林钠片与氢氯噻嗪片的精确分剂量
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摘要
将3D打印技术运用于药品分剂量,并对分剂量片进行评价,探索其可行性及技术可推广性。以医院常用分剂量药物为模型,取市售品研磨粉碎后混入稀释剂及黏结剂,以75%乙醇搅拌配成糊状得打印原浆料。在计算机软件中设置打印参数、生成打印模型,控制片剂剂量及物理化学性质。采用不同3D打印机制备分剂量片,评估器械对打印片的影响,同时打印不同药物考察分剂量技术的可推广性。结果表明,试制的3种分剂量片华法林钠片1 mg、2 mg和氢氯噻嗪片5 mg,药物含量分别为1.02±0.03、1.96±0.01和5.19±0.06 mg,含量均匀度分别为1.0、5.3和2.6。在45、45和30 min时药物溶出率为(99.3±1.2)%、(101.5±0.3)%和(98.1±0.8)%, 3种分剂量片机械性质及30天内稳定性均符合中国药典(2015年版)要求。研究发现打印参数与处方均可对分剂量片溶出性质产生影响。通过控制稀释辅料加入比例及分剂量片打印参数设置,可调整药物释放速率,达到个体化治疗的效果。两种不同模式的3D打印机均可制备小批量、高精度、高重复性的分剂量片,各项性质均符合药典规定,可作为一种新型的、可推广的分剂量方法。
The aim of this study is to apply 3D printing technology to hospital drug dosing operations,and explore its feasibility and scalability.Drugs often dosed in hospitals are selected as models.The commercially available drug was ground into powder,diluted with medicinal excipients and then mixed with 75% ethanol and binder to prepare a paste for 3D printing.The dose and physicochemical properties of divided tablets were controlled by setting print parameters and printing models in computer software.Different 3D printers were employed to evaluate the impact of the device on the dosing tablet.Two drugs were dosed in this study to explore the scalability of 3D printing technology between different drugs.The drug content of the three divided dose tablets(warfarin sodium 1 mg,2 mg,hydrochlorothiazide 5 mg) was 1.02 ± 0.03,1.96 ± 0.01,5.19 ± 0.06 mg.The content uniformity was 1.0,5.3,2.6,respectively.The drug dissolution rate was(99.3 ± 1.2) %,(101.5 ± 0.3) %,(98.1 ± 0.8) % in 45,45 and 30 min.The mechanical properties of the three sub-doses and the stability within 30 days were in line with the Chinese Pharmacopoeia(2015) requirements.At the same time,it was found that the printing parameters and prescriptions can affect the properties of the divided dose tablets.By controlling the dilution ratio of commercial drug and printing parameters,the drug release rate can be customized to achieve individualized treatment.Both different modes of 3D printers can produce qualified sub-doses,and 3D print dispensing technology was also versatile between the two drugs.3D printing can prepare small-volume,high-precision,high-repetition dosing tablets,with all properties in compliance with pharmacopoeia regulations.Thus,this method can be used as a new and scalable sub-dosing method.
The aim of this study is to apply 3D printing technology to hospital drug dosing operations,and explore its feasibility and scalability.Drugs often dosed in hospitals are selected as models.The commercially available drug was ground into powder,diluted with medicinal excipients and then mixed with 75% ethanol and binder to prepare a paste for 3D printing.The dose and physicochemical properties of divided tablets were controlled by setting print parameters and printing models in computer software.Different 3D printers were employed to evaluate the impact of the device on the dosing tablet.Two drugs were dosed in this study to explore the scalability of 3D printing technology between different drugs.The drug content of the three divided dose tablets(warfarin sodium 1 mg,2 mg,hydrochlorothiazide 5 mg) was 1.02 ± 0.03,1.96 ± 0.01,5.19 ± 0.06 mg.The content uniformity was 1.0,5.3,2.6,respectively.The drug dissolution rate was(99.3 ± 1.2) %,(101.5 ± 0.3) %,(98.1 ± 0.8) % in 45,45 and 30 min.The mechanical properties of the three sub-doses and the stability within 30 days were in line with the Chinese Pharmacopoeia(2015) requirements.At the same time,it was found that the printing parameters and prescriptions can affect the properties of the divided dose tablets.By controlling the dilution ratio of commercial drug and printing parameters,the drug release rate can be customized to achieve individualized treatment.Both different modes of 3D printers can produce qualified sub-doses,and 3D print dispensing technology was also versatile between the two drugs.3D printing can prepare small-volume,high-precision,high-repetition dosing tablets,with all properties in compliance with pharmacopoeia regulations.Thus,this method can be used as a new and scalable sub-dosing method.
引文
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[2]Liu YJ,Liao JW,Chen JY,et al.Reasons,problems and countermeasures of tablet dosages[J].Chin J Hosp Pharm(中国医院药学杂志),2011,31:692-695.
[3]Lin Y.Investigation on the Accuracy of Tablet Dosage and Its Influence on Children's Medication Safety(药片分剂量准确性考察及对儿童用药安全的影响)[D].Hangzhou:Zhejiang University,2014.
[4]Huang SY,Shi F,Li H,et al.Investigation of the use of high-risk tablets for oral administration in hospitals in a children's hospital in Shanghai[J].China Pharm(中国药师),2018,21:257-260.
[5]Zhang HX,You J.3D printing of aspirin immediate-release dual-layer tablets[J].Chin Pharm J(中国药学杂志),2017,52:298-302.
[6]Li QJ,Wen HY,Jia DY,et al.Preparation and investigation of controlled-release glipizide noveloral device with threedimensional printing[J].Int J Pharm,2017,525:5-11.
[7]Li QJ,Guan XY,Cui MS,et al.Preparation and investigation of novel gastro-floating tablets with 3D extrusion-based printing[J].Int J Pharm,2018,535:325-332.
[8]Chen XY,Peng Q,Hu DQ,et al.Correlation of CYP2C9and VKORCl polymorphisms with warfarin steady stable dose and computer model-predicted dose[J].Acta Med Univ Sci Technol Huazhong(华中科技大学学报医学版),2015,44:92-95.
[9]Hu J,Zhu JR,Yu F.Meta-analysis of safety and efficacy of warfarin dose prediction formulae for clinical use[J].Chin JClin Pharm Ther(中国临床药理学与治疗学),2015,20:296-303.
[10]Wei Y,Sun YY,Wang KS,et al.Pharmacokinetics of the combined preparation of lisinopril and hydrochlorothiazide on Chinese healthy volunteers[J].Acta Pharm Sin(药学学报),2011,46:955-961.
[11]Skowyra J,Pietrzak K,Alhnan MA.Fabrication of extendedrelease patient-tailored prednisolone tablets via fused deposition modelling(FDM)3D printing[J].Eur J Pharm Sci,2015,68:11-17.
[12]Pietrzak K,Isreb A,Alhnan MA.A flexible-dose dispenser for immediate and extended release 3D printed tablets[J].Eur J Pharm Biopharm,2015,96:380-387.
[13]Sadia M,Arafat B,Ahmed W,et al.Channelled tablets:an innovative approach to accelerating drug release from 3Dprinted tablets[J].J Control Release,2018,269:355-363.