A flexible-dose dispenser for immediate and extended release 3D printed tablets

The advances in personalised medicine increased the demand for a fast, accurate and reliable production method of tablets that can be digitally controlled by healthcare staff. A flexible dose tablet system is presented in this study that proved to be suitable for immediate and extended release tablets with a realistic drug loading and an easy-to-swallow tablet design. The method bridges the affordable and digitally controlled Fused Deposition Modelling (FDM) 3D printing with a standard pharmaceutical manufacturing process, Hot Melt Extrusion (HME). The reported method was compatible with three methacrylic polymers (Eudragit RL, RS and E) as well as a cellulose-based one (hydroxypropyl cellulose, HPC SSL). The use of a HME based pharmaceutical filament preserved the linear relationship between the mass and printed volume and was utilized to digitally control the dose via an input from computer software with dose accuracy in the range of 91–95%. Higher resolution printing quality doubled the printing time, but showed a little effect on in vitro release pattern of theophylline and weight accuracy. Physical characterization studies indicated that the majority of the model drug (theophylline) in the 3D printed tablet exists in a crystal form. Owing to the small size, ease of use and the highly adjustable nature of FDM 3D printers, the method holds promise for future individualised treatment.     

3D打印克拉霉素胃漂浮缓释片的质量评价

目的 使用基于半固态挤出的3D打印技术制备一种缓释12 h的克拉霉素(clarithromycin,CAM)胃漂浮片。方法 考察pH敏感型、温敏型、水不溶蚀型高分子凝胶骨架材料与HPMC K15MCR复合使用对CAM释放的影响,评价了CAM胃漂浮缓释片的片重差异、硬度、脆碎度、溶出曲线和溶出机理。结果 通过基于半固态挤出的3D打印技术,仅需使用HPMC K15MCR作为释放阻滞剂,即可制备载药量高达81.7%的CAM胃漂浮缓释片,相关指标符合中国药典2020年版的要求。结论 基于半固态挤出的3D打印技术在制备胃漂浮缓释递药系统领域具有较大的应用潜力。     

Extrusion printed polymer structures: a facile and versatile approach to tailored drug delivery platforms

A novel extrusion printing system was used to create drug delivery structures wherein dexamethasone-21-phosphate disodium salt (Dex21P) was encapsulated within a biodegradable polymer (PLGA) and water soluble poly(vinyl alcohol) (PVA) configurations. The ability to control the drug release profile through the spatial distribution of drug within the printed 3-dimensional structures is demonstrated. The fabricated configurations were characterised by optical microscopy and SEM to evaluate surface morphology. The results clearly demonstrate the successful encapsulation of dexamethasone within a laminated PLGA:PVA structure. The resulting drug release profiles from the structures show a two stage release profile with distinctly different release rates and minimal initial burst release observed. Dexamethasone release was monitored over a 4-month period. This approach clearly demonstrates that the extrusion printing technique provides a facile and versatile approach to fabrication of novel drug delivery platforms.     

Preparation and investigation of novel gastro-floating tablets with 3D extrusion-based printing

Three dimensional (3D) extrusion-based printing is a paste-based rapid prototyping process, which is capable of building complex 3D structures. The aim of this study was to explore the feasibility of 3D extrusion-based printing as a pharmaceutical manufacture technique for the fabrication of gastro-floating tablets. Novel low-density lattice internal structure gastro-floating tablets of dipyridamole were developed to prolong the gastric residence time in order to improve drug release rate and consequently, improve bioavailability and therapeutic efficacy. Excipients commonly employed in the pharmaceutical study could be efficiently applied in the room temperature 3D extrusion-based printing process. The tablets were designed with three kinds of infill percentage and prepared by hydroxypropyl methylcellulose (HPMC K4M) and hydroxypropyl methylcellulose (HPMC E15) as hydrophilic matrices and microcrystalline cellulose (MCC PH101) as extrusion molding agent. In vitro evaluation of the 3D printed gastro-floating tablets was performed by determining mechanical properties, content uniformity, and weight variation. Furthermore, re-floating ability, floating duration time, and drug release behavior were also evaluated. Dissolution profiles revealed the relationship between infill percentage and drug release behavior. The results of this study revealed the potential of 3D extrusion-based printing to fabricate gastro-floating tablets with more than 8 h floating process with traditional pharmaceutical excipients and lattice internal structure design.     

A Lower Temperature FDM 3D Printing for the Manufacture of Patient-Specific Immediate Release Tablets

Purpose

The fabrication of ready-to-use immediate release tablets via 3D printing provides a powerful tool to on-demand individualization of dosage form. This work aims to adapt a widely used pharmaceutical grade polymer, polyvinylpyrrolidone (PVP), for instant on-demand production of immediate release tablets via FDM 3D printing.

Methods

Dipyridamole or theophylline loaded filaments were produced via processing a physical mixture of API (10%) and PVP in the presence of plasticizer through hot-melt extrusion (HME). Computer software was utilized to design a caplet-shaped tablet. The surface morphology of the printed tablet was assessed using scanning electron microscopy (SEM). The physical form of the drugs and its integrity following an FDM 3D printing were assessed using x-ray powder diffractometry (XRPD), thermal analysis and HPLC. In vitro drug release studies for all 3D printed tablets were conducted in a USP II dissolution apparatus.

Results

Bridging 3D printing process with HME in the presence of a thermostable filler, talc, enabled the fabrication of immediate release tablets at temperatures as low as 110°C. The integrity of two model drugs was maintained following HME and FDM 3D printing. XRPD indicated that a portion of the loaded theophylline remained crystalline in the tablet. The fabricated tablets demonstrated excellent mechanical properties, acceptable in-batch variability and an immediate in vitro release pattern.

Conclusions

Combining the advantages of PVP as an impeding polymer with FDM 3D printing at low temperatures, this approach holds a potential in expanding the spectrum of drugs that could be used in FDM 3D printing for on demand manufacturing of individualised dosage forms.

     

Exploration and Preparation of Patient-specific Ciprofloxacin Implants Drug Delivery System Via 3D Printing Technologies

A suitable drug-loaded implant delivery system that can effectively release antibacterial drug in the postoperative lesion area and help repair bone infection is very significant in the clinical treatment of bone defect. The work was aimed to investigate the feasibility of applying three-dimensional (3D) printing technology to prepare drug-loaded implants for bone repair. Semi-solid extrusion (SSE) and Fuse deposition modeling® (FDM) technologies were implemented and ciprofloxacin (CIP) was chosen as the model drug. All of the implants exhibited a smooth surface, good mechanical properties and satisfactory structural integrity as well as accurate dimensional size. In vitro drug release showed that the implants made by 3D printing technologies slowed down the initial drug burst effect and expressed a long-term sustained release behavior, compared with the implants prepared with traditional method. In addition, the patient-specific macrostructure implants, consisting of interconnected and different shapes pores, were created using unique lay down patterns. As a result, the weakest burst release effect and the sustained drug release were achieved in the patient-specific implants with linear pattern. These results clearly stated that 3D printing technology offers a viable approach to prepare control-releasing implants with patient-specific macro-porosity and presents novel strategies for treating bone infections.     

Innovative color jet 3D printing of levetiracetam personalized paediatric preparations

3D printing is a promising technology used in the fabrication of complex oral dosage delivery pharmaceuticals. This study first reports an innovative color jet 3D printing (CJ-3DP) technology to produce colorful cartoon levetiracetam pediatric preparations with high accuracy and reproducibility. For this study, the ideal printing ink consisted of 40% (v/v) isopropanol aqueous solution containing 0.05% (w/w) polyvinylpyrrolidone and 4% (w/w) glycerin, which was satisfied with scale-up of the production. The external and internal spatial structures of the tablets were designed to control the appearance and release, and cartoon tablets with admirable appearances and immediate release characteristics were printed. The dosage model showed a good linear relationship between the model volume and the tablet strength (r > 0.999), which proved the potential of personalized administration. The surface roughness indicated that the appearance of the CJ-3DP tablets was significantly better than the first listed 3D printed drug (Spritam^Ⓡ). Moreover, the scanning electron microscopy and porosity results further showed that the tablets have a structure of loose interior and tight exterior, which could ensure good mechanical properties and rapid dispersion characteristics simultaneously. In conclusion, the innovative CJ-3DP technology can be used to fabricate personalized pediatric preparations for improved compliance. Due to the stable formulation and fabrication process, this technology has the potential in scale-up production.     

Fabricating a Shell-Core Delayed Release Tablet Using Dual FDM 3D Printing for Patient-Centred Therapy

Purpose

Individualizing gastric-resistant tablets is associated with major challenges for clinical staff in hospitals and healthcare centres. This work aims to fabricate gastric-resistant 3D printed tablets using dual FDM 3D printing.

Methods

The gastric-resistant tablets were engineered by employing a range of shell-core designs using polyvinylpyrrolidone (PVP) and methacrylic acid co-polymer for core and shell structures respectively. Filaments for both core and shell were compounded using a twin-screw hot-melt extruder (HME). CAD software was utilized to design a capsule-shaped core with a complementary shell of increasing thicknesses (0.17, 0.35, 0.52, 0.70 or 0.87 mm). The physical form of the drug and its integrity following an FDM 3D printing were assessed using x-ray powder diffractometry (XRPD), thermal analysis and HPLC.

Results

A shell thickness ≥0.52 mm was deemed necessary in order to achieve sufficient core protection in the acid medium. The technology proved viable for incorporating different drug candidates; theophylline, budesonide and diclofenac sodium. XRPD indicated the presence of theophylline crystals whilst budesonide and diclofenac sodium remained amorphous in the PVP matrix of the filaments and 3D printed tablets. Fabricated tablets demonstrated gastric resistant properties and a pH responsive drug release pattern in both phosphate and bicarbonate buffers.

Conclusions

Despite its relatively limited resolution, FDM 3D printing proved to be a suitable platform for a single-process fabrication of delayed release tablets. This work reveals the potential of dual FDM 3D printing as a unique platform for personalising delayed release tablets to suit an individual patient’s needs.

     

3D打印华法林钠片的质量评价

目的：对不同剂量的3D打印华法林钠片进行质量评价。方法：采用HPLC法进行样品含量及有关物质测定,含量均匀度测定;采用质构仪测定片剂的硬度和崩解时间;采用《中国药典》方法将3D打印华法林钠片溶出时间与传统压片制剂比较;采用《欧洲药典》方法将3D打印分剂量方式与传统分劈分剂量方式进行比较;采用光学显微镜和相机观察3D打印片剂的内部结构和外观。结果：3D打印华法林钠片的各项指标均合格,且溶出时间较传统片剂快,分剂量方式也更准确简便。结论：3D打印技术可作为片剂分剂量的一种重要手段。     

Properties of sustained-release tablets prepared by hot-melt extrusion

The objectives of the present study were to investigate the properties of polyethylene oxide (PEO) as a drug carrier and to study the release mechanism of chlorpheniramine maleate (CPM) from matrix tablets prepared by hot-melt extrusion. During the hot-melt extrusion process, a dry powder blend of drug, polymer, and other adjuvants was fed into the extruder and melted inside the barrel of the machine. The molten mass was extruded through a rod-shaped die and then cut manually into 400-mg tablets. CPM and PEO were shown to be stable under the processing conditions. The molecular weight of the PEO, the drug loading percentage, and the inclusion of polyethylene glycol as a processing aid, were all found to influence the processing conditions and the drug release properties of the extruded tablets. Faster release of CPM from the matrix tablets was observed in acidic medium than in purified water and phosphate buffer (pH 7.4). Drug release from the matrix tablet was controlled by erosion of the PEO matrix and the diffusion of the drug through the swollen gel layer at the surface of the tablets. CPM was dispersed at the molecular level in the PEO matrix at low drug loading level and recrystallization of CPM was observed at high drug loading levels. Hot-melt extrusion was demonstrated to be a viable novel method to prepare sustained-release tablets. PEO was shown to be a suitable polymeric carrier for this process.     

Tablets with material gradients fabricated by three-dimensional printing

Complex tablets with zero-order drug release characteristics were fabricated using three-dimensional printing processes. The matrix tablets exhibited material gradients in radial direction and had drug-free release-barrier layers on both bases. The content of model drug acetaminophen incorporated in the tablets through premixing reached up to 68% of the tablets' weight. Tablets with ethylcellulose gradients showed acceptable mechanical and pharmacotechnical properties, as indicated by crushing strength, friability, and content uniformity tests. The structure and the gradients of ethylcellulose in the tablets were envisaged through environmental scanning electron microscopy and fluorescence tracing technique. Erosion and dissolution studies in vitro indicated that drug was released via a two-dimensional surface erosion mechanism, and 98% of the drug could be released linearly in 12 h. Tablets with other release-retardation material gradients such as sodium lauryl sulfate, stearic acid, and Eudragit RS-100 showed similar release-retardation effects by different release-retardation mechanisms. Through the printing of release-retardation materials, 3DP processes could easily prepare tablets with high dosage and special design features for furnishing the desired drug release characteristics.     

Control of drug release by incorporation of sorbitol or mannitol in microcrystalline-cellulose-based pellets prepared by extrusion-spheronization

Mixtures of microcrystalline cellulose (MCC) with sorbitol (up to 50%) or mannitol (up to 80%) were investigated as major excipients for controlled accelerated release of the model poorly water-soluble drug hydrochlorothiazide from pellets prepared by extrusion/spheronization. Optimal wetting volume decreased with increasing polyol content and was always less than the volume required for maximum wet mass consistency. All pellet formulations had satisfactory morphological, mechanical and flow properties, although sorbitol/MCC pellets were rougher than mannitol/MCC pellets. Together they presented a wide range of drug release profiles in 0.1?M HCl, allowing the rate of drug release into aqueous media to be controlled by manipulation of sorbitol or mannitol content. Pellets with a 50% sorbitol content released hydrochlorothiazide faster than pellets with a 50% mannitol content because of their greater porosity and the greater solubility of sorbitol in water. Fastest release was from pellets with an 80% mannitol content, which rapidly underwent complete disintegration.     

熔融沉积成型3D打印法莫替丁口服脉冲制剂的研究（英文）

为了制备具有不同药物延迟释放时间,按照患者需求实现个性化给药的脉冲制剂,本研究将熔融沉积成型(fuseddepositionmodeling,FDM)3D打印技术引入制剂领域,探讨了以该技术结合传统工艺制备核壳型口服脉冲制剂的可行性。该制剂的“核”是以传统工艺制备的市售片剂,而不含药物的外层壳是以FDM 3D打印技术制备的。本研究采用不同参数设计了三种外壳的片剂,并对其形态、尺寸、片重、硬度和体外释药进行了表征和评价。结果表明3D打印片剂外型完好,无缺陷。脉冲片剂的大小、片重、硬度及体外释药行为均与外壳参数相关,通过调节外壳参数可以实现药物个性化的体外5–7小时的延迟释放。本研究探索了制备脉冲制剂的新方法和实现脉冲制剂个性化给药的新途径。     

3D Printed Intragastric Floating and Sustained-Release Tablets with Air Chambers

This work aimed to use hot-melt extrusion (HME) and dual fused deposition modeling (FDM) 3D printing technology to develop a novel intragastric floating and sustained-release drug delivery system. The intragastric floating and sustained-release tablet was engineered by employing hydroxypropyl methylcellulose (Affinisol^TM HPMC HME 15LV) for a drug-loaded core and polylactic acid (PLA) for an insoluble shell with an air chamber. Filaments for the drug-loaded core were compounded using a single-screw hot melt extruder. 3DMAX software was utilized to design a core with a complementary shell which consisted of a hollow chamber at the top and a drug-release window with different sizes (radius in 1.5, 2.5, 3, 3.5, 4.5 mm) at the bottom. Pharmaceutical characterization, solid dispersion evaluation, and drug release behavior were studied. The model drug in all formulations kept stable, and part of the drug in the extruded filaments and 3D printed tablets became amorphous. The introduction of an air chamber reduced the tablet density to below 0.9 g/cm³ and the 3D printed tablets floated immediately and continuously during the drug release process. The presence of the insoluble shell greatly prolonged the drug release time, and the drug release rate was positively correlated with the area of the release window. In addition, compared with shellless tablets, the 3D printed tablets with air chambers (radius in 4.5 mm) showed closer zero-order drug release for 24 h and released drug by diffusion-erosion combined mechanism. The developed intragastric floating and sustained-release tablets with air chambers could be applied to various drugs and provided a new way for the development of personalized drug delivery systems.     

Emergence of 3D Printed Dosage Forms: Opportunities and Challenges

The recent introduction of the first FDA approved 3D-printed drug has fuelled interest in 3D printing technology, which is set to revolutionize healthcare. Since its initial use, this rapid prototyping (RP) technology has evolved to such an extent that it is currently being used in a wide range of applications including in tissue engineering, dentistry, construction, automotive and aerospace. However, in the pharmaceutical industry this technology is still in its infancy and its potential yet to be fully explored. This paper presents various 3D printing technologies such as stereolithographic, powder based, selective laser sintering, fused deposition modelling and semi-solid extrusion 3D printing. It also provides a comprehensive review of previous attempts at using 3D printing technologies on the manufacturing dosage forms with a particular focus on oral tablets. Their advantages particularly with adaptability in the pharmaceutical field have been highlighted, which enables the preparation of dosage forms with complex designs and geometries, multiple actives and tailored release profiles. An insight into the technical challenges facing the different 3D printing technologies such as the formulation and processing parameters is provided. Light is also shed on the different regulatory challenges that need to be overcome for 3D printing to fulfil its real potential in the pharmaceutical industry.     

Formulation of 3D Printed Tablet for Rapid Drug Release by Fused Deposition Modeling: Screening Polymers for Drug Release,Drug-Polymer Miscibility and Printability

The primary aim of this study was to identify pharmaceutically acceptable amorphous polymers for producing 3D printed tablets of a model drug, haloperidol, for rapid release by fused deposition modeling. Filaments for 3D printing were prepared by hot melt extrusion at 150°C with 10% and 20% w/w of haloperidol using Kollidon^® VA64, Kollicoat^® IR, Affinsiol^?15 cP, and HPMCAS either individually or as binary blends (Kollidon^® VA64 + Affinisol^? 15 cP, 1:1; Kollidon^® VA64 + HPMCAS, 1:1). Dissolution of crushed extrudates was studied at pH 2 and 6.8, and formulations demonstrating rapid dissolution rates were then analyzed for drug-polymer, polymer-polymer and drug-polymer-polymer miscibility by film casting. Polymer-polymer (1:1) and drug-polymer-polymer (1:5:5 and 2:5:5) mixtures were found to be miscible. Tablets with 100% and 60% infill were printed using MakerBot printer at 210°C, and dissolution tests of tablets were conducted at pH 2 and 6.8. Extruded filaments of Kollidon^® VA64-Affinisol^? 15 cP mixtures were flexible and had optimum mechanical strength for 3D printing. Tablets containing 10% drug with 60% and 100% infill showed complete drug release at pH 2 in 45 and 120 min, respectively. Relatively high dissolution rates were also observed at pH 6.8. The 1:1-mixture of Kollidon^® VA64 and Affinisol^?15 cP was thus identified as a suitable polymer system for 3D printing and rapid drug release.     

Preparation and evaluation of Vinpocetine self-emulsifying pH gradient release pellets

The main objective of this study was to develop a pH gradient release pellet with self-emulsifying drug delivery system (SEDDS), which could not only improve the oral bioavailability of Vinpocetine (VIN), a poor soluble drug, but reduce the fluctuation of plasma concentration. First, the liquid VIN SEDDS formulation was prepared. Then the self-emulsifying pH gradient release pellets were prepared by extrusion spheronization technique, and formulation consisted by the liquid SEDDS, absorbent (colloidal silicon dioxide), penetration enhancer (sodium chloride), microcrystalline cellulose, ethyl alcohol, and three coating materials (HPMC, Eudragit L30D55, Eudragit FS30D) were eventually selected. Three kinds of coated pellets were mixed in capsules with the mass ratio of 1:1:1. The release curves of capsules were investigated in vitro under the simulated gastrointestinal conditions. In addition, the oral bioavailability and pharmacokinetics of VIN self-emulsifying pH gradient release pellets, commercial tablets and liquid VIN SEDDS were evaluated in Beagle dogs. The oral bioavailability of self-emulsifying pH gradient release pellets was about 149.8% of commercial VIN tablets, and it was about 86% of liquid VIN SEDDS, but there were no significant difference between liquid SEDDS and self-emulsifying pH gradient release pellets. In conclusion, the self-emulsifying pH gradient release pellets could significantly enhance the absorption of VIN and effectively achieve a pH gradient release. And the self-emulsifying pH gradient release pellet was a promising method to improve bioavailability of insoluble drugs.     

Effect of Tartrazine as Photoabsorber for Improved Printing Resolution of 3D Printed “Ghost Tablets”: Non-Erodible Inert Matrices

Stereolithography (SLA) 3D printing of pharmaceuticals suffers from the problem of light scattering, which leads to over-curing, resulting in the printing of objects that are non-compliant with design dimensions and the overloading of drugs. To minimize this problem, photoabsorbers such as tartrazine (food grade) can be used to absorb the stray light produced by scattering, leading to unintended photopolymerization. Ghost tablets (i.e., non-erodible inert matrices) were additively manufactured using SLA with varying ratios of polyethylene glycol diacrylate (PEGDA): polyethylene glycol (PEG) 300, along with tartrazine concentrations. The 3D printed ghost tablets containing maximum (0.03%) tartrazine were extremely precise in size and adhered to the nominal value of the metformin hydrochloride content. Resolution analysis reinstated the influence of tartrazine in achieving highly precise objects of even 0.07 mm² area. Furthermore, 3D printed ghost tablets were characterized using analytical means, and swelling studies. Additionally, ghost tablets were tested for their mechanical robustness using dynamic mechanical and texture analysis, and were able to withstand strains of up to 5.0% without structural failure. The printed ghost tablets displayed a fast metformin hydrochloride release profile, with 93.14% release after 12 h when the PEG 300 ratio was at its maximum. Ghost tablets were also subjected to in vivo X-ray imaging, and the tablets remained intact even after four hours of administration and were eventually excreted in an intact form through fecal excretion.     

The Precision and Accuracy of 3D Printing of Tablets by Fused Deposition Modelling

Tablet manufacture by fused deposition modelling (FDM) can be carried out individually (one tablet printed per run) or as a group (i.e., ‘multiple printing’ in one run) depending on patient's needs. The assessment of the process of printing must take into consideration the precision and the accuracy of the mass and dose of tablets, together with their solid-state properties and drug dissolution behaviour. Different mixtures made of either poly(vinyl alcohol) and paracetamol or hydroxypropylcellulose EF and hydrochlorothiazide were used to evaluate multiple printing of tablets by manufacturing batches of 30 tablets with nozzles of 0.4 and 0.7 mm, in two different printers. Besides testing for mass, drug content, density and dissolution performance, tablets were analysed for their thermal (DSC) and spectroscopic (NIR and FTIR) properties. Low standard deviations around mean values for the different properties measured suggested low intra-batch variability. Statistical analysis of data revealed no significant differences between the batches for most of the properties considered in the study. Inter-batch differences (p<0.05) were observed only for mass of tablets, possibly due to deviation on filament's diameter. The use of a smaller nozzle or a different printer enabled the manufacture of more reproducible tablets within a batch. Multiple printing revealed a significant saving on manufacturing time (>35%) in comparison to individual printing.     

响应面法优化富马酸喹硫平缓释片处方

目的:优化富马酸喹硫平缓释片处方。方法:以累积释放度综合评分作为响应值,采用3因素3水平的响应面法,确定富马酸喹硫平缓释片处方中羟丙甲纤维素(HPMC)的黏度、用量与枸橼酸钠、乳糖的用量,并探讨其体外释药机制。结果:骨架材料选择HPMC K15M,考虑到实际操作便利确定其用量为13.5%,枸橼酸钠用量为9.5%,乳糖用量为14%。缓释片体外释放符合Higuchi方程,释药机制为扩散和溶蚀并存的双重机制。结论:筛选所得的富马酸喹硫平缓释片处方工艺稳定可行,有一定的缓释作用。