Special Issue "Applications of Additive Manufacturing in Pharmaceutics"

A special issue of Pharmaceutics (ISSN 1999-4923). This special issue belongs to the section "Pharmaceutical Technology, Manufacturing and Devices".

Deadline for manuscript submissions: closed (31 March 2021).

Special Issue Editor

Assoc. Prof. Natalja Genina
E-Mail Website
Guest Editor
Department of Pharmacy, University of Copenhagen, 2100 Copenhagen, Denmark
Interests: printable dosage forms; particle engineering; medical devices; controlled drug delivery; cryptopharmaceuticals

Special Issue Information

Dear Colleagues,

We would like to invite you to contribute to this Special Issue, entitled “Applications of Additive Manufacturing in Pharmaceutics”.

Additive manufacturing technologies, namely 2D and 3D printing, have headily entered the pharmaceutical world, because the conventional manufacturing methods for drug products have some evident limitations. Traditional manufacturing solutions are limited in the provision of patient-tailored easily recognizable medicine. Furthermore, a simple design of the conventional dosage forms makes them easier to counterfeit. Finally, flexible on-demand production of dosage forms near end-users is scanty with the conventional operation procedures and regulations.

In this regard, the nature and operating principles of additive manufacturing technologies, open up new possibilities for development of innovative dosage forms with unique design and enhanced functionality that would overcome the physiological limitations of the gastrointestinal tract. However, these technologies if used alone have their own limitations. Therefore, combining e.g., 3D printing with another manufacturing solution(s) can minimize the drawbacks and couple the advantages of both technologies. Furthermore, a small footprint of 3D printers enables their incorporation in the settings near end-users, e.g., hospital pharmacies, for on-demand production of pharmaceuticals. This would require miniaturized, rapid and non-destructive quality control methods. In addition, such potential on-demand drug manufacturing would need to meet the requirements of the current regulations and/or lead to proposal and approval of new ones.

This Special Issue invites the submission of articles dealing with the following topics:

  • Innovative dosage forms with improved functionality
  • Pharmaceutical dosage forms manufactured by combination of two or more techniques, where one is 3D printing
  • Non-destructive and preferably portable quality control systems for printable pharmaceuticals
  • Regulatory challenges and possible scenarios to make flexible production of printable pharmaceuticals a reality

I am looking forward to receiving your contributions!

Sincerely,

Assoc. Prof. Natalja Genina
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All papers will be peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Pharmaceutics is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2200 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • 2D printing
  • 3D printing
  • combination
  • dosage forms
  • quality control systems
  • regulatory challenges

Published Papers (7 papers)

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Research

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Article
Data-Enriched Edible Pharmaceuticals (DEEP) with Bespoke Design, Dose and Drug Release
Pharmaceutics 2021, 13(11), 1866; https://doi.org/10.3390/pharmaceutics13111866 - 04 Nov 2021
Viewed by 551
Abstract
Data-enriched edible pharmaceuticals (DEEP) is an approach to obtain personalized medicine, in terms of flexible and precise drug doses, while at the same time containing data, embedded in quick response (QR) codes at a single dosage unit level. The aim of this study [...] Read more.
Data-enriched edible pharmaceuticals (DEEP) is an approach to obtain personalized medicine, in terms of flexible and precise drug doses, while at the same time containing data, embedded in quick response (QR) codes at a single dosage unit level. The aim of this study was to fabricate DEEP with a patient-tailored dose, modify drug release and design to meet patients’ preferences. It also aimed to investigate physical stability in terms of the readability of QR code patterns of DEEP during storage. Cannabinoids, namely, cannabidiol (CBD) and delta-9-tetrahydrocannabinol (THC), were used as the model active pharmaceutical ingredients (APIs). Three different substrates and two colorants for the ink were tested for their suitability to fabricate DEEP by desktop inkjet printing. Flexible doses and customizable designs of DEEP were obtained by manipulating the digital design of the QR code, particularly, by exploring different pattern types, embedded images and the physical size of the QR code pattern. Modification of the release of both APIs from DEEP was achieved by applying a hydroxypropyl cellulose (HPC) polymer coating. The appearance and readability of uncoated and polymer-coated DEEP did not change on storage in cold and dry conditions; however, the HPC polymer layer was insufficient in preserving the readability of the QR code pattern in the extreme storage condition (40 °C and 75% relative humidity). To sum up, the DEEP concept provides opportunities for the personalization of medicines, considering also patients’ preferences. Full article
(This article belongs to the Special Issue Applications of Additive Manufacturing in Pharmaceutics)
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Article
Coupling Additive Manufacturing with Hot Melt Extrusion Technologies to Validate a Ventilator-Associated Pneumonia Mouse Model
Pharmaceutics 2021, 13(6), 772; https://doi.org/10.3390/pharmaceutics13060772 - 21 May 2021
Cited by 1 | Viewed by 1447
Abstract
Additive manufacturing is widely used to produce highly complex structures. Moreover, this technology has proven its superiority in producing tools which can be used in different applications. We designed and produced an extrusion nozzle that allowed us to hot melt extrude drug-loaded tubes. [...] Read more.
Additive manufacturing is widely used to produce highly complex structures. Moreover, this technology has proven its superiority in producing tools which can be used in different applications. We designed and produced an extrusion nozzle that allowed us to hot melt extrude drug-loaded tubes. The tubes were an essential part of a new mouse ventilator-associated pneumonia (VAP) model. Ciprofloxacin (CPX) was selected for its expected activity against the pathogen Staphylococcus aureus and ease of incorporation into thermoplastic polyurethane (TPU). TPU was selected as the carrier polymer for its biocompatibility and use in a variety of medical devices such as tubing and catheters. The effect of loading CPX within the TPU polymeric matrix and the physicochemical properties of the produced tubes were investigated. CPX showed good thermal stability and in vitro activity in preventing S. aureus biofilm formation after loading within the tube’s polymeric matrix. Moreover, the produced tubes showed anti-infective efficacy in vivo. The produced tubes, which were extruded via our novel nozzle, were vital for the validation of our mouse VAP model. This model can be adopted to investigate other antibacterial and antibiofilm compounds incorporated in polymeric tubes using hot melt extrusion. Full article
(This article belongs to the Special Issue Applications of Additive Manufacturing in Pharmaceutics)
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Article
Stereolithography Apparatus Evolution: Enhancing Throughput and Efficiency of Pharmaceutical Formulation Development
Pharmaceutics 2021, 13(5), 616; https://doi.org/10.3390/pharmaceutics13050616 - 25 Apr 2021
Cited by 3 | Viewed by 929
Abstract
Pharmaceutical applications of 3D printing technologies are growing rapidly. Among these, vat photopolymerisation (VP) techniques, including Stereolithography (SLA) hold much promise for their potential to deliver personalised medicines on-demand. SLA 3D printing offers advantageous features for pharmaceutical production, such as operating at room [...] Read more.
Pharmaceutical applications of 3D printing technologies are growing rapidly. Among these, vat photopolymerisation (VP) techniques, including Stereolithography (SLA) hold much promise for their potential to deliver personalised medicines on-demand. SLA 3D printing offers advantageous features for pharmaceutical production, such as operating at room temperature and offering an unrivaled printing resolution. However, since conventional SLA apparatus are designed to operate with large volumes of a single photopolymer resin, significant throughput limitations remain. This, coupled with the limited choice of biocompatible polymers and photoinitiators available, hold back the pharmaceutical development using such technologies. Hence, the aim of this work was to develop a novel SLA apparatus specifically designed to allow rapid and efficient screening of pharmaceutical photopolymer formulations. A commercially available SLA apparatus was modified by designing and fabricating a novel resin tank and build platform able to 3D print up to 12 different formulations at a single time, reducing the amount of sample resin required by 20-fold. The novel SLA apparatus was subsequently used to conduct a high throughput screening of 156 placebo photopolymer formulations. The efficiency of the equipment and formulation printability outcomes were evaluated. Improved time and cost efficiency by 91.66% and 94.99%, respectively, has been confirmed using the modified SLA apparatus to deliver high quality, highly printable outputs, thus evidencing that such modifications offer a robust and reliable tool to optimize the throughput and efficiency of vat photopolymerisation techniques in formulation development processes, which can, in turn, support future clinical applications. Full article
(This article belongs to the Special Issue Applications of Additive Manufacturing in Pharmaceutics)
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Article
Fundamental Investigations into Metoprolol Tartrate Deposition on Orodispersible Films by Inkjet Printing for Individualised Drug Dosing
Pharmaceutics 2021, 13(2), 247; https://doi.org/10.3390/pharmaceutics13020247 - 10 Feb 2021
Viewed by 880
Abstract
Individualised medicine is continuously gaining attention in pharmaceutical research. New concepts and manufacturing technologies are required to realise this therapeutic approach. Off-label drugs used in paediatrics, such as metoprolol tartrate (MPT), are potential candidates for innovations in this context. Orodispersible films (ODFs) have [...] Read more.
Individualised medicine is continuously gaining attention in pharmaceutical research. New concepts and manufacturing technologies are required to realise this therapeutic approach. Off-label drugs used in paediatrics, such as metoprolol tartrate (MPT), are potential candidates for innovations in this context. Orodispersible films (ODFs) have been shown as an accepted alternative dosage form during the last years and inkjet printing is traded as seminal technology of precise deposition of active pharmaceutical ingredients (APIs). The objective of this study was to combine both technologies by developing imprinted ODFs based on hypromellose with therapeutically reasonable MPT single doses of 0.35 to 3.5 mg for paediatric use. After preselection, suitable ink compositions were analysed by confocal Raman microscopy regarding MPT distribution within the imprinted ODFs. Adjusted print settings, speed, print direction and angle, characterised the final ODF surface structure. The present investigations show that uniform dosages with acceptance values between 1 and 6 can be achieved. Nevertheless, changes in calibrated printed quantity due to nozzle aging have a significant effect on the final applied dose. At the lowest investigated quantity, the RSD was ±28% and at the highest, ±9%. This has to be considered for implementation of inkjet printing as a pharmaceutical production tool in the future. Full article
(This article belongs to the Special Issue Applications of Additive Manufacturing in Pharmaceutics)
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Article
3D-Printed Veterinary Dosage Forms—A Comparative Study of Three Semi-Solid Extrusion 3D Printers
Pharmaceutics 2020, 12(12), 1239; https://doi.org/10.3390/pharmaceutics12121239 - 19 Dec 2020
Cited by 5 | Viewed by 1148
Abstract
Currently, the number of approved veterinary medicines are limited, and human medications are used off-label. These approved human medications are of too high potencies for a cat or a small dog breed. Therefore, there is a dire demand for smaller doses of veterinary [...] Read more.
Currently, the number of approved veterinary medicines are limited, and human medications are used off-label. These approved human medications are of too high potencies for a cat or a small dog breed. Therefore, there is a dire demand for smaller doses of veterinary medicines. This study aims to investigate the use of three semi-solid extrusion 3D printers in a pharmacy or animal clinic setting for the extemporaneous manufacturing of prednisolone containing orodispersible films for veterinary use. Orodispersible films with adequate content uniformity and acceptance values as defined by the European Pharmacopoeia were produced with one of the studied printers, namely the Allevi 2 bioprinter. Smooth and flexible films with high mechanical strength, neutral pH, and low moisture content were produced with a high correlation between the prepared design and the obtained drug amount, indicating that the Allevi 2 printer could successfully be used to extemporaneously manufacture personalized doses for animals at the point-of-care. Full article
(This article belongs to the Special Issue Applications of Additive Manufacturing in Pharmaceutics)
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Article
Electro-Hydrodynamic Drop-on-Demand Printing of Aqueous Suspensions of Drug Nanoparticles
Pharmaceutics 2020, 12(11), 1034; https://doi.org/10.3390/pharmaceutics12111034 - 29 Oct 2020
Cited by 3 | Viewed by 828
Abstract
We demonstrate the ability to fabricate dosage forms of a poorly water-soluble drug by using wet stirred media milling of a drug powder to produce an aqueous suspension of nanoparticles and then print it onto a porous biocompatible film. Contrary to conventional printing [...] Read more.
We demonstrate the ability to fabricate dosage forms of a poorly water-soluble drug by using wet stirred media milling of a drug powder to produce an aqueous suspension of nanoparticles and then print it onto a porous biocompatible film. Contrary to conventional printing technologies, a deposited material is pulled out from the nozzle. This feature enables printing highly viscous materials with a precise control over the printed volume. Drug (griseofulvin) nanosuspensions prepared by wet media milling were printed onto porous hydroxypropyl methylcellulose films prepared by freeze-drying. The drug particles retained crystallinity and polymorphic form in the course of milling and printing. The versatility of this technique was demonstrated by printing the same amount of nanoparticles onto a film with droplets of different sizes. The mean drug content (0.19–3.80 mg) in the printed films was predicted by the number of droplets (5–100) and droplet volume (0.2–1.0 µL) (R2 = 0.9994, p-value < 10−4). Our results also suggest that for any targeted drug content, the number-volume of droplets could be modulated to achieve acceptable drug content uniformity. Analysis of the model-independent difference and similarity factors showed consistency of drug release profiles from films with a printed suspension. Zero-order kinetics described the griseofulvin release rate from 1.8% up to 82%. Overall, this study has successfully demonstrated that the electro-hydrodynamic drop-on-demand printing of an aqueous drug nanosuspension enables accurate and controllable drug dosing in porous polymer films, which exhibited acceptable content uniformity and reproducible drug release. Full article
(This article belongs to the Special Issue Applications of Additive Manufacturing in Pharmaceutics)
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Review

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Review
3D Printing of Pharmaceutical Application: Drug Screening and Drug Delivery
Pharmaceutics 2021, 13(9), 1373; https://doi.org/10.3390/pharmaceutics13091373 - 31 Aug 2021
Viewed by 791
Abstract
Advances in three-dimensional (3D) printing techniques and the development of tailored biomaterials have facilitated the precise fabrication of biological components and complex 3D geometrics over the past few decades. Moreover, the notable growth of 3D printing has facilitated pharmaceutical applications, enabling the development [...] Read more.
Advances in three-dimensional (3D) printing techniques and the development of tailored biomaterials have facilitated the precise fabrication of biological components and complex 3D geometrics over the past few decades. Moreover, the notable growth of 3D printing has facilitated pharmaceutical applications, enabling the development of customized drug screening and drug delivery systems for individual patients, breaking away from conventional approaches that primarily rely on transgenic animal experiments and mass production. This review provides an extensive overview of 3D printing research applied to drug screening and drug delivery systems that represent pharmaceutical applications. We classify several elements required by each application for advanced pharmaceutical techniques and briefly describe state-of-the-art 3D printing technology consisting of cells, bioinks, and printing strategies that satisfy requirements. Furthermore, we discuss the limitations of traditional approaches by providing concrete examples of drug screening (organoid, organ-on-a-chip, and tissue/organ equivalent) and drug delivery systems (oral/vaginal/rectal and transdermal/surgical drug delivery), followed by the introduction of recent pharmaceutical investigations using 3D printing-based strategies to overcome these challenges. Full article
(This article belongs to the Special Issue Applications of Additive Manufacturing in Pharmaceutics)
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