Lessons to Learn for 3D Printing of Drug Products by Semisolid Extrusion (SSE).

Semisolid extrusion (SSE) 3D printing (3DP) technology is emerging due to its simplicity and potential for on-site manufacturing of personalized drug products with tailored functionality (dose, release profile), as well as recognizability (size, shape, color). However, even a minor change in the composition of the ink (the feedstock material) and the printing process parameters can largely influence the outcome of printing. This paper summarizes the recent SSE 3DP studies, where the important factors affecting the quality of the printed drug products are discussed. Further challenges are showcased by introducing a case study focusing on the design of oral theophylline immediate-release drug products. The identified crucial factors, such as the printing hardware and connected software, printing parameters, and composition of the ink are discussed. Especially, the rheological properties of the ink during the printing process, together with solidification, mechanical properties, and morphology studies of already printed products are deliberated to gain more understanding of the printability of drug products by SSE. This work aims to provide an overview of design aspects related to SSE-based fabrication of personalized drug products.

Tailor-Made Doses of Pharmaceuticals by Tunable Modular Design: A Case Study on Tapering Antidepressant Medication.

An abrupt cessation of antidepressant medication can be challenging due to the appearance of withdrawal symptoms. A slow hyperbolic tapering of an antidepressant, such as citalopram hydrobromide (CHB), can mitigate the withdrawal syndrome. However, there are no viable dosage forms on the market to implement the tapering scheme. A solution using a tunable modular design (TMD) approach to produce flexible and accurate doses of CHB is proposed. This design consists of two parts: 1) a module with a fixed amount of preloaded CHB in a freeze-dried polymer matrix, and 2) fine-tuning the CHB dose by inkjet printing. A noncontact food-grade printer, used for the first time for printing pharmaceuticals, is modified to allow for accurate printing of the highly concentrated CHB ink on the porous CHB-free or CHB-preloaded modules. The produced modules with submilligram precision are bench-marked with commercially available CHB tablets that are manually divided. The TMD covers the entire range of doses needed for the tapering (0.5-23.8 mg). The greatest variance is 13% and 88% when comparing the TMD and self-tapering, respectively. Self-tapering is proven inaccurate and showcases the need for the TMD to make available accurate and personalized doses to wean off treatment with CHB.

Impact of drug load and polymer molecular weight on the 3D microstructure of printed tablets.

This study investigates the influence of drug load and polymer molecular weight on the structure of tablets three-dimensionally (3D) printed from the binary mixture of prednisolone and hydroxypropyl methylcellulose (HPMC). Three different HPMC grades, (AFFINISOLTM HPMC HME 15LV, 90 Da (HPMC 15LV); 100LV, 180 Da (HPMC 100LV); 4M, 500 Da (HPMC 4M)), which are suitable for hot-melt extrusion (HME), were used in this study. HME was used to fabricate feedstock material, i.e., filaments, at the lowest possible extrusion temperature. Filaments of the three HPMC grades were prepared to contain 2.5, 5, 10 and 20 % (w/w) prednisolone. The thermal degradation of the filaments was studied with thermogravimetric analysis, while solid-state properties of the drug-loaded filaments were assessed with the use of X-ray powder diffraction. Prednisolone in the freshly extruded filaments was determined to be amorphous for drug loads up to 10%. It remained physically stable for at least 6 months of storage, except for the filament containing 10% drug with HPMC 15LV, where recrystallization of prednisolone was detected. Fused deposition modeling was utilized to print honeycomb-shaped tablets from the HME filaments of HPMC 15LV and 100LV. The structural characteristics of the tablets were evaluated using X-ray microcomputed tomography, specifically porosity and size of structural elements were investigated. The tablets printed from HPMC 15LV possessed in general lower total porosity and pores of smaller size than tablets printed from the HPMC 100LV. The studied drug loads were shown to have minor effect on the total porosity of the tablets, though the lower the drug load was, the higher the variance of porosity along the height of the tablet was observed. It was found that tablets printed with HPMC 15LV showed higher structural similarity with the virtually designed model than tablets printed from HPMC 100LV. These findings highlight the relevance of the drug load and polymer molecular weight on the microstructure and structural properties of 3D printed tablets.

Binder jetting 3D printing in fabricating pharmaceutical solid products for precision medicine.

Current treatment strategies are moving towards patient-centricity, which emphasizes the need for new solutions allowing for medication tailored to a patient. This can be realized by precision medicine where patient diversity is considered during treatment. However, the broader use of precision medicine is restricted by the current technological solutions and rigid manufacturing of pharmaceutical products by mass production principles. Additive manufacturing of pharmaceutical products can provide a feasible solution to this challenge. In this review, a particular subtype of additive manufacturing, that is, binder jetting 3D printing, is introduced as a solution for fabricating pharmaceutical solid products that can be considered as precision medicine. Technical aspects, practical applications, unique advantages and challenges related to this technique are discussed, indicating that binder jetting 3D printing possesses the potential for fabricating already new product prototypes, where diversity in patient treatment in terms of the needs for specific drug type, dose and drug release can be accounted. To further advance this type of mass customization of pharmaceuticals, multidisciplinary research initiatives are needed not only to cover the engineering aspects but also to bridge these innovations with patient-centric perspectives.

Mucoadhesive chitosan- and cellulose derivative-based nanofiber-on-foam-on-film system for non-invasive peptide delivery.

Oromucosal administration is an attractive non-invasive route. However, drug absorption is challenged by salivary flow and the mucosa being a significant permeability barrier. The aim of this study was to design and investigate a multi-layered nanofiber-on-foam-on-film (NFF) drug delivery system with unique properties and based on polysaccharides combined as i) mucoadhesive chitosan-based nanofibers, ii) a peptide loaded hydroxypropyl methylcellulose foam, and iii) a saliva-repelling backing film based on ethylcellulose. NFF displays optimal mechanical properties shown by dynamic mechanical analysis, and biocompatibility demonstrated after exposure to a TR146 cell monolayer. Chitosan-based nanofibers provided the NFF with improved mucoadhesion compared to that of the foam alone. After 1 h, >80 % of the peptide desmopressin was released from the NFF. Ex vivo permeation studies across porcine buccal mucosa indicated that NFF improved the permeation of desmopressin compared to a commercial freeze-dried tablet. The findings demonstrate the potential of the NFF as a biocompatible drug delivery system.

Coating of Primary Powder Particles Improves the Quality of Binder Jetting 3D Printed Oral Solid Products.

Binder jetting (BJ) 3D printing is especially suitable for the fabrication of an orodispersible solid dosage form, as it is an efficient way to avoid the use of mechanical forces typical for compaction-based processes. However, one of the existing challenges related to pharmaceutical applications of BJ is the relatively high amount of binder needed in the primary powder to ensure the sufficient mechanical strength of printed products. In this study, a strategy based on pre-processing with a thin layer coating was explored. With this strategy, the matrix particles (lactose monohydrate) of the primary powder for BJ 3D printing were coated with the binder (polyvinylpyrrolidone, PVP). The investigated compositions of the primary powder contained PVP at three levels, namely, 10 %, 15% and 20% (w/w). The primary powder compositions were prepared with or without the coated lactose powder, and they were subsequently 3D BJ printed into oral solid products with paracetamol as a model active drug substance. The presence of coated lactose in the primary powder increased the interparticulate interactions in the BJ 3D printed products. Especially for the composition with a relatively small amount of binder (i.e., 10% and 15% w/w PVP in the primary powder), the use of coated particles significantly improved the resistance to crushing and decreased the disintegration time of printed products. In conclusion, thin layer coating is an effective way to pre-process primary powder particles for BJ 3D printing of oral solid products.

Magistral Compounding with 3D Printing: A Promising Way to Achieve Personalized Medicine.

BACKGROUND: Magistral compounding has always been an integral part of pharmacy practice. The increasing demand worldwide for personalized drug treatments might be accommodated by an increase in magistral compounding. The new, flexible technology of 3D medicine printing could advance this process even further. However, the issue of how 3D medicine printing can be implemented within the existing magistral compounding infrastructure has not been explored. AIMS: To investigate how 3D printing can be integrated into the existing compounding system by taking regulatory, economic, and profession-oriented aspects into account. METHODS: Semi-structured interviews were conducted with relevant Dutch stakeholders representing various health institutions, such as health ministries and boards, professional bodies, and different types of pharmacies. Participants were identified through purposeful sampling. Content analysis was applied to identify the main themes. RESULTS: A total of 15 Dutch stakeholders were interviewed. It was found that the prevalence of compounding in community pharmacies in the Netherlands has decreased as a result of the practice shifting to specialized compounding pharmacies due to higher costs, lack of space, and the need to fulfill quality requirements. All interviewees considered 3D printing to be a promising compounding technique for community pharmacies, as it offers an automated approach with high digital flexibility and enables adapted formulations, including 'polypills.' Regulatory and quality assurance challenges were considered comparable to those of normal magistral products; however, there remain pending regulatory issues regarding quality control, particularly for Active Pharmaceutical Ingredients containing intermediate feedstock materials (e.g., prefilled cartridges) in 3D printing. 3D printing was believed to become cost effective over time. CONCLUSION: In the Netherlands, specialized compounding pharmacies have largely taken over compounding activities. 3D printing could be introduced within this system; however, challenges regarding how to regulate prefilled cartridges have yet to be addressed. Compounding using 3D printing in regular community pharmacies could enhance patients' individualized treatment; however, this activity would require incentives to stimulate the return of compounding to normal pharmacy practice.

Data-enriched edible pharmaceuticals (DEEPs): Patients' preferences, perceptions, and acceptability of new dosage forms and their digital aspects - An interview study.

Background: In the field of pharmaceuticals, there is a shift away from the traditional "one-size-fits-all" concept to a more patient-centered one. A potential approach to obtain personalized medicine is with printed Data-Enriched Edible Pharmaceuticals (DEEPs). DEEPs that are printed in the pattern of QR codes contain both the patient-tailored dose and data that can be used to give patients personalized drug information and combat counterfeit medicines. Objectives: The study aims to explore patients' preferences, perceptions, and acceptability of DEEPs, and the digital aspects of them. Methods: Thirteen participants, living in Denmark, were interviewed twice using a semi-structured approach. Interviews were conducted face-to-face or via video calls. The interviews were transcribed, translated, and analyzed using thematic coding analysis. Results: The participants found it useful to participate in the design of their own medicine. The orodispersible nature of DEEPs and the possibility to select color, embedded images, flavors, and physical dimensions of DEEPs were considered beneficial for patients' adherence. Patients' personal preferences, convenience, and aesthetics were the main drivers for their favored design of DEEPs. The acceptability of digital healthcare in connection to DEEPs was found to be related to the participants' level of digital literacy. Conclusions: The participants generally had a positive attitude towards DEEPs and the digital aspects of them. However, to accept digital healthcare in connection to DEEPs, it should be adaptable and easy to use for everyone. The combination of digital healthcare and on-demand fabricated DEEPs could potentially contribute to higher patient adherence and safety in the future.

Data-Enriched Edible Pharmaceuticals (DEEP) with Bespoke Design, Dose and Drug Release.

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.

Integration of personalized drug delivery systems into digital health.

Personalized drug delivery systems (PDDS), implying the patient-tailored dose, dosage form, frequency of administration and drug release kinetics, and digital health platforms for diagnosis and treatment monitoring, patient adherence, and traceability of drug products, are emerging scientific areas. Both fields are advancing at a fast pace. However, despite the strong complementary nature of these disciplines, there are only a few successful examples of merging these areas. Therefore, it is important and timely to combine PDDS with an increasing number of high-end digital health solutions to create an interactive feedback loop between the actual needs of each patient and the drug products. This review provides an overview of advanced design solutions for new products such as interactive personalized treatment that would interconnect the pharmaceutical and digital worlds. Furthermore, we discuss the recent advancements in the pharmaceutical supply chain (PSC) management and related limitations of the current mass production model. We summarize the current state of the art and envision future directions and potential development areas.

Modular design principle based on compartmental drug delivery systems.

The current manufacturing solutions for oral solid dosage forms are fundamentally based on technologies from the 19th century. This approach is well suited for mass production of one-size-fits-all products; however, it does not allow for a straight-forward personalization and mass customization of the pharmaceutical end-product. In order to provide better therapies to the patients, a need for innovative manufacturing concepts and product design principles has been rising. Additive manufacturing opens up a possibility for compartmentalization of drug products, including design of spatially separated multidrug and functional excipient compartments. This compartmentalized solution can be further expanded to modular design thinking. Modular design is referring to combination of building blocks containing a given amount of drug compound(s) and related functional excipients into a larger final product. Implementation of modular design principles is paving the way for implementing the emerging personalization potential within health sciences by designing compartmental and reactive product structures that can be manufactured based on the individual needs of each patient. This review will introduce the existing compartmentalized product design principles and discuss the integration of these into edible electronics allowing for innovative control of drug release.

Exploration of in vitro drug release testing methods for saquinavir microenvironmental pH modifying buccal films.

Buccal films containing a pH modifying excipient may be able to increase bioavailability of drugs with pH-dependent solubility such as saquinavir. Access to suitable in vitro drug release testing methods may facilitate buccal formulation development. This study aimed to explore two release testing methods for characterising buccal films and to elucidate the relationship between microenvironmental pH (pHM, i.e. the pH around the swelling films) and saquinavir release. The Franz diffusion cell method was applicable to investigate the effect of hydroxypropyl methylcellulose (HPMC) grade on saquinavir release. Films containing HPMC K3 LV had a faster saquinavir release than films containing HPMC K100 LV. A UV/Vis imaging method was developed to visualise saquinavir release and pHM changes during the initial dissolution. Within 5 min, the pHM decreased from 6.8 to around 5.4 for HPMC K100 LV-based films containing 11.1 % or 16.6 % (w/w) malic acid. Subsequently, the pHM increased due to increasing concentrations of saquinavir. An increase in malic acid content led to a faster saquinavir release. The combination of methods may be broadly applicable for excipient screening in development of buccal formulations. The imaging approach holds promise for characterizing other pH modifying formulation principles.

Scenarios for 3D printing of personalized medicines - A case study.

Background: 3D printing is a promising new technology for medicines' production. It employs additive manufacturing techniques, and is ideal for producing personalized medicines (e.g., patient-tailored dose, dosage form, drug release kinetics). Objective: To investigate how 3D printing technologies can be implemented in a European pharmaceutical system, by suggesting different scenarios and assessing aspects that could affect its implementation. Method: Qualitative, semi-structured interviews were conducted with key stakeholders (e.g., from ministry, authorities, research organizations, pharmacies) in the Netherlands to elicit perspectives on 3D printing of personalized medicines. The Netherlands were chosen since it has a strong tradition in compounding. Five general scenarios were investigated: placing the 3D printers in industry, community pharmacies, hospital pharmacies, compounding facilities, and in patients' homes. Content analysis was used, building on verbatim transcripts. Results: Fifteen stakeholders were interviewed. Regulatory, economic, ethical and organizational challenges were identified to varying degrees in the different scenarios. The industry and home scenarios were associated with the most challenges, hospital pharmacies and compounding facilities with the least. Other important aspects identified were the role of community pharmacies, and who should design the tablets to be printed. Conclusion: All potential scenarios for 3D printing of personalized medicines include challenges. These should be taken into account when pursuing the use of 3D printing of medicine.

Data-enriched edible pharmaceuticals (DEEP) of medical cannabis by inkjet printing.

Medical cannabis has shown to be effective in various diseases that have not successfully been treated with other marketed drug products. However, the dose of cannabis is highly individual and additionally, medical cannabis is prone to misuse. To combat these challenges, the concept of data-enriched edible pharmaceuticals (DEEP) is introduced. Quick Response (QR) code patterns containing lipophilic cannabinoids, i.e., cannabidiol (CBD) and delta-9-tetrahydrocannabinol (THC), were printed using a desktop inkjet printer. This allows for simultaneously printing an individual dose and encapsulating information relevant to the end-users and other stakeholders in a single dosage unit, which is readable by a standard smartphone. Different doses of CBD and THC were incorporated in the DEEP by printing various (1-10) layers of the cannabinoid-containing ink on porous substrates, i.e., solid foams, prepared by solvent casting and subsequent freeze-drying. The printed DEEP were still readable after 8 weeks of storage in dry and cold conditions. This approach of 'in-drug labeling' instead of 'drug package labeling' provides a new possibility for developing a more efficient supply chain of pharmaceuticals and safer medication schemes by increasing the traceability of drug products at a single dosage unit level.

Manufacturing of hybrid drug delivery systems by utilizing the fused filament fabrication (FFF) technology.

The potential of fused filament fabrication (FFF) for the administration of active pharmaceutical compounds is a recent approach to develop complex and custom-made drug delivery systems (DDSs). However, the FFF technology is characterized by certain limitations, which are associated with the nature of the process, i.e., the required mechanical properties of the feedstock, as well as the thermal stability of the incorporated polymers, excipients and active compounds. Thus, hybrid DDSs have been recently introduced, to overcome these boundaries. The concept of these systems is defined by the effective coupling of FFF with conventional manufacturing technologies, as a novel pathway to expand the available pool of raw materials and pharmaceutical applications of FFF.

Perceptions, preferences and acceptability of patient designed 3D printed medicine by polypharmacy patients: a pilot study.

Background 3D-printing, compared to conventional medicine manufacturing technologies, is a versatile and highly modifiable technique that has the flexibility to produce medicine that meet patients' specific requirements such as individualized dosing, but also to customize the appearance of the dosage form, e.g., shape and colour. Objective To explore polypharmacy patients' perceptions and preferences regarding 3D-printed medicine, including their acceptability of patient-designed medicine. Setting The study was conducted in Zealand, Denmark. Method Polypharmacy patients were recruited using convenience sampling (mostly on Facebook) and interviewed twice using semi-structured interviews. Interviews were analysed thematically into five predetermined themes (shapes, colours, embossing designs, polypills, and patient-designed dosage forms). At the first interview patients were asked about their perceptions and preferences towards 3D-printed solid dosage forms, and were presented to different shapes, colours, embossing designs and examples of polypills. They were also invited to design their own medicine from the ones presented. Their self-designed medicines were presented at the second interview, where acceptability of both their self-designed medicine and the concept of designing one's own medicine, was investigated. Main outcome measure Patients' perceptions, preferences towards and acceptability of 3D-printed medicines. Results Eight patients were included. They tended to prefer shapes similar to conventional medicine. Different colours were preferred by different people. The presented embossing designs seemed to be irrelevant. Polypills were generally believed to be a good idea due to the reduction of number of medicines. Acceptability of patient-designed medicine was mainly determined by whether patients thought 3Dprinting technology was reliable or not. Conclusions The patients had various perceptions and preferences of 3D-printed medicine. Factors affecting the patient views were aesthetic (appealing), physiological (swallowing), practical (handling), pedagogical (understanding) and psychological (relate to). Trust in the technology seemed to be important for acceptability.

Quantification of Inkjet-Printed Pharmaceuticals on Porous Substrates Using Raman Spectroscopy and Near-Infrared Spectroscopy.

The use of inkjet printing for pharmaceutical manufacturing is gaining interest for production of personalized dosage forms tailored to specific patients. As part of the manufacturing, it is imperative to ensure that the correct dose is printed. The aim of this study was to use inkjet printing for manufacturing of personalized dosage forms combined with the use of near-infrared (NIR) and Raman spectroscopy as complementary analytical techniques for active pharmaceutical ingredient (API) quantification of the inkjet-printed dosage forms. Three APIs, propranolol (0.5-4.1 mg), montelukast (2.1-12.1 mg), and haloperidol (0.6-4.1 mg) were inkjet printed in 1 cm2 areas on a porous substrate. The printed doses were non-destructively analyzed by transmission NIR and Raman spectroscopy (both transmission and backscatter). X-ray computed microtomography (µ-CT) analysis was undertaken for porosity measurements of the substrate. The API content was confirmed using high-performance liquid chromatography (HPLC), and the content in the dosage forms was modeled from the NIR and Raman spectra using partial least squares regression (PLS). HPLC analysis revealed a linear correlation of the number of layers printed to the API content. The resulting PLS models for both NIR and Raman had R2 values between 0.95 and 0.99. The best predictive model was obtained using NIR, followed by Raman spectroscopy. µ-CT revealed the substrate to be highly porous and optimal for inkjet printing. In conclusion, NIR and Raman spectroscopic techniques could be used complementary as fast API quantification tools for inkjet-printed medicines.

Correction to: Quantification of Inkjet-Printed Pharmaceuticals on Porous Substrates Using Raman Spectroscopy and Near-Infrared Spectroscopy.

Mohammed Al-Sharabi's affiliation was incorrect at the time of publishing. The updated affiliation appears below.

Cryptopharmaceuticals: Increasing the Safety of Medication by a Blockchain of Pharmaceutical Products.

The future health-care system will contain an ever expanding number of digital elements. The data stored both at a centralized health-care level and at a local, patient level (e.g., on a smartphone) will be core elements when deciding treatment strategies in a health-care scenario with Internet of things-based elements. The current way of manufacturing pharmaceutical products and related existing logistic solutions is not ready for such a revolution. One of the key challenges is cybersecurity and related robust public key infrastructure solution. This work introduces one element of a potential solution at a prototype level: the concept of cryptopharmaceuticals where pharmaceutical products are connected in a patient-specific blockchain of individual dosage units. This technology is based on the concept where each produced dosage unit has a unique information-rich pattern. A proof-of-concept smartphone application was applied to demonstrate the visualization of this blockchain at different levels. This includes the manufacturing of the individualized dosage unit, the patient view for his/her personal blockchain, and integration of these products into a health Internet of things system. This unbreakable blockchain of personal medication history will provide means to avoid counterfeit products and to enable innovative logistic solutions.

The Use of 3D Printed Molds to Cast Tablets with a Designed Disintegration Profile.

Development of new product design principles is crucial for obtaining pharmaceutical products with controlled functionality. Four different molds were designed using a computer-aided design (CAD) software and 3D printed with polylactic acid (PLA). A hydroxypropyl methylcellulose (HPMC) and polyethylene glycol (PEG)-based formulation containing indomethacin as the active pharmaceutical ingredient (API) was casted into the molds. Each mold produced a tablet that was designed to disintegrate into a defined number of sections (2, 4, and 6). This was achieved by incorporating break lines (regions that were significantly thinner than the remainder of the tablet) to control the disintegration process. Disintegration and drug release from these designed tablets was contrasted with a casted tablet without break lines. Disintegration studies confirmed that the casted tablets disintegrated according to their design. Drug-release studies meanwhile demonstrated that tablets with a greater number of sections released the API at a faster rate than those with fewer sections; for example, the 6-sectioned tablet released the API at twice the rate of the tablet without any break lines. It is expected that by using this concept, it would be possible to produce tablets with a designed disintegration profile, which could potentially allow the tailoring of the drug release.