Fused deposition modeling 3D printing as a method for manufacturing personalized medicines

Additive manufacturing techniques, especially methods based on the deposition of thermoplastic material such as Fused deposition modeling (FDM), are gaining more and more applications. Due to the large variety of materials used and the quick ability to produce small batches of products in accordance with the computer project, these methods are considered as a method of dosage forms manufacturing both on an industrial scale as well as in small batches. Numerous scientific studies related to the printing of dosage forms of various structures have been published in recent years. These studies concern both preparations for oral administration, such as tablets and capsules with modified and immediate release of the active pharmaceutical ingredient (API), as well as intraocular dosage forms and wound dressings. In the case of the FDM method, the printing process is preceded by the material preparation step. It consists of the preparation of a drug-loaded filament in the hot-melt extrusion process. After feeding the filament into the printer's head, it is re-heated, liquefied, and precisely deposited on the printer's table in order to reproduce a spatial structure according to the computer design. The filaments used in the printing process of the dosage form should be characterized by, among others: appropriate mechanical strength, high diameter uniformity, and long-term stability. Apart from thermoplastic polymers, other excipients are also used in the composition of the formulation, i.e., disintegrants, plasticizers, and compounds inhibiting the API phase transformations in the polymer matrix. Printed dosage forms are often characterized by a complex internal spatial structure. For this reason, the API release depends not only on the properties of the excipients used, but especially on printouts’ surface area and porosity, as well as the shape and infill density. In addition, conditions during the extrusion and 3D printing processes may result in the dissolution of API in the polymer carrier and accelerate its dissolution rate

Multivariate design of 3D printed immediate-release tablets with liquid crystal-forming drug - itraconazole

The simplicity of object shape and composition modification make additive manufacturing a great option for customized dosage form production. To achieve this goal, the correlation between structural and functional attributes of the printed objects needs to be analyzed. So far, it has not been deeply investigated in 3D printing-related papers. The aim of our study was to modify the functionalities of printed tablets containing liquid crystal-forming drug itraconazole by introducing polyvinylpyrrolidone-based polymers into the filament-forming matrices composed predominantly of poly(vinyl alcohol). The e ect of the molecular reorganization of the drug and improved tablets’ disintegration was analyzed in terms of itraconazole dissolution. Micro-computed tomography was applied to analyze how the design of a printed object (in this case, a degree of an infill) a ects its reproducibility during printing. It was also used to analyze the structure of the printed dosage forms. The results indicated that the improved disintegration obtained due to the use of Kollidon®CL-M was more beneficial for the dissolution of itraconazole than the molecular rearrangement and liquid crystal phase transitions. The lower infill density favored faster dissolution of the drug from printed tablets. However, it negatively a ected the reproducibility of the 3D printed object

How to obtain the maximum properties flexibility of 3d printed ketoprofen tablets using only one drug-loaded filament?

The flexibility of dose and dosage forms makes 3D printing a very interesting tool for personalized medicine, with fused deposition modeling being the most promising and intensively developed method. In our research, we analyzed how various types of disintegrants and drug loading in poly(vinyl alcohol)-based filaments affect their mechanical properties and printability. We also assessed the effect of drug dosage and tablet spatial structure on the dissolution profiles. Given that the development of a method that allows the production of dosage forms with different properties from a single drug-loaded filament is desirable, we developed a method of printing ketoprofen tablets with different dose and dissolution profiles from a single feedstock filament. We optimized the filament preparation by hot-melt extrusion and characterized them. Then, we printed single, bi-, and tri-layer tablets varying with dose, infill density, internal structure, and composition. We analyzed the reproducibility of a spatial structure, phase, and degree of molecular order of ketoprofen in the tablets, and the dissolution profiles. We have printed tablets with immediateand sustained-release characteristics using one drug-loaded filament, which demonstrates that a single filament can serve as a versatile source for the manufacturing of tablets exhibiting various release characteristics

Applicability study of hot melt extrusion based additive manufacturing in pharmaceutical technology

Tabletki są najwygodniejszą w użyciu, najczęściej stosowaną przez pacjentów postacią leku. W związku z tym istnieje potrzeba ciągłego poszukiwania nowych sposobów ich wytwarzania, dzięki czemu możliwa będzie produkcja postaci leku optymalizowanych pod kątem zróżnicowanych potrzeb pacjentów. Prowadzone badania miały na celu sprawdzenie możliwości wykorzystania druku 3D w technologii postaci leku do wytwarzania tabletek. Przy zastosowaniu metody formowania addytywnego polegającej na stapianiu termoplastycznego filamentu wydrukowano stałe postaci leku zawierające arypiprazol i analizowano wpływ czynników takich jak temperatura ekstruzji, stopień i rodzaj wypełnienia na szybkość uwalniania substancji leczniczej. Dodatkowo określono możliwość wykorzystania druku przestrzennego do otrzymywania spersonalizowanych postaci leku pod kątem zawartości arypiprazolu. Stwierdzono, że w przypadku zastosowanego polimeru, Kollicoat® IR, zmiany parametrów druku nie wpływają na szybkość uwalniania substancji czynnej z drukowanych postaci leku. Wynika to z właściwości użytego polimeru, który charakteryzuje się dobrą rozpuszczalnością w wodzie i jest stosowany w postaciach leku o natychmiastowym uwalnianiu substancji czynnej. Na podstawie wyników badań dostępności farmaceutycznej aripiprazolu wykazano, że z każdej z wydrukowanych tabletek uwolniło się ponad 90% substancji leczniczej w ciągu 15 min. badania. Druk 3D zastosowano również do wytwarzania nierozpuszczalnych, porowatych otoczek regulujących uwalnianie modelowej substancji leczniczej (ibuprofen) z tabletek. Opracowano metodę zamykania tabletek w otoczce w trakcie procesu jej wydruku. Porowata otoczka powodowała od 2,6 do 6,8–krotne zmniejszenie ilości uwalnianej substancji leczniczej w porównaniu z formulacjami wykonanymi w ten sam sposób, nie zawierającymi otoczki.Powyższe wyniki wskazują na możliwość zastosowania druku 3D do wytwarzania tabletek o określonym składzie i profilu uwalniania substancji czynnej.Tablet is the most common form of drugs. Therefore, there is a need to explore new ways of tablet manufacturing in order to produce customized dosage forms for patients’ various needs. The aim of this study was to investigate the potential use of three dimensional printing in tablet formulation technology.Tablets containing aripiprazole were made using the 3D printing method based on melting the thermoplastic filament. The impact of factors such as extrusion temperature, type and percentage of filling on the release rate of the aripiprazole was investigated. In addition, the possibility of using additive manufacturing to obtain drug formulations containing personalized aripiprazole dose was determined.It has been proven that these parameters do not affect the rate of release of the active substance from printed tablets, because of the properties of the Kollicoat® IR, which caused immediate release of drug. More than 90% of the active ingredient were released from each tablet within 15 minutes.3D printing has also been used to produce insoluble, porous coatings that regulate the release of the model drug (ibuprofen) from tablets. A method of inserting previously prepared tablets into coatings during the printing process was developed. The porous coating caused a 2.6 to 6.8–fold decrease in the amount of released drug, compared to formulations made in the same way without coating.These results indicate the possibility of using of 3D printing in production of tablets with a defined active ingredient release profile and composition

Application and multi-stage optimization of daylight Polymer 3D printing of personalized medicine products

Additive technologies have undoubtedly become one of the most intensively developing manufacturing methods in recent years. Among the numerous applications, the interest in 3D printing also includes its application in pharmacy for production of small batches of personalized drugs. For this reason, we conducted multi-stage pre-formulation studies to optimize the process of manufacturing solid dosage forms by photopolymerization with visible light. Based on tests planned and executed according to the design of the experiment (DoE), we selected the optimal quantitative composition of photocurable resin made of PEG 400, PEGDA MW 575, water, and riboflavin, a non-toxic photoinitiator. In subsequent stages, we adjusted the printer set-up and process parameters. Moreover, we assessed the influence of the co-initiators ascorbic acid or triethanolamine on the resin’s polymerization process. Next, based on an optimized formulation, we printed and analyzed drug-loaded tablets containing mebeverine hydrochloride, characterized by a gradual release of active pharmaceutical ingredient (API), reaching 80% after 6 h. We proved the possibility of reusing the drug-loaded resin that was not hardened during printing and determined the linear correlation between the volume of the designed tablets and the amount of API, confirming the possibility of printing personalized modified-release tablets

Fused deposition modeling as a possible approach for the preparation of orodispersible tablets

Additive manufacturing technologies are considered as a potential way to support individualized pharmacotherapy due to the possibility of the production of small batches of customized tablets characterized by complex structures. We designed five different shapes and analyzed the effect of the surface/mass ratio, the influence of excipients, and storage conditions on the disintegration time of tablets printed using the fused deposition modeling method. As model pharmaceutical active ingredients (APIs), we used paracetamol and domperidone, characterized by different thermal properties, classified into the various Biopharmaceutical Classification System groups. We found that the high surface/mass ratio of the designed tablet shapes together with the addition of mannitol and controlled humidity storage conditions turned out to be crucial for fast tablet’s disintegration. As a result, mean disintegration time was reduced from 5 min 46 s to 2 min 22 s, and from 11 min 43 s to 2 min 25 s for paracetamol- and domperidone-loaded tablets, respectively, fulfilling the European Pharmacopeia requirement for orodispersible tablets (ODTs). The tablet’s immediate release characteristics were confirmed during the dissolution study: over 80% of APIs were released from printlets within 15 min. Thus, this study proved the possibility of using fused deposition modeling for the preparation of ODTs