Introduction to 3D-printing

Dissertation by Ilias El Aita: Part 1

For years, patients were viewed as a homogeneous group and selected drug treatment was based on experience from clinical studies. Consequently, individual factors such as age, physiological condition and especially genetic pattern were ignored during the selection of appropriate drug treatment. Scientific breakthroughs in molecular medicine and human genome research triggered a paradigm shift in health care systems away from the traditional “one size fits all” concept towards a more personalized approach [1]. The concept of personalized medicine intends to provide the right drug with the appropriate dose at the right time to the right patient [2]. Especially, improved understanding of a person´s unique molecular and genetic profile enables to individualize the treatment of patients [3]. By individualizing the drug therapy, the response rate of an applied drug treatment might increase while minimizing the occurrence of adverse effects [4].

Besides the individualized treatment of patients, novel diagnostic methods enable the identification of certain predisposition for a specific disease [5]. An early recognition allows the initiation of preventive measures much sooner, which promotes a shift of emphasis in medicine from reaction to prevention.

Currently, individualized drug treatment has been implemented successfully in many examples. The introduction of the individualized concept has fundamentally changed the strategies in breast cancer treatment. Through the above mentioned newly available genetic diagnostic possibilities, breast tumor cells can be analyzed regarding a possible overproduction of human epidermal growth factor receptor 2 (HER-2) protein. A positive test outcome (HER-2-positive breast cancer) for this specific protein helps the physician to individualize the treatment by selecting drugs which target the HER-2-protein [6] specifically. By individualizing the treatment, the survival rate of patients might increase significantly, while the risk of adverse effects might decrease.

Besides breast cancer, individualized medicine is expanded for other cancer types like colorectal cancer, lung cancer or melanoma. The concept is currently also being tested further for Alzheimer´s disease [7], Parkinson´s disease [8] or multiple sclerosis [9].

Alongside with enhancements in diagnostic procedures and drug treatment selection, changes in drug manufacturing are mandatory to ensure successful implementation of individualized medicine into existing health care structures.

For decades, solid dosage forms like tablets or capsules are manufactured at large scales. Pharmaceutical equipment has been designed and optimized to increase the overall throughput and therefore to maximize the revenues of the pharmaceutical industry. This profitoriented strategy does not allow research and development activities on individualizing the manufactured product in order to fulfil patient’s needs. Besides the economical view, there is also a lack of suitable equipment that enable a fast adapting manufacturing of tailored dosage forms in smaller batch sizes.

One of the oldest approaches to individualize the administered dose are liquid dosage forms (LDF). Especially for the treatment of special patient groups with swallowing difficulties, for example pediatrics or geriatrics, LDF were utilized as first choice treatment for individualized drug therapy. LDF are delivered to the patient with a dosing device, which helps to achieve the right dose [10]. Thereby, the dose can be varied easily and precise by changing the administered volume [11]. The LDF show a high patient acceptability and compliance since flavor can be added to achieve a taste masking and LDFs are also easy to swallow. Nevertheless, most of the available active pharmaceutical ingredients (APIs) are not processable due to their solubility. Further, LDF face stability issues and microbiological instability, which limit the storage of LDFs.

The academic research community introduced various new manufacturing technologies as well as new dosage forms to individualize the dispensed dose. The research was often combined with the development of child-appropriate dosage forms. Multiparticulate dosage forms like minitablets (MT) [12-14] or orodispersible minitablets (ODMT) [15, 16] were found as promising to adjust the required dose according to the needs of the patients. Combined with the development of dispensing devices, MT and/or ODMT dispensed accurate by ensuring the required amount of dose. The use of these dosage forms is limited to high potent drugs since the processing of low potency drugs require the daily intake of a high number of units. Furthermore, academic studies revealed challenges in achieving an acceptable dosage uniformity according to the European Pharmacopoeia (Ph. Eur.). Currently, test methods for MT and ODMT are lacking and need further research and guidance by health authorities.

Academic research further demonstrated the potential of implementing orodispersible films (ODFs) in regard to individualizing the dispensed dose [17, 18]. According to the literature, ODFs are single- or multilayer sheets consisting of suitable polymers, which are intended to be placed into the oral cavity where they dissolve rapidly without the need of beverages [19]. Due to the rapid disintegration in the oral cavity, ODFs are highly suitable for patients with swallowing difficulties especially pediatrics and geriatrics [17]. ODFs have the advantage that they can be cut into different sizes after production, which enables an individual dose adaption [20]. Alongside with the advantages provided by ODFs there are some challenges limiting the commercial use of ODFs. Currently, manufacturing of larger batches is not applicable. Furthermore, the maximum possible drug-load is limited making the dosage forms currently only suitable for high-potent APIs, which are dispended in a low dose.

A recent approach that has been studied intensively to individualize drug therapy is the inkjet printing (IJP) of drug-loaded inks onto substrates like ODFs [21-23]. In this application, a preformulated drug-loaded ink is printed dropwise with a print head (thermal or piezoelectric print heads) onto a substrate [21]. The interesting point about IJP is that the dose can be precisely controlled by varying the number of printed layers. Also, the number of printed drugs can be varied to achieve fixed dose combinations [24-26]. Nevertheless, besides the provided advantages of IJP, the preparation of suitable drug-loaded inks for printing purposes appears to be challenging [27].

In regard to suitable manufacturing processes for individualization purposes, three-dimensional printing (3DP) has been explored as a new potential manufacturing technology. The healthcare system already recognized 3DP as a promising approach [28-30] for the production of customized prosthetics, required surgical instruments, bone replacement and implants [31], whereas the use of 3DP for manufacturing pharmaceutical dosage forms is in its infancy.

According to the Government Accountability Office (GAO) of the United States, 3DP is defined as a layer-by-layer process of producing 3D objects directly from a digital model [32]. The digital model is created using a computer-aided design (CAD) software. Since the designed digital model can be adapted relatively easily and fast to changing requirements, a high variability of possible structures is given. Furthermore, it is also possible to design complex structures, which are rather challenging to obtain by conventional processes [33].

Due to these possibilities, 3DP has been recognized as a highly potent manufacturing process for individualized dosage forms. Aside from this, dosage forms with customized drug release characteristics can be manufactured using 3DP [34].

With the approval of the first printed tablet, Spritam® by Aprecia, by the Food and Drug Administration (FDA) in 2015, 3DP technology made its way into the pharmaceutical market [35]. By this milestone, the technology was taken out of its niche existence and placed into the spotlight as future manufacturing process for individualized dosage forms.

See Part 2: “Technologies in 3D-printing” here and Part 3: “Advantages and challenges of pharmaceutical 3D printing” here!

Article information: Ilias El Aita. Inaugural-Dissertation: Manufacturing of solid dosage forms using pressure-assisted microsyringe 3D-printing, 2021. Heinrich-Heine-University Düsseldorf.

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