Characterization and Validation of a New 3D Printing Ink for Reducing Therapeutic Gap in Pediatrics through Individualized Medicines

Abstract

3D printing technology can be used to develop individualized medicines in hospitals and pharmacies, allowing a high degree of personalization and the possibility to adjust the dose of the API based on the quantity of material extruded. The main goal of incorporating this technology is to have a stock of API-load print cartridges that could be used at different storage times and for different patients. However, it is necessary to study the extrudability, stability, and buildability of these print cartridges during storage time. A paste-like formulation containing hydrochlorothiazide as a model drug was prepared and distributed in five print cartridges, each of which was studied for different storage times (0 h–72 h) and conditions, for repeated use on different days. For each print cartridge, an extrudability analysis was performed, and subsequently, 100 unit forms of 10 mg hydrochlorothiazide were printed. Finally, various dosage units containing different doses were printed, taking into account the optimized printing parameters based on the results of the extrudability analysis carried out previously. An appropriate methodology for the rapid development of appropriate SSE 3DP inks for pediatrics was established and evaluated. The extrudability analysis and several parameters allowed the detection of changes in the mechanical behavior of the printing inks, the pressure interval of the steady flow, and the selection of the volume of ink to be extruded to obtain each of the required doses. The print cartridges were stable for up to 72 h after processing, and orodispersible printlets containing 6 mg to 24 mg of hydrochlorothiazide can be produced using the same print cartridge and during the same printing process with guaranteed content and chemical stability. The proposed workflow for the development of new printing inks containing APIs will allow the optimization of feedstock material and human resources in pharmacy or hospital pharmacy services, thus speeding up their development and reducing costs.

Introduction

The development of individualized medicines in hospitals, pharmacy services, and pharmacies is beneficial in closing the therapeutic gap within the pediatric population. In this sense, this procedure provides the opportunity to formulate the active pharmaceutical ingredient (API) in a medicine that is individualized to a certain patient according to, for example, ability to swallow, intolerance to some excipients, preference for a certain taste or mouthfeel, etc. A high degree of personalization is possible using 3D printing technology, as excipients can be added to provide a specific taste or color, and the shape or size of the dosage form can be modified to accommodate, if necessary, the patient’s ability to swallow, taste, acceptability, etc. The most important feature, however, is the ability to adjust the dose based on the material extruded, similar to traditional liquid formulations, but offering increased stability, similar to solid formulations [1]. In this regard, healthcare professionals have a good understanding of the benefits and possibilities of 3D printing for the development of individualized medicines [2,3]. Such is the interest in this opportunity that clinical studies have already been made for the administration of chewable printlets for treating Maple Syrup Urine Disease in pediatrics [4,5]. Semi-solid extrusion (SSE) is one of the multiple 3D printing technologies available in the market. Generally speaking, this technique involves creating a semi-solid gel or paste (printing ink) with great extrudability, flowability, and buildability, depositing the material, solidifying it, and ending with solvent evaporation and solidification until getting the final dosage form, called a printlet [6,7].

In comparison to other 3D printing processes, SSE offers the most potential for usage in health-related situations (hospitals or pharmacies) because of lower costs and the fact that higher temperatures, which can degrade the API, are not required to produce dosage forms. Pre-filled and disposable materials can be used; thus, cross-contamination is reduced, and safety is ensured [7]. The main goal of incorporating this technology in hospitals and pharmacies would be to have a stock of printing inks of various APIs that could be used at different storage times and for different patients, as doses could be modified based on the amount of material extruded in each dosage form. However, it is essential to ensure the printability and stability of the print cartridge, which consists of the primary packaging (e.g., syringe) and the paste-like printing ink containing the API, during storage and multiple extrusion cycles. For this purpose, it is necessary to study their rheological behavior. Paste and gel-like materials have already been analyzed for 3D printing using an oscillating rheometer and texturometer, but it has been concluded that data from the last study were more accurate in predicting the printing pressures of pastes due to the better analogy to SSE printing conditions [8,9,10,11,12]. Therefore, the extrudability profiles will provide essential information, such as extrusion pressure, yield stress, steady flow, etc., which will determine the extrudability and flowability of the paste and, lastly, the quality of the printlets. However, changes in these parameters have not been studied during storage or in normal conditions in a pharmacy service, where multiple extrusion cycles could be performed with the same print cartridge [12].

One API for which a print cartridge is required is hydrochlorothiazide (HCT), a diuretic API used to treat hypertension, edema, idiopathic renal hypercalciuria, and insipid diabetes with a dosage of 1–2 mg/kg. Since there are currently no commercially available child-friendly formulations that take into account the World Health Organization’s (WHO) Child Growth Standards, printlets with doses ranging from 6 mg to 24 mg will be necessary and, consequently, newborn and children up to 8 years old could be treated [13,14]. Studies related to dose adjustments have been carried out, taking into account the number of layers deposited at the printing platform [1,15]. However, this procedure has limitations, as the dose of API is restricted to the amount of API per layer. Therefore, the possibility of small dose adjustments is limited. For example, only dose multiples of 2 could be obtained if 2 mg of API were applied layer by layer. In addition, the ability to adjust a wider range of doses would be beneficial to print different patient prescriptions (same API/different doses) in the same printing process, saving time, materials, and resources. In terms of quality by test (QbT) evaluation of these printlets, international pharmacopeias have not published recommendations in this sense, but, at the very least, mass and content uniformity must be ensured. In order to study the API content in each dosage form, tests such as the uniformity of dosage units or uniformity of content of single-dose preparations should be performed [16,17]. However, this procedure means the analysis of up to 30 printlets, which would require the preparation of specific batches in pharmacies and hospital pharmacy services for quality control.

For this reason, a pressure sensor control that can characterize the printing ink and have perfect control over the pressure applied during the whole printing process, as well as the ability to detect printlets that do not meet quality standards, has just been added to SSE 3D printing platforms [7]. This is a component of the process analytical technology (PAT) strategy that enables in-line manufacturing process control with the ability to identify dose units with poor quality features [18]. In addition, other analytical techniques could be included as part of the PAT. For example, computer vision to determine the area and perimeter of the printlet as indicative of the buildability of the printing ink, the surface reduction as a drying check parameter of the printlet, or the printability of square pores in the case of scaffolds [19,20,21,22]. The incorporation of this strategy opens the door to a more efficient, cost-effective, and high-quality 3D printing, particularly for incorporation into pharmacy services, because fewer QbT would be required. Moreover, in the future, no unit will be wasted in performing such tests. This will allow a decentralized manufacturing process to be put in place without giving up a unified quality control that allows the production of dosage forms with the required final quality attributes (CQA) [23].

Taking into account everything mentioned above, this study aims to provide a valid methodology for the rapid development of appropriate SSE 3DP inks for pediatrics, containing HCT as a model API and evaluate changes in the extrudability profile during storage or after multiple extrusion cycles, in order to explain and address any issues that might develop following application in hospitals or pharmacy services. In addition, the possibility of printing several dosage units with different doses was also studied, as well as the stability of these printlets once elaborated. Finally, in-line measurements of pressure and computer vision were taken within the process to control it as part of the strategy to reduce QbT on behalf of the PAT.

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Materials

Hydrochlorothiazide (HCT) and polyvinylpyrrolidone (PVP) were provided by Acofarma® (Madrid, Spain). Ac-Di-Sol® (Croscarmellose Sodium) was kindly provided by IMCD España (Barcelona, Spain). Lactose monohydrate was purchased from Sigma-Aldrich (Burlington, MA, USA). A FabRx M3dimaker printing platform (London, UK) equipped with a pressure instrumentalized SSE motor-driven printhead (Laguna SSE printhead, FabRx Ltd., London, UK) was used to elaborate printlets. Injekt™ Syringe 20 mL Luer Lock (B. Braun Medical Inc. OEM, Melsungen, Germany) with Fisnar QuantX™ 20 ga Pink nozzles (Fisnar, Glasgow, UK) was also used.

Díaz-Torres, E.; Suárez-González, J.; Monzón-Rodríguez, C.N.; Santoveña-Estévez, A.; Fariña, J.B. Characterization and Validation of a New 3D Printing Ink for Reducing Therapeutic Gap in Pediatrics through Individualized Medicines. Pharmaceutics 2023, 15, 1642. https://doi.org/10.3390/pharmaceutics15061642