Three-Dimensional Printing of PVA Capsular Devices for Applications in Compounding Pharmacy: Effect of Design Parameters on Pharmaceutical Performance

Abstract

Magistral compounding is defined as any medicinal product prescribed in a medical prescription for an individualized patient, subsequently prepared, packaged, and labeled by a pharmacist in the laboratory of their pharmacy and dispensed therein [1]. Magistral compounding has been, for centuries, and until a few decades ago, the only alternative to properly produce medications in pharmacies. However, industrialization has led to a certain degree of depersonalization of medication. In this sense, magistral compounding takes on a special role by providing a personalized approach to pharmacological treatment, adapting the medication to the unique physio-pathological characteristics of each person, thereby reducing the risk of potential adverse reactions [2,3]. In addition, magistral compounding can address therapeutic formulation gaps as orphan formulations, which are crucial for certain patients (children and elderly people) and for pathologies without specific industrial medicine (i.e., rare diseases) [4]. It is worth noting that magistral formulation has evolved by incorporating new pharmaceutical forms and small-scale procedures, along with rigorous quality controls for raw materials (drugs and excipients) and final formulations, aiming to reduce associated risks [5]. However, it remains an artisanal process that takes time and does not allow us to produce modified drug delivery systems [6].

Hard-gelatin capsules (HGC) are one of the most used pharmaceutical forms in magistral compounding, where hand-filling of one capsule at a time is a common practice. This method implies the introduction of the inverted capsule body into a pile of drug powder until the capsule body is filled up and has the desired weight. Another method employed is a capsule-filling jig, also called a hand-filling capsule machine. As can be seen, hand-filling is an easy but slow procedure that is not scalable to faster modes of production [7]. In this sense, the magistral compounding together with three-dimensional (3D) printing represents a promising tool to promote the improvement in the personalization of medicines [8]. Regarding this, Fused Deposition Modeling (FDM), a type of 3D printing technology, allows the design and production of tailored pharmaceutical dosage forms by transforming a 3D digital model into a 3D physical object. To this end, the printer deposits a polymeric material (in the form of filament) layer-by-layer under the control of computer software [9,10]. Hence, FDM 3D printing enables the personalization of medicine to produce both immediate and modified drug-delivery systems. Moreover, this technology offers the possibility of automating the printing process by incorporating multiple heads, thus accelerating the production process. Consequently, FDM process automation, coupled with high printing precision, reduces the risks associated with magistral compounding [11,12,13]. These characteristics position FDM 3D printing as a relevant technology to enhance the development of personalized pharmaceutical dosage forms in magistral compounding [6]. It is important to note that regulatory aspects of introducing 3D printing in the compounding pharmacy remain a challenge.

This will require validating 3D-printed medicine, including quality assurance for raw materials, software, design files, and printers [8]. For FDM 3D printing of pharmaceutical forms, achieving a proper understanding of the effect of printing parameters (e.g., extrusion temperature, build platform temperature, printing speed, and layer height) and physicochemical properties of polymeric filament is essential [14]. Indeed, several biocompatible polymers have been used to produce filaments, such as ethyl cellulose, polycaprolactone, polylactic acid polyvinylpyrrolidone, and polyvinyl alcohol (PVA) [15,16]. This last polymer is one of the most used due to its biodegradability and stability when extruded through the printing nozzle [14,15,16,17]. However, the loading of a drug in PVA filament constitutes a challenge due to the requirement of suitable physicochemical properties for extrusion and printing (e.g., crystallinity, melting point, glass transition temperature, etc.). Moreover, relatively low drug loading was achieved by the methods usually used (i.e., incorporation of the drug during the production of PVA filament by hot-melt extrusion and impregnation process) [18,19]. In this regard, FDM 3D printing of hollow systems (similar to HGC) for oral administration represents a highly attractive strategy [11]. Among the alternatives explored for printed hollow systems (i.e., capsular devices, CDs), Melocchi et al. [20] manufactured CDs for oral pulsatile release based on hydroxypropyl cellulose composed of a cover and a body to be filled with a drug and assembled after printing. Maroni et al. [21] designed a two-compartment CD with soluble, swellable/erodible, and enteric soluble polymers to obtain successive drug release pulses. The CDs were filled and assembled after the printing stage. Kempin et al. [22] produced a CD body in a gastro-resistant cellulose acetate phthalate and filled it with a pre-printed tablet containing a thermo- and acid-labile drug. Posteriorly, the FDM process continued to complete the top of the CD in a nearly insoluble polycaprolactone.

Charoenying et al. [23] created a floating CD consisting of a cover and body in PVA followed by a thermal crosslinking process. Then, a commercial HGC containing amoxicillin was embedded inside the CD, achieving a gastro-retentive drug delivery system. Smith et al. [24] printed CDs in PVA to assess the regional absorption of a new drug in preclinical studies. In this case, the printing process was stopped to allow manual filling of the CD with the drug. Then, the process resumed to close the structure. Basa et al. [25] also printed PVA-CDs with and without orifices to evaluate the behavior of PVA under in vitro drug dissolution conditions. From these relevant contributions, it can be observed that the design and production of CDs by FDM 3D printing has not yet been explored as an alternative technology for magistral compounding. In previous work, we provided a design of a PVA-CD by FDM printed, which was filled (with sodium cromoglicate, an antiallergic drug) and closed in the same procedure [26]. To continue the development of FDM 3D printed PVA-CDs for the potential adoption in magistral compounding, the objective of this work was the design and production of immediate drug release PVA-CDs of similar dimensions to a commercial HGC (size n° 0) with different wall thicknesses (0.2, 0.3, 0.4, 0.6, and 0.9 mm). The designs were printed and filled with an antihypertensive model drug (losartan potassium) during the printing process. To this end, different printing parameters, such as extrusion temperature, printing speed, material flow rate, and nozzle diameter were investigated.

Then, physical characterizations, disintegration time, and in vitro dissolution studies of the CDs were performed. The CD with the wall thickness that showed the disintegration time and dissolution profile most similar to the HGC was designed and printed in different sizes (similar to HGC sizes n° 1 and 2) and also used in compounding pharmacy. In addition, mathematical modeling and prediction of drug release has become an increasingly vital area in both academic and industrial sectors, holding immense future potential. The in silico optimization of new drug delivery systems presents the potential to significantly enhance accuracy and ease of application. In fact, mathematical predictions enable prior estimates of the required composition, geometry, dimensions, and preparation methods of the respective dosage forms. Thus, one of the major driving forces for the use of mathematical modeling in drug delivery is to save time and to reduce costs since the number of required experimental studies to develop a new and/or optimize an existing product can significantly be reduced [27]. Hence, in this contribution, a mathematical function derived from the Weibull model including a functionality with the CD wall thickness was proposed and adjusted to predict the drug release with the aim of aiding the design process.

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Materials and Methods