**1. Introduction**

Among the challenges of pharmaceutical technology and drug development, the desire to produce the perfect treatment fit for the individuals via the construction of the drug delivery system is inevitable. The aspect of producing personalized medicine with optimal pharmacokinetics and physicochemical properties engineered strictly to the patient's needs is gaining more and more attention. 3D printing can change the ways of traditional drug production. The precedent of Spritam®, the first 3D printed pharmaceutical product, shows the enormous potential which hides in so-called Additive Manufacturing (AM) [1]. During this process, the number of unit operations is minimalized [2], and the opportunity to fabricate every single prototype shaped according to the individuals' profile with only minimal human intervention can be the cause of the increased research activity in this field [3]. An additional benefit of this type of manufacturing is the capability of producing customized ways of medication for patients suffering from organ dysfunctions, avoiding the slightest chance of reaching toxic doses in their body. Moreover, preferred patient groups are pediatrics [4] and geriatrics [5] where therapeutic doses perform great variance [6]. Further fields of interest can be the production of orphan drugs due to the low amount of produced medication. With the utilization of 3D printing, these single batches can be microfabricated without retooling all the manufacturing devices [7]. However, revolutionizing pharmaceutical manufacturing also requires a new regulatory attitude [8].

A vast number of methods are available beyond 3D Printing, and few of them which can be employed for tailored pharmaceutical manufacturing [9]. The most widely investigated type of free form fabrication is extrusion printing, in which the technique can

**Citation:** Basa, B.; Jakab, G.; Kállai-Szabó, N.; Borbás, B.; Fülöp, V.; Balogh, E.; Antal, I. Evaluation of Biodegradable PVA-Based 3D Printed Carriers during Dissolution. *Materials* **2021**, *14*, 1350. https://doi.org/ 10.3390/ma14061350

Academic Editor: Iza Radecka

Received: 29 January 2021 Accepted: 8 March 2021 Published: 11 March 2021

**Publisher's Note:** MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

**Copyright:** © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).

be divided by the step of melting the used materials or not. The Pressure Assisted Microsyringe System (PAM) utilizes the components without melting them [10], while Fused Deposition Modeling (FDM) uses the melted excipients to create the layer-by-layer structure of the 3D object [9]. The mixture of active pharmaceutical ingredients (API), polymers, and other excipients gives a great opportunity to modify the viscosity of the preprinted materials, and therefore there is no need for melting the semi-solid substrates [11]. Via the formulation of the containers, several modified releasing strategies can be applied in the same printlet. The idea of combining osmotic release items into a diffusible containing shell gives a great opportunity to tailor the released doses according to the patient's condition [12]. Moreover, the idea of producing "polypills" containing at least three or more different APIs with different release profiles also seems to be reachable with this technology [13]. In the case of harmonizing these strategies, a whole new dimension of pharmaceutical engineering and manufacturing can be established [2]. Another approach of this layering method is melting the thermoplastic polymers just above their melting temperature, then the melted excipients adhere to the heatable printing bed [14]. Due to the adaptability of the heat of the printing nozzle, the resolution of the printing is much better than in the instance of PAM. The pre-designed modifications inside the CAD file are easier to execute because of the better printing. The great variability of printable filaments and the low cost of this type of manufacturing generated an enormous breakthrough in the field of pharmaceutical manufacturing [15]. Among the most critical printing parameters, the infill and its patterns [16] and the height of the printed layers [17] can be an outstanding opportunity to modify the release kinetics of the microfabricated drugs [18]. In the development of patient-friendly drug delivery, designing and producing various geometries with a standard quality in order to maintain different kinetics is an important objective [19]. FDM printing gives the chance to fabricate unique designs for each object, and these delivery systems can be tailored to the individual's preferences [20]. The FDM extrusion-based technology includes a heating step in which the metal extruder can reach high processing temperature, excluding the possibility of printing thermolabile API filled filaments [21]. In order to formulate dosage forms suited for heat-sensitive APIs, novel nanocomposites have been developed lately [22]. Thermostable APIs can be impregnated onto the surface of the filament, which allows a minimal drug loading percentage [23,24]. The other and widely used method is hot-melt extrusion, where the parallelly co-rotating extruders make the homogenous drug-loaded filaments ready for printing [25]. In most studies, this preparation step was the basis of fabricating tablets and capsules having different geometries containing variant drugs and doses [26–28].

Beside producing drug-loaded filaments, another way to place API into the delivery system is printing separate capsule or carrier parts then filled and assembled in the postprinting phase [29–31]. There was only one previous formulation which aimed at printing a capsule which can be filled with liquid or solid API and excipients mid-printing [32]. Since, in case of this study, the basis of the formulation strategy is a thin-walled carrier, the buckling behavior of the printed structures should be monitored in order to ensure the desired quality [33].

Several types were previously microfabricated: immediate-release tablets [34], fastdisintegrating tablets and orodispersible films [35], floating drug delivery systems [27,36], pulsatile drug release tablets [30], biphasic and multi-active solid dosage forms, and zeroorder release tablets [37]. Overcoming the difficulties of on-demand manufacturing of personalized carriers can lead to the spread of the clinical application of pharmaceutical additive manufacturing [38]. The reproducibility of dose dispensing and carrier filling is promising for the future [39].

Polyvinyl alcohol (PVA) is a non-toxic, hydrophilic, synthetic, biodegradable polymer produced via the hydrolysis of vinyl acetate [40], which is the most widespread supporting material in the field of fused deposition modeling. The variants of PVA are usually chosen as supporting structure due to its good solubility in water. The spread of biodegradable excipients in the industrial production not only decreases the ecological footprint [41] but is also an adequate step towards a sustainable, zero-waste manufacturing [42]. Polyvinyl alcohol is used primarily in topical pharmaceutical and ophthalmic formulations [43]. It has also been used as an emulsifier in the formulation of drug loaded micro sponges [44]. In solid dosage forms PVA is used in coating formulations for tablets as a film forming polymer [45]. In this study our aim was to characterize the erosion of water-soluble PVAbased 3D printed systems with particle size analysis of colloidal PVA particles which appeared during in vitro mimicked dissolution conditions. The effect of pH, and the presence of bile salts were also simulated. An additional objective was to evaluate the effect of orifice numbers on the riboflavin release as a function of time. The optimal setting of this adjustment through CAD design ensures a perfect dose release which is inevitable for personalized therapy. The results of these investigations are intended to promote the spread of the 3D printed production of fillable water-soluble shells. With the opportunity of mixing different API between different layers of the carrier, the individualized medication can gain more emphasis.
