Fused-filament 3D printing of drug products: Microstructure analysis and drug release characteristics of PVA-based caplets

Abstract

Fused deposition modeling (FDM) 3–Dimensional (3D) printing is becoming an increasingly important technology in the pharmaceutical sciences, since it allows the manufacture of personalized oral dosage forms by deposition of thin layers of material. Here, a filament extruder was used to obtain filaments of polyvinyl alcohol (PVA) containing paracetamol or caffeine appropriate for 3D printing. The filaments were used to manufacture caplets for oral administration by FDM 3D printing, with the aim of evaluating the effect of the internal structure (micropore volume), drug loading and composition on drug dissolution behaviour. Micropore volume of the caplets was primarily determined by the presence of large pores due to gaps in the printed layers/net while printing, and the porosity of the caplets was 10 fold higher than the porosity of the extruded filament. Dynamic dissolution drug release tests on the caplets in biorelevant bicarbonate media revealed distinctive release profiles, which were dependent on drug solubility and drug loading. Porosity of the caplets did not help to predict the different drug release profiles. This study confirms the potential of 3D printing to fabricate caplets and helps to elucidate which factors influence drug release from this type of new dosage form.

Introduction

3D printing (3DP) is an increasingly popular manufacturing technique that allows creation of solid objects by deposition of many thin layers. 3DP is now used as a production tool or for rapid prototyping in many areas, from research to industry. It is destined to be the next industrial revolution because it is changing the way objects are created, transported and stored (Barnatt, 2013).

The pharmaceutical sector has embraced 3DP. The claimed advantages of the in situ fabrication of unit dosage forms with doses and/or drug combinations personalised to the patient may lead to a change in the way medicines are designed and manufactured. It is predicted that 3DP will herald a change from limited dose-range unit forms manufactured in big industries to medicines tailored to the patient, prepared in community pharmacies or hospitals (Alomari et al., 2015).

3DP could also be used as a standard manufacturing technology instead of tableting or capsule filling, even facilitating patient compliance to the treatment. For instance, in 2015, the first 3D printed medicine (Spritam®) received approval from the U.S. Food and Drug Administration (FDA) for oral use in the treatment of seizures in patients with epilepsy (Aprecia_Pharmaceuticals, 2015). The 3DP system (ZipDose®) allows manufacturing fast disintegrating formulations incorporating high drug dose, facilitating intake in patients with difficulty swallowing.

Several commercially available 3DP systems are in current usage in the pharmaceutical arena (Goyanes et al., 2015b, Goyanes et al., 2016, Jonathan and Karim, 2016, Khaled et al., 2015, Wang et al., 2016, Yu et al., 2009). One of the barriers to the wider use of the technology is the need to adapt the printers to the specific needs of the pharmaceutical field and the high quality standards demanded and regulated by the pharmaceutical industry.

Fused-deposition modeling (FDM) is possibly the most common and affordable printing technology with the greatest potential for unit dose fabrication. In FDM 3DP a polymer filament is passed through a heated nozzle that partially melts the polymer and it is then deposited on a build plate, in the x-y dimensions, creating one layer of the object to be fabricated (previously designed with computer-aided design (CAD) software). The build plate then moves down and the next layer is deposited. Thus, the object is fabricated in three dimensions and in a matter of minutes. Since the printer feedstock is an extruded polymer filament, it is possible to blend drug and polymers into a solid dispersion prior to extrusion, and print drug-loaded dosage forms. FDM 3DP technology in pharmaceutics allows printing, at a relatively low cost, with different materials, polylactic acid (PLA) or polycaprolactone (PCL) for medical devices (Goyanes et al., 2016, Sandler et al., 2014, Water et al., 2015) or mainly polyvinyl alcohol (PVA) in the case of oral dosage forms (Goyanes et al., 2014, Goyanes et al., 2015a, Goyanes et al., 2015e, Melocchi et al., 2015, Skowyra et al., 2015).

The creation of drug-loaded filaments suitable for 3D printing medicines has been demonstrated with different drugs by soaking water-soluble filaments in concentrated alcoholic solutions of drug: e.g. for fluorescein (Goyanes et al., 2014), 4-aminosalicylic acid (4-ASA) and 5-aminosalicylic acid (5-ASA) (Goyanes et al., 2015a) and prednisolone (Skowyra et al., 2015). However, hot melt extrusion (HME), a widely used technique in pharmaceutics, has been evaluated to produce better drug-loaded 3D printable filaments with higher percentage of drug (Goyanes et al., 2015e, Goyanes et al., 2015f). In HME, the raw materials are forced to mix in a rotating screw at elevated temperatures before being extruded through a die to produce a strand of uniform characteristics (Repka et al., 2012).

The microstructure of the extruded filament and the 3D printed solid dosage forms and its effects on drug dissolution rate have not been investigated previously. The porosity of the printed material, a measure of the void spaces in the material, is a parameter that may control drug release rates of oral dosage forms, especially in matrix formulations such as uncoated pellets (Goyanes et al., 2010). Porosity is relevant also in HME, where changes in the porosity of the extrudates by different methods (e.g. CO₂ injection) have been evaluated and used to modify the drug release rate (Verreck et al., 2006).

The aims of this study therefore are to (a) manufacture different filaments containing paracetamol or caffeine (used as model drugs) in a water soluble polymer (polyvinyl alcohol, PVA) suitable for printing pharmaceutical dosage forms (caplets) and (b) to evaluate the effect of the internal structure (micropore volume was determined using mercury intrusion porosimetry), drug loading and composition of the 3D printed caplets on the drug dissolution behaviour in biorelevant media.