Hydroxypropyl Methylcellulose E15: A Hydrophilic Polymer for Fabrication of Orodispersible Film Using Syringe Extrusion 3D Printer

1. Introduction

Over the last few decades, there has been a growing interest in the use of three-dimensional (3D) printing technology within the medical and pharmaceutical fields to fabricate the customizable solid dosage forms that suit different needs, preferences and individual characteristics of each patient [ 1 ]. Three-dimensional printing is a manufacturing method that can fabricate 3D-printed products of any shape and size on-demand from digital design software through depositing materials layer-by-layer [ 2 ]. This technology involves three commonly used techniques: printing-based inkjet (IJ) systems, nozzle-based deposition systems or extrusion (solid or semi-solid)-based printing technique and laser-based writing systems. Among these, the extrusion-based printing technique has been recognized as the most popular technique for the fabrication of solid oral dosage forms owing to their excellent capability to print with a wider selection of polymers and drugs at room temperature and the capability to incorporate high amounts of drugs with low-cost [ 1 3 ]. Numerous studies have been performed regarding the benefits of extrusion-based 3D printing to design various novel dosage forms such as polypills, gastro-floating tablets and orodispersible films (ODFs) [ 4 ]. ODFs are the relatively novel dosage form prepared by using hydrophilic polymers and designed to rapidly disintegrate within a minute in the buccal cavity, without requiring water [ 5 ]. This dosage form exhibits several advantages over other oral dosage forms, including ease of administration to pediatric and geriatric patients experiencing dysphagia (swallowing difficulty), dose flexibility and improving the bioavailability of drugs due to high vascularity and high permeability in the buccal cavity [ 6 ]. The major advantages of preparing an ODF by 3D printing over the standard film solvent casting are the ability to print objects with different filling (hollow, matrix or full) and the dose of drugs can be controlled by calculating the material consumption during the resizing of the printed object at the design stage, which is proper for personalized therapy. Moreover, 3D-printed films can be formulated with less amount of time.

A variety of hydrophilic polymers such as polyvinyl alcohol (PVA), polyvinylpyrrolidone (PVP), polyethylene glycol (PEG), hydroxypropyl cellulose (HPC) and hydroxypropyl methylcellulose (HPMC) are used as film-forming polymers for the preparation of ODFs, and most of them can also be used as printing materials for extrusion-based 3D printers [ 7 8 ]. Hydroxypropyl methylcellulose (HPMC), also known as hypromellose, is widely implemented in pharmaceutical manufacturing as a binder, thickening agent, hydrophilic matrix material and film-forming material. It is classified into several grades based on viscosity, degree of hydroxypropyl substitution and degree of methoxy substitution. The low viscosity HPMC grades (e.g., HPMC E3, HPMC E5 and HPMC E15) are often used for ODFs preparation and suitable for extrusion-based 3D printing of oral dosage forms [ 8 10 ]. Moreover, the use of HPMC, which is a hydrophilic polymer, can further be advantageous in terms of enhancing the solubility and dissolution of poorly water-soluble drugs in the manufacture of solid dispersion. However, there are still limited studies available on the preparation of 3D-printed ODFs while using low viscosity HPMC as a film-forming polymer. In a previous study, levocetirizine dihydrochloride ODFs consisting of HPMC E15 and pregelatinized starch were prepared using semi-solid extrusion (SSE) 3D printer. The 3D-printed ODFs exhibited good flexibility and rapid drug release in vitro by dissolving completely in two minutes [ 11 ]. In addition, previous work on the extrusion-based 3D-printing of HPMC in the pharmaceutical field can be found [ 12 ]. The extrusion-based (fused-deposition modeling) 3D printer was used to fabricate 3D-printed tablets by using their developed HPMC filament.

Phenytoin, which was selected as a model drug in this study, is an antiepileptic drug widely used in the treatment of partial seizures, generalized seizures and status epilepticus [ 13 ]. It belongs to the Biopharmaceutical Classification System (BCS) class II drug in which its bioavailability is limited due to poor water solubility (32 μg/mL). Various approaches were employed to overcome the solubility problem. Solid dispersion of the drug in a hydrophilic polymer is also one of the promising techniques for enhancing its solubility. There are many available dosage forms of phenytoin in the market, such as oral suspension, chewable tablets, capsules, and intravenous injections. However, the commercial production of orodispersible phenytoin dosage form has not yet been available. The development of phenytoin ODF has numerous advantages over conventional dosage forms such as convenience for patient administration, accurate drug dosing, rapid onset of action with increased bioavailability due to bypassing hepatic first-pass effect and noninvasiveness. Moreover, phenytoin ODF can be used for dysphasic and schizophrenic patients and can be taken without water due to their ability to disintegrate within a few minutes to release medication in the mouth.

Consequently, the present study aimed to assess the possibility of phenytoin ODFs fabrication by syringe extrusion 3D printer using two different low viscosity grades of HPMC (HPMC E5 and HPMC E15) as film-forming polymers. The extrudability and printability of different grades of HPMC were investigated and discussed. Then, the developed 3D-printed ODFs were evaluated for their physicochemical properties, mechanical properties, in vitro disintegration time and in vitro release profiles. The most important impact of our work is the use of the syringe extrusion 3D printer developed by Biomedical Engineering Institute, Chiang Mai University, Thailand and the use of a polymer (HPMC E15) with optimum viscosity as a single printing material to fabricate phenytoin-loaded ODFs for leading to personalized medicine. Until now, there has been no previous study/experiment that has used this syringe extrusion 3D printer to fabricate 3D-printed products. Our syringe extrusion 3D printer was developed to print varieties of fluid gels like materials, such as hydrogels and pastes. Moreover, it can control the printing material temperature by using a temperature control system on the syringe socket. This temperature control system will help control the viscosity of printing material and keep the printing material in a semi-solid state, which makes the material printable through the 3D printer.