Development of phenytoin oral fast dissolving film using 3D printing technology

Abstract

This research aimed at developing the novel solid dosage form of phenytoin as an oral fast dissolving film (ODF) that can quickly disintegrate and release the drug upon contact with the salivary fluid without needing water by the two manufacturing methods, conventional solvent casting technique and three-dimensional (3D) printing technology. Evidently, this advanced oral administration of fast dissolving drug delivery systems holds great promise for improving medication administration safety in patients with swallowing difficulties or dysphagia, as well as for enhancing phenytoin bioavailability via rapid drug absorption through the oral mucosa and avoiding the drug being metabolized by the liver (hepatic first-pass effect). The main findings of this study demonstrated the critical role of cosolvent system in the development of ODFs containing poorly water-soluble drugs via solvent casting technique, particularly in improving drug uniformity inside the ODFs and enhancing drug solubility via the amorphization process. Notably, it was determined that the drug content of ODFs without a cosolvent system exceeded the pharmacopeia range because the drug was not distributed uniformly throughout the films. In contrast, the ODFs with a cosolvent system composed of polyethylene glycol (PEG) 400, glycerin, and water exhibited a uniform film appearance with acceptable drug content uniformity and disintegration time that met the pharmacopeia endorsed-limits. The PVA-S4 ODFs (1% w/w PVA and 0.04% w/w sodium starch glycolate (SSG)) were found to disintegrate the fastest in 1.44 min of all ODFs with a cosolvent system. However, even with cosolvent solubilization, only a small amount of phenytoin could be incorporated into these phenytoin ODFs, indicating that further development is needed before being used in real-life practice. With the introduction of 3D printing technology in the fabrication of ODFs, it became possible to load a larger amount of drug with high precision drug dosing. In this study, the 3D-printed phenytoin ODFs were fabricated through a syringe extrusion 3D printer while using hydroxypropyl methylcellulose (HPMC) E5 and HPMC E15 as polymeric printing materials and using glycerin and propylene glycol as plasticizers. According to the findings, all E15-based phenytoin ODFs outperformed E5-based ODFs in aspects of better mechanical properties, faster disintegration (within 5 s) and rapid drug release of up to 80% in 10 min. In addition, the drug content in all E15-based phenytoin ODFs were in accordance with the theoretical drug loading (30 mg) and complied with pharmacopeia specifications, thus proving the accuracy and precision of the 3D printing process. Moreover, this study also confirmed the suitability and feasibility of HPMC E15 to be utilized as printing material for extrusion-based 3D printing technique. Aside from HPMC E15, several other hydrophilic polymers, such as HPMC E50, HMP, and sodium carboxymethylcellulose (SCMC), were found to exhibited the appropriate flowability to be printed through a syringe extrusion 3D printer with high dimensional printing accuracy, thus indicating that all these polymers have the potentials to serve as the base for the manufacture of 3D-printed pharmaceutical products. All of the printing inks consisting of HPMC E15, HPMC E50, HMP, or SCMC exhibited non-Newtonian pseudoplastic behaviors, implying that they could be easily extruded through the very small extrusion nozzle when a high force was applied to the movable syringe system by the screw drive. The optimal HPMC E15, HPMC E50, HMP, and SCMC concentrations for 3D printing were determined to be 20%, 15%, 15%, and 5% w/v, respectively. Among all the 3D-printed phenytoin ODFs obtained from the aforementioned polymers, the SCMC-5 ODFs, which consisted of 5% of SCMC demonstrated the fastest disintegration in only 2.08 s due to its high surface roughness and porosity inside the structure. However, the mechanical properties of this SCMC-5 ODFs were found to be inadequate, thus further development may be required prior to incorporating drug or being used in pharmaceutical practice.