Hydroxypropyl Methylcellulose E15: A Hydrophilic Polymer ...

Extrusion-based 3D printing technology is an innovative method with significant potential in producing pharmaceutical products in various dosage forms. It has numerous advantages over traditional manufacturing methods, including precise drug dosing, which is critical for drugs with a narrow therapeutic index. In this study, phenytoin-loaded orodispersible films (ODFs) were successfully fabricated using syringe extrusion 3D printing. Hydroxypropyl methylcellulose grades (HPMC E5 and HPMC E15) served as film-forming polymers, accompanied by glycerin and propylene glycol as plasticizers. These 3D-printed ODFs were evaluated for their physicochemical and mechanical properties and in vitro disintegration time. The optimal ODFs, which exhibited good mechanical properties and rapid disintegration time, were assessed for drug content and dissolution profiles. The results showed that phenytoin-loaded E15 ODFs outperformed the E5 films with a disintegration time of under 5 seconds and achieving up to 80% drug release in 10 minutes. Additionally, they exhibited uniform drug content within the United States Pharmacopeia (USP) acceptable range and demonstrated desirable mechanical properties, including low puncture strength, low Young’s modulus, and high elongation, ensuring easy handling and application. The HPMC E15 printing dispersions with a 10% w/v concentration exhibited non-Newtonian (shear-thinning) pseudoplastic behavior and excellent extrudability through the extrusion nozzle, making HPMC E15 suitable for 3D printing using a syringe extrusion printer.

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1. Introduction

Over the past few decades, there's been increasing interest in employing three-dimensional (3D) printing technology in the medical and pharmaceutical fields to create customizable solid dosage forms tailored to patients' distinct needs, preferences, and characteristics. 3D printing can fabricate products of any shape and size on-demand from digital design software by depositing materials layer-by-layer. This technology typically involves three techniques: inkjet (IJ) systems, nozzle-based deposition systems or extrusion-based printing, and laser-based writing systems. Among these, extrusion-based printing is recognized as the most popular for fabricating solid oral dosage forms due to its capability to print various polymers and drugs at room temperature, incorporating high amounts of drugs at low cost. Multiple studies highlight the benefits of this technique for designing novel dosage forms like polypills, gastro-floating tablets, and orodispersible films (ODFs). ODFs are a relatively new dosage form prepared using hydrophilic polymers, designed to disintegrate rapidly in the buccal cavity within a minute, without requiring water. This form offers several advantages over other oral dosage forms, making it easier for pediatric and geriatric patients with dysphagia and improving drug bioavailability due to the high vascularity and permeability of the buccal cavity. Furthermore, 3D-printed ODFs provide personalized therapy through the ability to control the dosage by calculating material consumption during the design stage and formulating with reduced time.

Various hydrophilic polymers like polyvinyl alcohol (PVA), polyvinylpyrrolidone (PVP), polyethylene glycol (PEG), hydroxypropyl cellulose (HPC), and hydroxypropyl methylcellulose (HPMC) are employed as film-forming polymers for preparing ODFs. HPMC, also known as hypromellose, is widely used in pharmaceutical manufacturing as a binder, thickening agent, hydrophilic matrix material, and film-forming material. It is classified into several grades based on viscosity and degrees of hydroxypropyl and methoxy substitution. Low viscosity grades like HPMC E3, HPMC E5, and HPMC E15 are often preferred for ODF preparation and suitable for extrusion-based 3D printing of oral dosage forms. Using HPMC, a hydrophilic polymer, enhances the solubility and dissolution of poorly water-soluble drugs in solid dispersion manufacturing. Notably, there are limited studies on 3D-printed ODFs using low viscosity HPMC as the film-forming polymer. Previous research demonstrated that levocetirizine dihydrochloride ODFs prepared using HPMC E15 and pregelatinized starch exhibited good flexibility and rapid drug release in vitro. Additionally, extrusion-based 3D printing with HPMC has shown promise in fabricating tablets using developed HPMC filaments.

Phenytoin, chosen as the model drug for this study, is commonly used to treat partial seizures, generalized seizures, and status epilepticus. It falls under the Biopharmaceutical Classification System (BCS) class II, indicating its limited bioavailability due to poor water solubility. Various techniques, including solid dispersion in hydrophilic polymers, have been employed to enhance its solubility. Existing phenytoin dosage forms include oral suspension, chewable tablets, capsules, and intravenous injections, but commercially available orodispersible phenytoin dosage forms are absent. Developing phenytoin ODFs offers numerous advantages over conventional forms, such as convenient patient administration, precise drug dosing, rapid onset of action, increased bioavailability by bypassing the hepatic first-pass effect, and noninvasiveness. They are also suitable for dysphasic and schizophrenic patients and can be taken without water due to their fast disintegration in the mouth.

This study aimed to explore the possibility of fabricating phenytoin ODFs using a syringe extrusion 3D printer with HPMC E5 and HPMC E15 as film-forming polymers. The extrudability and printability of the different HPMC grades were examined. The developed 3D-printed ODFs were evaluated for physicochemical properties, mechanical properties, in vitro disintegration time, and in vitro release profiles. The significant contribution of this study lies in using a syringe extrusion 3D printer developed by the Biomedical Engineering Institute, Chiang Mai University, Thailand, and using an optimum viscosity polymer (HPMC E15) to fabricate phenytoin-loaded ODFs, paving the way for personalized medicine. This is the first study to employ this specific 3D printer for fabricating such products, which can print fluid gels like materials, such as hydrogels and pastes. Additionally, the printer's temperature control system ensures the viscosity of the printing material remains in a semi-solid state, facilitating printability.

HPMC is a water-soluble, non-ionic hydroxypropyl cellulose ether derived from natural renewable polymers like cotton or wood pulp. WOTAIchem hydroxypropyl methyl cellulose commonly serves as a water retention agent and thickener.

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