Fabrication of Hydroxypropyl Methylcellulose Orodispersible Film Loaded Mirtazapine Using a Syringe Extrusion 3D Printer

03 Mar.,2023


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1. Introduction

Major depressive disorder or depression is a compound mood disorder and a serious mental health problem. According to the World Health Organization (WHO), people around the world (about 280 million) have depression. During a depressive episode, the patients are in a depressed mood, including feeling of sadness, irritableness and emptiness, and a loss of interest in activities. Other symptoms are a loss of concentration, feelings of excessive guilt, feeling low in energy, changing sleep behaviour, changes in weight or appetite, low self-esteem, and hopelessness. Depression can also affect patients to suffer greatly and function poorly in society. Importantly, it can lead to suicide [ 1 ].

Mirtazapine (MTZ), [±]-2-methyl-1,2,3,4,10,14b-hexahydropyrazino [2,1-a] pyrido [2,3-e] benzazepine, is considered to be a safe and versatile antidepressant [ 2 3 ], which is used in hospitals to cure moderate to severe depression and anxiety. MTZ is insoluble in water, with a logarithm partition coefficient (octanol–water) of 2.9. This indicates a high hydrophobicity, but it does dissolve in ethanol and an acidic condition. The MTZ has a low bioavailability (50%), high protein-binding (85%), and a long half-life (20–40 h) [ 4 ]. MTZ has a relatively narrow therapeutic index and should be individually optimized to obtain a therapeutic effect [ 5 ]. Its chemical structure is presented in Figure 1 . Generally, tablets are the available dosage form of MTZ in doses of 15, 30, and 45 mg, respectively. The tablet dosage form lacks patient compliance in long-term use. It is also unsuitable for patients who cannot swallow a tablet and are uncooperative with treatment in physiological therapy centres. Furthermore, in the hospital, the pharmacy compounding of the MTZ liquid formulation was done by crushing tablets in a mortar to a fine powder and mixing with the vehicle until the liquid was formed. The suspension of MTZ was then transferred into a container. The main disadvantage of the compounded MTZ liquid formulation is its homogeneity, which may affect the dose accuracy.

Orodispersible films (ODFs) have been developed to overcome the compliance problem. ODF is a thin film, loaded with a drug, for the fast disintegration of a dosage form in the oral cavity immediately after placing on the tongue [ 6 ]. It is simple to administer oral drugs for paediatric and geriatric patients with swallowing difficulties [ 7 ]. ODFs are generally produced by the solvent-casting method, preparing a film by dissolving a drug and polymer in a solvent, and casting it onto a plate and drying [ 8 ].

Three-dimensional (3D) printing technology is a novel and exciting technology in the pharmaceutical field, since it is able to produce several pharmaceutical formulations, which are designed in the desired shape and size, and customize a drug for a specific patient [ 9 10 ]. The extrusion (solid or semi-solid)-based printing technique is one of the most well-known 3D-printing techniques to produce novel, solid pharmaceutical dosages, such as polypills, multilayer tablets, floating drug delivery platforms, and orodispersible films (ODFs), because of its high capacity to load a drug, its low-cost and capability to print a 3D object with various types of polymers at room temperature [ 11 12 ]. Furthermore, the 3D printing can fabricate a dosage form with a highly accurate drug content because it can calculate the material consumption to control or adjust the dose of the drug. This property is appropiate for a relatively narrow therapeutic index and personalized medicines, such as MTZ. Thus, 3D printing can resolve the drug accuracy issue of MTZ.


Various polymers, such as polyvinylpyrrolidone (PVP), polylactic acid (PLA), polyvinyl alcohol (PVA) and hydroxypropyl methylcellulose (HPMC), can be applied for ODFs preparation with the 3D-printing technique [ 13 14 ]. HPMC is a hydrophilic polymer that dissolves in water and ethanol. It is widely used as an excipient in pharmaceutical applications for several functions, such as a binder, suspending agent, thickening agent, gelling agent, and film-forming agent. HPMC is classified by several factors, such as viscosity and degree of substitution. HPMC E15, that is, low-viscosity HPMC, is used for ODFs preparation and is appropriate for extrusion based-3D printing to produce an oral dosage form [ 13 16 ]. In a previous study, HPMC E15 and pregelatinized starch ODFs containing levocetirizine dihydrochloride showed an ability to be used for semi-solid extrusion 3D printing. It manifested good mechanical properties and rapidly released the levocetirizine dihydrochloride from the formulation [ 17 ].

Consequently, the present study investigated mirtazapine ODFs fabricated by a syringe extrusion 3D printer using HPMC E15 as a polymer. The polymeric solution was determined by its rheological characteristics. The 3D-printing process was investigated for accuracy by a printability study. The printed ODFs were characterised by a thickness and weight validation, morphological study, crystalline state investigation, disintegration time, mechanical properties, drug content and drug release, and were compared with the ODFs obtained from the casting method.

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