3D Printing of Tailored Veterinary Dual-Release Tablets: A Semi- Solid Extrusion Approach for Metoclopramide
Abstract
Metoclopramide (MCP) is frequently used to control nausea and vomiting in animals, but its short half-life requires it to be administered thrice daily. In addition, commercial veterinary MCP formulations are currently lacking. As a result,
veterinary practitioners often resort to off-label use of human medications, which can lead to inconsistent patient
outcomes and complications arising from inadequate dosing. Thus, there is a growing recognized need for individualized treatment strategies also within veterinary practice, as they can offer tailored doses and improved options for animal patients. To address this unmet need and overcome these challenges, our study focused on developing a once-daily dualrelease tailored dose for different-sized cats and dogs utilizing semi-solid extrusion (SSE) 3D printing. The dual-release system containing different cellulosic polymers is designed to provide a rapid onset and sustained action to ensure prolonged drug release and minimize the frequency of administration. The produced printing ink formulations were successfully used to obtain different-sized tailored doses with a significant correlation between the designs and the obtained drug amounts. Dissolution studies revealed the impact of polymer combinations and tablet surface area on drug release profiles. Kinetic modeling indicated that both diffusion and erosion are involved in the release mechanisms. This research emphasizes the practical use of SSE 3D printing in developing dual-release delivery systems by producing precise and pet-friendly tailored tablets to enhance veterinary treatments close to the point-of-care.
Introduction
Nausea and vomiting are the most common issues that occur alone or together; they arise from improper diet, underlying medical conditions like gastritis, or treatments such as chemo- and radiotherapy. These symptoms not only affect humans but also cause significant distress in animals.1–3 Metoclopramide (MCP) is highly water-soluble due to its hydrochloride salt form. It is a dopamine D2 receptor antagonist recognized for its anti-emetic and prokinetic properties.4,5 The substituted benzamide ring in MCP allows interaction with receptors in the central nervous system and the gastrointestinal tract, making it practical for managing nausea and vomiting in humans and animals, including cats and dogs.6,7 MCP has a short biological half-life of 2.5-5 h and typically requires continuous administration to maintain therapeutic levels.5,8 Currently, no MCP animal products are approved by the European Medical Agency (EMA) or the US Food and Drug Administration (FDA). Therefore, veterinarians often prescribe human formulations off-label for cats and dogs, with a recommended oral dose of 0.2 to 0.5 mg/kg every 8 h.5,9–11 To fill this gap, MCP has been compounded from humanuse medications, allowing for greater flexibility in treating a range of species and sizes in veterinary practice.12,13
A standard treatment approach often involves using one-size-fits-all tablets produced by traditional mass-production methods.14 However, the one-size-fits-all treatment strategy can lead to different challenges, such as formulation errors, inaccurate dosing, limited customization, difficulties in achieving a steady release, and poor patient compliance.15–17 The tailored medicine approach would be a great alternative to the one-size-fits-all treatment, as this provides suitable dosing to meet individual patient needs and potentially revolutionizes the current animal healthcare system, allowing veterinarians with many options to achieve improved treatments. Additive manufacturing (AM), or 3D printing technology, has been recognized as a promising technology capable of producing both simple and complex designs in a controlled manner. The inclusion of AM technologies in pharmaceutical fabrication allows for precise dosing and the customization of release profiles by altering tablet structures and geometries.18,19 Semi-solid extrusion (SSE) 3D printing technique would be the alternative solution to overcome these challenges by providing precise medicine to patients according to their body weight, size, and disease severity. This process involves 3D printing of semi-solid paste and gel-like ink formulations by layer-by-layer extrusion, offering precise control while printing complex designs. The usage of disposable syringes in SSE 3D printing minimizes the risk of contamination compared to the tablet-pressing method.20–22 This robust technology allows manufacturing at low temperatures, making it suitable for thermo-sensitive excipients and active pharmaceutical ingredients (APIs). SSE 3D printing is highly dependent on the rheological properties of printing ink formulation. Therefore, it is important to evaluate the viscoelastic properties of printing inks before 3D printing. A homogeneous formulation with no phase separations as printing ink is expected to provide uniform distribution throughout the tablet, resulting in precise and flexible dosage forms. These advantages make SSE an appropriate method for manufacturing tailored doses on-demand, close to the point-ofcare. 23–26
In this study, tailored doses of dual-release tablets were compounded by SSE 3D printing to reduce frequent dosing and achieve stable drug release. The prepared formulation is intended to provide quick-onset actions and a slow release over an extended time for different-sized cats and dogs by reducing the frequency of administration. Developing a dual-release matrix system using the same or different APIs offers cost-effective treatment, flexible formulation design, reduces the adverse effects of frequent dosing, and dosing convenience design.27–29 Furthermore, this delivery system eases the administration difficulties for pet owners and veterinarians, resulting in safe treatments, improved patient compliance, and treatment outcomes.
In the past two decades, many researchers have employed 3D printing technologies to achieve more complex drug delivery systems to meet the challenges associated with traditional compounding by conventional methods and to achieve stable, personalized drug-delivery systems.30 Zhang et al. developed combipills containing model drugs tranexamic acid and indomethacin using SSE 3D printing technology coupled with fused deposition modeling (FDM).31 A bilayer tablet containing diclofenac sodium sustained-release drug delivery system was produced coupled with hot melt extrusion and FDM.32 In addition, Genina et al. and Ghanizadeh Tabriz et al. used FDM to develop a controlled-release bilayer tablet containing a combination of two anti-tuberculosis drugs, rifampicin and isoniazid.33,34 Two published studies found dual-release systems developed using SSE 3D printing techniques; namely, Khaled et al. manufactured a bi-layer tablet containing guaifenesin as a model drug, and Fang et al. prepared an ofloxacincontaining dual-release system.35,36
To the extent of our knowledge, no studies have developed tailored doses containing MCP using 3D printing technologies. In this study, we aim to manufacture four different-sized dual-release tailored dose tablets for cats and small to medium-sized dogs utilizing SSE 3D printing. We developed a formulation system with widely used cellulosic polymers to achieve immediate and extended release in one tablet matrix system. We hypothesize that the prolonged release could be achieved by swelling such polymers, forming a gelling layer when in contact with water. Hydroxypropyl methylcellulose (HPMC) was used to prepare the immediate-release (IR) formulation. For the extended release (ER) formulation, a combination of hydrophilic and hydrophobic polymers was utilized, namely hydroxypropyl cellulose (HPC), sodium carboxymethyl cellulose (CMC), and ethyl cellulose (EC) was used as primary matrix forming materials. Liver powder (LP) was incorporated into the IR formulation to enhance the taste and palatability of the tablets. The developed formulations were successfully used to fabricate tailored doses using SSE 3D printing, which exhibited sufficient mechanical properties. The drug release profile and kinetics were investigated on the fabricated dual-release tablets. Our study findings address the current veterinary treatment landscape and provide improved treatment options for small animals by offering tailored doses that minimize the need for off-label treatments. The obtained dualrelease tablets, using advanced technology, provide safe and efficient treatments in veterinary practice.
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Materials
Metoclopramide hydrochloride (MCP) was purchased and used as the API (Sigma Aldrich, St. Louis, MO, USA). The immediate-release (IR) formulation was first screened with various grades of hydroxypropyl methylcellulose (HPMC) polymer, Methocel K3 Premium, which was kindly donated by Dupont (Luzern, Switzerland). Crospovidone (Kollidon CL), a super disintegrant, was kindly donated by BASF (Ludwigshafen, Germany), and D-mannitol (Ph. Eur., Merck, Darmstadt, Germany) was purchased to use as a filler and a disintegration enhancer in the formulations. Glycerol 85% (Fagron, Barsbüttel, Germany) and pure liver powder (LP), CC Moore & Co., Stalbridge, UK) were purchased and used as a plasticizer and taste enhancer.
The extended-release (ER) formulation was screened separately with different polymers to formulate a matrix system. Klucel TM XTEND hydroxypropyl cellulose (HPC), HPC JXF Pharm, was kindly gifted by Ashland (Schaffhausen, Switzerland). Microcrystalline cellulose (MCC), Avicel® PH 101 TM (Orion, Finland), and Blanose TM sodium carboxymethylcellulose (CMC) (Schaffhausen, Switzerland) were kindly donated and used as a filler and release modifier. Ethyl cellulose (EC) was purchased from (Sigma Aldrich St. Louis, MO, USA), and used as a release modifier. Polyvinyl alcohol-polyethylene glycol graft copolymer PEG-PVA (Kollicoat® Protect KP) (Ludwigshafen, Germany) was kindly donated and used as a binder to enhance the smoothness of formulations. Ethanol (EtOH), 96% v/v (VWR International, France), and purified water (Milli-Q® Merck Millipore, Molsheim, France) were used as solvents. Sodium dihydrogen phosphate (Honeywell FlukaTM, Seelze, Germany), potassium dihydrogen phosphate (Merck, Germany), and 37% hydrochloric acid (HCl) were purchased from Sigma Aldrich (Steinheim, Germany).
Rathna Mathiyalagan, Max Westerlund, Alaa Mahran, Rabia Altunay, Jarkko Suuronen, Mirja Palo, Johan O. Nyman, Eero Immonen, Jessica M. Rosenholm, Erica Monaco and Xiaoju Wang, 3D Printing of Tailored Veterinary Dual-Release Tablets: A Semi-Solid Extrusion Approach for Metoclopramide, Received 00th January 20xx, Accepted 00th January 20xx, DOI: 10.1039/D4PM00322E
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