Development and Evaluation of 3D Printed Allopurinol Tablets for Veterinary Use

Abstract

Purpose

Canine leishmaniasis is one of the most important endemic zoonotic diseases in Latin America, affecting thousands of individuals. Treatment in dogs commonly involves the use of agents with leishmanicidal activity such as allopurinol, typically administered in combination with miltefosine or meglumine antimoniate. Long-term management frequently relies on the off-label use of human formulations (100 or 300 mg tablets), requiring tablet splitting to achieve dose adjustment for infected dogs, which may compromise dosing accuracy.

Methods

To address this limitation, allopurinol printlets were developed using semi-solid extrusion (SSE) 3D printing (ALLO-3D) to enable dose personalization for small- to medium-sized dogs. The drug dissolution and release kinetics of the printlets were investigated. The greenness profile of the 3D printing was evaluated using the Index of Greenness Assessment of Printed Pharmaceuticals (iGAPP).

Results

The optimized formulation, composed of hydroxypropyl methylcellulose (HPMC), lactose monohydrate, croscarmellose sodium (CCS-Na), and a water–ethanol (7:3, v/v) binder solution, exhibited an immediate-release profile (Q = 75%; 45 min). The developed printlets showed a mean weight of 390.1 mg (RSD = 1.65), drug content of 39.83 ± 0.75 mg printlet⁻¹, and content uniformity of 104.74 ± 2.36% (AV = 5.4). All quality control tests complied with the requirements established in the official codes for oral solid dosage forms. The drug release profile was best described by the First-order model (R² > 0.95).

Conclusion

These findings demonstrate that SSE 3D printing represents a promising strategy to produce personalized printlets containing allopurinol, enabling accurate dose adjustment and potentially improving therapeutic management in canine leishmaniasis. Additionally, the ALLO-3D manufacturing process proved to be suitable from an environmental impact perspective according to the iGAPP metric.

Introduction

The advent of three-dimensional (3D) printing has garnered increasing attention in the pharmaceutical field due to its ability to enable precise dose tailoring and the fabrication of individualized dosage forms [1,2,3]. In addition to its versatility, this technology has been recognized as a more sustainable manufacturing approach, characterized by reduced generation of hazardous waste and simplified production processes [4]. In the context of pharmaceutical compounding, the incorporation of 3D printing offers further advantages over conventional small-scale manufacturing, including process automation and a reduction in risks associated with quality deviations, thereby contributing to improved reproducibility and reliability [5,6,7].

Among the available 3D printing techniques, semisolid extrusion (SSE) has emerged as a particularly feasible and advantageous strategy for the production of solid oral dosage forms. This approach employs semisolid inks, such as gels or pastes, which facilitate the incorporation of active pharmaceutical ingredients and enable the fabrication of printlets with high dose uniformity and reproducibility [8–9]. Furthermore, as SSE operates at low temperature, it minimizes the risk of thermal degradation, making it especially suitable for thermosensitive compounds and contributing to the overall stability of the final formulation [10]. The use of low temperatures in SSE provides an additional advantage associated with improved energy efficiency, making this printing modality more sustainable when compared with other pharmaceutical printing processes [11].

Within this framework, the potential of SSE printing becomes particularly evident in veterinary medicine [9, 12,13,14,15,16]. In this field, interspecies variability and wide differences in body size demand individualized dosing regimens. Beyond dose adjustment, SSE printing allows the customization of critical attributes such as size, shape, and the incorporation of palatability-enhancing excipients, which may improve treatment adherence. Additionally, from a toxicological perspective, personalized formulations can reduce the exposure of animals to potentially harmful excipients, an issue frequently associated with the off-label use of human medicines in veterinary practice.

In addition to pharmacotechnical benefits such as dose individualization, SSE printing offers the potential to support the production of medicines of public health interest, particularly for neglected diseases that require accessible, cost-effective, and integrated control strategies [17]. This gap is even more pronounced in the context of neglected zoonotic diseases in endemic regions, for which there is a notable scarcity of studies addressing the development of personalized medicines [18]. Importantly, this technology may be implemented in compounding pharmacies and adapted to resource-limited or hard-to-reach settings, expanding access to tailored treatments.

Despite these advantages, the development of 3D-printed medicines must be accompanied by rigorous quality assessment. Additive manufacturing processes such as 3D printing may induce physical and structural modifications that can influence drug release behavior when compared to conventionally manufactured dosage forms. Thus, ensuring the quality, safety, and efficacy of 3D-printed formulations requires the implementation of robust characterization and quality control strategies encompassing all stages of production, from paste preparation to the final dosage form [19].

In this context, the present study proposes the development of allopurinol printlets using SSE 3D printing (ALLO-3D). A 40-mg strength was selected as a proof-of-concept lower-dose formulation to demonstrate the feasibility of producing dosage forms suitable for weight-based dose personalization in the treatment of canine leishmaniasis. Leishmaniasis is one of the most important zoonotic diseases in Latin America, affecting both animals and humans [20,21,22]. In canine leishmaniasis, allopurinol is widely used as a leishmanistatic agent, typically administered at a dosage of 10 mg/kg for long-term management [23]. However, veterinary-specific formulations containing allopurinol are not commercially available, and clinical practice frequently relies on the off-label use of 100 or 300 mg tablets originally developed for human patients, which often require splitting to achieve the desired dose. This practice raises significant concerns regarding dose accuracy and content uniformity, thereby highlighting the need for alternative pharmaceutical strategies capable of delivering precise and individualized dosing.

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Materials

Allopurinol was obtained from Fragon® Ltda (São Paulo, Brazil) and used as the active pharmaceutical ingredient (API) to produce 3D-printed tablets. Sodium carboxymethylcellulose (CMC-Na), hydroxypropyl methylcellulose (HPMC), lactose monohydrate, corn starch (C-starch), and croscarmellose sodium (CCS) were purchased from Pharmakos Compounding Pharmacy (Rio Grande do Sul, Brazil). Ethanol (96% v/v; Dinâmica®, Brazil) and purified water (Milli-Q®, Merck Millipore, France) were used as solvents in the preparation of the printing formulations. All other reagents and solvents were of analytical grade and used as received.

Escobar, B.M., Kaufmann, A.I., Mezadri, J.V. et al. Development and Evaluation of 3D Printed Allopurinol Tablets for Veterinary Use. J Pharm Innov 22, 271 (2027). https://doi.org/10.1007/s12247-026-11134-4