Semi-solid extrusion 3D printing of milk formula-based paediatric chewable dosage forms

Medication adherence is a decisive factor for therapeutic success, particularly in sensitive populations such as paediatric and geriatric patients.1 However, conventional oral dosage forms such as tablets and capsules present major challenges for these groups. Swallowing difficulties are common among children, with a substantial proportion, especially those under ten years old, being unable or unwilling to swallow standard solid forms,2 leading to poor compliance and treatment failure. As a result, caregivers and clinicians frequently resort to off-label or extemporaneous preparations,3 which may compromise dose accuracy, stability, and safety.

Among the available alternatives, chewable4,5 and orally disintegrating formulations6 have shown promise for improving acceptability and compliance. Chewables, in particular, offer an intuitive and water-free mode of administration and are preferred by children due to their familiarity and ease of swallowing.7 Recent developments include candy-like or gummy-type dosage forms designed to enhance palatability and patient engagement.8,9 However, despite these advances, chewable dosage forms often exhibit gritty or chalky mouthfeel, limited flexibility in dose adjustment, and difficulty in masking unpleasant drug tastes without heavy use of sweeteners. Furthermore, the manufacturing rigidity of commercial products prevents adaptation to individual patient needs, which is one of the key advantages that pharmacy compounding traditionally offers.

In this context, semi-solid extrusion (SSE) 3D printing has emerged as a disruptive tool capable of transforming compounding practice within hospital and community pharmacies. It enables on-demand fabrication of personalized medicines, uniting the flexibility of extemporaneous compounding with the precision and reproducibility of digital manufacturing.10 Clinical progress in this field, such as 3D printed isoleucine formulations for Maple Syrup Urine Disease,11 sildenafil printlets produced in hospital pharmacies12 and hydrocortisone formulations under paediatric evaluation,13 has established the feasibility of regulatory-compliant point-of-care printing. Despite these developments, few studies have bridged 3D printing with classical pharmacy compounding, where approved commercial tablets are reformulated into new patient-tailored dosage forms.

Parallel to these technological advances, food-derived and biocompatible excipients have been explored to enhance the sensory and nutritional value of paediatric formulations. Starch-based,14 cereal-based,15 gelatin- and HPMC-based8 and pectin-based16 systems have been used to produce soft, chewable, or gummy-like structures. Chocolate- and cacao-based matrices,17,18 have also been developed to combine therapeutic and nutritional functions. However, milk-based formulations, though widely accepted nutritionally and sensorially, remain underexplored as printable matrices for drug delivery.

Milk offers several pharmaceutical advantages. It enhances solubility of poorly water-soluble drugs19, 20, 21, 22, 23, 24, 25, 26 provides a natural taste-masking and gastroprotective environment27,28 and contains GRAS-listed proteins and lipids that can stabilize drugs and modulate release.29 In particular, milk-based systems enhance drug solubilization through partitioning into lipid phases and interactions with casein micelles,31 which act as natural carriers for hydrophobic compounds. Among different milk types, infant milk formulas, are standardized, low-cost,30 and readily available, making them ideal candidates for safe, nutritionally acceptable, and point-of-care printable excipients. Despite these advantages, milk systems also introduce formulation caveats, including potential variability across brands with different compositions, susceptibility to microbial growth in high-moisture products, allergenicity (cow’s milk proteins) and lactose intolerance considerations, and the fact that gastric digestion of proteins and lipids can change colloidal structures and thereby influence release and supersaturation behavior. Nevertheless, these limitations can be mitigated through appropriate formulation design and controlled processing conditions, supporting the feasibility of milk-based systems for pharmaceutical applications.

Building on this rationale, the present study introduces a milk-based, chewable, semi-solid 3D printed drug delivery platform designed for paediatric patients. The platform uses commercial infant formula as a ready-to-use matrix for both pure active pharmaceutical ingredients and powders compounded from commercial tablets, thereby bridging digital manufacturing and classical extemporaneous pharmacy practice (Fig. 1). Four model drugs were selected to represent a broad range of physicochemical properties and paediatric applications: paracetamol and sodium valproate as highly soluble/ionizable compounds, and ibuprofen and carbamazepine as poorly soluble drugs with known formulation challenges, enabling evaluation of the milk platform across a wide solubility spectrum and clinically relevant paediatric use-cases.

From a translational and regulatory standpoint, these dosage forms are positioned as extemporaneously prepared products rather than centrally manufactured medicines. Accordingly, their implementation would require alignment with national compounding frameworks, quality risk management, and fit-for-purpose controls (dose uniformity, microbial quality, stability, and appropriate documentation).32

At the same time, SSE 3D printing enables flexible control over geometry, surface-area-to-volume ratio, and internal infill, which can be tuned to modulate dissolution. In this study, printing parameters were kept constant to enable quantitative comparisons, while child-friendly shapes were used to illustrate manufacturability and acceptability potential.

Using this approach, we demonstrate optimized rheological behaviour for cold extrusion, excellent print fidelity, linear dose scaling, favourable texture, and enhanced dissolution, particularly for poorly soluble drugs such as CBZ. While milk proteins (e.g., casein) are widely explored as pharmaceutical excipients, milk-formula-based, chewable 3D printed medicines are not yet established as marketed drug products. Thus, stability and in vivo performance remain key translational steps.

This work proposes a practical and patient-friendly route for personalized, palatable, and nutritionally acceptable drug delivery directly within pharmacy compounding settings.