3D Printing of Dietary Products for the Management of Inborn Errors of Intermediary Metabolism in Pediatric Populations

Abstract

The incidence of Inborn Error of Intermediary Metabolism (IEiM) diseases may be low, yet collectively, they impact approximately 6-10% of the global population, primarily affecting children. Precise treatment doses and strict adherence to prescribed diet and pharmacological treatment regimens are imperative to avert metabolic disturbances in patients. However, the existing dietary and pharmacological products suffer from poor palatability, posing challenges to patient adherence. Furthermore, frequent dose adjustments contingent on age and drug blood levels further complicate treatment. Semi-solid extrusion (SSE) 3D printing technology is currently under assessment as a pioneering method for crafting customized chewable dosage forms, surmounting the primary limitations prevalent in present therapies. This method offers a spectrum of advantages, including the flexibility to tailor patient-specific doses, excipients, and organoleptic properties. These elements are pivotal in ensuring the treatment's efficacy, safety, and adherence. This comprehensive review presents the current landscape of available dietary products, diagnostic methods, therapeutic monitoring, and the latest advancements in SSE technology. It highlights the rationale underpinning their adoption while addressing regulatory aspects imperative for their seamless integration into clinical practice.

Keywords: chewable formulations and oral drug products; dietary therapy and supplements; direct ink writing 3D-printed drug delivery systems; extrusion-based three-dimensional printing of personalized pharma-inks; intermediary metabolic diseases; on-demand dispensing of pharmaceuticals and medicines; pediatric patients.

Figure 1

Schematic representation of an enzymatic metabolic pathway alongside established and emerging treatments for Inherited Metabolic Disorders: (a) Substrate Reduction Therapy (SRT); (b) Dietary Restriction; (c) Scavenger Therapy; (d) Cofactor Supplementation; (e) Enzyme Replacement Therapy, Gene Therapy and Liver Transplantation; (f) Product Supplementation; and (g) Dietary Supplementation.

Figure 2

The iterative process of the virtuous cycle of personalized medicine: (1) a clinician prescribes a tailored dose based on the patient’s disease state; (2) utilizing computer-aided design software, a suitable dosage form is digitally modeled in 3D; (3) the design is transmitted to a 3D printer situated in a hospital or pharmacy; (4) personalized medication meeting specific patient needs and preferences (e.g., dosage, form, flavor, aesthetics) is manufactured and dispensed; (5) the medication is administered to the patient; and, finally, (6) remote monitoring of drug blood levels and performance facilitates continuous adjustments in the treatment plan to achieve optimal therapeutic outcomes. Artificial intelligence is integrated throughout the entire process to streamline operations.

Figure 3

Examples of wearable biosensors: (a) colorimetric sensing patch detecting pH, calcium, and chloride ions in sweat [66]; (b) iontophoretic-biosensing temporary tattoo for ethanol quantification in sweat [67]; (c) electrochemical wearable glove-embedded sensors measuring uric acid, paracetamol, paroxetine, and ethinylestradiol in sweat [58]; (d) surface-enhanced Raman scattering (SERS) sensor monitoring paracetamol in sweat [68]; (e) electrochemical ring sensor simultaneously measuring tetrahydrocannabinol and alcohol in saliva (scale bar: 15 mm) [61]; (f) electromagnetic wave sensing technology for glucose monitoring: (i) schematic representation of the biosensor; and (ii) the sensor is worn within the sock apparatus [69]; and (g) electrochemical sensor for levodopa detection in sweat [70]. All figures were reprinted with permission from their original sources.

Figure 4

Schematic diagram of the steps included in the active ingredients’ 3D printing process.

Figure 5

Pharmaceutical products created using SSE 3D printing: (a) a multi-drug loaded suppository [98]; (b) multi-active tablet containing captopril, nifedipine, and glipizide [88]; (c) (left) 3D printed gastro-floating tablets with different infilling percentage and (right) their respective cross-sections showing (from left to right) 30%, 50%, and 70% infill percentages [104]; and (d) flexible warfarin-loaded films [91]. All figures were reprinted with permission from their original sources.

Figure 6

Advancements in chewable formulations: (a) chewable tablets shaped like gummy bears containing propranolol hydrochloride: F1–F11 formulations contain different amounts of gelatin and carrageenan [129]; (b) chewable isoleucine printlets offered in various flavors, colors, and doses [74]; (c) chewable tablets loaded with amlodipine besylate [120]; (d) chewable formulations containing indomethacin [121]; (e) gummies of different shapes containing ranitidine [122]. All figures were reprinted with permission from their original sources.