Abstract
The development of age-appropriate and personalized medicines is still a necessity. For pediatric use, formulations must be tailored to accommodate child-specific characteristics such as age, weight, and swallowing ability. Moreover, specifically to antibiotic therapy, relevant limitations can be mentioned such as drug inappropriate biopharmaceutical properties, low stability in the gastrointestinal tract and bitter taste. The project p3Diatrics explored and combined innovative strategies with the final aim of obtaining suitable oral antibiotic formulations, specifically designed for various pediatric age groups. Formulations were manufactured using different 3D printing methodologies and characterized as regard the physico-chemical, technological, and functional properties. By combining both materials science and formulation technology fields, p3diatrics could impact current clinical scenarios, providing personalized dosage forms able to improve patient adherence to the therapy.
Results achieved
The p3Diatrics project combined innovative strategies to obtain improved oral antibiotic formulations including gummies, films, micellar solutions or microemulsions, specifically designed for various pediatric age groups, through the advancement of new manufacturing approaches, such the 3D printing (3DP). Three antibiotics, amoxicillin (AMOX), azithromycin (AZT) and ceftriaxone (CFX) were used. Firstly, systematic screening demonstrated the possibility of obtaining stable coamorphous systems. Specifically, the formation of amorphous phases was consistently achieved in five AZT-based systems (i.e., AZT–2-, 3-, and 4- aminobenzoic acids (A2AB, A3AB, A4AB), –salicylic acid (ASLC) and –caprylic acid (ACPL)). Stability tests (performed at 40 °C) highlighted the advantages of coamorphization over the single-component amorphous form of AZT. Notably, in vitro dissolution tests demonstrated a faster dissolution profile of the coamorphous systems especially for AZT-ACPL and AZT-A3AB, compared to both crystalline and amorphous AZT, highlighting the effectiveness of the coamorphization technology for improving the dissolution profile of the drug. Then two formulations were developed for AMOX oral administration: i) liquid (micellar solution); ii) gummy tablets. AMOX encapsulation in Soluplus® based-micelles allowed to obtain a solution of this antibiotic, generally formulated as suspension. In the micellar solution the drug exhibited a twofold increase in solubility compared to the crystalline form. Moreover, the micellar solution demonstrated to be a suitable platform able to improve the drug permeability, through the biomimetic membrane PermeaPad®, suggesting improved potential for gastrointestinal absorption. It is also important to underline that stability studies showed that the micellar encapsulation conferred protection against degradation, particularly under storage temperature of 4 °C, extending the potential shelf life of the product. By freeze drying it is possible to obtain a powder with improved shelf-life that, after reconstitution with water, possesses the same features of the starting micellar solution. AMOX was formulated in gummy tablets with a “teddy bear” shape produced by PAM 3D printing. The gummies were mild-yellow in color, visually attractive, and small enough to be easily consumed by the paediatric population. AMOX was homogeneously distributed in the gummy tablets (200 mg/single dose unit), maintaining its crystalline structure within the matrix as demonstrated by FTIR spectra and PXRD patterns. In vitro dissolution and permeability assays showed a maximum AMOX release of 90 % within 120 min and a promising permeation profile, respectively. Three different formulations were developed for AZT oral administration: i) liquid (microemulsion); ii) gummy tablets; iii) bi-layered buccal films. AZT was formulated in an oil in water (O/W) microemulsion in order to obtain a product in which the drug is solubilized thus, immediately available for the absorption. Microemulsions were produced by high power ultrasonic (HPU) by using pumpkin seed oil, Soluplus®, soy lecithin, the clay hydrophilic bentonite (NHB). The obtained formulation resulted stable allowing an easy and precise dosing. The microemulsion composition was then optimized in order to be used for the production of 3D printed gummies. In order to increase the amount of AZT loaded, the solubilizer Labrasol was introduced in the composition in place of Soluplus®. In order to make the microemulsion suitable for PAM 3D printing processing it was necessary to introduce in the composition a gelling agent and carrageenan was selected. Moreover, vanilla powder flavour and saccharin sodium were used as flavoring and sweetening agents respectively. Content uniformity complied with pharmacopoeia standards since the measured content range was within the 85–115% marked by the general monograph, demonstrating that no drug degradation occurred during printing. Finally, in vitro antimicrobial studies highlighted that AZT retained its efficacy when included in the developed formulation. In regard to the study involving the preparation of AZT based bi-layered buccal films, results allowed selecting adequate materials to obtain a primary polymeric layer, able to adhere to the buccal mucosa and control drug release over time, and a secondary backing layer, which could limit drug diffusion in the buccal cavity. Films based on alginate or hyaluronic acid and Soluplus were easily developed through the solvent casting method and removed from the mould. Moreover, they were characterized by a good homogeneity in terms of weight, thickness and drug content and presented good mucoadhesion and ability to control the drug release. Finally, hyaluronic film favored the drug permeation through the buccal mucosa, maintaining at the same time the antimicrobial activity of the drug. CFX was formulated in bi-layered films intended for sublingual administration. Circular films were prepared using safe and cheap polymers. The baking layer consisting in alginate reinforced with bentonite was suitable for the deposition by casting of the gel for the mucoadhesive layer formation. The latter was prepared combining carboxymethylcellulose to glycerol and the penetration enhancers Soluplus® or cyclic dextrin. The preparation procedure allows to obtain a final product in which CFX original features are maintained. The film, thin and easily applicable, was able to adhere to sublingual mucosa. The in vitro dissolution studies demonstrated that the drug is released from the formulation in a period of 6 hours. The antimicrobial activity studies demonstrated that the drug in the formulation maintains its activity. Ongoing studies are focused on the evaluation of CFX permeability. Overall, considering all the results obtained it can be stated that the developed formulations could be a suitable alternative to the formulations available for the pediatric population, facilitating the administration procedures and improving patient compliance. The scientific results were published in open access journals: • Imbriano, C. Fratini, G. Bondi, I. D’Abbrunzo, S. Bertoni, M. Tiboni, A. Abruzzo, D. Hasa, C. Pagano, L. Casettari. 3D-printed chewable gummy tablets: a new tool for oral amoxicillin administration in paediatric population. Int. J. Pharm. 677, 125645, 2025. • G. Bondi, I. D’Abbrunzo, D. Hasa, C. Parolin, B. Vitali, S. Bertoni, A. Imbriano, C. Pagano, C. Fratini, B. Sabbatini, F. Bigucci, A. Abruzzo*. Innovative bilayered buccal films: a paediatric-friendly dosage form for transmucosal azithromycin delivery. International Journal of Pharmaceutics 684, 126164, 2025 Corrigendum to "Innovative bilayered buccal films: A paediatric-friendly dosage form for transmucosal azithromycin delivery". Int J Pharm. 687, 126375, 2025. • D’ Abbrunzo I., Battaiotto L., Abruzzo A., Bondi G., Bigucci F., Pagano C., Imbriano A., Fratini C., Casettari L., Voinovich D., Hasa D. Structural Insights into Novel Coamorphous Systems of Azithromycin with enhanced Dissolution Profile. Eur. J. Pharm. Biopharm. 216, 114873, 2025. • C. Fratini, A. Imbriano, I. D’Abbrunzo, F. Bigucci, M. Tiboni, C. Parolin, A. Abruzzo, D. Hasa, C. Pagano, L. Casettari. 3D printing of azithromycin loaded gummies for paediatric patients using a carrageenan-based thermoresponsive system. Carbohydrate Polymer Technologies and Applications 13, 101096 2026 • A. Imbriano, A. Di Michele, M.R. Ceccarini, A. Abruzzo, F. Bigucci, D. Hasa, I. D’Abbrunzo, L. Casettari, C. Fratini, S. Primavilla, L. Tazza, L. Tensi, L. Perioli, C. Pagano. Nanoemulsion-based strategy for azithromycin administration in pediatrics Journal of Drug Delivery Science and Technology 121, 108368 2026 The results were also disseminated in national and international conferences and workshops: • Fratini C. et al., 3D Bioprinting of amoxicillin-loaded hydrogels targeting paediatrics: a feasibility study. CRS meeting and conference, Bologna, July 2024. • Bonafè S. et al., Design and characterization of child-friendly chewable-gummy tablets for amoxicillin administration. CRS Italy Local Chapter, Workshop 2025, Bari 15 – 17 May • Abruzzo A. et al., Bilayered buccal films for azithromycin administration in children: preliminary studies. 5th European Conference on Pharmaceutics, Porto (Portugal) 24-25 March 2025 • Bondi G. et al., Design of bilayered buccal films for azithromycin administration in pediatric population. EPTRI Scientific Meeting 2025, Bologna 13-15 March 2025 • D’Abbrunzo I. et al., Novel coamorphous systems of the antibiotic azithromycin. 13th Crystal Forms Convention, Bologna 7-9 September 2025 Moreover, we developed and maintained a dedicated project website (https://pharmatech.uniurb.it/P3diatrics/) that serves as a central hub for disseminating detailed information about the project objectives, activities, publications, events, and outcomesDettagli del progetto
Responsabile scientifico: Angela Abruzzo
Strutture Unibo coinvolte:
Dipartimento di Farmacia e Biotecnologie
Coordinatore:
Università degli Studi di URBINO "Carlo Bo"(Italy)
Contributo totale Unibo: Euro (EUR) 57.786,00
Durata del progetto in mesi: 24
Data di inizio
16/10/2023
Data di fine:
15/10/2025
