Innovative Pharmaceutical Techniques for Paediatric Dosage Forms: A Systematic Review on 3D Printing, Prilling/Vibration and Microfluidic Platform.

The production of paediatric pharmaceutical forms represents a unique challenge within the pharmaceutical industry. The primary goal of these formulations is to ensure therapeutic efficacy, safety, and tolerability in paediatric patients, who have specific physiological needs and characteristics. In recent years, there has been a significant increase in attention towards this area, driven by the need to improve drug administration to children and ensure optimal and specific treatments. Technological innovation has played a crucial role in meeting these requirements, opening new frontiers in the design and production of paediatric pharmaceutical forms. In particular, three emerging technologies have garnered considerable interest and attention within the scientific and industrial community: 3D printing, prilling/vibration, and microfluidics. These technologies offer advanced approaches for the design, production, and customization of paediatric pharmaceutical forms, allowing for more precise dosage modulation, improved solubility, and greater drug acceptability. In this review, we delve into these cutting-edge technologies and their impact on the production of paediatric pharmaceutical forms. We analyse their potential, associated challenges, and recent developments, providing a comprehensive overview of the opportunities that these innovative methodologies offer to the pharmaceutical sector. We examine different pharmaceutical forms generated using these techniques, evaluating their advantages and disadvantages.

3D printed mucoadhesive orodispersible films manufactured by direct powder extrusion for personalized clobetasol propionate based paediatric therapies.

The aim of this work is the development and production by Direct Powder Extrusion (DPE) 3D printing technique of novel oral mucoadhesive films delivering Clobetasol propionate (CBS), useful in paediatric treatment of Oral Lichen Planus (OLP), a rare chronic disease. The DPE 3D printing of these dosage forms can allow the reduction of frequency regimen, the therapy personalization, and reduction of oral cavity administration discomfort. To obtain suitable mucoadhesive films, different polymeric materials, namely hydroxypropylmethylcellulose or polyethylene oxide blended with chitosan (CS), were tested and hydroxypropyl-ß-cyclodextrin was added to increase the CBS solubility. The formulations were tested in terms of mechanical, physico-chemical, and in vitro biopharmaceutical properties. The film showed a tenacious structure, with drug chemical-physical characteristics enhancement due to its partial amorphization during the printing stage and owing to cyclodextrins multicomponent complex formation. The presence of CS enhanced the mucoadhesive properties leading to a significant increase of drug exposure time on the mucosa. Finally, the printed films permeation and retention studies through porcine mucosae showed a marked retention of the drug inside the epithelium, avoiding drug systemic absorption. Therefore, DPE-printed films could represent a suitable technique for the preparation of mucoadhesive film potentially usable for paediatric therapy including OLP.

Direct cyclodextrin based powder extrusion 3D printing of budesonide loaded mini-tablets for the treatment of eosinophilic colitis in paediatric patients.

The purpose of this study was to combine direct powder extrusion (DPE) 3D printing and fluid bed coating techniques to create a budesonide (BD) loaded solid oral formulations for the treatment of eosinophilic colitis (EC) in paediatric patients. The preferred medication for EC treatment is BD, which has drawbacks due to its poor water solubility and low absorption. Additionally, since commercially available medications for EC treatment are created and approved for adult patients, administering them to children sometimes requires an off-label use and an impromptu handling, which can result in therapeutic ineffectiveness. The DPE 3D approach was investigated to create Mini-Tablets (MTs) to suit the swallowing, palatability, and dose flexibility control requirements needed by paediatric patients. Additionally, DPE 3D and the inclusion of hydroxypropyl-ß-cyclodextrin in the initial powder mixture allowed for an improvement in the solubility and rate of BD dissolution in aqueous medium. Then, to accomplish a site-specific drug release at the intestinal level, MTs were coated with a layer of Eudragit FS 30D, an enteric polymer responsive at pH > 7.0 values. In vitro release experiments showed that film-coated MTs were suitable in terms of size and dose, enabling potential therapeutic customization and targeted delivery of BD to the colon.

Direct cyclodextrin-based powder extrusion 3D printing for one-step production of the BCS class II model drug niclosamide.

Niclosamide (NCS) is a drug that has been used as an anthelmintic and anti-parasitic drug for about 40 years. Recently, some studies have highlighted its potential in treating various tumors, allowing a repositioning of this drug. Despite its potential, NCS is a Biopharmaceutical Classification System (BCS) Class II drug and is consequently characterized by low aqueous solubility, poor dissolution rate and reduced bioavailability, which limits its applicability. In this work, we utilize a very novel technique, direct powder extrusion (DPE) 3D printing, which overcomes the limitations of previously used techniques (fused deposition modelling, FDM) to achieve direct extrusion of powder mixtures consisting of NCS, hydroxypropyl methylcellulose (HPMC, Affinisol 15 LV), hydroxypropyl-ß-cyclodextrin (HP-ß-CD) and polyethylene glycol (PEG) 6000. For the first time, direct printing of powder blends containing HP-ß-CD was conducted. For all tablets, in vitro dissolution studies showed sustained drug release over 48 h, but for tablets containing HP-ß-CD, the release was faster. Solid-state characterization studies showed that during extrusion, the drug lost its crystal structure and was evenly distributed within the polymer matrix. All printed tablets have exhibited good mechanical and physical features and a stability of the drug content for up to 3 months. This innovative printing technique has demonstrated the possibility to produce personalized pharmaceutical forms directly from powders, avoiding the use of filament used by FDM.