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Background: Adrenal insufficiency is usually diagnosed in children who will need lifelong hydrocortisone therapy. However, medicines for pediatrics, in terms of dosage and acceptability, are currently unavailable., Research Design and Methods: Semi-solid extrusion (SSE) 3D printing (3DP) was utilized for manufacturing of personalized and chewable hydrocortisone formulations (printlets) for an upcoming clinical study in children at Vall d'Hebron University Hospital in Barcelona, Spain. The 3DP process was validated using a specific software for dynamic dose modulation., Results: The printlets contained doses ranging from 1 to 6 mg hydrocortisone in three different flavor and color combinations to aid adherence among the pediatric patients. The pharma-ink (mixture of drugs and excipients) was assessed for its rheological behavior to ensure reproducibility of printlets through repeated printing cycles. The printlets showed immediate hydrocortisone release and were stable for 1 month of storage, adequate for prescribing instructions during the clinical trial., Conclusions: The results confirm the suitability and safety of the developed printlets for use in the clinical trial. The required technical information from The Spanish Medicines Agency for this clinical trial application was compiled to serve as guidelines for healthcare professionals seeking to apply for and conduct clinical trials on 3DP oral dosage forms.

Introduction : Three-dimensional (3D) printing is a relatively new, rapid manufacturing technology that has found promising applications in the drug delivery and medical sectors. Arguably, never before has the healthcare industry experienced such a transformative technology. This review aims to discuss the state of the art of 3D printing technology in healthcare and drug delivery. Areas covered : The current and future applications of printing technologies within drug delivery and medicine have been discussed. The latest innovations in 3D printing of customized medical devices, drug-eluting implants, and printlets (3D-printed tablets) with a tailored dose, shape, size, and release characteristics have been covered. The review also covers the state of the art of 3D printing in healthcare (covering topics such as dentistry, surgical and bioprinting of patient-specific organs), as well as the potential of recent innovations, such as 4D printing, to shape the future of drug delivery and to improve treatment pathways for patients. Expert opinion : A future perspective is provided on the potential for 3D printing in healthcare, covering strategies to overcome the major barriers to integration that are faced today.

In this study, a new co-processed excipient composed of microcrystalline cellulose (MCC), sorbitol, chitosan and Eudragit® E, easily obtained by wet massing, to increase the dissolution rate of active ingredients of low water solubility from pellets prepared by extrusion-spheronization is evaluated. Indomethacin, nifedipine, furosemide, ibuprofen, prednisolone and hydrochlorothiazide are used as model drugs of different solubility. All pellet formulations evaluated showed adequate morphological, flow and mechanical properties. Pellets prepared with the co-processed excipient show a higher drug dissolution rate than those prepared with MCC and even higher than the pure drug powder. The fast drug dissolution and the complete disintegration (<3 min) of the pellets can be explained by the great porosity of the formulations, the high solubility of the sorbitol, the disintegrant capacity of the chitosan and the distribution of the Eudragit® E polymer particles in-between the other components of the co-processed mixture. In conclusion, this new co-processed excipient is very suitable to increase the dissolution rate of poorly soluble drugs from pellets prepared by extrusion-spheronization. Moreover, the drug release rate can be estimated from the Ln of the drug solubility in acidic medium.

The usefulness of a coprecipitate of chitosan and kaolin as disintegrant in the pellets of microcrystalline cellulose (MCC) and hydrochlorothiazide (HCT) (as a model of poorly water-soluble drug) produced by extrusion-spheronization was evaluated in this study. The effectiveness of chitosan-kaolin coprecipitate to increase the dissolution rate was compared with that of kaolin and chitosan. A possible synergy effect was also evaluated between the coprecipitate, kaolin or chitosan and sorbitol, added to the pellets as a very water-soluble diluent. The chitosan-kaolin coprecipitate, the kaolin or the chitosan allowed pellets to be obtained of adequate size, roundness, mechanical strength and flow properties. Furthermore, the incorporation of chitosan-kaolin coprecipitate or chitosan significantly increased the dissolution rate of HCT independently of the sorbitol content. The effects on the dissolution of HCT derived from the incorporation of coprecipitate to the pellets can be attributed to its content of chitosan. However, the addition of kaolin into the pellets did not significantly affect the HCT dissolution process. The pellets incorporating coprecipitated chitosan-kaolin or chitosan and the maximum proportion of sorbitol (50%) led to the highest HCT dissolution rate and experienced a rapid and complete disintegration in the dissolution medium.

Chitosan-silica coprecipitate (C-S) has recently been proposed as a tablet disintegrant. In this study we compared it with a 1:1 physical mixture of chitosan and silica (C/S) at the same composition as the coprecipitate, and with the widely used commercial disintegrant sodium starch glycolate (SSG), as regards to its behavior in spheronized extruded pellets of microcrystalline cellulose (MCC) containing hydrochlorothiazide as a typical poorly water-soluble drug. In all three cases, possible synergism between the disintegrant (0-5%) and sorbitol (0-50%) was also evaluated. All the formulations examined exhibited appropriate morphology and had satisfactory mechanical and flow properties. Drug release depended mainly on sorbitol content, however C-S accelerated drug release at all sorbitol levels (the fastest release was from 50% sorbitol pellets with C-S, which disintegrated), whereas C/S did not vary drug release from pellets, and SSG depressed drug release, especially from 50% sorbitol pellets.

Mixtures of microcrystalline cellulose (MCC) with sorbitol (up to 50%) or mannitol (up to 80%) were investigated as major excipients for controlled accelerated release of the model poorly water-soluble drug hydrochlorothiazide from pellets prepared by extrusion/spheronization. Optimal wetting volume decreased with increasing polyol content and was always less than the volume required for maximum wet mass consistency. All pellet formulations had satisfactory morphological, mechanical and flow properties, although sorbitol/MCC pellets were rougher than mannitol/MCC pellets. Together they presented a wide range of drug release profiles in 0.1 M HCl, allowing the rate of drug release into aqueous media to be controlled by manipulation of sorbitol or mannitol content. Pellets with a 50% sorbitol content released hydrochlorothiazide faster than pellets with a 50% mannitol content because of their greater porosity and the greater solubility of sorbitol in water. Fastest release was from pellets with an 80% mannitol content, which rapidly underwent complete disintegration.