(T1230-08-53) Application of 3D Printing Technology for Development of Dose Adjustable Geriatric and Pediatric Formulation of Celecoxib

Purpose: Developing safe and effective formulations for the geriatric and pediatric population is a complicated task that poses challenges related to swallowability and palatability. Specifically, creating age-appropriate formulations for the pediatric population is particularly challenging due to the lack of standardized procedures that are well-characterized for this population. One way of preparing extemporaneous formulations for children is by manipulating adult formulations, but this may result in suboptimal efficacy and safety concerns due to medication errors. To address this challenge, minitablets, or spinklets, have been proven to be the preferred administration for the geriatric and pediatric population due to their smaller size and flexible dose adjustment. The development of age-appropriate formulations for pediatric patients requires careful consideration of various aspects and parameters to ensure safety and efficacy. Challenges and limitations associated with pediatric formulations include poor swallowability and palatability, dose customization, medication error, and choice of excipients. To overcome these limitations and provide a safe and effective solution, this study aims to develop a 3D printed “spinklets” formulation of celecoxib, a nonsteroidal anti-inflammatory drug used in the treatment of mild to moderate pain and arthritis, using hot melt extrusion. This study presents a novel approach to overcome the limitations of traditional manufacturing methods and provides a solution to the issues with swallowability and palatability

Methods: Three different formulations of Celecoxib with 10% drug load were prepared using Aquazol by using the 11mm parallel twin-screw hot melt extruder, with and without surfactant (TPGS or Sophorolipids). For HME processing, the powder mixture was fed at a rate of 2g/min at a temperature of 150 C and a screw speed of 100 rpm. Resultant drug-loaded filaments were characterized further for mechanical properties, solid state characterization, and solubility studies. The mechanical properties of HME filaments were evaluated using the three-point bend test performed with TA.XTplus Texture Analyzer. Saturation solubility of the drug-loaded filaments was studied in aqueous media. Differential Scanning Calorimetry (DSC) and Powder X-Ray Diffraction (PXRD) were used for solid state characterization of powders of pure drug, polymer, surfactant, and extruded filaments. The spinklets design was created using computer-aided design software Tinkercad®, and the spinklets were printed with a 95% infill using fused deposition modeling (FDM) 3D printer. The printing settings were optimized to achieve reproducible printing of the spinklets. Finally, in vitro dissolution of the spinklets was evaluated in 250 mL of 0.1N Hydrochloric Acid (HCl) at 75 rpm at 37°C (n=3). A graphical representation of the study has been shown in Fig. 1.

Results: Drug-loaded filaments with a diameter of 1.55 mm were prepared using hot melt extrusion (HME), yielding filaments with different appearances and properties depending on the surfactant used. Filaments containing CXB and surfactant exhibited a light-yellow color and had lower % torque during extrusion, while clear glassy filaments were obtained with Sophorolipid (SPL) and rough surface filaments were obtained with Aquazol. Filaments with Aquazol were brittle and had poor elasticity, while TPGS filaments showed higher flexibility but lower tensile strength. The CXB-Aquazol-SPL filament had optimum strength and elasticity for 3D printing of Sprinklets, with dimensions of 4mm × 4mm × 1.5mm. Solid-state characterization using DSC and XRD confirmed the amorphization of Celecoxib in the filaments, with no crystalline melting endotherm observed (Fig. 2.). In vitro drug release studies showed that the 3D printed Sprinklets containing SPL exhibited the highest drug release of ~ 80% within 60 min at pH 1.2. Additionally, SPL significantly improved the aqueous solubility of Celecoxib, as confirmed by an increase in saturation solubility studies.

Conclusion: 3D printing technology has been shown to have great potential in the development of personalized medication formulations for geriatric and pediatric patients. The combination of hot-melt extrusion and FDM-3D printing has been successfully used to produce dosage forms with adjustable doses and diameters suitable for these populations. This study specifically demonstrated the successful development of a pediatric formulation of Celecoxib, as well as the creation of an amorphous solid dispersion with enhanced drug release. The use of 3D printing technology in pharmaceutical manufacturing has the potential to improve patient compliance, reduce dosing errors, and improve overall therapeutic outcomes for vulnerable populations. Further research in this area can pave the way for the widespread use of personalized medication formulations in the future.

Graphical Representation for the development of age-appropriate celecoxib spinklets and characterization.

Solid state characterization of CXB-ASD by (a) Differential scanning calorimetry (DSC) and (b) X-ray powder diffraction (XRD). A distinct sharp melting endothermic peak corresponding to CXB is observed to be absent from the formulation endotherms, suggesting that CXB is present in an amorphous/molecularly dispersed phase.

In vitro release of CXB 3D spinklets in 0.1N HCl (n=3). It can be observed that in presence of SPL, there was a significant increase in the rate of release as compared to other batches.