(M1330-07-40) Development of Caffeine Customized-Release Tablets Using 3D Printing System and IVIVC Prediction

Purpose: Caffeine is a well-known stimulant used to endure performance in the context of sleep deprivation and sedation. However, the effect of the drug can be limited by a short duration of action and dose-dependent side effects, including the phenomenon known as 'caffeine crash' [1,2]. To overcome these limitations and achieve more effective and sustained caffeine delivery, we developed a novel customized caffeine delivery system using In-Vitro In-Vivo Correlation (IVIVC) and 3D printing technology. In this study, a novel controlled-release caffeine formulation was prepared by printing 2-layered structure with 3D printing technology. The 3D-printed tablet consists of immediate-release layer and sustained-release layer in a single dosage unit, inducing quick onset and extended alerting effect. To validate this formulation, we performed in vitro dissolution tests, in vivo pharmacokinetic (PK) studies, and established an IVIVC.

Methods: Tablets were printed by single-nozzle extrusion 3D printer manufactured by Linc Solution(Korea). To monitor  the release profile in accordance with the content of sustained releasing agent, Eudragit RSPO was added to the 3D-printed formulations at concentrations of 5, 10, and 20% w/w, respectively. Then, 3D-shape of tablet was designed with varying the infill density from 30% to 90%. The in vitro dissolution pattern was evaluated using USP Apparatus II method over a 12-hour period and quantitative analysis was performed by HPLC-UV.
To assume the desired formulation by IVIVC, in vivo PK study using beagle dogs was performed with three formulations, showing differentin vitro dissolution profiles (immediate-release(IR), intermediate-release(IMR), and slow-release(SR)). PK parameters of each formulation, including C_max, T_max, AUC_0-t, t_1/2, and MRT, were determined via non-compartmental analysis and were correlated with in vitro dissolution results to establish the IVIVC. In the prediction model, the sustained-release agent concentration and infill density was considered as key variables, facilitating the formulation to achieve desired release patterns mathematically. Additionally, through IVIVC, caffeine's pharmacokinetic profile of optimized formulation was predicted using a one-compartment model. The optimized tablets were designed to maintain the alertness according to two-user scenarios; A 6-hour customized-release designed to focus during standard work hours (DRT1; IR+IMR) and a 10-hour for all-day cognitive enhancement (DRT2; IR+SR). The actual dissolution of these tablets was compared with the model's predictions to assess the capability and validate the suitability of the mathematical model.

Results: Eudragit RSPO-based 3D printing formulation containing caffeine(30%) was prepared with MCC(diluent), PVP K90(binder), respectively. In in vitro dissolution study, the profile of dissolution (Figure 1.) was demonstrated that increasing the content of sustained releasing agent(5%, 10%, 20%) and infill density(30%, 70%, 80%, 90%) in 3D-printed tablets resulted in progressively delayed release rates. These findings indicate that precise control of the content of Eudragit RSPO and infill density enables the customization of release profiles. The pharmacokinetic study of IR-, IMR-, and SR-formulation in beagle dogs revealed distinct profiles, including Tmax values (IR: 1 hr, IMR: 2 hr, SR: 3 hr) and MRT (IR: 6.1 hr, IMR: 6.6 hr, SR: 7.2 hr), and correlated with designed release rates (Figure 2.). These results were applied to design 3D-printing customized formulations using mathematic model.
[Mathematical Dissolution Model for Final Formulation Design]
d/dt(Qdiss)=Dose*exp(-(Time)/Kdis)/Kdis
Kdis=(0.1905*(sustained-release agent composition%)+1.4737)-(0.071*(100-infill ratio))
Qdiss: the amount of caffeine dissolved,
Dose: the amount of caffeine administered,
Time: the dissolution time,
Kdis: the dissolution rate constant.
[Mathematical IVIVC Model for Final Formulation Design]
d/dt(Qcaf) =Dose_IR*exp(-(Time)/(Kdiss_IR*Cor_vivo))/(Kdiss_IR*Cor_vivo) +
          Dose_SR*exp(-(Time)/(Kdiss_SR*Cor_vivo))/(Kdiss_SR*Cor_vivo) -
          (Kel*Qcaf)
Kdis=(0.1905*(sustained-release agent composition%)+1.4737)-(0.071*(100-infill ratio))
Qcaf: total amount of caffeine in the body
Dose_IR: the amount of the immediate-release (IR) caffeine administered
Kdiss_IR: dissolution rate constant of the immediate-release caffeine portion
Dose_SR: the amount of the sustained-release (SR) caffeine administered
Kdiss_SR: dissolution rate constant of the sustained-release caffeine portion
Cor_vivo: In vitro-in vivo correlation coefficient
Kel: Elimination rate constant
Two optimized tablets(DRT1, DRT2) were designed by 3D modeling suitably within seamless dosage unit (Figure 3.(a)). With notable coefficients of determination (R² > 0.99) between predicted and actual release patterns, this prediction model showed excellent predictive accuracy, making it a valuable tool for designing 3D-printed caffeine with customized release profiles for various purposes (Figure 3.(b)). The IVIVC model's predictions in PK behavior of two caffeine tablets demonstrated that each formulation achieved its targeted duration of effective concentration, maintaining therapeutic levels for 6 and 10 hours (Figure 3.(c)), respectively.

Conclusion: A novel caffeine formulations showing tailored drug release profiles ranging from immediate to sustained release were developed using 3D-printing. The study demonstrated that the developed models not only provide highly accurate predictions of the formulation's release rate but also predict the pharmacokinetics of caffeine in in vivo condition, effectively. This approach is expected to customize caffeine delivery with diverse needs, from maintaining prolonged alertness for jet lag adaptation to sustaining concentration during work hours, for example.

References: 1.Committee on Military Nutrition Research. Caffeine for the sustainment of mental task performance: formulations for military operations. National Academies Press, 2001.
2.Saraiva, Sofia M., et al. "Overview of caffeine effects on human health and emerging delivery strategies." Pharmaceuticals 16.8 (2023): 1067.

Acknowledgements: This research was supported by the Technology Innovation Program (20015288, Development of personalized-dose medicine based on 3D Printing) funded by the Ministry of Trade, Industry & Energy(MOTIE, Korea)

Caffeine release profiles: Effect of changes in Eudragit RS PO ratios and infill ratio

Pharmacokinetic profiles and parameters of IR, IMR, and SR 3D-printed tablets in beagles

3D-printed caffeine tablets: (a) Designed models and actual printed tablets, (b) Predicted vs. actual in vitro release profiles, and (c) Model-predicted pharmacokinetic profiles