Purpose

The study aimed to develop and optimize apremilast (APST) solid dispersion formulations using copovidone (Kollidon VA64) as the carrier and vitamin E TPGS as the surfactant to enhance solubility and dissolution, and to utilize in silico Physiologically Based Biopharmaceutics Modeling (PBBM) in GastroPlus to simulate the in vivo behaviour of the optimized formulation, predicting its potential for enhancing oral bioavailability.

Methods

Solid dispersion formulations of APST were prepared via the hot melt extrusion (HME) technique, utilizing copovidone (commercially known as Kollidon VA64) as the polymeric carrier. The selection of suitable polymeric carriers as well as surfactant was initially performed through phase solubility studies. The second-generation amorphous solid dispersion (ASD) was formulated with Kollidon VA64. Following this, the third-generation solid dispersions were engineered by choosing vitamin E TPGS as the surfactant carrier, a decision informed by comprehensive screening studies. The formulation of these batches employed a twin-screw configuration in the HME process. Design of Experiments (DoE) approach was utilized to ascertain the optimal ratio of drug: polymer: surfactant to achieve maximum solubility and dissolution enhancement. Drug release studies were conducted in 6.8 phosphate buffer solution. The developed formulations were subjected to a variety of characterization techniques to assess their properties. Stability studies were conducted for the final formulation over a period of up to three months.

Results

Based on the DoE studies, the optimized formulation was identified as APST with copovidone (Kollidon VA64) in a 1:5 ratio, supplemented with 3% vitamin E TPGS. Furthermore, PBBM in GastroPlus was utilized to simulate the in vivo behaviour of the optimized formulation.

Conclusion

The amorphous solid dispersion (ASD) of APST, developed via the HME technique, demonstrated a substantial enhancement in solubility, exhibiting an increase of up to 248-fold relative to the unprocessed drug over a 24-hour period. A noteworthy increase in the percentage of drug release during dissolution was observed in comparison to the pure drug. The observed improvements in solubility and dissolution were corroborated through PBBM in GastroPlus, thereby suggesting a viable strategy for enhancing the oral bioavailability of APST. This investigation effectively illustrates the formulation of a third-generation ASD of APST, significantly ameliorating its solubility and pharmacokinetic parameters, and indicating potential for industrial-scale manufacturing.

By Anuj Kumar Fanda, Ajinkya Jadhav, Pushpendra S. Naruka, Dhwani Rana & Derajram Benival