2.2.1. Preparation of Formulations

EZ and ATV raw materials (EZ-RM and ATV-RM) were used as references in the “in vitro” and “in vivo” studies. The physical mixture of EZ (PM-EZ 1:2.5) was formulated by mixing 100 mg of EZ and 250 mg of croscarmellose sodium. The physical mixture of ATV (PM-ATV 1:1) was prepared using the same process but mixing 100 mg of ATV and 100 mg of croscarmellose sodium.

The solid dispersion of ezetimibe (SD-EZ) were prepared by dissolving 100 mg of EZ in 500 μL of ethanol, dissolved by the vortex (Fisherbrand TM; Milan, Italy) at 2500 rpm for 2 min. The dissolution of EZ was mixed in a ceramic bowl with 250 mg of croscarmellose for the SD-EZ (1:2.5) and 500 mg of croscarmellose for the SD-EZ (1:5), then dried using a drying oven (Memmert UN30, Schwabach, Germany) at 40 °C for 24 h. The solid dispersions were sieved to isolate the 0.297–0.850 mm fraction.

For the preparation of the micellar systems of ezetimibe (MS-EZ), 100 mg of EZ was dissolved in 500 μL of ethanol with 25 mg and 100 mg of Kolliphor RH40 for MS-EZ (1:0.25) and MS-EZ (1:1), respectively. Each solution was mixed with 250 mg of sodium croscarmellose and then dried at 40 °C for 24 h. The final product was screened to isolate the 0.297–0.840 mm fraction.

The solid dispersion of atorvastatin (SD-ATV) was made following a similar process. A solution of 100 mg of ATV in 500 μL of ethanol was mixed with 100 and 300 mg of croscarmellose sodium for SD-ATV (1:1) and SD-ATV (1:3), respectively. The solid dispersions were dried at 40 °C for 24 h. The final product was screened to isolate the 0.297–0.840 mm fraction.

Finally, the multiparticulate system formulations of EZ and ATV (MPS-I and MPS-II) were prepared with MS-EZ (1:1) and SD-ATV (1:1) formulations. MPS-I was prepared by mixing 380 mg of MS-EZ (1:1) and 583 mg of SD-ATV (1:1), and MPS-II by adding 253 mg of MS-EZ (1:1) and 390 mg of SD-ATV (1:1).