Solubility Enhanced Formulation Approaches to Overcome Oral Delivery Obstacles of PROTACs

Abstract

PROteolysis TArgeting Chimaeras (PROTACs) offer new opportunities in modern medicine by targeting proteins that are undruggable to classic inhibitors. However, due to their hydrophobic structure, PROTACs typically suffer from low solubility, and oral bioavailability remains challenging. At the same time, due to their investigative state, the drug supply is meager, leading to limited possibilities in terms of formulation development. Therefore, we investigated the solubility enhancement employing mini-scale formulations of amorphous solid dispersions (ASDs) and liquisolid formulations of the prototypic PROTAC ARCC-4. Based on preliminary supersaturation testing, HPMCAS (L Grade) and Eudragit^® L 100-55 (EL 100-55) were demonstrated to be suitable polymers for supersaturation stabilization of ARCC-4. These two polymers were selected for preparing ASDs via vacuum compression molding (VCM), using drug loads of 10 and 20%, respectively. The ASDs were subsequently characterized with respect to their solid state via differential scanning calorimetry (DSC). Non-sink dissolution testing revealed that the physical mixtures (PMs) did not improve dissolution. At the same time, all ASDs enabled pronounced supersaturation of ARCC-4 without precipitation for the entire dissolution period. In contrast, liquisolid formulations failed in increasing ARCC-4 solubility. Hence, we demonstrated that ASD formation is a promising principle to overcome the low solubility of PROTACs.

Keywords: ARCC-4; PROTAC; amorphous solid dispersion; dissolution; solubility enhancement; supersaturation; vacuum compression molding.

Figure 1

Selected cereblon- and VHL-based PROTACs and key physicochemical properties.

Figure 2

X-ray powder diffraction (XRPD) diffractograms of neat ARCC-4.

Figure 3

Solid state analysis of neat ARCC-4: (a) Differential scanning calorimetry (DSC) thermogram (exo up); (b) Thermogravimetric analysis (TGA).

Figure 4

Supersaturation assay of 0.2 mg/mL ARCC-4 (=100%) in 20 mL 0.05 M phosphate buffer at pH 6.8 (37 °C, 75 rpm paddle speed) dependent on pre-dissolved single polymers ● HPMCAS, ■ EL 100-55, ○ HPMC HME 15 LV, □ HPC-SSL, ▲ Copovidone, and ▼ without polymer. For each experiment, the total polymer concentration was 1.25 mg/mL.

Figure 5

DSC thermograms (exo up) of (a) HPMCAS ASDs (10 and 20% drug load) and (b) EL 100-55 ASD (10 and 20%) compared to neat ARCC-4 and neat polymers.

Figure 6

Dissolution profiles of (a) HPMCAS ASDs (● 10 and ○ 20% drug load) compared to the corresponding PMs (■ 10 and □ 20% drug content) and ▼ neat ARCC-4 and of (b) EL 100-55 ASDs (● 10 and ○ 20% drug load) compared to the corresponding PMs (■ 10 and □ 20% drug content) and ▼ neat ARCC-4. Non-sink dissolution study was conducted in 20 mL 0.05 M phosphate buffer at pH 6.8 (37 °C, 75 rpm paddle speed).

Figure 7

Dissolution profiles of liquisolid formulations ■ ARCC-4: PC: Silsol, ● ARCC-4: NMP: Silsol, and ▲ ARCC-4: DMSO: Silsol compared to ▼ neat ARCC-4. Non-sink dissolution study was conducted in 20 mL 0.05 M phosphate buffer at pH 6.8 (37 °C, 75 rpm paddle speed).