Concomitant solubility-permeability increase: Vitamin E TPGS vs. amorphous solid dispersion as oral delivery systems...

Area of Science:

• Pharmaceutical Sciences
• Drug Delivery Systems
• Biopharmaceutics

Background:

• Vitamin E TPGS (TPGS) exhibits surfactant and P-glycoprotein (P-gp) inhibitory properties.
• Surfactants typically cause a solubility-permeability tradeoff, but TPGS's P-gp inhibition may alter this.
• Etoposide, a lipophilic anticancer drug and P-gp substrate, is used to study oral drug delivery systems.

Purpose of the Study:

• To investigate the solubility-permeability interplay of etoposide using TPGS and amorphous solid dispersions (ASD).
• To compare the effects of TPGS and ASD on etoposide solubility and in-vitro/in-vivo permeability.
• To analyze how P-gp inhibition/saturation influences the solubility-permeability relationship.

Main Methods:

• Evaluated concentration-dependent effects of TPGS (0-100mg/mL) and ASD on etoposide solubility.
• Assessed in-vitro (PAMPA) and in-vivo (rat intestinal perfusion) permeability of etoposide.
• Compared TPGS effects with a known P-gp inhibitor (GF120918).

Main Results:

• TPGS increased etoposide solubility linearly above its CMC (0.3mg/mL); ASD enabled significant supersaturation.
• In-vitro PAMPA permeability decreased with increasing TPGS, consistent with a surfactant tradeoff.
• In-vivo rat permeability significantly increased with TPGS, attributed to P-gp inhibition, similar to GF120918.
• High supersaturation via ASD also increased in-vivo permeability, suggesting P-gp saturation.

Conclusions:

• A unique solubility-permeability interplay was observed, with simultaneous increases in both parameters.
• TPGS and ASD facilitate increased solubility and permeability, unlike traditional methods or supersaturation alone.
• P-gp inhibition/saturation by TPGS or supersaturation offers a significant advantage for oral drug delivery systems.