A novel combined lipolysis-permeation screening approach in 96-well format: Method development using type I...

Area of Science:

• Pharmaceutical Sciences
• Drug Delivery
• Formulation Development

Background:

• Traditional lipid digestion testing (pH-stat) for lipid-based formulations (LBFs) is time-consuming and has limited predictive power for in vivo performance.
• This limitation stems from its inability to differentiate between drug fractions that are readily absorbable and those that are less absorbable.
• An improved in vitro method is needed to accurately predict oral bioavailability of LBFs.

Purpose of the Study:

• To develop and validate a novel, time-efficient, and material-sparing high throughput screening (HTS) method for LBF release testing.
• To compare the predictive capability of the new HTS lipolysis-permeation assay against the conventional pH-stat method using cinnarizine-loaded LBFs.
• To evaluate the influence of formulation variables (supersaturation, lipase inhibition, lipid chain length, precipitation inhibitor) on in vitro and in vivo performance.

Main Methods:

• Development of a combined lipolysis-permeation assay in a 96-well microtiter plate format.
• Utilized a highly buffered medium to eliminate the need for pH stabilization, enhancing efficiency.
• Evaluated cinnarizine-loaded Type I LBFs, assessing supersaturation, lipase inhibition, lipid chain length, and amphiphilic polymer effects, comparing results with in vivo rat bioavailability data.

Main Results:

• The HTS method accurately predicted the in vivo impact of supersaturation and lipase inhibition, unlike the pH-stat method which showed discrepancies.
• Neither method perfectly predicted effects of lipid chain length or precipitation inhibitors, though HTS showed better prediction for long-chain systems.
• The HTS assay demonstrated excellent in vitro-in vivo correlation (IVIVC) up to 0.91 for Type I LBFs and correctly captured the performance of supersaturated formulations.

Conclusions:

• The developed HTS lipolysis-permeation method is a promising, efficient alternative to the pH-stat approach for predicting the in vivo performance of Type I LBFs.
• This HTS assay offers significant advantages in terms of speed, material usage, and improved predictivity, particularly for supersaturated formulations.
• The method's ability to differentiate drug fractions and its high IVIVC support its utility in formulation development and drug release testing.