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<p>Optimization of lipid-based formulations (LBF) for moderately lipophilic neutral drugs is often challenging. The low drug loading and precipitation of supersaturated state of drug after digestion and dispersion warrants attention. Herein, we attempted supersaturated LBF of olaparib (OLA) and evaluated them for lipid composition, thermal-induced supersaturation, and precipitation inhibition and its impact on biopharmaceutical performance. Conventional and supersaturated type II and type III LBFs were developed using medium-chain (MCT) lipid excipients, with and without polymeric precipitation inhibitor (PI). Formulations were characterized in terms of solubility, supersaturation stability, colloidal properties, in vitro lipolysis, permeability, and in vivo pharmacokinetics in rats. Thermal processing significantly increased drug loading in all systems, achieving two-fold increase in the apparent degrees of supersaturation. MCT based LBFs exhibited superior solubilization capacity compared to long-chain systems. Among the screened PIs, PVP-VA most effectively stabilized the supersaturated state of OLA by delaying the precipitation and hence sustain higher aqueous drug concentrations. Type III LBFs demonstrated enhanced dispersion, smaller droplet sizes, and higher negative zeta potentials, translating to higher in vitro permeability and in vivo exposure relative to Type II systems. This work establishes mechanistic relationships between lipid composition, supersaturation stabilization, and oral drug absorption in the development of LBFs of moderately lipophilic neutral drugs.</p>

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Supersaturated Lipid-Based Formulations of Moderately Lipophilic Neutral Drug: Impact of Formulation type, Colloidal Behaviour and Precipitation Inhibition on In Vitro-In Vivo Performance

  • 期刊论文

  • 发表日期：

    2026年3月23日

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  • Kajal Guleria,
  • Shubham Debaje,
  • Abhay T. Sangamwar

摘要

Optimization of lipid-based formulations (LBF) for moderately lipophilic neutral drugs is often challenging. The low drug loading and precipitation of supersaturated state of drug after digestion and dispersion warrants attention. Herein, we attempted supersaturated LBF of olaparib (OLA) and evaluated them for lipid composition, thermal-induced supersaturation, and precipitation inhibition and its impact on biopharmaceutical performance. Conventional and supersaturated type II and type III LBFs were developed using medium-chain (MCT) lipid excipients, with and without polymeric precipitation inhibitor (PI). Formulations were characterized in terms of solubility, supersaturation stability, colloidal properties, in vitro lipolysis, permeability, and in vivo pharmacokinetics in rats. Thermal processing significantly increased drug loading in all systems, achieving two-fold increase in the apparent degrees of supersaturation. MCT based LBFs exhibited superior solubilization capacity compared to long-chain systems. Among the screened PIs, PVP-VA most effectively stabilized the supersaturated state of OLA by delaying the precipitation and hence sustain higher aqueous drug concentrations. Type III LBFs demonstrated enhanced dispersion, smaller droplet sizes, and higher negative zeta potentials, translating to higher in vitro permeability and in vivo exposure relative to Type II systems. This work establishes mechanistic relationships between lipid composition, supersaturation stabilization, and oral drug absorption in the development of LBFs of moderately lipophilic neutral drugs.