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Background <p>Invasive fungal infections (IFIs) caused by Candida, Aspergillus, and Cryptococcus species are a major cause of morbidity and mortality in immunocompromised hosts, further complicated by the relative ineffectiveness of the existing antifungal treatments. Posaconazole (PSZ), a broad-spectrum triazole antifungal agent, is hindered by its designation under the Biopharmaceutics Classification System (BCS) Class II, having low water solubility (&lt; 1 µg/mL) and fluctuating oral bioavailability (8-47%) resulting in erratic therapeutic activity. Conventional PSZ formulations like oral suspensions and delayed-release tablets suffer from food-dependent absorption, decreased systemic exposure, and process complexity. Further, current nanocarrier systems lack Quality by Design (QbD)-guided optimization for oral delivery. </p> Objective <p>The aim of this investigation was to develop polymeric micelles based on the concepts of QbD employing polyvinyl caprolactam–polyvinyl acetate–polyethylene glycol graft copolymer (Soluplus®) and D-α-Tocopheryl polyethylene glycol 1000 succinate (TPGS) as aids to enhance the solubility, systemic bioavailability, and antifungal efficacy of PSZ against IFIs. </p> Methods and Results <p>PSZ-loaded micelles were prepared using thin-film hydration method and optimized using Design of Experiments (DoE) strategy to establish critical quality attributes: critical micelle concentration (~ 7.6 µg/mL), particle size 176.5 ± 3.49 nm, polydispersity index 0.323 ± 0.01, zeta potential -9.37 ± 0.28 mV, and encapsulation efficiency 91.11 ± 0.85%. In vitro experiments exhibited 10-fold increase in solubility of PSZ and prolonged drug release for 24 h (80.21 ± 5.89%). Antifungal susceptibility testing revealed a two-fold decrease in MIC against Candida albicans compared to free PSZ. Pharmacokinetic studies in Male Albino Wistar rats showed a ⁓2-fold increase in Cmax, area under the curve (AUC) and area under the first moment curve (AUMC) which proved enhanced systemic exposure. </p> Conclusion <p>The results validate the QbD-optimized Soluplus® and TPGS micelles as an effective, scalable, and drug-compatible nanocarrier system that enhances PSZ oral delivery for the treatment of IFIs.</p> Graphical Abstract <p></p>

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Quality by Design (QbD)-Improved Polymeric Micelles of Posaconazole with Increased Solubility, Oral Bioavailability, and Antifungal Activity against Invasive Fungal Infections

  • 期刊论文

  • 发表日期：

    2026年1月14日

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  • Sakshi Gadewar,
  • Preeti Sangave,
  • Suprit Saoji,
  • Kasi Viswanadh Matte,
  • Chakravarthy Guntupalli,
  • Ketan Hatware,
  • Datta Maroti Pawde

摘要

Background

Invasive fungal infections (IFIs) caused by Candida, Aspergillus, and Cryptococcus species are a major cause of morbidity and mortality in immunocompromised hosts, further complicated by the relative ineffectiveness of the existing antifungal treatments. Posaconazole (PSZ), a broad-spectrum triazole antifungal agent, is hindered by its designation under the Biopharmaceutics Classification System (BCS) Class II, having low water solubility (< 1 µg/mL) and fluctuating oral bioavailability (8-47%) resulting in erratic therapeutic activity. Conventional PSZ formulations like oral suspensions and delayed-release tablets suffer from food-dependent absorption, decreased systemic exposure, and process complexity. Further, current nanocarrier systems lack Quality by Design (QbD)-guided optimization for oral delivery.

Objective

The aim of this investigation was to develop polymeric micelles based on the concepts of QbD employing polyvinyl caprolactam–polyvinyl acetate–polyethylene glycol graft copolymer (Soluplus®) and D-α-Tocopheryl polyethylene glycol 1000 succinate (TPGS) as aids to enhance the solubility, systemic bioavailability, and antifungal efficacy of PSZ against IFIs.

Methods and Results

PSZ-loaded micelles were prepared using thin-film hydration method and optimized using Design of Experiments (DoE) strategy to establish critical quality attributes: critical micelle concentration (~ 7.6 µg/mL), particle size 176.5 ± 3.49 nm, polydispersity index 0.323 ± 0.01, zeta potential -9.37 ± 0.28 mV, and encapsulation efficiency 91.11 ± 0.85%. In vitro experiments exhibited 10-fold increase in solubility of PSZ and prolonged drug release for 24 h (80.21 ± 5.89%). Antifungal susceptibility testing revealed a two-fold decrease in MIC against Candida albicans compared to free PSZ. Pharmacokinetic studies in Male Albino Wistar rats showed a ⁓2-fold increase in Cmax, area under the curve (AUC) and area under the first moment curve (AUMC) which proved enhanced systemic exposure.

Conclusion

The results validate the QbD-optimized Soluplus® and TPGS micelles as an effective, scalable, and drug-compatible nanocarrier system that enhances PSZ oral delivery for the treatment of IFIs.

Graphical Abstract