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Purpose <p>To integrate preclinical dose justification with Quality-by-Design (QbD)–guided formulation development of a colon-targeted nanoparticle system for the novel anti-colorectal cancer candidate NCE-14a.</p> Methods <p>Acute toxicity (LD₅₀) and efficacy (ED₅₀) were established in BALB/c mice to define a rational dose window. PLGA/Eudragit<sup>®</sup> RS PO nanoparticles were developed using a three-factor Box–Behnken design, with particle size and controlled release as critical quality attributes (CQAs). The optimized formulation was enteric-coated with Eudragit<sup>®</sup> S100 and evaluated for physicochemical properties, solid-state characteristics, and pH-transition release behavior.</p> Results <p>The LD₅₀ (19.3&#xa0;mg/kg) and ED₅₀ (2&#xa0;mg/kg) established a favorable preclinical safety margin. The validated quadratic model (R² &gt; 0.98) defined a robust design space governing particle size and release kinetics. The optimized nanoparticles (~ 230&#xa0;nm, + 28 mV, &gt; 98% encapsulation) demonstrated minimal release in gastric and intestinal conditions followed by sustained colonic release (~ 90–95% at 22&#xa0;h).</p> Conclusion <p>This work establishes an integrated, QbD-driven pharmaceutical development strategy linking dose justification with colon-targeted nanoparticle design, providing a reproducible translational framework for formulation of novel NCEs.</p> Graphical Abstract <p></p>

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QbD Optimized Colon Targeted PLGA Nanoparticles of NCE-14a: Integrating Preclinical Dose Justification with Formulation Design

  • 期刊论文

  • 发表日期：

    2026年4月28日

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  • V V Siva Krishna Pushadapu,
  • Grandhi Srikar

摘要

Purpose

To integrate preclinical dose justification with Quality-by-Design (QbD)–guided formulation development of a colon-targeted nanoparticle system for the novel anti-colorectal cancer candidate NCE-14a.

Methods

Acute toxicity (LD₅₀) and efficacy (ED₅₀) were established in BALB/c mice to define a rational dose window. PLGA/Eudragit® RS PO nanoparticles were developed using a three-factor Box–Behnken design, with particle size and controlled release as critical quality attributes (CQAs). The optimized formulation was enteric-coated with Eudragit® S100 and evaluated for physicochemical properties, solid-state characteristics, and pH-transition release behavior.

Results

The LD₅₀ (19.3 mg/kg) and ED₅₀ (2 mg/kg) established a favorable preclinical safety margin. The validated quadratic model (R² > 0.98) defined a robust design space governing particle size and release kinetics. The optimized nanoparticles (~ 230 nm, + 28 mV, > 98% encapsulation) demonstrated minimal release in gastric and intestinal conditions followed by sustained colonic release (~ 90–95% at 22 h).

Conclusion

This work establishes an integrated, QbD-driven pharmaceutical development strategy linking dose justification with colon-targeted nanoparticle design, providing a reproducible translational framework for formulation of novel NCEs.

Graphical Abstract