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<p>The formulation and manufacture of macromolecules for oral delivery present persistent challenges owing to high molecular weight, pH sensitivity and manufacturing complexity. Consequently, over 90% of FDA-approved biologics are administered by invasive methods. Buccal delivery offers a promising non-invasive alternative, as it bypasses first-pass metabolism, avoids gastrointestinal degradation, and can improve patient compliance. Here we evaluate isothermal dry particle coating (iDPC) as a scalable, solvent-free approach to enhance buccal permeation by forming ion-pair coatings on drug particles. In iDPC, centrifugal and gas-drag forces promote systematic collisions between host and guest particles, here vancomycin and L-glutamic acid, yielding uniform surface coverage that facilitates buccal permeation. This study utilised a Design of Experiments (DoE) methodology within a Quality by Design (QbD) framework to optimise iDPC processing for vancomycin, a Biopharmaceutics Classification System (BCS) Class III glycopeptide with poor oral bioavailability. A Central Composite Face (CCF) design was utilised to investigate the interactive effects of five critical process parameters (CPPs): pre-processing time, processing time, nitrogen flow rate, drum speed and amino acid concentration, on two critical quality attributes (CQAs): content uniformity and 60-minute permeation across TR146 buccal epithelium. Regression modelling identified that increases in L-glutamic acid concentration and drum speed were the key factors enhancing permeation, while processing time and drum speed were the key variables improving content uniformity. A predictive 4D design space identified operating regions with a high probability of simultaneously meeting prespecified targets (permeation ≥ 40% and RSD ≤ 5%). The models demonstrated strong fit (R<sup>2</sup> = 0.767 for permeation; 0.774 for content uniformity), with non-significant lack-of-fit, and performance improved markedly, with content uniformity ranging from 0.93 to 6.29% RSD and permeation increasing from 36% to 60% under optimised conditions. Mechanistic analysis indicated that drag from the nitrogen curtain impacted the fluidisation of cohesive L-glutamic acid fine particles, while total energy input promoted deagglomeration and dispersion, thereby improving uniformity. These findings demonstrate that iDPC is a robust manufacturing approach for buccal delivery of biologics, providing controlled particle level modification without the use of solvents. The QbD-driven DoE establishes clear links between CPPs and CQAs, supports the development of control strategies, and provides a basis for regulatory flexibility in the non-invasive delivery of large molecule therapeutics.</p>

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Quality by design optimisation of isothermal dry particle coating for enhanced buccal permeation of vancomycin

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年11月25日

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  • Anthony Rajabi,
  • Affiong Iyire,
  • David Wyatt,
  • Jasdip Koner,
  • Afzal R. Mohammed

摘要

The formulation and manufacture of macromolecules for oral delivery present persistent challenges owing to high molecular weight, pH sensitivity and manufacturing complexity. Consequently, over 90% of FDA-approved biologics are administered by invasive methods. Buccal delivery offers a promising non-invasive alternative, as it bypasses first-pass metabolism, avoids gastrointestinal degradation, and can improve patient compliance. Here we evaluate isothermal dry particle coating (iDPC) as a scalable, solvent-free approach to enhance buccal permeation by forming ion-pair coatings on drug particles. In iDPC, centrifugal and gas-drag forces promote systematic collisions between host and guest particles, here vancomycin and L-glutamic acid, yielding uniform surface coverage that facilitates buccal permeation. This study utilised a Design of Experiments (DoE) methodology within a Quality by Design (QbD) framework to optimise iDPC processing for vancomycin, a Biopharmaceutics Classification System (BCS) Class III glycopeptide with poor oral bioavailability. A Central Composite Face (CCF) design was utilised to investigate the interactive effects of five critical process parameters (CPPs): pre-processing time, processing time, nitrogen flow rate, drum speed and amino acid concentration, on two critical quality attributes (CQAs): content uniformity and 60-minute permeation across TR146 buccal epithelium. Regression modelling identified that increases in L-glutamic acid concentration and drum speed were the key factors enhancing permeation, while processing time and drum speed were the key variables improving content uniformity. A predictive 4D design space identified operating regions with a high probability of simultaneously meeting prespecified targets (permeation ≥ 40% and RSD ≤ 5%). The models demonstrated strong fit (R2 = 0.767 for permeation; 0.774 for content uniformity), with non-significant lack-of-fit, and performance improved markedly, with content uniformity ranging from 0.93 to 6.29% RSD and permeation increasing from 36% to 60% under optimised conditions. Mechanistic analysis indicated that drag from the nitrogen curtain impacted the fluidisation of cohesive L-glutamic acid fine particles, while total energy input promoted deagglomeration and dispersion, thereby improving uniformity. These findings demonstrate that iDPC is a robust manufacturing approach for buccal delivery of biologics, providing controlled particle level modification without the use of solvents. The QbD-driven DoE establishes clear links between CPPs and CQAs, supports the development of control strategies, and provides a basis for regulatory flexibility in the non-invasive delivery of large molecule therapeutics.