Formulation and Scale-Up of Fast-Dissolving Lumefantrine Nanoparticles for Oral Malaria Therapy

Madeleine Armstrong, Leon Wang, Kurt Ristroph, Chang Tian, Jiankai Yang, Lirong Ma, Santipharp Panmai, Donglu Zhang, Karthik Nagapudi, Robert K. Prud'homme

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

Abstract

Lumefantrine (LMN) is one of the first-line drugs in the treatment of malaria due to its long circulation half-life, which results in enhanced effectiveness against drug-resistant strains of malaria. However, LMN's therapeutic efficacy is diminished due to its low bioavailability when dosed as a crystalline solid. The goal of this work was to produce low-cost, highly bioavailable, stable LMN powders for oral delivery that would be suitable for global health applications. We report the development of a LMN nanoparticle formulation and the translation of that formulation from laboratory to industrial scale. We applied Flash NanoPrecipitation (FNP) to develop nanoparticles with 90% LMN loading and sizes of 200-260 nm. The integrated process involves nanoparticle formation, concentration by tangential flow ultrafiltration, and then spray drying to obtain a dry powder. The final powders are readily redispersible and stable over accelerated aging conditions (50°C, 75% RH, open vial) for at least 4 weeks and give equivalent and fast drug release kinetics in both simulated fed and fasted state intestinal fluids, making them suitable for pediatric administration. The nanoparticle-based formulations increase the bioavailability of LMN 4.8-fold in vivo when compared to the control crystalline LMN. We describe the translation of the laboratory-scale process at Princeton University to the clinical manufacturing scale at WuXi AppTec.

Original languageEnglish (US)
Pages (from-to)2267-2275
Number of pages9
JournalJournal of Pharmaceutical Sciences
Volume112
Issue number8
DOIs
StatePublished - Aug 2023

All Science Journal Classification (ASJC) codes

  • Pharmaceutical Science

Keywords

  • Dissolution kinetics
  • Flash NanoPrecipitation
  • HPMCAS
  • Lumefantrine
  • Malaria
  • Nanocarrier
  • Nanoparticle
  • PK
  • Scaleup
  • Spray drying

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