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Pre-referral intranasal artesunate powder for cerebral malaria: a proof-of-concept study
Yobouet Ines Kouakou1,2, Aurelien Millet3, Elodie Fromentin4
1Univ Lyon, Malaria Research Unit, SMITh, ICBMS, UMR 5246 CNRS-INSA-CPE-University Lyon1, 69622, Villeurbanne, France.
Insights
Intranasal artesunate powder offers a promising alternative for malaria pre-referral treatment, demonstrating efficient nasal mucosa permeation and potential for rapid nose-to-brain and systemic delivery.
Area of Science:
- Pharmacology
- Drug Delivery
- Tropical Medicine
Background:
- Malaria remains a significant threat to young children in endemic areas due to delayed treatment.
- Current World Health Organization recommendations include artesunate suppositories for pre-referral treatment when parenteral or oral options are unavailable.
- Limitations such as negative cultural perceptions of rectal administration and supply issues necessitate alternative routes for malaria pre-referral treatment.
Purpose of the Study:
- To evaluate the potential of the intranasal route for artesunate administration as a malaria pre-referral treatment.
- To assess artesunate permeability through human nasal mucosa in vitro.
- To investigate the deposition and delivery of intranasal artesunate using a unidose device.
Main Methods:
- In vitro permeability studies of artesunate across human nasal mucosa, monitoring Transepithelial Electrical Resistance (TEER).
- Assessment of regional artesunate powder deposition in a nasal cast using a unidose drug delivery device.
- Quantification of artesunate using Liquid Chromatography coupled to tandem Mass Spectrometry (LC-MS/MS).
Main Results:
- Artesunate powder exhibited significantly higher permeation rates (26.8%) through nasal mucosa compared to solution (2.1%).
- Over 60% of the sprayed artesunate dose was recovered in the olfactory and turbinate regions of the nasal cast.
- These findings indicate potential for both nose-to-brain and systemic drug diffusion via the intranasal route.
Conclusions:
- Artesunate powder demonstrates efficient permeation and deposition within the nasal cavity.
- The intranasal route, facilitated by a unidose device, allows for rapid nose-to-brain and systemic delivery of artesunate.
- These results provide proof-of-concept for intranasal artesunate as a viable malaria pre-referral treatment option.
Background:
Malaria still kills young children in rural endemic areas because early treatment is not available. Thus, the World Health Organization recommends the administration of artesunate suppositories as pre-referral treatment before transportation to the hospital in case of severe symptoms with an unavailable parenteral and oral treatment. However, negative cultural perception of the rectal route, and limited access to artesunate suppositories, could limit the use of artesunate suppositories. There is, therefore, a need for an alternative route for malaria pre-referral treatment. The aim of this study was to assess the potential of intranasal route for malaria pre-referral treatment.
Methods:
The permeability of artesunate through human nasal mucosa was tested in vitro. The Transepithelial Electrical Resistance (TEER) of the nasal mucosa was followed during the permeation tests. Beside, regional deposition of artesunate powder was assessed with an unidose drug delivery device in each nostril of a nasal cast. Artesunate quantification was performed using Liquid Chromatography coupled to tandem Mass Spectrometry.
Results:
The experimental model of human nasal mucosa was successfully implemented. Using this model, artesunate powder showed a much better passage rate through human nasal mucosa than solution (26.8 ± 6.6% versus 2.1 ± 0.3%). More than half (62.3%) of the artesunate dose sprayed in the nostrils of the nasal cast was recovered in the olfactory areas (44.7 ± 8.6%) and turbinates (17.6 ± 3.3%) allowing nose-to-brain and systemic drug diffusion, respectively.
Conclusion:
Artesunate powder showed a good permeation efficiency on human nasal mucosa. Moreover it can be efficiently sprayed in the nostrils using unidose device to reach the olfactory area leading to a fast nose-to-brain delivery as well as a systemic effect. Taken together, those results are part of the proof-of-concept for the use of intranasal artesunate as a malaria pre-referral treatment.
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