Development of fenfluramine in albumin nanoparticles for nasal administration

Introduction and Objective
Fenfluramine (FF) is used orally to treat drug-resistant forms of epilepsy in children. Norfenfluramine (NFF), its main metabolite, has significant cardiovascular toxicity, which led to the withdrawal of FF from the market in 1997.
Nasal administration (NA) of drugs renewed interest as it enhances brain bioavailability by promoting drug absorption through the olfactory and trigeminal nerves while minimizing plasma absorption.
Our hypothesis is that encapsulating FF in albumin nanoparticles (ANP) would protect FF from local metabolism into NFF and improve FF delivery to the brain.
Objective: to develop an innovative formulation of FF encapsulated in ANP for NA.

Methods
NA requires a very low administered volume, which means a concentrated formulation. To overcome mucociliary clearance and prolong residence time in the nasal cavity, a gelling agent or mucoadhesive is included in the formulation. Since nasal mucus forms pores of approximately 150 nm, the albumin nanoparticles (ANPs) must be smaller to allow them to pass through.
The formulation developed, which complies with the European Pharmacopoeia, consists of FF-loaded ANP dispersed in an aqueous solution of pectin, a mucoadhesive.
The ANP generated by desolvation in ethanol and then cross-linking with 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide are analyzed by Dynamic Light Scattering to determine their size. Centrifugation on a 100 kDa pore filter concentrates the preparation and removes free FF and ethanol.
The stability of the FF-ANP bond is studied by quantifying the FF released from the formulation through a dialysis membrane permeable only to FF, at 37°C and under agitation.
In vitro tolerance is studied using a Lactate Deshydrogénase (LDH) necrosis test.

Results
The size of the ANP obtained is 107 to 135 nm.
Following formulation, 100% of the FF is bound to the ANP. After adding of pectin, the final FF concentration is 10 mg/mL.
After 3 hours, 18.6 ± 3.6% of FF is released.
In contrast to FF in solution, the developed formulation did not cause any cell necrosis.

Conclusion and Discussion
The size of the ANP is suitable for passing through the nasal mucus.
The concentration of the formulation is sufficient for therapeutic application at effective dosages.
The low percentage of FF released after 3 hours suggests sufficient stability of the FF-ANP bond and that the majority of the absorbed FF will be in encapsulated form.
The results suggest that encapsulation of FF protects against its local toxicity.
Further studies, including in vitro membrane permeability assays, will be performed to confirm the formulation. Following completion of the stability study, in vivo evaluation of the formulation’s toxicity and pharmacokinetics of FF and NFF after NA will be carried out in mice.