Development of vinorelbine oral formulations for pediatric use

5 October 2022

L. Macqueron, L. Regnier, P. Robinet, A-L. Leroy, M-A. Lester, P-N. Boivin, P. Le Corre
Centre Hospitalier Universitaire de Rennes, France

Vinorelbine is used for maintenance treatment in pediatric patients with high-risk rhabdomyosarcoma. Only an intravenous solution and soft capsules are available. The intravenous route requires a day hospitalization and soft capsules are not suitable for children and do not allow precise dosage adjustment.
This study aimed to develop two vinorelbine oral formulations, in order to make dosage adjustments easier and use in the outpatient pediatric population possible. A stability indicating method was developed to lead stability studies and to determine the shelf life of each formulation.

Two formulations were prepared: a vinorelbine oral solution with Inorpha®, and an oral suspension with Syrspend® SF PH4 liquid, both at 10 mg/mL.
A HPLC-DAD method was developed, validated, and used for analysis. Forced degradation studies (acid and basic hydrolysis, oxidation, and heat stress) of vinorelbine were performed to observe potential degradation products.
To evaluate chemical and physical stability, one batch of each formulation was prepared, packaged in three amber glass vials (type 1), and stored between +2 °C and +8 °C. Several parameters, like visual aspect, vinorelbine concentration, pH, and osmolality, were assessed throughout the study period (56 days).

The chromatographic method showed well-separated degradation products of vinorelbine. The method was validated following International Council for Harmonisation (ICH) guidelines.
The vinorelbine concentration remained above 95 % of the initial one in both formulations (99.5 < CD56 < 100.6 % with Inorpha® and 98.6 < CD56 < 100.9 % with Syrspend® SF PH4 liquid). The pH (4.0 at D0 with Inorpha®and 3.8 with Syrspend® SF PH4 liquid) and the osmolality (201 mosmol/kg at D0 with Inorpha® and 78 mosmol/kg with liquid Syrspend® SF PH4) were also constant during the whole studies. The visual aspect stayed unchanged for both formulations.

A vinorelbine oral formulation can be compounded with the liquid vehicle Inorpha® or with the Syrspend® SF PH4 liquid and stored for 56 days between +2 °C and +8 °C away from light, allowing easier administration for young children.

Key words
Rhabdomyosarcoma, vinorelbine, oral formulation, stability study

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