Stability of high concentrated triple intrathecal therapy for pediatrics and mitigation strategies

Stringent formulation requirements are defined to intrathecally administer drug substances, avoiding neurological complications. In case of pediatric patients, these are further complicated due to the limited volumes of the celebrospinal fluid and, therefore, high concentrated solutions of methotrexate (MTX), cytarabine and corticosteroids (i.e., methylprednisolone or hydrocortisone) are prepared based on the patient's age. This work aims to assess the chemical and physical stability of triple intrathecal mixtures differing in volume and compositions by a bracketing approach and to identify possible stress causes and mitigation strategies. Low solubility of MTX was the main factor limiting the physical stability of triple mixtures. Regarding solutions containing methylprednisolone, the amount of MTX remaining was about 95% in the solution at highest concentrations with the concomitant formation of a visible particulate sizing bigger than 1 µm after 24 h of storage at 25°C. This behavior was mainly driven the pH reduction induced by the pH value of the cytarabine solution used; the shear stress also caused the drug precipitation. In case of the hydrocortisone based mixtures, the formation of a precipitate occurred at a slow rate. To improve the physical stability, a better control of the mixture pH (optimal value ≈ 7) is required or the addition of the cytarabine solution to a pre-mixed binary mixture containing MTX and a corticosteroid should be preferred.