Formulation of a new paediatric phenobarbital oral solution
1 Faculty of Pharmacy of Paris, Paris, France
2 Faculty of Pharmacy Paris-Saclay, Châtenay-Malabry, France
3 Pharmacy, Armand Trousseau Hospital, APHP, Paris, France
Phenobarbital (PB) is a barbiturate, used to treat focal and generalized epilepsies. Since the end of commercialization of KANEURON® 5.4%, in 2017, PB tablets remain the only available dosage form. Development of an oral PB solution for paediatric use is therefore essential to fill the clinician needs.
To develop a new formulation of PB (sensitive to alkaline pH, insoluble in water and bitter active pharmaceutical ingredient (API)), suitable for paediatric population and to carry out a stability study.
Material & Method
The PB oral solution is composed of 600 mg of PB, 4.8 g of hydroxypropyl-β-cyclodextrins (KLEPTOSE®), 120 mg of potassium sorbate (preservative), 2.25 g of sucralose (sweetener), 19.8 mL of pH 5 buffer (1.96 g of citric acid monohydrate + 7.06 g of sodium citrate dihydrate + water for injection qs 100 mL) and water for injection (qs 60 mL).
Physico-chemical stability was studied on weeks W1, W2, W3, W4, W6, W8. Samples were stored at room temperature (n = 3) and at 5°C ± 3°C (n = 3). Content of API, pH, osmolality, and degradation products were followed up.
The assay method was previously validated: HPLC-method, thermostatically controlled at 25°C C18 column, mobile phase consisting of NaH2PO4 buffer at pH 3 and methanol (proportions 50:50 v/v), wavelength set at 216 nm + scan 190 to 400 nm.
According to ICH, formulation is stable if content of API is > 95% and if degradation products is < 0.2% for a daily dose between 10 mg and 2 g.
The formulation is currently stable (at 2 months), regarding pH monitoring checks (average of 5.334 ± 0.059 at room temperature and 5.315 ± 0.094 at 5°C ± 3°C), data on osmolality (average of 448.4 ± 3.4 mOsm/kg H2O at room temperature and 447.9 ± 3.3 mOsm/kg H2O at 5°C ± 3°C), API content (loss of content of 0.99% at 2 months at room temperature and 0.60% at 5°C ± 3°C). No PB degradation product (> 0.01%) was observed in the chromatograms for solutions throughout the 2 months.
Hydroxypropyl-β-cyclodextrins contribute to solubilize PB and create a homogeneous solution. Sucralose masks the bitterness of PB.
Stability study will be continued until 6 months. First results are compatible with a use of the oral solution at hospital. However, a microbiological study should be carried out soon.