Design and stability study of oral capsules and suspension of riboflavin for the treatment of metabolic disease

P.Gohier1, B. Dessane1,2, J-M. Bernadou1, H. Boulestreau2, F. Xuereb1,4, A. Venet1, S. Crauste-Manciet1,3
1 Pharmaceutical Technology Department, Bordeaux university hospital (CHU de Bordeaux), France
2 Infection Control Unit, Bordeaux university hospital (CHU de Bordeaux), France
3 ARNA ChemBioPharm U1212 INSERM – UMR 5320 CNRS, Bordeaux University, France
4 Univ. Bordeaux, INSERM, Biologie des maladies cardiovasculaires, U1034, F-33600 Pessac, France

Objective
Riboflavin, or vitamin B2, is one of the recommended treatments for metabolic diseases. Riboflavin is a long-term treatment started in the childhood, which requires dose adjustments. Beflavine® (tablets of riboflavin at 10mg) was recommended for vitamin B2 carency but is no longer marketed. The objective of this study was to develop an oral suspension and capsules of riboflavin to fulfill the lack of treatment.

Material/Methods
In first place, we studied different vehicles to determine the most adequate for the formulation of the drinkable form and for its use in pediatric. Then we developed an extemporaneous 10 mg/mL riboflavin suspension in InOrpha® (vehicle for oral use) for pediatric use and capsules at 50 mg for adult patients. A high-performance ion-pair chromatography stability-indicating method was developed and validated in accordance with Q2 ICH guidelines. Capsules were stored at room temperature protected from light (20-25°C) and its concentrations were evaluated at different intervals during six months (J0, J3, J7, J14, J28, J56, J84, M6). The liquid formulation was stored at refrigerate (2-8°C) and room temperature (20-25°C). Concentration and physical parameters (pH and osmolality) of the suspension were determined for three months (J0, J3, J7, J14, J28, J56, J84). The microbiological quality of the suspension was performed according to European Pharmacopoeia monographs 2.6.12 and 5.1.4 for microbiological examination of non-sterile products using the surface-spread method and assessed for three months (J0, J14, J28, J56, J84).

Results- Discussion
Riboflavin concentration remained above 95% of the initial concentration (10.10 ± 0.11 mg at day 90 for suspension and 48,56 ± 0,72 mg at 6 months for the capsules). Organoleptic parameters, pH and osmolality of the suspension remained stable during the study and throughout storage (maximum variation of ± 4.61% and ± 1.27% for osmolality and pH respectively). Moreover, the suspension fulfilled the Pharmacopoeia specifications for microbiological contaminations (< 102 total aerobic microbial counts, < 101 total yeast and mold counts and 0 Escherichia coli).

Conclusion
Our study demonstrated the physico-chemical stability of riboflavin capsules at 50mg and suspension at 10 mg/ml. Microbiological stability of the suspension was demonstrated. This suspension and these capsules allow us to offer a treatment for both pediatric and adult patients with appropriate formulation and ensure the continuity of treatment after the end of the commercialization of Beflavine®.

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