Orphan Formulations for Pediatric Use: Development and Stability Control of Two Sildenafil Citrate Solutions for the Tre
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Research Article Orphan Formulations for Pediatric Use: Development and Stability Control of Two Sildenafil Citrate Solutions for the Treatment of Pulmonary Hypertension Mauro Morri,1 Cecilia Casabonne,2 Darío Leonardi,3,4,6 and Silvana Vignaduzzo4,5,6
Received 1 May 2020; accepted 21 July 2020 Abstract. Sildenafil citrate causes vasodilatation, relaxation of the smooth muscle, and reduction of pulmonary arterial pressure. The latter property makes sildenafil citrate efficient for the treatment of cardiovascular diseases, including pulmonary arterial hypertension. Pediatric patients with pulmonary arterial hypertension are more susceptible to errors in drug administration than adults because of a lack of suitable drug dosages. Thus, the purpose of this study was to develop stable (chemically and microbiologically) sildenafil citrate drop liquid formulation, suitable for pediatric patients (including diabetics), ensuring safety during preparation and storing and improving palatability by using milk as a carrier for administration. The significant factors that affect the sildenafil solubility were evaluated by applying a Plackett-Burman design using two levels with six variables. The experiment showed that the type of buffer and glycerin content influenced the sildenafil solubility. The developed formulations proved to be stable for 6 months at all three assayed conditions (40± 2°C, 75 ± 5% RH; 25± 2°C, 60 ± 5% RH; and 4 ± 2°C). The microbiological tests fit with the requirement of the pharmacopeia at day 0 and 90 and even more at day 180. Finally, the palatability assay showed that 0.82 mL of the formulation containing buffer phosphate, 20% glycerin, and 4 mg mL−1 of sildenafil citrate diluted in 4.8 mL milk (which fits the medium pediatric dose) presented similar palatability to milk alone, and no precipitate or turbidity was observed. KEY WORDS: sildenafil citrate; pediatric patients; Plackett-Burman; drops liquid formulation; stability.
INTRODUCTION Sildenafil citrate is widely used in the treatment of erectile dysfunction. This drug causes vasodilatation, relaxation of the smooth muscle, and reduction of pulmonary arterial pressure. The latter property makes sildenafil citrate also able to treat cardiovascular diseases, such as pulmonary arterial hypertension (1–3). Such disease manifests as an 1
Planta piloto de Producción de Medicamentos, Facultad de Ciencias Bioquímicas y Farmacéuticas, Universidad Nacional de Rosario, Suipacha 531, S2002LRK, Rosario, Argentina. 2 Área de Bacteriología. Facultad de Ciencias Bioquímicas y Farmacéuticas, Universidad Nacional de Rosario, Suipacha 531, S2002LRK, Rosario, Argentina. 3 Área Técnica Farmacéutica, Departamento Farmacia, Facultad de Ciencias Bioquímicas y Farmacéuticas, Universidad Nacional de Rosario, Suipacha 531, S2002LRK, Rosario, Argentina. 4 IQUIR-CONICET, Suipacha 570, S2002LRK, Rosario, Argentina. 5 Área Análisis de Medicamentos, Departamento Química Orgánica, Facultad de Ciencias Bioquímicas y Farmacéuticas, Universidad Nacional de Rosario, Suipacha 531, S2002LRK, Rosar
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