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Orphan Formulations for Pediatric Use: Development and Stability Control of Two Sildenafil Citrate Solutions for the
Mauro Morri1, Cecilia Casabonne2, Darío Leonardi3,4
1Planta piloto de Producción de Medicamentos, Facultad de Ciencias Bioquímicas y Farmacéuticas, Universidad Nacional de Rosario, Suipacha 531, S2002LRK, Rosario, Argentina.
Insights
A stable sildenafil citrate liquid formulation was developed for pediatric pulmonary arterial hypertension patients. This new formulation ensures safety, stability, and improved palatability using milk as a carrier.
Area of Science:
- Pharmaceutical Sciences
- Pediatric Pharmacology
- Cardiovascular Research
Background:
- Sildenafil citrate is effective for cardiovascular diseases like pulmonary arterial hypertension due to its vasodilatory properties.
- Pediatric patients require specific drug formulations due to dosage sensitivities and lack of suitable options.
- Existing sildenafil citrate formulations may not be optimal for pediatric use, particularly regarding accurate dosing and palatability.
Purpose of the Study:
- To develop a stable, safe, and palatable liquid sildenafil citrate formulation for pediatric patients, including those with diabetes.
- To ensure chemical and microbiological stability for extended storage periods.
- To enhance ease of administration and improve patient compliance through palatability.
Main Methods:
- Utilized a Plackett-Burman design to identify significant factors affecting sildenafil citrate solubility.
- Evaluated chemical and microbiological stability under various storage conditions (temperature and humidity) for six months.
- Conducted palatability assays comparing the formulation diluted in milk to milk alone.
Main Results:
- Buffer type and glycerin content were identified as key factors influencing sildenafil citrate solubility.
- The developed liquid formulation demonstrated stability for six months across tested conditions (40°C, 25°C, and 4°C).
- Microbiological tests met pharmacopeial requirements at 0, 90, and 180 days; palatability was comparable to milk alone.
Conclusions:
- A stable, palatable sildenafil citrate liquid formulation suitable for pediatric use, including diabetics, has been successfully developed.
- The formulation ensures safety and stability, addressing critical needs in pediatric pulmonary arterial hypertension management.
- Milk as a carrier significantly improved palatability, facilitating administration of a medium pediatric dose.
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. Graphical abstract.
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