Development of a stable oral pediatric solution of hydrochlorothiazide by the combined use of cyclodextrins and hydrophilic polymers

Hydrochlorothiazide (HCT) is widely used in pediatrics for hypertension management. Due to the lack of pediatric commercial forms, community or hospital pharmacies generally prepare HCT extemporaneous pediatric suspensions by dispersing in water a portion of a crushed tablet or the drug powder; however, any dose or stability control is usually done on these preparations. Obtaining stable HCT solutions is very challenging, due to its low water-solubility and pH-dependent degradation. The aim of this work was to develop a stable 2 mg/mL-HCT oral pediatric solution without using co-solvents.

Highlights

• A 2 mg/mL hydrochlorothiazide (HCT) stable oral pediatric solution has been developed.

• Evaluation of polymers-cyclodextrins (CD) joined use on HCT solubility and stability.

•PVP was the most effective polymer in improving CD solubilizing efficiency.

• SBEβCD was more effective than HPβCD as HCT solubilizing and stabilizing agent.

•SBEβCD-based HCT solution showed faster and higher diuretic effect than HCT suspension.

Combined use of cyclodextrins (CD) and hydrophilic polymers was exploited to improve poor HCT solubility and stability. HPβCD and SBEβCD were selected, considering their safe toxicological profiles, while PVP resulted the best among the tested polymers. Low PVP concentrations (0.2–1.0%) improved the solubilizing efficiency of both CDs, allowing to reach the prefixed HCT concentration. Different CD-PVP concentrations were used to prepare several 2 mg/mL-HCT solutions in pH 5.5 buffer. The best stability was shown by solutions containing the highest SBEβCD concentration (25 mM), which allowed a 3-months stability at 4 °C. In vivo studies on rats showed that such formulation allowed a more pronounced and more reproducible diuretic effect than the corresponding HCT suspension. Continue on Development of a stable oral pediatric solution of hydrochlorothiazide by the combined use of cyclodextrins and hydrophilic polymers

Keywords Hydrochlorothiazide, Pediatric solution, Hydroxypropyl-β-cyclodextrin (Kleptose®HP, HPβCD), Sulfobutylether-β-cyclodextrin (Captisol®, SBEβCD), Hydrophilic polymers, Stability, In vivo diuretic effect

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