Development of a Hydroxypropyl-β-Cyclodextrin-Based Liquid Formulation for the Oral Administration of Propranolol in Pediatric Therapy

Abstract

Propranolol (PPN) is widely used in children to treat various cardiovascular diseases. The availability of a suitable PPN solution should avoid recourse to extemporaneous preparations of unknown/limited stability, as commonly made in hospital pharmacies. However, the development of pediatric PPN solutions is hindered by their instability to light and stability at pH ≈ 3, bitter taste, and the need to improve palatability and avoid co-solvents, flavoring agents, or preservatives that are potentially toxic. In this study, cyclodextrin (CD) complexation has been exploited to develop a safe, stable, and palatable oral pediatric solution of PPN. An initial screening among various CDs allowed us to select HPβCD for its good complexing ability and no toxicity. Drug-HPβCD physical mixtures or co-ground systems (1:1 or 1:2 mol:mol) were used to prepare 0.2% w/v drug solutions. Photo stability studies evidenced the protective effect of HPβCD, revealing a reduction of up to 75% in the drug degradation rate after 1 h of exposure to UV radiation. Storage stability studies showed unchanged physical–chemical properties and almost constant drug concentration after 6 months and under accelerated conditions (40 °C), despite the less aggressive pH (≈5.5) of the solution. The electronic tongue test proved that the HPβCD taste-masking properties improved the formulation palatability, with a 30% reduction in drug bitterness.

Critical View on the Qualification of Electronic Tongues Regarding Their Performance in the Development of Peroral Drug Formulations with Bitter Ingredients

“…By evaluating the sensitivity of the e-tongue sensors for the drug of interest, a decision can be made about whether an e-tongue can be employed to evaluate a taste-masking success, e.g., by adding different excipients to the solution [5]. In this way, for example, a successful encapsulation of bitter drug molecules in cyclodextrins [70][71][72], liposomes [73], and taste-masking by sweeteners [58] could be demonstrated. In these studies, the drug substances have initially been dissolved in water, citric buffer (pH 4.4), or a water-ethanol mixture.…”

“…Subsequently, the drug solutions were mixed with the taste-masking agents, and the samples were measured [5,58,74]. In studies involving the use of cyclodextrins (specifically hydroxypropyl-β-cyclodextrin) for taste masking [70,71], the cyclodextrin solutions were mixed with the drug solutions in varying ratios to facilitate interaction between the complexes and the drug molecules, or the cyclodextrins were milled together with the drug and the physical mixture was dissolved in water afterward [72]. In one of the mentioned studies, the dispersions were filtered prior to the e-tongue measurements to prevent sensor damage caused by particles [71].…”

“…Two projects presented a successful taste-masking strategy for propranolol hydrochloride (HCl) [72,98]. A comparable approach seemed to be the basis for supporting the taste-masking strategy in an EMA report on the human use of the preparation Hemangiol ® .…”

Formulation and Evaluation of Polysaccharide Microparticles for the Controlled Release of Propranolol Hydrochloride

“…The commercially available oral solution of propranolol contains citric acid as a stabilizer (pH around 3), sodium saccharin as a sweetener, strawberry and vanilla as flavoring agents to mask the drug’s bitter taste, and propylene glycol (2.6 mg/mL) as a solvent. Daily intake should be limited since they are all labeled as potentially harmful in children and have been associated with toxicity, principally in neonates [ 22 ]. According to the provisional pediatric biopharmaceutics classification system (pBCS), propranolol hydrochloride has been reported as one of the drugs with no changes between pBCS and adult BCS.…”