Development of a Carvedilol Oral Liquid Formulation for Paediatric Use

Abstract

Carvedilol (CARV) is an ‘off-label’ β-blocker drug to treat cardiovascular diseases in children. Since CARV is nearly insoluble in water, only CARV solid forms are commercialized. Usually, CARV tablets are manipulated to prepare an extemporaneous liquid formulation for children in hospitals. We studied CARV to improve its aqueous solubility and develop an oral solution. In this study, we assessed the solubility and preliminary stability of CARV in different pH media. Using malic acid as a solubility enhancer had satisfactory results. We studied the chemical, physical, and microbiological stability of 1 mg/mL CARV–malic acid solution. A design of experiment (DoE) was used to optimize the CARV solution’s preparation parameters. A 1 mg/mL CARV solution containing malic acid was stable for up to 12 months at 25 °C and 30 °C and 6 months at 40 °C. An equation associating malic acid with CARV concentrations was obtained using DoE. Microbiological data showed that the use of methylparaben was not necessary for this period of time. We successfully developed an aqueous CARV solution suitable for paediatrics and proven to be stable over a 12-month period.

Palatability and Stability Studies to Optimize a Carvedilol Oral Liquid Formulation for Pediatric Use

“…The initial C8_P2 pH value was 2.47, and initial data on the C8_P2 appearance indicated that it was a clear, translucent solution without any undissolved particles. C8_P2 exhibited identical physicochemical characteristics to those of the reference CARV solution on which it is based [ 10 ]. pH results for C8_P2 were highly stable over time with a range of variation ± 0.03.…”

“…CARV formulations we studied herein were based on the optimized CARV formulation described in our last research [ 10 ]. The characteristics of the CARV formulation we developed are presented in Table 2 .…”

“…However, CARV has only been commercialized in an oral solid dosage form as a tablet; hence, the development of a pediatric-appropriate pharmaceutical formulation for CARV is necessary [ 9 ]. We successfully developed a stable aqueous CARV liquid formulation suitable for pediatrics [ 10 ]. However, optimization of this formulation is the next step, which includes taste assessment and a stability study in order to make CARV formulation more palatable.…”

“…CARV tablets are often manipulated prior to use in hospitals with the aim of improving patient compliance and adherence to prepare a CARV liquid suspension [ 10 ]. The most common excipient used to prepare a suspension with triturated CARV tablets is a mixture of Ora-Sweet–Ora-Plus (1:1) or Ora-Blend.…”

“…Considering these findings, the goal of this work was the development of an oral palatable solution of CARV for pediatric use, exploiting taste masking in association with different flavoring agents and a sweetener. Different combinations of flavorings and a sweetening agent were selected to prepare CARV solutions and were subject to a human taste assessment to evaluate their actual ability to mask the unpleasant taste of the CARV in comparison with the reference CARV solution [ 10 ].…”