Combined Use of Cyclodextrins and Amino Acids for the Development of Cefixime Oral Solutions for Pediatric Use

Cefixime (CEF) is a cephalosporin included in the WHO Model List of Essential Medicines for Children. Liquid formulations are considered the best choice for pediatric use, due to their great ease of administration and dose-adaptability. Owing to its very low aqueous solubility and poor stability, CEF is only available as a powder for oral suspensions, which can lead to reduced compliance by children, due to its unpleasant texture and taste, and possible non-homogeneous dosage.

The aim of this work was to develop an oral pediatric CEF solution endowed with good palatability, exploiting the solubilizing and taste-masking properties of cyclodextrins (CDs), joined to the use of amino acids as an auxiliary third component. Solubility studies indicated sulfobutylether-β-cyclodextrin (SBEβCD) and Histidine (His) as the most effective CD and amino acid, respectively, even though no synergistic effect on drug solubility improvement by their combined use was found.

Molecular Dynamic and ¹H-NMR studies provided insight into the interactions of binary CEF: His and ternary CEF:His:SBEβCD systems used to prepare CEF solutions, which resulted stable and maintained unchanged antimicrobial activity during the two-weeks-use in therapy. The ternary solution was superior in terms of more tolerable pH (5.6 vs. 4.7) and better palatability, being resulted completely odorless by a panel test.

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Materials: Cefixime trihydrate (CEF) was a gift from Menarini (Florence, Italy); hydroxypropyl-β-cyclodextrin (HPβCD, average molar substitution 0.62) was kindly donated by Roquette (Lestrem, France), sulfobutylether-β-cyclodextrin (SBEβCD, Captisol®, average substitution degree 6.8) by CyDex Pharmaceuticals Inc. (San Diego, CA, USA) and γ–cyclodextrin (γ-CD) from Cyclolab (Budapest, Hungary); l-Arginine (Arg), l-Histidine (His), l-Lysine (Lys), l-Glycine (Gly), l-Alanine (Ala), l-Proline (Pro), l-Serine (Ser), l-Leucine (Leu), l-Threonine (Thr), l-Glutamic Acid (Glu), l-Aspartic Acid (Asp) and sodium benzoate were provided from Merck KGaA (Darmstadt, Germany). Purified water from Elix® (Millipore, Burlington, MA, USA) and reagents of analytical grade were used.

Article information: Cirri, M.; Mennini, N.; Nerli, G.; Rubia, J.; Casalone, E.; Melani, F.; Maestrelli, F.; Mura, P. Combined Use of Cyclodextrins and Amino Acids for the Development of Cefixime Oral Solutions for Pediatric Use. Pharmaceutics 2021, 13, 1923. https://doi.org/10.3390/pharmaceutics13111923