Abstract
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.
Highlights
Introduction with regard to jurisdictional claims in Cefixime (CEF) (Figure 1) is a third-generation cephalosporin considered essential for children up to 12-years old, being included in the WHO Model List of Essential Medicines for Children among the ‘Watch group antibiotics’ and recommended as essential second choice treatment for gastroenteritis and colitis without specification of infectious agent [1]
Cefixime trihydrate (CEF) was a gift from Menarini (Florence, Italy); hydroxypropylβ-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 (Darmstad, Germany)
No drug solubility variations were observed in the presence of complexes with γCD, HPβCD or SBEβCD in water at 25 ◦ C
Summary
Molecular Dynamic and 1 H-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. In the European market, CEF-based formulations are present as powders for oral suspensions (100 mg/5 mL) and tablets (200 and 400 mg). In order to meet the needs of the pediatric population and obtain acceptable formulation in the appropriate dose, dosage forms intended for adults such as tablets, capsules or concentrated suspensions are usually extemporaneously manipulated by crashing, opening or diluting, respectively
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