Intestinal Safety of Water-soluble β-Cyclodextrins in Paediatric Oral Solutions of Spironolactone: Effects on Human Intestinal Epithelial Caco-2 Cells

Abstract

Effects of water-soluble beta-cyclodextrins (beta CDs) on intestinal epithelial integrity were investigated, to establish the safe use of these beta CDs as solubilizers of spironolactone in paediatric enteral solutions. Mannitol permeability and transepithelial resistance (TER) of human intestinal epithelial Caco-2 cell monolayers during exposure to dimethyl-beta-cyclodextrin (DM beta CD), hydroxypropyl-beta-cyclodextrin (HP beta CD) and sulphobutyl ether beta-cyclodextrin (SBE beta CD) were followed. Staining methods were used to discern cells with damaged membranes and to study the integrity of cytoskeletal actin and tight junctions. Cytotoxicity of the beta CDs was tested by effects on intracellular dehydrogenase activity. Exposure to HP beta CD and SBE beta CD solutions had only minor effects on the integrity of Caco-2 cell monolayers. In contrast, DM beta CD clearly increased the epithelial permeability for the hydrophilic marker [14C]mannitol across Caco-2 monolayers, decreased TER and showed a dose-dependent cytotoxicity. According to staining, DM beta CD increased the permeability of the apical cell membrane without discernable effects on cytoskeletal actin. HP beta CD and SBE beta CD appear to be safe additives for use in enteral spironolactone preparations with respect to their acute local effects on epithelial integrity.

Sulfobutyl Ether7 β-Cyclodextrin (SBE7 β-CD) Carbamazepine Complex: Preparation, Characterization, Molecular Modeling, and Evaluation of In Vivo Anti-epileptic Activity

“…It has been demonstrated by Tötterman et al. that SBE 7 β-CD does not show any cytotoxic effects on intestinal epithelial Caco-2 cells (8,10). Thus, SBE 7 β-CD can be considered to be very safe for oral administration.…”

Ursodeoxycholic Acid Complexation with 2-Hydroxypropyl-β-Cyclodextrin Increases Ursodeoxycholic Acid Biliary Excretion after Single Oral Administration in Rats

“…Among hydrophilic cyclodextrins, HPßCD seems a suitable complexing agent because its safety has been thoroughly documented. The compound is free of local adverse effects on the gastrointestinal mucosa [27]. Unlike lipophilic derivatives, HPßCD has no significant nephrotoxicity, does not exert detergent-like effects or damage cell membranes, including red blood cells [27,28].…”

Aspectos biofarmacêuticos da formulação de medicamentos para neonatos: fundamentos da complexação de indometacina com hidroxipropil-beta-ciclodextrina para tratamento oral do fechamento do canal arterial

“…A inibição da captação destes poderá levar ao aumento da sua síntese e possivelmente ao aumento do tamanho do fígado (Duchêne, Wouessidjewe, 1990b;Gerloczy et al, 1994;Pitha, Pitha, 1985). Estudos realizados em células humanas de epitélio intestinal (Caco-2) para testar a resistência transepitelial demonstraram que a HP-β-CD não afeta a sua integridade e não evidencia toxicidade na atividade enzimática intracelular da desidrogenase, parecendo, assim, ser segura no que respeita aos efeitos locais no intestino (Tötterman et al, 1997). Avaliou-se, também, a segurança da HP-β-CD em ratos por um período de 2 anos.…”

“…Considerou-se, assim, que a utilização de derivados das ciclodextrinas altamente solúveis em água seria uma alternativa para a formulação de preparações líquidas aquosas de fármacos fracamente solúveis, aliada à melhoria de biodisponibilidade e de segurança (Kaukonen et al, 1998;Tötterman et al, 1997).…”