Cyclodextrins as multifunctional excipients: Influence of inclusion into β-cyclodextrin on physicochemical and biological properties of tebipenem pivoxil

Abstract

A novel approach for drug design based on the oral carbapenem analog tebipenem pivoxil (TP) has been proposed. The formation of the tebipenem pivoxil-β-cyclodextrin (TP-β-CD) complex resulted in changes concerning physicochemical properties of TP, which is significant for planning the development of an innovative pharmaceutical formulation as well as in the modifications of biological activity profile of the studied delivery system. The inclusion of TP into β-cyclodextrin (β-CD) was confirmed by spectral (infrared and Raman spectroscopies) and thermal method (differential scanning calorimetry). Precise indications of TP domains responsible for interaction with β-CD were possible through a theoretical approach. The most important physicochemical modifications obtained as an effect of TP inclusion were changes in solubility and its rate depending on acceptor fluids, and an increase in chemical stability in the solid state. Biologically essential effects of TP and β-CD interactions were decreased TP permeability through Caco–2 cell monolayers with the use of efflux effect inhibition and increased antibacterial activity. The proposed approach is an opportunity for development of the treatment in resistant bacterial infections, in which along with physicochemical modifications induced by a drug carrier impact, a carrier synergy with a pharmacological potential of an active pharmaceutical substance could be used.

Computer-Aided Design of Cefuroxime Axetil/Cyclodextrin System with Enhanced Solubility and Antimicrobial Activity

“…Athanassiou et al's study of several β-lactam antibiotics with cyclodextrins showed a positive correlation between the presence of cyclodextrin and increased minimal inhibitory concentration (MIC) of antibiotics [10]. Similar observations were made by our group in studies of βCD systems with meropenem [11] and tebipenem pivoxil [12], leading to the conclusion that antimicrobial efficacy tests should be conducted routinely for each antibiotic-CD system to assess change in the system's pharmacodynamics compared to pure API.…”

“…Taking into account a significant decrease of Klebsiella pneumoniae and Pseudomonas aeruginosa MICs for the CA-HPβCD system, two pathways leading to increased efficacy may be suggested. Firstly, blocking porin channels may be contributed to inhibiting the efflux effect in bacteria by HPβCD [12]. Limitations of efflux transport in the case of the derivatives of cyclodextrin were observed by the authors as early as the stage of the permeability studies.…”

“…The eligibility of certain kinds of cyclodextrin to achieve the desired stability of the system in solution is determined by the structure of CD and guest API [13]. The thermodynamic effect described by Gibbs free energy of complex formation, as well as by entailed stability constant Ks, can be estimated by structure-based modeling with in silico methods [11,12,[14][15][16][17][18]. Application of theoretical approaches, considering a vast number of testable cyclodextrin derivatives, is an essential tool for streamlining experimental investigation.…”

Hydroxypropyl-β-cyclodextrin as an effective carrier of curcumin – piperine nutraceutical system with improved enzyme inhibition properties

“…Antimicrobial activity for curcumin and piperine in free forms was previously confirmed 59,60 . Also, 2-hydroxypropyl-b-cyclodextrin showed some antibacterial effect 61 , but more importantly, it increases bactericidal effect of other substances 62,63 . Cyclodextrins, according to many mechanisms, can counteract infections by decreasing antibiotic resistance via complexation 64 , lowering the cell-to-cell (quorum sensing) communication 65 , and blocking poreforming toxins 66 .…”

An update on cyclodextrins as drug vehicles for antimicrobial applications

“…Biologically primary effects of TP and β-CD interactions decreased TP permeability through Caco-2 cell using efflux effect inhibition and enhanced antibacterial activity. The pharmaceutical formulation showed a great opportunity for the treatment of resistant bacterial infections [38].…”