Abstract
Progressive increase in bacterial resistance has caused an urgent need to introduce new antibiotics, one of them being oxazolidinones with their representative tedizolid. Despite the broad spectrum of activity of the parent tedizolid, it is characterized by low water solubility, which limits its use. The combination of the active molecule with a multifunctional excipient, which is cyclodextrins, allows preservation of its pharmacological activity and modification of its physicochemical properties. Therefore, the aim of the study was to change the dissolution rate and permeability through the model membrane of tedizolid by formation of solid dispersions with a cyclodextrin. The research included identification of tedizolid-hydroxypropyl-β-cyclodextrin (tedizolid/HP-β-CD) inclusion complex by thermal method (Differential Scanning Colorimetry), spectroscopic methods (powder X-ray diffraction, Fourier-Transform Infrared spectroscopy), and molecular docking. The second part of the research concerned the physicochemical properties (dissolution and permeability) and the biological properties of the system in terms of its microbiological activity. An increase in the dissolution rate was observed in the presence of cyclodextrin, while maintaining a high permeation coefficient and high microbiological activity. The proposed approach is an opportunity to develop drug delivery systems used in the treatment of resistant bacterial infections, in which, in addition to modifying the physicochemical properties caused by cyclodextrin, we observe a favorable change in the pharmacological potential of the bioactives.
Highlights
Continuous, progressive increase in bacterial resistance has caused an urgent need to introduce effective and safe new antibiotics or antibacterial agents with a completely new mechanism of action that could effectively inhibit the growth of infections caused by drug-resistant bacteria
Our research hypotheses assumed that combining the parent tedizolid with cyclodextrin would allow for better solubility and modify bioavailability, improve bactericidal activity and mask specific taste
The following XRPD, differential scanning calorimetry (DSC) and FT-IR techniques with theoretical calculations were used as methods to confirm the identity of the obtained system
Summary
Continuous, progressive increase in bacterial resistance has caused an urgent need to introduce effective and safe new antibiotics or antibacterial agents with a completely new mechanism of action that could effectively inhibit the growth of infections caused by drug-resistant bacteria. Despite increased efficacy against strains with the cfr methyltransferase gene responsible for the resistance of staphylococci to linezolid, tedizolid is low soluble in water with a solubility of 0.136 mg/mL [6] To solve this problem, the hydroxymethyl substituent at the C5 position of the oxazolidinone ring is first converted into a phosphate ester, and reacted with sodium metoxide to give the phosphate disodium salt [7]. Pharmacokinetic (PK) and pharmacodynamics (PD) properties of tedizolid phosphate allow the administration of convenient once-daily dosing, a 6-day course of therapy, availability of both oral and intravenous routes of administration Oxazolidinones, such as beta-lactams, including penicillin and penems, and glycopeptides, macrolides, azalides, and lincosamides are time-dependent antibiotics, meaning that the time that the concentration of a drug remains above the minimum inhibitory concentration (MIC) (T > MIC) is the PK-PD index correlating with efficacy [8]. Increasing the amount of phosphate in the human body, administered in the form of a phosphate prodrug, can cause a decrease in calcium levels, which further results in bone weakness [11], and this will be seriously disadvantageous, especially in the case of tedizolid use in off-label indication for the treatment of bone and joint infections [12]
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