Abstract
Florfenicol (FF) is a novel animal-specific amidohydrin broad-spectrum antibiotic. However, its aqueous solubility is extremely poor, far below the effective dose required for veterinary clinic. Thus, FF is often used in large doses, which significantly limits its preparation and application. To overcome these shortcomings, the FF-hydroxypropyl-β-cyclodextrin (FF-HP-β-CD) inclusion complexes were developed using the solution-stirring method. The physical properties of FF-HP-β-CD were characterized. A comparison was conducted between FF and FF-HP-β-CD freeze-dried powder injection of their muscle irritation and the pharmacokinetics. The drug loading and saturated solubility of FF-HP-β-CD at 37 °C were 11.78% ± 0.04% and 78.93 ± 0.42 mg/mL, respectively (35.4-fold compared with FF). Results of scanning electron microscopy, differential scanning calorimetry, X-ray diffraction, and Fourier transform infrared showed that FF was entrapped in the inner cavity of HP-β-CD, and the inclusion complex formed in an amorphous state. In comparison with FF commercial injection, FF-HP-β-CD increased the elimination half-life (t1/2β), transport rate constant (K10, K12, K21), and maximum concentration (Cmax) after intramuscular injection in beagle dogs. Conversely, it decreased the distribution half-life (t1/2α), absorption rate constant (Ka), apparent volume of distribution (V1/F), and peak time (Tmax). These results suggest that FF-HP-β-CD freeze-dried powder injection is a promising formulation for clinical application.
Highlights
Florfenicol (FF) is a novel animal-specific amidohydrin broad-spectrum antibiotic
HP-β-CD is a derivative of CD and has its advantages and has good water solubility at room temperature; it is stable to heat and nontoxic to kidneys
The current study selected the solution-stirring method, and FF-HP-β-CD was successfully prepared on the basis of single-factor experiment and orthogonal design
Summary
The crystal form of FF-HP-β-CD shows no obvious characteristic diffraction peaks It only exhibits two broad diffraction peak bands around 10° and 20°, indicating the amorphous state of HP-β-CD. PM shows a superposition of FF and HP-β-CD; the lower relative content of FF after mixing leads to a decrease in the intensity of the characteristic diffraction peaks This finding indicates that the physical form of PM does not change. FF is inferred to possibly be encapsulated in the HP-β-CD cavity from the side containing the dichloromethyl (–CHCl2) structure, whereas the FF sulfonyl side is outside the CD cavity (Fig. 6) These slight changes in chemical shifts indicate that the two are bound in a non-covalent bond, which is consistent with the principle of clathrate formation. Our study suggests FF-HP-β-CD freeze-dried powder, a water-soluble FF injection is a promising formulation for solving these problems and clinical application
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