Permeability of Ciprofloxacin-Loaded Polymeric Micelles Including Ginsenoside as P-glycoprotein Inhibitor through a Caco-2 Cells Monolayer as an Intestinal Absorption Model.

Behzad Sharif Makhmal Zadeh,Golbarg Esfahani,Anayatollah Salimi

doi:10.3390/molecules23081904

Behzad Sharif Makhmal Zadeh, Golbarg Esfahani + Show 1 more

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https://doi.org/10.3390/molecules23081904

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Abstract

The low oral bioavailability of ciprofloxacin is associated with two distinct challenges: its low aqueous solubility and efflux by p-glycoproteins (P-gp) in the intestinal membrane. Several studies were conducted in order to improve its solubility and permeability through the gastrointestinal membrane. In this study, in a full factorial design study, eight polymeric micelles were prepared and their characteristics, including particle size, loading and release rate were evaluated. Polymeric micelles demonstrated particle sizes below 190 nm and 27–88% loading efficiency. Drug release was affected by drug solubility, polymeric micelle erosion and swelling in simulated gastrointestinal fluids. An optimized polymeric micelle was prepared based on appropriate characteristics such as high drug loading and low particle size; and was used for a permeation study on Caco-2 cells. Optimized polymeric micelles with and without ginsenoside and ginsenoside alone enhanced drug permeability through Caco-2 cells significantly in the absorptive direction. The effect of ginsenoside was dose dependent and the maximum effect was seen in 0.23 mg/mL concentration. Results showed that P-gp may not be responsible for ciprofloxacin secretion into the gut. The main mechanism of ciprofloxacin transport through Caco-2 cells in both directions is active diffusion and P-gp has inhibitory effects on ciprofloxacin permeability in the absorptive direction that was blocked by ginsenoside and micelles without ginsenoside.

Highlights

Ciprofloxacin is a wide spectrum antibiotic approved by the U.S Food and Drug Administration (FDA) for 14 infections, especially urinary and respiratory infections such as acute uncomplicated bladder, chronic bacterial prostate and upper respiratory tract infections [1]
The results indicate polymer addition to the labrasol and labrafil mixture decreased the Critical Micelle Concentration (CMC) value significantly (p < 0.05), which increases the micelle stability, since the critical micelle concentration is achieved at a lower concentration of surfactant
The CMC was calculated with and without ciprofloxacin, which showed no significant differences induced by ciprofloxacin

Summary

Introduction

Ciprofloxacin is a wide spectrum antibiotic approved by the U.S Food and Drug Administration (FDA) for 14 infections, especially urinary and respiratory infections such as acute uncomplicated bladder, chronic bacterial prostate and upper respiratory tract infections [1]. The oral bioavailability of ciprofloxacin is about 59 ± 60% [2,3] and it is associated with two distinct challenges: (1). Solubility in gastrointestinal fluids; (2) efflux by p-glycoprotein (P-gp) in the intestinal membrane [4,5]. Ciprofloxacin is a zwitterion, which means its aqueous solubility is affected by pH. The maximum aqueous solubility of ciprofloxacin occurs at pH 10. Precipitation of this drug in the small intestine may occur [1,6]. The decrease in oral bioavailability of ciprofloxacin due to the Molecules 2018, 23, 1904; doi:10.3390/molecules23081904 www.mdpi.com/journal/molecules

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