Nanosized Liposomes Containing Bile Salt: A Vesicular Nanocarrier for Enhancing Oral Bioavailability of BCS Class III Drug

Abstract

-PURPOSE: Liposomes have been studied as a colloidal carrier in drug delivery systems, especially for oral administration. However, their low structural integrity in the gut is still a major shortcoming. Membrane disruptive effects of physiological bile salts in the small intestine result in premature drug release prior to intestinal absorption. Thus, we analyzed the stabilizing effect of sodium deoxycholate when incorporated into nano-sized liposomes. METHOD: Cefotaxime-loaded liposomes were prepared with different sodium deoxycholate concentrations (3.75-30 mM) by rotary film evaporation followed by nanosize reduction. The physical integrity of liposomes was evaluated by monitoring cefotaxime leakage, particle sizes in different simulated physiological media. The oral bioavailability and pharmacokinetics of cefotaxime was assessed in rats (n = 6 per group) after single dose of drug-encapsulated in liposomes containing bile salt, drug in conventional liposomes, and cefotaxime solution (oral and intravenous). RESULTS: Simulated gastric fluid with low pH showed less effect on the stability of liposomes in comparison to media containing physiological bile salts. Liposomes containing 15 mM sodium deoxycholate were most stable in size and retained the majority of encapsulated cefotaxime even in fed state of simulated intestinal fluid being the most destructive media. Pharmacokinetics data showed an increase in Cmax and AUC0-inf in the following order: cefotaxime solution < conventional liposomes < liposomes made with bile salts. The total oral bioavailability of cefotaxime in liposomes containing bile salt was found to be 5-times higher compared to cefotaxime solution and twice as much as in conventional liposomes. CONCLUSION: Incorporation of bile salts, initially used as membrane permeation enhancer, also acted as a stabilizer against physiological bile salts. The nanosized liposomes containing sodium deoxycholate were able to reduce the leakage of encapsulated cefotaxime in the gut due to the improved vesicle stability and to enhance the oral bioavailability of acid-labile drugs up to 5-fold.

Bile Acids and Their Derivatives as Potential Modifiers of Drug Release and Pharmacokinetic Profiles

“…Accordingly, the oral bioavailability of cefotaxime in DCA-bilosomes was five-times higher compared to cefotaxime solution and twice as much as in conventional liposomes. The key factor for enhanced stability of DCA-bilosomes and improved intestinal permeability of the active principle was suggested to be the change in physical structural properties of vesicles, such as additional elasticity, fluidity and negative charge ( Arafat et al, 2017b ). These results suggest that bilosomes might extend the application of cefotaxime from parenteral only to oral application.…”

Nano-sized Droplets of Self-Emulsifying System for Enhancing Oral Bioavailability of Chemotherapeutic Agent VP-16 in Rats: A Nano Lipid Carrier for BCS Class IV Drugs

“…All PK parameters were determined as reported previously (29). All data were expressed as mean ± SD.…”

“…The stirring speed was fixed at 100 ± 2 rpm and temperature at 37 ± 0.5°. 150 mL of simulated intestinal fluid under fast condition (FaSSIF) media which prepared as described in the literature (29) was used and media pH value was maintained at pH 6.5. After sink condition was maintained, 1 mL of sample was taken at various time intervals (0, 10, 20, 30, 40, 50, and 60 min) and replaced with fresh medium to keep the total volume constant at 150 mL.…”

Transdermal patches: Design and current approaches to painless drug delivery

“…Increased fluidity in the stratum corneum results in increased skin permeability (76). Permeation enhancing compounds include terpenes, sulphoxides, pyrrolidones, laurocapram, fatty acids, alcohols, fatty alcohols, surfactants, glycols, urea, and bile salts (77)(78)(79).…”