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. 2010 Feb 2:5:13-23.

Pharmacokinetics and enhanced oral bioavailability in beagle dogs of cyclosporine A encapsulated in glyceryl monooleate/poloxamer 407 cubic nanoparticles

Jie Lai  1 , Yi Lu, Zongning Yin, Fuqiang Hu, Wei Wu
Affiliations

Pharmacokinetics and enhanced oral bioavailability in beagle dogs of cyclosporine A encapsulated in glyceryl monooleate/poloxamer 407 cubic nanoparticles

Jie Lai et al. Int J Nanomedicine. .

Abstract

Efforts to improve the oral bioavailability of cyclosporine A (CyA) remains a challenge in the field of drug delivery. In this study, glyceryl monooleate (GMO)/poloxamer 407 cubic nanoparticles were evaluated as potential vehicles to improve the oral bioavailability of CyA. Cubic nanoparticles were prepared via the fragmentation of a bulk GMO/poloxamer 407 cubic phase gel by sonication and homogenization. The cubic inner structure formed was verified using Cryo-TEM. The mean diameters of the nanoparticles were about 180 nm, and the entrapment efficiency of these particles for CyA was over 85%. The in vitro release of CyA from these nanoparticles was less than 5% at 12 h. The results of a pharmacokinetic study in beagle dogs showed improved absorption of CyA from cubic nanoparticles as compared to microemulsion-based Neoral((R)); higher C(max) (1371.18 +/- 37.34 vs 969.68 +/- 176.3 ng mL(-1)), higher AUC(0-t) (7757.21 +/- 1093.64 vs 4739.52 +/- 806.30 ng h mL(-1)) and AUC(0-infinity) (9004.77 +/- 1090.38 vs 5462.31 +/- 930.76 ng h mL(-1)). The relative oral bioavailability of CyA cubic nanoparticles calculated on the basis of AUC(0-infinity) was about 178% as compared to Neoral((R)). The enhanced bioavailability of CyA is likely due to facilitated absorption by cubic nanoparticles rather than improved release.

Keywords: beagle dogs; bioavailability; cubosomes; cyclosporine A; glyceryl monooleate; nanoparticles; oral drug delivery.

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Figures

Figure 1
Figure 1
Cryo-TEM photographs of blank A) and CyA-loaded B) cubic nanoparticles. The bars equal 200 nm.
Figure 2
Figure 2
Size distribution of CyA-loaded cubic nanoparticles after sonication A) and homogenization at 689 bar for five cycles B).
Figure 3
Figure 3
Effect of GMO/poloxamer 407 ratio A) and homogenization pressure and cycles B) on mean diameter of CyA-loaded cubic nanoparticles (n = 3). Note: *P < 0.01 compared to any other group.
Figure 4
Figure 4
Effect of GMO/poloxamer 407 ratios A) and homogenization pressure and cycles B) on entrapment efficiency of CyA-loaded cubic nanoparticles (n = 3). Notes: *P < 0.05 as compared to any other group; **P < 0.05 as compared to any other group except these two groups.
Figure 5
Figure 5
Release profiles of CyA-loaded GMO/poloxamer 407 cubic nanoparticles and Neoral® capsules (n = 3).
Figure 6
Figure 6
Beagle dog plasma CyA concentrations versus time plot after a single oral dose of 100 mg equivalent CyA cubic nanoparticles or Sandimmun Neoral® (n = 6).
See this image and copyright information in PMC

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