Fabrication and evaluation of valsartan-polymer- surfactant composite nanoparticles by using the supercritical antisolvent process

Abstract

The aim of this study was to fabricate valsartan composite nanoparticles by using the supercritical antisolvent (SAS) process, and to evaluate the correlation between in vitro dissolution and in vivo pharmacokinetic parameters for the poorly water-soluble drug valsartan. Spherical composite nanoparticles with a mean size smaller than 400 nm, which contained valsartan, were successfully fabricated by using the SAS process. X-ray diffraction and thermal analyses indicated that valsartan was present in an amorphous form within the composite nanoparticles. The in vitro dissolution and oral bioavailability of valsartan were dramatically enhanced by the composite nanoparticles. Valsartan-hydroxypropyl methylcellulose-poloxamer 407 nanoparticles exhibited faster drug release (up to 90% within 10 minutes under all dissolution conditions) and higher oral bioavailability than the raw material, with an approximately 7.2-fold higher maximum plasma concentration. In addition, there was a positive linear correlation between the pharmacokinetic parameters and the in vitro dissolution efficiency. Therefore, the preparation of composite nanoparticles with valsartan-hydroxypropyl methylcellulose and poloxamer 407 by using the SAS process could be an effective formulation strategy for the development of a new dosage form of valsartan with high oral bioavailability.

Keywords: bioavailability; dissolution; solid dispersion; supercritical fluid; supersaturation.

Figure 1

Scanning electron micrographs (A), kinetic solubility profile (B), differential scanning calorimetry thermograms (C), and powder X-ray diffraction patterns (D) of valsartan–polymer composite nanoparticles prepared by using the SAS process. Abbreviations: HPC, hydroxypropyl cellulose; HPMC, hydroxypropyl methylcellulose; PVP, polyvinylpyrrolidone; PVP VA64, polyvinylpyrrolidone-vinyl acetate; SAS, supercritical antisolvent.

Figure 2

Scanning electron micrographs of valsartan–HPMC–surfactant composite nanoparticles prepared by using the SAS process. Notes: (A) Valsartan–HPMC; (B) valsartan–HPMC–poloxamer 407; (C) valsartan–HPMC–Ryoto sugar ester L1695; and (D) valsartan–HPMC–TPGS. Abbreviations: HPMC, hydroxypropyl methylcellulose; SAS, supercritical antisolvent; TPGS, D-α-Tocopheryl polyethylene glycol 1000 succinate.

Figure 3

Differential scanning calorimetry thermograms (A), and powder X-ray diffraction patterns (B) of valsartan–HPMC–surfactant composite nanoparticles prepared by using the SAS process. Abbreviations: HPMC, hydroxypropyl methylcellulose; SAS, supercritical antisolvent; TPGS, D-α-Tocopheryl polyethylene glycol 1000 succinate.

Figure 4

Kinetic solubility profiles of valsartan–HPMC–surfactant composite nanoparticles prepared by using the SAS process. Note: Data are expressed as the mean ± standard deviation (n=3). Abbreviations: HPMC, hydroxypropyl methylcellulose; SAS, supercritical antisolvent; TPGS, D-α-Tocopheryl polyethylene glycol 1000 succinate.

Figure 5

Dissolution profiles of valsartan–HPMC–surfactant composite nanoparticles prepared by using the SAS process. Notes: pH 1.2 (A); pH 4.0 (B); and pH 6.8 (C) dissolution media. Data are expressed as the mean ± standard deviation (n=3). Abbreviations: HPMC, hydroxypropyl methylcellulose; SAS, supercritical antisolvent; TPGS, D-α-Tocopheryl polyethylene glycol 1000 succinate.

Figure 6

Plasma concentration-time profile of valsartan in rats after oral administration of the raw material and valsartan composite nanoparticles prepared by using the SAS process. Note: Data are expressed as the mean ± standard deviation (n=5). Abbreviations: HPMC, hydroxypropyl methylcellulose; SAS, supercritical antisolvent; TPGS, D-α-Tocopheryl polyethylene glycol 1000 succinate.

Figure 7

Correlation between the in vitro dissolution efficiency and in vivo pharmacokinetic parameters. Notes: (A) AUC_0–24h; (B) C_max. Abbreviations: AUC_{0–24 h}, area under the concentration-time curve; C_max, peak concentration; DE, dissolution efficiency; R², coefficient of determination.