Nanosizing of valsartan by high pressure homogenization to produce dissolution enhanced nanosuspension: pharmacokinetics and pharmacodyanamic study

Abstract

Purpose: The purpose of the present study was to formulate and evaluate nanosuspension of Valsartan (VAL), a poorly water soluble and low bioavailable drug (solubility of 0.18 mg mL⁻¹; 23% of oral bioavailability) with the aim of improving the aqueous solubility thus the bioavailability and consequently better anti-hypertensive activity.

Methods: Valsartan nanosuspension (VAL-NS) was prepared using high-pressure homogenization followed by lyophilisation. The screening of homogenization factors influencing nanosuspension was done by 3-factorial, 3-level Box-Behnken statistical design. Model suggested the influential role of homogenization pressure and cycles on drug nanosizing. The optimized formulation containing Poloxamer⁻¹88 (PXM 188) was homogenized for 2 cycles at 500 and 1000 bar, followed by 5 cycles at 1500 bars.

Results: The size analysis and transmission electron microscopy showed nanometric size range and uniform shape of the nanosuspension. The in vitro dissolution showed an enhanced release of VAL from nanosuspension (VAL-NS) compared to physical mixture with PXM 188. Pharmacodynamic results showed that, oral administration of VAL-NS significantly lowered (p ≤ 0.001) blood pressure in comparison to non-homogenized VAL (VAL-Susp) in Wistar rat. The level of VAL in rat plasma treated with VAL-NS showed significant difference (p ≤ 0.005) in C_max (1627.47 ± 112.05 ng mL⁻¹), T_max (2.00 h) and AUC_0→24 (13279.2 ± 589.426 ng h mL⁻¹) compared to VAL-Susp that was found to be 1384.73 ± 98.76 ng mL⁻¹, 3.00 h and 9416.24 ± 218.48 ng h mL⁻¹ respectively. The lower T_max value, proved the enhanced dissolution rate of VAL.

Conclusion: The overall results proved that newly developed VAL-NS increased the plasma bioavailability and pharmacodyanamic potential over the reference formulation containing crude VAL.

• Anti-hypertensive
• high-pressure homogenizer
• nanosizing
• particle size distribution
• scanning electron microscopy
• valsartan

Acknowledgements

The authors are also thankful to Jubilant Life Sciences Ltd. (Noida, India) for providing Valsartan and BASF (Mumbai, India) for Poloxamer 188 as a gift sample.

Declaration of interest

Authors have no financial and competing interests. The authors have no financial involvement with any organization or entity with financial interests in or financial conflict with the subject matter or material discussed in the manuscript. No writing assistance was utilized in the production of this manuscript. Authors are thankful to All India Council for Technical Education (AICTE), Govt. of INDIA, New Delhi for providing fellowship.