title: Nanosizing of valsartan by high pressure homogenization to produce dissolution enhanced nanosuspension: pharmacokinetics and pharmacodyanamic study.
abstract: OBJECTIVE
  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(-1)88 (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 Cmax (1627.47 ± 112.05 ng mL(-1)), Tmax (2.00 h) and AUC0→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 Tmax value, proved the enhanced dissolution rate of VAL.
  
  
  CONCLUSIONS
  The overall results proved that newly developed VAL-NS increased the plasma bioavailability and pharmacodyanamic potential over the reference formulation containing crude VAL.
authors.affiliation: a Department of Pharmaceutics, Faculty of Pharmacy , Hamdard University , Hamdard Nagar , New Delhi , India.
authors.forename: Shayana
authors.initials: S
authors.lastname: Gora
authors.affiliation: a Department of Pharmaceutics, Faculty of Pharmacy , Hamdard University , Hamdard Nagar , New Delhi , India.
authors.forename: Gulam
authors.initials: G
authors.lastname: Mustafa
authors.affiliation: a Department of Pharmaceutics, Faculty of Pharmacy , Hamdard University , Hamdard Nagar , New Delhi , India.
authors.forename: Jasjeet Kaur
authors.initials: JK
authors.lastname: Sahni
authors.affiliation: a Department of Pharmaceutics, Faculty of Pharmacy , Hamdard University , Hamdard Nagar , New Delhi , India.
authors.forename: Javed
authors.initials: J
authors.lastname: Ali
authors.affiliation: a Department of Pharmaceutics, Faculty of Pharmacy , Hamdard University , Hamdard Nagar , New Delhi , India.
authors.forename: Sanjula
authors.initials: S
authors.lastname: Baboota
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000959:Antihypertensive Agents / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D001682:Biological Availability; D002626:Chemistry, Pharmaceutical / Q000379:methods; D004339:Drug Compounding / Q000379:methods; D005079:Excipients / Q000737:chemistry; D005612:Freeze Drying / Q000379:methods; D046529:Microscopy, Electron, Transmission / Q000379:methods; D053758:Nanoparticles / Q000737:chemistry*; D010316:Particle Size; D020442:Poloxamer / Q000737:chemistry; D011312:Pressure; D051381:Rats; D017208:Rats, Wistar; D012995:Solubility; D013535:Suspensions / Q000737:chemistry* / Q000493:pharmacokinetics* / Q000494:pharmacology; D000068756:Valsartan / Q000737:chemistry* / Q000493:pharmacokinetics* / Q000494:pharmacology; D014867:Water / Q000737:chemistry
chemical_list: D000959:Antihypertensive Agents; D005079:Excipients; D013535:Suspensions; D014867:Water; D020442:Poloxamer; D000068756:Valsartan
keywords: Anti-hypertensive; high-pressure homogenizer; nanosizing; particle size distribution; scanning electron microscopy; valsartan