title: Pharmacokinetic and pharmacodynamic studies of nisoldipine-loaded solid lipid nanoparticles developed by central composite design.
abstract: OBJECTIVE
  Nisoldipine (ND) is a potential antihypertensive drug with low oral bioavailability. The aim was to develop an optimal formulation of ND-loaded solid lipid nanoparticles (ND-SLNs) for improved oral bioavailability and pharmacodynamic effect by using a two-factor, three-level central composite design. Glyceryl trimyristate (Dynasan 114) and egg lecithin were selected as independent variables. Particle size (Y1), PDI (Y2) and entrapment efficiency (EE) (Y3) of SLNs were selected as dependent response variables.
  
  
  METHODS
  The ND-SLNs were prepared by hot homogenization followed by ultrasonication. The size, PDI, zeta potential, EE, assay, in vitro release and morphology of ND-SLNs were characterized. Further, the pharmacokinetic (PK) and pharmacodynamic behavior of ND-SLNs was evaluated in male Wistar rats.
  
  
  RESULTS
  The optimal ND-SLN formulation had particle size of 104.4 ± 2.13 nm, PDI of 0.241 ± 0.02 and EE of 89.84 ± 0.52%. The differential scanning calorimetry and X-ray diffraction analyses indicated that the drug incorporated into ND-SLNs was in amorphous form. The morphology of ND-SLNs was found to be nearly spherical by scanning electron microscopy. The optimized formulation was stable at refrigerated and room temperature for 3 months. PK studies showed that 2.17-fold increase in oral bioavailability when compared with a drug suspension. In pharmacodynamic studies, a significant reduction in the systolic blood pressure was observed, which sustained for a period of 36 h when compared with a controlled suspension.
  
  
  CONCLUSIONS
  Taken together, the results conclusively demonstrated that the developed optimal ND-SLNs caused significant enhancement in oral bioavailability along with pharmacodynamic effect.
authors.affiliation: a Department of Pharmaceutical Sciences , Laboratory of Nanotechnology, University College of Pharmaceutical Sciences, Kakatiya University , Warangal , Telangana , India.
authors.forename: Narendar
authors.initials: N
authors.lastname: Dudhipala
authors.affiliation: a Department of Pharmaceutical Sciences , Laboratory of Nanotechnology, University College of Pharmaceutical Sciences, Kakatiya University , Warangal , Telangana , India.
authors.forename: Kishan
authors.initials: K
authors.lastname: Veerabrahma
mesh_terms: D000818:Animals; D000959:Antihypertensive Agents / Q000138:chemical synthesis / Q000493:pharmacokinetics; D004337:Drug Carriers / Q000138:chemical synthesis / Q000493:pharmacokinetics; D015195:Drug Design; D008055:Lipids; D008297:Male; D053758:Nanoparticles / Q000737:chemistry* / Q000378:metabolism*; D015737:Nisoldipine / Q000138:chemical synthesis* / Q000493:pharmacokinetics*; D010316:Particle Size; D051381:Rats; D017208:Rats, Wistar; D014961:X-Ray Diffraction
chemical_list: D000959:Antihypertensive Agents; D004337:Drug Carriers; D008055:Lipids; D015737:Nisoldipine
keywords: Central composite design; nisoldipine; pharmacodynamics; pharmacokinetics; solid lipid nanoparticles