title: A Novel Proliposomal Ropivacaine Oil: Pharmacokinetic-Pharmacodynamic Studies After Subcutaneous Administration in Pigs.
abstract: BACKGROUND
  Liposomal local anesthetics are limited by a short liposomal shelf-life, even when under refrigeration. We describe a novel proliposomal ropivacaine that produces liposomes in situ, only after exposure to aqueous media.
  
  
  METHODS
  In vitro: Nanoparticles were assessed (particle size distribution analyzer, cryo-transmission electron microscopy) at baseline and after exposure to saline/plasma.
  
  
  RESULTS
  In porcine wound healing study (n = 12), healing was assessed by photography, clinical assessment, and histology. Pharmacodynamics: Seventeen young piglets were randomly assigned to plain 0.5% ropivacaine (n = 5), proliposomal 4% ropivacaine (n = 6), or sham (n = 6). Tactile threshold was assessed using von Frey filaments applied to the surgical wound; the nonoperated skin was used as a control. Tactile threshold over time was determined using area under the curve (AUC) and assessed by 1-way analysis of variance.
  
  
  RESULTS
  8 young piglets were randomly assigned to plain 0.5% (25 mg, n = 4) or proliposomal 4% (200 mg, n = 4) ropivacaine. Plasma ropivacaine was assessed by high-performance liquid chromatography at baseline and at intervals over 36 hours. Paired ropivacaine concentration (from wound exudate and plasma) was obtained at 96 hours. Data were analyzed using noncompartmental and compartmental models.
  
  
  RESULTS
  In vitro: On exposure to saline and plasma, the study drug was transformed from a homogenous oil to an emulsion containing liposomes of approximately 1.4-μm diameter; this effect was dilution dependent and stable over time.
  
  
  RESULTS
  All wounds healed well; no effect of drug group was observed. Pharmacodynamics: Plain and proliposomal ropivacaine provided sensory anesthesia for approximately 6 and 30 hours, respectively. There was an approximately 7-fold increase in the AUC of anesthesia for proliposomal ropivacaine compared with plain ropivacaine (mean difference, 1010; 95% confidence interval [CI], 625-1396 g·h/mm; P < 0.0001).
  
  
  RESULTS
  There was no difference in Cmax (2.31 ± 0.74 vs 2.32 ± 0.46 mg/L), despite an approximately 8-fold difference in dose. However, proliposomal ropivacaine was associated with a marked prolongation of Tmax (6.50 ± 6.35 vs 0.5 ± 0.0 hours), terminal half-life (16.07 ± 5.38 vs 3.46 ± 0.88 hours; P = 0.0036), and ropivacaine-time AUC (47.72 ± 7.16 vs 6.36 ± 2.07 h·mg/L; P < 0.0001), when compared with plain ropivacaine. The proliposomal formulation provided an approximately 250-fold higher ropivacaine concentration in the surgical wound (mean difference, 3783 ng/mL; 95% CI, 1708-5858; P = 0.001) and an approximately 25-fold higher wound:plasma ropivacaine concentration ratio (mean difference, 126; 95% CI 38-213; P = 0.011).
  
  
  CONCLUSIONS
  Proliposomal ropivacaine exerted prolonged anesthesia with delayed elimination, typical for liposomal drugs. The advantage of this novel proliposomal ropivacaine is its ease of preparation and its extended shelf-stability (>2 years) at room temperature.
authors.affiliation: From the *Department of Anesthesiology and Critical Care Medicine, Hadassah-Hebrew University Medical Center, Jerusalem, Israel; †Department of Anesthesiology, Washington University School of Medicine, St. Louis, Missouri; ‡Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, New Jersey; §Painreform Ltd., Israel; and ∥R&D Integrative Solutions, Israel.
authors.forename: Elyad M
authors.initials: EM
authors.lastname: Davidson
authors.forename: Simon
authors.initials: S
authors.lastname: Haroutounian
authors.forename: Leonid
authors.initials: L
authors.lastname: Kagan
authors.forename: Michael
authors.initials: M
authors.lastname: Naveh
authors.forename: Arnon
authors.initials: A
authors.lastname: Aharon
authors.forename: Yehuda
authors.initials: Y
authors.lastname: Ginosar
mesh_terms: D000577:Amides / Q000008:administration & dosage* / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics*; D000779:Anesthetics, Local / Q000008:administration & dosage* / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics*; D000818:Animals; D019540:Area Under Curve; D002626:Chemistry, Pharmaceutical; D002851:Chromatography, High Pressure Liquid; D004195:Disease Models, Animal; D004355:Drug Stability; D004655:Emulsions; D007279:Injections, Subcutaneous; D008081:Liposomes; D008657:Metabolic Clearance Rate; D008954:Models, Biological; D053758:Nanoparticles; D009821:Oils; D017288:Pain Threshold / Q000187:drug effects*; D000077212:Ropivacaine; D012867:Skin / Q000187:drug effects* / Q000293:injuries / Q000294:innervation / Q000378:metabolism / Q000473:pathology; D013552:Swine; D013556:Swine, Miniature; D013696:Temperature; D014945:Wound Healing / Q000187:drug effects; D014950:Wounds, Penetrating / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology
chemical_list: D000577:Amides; D000779:Anesthetics, Local; D004655:Emulsions; D008081:Liposomes; D009821:Oils; D000077212:Ropivacaine