title: Pharmacokinetic and pharmacodynamic evaluation of a nanotechnological topical formulation of lidocaine/prilocaine (nanorap) in healthy volunteers.
abstract: BACKGROUND
  Nanorap is a new nanotechnological formulation for topical anesthesia composed of lidocaine (2.5%) and prilocaine (2.5%). This study evaluated the pharmacokinetics of Nanorap. For the determination of lidocaine and prilocaine in human plasma, a new method using high-performance liquid chromatography coupled with tandem mass spectrometry was developed. Nanorap pharmacodynamic (PD) and its physical proprieties were also evaluated.
  
  
  METHODS
  Nanorap was administered by topical application of 2 g to healthy volunteers, and blood samples were collected for the pharmacokinetics analysis. The drugs were extracted from plasma by liquid-liquid extraction with ether/hexane (80/20, vol/vol). The chromatography separation was performed on a Genesis C18 analytical column 4 μm (100 × 2.1 mm i.d.) with a mobile phase of methanol/acetonitrile/water (40/30/30, for lidocaine, and 50/30/20, for prilocaine, vol/vol/vol) + 2 mM of ammonium acetate and ropivacaine as internal standard. The drugs were quantified using a mass spectrometer with an electrospray source in the electrospray ionization positive mode configured for multiple reaction monitoring. The PD of Nanorap was evaluated with the use of a visual analog scale. Nanorap was characterized by cryofracture.
  
  
  RESULTS
  The chromatography run-time was 5.5 minutes for lidocaine and 3.3 minutes for prilocaine, and the lower limit of quantification was 0.05 ng/mL for both drugs. Mean Cmax was 6.62 and 1.72 ng/mL for lidocaine and prilocaine, respectively. Median Tmax was 6.5 hours for both drugs. Nanocapsules had a mean size of 88 nm and mean drug association of 92.5% and 89% for lidocaine and prilocaine, respectively. The PD study showed that Nanorap has a sufficient analgesic effect (>30% reduction in pain) after 10 minutes of application.
  
  
  CONCLUSIONS
  A new simple, selective, and sensitive method for determination of lidocaine and prilocaine in human plasma was developed. Nanorap generated safe plasma levels of the drugs and satisfactory analgesic effect.
authors.affiliation: *Institute of Biophysics Carlos Chagas Filho, Federal University of Rio de Janeiro (UFRJ); †Galeno Research Unit, Campinas; ‡Department of Pharmacology, Faculty of Medical Sciences, State University of Campinas (UNICAMP); §Department of Surgery, Faculty of Odontology, University Camilo Castelo Branco (UNICASTELO); ¶Department of Surgery, Faculty of Odontology, University of Sao Francisco (USF), Braganca Paulista; ‖ECA-University of Sao Paulo; **Instituto Nacional de Metrologia, Qualidade e Tecnologia-Inmetro, Rio de Janeiro; and ††Department of Pharmacology, Institute of Biomedical Sciences, University of Sao Paulo, Brazil.
authors.forename: Thiago
authors.initials: T
authors.lastname: Gagliano-Jucá
authors.forename: Maísa R
authors.initials: MR
authors.lastname: Castelli
authors.forename: Gustavo D
authors.initials: GD
authors.lastname: Mendes
authors.forename: André M M
authors.initials: AM
authors.lastname: Arruda
authors.forename: Lu Shi
authors.initials: LS
authors.lastname: Chen
authors.forename: Marco A
authors.initials: MA
authors.lastname: de Oliveira
authors.forename: Sérgio F
authors.initials: SF
authors.lastname: Costa
authors.forename: Anibal Gil
authors.initials: AG
authors.lastname: Lopes
authors.forename: Wanderley
authors.initials: W
authors.lastname: de Souza
authors.forename: Gilberto
authors.initials: G
authors.lastname: De Nucci
mesh_terms: D000287:Administration, Topical; D000293:Adolescent; D000328:Adult; D000779:Anesthetics, Local / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D002626:Chemistry, Pharmaceutical; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D005260:Female; D064368:Healthy Volunteers; D006801:Humans; D008012:Lidocaine / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D000077442:Lidocaine, Prilocaine Drug Combination; D008297:Male; D008875:Middle Aged; D053769:Nanocapsules / Q000008:administration & dosage* / Q000737:chemistry*; D010147:Pain Measurement / Q000187:drug effects; D011318:Prilocaine / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D055815:Young Adult
chemical_list: D000779:Anesthetics, Local; D000077442:Lidocaine, Prilocaine Drug Combination; D053769:Nanocapsules; D011318:Prilocaine; D008012:Lidocaine