title: Pharmacokinetic and pharmacodynamic evaluation of insulin dissolving microneedles in dogs.
abstract: BACKGROUND
  This study tested the hypothesis that dissolving microneedles are a useful transdermal drug delivery system (TDDS) for insulin.
  
  
  METHODS
  Insulin was loaded on a patch (1.0 cm2) that had 100 dissolving microneedles with chondroitin sulfate by microfabrication technology. Pharmacodynamic evaluation was performed by applying two or four patches to the shaved abdominal skin of dogs, and blood samples were collected for 360 min to measure plasma glucose and insulin levels. In diffusion experiment, microneedles containing fluorescein isothiocyanate-insulin and/or Evans blue were administered to the rat skin, and the diffusion rates of tracers were recorded.
  
  
  RESULTS
  The mean length, diameter of basement, and drug-loaded space from the top of the microneedles were 492.6 +/- 2.4, 290.0 +/- 3.6, and 316.0 +/- 7.3 microm, respectively. The insulin content was 1.67 +/- 0.17 IU per patch. The time when the minimum plasma glucose level was obtained was 50.0 +/- 8.7 min for two-patch and 82.5 +/- 14.4 min for four-patch studies. A dose-dependent hypoglycemic effect was observed. By comparing the cumulative percentage change in the plasma glucose level between insulin microneedles and solution, the relative physiological availabilities were calculated to be 71.1 +/- 17.8% (for two patches) and 59.3 +/- 4.4% (for four patches). Bioavailabilities of insulin from microneedles were 72.1 +/- 11.6% (for two patches) and 72.4 +/- 8.3% (for four patches). High diffusion rates of fluorescein isothiocyanate-insulin and Evans blue were observed at the administered skin site and correlated well with the high absorption rate of insulin into the systemic circulation. Insulin was stable in dissolving microneedles for 1 month at 4 degrees C; the recovered percentage was 99.2 +/- 13.9%.
  
  
  CONCLUSIONS
  Dissolving microneedles were demonstrated to be a useful TDDS as an immediate-acting insulin preparation.
authors.affiliation: Department of Pharmacokinetics, Kyoto Pharmaceutical University, Kyoto, Japan. keizo@mb.kyoto-phu.ac.jp
authors.forename: Keizo
authors.initials: K
authors.lastname: Fukushima
authors.forename: Takenao
authors.initials: T
authors.lastname: Yamazaki
authors.forename: Ryo
authors.initials: R
authors.lastname: Hasegawa
authors.forename: Yukako
authors.initials: Y
authors.lastname: Ito
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Sugioka
authors.forename: Kanji
authors.initials: K
authors.lastname: Takada
mesh_terms: D000279:Administration, Cutaneous; D000818:Animals; D019540:Area Under Curve; D001682:Biological Availability; D001786:Blood Glucose; D002851:Chromatography, High Pressure Liquid; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D016503:Drug Delivery Systems; D016650:Fluorescein-5-isothiocyanate / Q000031:analogs & derivatives; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics; D007328:Insulin / Q000008:administration & dosage* / Q000031:analogs & derivatives / Q000097:blood / Q000493:pharmacokinetics*; D008297:Male; D051381:Rats; D017208:Rats, Wistar
chemical_list: D001786:Blood Glucose; D007004:Hypoglycemic Agents; D007328:Insulin; C031573:insulin, fluorescein-isothiocyanated-; D016650:Fluorescein-5-isothiocyanate