Pharmacokinetic and pharmacodynamic evaluation of insulin dissolving microneedles in dogs.
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.
Fukushima
Keizo
K
Department of Pharmacokinetics, Kyoto Pharmaceutical University, Kyoto, Japan. keizo@mb.kyoto-phu.ac.jp
Yamazaki
Takenao
T
Hasegawa
Ryo
R
Ito
Yukako
Y
Sugioka
Nobuyuki
N
Takada
Kanji
K
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
D001786:Blood Glucose; D007004:Hypoglycemic Agents; D007328:Insulin; C031573:insulin, fluorescein-isothiocyanated-; D016650:Fluorescein-5-isothiocyanate