Absorption of interferon alpha from patches in rats.
Interferon alpha (IFN-alpha), patch preparations composed of three layers, water-insoluble backing layer, drug containing layer with absorption enhancer and surface layer containing pH-dependent polymer were prepared. As absorption enhancer, three surfactants, Gelucire44/14 (Lauroyl macrogol-32 glycerides), Labrasol (Caprylocaproyl macrogol-8 glycerides) and HCO-60 (polyoxyethylated hydrogenerated castor oil) were used in preparing IFN-alpha patch preparations. The intestinal absorption of IFN-alpha was studied after the administration of test patch preparations into the rat jejunum, 50,000 IU/kg. The serum IFN-alpha levels were measured by an ELISA method and both C(max) and AUC were determined as the index of absorption of IFN-alpha. Gelucire44/14 preparation including Pharmasol for the stable solidification showed the higher C(max), 7.66 +/- 0.82 IU/ml, and AUC, 12.85 +/- 1.49 IU h/ml, than Labrasol (6.51 +/- 0.89 and 8.30 +/- 1.34 IU h/ml) and HCO-60 (6.02 +/- 1.14, 7.53 +/- 1.84 IU h/ml) preparations, respectively. By comparing to the AUC obtained after s.c. injection of the same dose of IFN-alpha to rats, bioavailability (BA) was estimated to be 7.8% in Gelucire44/14 preparation. In vitro release study showed that the T50%s, the time when half of the formulated IFN-alpha is released from the patches, were 3.4 +/- 0.1 min for HCO-60, 7.8 +/- 0.1 min for Gelucire44/14 and 11.4 +/- 0.1 min for Labrasol preparations. To study the effect of absorption site, Gelucire44/14 preparation was administered into the rat duodenum and ileum. However, there were not significant differences on AUC among the three absorption sites. By reducing the IFN-alpha dose from 50,000 to 25,000 IU/kg, the serum IFN-alpha levels vs time profile showed a tendency of dose-dependency. When the histological examination of small intestinal mucosa was carried out in this study, the small intestinal mucosa after the Gelucire44/14 patches administered and before it was administered, could not recognize impaired. From these results, the usefulness of oral patch system for the oral delivery of IFN-alpha has been proved in rats.
Ito
Yukako
Y
Department of Pharmacokinetics, Kyoto Pharmaceutical University, Yamashina-ku, Kyoto, Japan. yukako@mb.kyoto-phu.ac.jp
Tosh
Biranchinarayan
B
Togashi
Yusuke
Y
Amagase
Kikuko
K
Kishida
Tsunao
T
Kishida
Tsunataro
T
Sugioka
Nobuyuki
N
Shibata
Nobuhito
N
Takada
Kanji
K
D000818:Animals; D019540:Area Under Curve; D001682:Biological Availability; D002368:Castor Oil / Q000031:analogs & derivatives / Q000494:pharmacology; D002626:Chemistry, Pharmaceutical; D005989:Glycerides; D016898:Interferon-alpha / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D007408:Intestinal Absorption / Q000187:drug effects; D007583:Jejunum / Q000378:metabolism; D008297:Male; D009930:Organic Chemicals / Q000494:pharmacology; D011092:Polyethylene Glycols / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D013501:Surface-Active Agents / Q000494:pharmacology*
D005989:Glycerides; D016898:Interferon-alpha; D009930:Organic Chemicals; D013501:Surface-Active Agents; C440220:Labrasol; C104509:gelucire 44-14; D011092:Polyethylene Glycols; C023040:polyethoxylated castor oil; D002368:Castor Oil