Gastro-intestinal patch system for the delivery of erythropoietin.
The absorption of erythropoietin (EPO) from rat small intestine was studied using gastro-intestinal patches (GI-PS) in the presence of absorption enhancers. Surfactants such as a saturated polyglycolysed C8-C18 glyceride (Gelucire 44/14), PEG-8 capryl/caprylic acid glycerides (Labrasol), and polyoxyethylene hydrogenated castor oil derivative (HCO-60) were used as absorption enhancers at 143, 94 and 20 mg/kg, respectively. The absorption of EPO was studied by measuring serum EPO levels by an ELISA method after small intestinal administration of EPO-GI-PS preparation in rats at the EPO dose level of 100 IU/kg. Labrasol showed the highest absorption enhancing effect after intrajejunum administration with maximum serum EPO level of 84.1+/-11.4 mIU/ml while Gelucire 44/14 and HCO-60 showed 43.5+/-9.8 and 26.5+/-2.3 mIU/ml, respectively. The appropriate site for EPO absorption was also investigated. Jejunum was found to be the most efficient absorption site for the absorption of EPO from GI-PS. Using Labrasol as the absorption enhancer and jejunum as the absorption site, the effect of EPO dose on EPO absorption was studied by increasing the EPO dose from 50, to 100, 300 and 600 IU/kg. It was found that 100 IU/kg was the optimum dose with a serum EPO level of 84.1+/-11.4 mIU/ml while escalating doses showed decreases in serum EPO levels 48.3+/-5.6 for 300 IU/kg and 50.6+/-10.3 mIU/ml for 600 IU/kg. The percent bioavailability (BA) of EPO-GI-PS with Labrasol as absorption enhancer was 7.9 at 50 IU/kg, 12.1 at 100 IU/kg, 3.2 at 300 IU/kg and 1.2 at 600 IU/kg. Histological studies showed no adverse effect at the site of administration.
Venkatesan
N
N
Department of Pharmacokinetics, Kyoto Pharmaceutical University, Nakauchi-cho 5, Misasagi, Yamashina-ku, Kyoto 607 8414, Japan.
Uchino
K
K
Amagase
K
K
Ito
Y
Y
Shibata
N
N
Takada
K
K
D000284:Administration, Oral; D000465:Algorithms; D000818:Animals; D019540:Area Under Curve; D002368:Castor Oil / Q000031:analogs & derivatives / Q000737:chemistry; D004337:Drug Carriers / Q000737:chemistry*; D016503:Drug Delivery Systems; D004921:Erythropoietin / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D041981:Gastrointestinal Tract / Q000378:metabolism*; D005989:Glycerides; D007408:Intestinal Absorption; D007583:Jejunum / Q000378:metabolism; D008297:Male; D008657:Metabolic Clearance Rate; D009930:Organic Chemicals / Q000737:chemistry; D011092:Polyethylene Glycols / Q000737:chemistry; D051381:Rats; D017208:Rats, Wistar
D004337:Drug Carriers; D005989:Glycerides; D009930:Organic Chemicals; C440220:Labrasol; D004921:Erythropoietin; C104509:gelucire 44-14; D011092:Polyethylene Glycols; C023040:polyethoxylated castor oil; D002368:Castor Oil