Aminated gelatin as a nasal absorption enhancer for peptide drugs: evaluation of absorption enhancing effect and nasal mucosa perturbation in rats.
This study was carried out to evaluate the potential of aminated gelatin as a nasal absorption enhancer for peptide drugs. The absorption-enhancing effect was investigated in rats using insulin and fluorescein isothiocyanate-dextran with a molecular weight of 4.4 kDa (FD-4) as model drugs. The absorption of insulin was estimated by measuring the changes in plasma glucose levels following intranasal administration, and that of FD-4 was determined by measuring its plasma concentration after dosing. The hypoglycaemic effect after intranasal administration of insulin with aminated gelatin significantly increased compared with that after intranasal administration of insulin in phosphate buffered saline, indicating that aminated gelatin effectively enhanced the nasal absorption of insulin. In contrast, neither kind of native gelatin (isoelectric point = 5.0 and 9.0) showed any absorption-enhancing effect. The pH of the formulations and the concentration of aminated gelatin were found to affect the hypoglycaemic effect. In addition, aminated gelatin at a concentration of 0.2% significantly enhanced the absorption and the efflux of FD-4 through the rat nasal mucosa. The possible perturbation of aminated gelatin to nasal mucosa was evaluated by measuring the leaching of lactate dehydrogenase (LDH) using an in-situ perfusion rat model. Aminated gelatin presented a concentration-dependent (0.1-0.4%) but relatively small effect on the LDH leaching from the rat nasal epithelial membrane. These results suggest that positively charged aminated gelatin could be a new absorption enhancer for nasal delivery of peptide drugs.
Wang
Jian
J
Department of Pharmaceutics, Hokkaido College of Pharmacy, Otaru City, Japan.
Sakai
Shigeko
S
Deguchi
Yoshiharu
Y
Bi
Dianzhou
D
Tabata
Yasuhiko
Y
Morimoto
Kazuhiro
K
D000042:Absorption; D000281:Administration, Intranasal; D000586:Amination; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D003911:Dextrans / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics; D004337:Drug Carriers / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics*; D016650:Fluorescein-5-isothiocyanate / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D005780:Gelatin / Q000008:administration & dosage* / Q000737:chemistry / Q000494:pharmacology*; D007328:Insulin / Q000008:administration & dosage / Q000493:pharmacokinetics; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008297:Male; D009297:Nasal Mucosa / Q000201:enzymology / Q000378:metabolism*; D010455:Peptides / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D051381:Rats; D017208:Rats, Wistar
D001786:Blood Glucose; D003911:Dextrans; D004337:Drug Carriers; D007328:Insulin; D010455:Peptides; C015219:fluorescein isothiocyanate dextran; D005780:Gelatin; D007770:L-Lactate Dehydrogenase; D016650:Fluorescein-5-isothiocyanate