Aminated gelatin as a nasal absorption enhancer for peptide drugs: evaluation of absorption enhancing effect and nasal mucosa perturbation in rats

Abstract

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.

Ability of Poly-<small>L</small>-arginine to Enhance Drug Absorption into Aqueous Humor and Vitreous Body after Instillation in Rabbits

“…22) Although Wang et al 23) reported that cationized gelatin with ethylenediamine enhanced the absorption of FD-4 after nasal administration, its enhancing potency were lower than that of PLA, 24) suggesting that amount of positive charge in a molecule may have a significance for the enhancing potency of polycations because there is a significant difference in number of amine residue between PLA and ethylenediaminated gelatin with comparable molecular weight. Thus, PLA appears to have the ability to increase drug absorption into the aqueous humor in a manner similar to that of those enhancers.…”

“…Among the penetration enhancers studied previously, cationic polymers such as chitosan, aminated gelatin, and poly-L-arginine are reported to increase the transepithelial absorption of peptide drugs by dissociation of tight junction assemblies which restrict the paracellular permeation in intestinal and nasal epithelia without producing significant epithelial damage. [2][3][4][5][6] Thus, polycationic polymers may be useful penetration enhancers for ocular drug delivery.…”

Effect of Aminated Gelatin on the Nasal Absorption of Insulin in Rats

“…11) In brief, H-gelatin or L-gelatin (10 g) was dissolved in 0.1 M phosphate buffer (pH 5.0, 250 ml). 1,2-Ethylenediamine (0.28, 5.6 or 28 g) was added to the solution and then the pH ) and the total volume was adjusted to 500 ml by addition of phosphate buffer (pH 5.0).…”

Complexation of a Poly-l-Arginine with Low Molecular Weight Heparin Enhances Pulmonary Absorption of the Drug

“…The bioavailabilities of FITC-dextran (4.4 kDa) following nasal administration were 24.7, 62.9 and 78.7% when PLAs with molecular weights of 8.9, 45.5 and 92.0 kDa, respectively, were used as absorption enhancers. Furthermore, Wang et al (43) reported that the high molecular weight of aminated gelatin might have contributed to its absorption-enhancing effect and speculated that higher molecular weight enhancers themselves would present a low level of penetration through the membrane, therefore demonstrating a stronger interaction with the mucosa and a stronger absorption-enhancing effect. In our view also, high molecular weight cationic permeation enhancers retained over the membrane for a prolonged time should elicit heightened membrane permeability.…”