Oral delivery of insulin by using surface coating liposomes: Improvement of stability of insulin in GI tract
Introduction
Most peptides are ineffective by oral administration due to the low stability in the GI tract and their poor absorption. In order to improve their oral bioavailability, many strategies have been tested, such as a co-administration of absorption enhancers which increase the permeability of peptides through the intestinal membrane (Morishita et al., 1993, Hovgaard et al., 1995), a synthesis of their stable derivatives (Bruce and Susanna, 1995) and the development of special dosage forms by utilizing the micro or nano-particles as a drug carrier (Michel et al., 1991, Jenkins et al., 1994, Damge et al., 1995). Absorption enhancers showed several safety problems for clinical use. The bioactivity of peptides might be reduced through their required derivatization. On the contrary, a drug carrier system has many advantages. It is possible to control the release rate of peptides from particles after oral administration. Biodegradable materials can be used as components of particles for their safety in clinical use. Liposomes are one of the most potent candidates for such a drug carrier system. However, the efficacy of liposomes as an oral delivery system of peptide drugs has not yet been established. One of the reason for this problem is the instability of liposomes in GI tract. Liposomes were easily degraded by bile salts in GI tract because they interact with liposomes as surfactants. In order to use liposomes for oral dosage forms, a method to avoid this interaction was important.
In this study, we used insulin as a model peptide and investigated the possibility of surface coating liposomes as a tool for the oral delivery of peptide drugs.
Section snippets
Materials
Dipalmitoylphosphatidylcholine (DPPC), cholesterol (CHOL) and distearoylphosphatidylethanolamine-polyethyleneglycol 2000 (DSPE-PEG) were donated by Nippon Fine Chemical (Tokyo, Japan). Bovine insulin (25.7 IU/mg) and stearylamine (SA) were purchased from Sigma (St. Louis, MO). The other chemicals were of analytical grade.
Cetyl-mucin, one of the surface coating materials, was synthetized as follows: Mucin from pig stomach (Wako Pure Chemical, Osaka, Japan) was trypsinized for 5 h at 37°C,
Release of insulin from liposomes
The release profiles of insulin from liposomes are shown in Fig. 2. In the acidic solution (pH 2.0), four liposomes remained stable during the experimental period and no significant release of insulin was observed. Addition of bile salts into test solutions dramatically enhanced the release rate of insulin from the uncoated liposomes. Released amounts of insulin from uncoated liposomes reached ≈30% with sodium glycocholate and 20–50% with sodium taurocholate within 6 h. On the other hand, even
Discussion
It was reported that insulin entrapped by liposomes significantly reduced the plasma glucose levels of diabetic dogs by oral administration (Patel and Ryman, 1976), suggesting the possibility of liposomes as a tool of oral delivery of peptide drugs. However, the efficacy of liposomes as an oral dosage form has not been defined yet because of the complex behavior of liposomes in GI tract (Spangler, 1990, Fukunaga et al., 1991, Chodhari et al., 1994). As one of the main problems, liposomes were
Acknowledgements
We thank Dr Y. Namba (Nippon Fine Chemical) for the synthesis of DSPE-PEG and the gift of phospholipids. We also thank Ms K. Doi and Ms N. Saito (University of Shizuoka) for their technical assistance.
References (16)
- et al.
Drug delivery studies in Caco-2 monolayers 2. Absorption enhancer effects of lysophosphatidylcholines
Int. J. Pharm.
(1995) - et al.
Microparticulate absorption from the rat intestine
J. Control Release
(1994) - et al.
Disposition kinetics and oral bioavailability of vincamine-loaded polyalkylcyanoacrylate nanopaticles
J. Pharm. Sci.
(1986) - et al.
Oral administration of insulin by encapsulation within liposomes
FEBS Lett.
(1976) - et al.
Stability of liposomes in vitro and their uptake by rat Peyer's patches following oral administration
Pharm. Res.
(1993) - et al.
Stability of acyl derivatives of insulin in the small intestine: Relative importance of insulin association characteristics in aqueous solution
Pharm. Res.
(1994) - et al.
Diffusion of univalent ions across the lamellae of swollen phospholipids
J. Mol. Biol.
(1965) - et al.
Metabolism of a neurotensin (8–13) analog by intestinal and nasal enzymes and approaches to stabilize this peptide at these absorption sites
Int. J. Pharm.
(1995)