Studies On The Properties Of Aminated Gelatin And Its Application In Nasal Drug Delivery System

A new cationic polymer, aminated gelatin, was synthesized by modification of gelatin with 1,2-ethylenediamine in the presence of a kind of water-soluble carbodiimide. Aminated gelatin presents a higher amino group content, a higher level of solubility, a lower gelling temperature and a higher molecular flexibility and chain mobility.The mucoadhesive properties of aminated gelatin were evaluated systemically by using two kinds of commercial mucin (type I -S and type III) as mucus models and using water, simulated gastric fluid and simulated intestinal fluid as medium models respectively. Colloidal and rheological studies showed that aminated gelatin demonstrates a stronger interaction with mucin in all of the experimental conditions tested in comparison with that of native gelatin, and the electrostatic interaction is the main force involved in these interactions. Mechanical studies showed that aminated gelatin possesses stronger mucoadhesive strengths than the native gelatins, which is ascribed to the properties of quick hydration and the higher flexibility of aminated gelatin. The results of thermodynarnic studies indicated that the interfacial interaction between hydrated aminated gelatin and mucin is a process accompanied with a negative Gibbs free energy, and aminated gelatin solution can spread over the surface of mucin solution spontaneously. The change of interaction surface energy between aminated gelatin film and mucin is also negative. Both the dispersive and polar components of the Gibbs free energy contribute to this phenomenon. However, the difference between gelatin and aminated gelatin mainly comes from polar component of surface energy.To further investigate the bioadhesive properties and the mechanisms of bioadhesion of aminated gelatin, aminated gelatin microspheres were prepared by surfactant-free emulsification of aminated gelatin solution in olive oil, followed by cross-linking reaction with glutaraldehyde. The microspheres are in a sphere shape, with a mean diameter of about 40-50 um, and present a good biodegradability. The amino group contents of the aminated gelatin microspheres were determined using a 2,4,6-trinitrobenzenesulfonic acid method. Aminated gelatin microsphere presents a significantly higher amino group content than the two kinds of native gelatin microspheres. However, with the increase of the glutaraldehyde concentration and/or cross-linking reaction time, the amino group content of the microspheres decreased accordingly.The mucoadhesive properties of aminated gelatin microspheres were evaluated both in vitro and in vivo in rats and healthy volunteers. The interactions of native andaminated gelatin microspheres with two kinds of commercial mucin (type I -S and type III) were investigated in different aqueous media. As a result, a larger amount of mucin was adsorbed to aminated gelatin microspheres than to either of the native gelatin microspheres under all the conditions investigated, although the amount of mucin adsorbed to microspheres varied significantly in different media. These results indicated that there is a stronger interaction between mucin and aminated gelatin microspheres than that between mucin and native gelatin microspheres. The electrostatic attraction is the main force for these interactions.In the in vitro model of isolated and perfused rat stomach, the amount of aminated gelatin microspheres that remained in the stomach after perfusion was significantly larger than that of the native gelatin microspheres. No significant difference in gastric retention was observed whether the test was performed in simulated gastric fluid (SGF) or in phosphate buffered saline (PBS, pH7.4), nor differences observed between the two native gelatin microspheres. These results suggested that the electrostatic interaction is not the decisive force for the mucoadhesion of the microspheres in this model.In the in vivo mucoadhesion experiment, the amount of aminated gelatin microspheres remained in the stomach two hours after oral administration in a capsule inc...