INVESTIGATION OF A PMDI SYSTEM CONTAINING CHITOSAN MICROSPHERES AND P134A

Microspheres made of chitosan, a biodegradable polymer, were investiga ted as a potential carrier for therapeutic proteins, peptides and plas mid DNA for administration to the lung from a pressurized metered dose inhaler (pMDI). Through the use of different cross-linking agents and additives, the physicochemical properties of chitosan microspheres we re modified to improve compatibility in a pMDI delivery system. Their density, thermal properties, surface hydrophobicity, surface charge an d free amino group content were determined before and after formulatio n in a pMDI system utilizing P134a. Also, the in vitro delivery charac teristics of the pMDI systems were ascertained by cascade impaction. T he densities of the non cross-linked and the glutaraldehyde cross-link ed chitosan microspheres closely matched that of liquid P134a. An incr ease in the median particle size and the polydispersity after exposure to P134a was found for all types of chitosan microspheres tested exce pt for those cross-linked with glutaraldehyde. This was due to the pre sence of water in P134a which hydrated and plasticized the chitosan mi crospheres causing aggregation during storage of the pMDI formulations . The change in the mass median aerodynamic diameter (MMAD) of the emi tted dose of the pMDI systems reflected the influence of water on the particle size distribution of the chitosan microsphere pMDI suspension formulations. The pMDI systems studied produced respirable fractions (%RF) of 18% and multiple determinations of the dose delivery through- the-valve (DDV) of the pMDI systems were consistent. The surface hydro phobicity of the glutaraldehyde cross-linked chitosan microspheres was significantly greater than non cross-linked or tripolyphosphate (TPP) cross-linked chitosan microspheres. The addition of aluminum hydroxid e (Al(OH3)) to non cross-linked chitosan microspheres did not signific antly influence the surface hydrophobicity. A decrease in the free sur face amine content and the zeta potential after exposure to P134a was related to hydration and plasticization by water contained in the pMDI formulations. The non cross-linked and the glutaraldehyde cross-linke d chitosan microspheres were found to be potential candidates for carr ying biotherapeutic compounds to the lung via a pMDI system due to the ir compatability with P134a and their physicochemical characteristics. (C) 1998 Elsevier Science B.V. All rights reserved.