Constructing stable chitosan and pectin peptide-delivery systems for nose and gut

In order to treat disease it is often necessary to administer a drug into the blood system of a patient: the blood system will then take the drug to the right spot. Direct injections of drug into the bloodstream are not very nice, so the most popular method - for the doctor and the patient alike - is, if it is possible, to take a drug through the mouth or place it in the nasal cavity: the drug will then hopefully get absorbed though pores that line your intestine and the inside of your nose, pores which are covered by a sticky substance called mucus. Both routes can be very wasteful because of the body's natural clearance mechanisms, but we can use special large molecules or 'polymers' which adhere to the mucus layer and help stop the drug from being washed away too quickly. Formulations involving these sticky polymers have to be both non-poisonous and be stable (not to go-off too quickly). They need to be able to hold and then release the drug when required. Chitosans - which come from the shells of crabs, lobsters and related sea-creatures - and pectins, which come from the cell walls of fruit, are very attractive in this regard, and much important research has already been done. And there are a wide variety of them, varying in their size and the amount if positive charge (chitosan) or negative charge (pectin) on them. However, before they can successfully lead to products on the shelves of Pharmacy shops their stability (resistance to being broken down) needs to be thoroughly explored, not only for the polymers but also the complicated structures of the polymer used to carry the drug. If we can find a stable system that still delivers the drug into the bloodstream then the chances of getting a product into the Dispensaries for use by patients will be good.

The oral and nasal routes are the most popular routes for drug administration for both patient and doctor alike but there are major problems of efficiency. Polysaccharide delivery vehicles have been considered, and much important groundwork has been done but there are still important unresolved issues particularly with regard to product stability before products can reach the pharmacist's shelf. The aim of this research is to provide a rigorous scientific basis for the construction of safe, stable and efficient macromolecular oral or nasal drug delivery systems from two different types of polysaccharide: low methoxy pectins (anionic) and chitosans (cationic). We consider chitosan solutions/powders and pectin gels for the nose, Chitosan complexes (TPP-or tripolyphosphate chitosan nanoparticles) for the oral route. We focus on the delivery of a representative peptide drug, namely insulin. To achieve this aim we have combined the expertise of academic researchers at the National Centre for Macromolecular Hydrodynamics at Nottingham University with industrial researchers at Archimedes Development Limited (formerly West Pharmaceutical Services), also conveniently based at Nottingham. We will firstly establish the solubility of these polymers using simple ultracentrifugation. Then using the tools of SEC-MALLs (size-exclusion chromatography coupled to multi angle laser light scattering) and analytical ultracentrifugation we will study the molecular integrity of solutions of pectins and chitosans of a variety of chemical compositions, and then assay their stability using these methods and precision viscometry. The stability of TPP-chitosans will be assessed using disc centrifugation reinforced by atomic force microscopy. The stability of pectin gels will be assessed using Texture Analysis. Obviously it is no good having a stable system if drug cannot be delivered, so, using insulin as a representative peptide drug (a substanec we have considerable experience with)the holding/diffusive properties of the pectin gels will then be studied using a special adaptation of the optical system on the analytical ultracentrifuge, (selectively detecting insulin transport from uv-absorption at 280nm), coupled with equilibrium dialysis measurements. Drug holding/diffusive properties of the TPP-chitosan will be studied by disc centrifugation. Successful release of the drug into the bloodstream for oral TPP-chitosan, nasal chitosan solution and nasal pectin gel systems will be assessed using sheep as suitable animal models. If we find appropriate stable chitosan, TPP-chitosan or pectin systems that still effectively deliver drug then we may have the basis of a pharmaceutical product (i.e. one that makes the shelf at the local Dispensary).