Compounds for enhanced delivery of pharmaceuticals via mucosal surface

Aim of the project: The aim of this project is to provide fundamental understanding to underpin the design and early development of pharmaceutical formulations for mucosal delivery of small drugs with absorption problems as well as biologicals, based on the compounds of interest to the industrial sponsor. The project sits within the current collaborative activities of Honda and 'eminate' (S Minter) as well as Drug Delivery and Tissue Engineering Division at the School (S Stolnik), the later involving current projects to assess the potential of mucosal surfaces for delivery of antibodies, a collaboration with the Cell Biophysics and Optics Groups at Nottingham to develop a technique for imaging cell surface processes (Byrne 2008) and involvement with the University Division of Medicine - Gastroenterology group. From the drug delivery perspective the project seeks to answer whether the natural products currently of interest to Honda can produce effects sufficient for therapeutic administration of drugs and biologicals via mucosal route, particularly from gastrointestinal tract following oral administration. Background to the project: Molecular and physicochemical properties of some small molecular weight drugs and well as biologicals are such that with current drug delivery technologies these therapeutic agents can only be administered via injection. Approaches to formation of systems for delivery of active compounds across mucosal surfaces are now resulting in first medicines reaching the market eg (Fortical, Ora-lyn) (Brown 2005). The systems under research are often based on designing nano-sized carriers, the area of expertise in the Drug Delivery Group (Stolnik 1995, Govender 1999, Rungsardthong 2001, Lam 2004). This project focuses on investigating compounds, initially suggested by Honda and now produced by 'eminate', to have an effect at the gastric mucosal surfaces in order to provide understanding of the phenomenon and to apply gained knowledge to the design of a new delivery system. Phase 1. Establishment of a realistic cell culture model The routine CaCo2 monolayer model, together with Calu3 and IEC6 lines, are available in the group and will be established for the project as required. Labelled active compounds will be used to investigate routes of entry and translocation in vitro. Phase 2. Cell translocation and mechanistic studies This project utilises the compounds initially suggested by the company to have an effect on the absorption via mucosal epithelium. As part of these studies, we will test the effect of these compounds on the cells in culture as well as on the excised tissue (pig or human, the later from a collaboration with Division of Medicine - Gastroenterology at Nottingham) and ascertain the effects on the mechanism of translocation. We will probe possible routes of cellular entry using both approaches applying a series of established inhibitors to particular pathways of the cells and monitor the endocytosis process as well as using the total internal reflection microscope (Byrne et al 2008), an analytical tool designed for real time monitoring of cell membrane events. Phase 3. Development of enhanced mucosal delivery systems In this phase of the project we will incorporate key features of the systems design - colloidal carrier and a compound identified to promote translocation across epithelial cells. The focus will be on how can these components be incorporated to formulate into useful delivery systems. The expertise in production and characterisation of colloidal system and their surface modification will be exploited for this stage. References: Byrne et al 2008 Journal of Microscopy-Oxford 231:168., Brown 2005 Expert Opinion Drug Del 2:29. , Stolnik et al 1995 Advanced Drug Delivery Reviews 16:195. ,Govender et al 1999 Journal of Controlled Release, 57:171., Rungsardthong et al 2001 Journal of Controlled Release 73:359., Lam et al 2004 Journal of Controlled Release 100: 293.