Evaluation of a novel absorption promoter - criticalsorb for the nasal delivery of drugs.

The project will evaluate a novel absorption promoter system - CriticalSorb for the nasal delivery of drugs. The project will focus on four key areas: evaluation of the physico-chemical properties of the formulations and identify essential characteristics, investigate its mechanisms of action using appropriate cell culture models, identify synergistic effects with other known absorption promoters and the final part of the project will look at developing a robust in vitro cell culture model in order to replace animal models when evaluating the nasal absorption of drugs. Background The nasal route of delivery can be exploited for the systemic delivery of drugs such as small molecular weight polar drug, peptides and proteins that are not easily administered via other routes than by injection. Despite the large surface area of the nasal cavity and extensive blood supply absorption of polar molecules, peptides and proteins is low but can be greatly improved if administered in conjunction with an absorption promoting agent. The enhancer systems work by a number of mechanisms however; animal studies have shown that most often there is a direct correlation between the absorption enhancing effect obtained and the damage caused to the nasal membrane. It is therefore important to discover and evaluate new absorption promoter systems. Critical Pharmaceuticals is a small specialty pharmaceutical company and have developed a nasal drug delivery platform based on an absorption promoter called CriticalSorb which has shown to be non-toxic to the nasal membrane in repeat dosing studies Task1. Physico-chemical characterisation of the formulations The first stage of the project will evaluate at the physico-chemical characterization of formulations containing CriticalSorb and a model drug in the form of a peptides or a protein. The CriticalSorb aqueous solutions form micelles and experiments will be carried out to determine the position of drug within such the micellar solutions, as well as the micellar properties. It will apply a combination of routine and state of the art 'nanotechnology' analytical techniques including: particle size and distribution, dye incorporation, morphology (cryo-TEM). Task 2. Evaluation of CriticalSorb mechanism of action The second stage of the project will study and describe the mechanism of action of the absorption enhancing effect of CriticalSorb and its principal components. This will focus on cell culture monolayers of either Calu-3 cells or HBEC (human bronchial epithelial) cells lines and will assess the mechanism of transport across the mucosal membrane, potentially transcellular or paracellular route. Specific mechanism of action will be investigated, such as the tight junction opening, clathrin or calveolin cellular pathway and effect on the 170 kDa membrane bound P-glycoprotein. Task 3. Potential synergistic effects of CriticalSorb with other known absorption enhancers CriticalSorb will be combined with other known absorption enhancers with alternative modes of action such as the typically investigated bioadhesive polysaccharide Chitosan to determine potential synergistic effects between the enhancers. Task 4. In vitro - in vivo correlation of absorption enhancing effect The final stage of the project will include comparisons of absorption enhancing effect from in vitro cell culture models with the in vivo data presently available, and those that will be created in animal studies by Critical Pharmaceuticals through another project. Wagner-Nelson modeling of the data will be carried out to determine the in vitro-in vivo correlation and the suitability of the in vitro cell culture model.