Migraine is an extremely common, disabling condition which ruins the lives of millions of patients worldwide and is hard to treat effectively. Existing migraine medications are only partially effective, they have unwanted side effects and some patients are resistant to any current treatment.
CGRP is an abundant neuropeptide, consisting of 37 amino acids that plays key roles in cardiovascular homeostasis and nociception and is recognised as an important mediator of neurogenic inflammation and a very likely key contributor to migraine pathology. GPCRs in general have proved to be prime targets for drug discovery, and selective CGRP antagonists with clinical efficacy against migraine have now been produced. Our approach has been to design small 8-10 amino acid peptide antagonists of the CGRP receptor.
Peptides are naturally occurring biologics and, hence, tend to be safer than synthetic drugs and less immunogenic than proteins and antibodies. However, it is challenging to effectively deliver peptides via the oral route due to the harsh stomach environment that results in degradation. By comparison, the nasal route offers several advantages for both local and systemic delivery such as; a large surface area, a thin epithelium, dense vasculature, less enzymatic activity and is non-invasive. For delivery to the brain, the nasal route offers the possibility of adsorption via the nasal mucosa or direct delivery via the olfactory nerve. We have utilized design of experiment to prepare peptide loaded; Poly lactic-co-glycolic acid (PLGA), poly(glycerol adipate-co-ω-pentadecalactone), PGA-co-PDL and various chitosans nanoparticles (NPs). Mucoadhesive microparticles containing either peptide or peptide loaded NPS were prepared by spray drying from chitosans.
The small peptide antagonists that we have developed to date have demonstrated high potency in in vitro pharmacological testing and further pre-clinical development is now underway.