Hydrogel-Based Intranasal Drug Delivery Platforms

Abstract

Current strategies for oral or injectable antipsychotic drug delivery typically demonstrate low bioavailability to targeted brain regions, incentivizing the development of novel delivery strategies. Delivery via the nasal cavity circumvents multiple barriers to the reaching the brain: the blood-brain barrier, first-pass metabolism and gut degradation, but requires specific drug-carrier characteristics (e.g. pH, mucoadhesion) to be effective. Employing the use of nanoparticle drug carriers (~50nm in size) within this route can further improve efficacy, due to their enhanced tissue penetration abilities. Although existing intranasal delivery platforms have demonstrated great therapeutic value, there is a lack of controlled release features–an extremely valuable addition to this pathway. Described in this thesis are biodegradable bulk hydrogels consisting of oxidized starch nanoparticles (SNPs) and carboxymethyl-chitosan (CMC) which allow for both intranasal mucosal adherence and functional controlled release of anti-psychotic drug (PAOPA) in an MK-801 pre-clinical model of schizophrenia. Results indicate that PAOPA-loaded SNP-CMC in-situ gelled hydrogels provide a sustained released profile such that they alleviate negative symptoms associated with schizophrenia (decreased social interaction time) for up to 72 hours at a decreased dosage (0.5mg/kg) when compared to acute symptom alleviation at a higher (1mg/kg) intra-peritoneal drug dosage. Also described is the formulation of nanoemulsion templated nanogels (~200nm) for eventual intranasal delivery applications. Nanogels (also consisting of SNP-CMC) demonstrated relevant degradation profiles resulting in SNP release, which may be employed for future tissue penetration applications within the nasal cavity. It is anticipated the bulk hydrogel platform (and nanogel system, once further studied) will lower required drug doses and ultimately improve clinical outcomes in treating mental illness.