Le, Hang Thi Bich; (2008) The oral delivery of hydrophobic drugs - a role for amphiphilic polymers. Doctoral thesis (Ph.D.), University College London (United Kingdom).

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Abstract

Nine poly(ethylenimine) (PEI) and glycol chitosan based amphiphiles were synthesised with the aim of creating effective carriers for the oral delivery of poorly soluble drugs. The architecture of the amphiphilic molecules was controlled through varying hydrophobic substitution levels, varying molecular weight and using both branched and linear molecules. The molecular weights of the nine amphiphiles ranged from 1.3 kDa – 22 kDa. Amphiphiles dispersed well in aqueous media and formed positively charged nanoparticles of 100 – 300 nm in diameter above the critical aggregation concentration (CAC). Glycol chitosan based amphiphiles formed a polydisperse mixture of microparticles and nanoparticles. The CAC ranged from 0.01 mM to 0.4 mM, depending on the chemical structure of amphiphiles. It was observed that the CAC values and aggregate sizes decreased with an increase in the hydrophobicity and molecular weight of amphiphiles. Low molecular weight amphiphiles formed larger aggregates than their higher molecular weight derivatives. In addition, aggregates from linear polymers were also larger than these from the branched counterparts. The viscosity of the polymers increased with an increase in the intermolecular interactions caused by an increase in polymer concentration, number of hydrophobic pendants on the polymer backbones and polymer molecular weight. Amphiphilic polymers encapsulated cyclosporine A, (CsA) a lipophilic Class II drug in the Biopharmaceutical Classification System. The drug loading in polymer dispersions was favoured by an increase in polymer hydrophobicity, molecular weight and concentration and liquid formulations were stable for 6 months. The polymers increased the dissolution rate from CsA tablet formulations after 2 hours. Amphiphilic PEIs however demonstrated high levels of cytotoxicity and haemolysis on the epidermoid carcinoma cells and red blood cells, respectively. Meanwhile quaternary palmitoyl glycol chitosan (GCPQ) proved to be less toxic. The polymers improved drug oral absorption by up to 550% in a rat model compared to drug alone. Drug absorption enhancement was favoured by increasing the polymer concentration (up to a point), hydrophobicity and molecular weight and by reducing polymer aggregate size. The mechanism of oral absorption enhancement of polycationic amphiphiles was hypothesized to involve: a) an increase in the dissolution rate and/or aqueous solubility of the drug and b) adhesion to absorptive epithelium to promote drug residence time at the gastrointestinal absorption sites.

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