The development of chemically engineered pullulan for drug delivery
Pullulan has been chemically modified by the incorporation of various hydrophobic molecules, to produce two types of derivatives (hydrophobically modified carboxymethyl pullulans (HMCMPs), and crosslinked carboxymethyl pullulan). The foregoing modifications were performed in two steps from the parent pullulan. The first step involved carboxylation of pullulan with sodium chloroacetate yielding carboxymethyl pullulan (CMP). The second step involved the medication of CMP by coupling different amine functionalized molecules onto the carboxylic groups of CMP, using the coupling agent dicyclohexylcarbodiimide. The amines used in this modification step were: hexadecylamine, decylamine, cadaverine (1-5 diaminopentane), and three jeffamine® (polyoxypropylenediamine) compounds of differing molecular weights (230, 400 and 2000). Results concluded that all six pullulan derivatives show an increase in reduced viscosity to varying degrees, compared to the parent pullulan. Characterization of pullulan and the derivatives concluded that the correct structures have been synthesised. Gel permeation chromatography confirmed that four pullulan derivatives had been crosslinked (due to doubled molecular weight terms), and a further two have increased in molecular weights, with no increase in polydispersity indices. Isothermal titration calorimetry experiments were initially performed on model systems (two different ß-cyclodextrins, and benzoic acid and eletriptan hydrobromide), and then on pullulan and the derivatives with eletriptan hydrobromide. These experiments probed the nature and extent of drug binding interactions. Results concluded that pullulan derivatives showed exothermic drug binding interactions with the named drug, with the exception of jeffamine 2000 crosslinked CMP, which exhibited endothermic interactions with the titrated drug. Pullulans excellent film forming capabilities may lead these polymers to a novel oral dosage form containing active (dissolving films).