Abstract/Summary

My PhD project was aimed to synthesize and evaluate linear polyethyleneimine and its derivatives as potential biomaterials and excipients for drug delivery. L-PEI was synthesized successfully by acidic hydrolysis of poly(2-ethyl-2-oxazoline) or PEOZ to remove all amide groups from the side groups. The complete conversion to L-PEI was confirmed by 1H-NMR and FTIR spectroscopies. Then, L-PEI was used to prepare physically crosslinked cryogels. Dissolution of L-PEI in deionized water was achieved at 80 oC and resulted in a transparent solution, leading to an opaque gel forming upon freezing and subsequent thawing. The cryogels exhibited reversibility and after heating at 80 oC formed a clear solution due to the melting of the crystalline domains of L-PEI. Different cooling temperatures and the use of various solvent compositions on L-PEI gelation have an effect on the enthalpy of melting, degree of crystallinity, viscosity and mechanical strength of L-PEI cryogels. This study demonstrates that the physical properties of L-PEI cryogels can be manipulated by controlling the cooling rate and solvent composition used to form the cryogels and its applications for drug delivery systems or antimicrobial wound dressings. Chemical modification of L-PEI is one approach to develop water solubility and properties of polymers. Therefore, we attempted to synthesize poly(2-hydroxyethyl ethyleneimine), P2HEEI and poly(3-hydroxypropyl ethyleneimine), P3HPEI as novel water�soluble polymers for pharmaceutical applications. P2HEEI and P3HPEI were synthesized via nucleophilic substitution reaction between L-PEI and 2-bromoethanol and 3-bromo-1- propanol, respectively. Both polymers had a good water solubility, low toxicity, and a low glass transition temperature. Due to the lower glass transition below 0 oC, these novel polymers were blended with chitosan to improve mechanical properties and the resulting polymeric films were evaluated for their applicability in transmucosal drug delivery. Chitosan and P3HPEI in the blends were fully miscible in solid stage. Blending of chitosan with P3HPEI also significantly enhanced elasticity and strength of the resulting films. A 35:65 (%w/w) blend of chitosan-P3HPEI provided the optimum Tg for transmucosal drug delivery and so was selected for further investigation with haloperidol, which was chosen as a model hydrophobic drug. Microscopic and X-ray diffractogram (XRD) data indicated that the solubility of the drug in the films was ~1.5%. The inclusion of the hydrophilic polymer P3HPEI allowed rapid drug release within ~30 min, after which films disintegrated, demonstrating that the formulations are suitable for application to mucosal surfaces, such as in buccal drug delivery. Mucoadhesive films are one of commercially relevant formulations for buccal drug delivery due to their adaptability and ease of use. Additionally, the use of these films can prolong the time spent on the mucosa, directly delivering a precise dose of the drug to the tissue. Hence, this study aimed to synthesize poly(2-hydroxyethyl ethyleneimine) or P2HEEI and its mucoadhesive film formulations based on blends with chitosan for buccal delivery of haloperidol. Initially, P2HEEI was synthesized via nucleophilic substitution of linear polyethyleneimine (L-PEI) with 2-bromoethanol. P2HEEI exhibited good solubility in water, low toxicity in human dermal skin fibroblast cells, and low glass transition temperature (-31.6 oC). This polymer was then blended with chitosan to improve mechanical properties and these materials were used for the buccal delivery of haloperidol. Chitosan and P2HEEI formed completely miscible blends. Blending chitosan with P2HEEI improved the mechanical properties of the films, resulting in more elastic materials. Blend films were also prepared loaded with haloperidol as a model poorly water-soluble drug. The cumulative release of haloperidol from the films increased when the blends were prepared with greater P2HEEI content. Mucoadhesive properties of these films with respect to freshly excised sheep buccal mucosa were evaluated using a tensile method. It was found that all films are mucoadhesive; however, an increase in P2HEEI content in the blend resulted in a gradual reduction of their ability to adhere to the buccal mucosa. These films could potentially find applications in buccal drug delivery. Hence, L-PEI and its derivatives have potential as biomaterials and excipients for drug delivery, enabling the development of novel formulations such as cryogels, drug-loaded films for poorly water-soluble drug administration, and mucoadhesive drug delivery system.