Linear polyethyleneimine and derivatives as potential biomaterials and excipients for drug delivery

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

Physically crosslinked cryogels of linear polyethyleneimine: influence of cooling temperature and solvent composition

Physically crosslinked cryogels can be prepared using linear polyethyleneimine (L-PEI) and a freeze-thawing technique. L-PEI was synthesized by hydrolysis of poly(2-ethyl-2-oxazoline) under acidic conditions. 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. The effects of different cooling temperatures and the use of various solvent compositions on L-PEI gelation were also studied. L-PEI cryogels were produced by freezing aqueous solutions to various temperatures (-196, -80, -30, and 0 °C) for 3 h and subsequent thawing at 25°C for 24 h. Gel rigidity correlated with the freezing temperature and was strongest when cooled to -196 oC, consistent with determinations of the degree of crystallinity in the gels, the enthalpy of fusion and rheological behaviour. The effect of solvent mixtures on the crystallinity and rheological properties of L-PEI cryogels was also investigated. Water/ethanol mixtures containing a higher proportion of ethanol significantly reduced the strength, viscosity and degree of crystallinity of the L-PEI cryogels. Thus, by controlling the freezing temperature or modifying the solvent, L-PEI cryogels can be designed with desired mechanical properties for applications ranging from cell immobilisation and tissue culture scaffolds to drug delivery systems or antimicrobial wound dressings

Development of Wax-Incorporated Emulsion Gel Beads for the Encapsulation and Intragastric Floating Delivery of the Active Antioxidant from Tamarindus indica L.

In this study, tamarind (Tamarindus indica L.) seed extracts with potential antioxidant activity and toxicity to cancer cells were developed as functional foods and nutraceutical ingredients in the form of emulsion gel beads. Three extracts were obtained from ethanol and water: TSCH50, TSCH95 and TSCH. All extracts exhibited high potential for superoxide anion scavenging activity over the IC50 range < 5–11 µg/mL and had no toxic effects on normal cells, however, the water extract (TSCH) was the most effective due to its free radical scavenging activity and toxicity in mitochondrial membranes of cancer cells. Next a study was designed to develop a new formulation for encapsulation and intragastric floating delivery of tamarind seed extract (TSCH) using wax-incorporated emulsion gel beads, which were prepared using a modified ionotropic gelation technique. Tamarind seed extract at 1% (w/w) was used as the active ingredient in all formulations. The effect of the types and amounts of wax on the encapsulation efficiency and percentage of the active release of alginate gel beads was also investigated. The results demonstrated that the incorporation of both waxes into the gel beads had an effect on the percentage of encapsulation efficiency (%) and the percentage of the active ingredient release. Furthermore, the addition of water insoluble waxes (carnauba and bee wax) significantly retarded the release of the active ingredient. The addition of both waxes had a slight effect on drug release behavior. Nevertheless, the increase in incorporated waxes in all formulations could sustain the percentage of active ingredient release. In conclusion, wax-incorporated emulsion gel beads using a modified ionotropic gelation technique could be applied for the intragastric floating delivery and controlled release of functional food and nutraceutical products for their antioxidant and anticancer capacity

Synthesis and evaluation of poly(3-hydroxypropyl ethylene-imine) and its blends with chitosan forming novel elastic films for delivery of haloperidol

This study aimed to develop novel elastic films based on chitosan and poly(3-hydroxypropyl ethyleneimine) or P3HPEI for the rapid delivery of haloperidol. P3HPEI was synthesized using a nucleophilic substitution reaction of linear polyethyleneimine (L-PEI) with 3-bromo-1-propanol. 1H-NMR and FTIR spectroscopies confirmed the successful conversion of L-PEI to P3HPEI, and the physicochemical properties and cytotoxicity of P3HPEI were investigated. P3HPEI had good solubility in water and was significantly less toxic than the parent L-PEI. It had a low glass transition temperature (Tg = −38.6 °C). Consequently, this new polymer was blended with chitosan to improve mechanical properties, and these materials were used for the rapid delivery of haloperidol. Films were prepared by casting from aqueous solutions and then evaporating the solvent. The miscibility of polymers, mechanical properties of blend films, and drug release profiles from these formulations were investigated. The blends of chitosan and P3HPEI were miscible in the solid state and the inclusion of P3HPEI improved the mechanical properties of the films, producing more elastic materials. A 35:65 (%w/w) blend of chitosan–P3HPEI provided the optimum glass transition temperature 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. Higher release with increasing drug loading allows flexible dosing. Blending P3HPEI with chitosan thus allows the selection of desirable