Abstract Many hydrophilic drugs do not easily cross biological membranes. One approach to improve intestinal absorption of hydrophilic compounds is to co-administer these drug molecules with absorption enhancers to optimize their physico-chemical properties. In this project, novel liposaccharides were used to modulate the aqueous solubility as well as increase the lipophilicity, improve the intestinal permeability and hence, oral bioavailability of hydrophilic molecules. However, the solubility of the drug/liposaccharide mixtures in aqueous system might be poor, therefore, introducing a hydrophilic component such as quaternization of amine derivatives or sodium salt of carboxylic acid is required to modulate hydrophilic/lipophilic balance and in the same time and promote surfactant and ion pairing characteristics of these derivatives. This dissertation illustrates the development of novel liposaccharide absorption enhancers to be used for oral delivery of hydrophilic drugs. This research includes chemical synthesis of new ionic liposaccharides, examination of their physico-chemical properties, and their in vitro and in vivo biological examinations. The work consists of two parts; cationic and anionic liposaccharide absorption enhancers. a) Cationic Liposaccharide Absorption Enhancers The focus of this work was on the molecular design, synthesis, and evaluation of novel cationic liposaccharide derivatives as drug delivery agents to improve the oral bioavailability of piperacillin as a model hydrophilic drug. These derivatives were designed to possess surfactant as well as ion pairing properties, and were synthesized from biocompatible and biodegradable materials such as glucose, lipoamino acids and lipophilic amino acids. Thermodynamic profiles of these derivatives as well as haemolytic activity were examined. Minimum inhibitory concentrations of piperacillin/liposaccharide conjugates were studied to investigate the effect of liposaccharides on piperacillin activity. The usefulness of these derivatives as absorption enhancers for the oral delivery of piperacillin was assessed in vitro (Caco-2 cells) and in vivo (rat oral absorption). It was concluded that these derivatives did show hemolytic activity in low concentration (suitable for enhancing activity), while they increased permeability of piperacillin through Caco-2 cells. However, these promising results obtained from in vitro assay were not confirmed in vivo. viii b) Anionic Liposaccharide Absorption Enhancers In this thesis, molecular design, synthesis, and evaluation of novel anionic liposaccharide derivatives as absorption enhancers to improve the intestinal permeability of a model hydrophilic drug such as tobramycin were carried out. These derivatives were designed to have surfactant as well as ion pairing properties, and were synthesized from biocompatible materials such as sugar, lipoamino acids and amino acids. Thermodynamic profiles of these derivatives as well as haemolytic activity were examined. Many absorption enhancers have (to some extent) cytotoxic activity, therefore, cytotoxic activity of the novel anionic liposaccharides were examined. The usefulness of these derivatives as absorption enhancers to increase the lipophilicity of tobramycin and hence, its oral bioavailability, was evaluated through carrying out partition coefficient examination. It was concluded that these derivatives did not show haemolytic and cytotoxic activities in low concentration (suitable for enhancing activity). In addition, the permeability of tobramycin into the organic phase (n-octanol) was increased when liposaccharide derivatives were used. The obtained results are promising and encouraging to continue the work to include Caco-2 cells assay (in vitro assay) and oral absorption in rats (in vivo assay) as a prospective work in the future.
| Identifer | oai:union.ndltd.org:ADTP/282070 |
| Creators | Adel Abdel Rahim |
| Source Sets | Australiasian Digital Theses Program |
| Detected Language | English |
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