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Ionic liquids as potential drug delivery vehicles
thesisposted on 21.02.2017, 00:09 by Sahbaz, Yasemin
For drugs with intrinsically low water solubility, effective intestinal absorption after oral administration remains a challenge. Molecular dispersion of a drug is, in almost all cases, an essential determinant of absorption across biological membranes and drugs must be dissolved in the gastrointestinal (GI) fluids in order to pass through the absorptive cells lining the small intestine (enterocytes). The solubility of a drug in aqueous medium is thus crucial for absorption and bioavailability. In spite of this requirement, recent estimates suggest that up to 70% of drug candidates are classified as poorly water soluble. Poor oral bioavailability resulting from insufficient aqueous solubility and low dissolution rate is therefore a significant issue in the pharmaceutical industry. Lipid-based formulations (LBF) are one means by which the absorption of poorly water soluble drugs (PWSD) may be enhanced. LBF commonly comprise an isotropic combination of oils, surfactants and co-solvents that are designed to emulsify spontaneously in the GI environment. These Self-Emulsifying Drug Delivery Systems (SEDDS) improve the oral bioavailability of PWSD by pre-dissolving drugs in the non-aqueous vehicle (thereby avoiding traditional dissolution) and seek to maintain drug solubilisation whilst the formulation is dispersed and digested in the GI tract. Whilst this approach has proven successful, one significant limitation to utility is the requirement for the prospective drug dose to dissolve completely in the formulation. Many PWSD are relatively poorly soluble in lipids and this inherently limits the application of LBF technology. The current project explores two approaches to promote PWSD absorption using LBF by applying ionic liquids (ILs) to enhance LBF utility. Firstly, novel ILs were synthesized to generate excipients with very high solvent capacities for drug molecules that are poorly water soluble and also insufficiently soluble to be administered in LBF. To this end, water-immiscible ILs were synthesised and employed as a lipid substitute in SEDDS formulation and evaluated for their ability as drug carriers. Lipid-like ILs exhibited very high solvent properties (20-500 fold) for the poorly water-soluble drugs danazol and itraconazole when compared with soybean oil, a common lipid excipient. Subsequent in vivo evaluation in rats, revealed that a danazol-containing self-emulsifying IL formulation gave rise to higher (4.3-fold) exposure than a suspension of crystalline drug and more prolonged exposure when compared with a standard LBF. Secondly, PWSD were directly transformed into lipophilic ILs using a range of lipophilic counterions. The drug-IL so formed displayed remarkably higher solubility in LBF and allowed for excellent drug absorption from LBF at very high drug doses. The weakly basic, PWSDs itraconazole, cinnarizine and halofantrine were initially converted into lipophilic ILs to facilitate incorporation into LBF. The resultant active pharmaceutical ingredient – ionic liquids (API-ILs) were liquids or low melting point solids at room temperature and either completely miscible or highly soluble in lipid-based SEDDS. They also readily incorporated into the colloids formed in intestinal fluids during lipid digestion. In vivo, itraconazole docusate or cinnarizine decylsulfate ILs in SEDDS provided for significantly higher plasma exposure (2-fold for cinnarizine and 20-fold for itraconazole), when compared to lipid suspension formulations of the free base at the same dose. The data suggest that the formation of lipophilic ionic liquids provides a means of increasing dissolved-drug loading in lipid based formulations thereby promoting the exposure of poorly water soluble drugs after oral administration. The second approach was also applied to the weakly acidic, PWSDs tolfenamic acid, meclofenamic acid, diclofenac and ibuprofen. In a similar fashion, pairing of the crystalline acidic drugs with lipophilic counterions resulted in the formation of low melting point solid or liquid API-ILs, which were highly soluble or completely miscible in LBF. In vivo, oral administration of IL forms of tolfenamic acid resulted in similar total exposure to LBF containing suspensions of the free acid form of tolfenamic acid, but interestingly, reduced the peak plasma concentration and significantly extended the period of exposure for up to 48 h. In summary, the current studies suggest that customized ILs offer great promise as novel delivery vehicles for PWSD. Water-immiscible ILs provide potential as novel excipients significantly enhancing drug solubility in lipid formulations and enhancing and sustaining drug exposure after oral administration. Second, lipophilic IL forms of PWSD offer a novel strategy to increase oral exposure via increasing drug incorporation into LBF. The liquid SEDDS formulations, made possible by the use of the API-ILs, promote drug absorption for PWSD and also deliver advantages in dose uniformity, capsule filling and stability compared to similar suspension formulations.