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dc.contributor.authorCallender, Shannon
dc.date.accessioned2020-09-28 14:17:33 (GMT)
dc.date.available2020-09-28 14:17:33 (GMT)
dc.date.issued2020-09-28
dc.date.submitted2020-09-22
dc.identifier.urihttp://hdl.handle.net/10012/16384
dc.description.abstractConcurrent chronic disease and ensuing multi-morbidity are a debilitating reality for millions of Canadians. This adversity is compounded by increased pill burden and decreased patient adherence. Microemulsions (MEs) serve as a potential multi-drug therapy solution. MEs are thermodynamically stable, colloidal systems whose oil and water compositions and nano-sized droplets have the potential to facilitate simultaneous hydrophilic and lipophilic drug delivery, while improving bioavailability. However, the area of multi-drug delivery using ME technology is largely unexplored and unfulfilled. In order to develop a ME capable of simultaneous multi-drug delivery, emulsifying agents as the heart of these systems must be investigated. In this work, the potential for multi-drug delivery using ME systems was explored with a particular focus on emulsifying agent properties conducive to this purpose. A prenatal supplement comprised of eleven active pharmaceutical ingredients (APIs) of varying hydro- and lipophilicity was selected as a proof of concept. Five non-ionic surfactants were subjected to extensive ternary phase diagram (TPD) mapping with a medium chain triglyceride, Miglyol 812 in order to identify regions of monophasic microemulsion formation. Optimization was performed via critical micelle concentration determination and the hydrophilic-lipophilic deviation (HLD) equation. A final microemulsion comprised of 3:1 Polysorbate 80:Cremophor RH 40 surfactant, Miglyol 812 and water in a surfactant:oil:water (S:O:W) ratio of 50:40:10, was identified as optimal for monophasic, microemulsion formation. Eleven active pharmaceutical ingredients- five lipophilic (Vitamins A, D, E, K and docosahexaenoic acid) and six hydrophilic (Vitamins B1, B2, B3, B6, B9, B12) were then successfully incorporated. The resulting microemulsion was determined to be of a bicontinuous nature and after 100x aqueous dilution, spherical droplets were identified via TEM with a diameter of 164 ± 37 nm, a charge of -14.1 ± 2.2 mV and a low viscosity of 1.04 ± 0.04 mPa/s. Twelve additional non-ionic surfactants were screened for possible use in the formulation. Polysorbate 81, with 15 less ethylene oxide head groups but equivalent carbon chain length to Polysorbate 80, was identified as most promising based on droplet diameter and zeta potential. Thus, this type of multi-drug formulation appeared to be tolerable to larger changes in non-ionic surfactant head group than hydrocarbon chain length; Hydrophilic-lipophilic balance (HLB), in contrast, appeared to have little to no effect. Two additional drug-loaded microemulsion formulations comprised of 3:1 Polysorbate 81:Cremophor RH 40 surfactant, Miglyol 812 oil and water in S:O:W ratios of 40:50:10 and 50:40:10, resulted in droplet diameters of 94 ± 15 nm and 81 ± 2.4 nm, and zeta potential values of -17 ± 4 mV and -23 ± 6 mV, respectively after 100x aqueous dilution. All final multi-drug loaded MEs demonstrated >70% dissolution improvement of folic acid and >90% dissolution improvement of riboflavin in 50 mM phosphate buffer (pH 7.4) as compared to a commercial prenatal supplement in suspension form. Overall, it was demonstrated that the process of TPD mapping, HLD optimization and careful surfactant screening was instrumental in the successful development of a multi-drug microemulsion system with the potential to treat concurrent, chronic diseases in a single dose.en
dc.language.isoenen
dc.publisherUniversity of Waterlooen
dc.subjectmicroemulsionen
dc.subjectdrug deliveryen
dc.subjectsurfactanten
dc.subjectmulti-drug therapyen
dc.titleDevelopment of a Novel, Microemulsion System for the Simultaneous Delivery of Hydrophilic and Hydrophobic Active Pharmaceutical Ingredients (APIs)en
dc.typeDoctoral Thesisen
dc.pendingfalse
uws-etd.degree.departmentSchool of Pharmacyen
uws-etd.degree.disciplinePharmacyen
uws-etd.degree.grantorUniversity of Waterlooen
uws-etd.degreeDoctor of Philosophyen
uws.contributor.advisorWettig, Shawn
uws.contributor.affiliation1Faculty of Scienceen
uws.published.cityWaterlooen
uws.published.countryCanadaen
uws.published.provinceOntarioen
uws.typeOfResourceTexten
uws.peerReviewStatusUnrevieweden
uws.scholarLevelGraduateen


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