Evaluation of the effects of non-medicinal ingredients on the in vitro characteristics and in vivo bioavailability of a sublingual tablet formulation of epinephrine

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dc.contributor.authorRachid, Ousama
dc.contributor.examiningcommitteeGong, Yuewen (Pharmacy) Hasinoff, Brian (Pharmacy) McNicol, Archie (Oral Biology) Wu, Shirley (University of Toronto)en_US
dc.contributor.supervisorSimons, Keith (Pharmacy) Simons, Estelle (Pediatrics and Child Health)en_US
dc.date.accessioned2013-04-01T20:41:04Z
dc.date.available2013-04-01T20:41:04Z
dc.date.issued2012-11-22en_US
dc.date.issued2012-06-07en_US
dc.date.issued2011-04-27en_US
dc.date.issued2010-03-30en_US
dc.degree.disciplinePharmacyen_US
dc.degree.levelDoctor of Philosophy (Ph.D.)en_US
dc.description.abstractObjectives: To review, develop, and validate appropriate methods for quality control testing of sublingual (SL) tablets; to formulate and characterize new generations of SL tablets of epinephrine (E) for the potential first-aid treatment of anaphylaxis; and to evaluate the effects of non-medicinal ingredients (NMIs) on the in vitro characteristics and in vivo bioavailability of the formulated tablets. Methods: A custom-made apparatus and a novel method that simulates SL conditions were evaluated for dissolution testing of SL tablets. An electronic tongue (e-Tongue) was used to assess the degree of E bitterness and to demonstrate the masking effects of sweetening and/or flavoring agents. The effect of several NMIs in various properties on the in vitro characteristics of new generations of E SL tablets was evaluated. Formulations with the best in vitro characteristics, containing E 30 mg and 40 mg, were evaluated in vivo using our validated rabbit model and compared with placebo SL tablets (negative control) and E 0.3 mg intramuscular (IM) injection (positive control). Results: The novel in vitro dissolution testing resulted in accurate and reproducible data and was capable of detecting the effect of minor changes in formulations. Using the e-Tongue, E bitartrate had an extremely bitter taste which was masked to various degrees by the addition of aspartame, acesulfame potassium, and citric acid alone or in combination. Citric acid alone masked the bitter taste by >80%. The evaluation of NMIs revealed that the best formulation contained specific proportions of mannitol and coarse and fine grades of microcrystalline cellulose. Appropriate comparative testing resulted in the selection of a taste-masked E SL formulation with optimum in vitro characteristics. This formulation containing E 40 mg resulted in similar bioavailability to E 0.3 mg IM. This formulation containing E 30 mg had higher bioavailability than placebo, but lower bioavailability than E 40 mg tablets. Conclusions: Grades and proportions of NMIs carefully selected using appropriate in vitro testing resulted in successful formulations. The results of these in vitro tests enabled the development of the optimum E SL tablet formulation which was bioequivalent to the EpiPen. These tablets are potentially suitable for Phase 1 studies in humans and might transform the first-aid treatment of anaphylaxis in community settings.en_US
dc.description.noteMay 2013en_US
dc.identifier.citationJ Allergy Clin Immunol. 2013;131(1):236-8en_US
dc.identifier.citationEur J Pharm Biopharm. 2012;82(3):598-604en_US
dc.identifier.citationAAPS PharmSciTech. 2011;12(2):544-52en_US
dc.identifier.citationAAPS PharmSciTech. 2010;11(2):550-7en_US
dc.identifier.urihttp://hdl.handle.net/1993/18315
dc.language.isoengen_US
dc.publisherElsevier: J Allergy Clin Immunolen_US
dc.publisherElsevier: Eur J Pharm Biopharmen_US
dc.publisherSpringer: AAPS PharmSciTechen_US
dc.publisherSpringer: AAPS PharmSciTechen_US
dc.rightsopen accessen_US
dc.subjectepinephrineen_US
dc.subjectanaphylaxisen_US
dc.subjectsublingulen_US
dc.subjectrapidly-disintegratingen_US
dc.subjecttabletsen_US
dc.subjectdissolutionen_US
dc.subjectexcipientsen_US
dc.subjectnon-medicinal ingredientsen_US
dc.subjectelectronic tongueen_US
dc.titleEvaluation of the effects of non-medicinal ingredients on the in vitro characteristics and in vivo bioavailability of a sublingual tablet formulation of epinephrineen_US
dc.typedoctoral thesisen_US
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