Objectives: 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.

Objectives: 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.

Bibliography: leaves 515-531 / The Brooklyn Papyrus (47.218.48 and 47.218.85) is the handbook of the Priests of Serqet who were called upon to treat snakebite victims in ancient Egypt. The first part of the Brooklyn Papyrus describes various snakes encountered by the ancient Egyptians, and the effects of the bites of these snakes. The second part of the Papyrus contains the numerous treatments that were used to treat the snakebite victims. The primary question of the thesis is to address how the ancient Egyptians treated snakebite victims; and if it is possible to identify the snakes that they encountered, as treatment often hinges on this identification. Additional questions are addressed, namely: What is the Brooklyn Papyrus exactly and what is its background? How does the Brooklyn Papyrus compare to the well-known ancient Egyptian medical papyri? How does the snakebite treatment of the ancient Egyptians compare to that of today’s treatment protocol? In order to answer these questions, this thesis provides my transliteration of the hieroglyphic writing into Latin script, and my translation into English, based on the hieratic to hieroglyphic transliteration done by Serge Sauneron in the late 1960s, and published in 1989 as Un Traité Egyptien d’Ophiologie. The primary aim of this thesis is to provide a transliteration and full English translation of the Brooklyn Papyrus, as none is currently available. It is clear that from the translation that one can discover exactly how snakebite was treated in ancient Egypt: what medicinal ingredients were used and how the patient was treated. Furthermore, from the text describing the snakes and the effects of their bites, one can indeed attempt to identify the species of snakes. It is also apparent from the Brooklyn Papyrus that the ancient Egyptians did recognise and accurately describe many effects of snakebite on the human body, as well as the different types of bite wounds: and they also understood the importance of being able to identify a species of snake as it very often impacted on the treatment to be prescribed—exactly as snakebite treatment is considered in medicine today / Biblical and Ancient studies / D. Litt. et Phil. (Ancient Near Eastern Studies)