Student Theses, Dissertations and Capstones

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD) in Pharmacy

Copyright Statement

All rights reserved. This publication is intended for use solely by faculty, students, and staff of Nova Southeastern University. No part of this publication may be reproduced, distributed, or transmitted in any form or by any means, now known or later developed, including but not limited to photocopying, recording, or other electronic or mechanical methods, without the prior written permission of the author or the publisher.

Department

College of Pharmacy

First Advisor

Mutasem Rawas-Qalaji

Second Advisor

Sami Nazzal

Third Advisor

Young Kwon

Publication Date / Copyright Date

2017

Publisher

Nova Southeastern University

Abstract

Organophosphates (OP) are chemicals found in certain pesticides and in nerve agents such as sarin. Toxicity with these agents can lead to death. On August 2013, 1,300 civilians were killed using sarin gas in Syria by the Assad regimen. The lack of prepared medical facilities, and the availability of appropriate treatmentsignificantly contributed to the high percent of causality. Further, worldwide pesticides toxicity affects 3 million people annually. Therefore, it is imperative that antidote to treat OP toxicity are readily available in a dosage form that is acceptable cost, effective, and user friendly. Atropine sulfate (AS) is the first-line antidote forOP toxicity. Since the only emergency dosage forms available are parenteral, we developed a sublingual tablet to deliver AS for the initial treatment of OP toxicity. AS fast disintegrating sublingual tablets (AS FDSTs) were formulated, manufactured, quality control tested, and evaluated for their feasibility for in vitro and ex vivo AS diffusion.

Nine AS FDSTs batches were manufactured by direct compression and tested for quality control. Two tablet sizes, group A weighing 150 mg and group B weighing 50 mg, were formulated with a range of AS doses, 0 mg (A1 and B1), 2 mg (A2 and B2), 4 mg (A3 and B3), and 8 mg (A4, B4a, B4b). AS FDSTs' characteristics were evaluated using United States Pharmacopeia (USP) and non-USP tests. AS in vitro diffusion and the ex vivo permeation were investigated using synthetic cellulose membrane and excised porcine sublingual membrane in Franz cells. The effect of AS load and tablet size on sublingual permeation were also evaluated.

All AS FDSTs batches passed quality control tests, FDSTs disintegrated within 30 seconds, and AS was dissolved within 60 seconds. In vitro and ex vivo cumulative AS (JAUC0-90) and influx (J) increased linearly with increasing AS dose and both results correlated linearly. Group B FDSTs had a faster tablet disintegration and higher initial permeation (JAUC0-15) than group A FDSTs, which made group B FDSTs a better candidate for sublingual administration.

These AS FDSTs have the potential as an alternative dosage form for OP toxicity treatment. Further animal studies are required to determine the required bioequivalent dose.

Disciplines

Pharmacy and Pharmaceutical Sciences

Keywords

Antidote, Atropine sulfate, Formulation, ODT, Organophosphates, Toxicity

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