Research Article Effect of Fast-Disintegrating Tablets’ Characteristics on the Sublingual Permeability of Atropine Sulfate for the Potential Treatment of Organophosphates Toxicity Alhussain Aodah, 1,2 Mohamad Rawas-Qalaji, 3 Rawan Bafail, 1,4 and Mutasem Rawas-Qalaji 1,5,6 Received 23 January 2019; accepted 16 May 2019; published online 21 June 2019 Abstract. Atropine sulfate (AS) fast-disintegrating sublingual tablets (FDSTs) were tested for AS sublingual permeation’s feasibility as a potential alternative dosage form to treat organophosphates (OP) toxicity. More than 12,000 OP pesticide toxicity cases were reported in the USA from 2011 to 2014. AS is the recommended antidote for OP toxicity; however, it is only available as an ATROPEN® auto-injector, an IM injection, for self-administration, which is associated with several drawbacks and limitations. Six AS FDST batches were formulated and characterized. Two tablet sizes, group A weighing 150 mg and group B weighing 50 mg, were formulated with three different AS doses: 2 mg (A1 and B1), 4 mg (A2 and B2), and 8 mg (A3 and B3). AS in vitro diffusion and sublingual permeation were investigated in Franz cells using a cellulose membrane and an excised porcine sublingual membrane. The effect of AS load and tablet size on sublingual permeation was also evaluated. All batches passed quality control tests. AS FDSTs’ size and AS load had a significant effect on tablet disintegration time and drug dissolution, which significantly impacted AS concentration gradient across the diffusional membrane. Group B FDSTs (smaller tablets) resulted in a significantly higher initial permeation (JAUC 0–15 ) compared to group A FDSTs. Also, the cumulative AS (JAUC 0–90 ) and AS influx (J) increased linearly with increasing AS dose. These AS FDSTs have the potential to be explored in vivo to determine the required bioequivalent sublingual AS dose as an alternative dosage form for the treatment of OP toxicity. KEY WORDS: Atropine; Fast Disintegrating Tablets; Organophosphates; Pesticides; Sublingual. INTRODUCTION Organophosphates (OP) were first developed in 1854 for use as pesticides and later as nerve gas agents in 1936 (1,2). In the USA, there are more than 37 types of OP pesticides used in agriculture and almost 20,000 OP toxicity cases reported yearly (3–5). Worldwide, three million OP toxicity cases were estimated annually by the World Health Organization (6). Organophosphates irreversibly inhibit acetylcholine es- terase (AChE) and result in the accumulation of ACh in the synaptic cleft, which can lead to respiratory failure and victim’s death (7–9). According to the World Health Organi- zation’s guidelines, when a patient is in doubt about having been intoxicated with OP, he or she should be removed from the intoxicated area, have their airways and blood circulation checked, and be immediately injected with 2 mg of atropine sulfate (AS) to block and prevent the accumulated ACh from binding with the muscarinic receptors peripherally, nullifying the lethality of OP. The AS dose should be doubled every 5 min until the atropinization symptoms appear (4,10–12). ATROPEN®, a prefilled AS auto-injector device, is available in some countries for self-intramuscular (IM) administration by patients and medical professionals (13). ATROPEN® can deliver a fixed single dose of AS, and it is available in four different preloaded AS doses for adults and children of varying weight. However, the IM administration of multiple doses of AS to achieve atropinization is imprac- tical and very invasive (4,10,12,14,15). It creates the need to carry and store multiple AtroPen® devices, which is incon- venient especially considering that manufactuerer guidelines 1 College of Pharmacy, Nova Southeastern University, 3200 South University Drive, Fort Lauderdale, Florida 33328, USA. 2 College of Pharmacy, Prince Sattam Ibn Abdulaziz University, Al- Kharj, Saudi Arabia. 3 Dietrich School of Arts and Sciences, University of Pittsburgh, Pittsburgh, Pennsylvania, USA. 4 College of Pharmacy, Taibah University, Medina, Saudi Arabia. 5 Dr. Kiran C. Patel College of Allopathic Medicine, Nova South- eastern University, Fort Lauderdale, Florida, USA. 6 To whom correspondence should be addressed. (e–mail: mr.qalaji@nova.edu) AAPS PharmSciTech (2019) 20: 229 DOI: 10.1208/s12249-019-1420-1 1530-9932/19/0600-0001/0 # 2019 American Association of Pharmaceutical Scientists