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Reduction of Acetaminophen-Induced Hepatotoxicity via Combination Tablet Formulation with N-Acetylcysteine Jeffrey Burgess, Timothy Padawer, & Srinivas Tipparaju University of South Florida College of Pharmacy Introduction Results This study will focus on acetaminophen (APAP), which is an analgesic used for mild pain. This drug may be used to treat pathologies, such as acute mild pain, chronic mild pain, fever, and osteoarthritis. Its mechanism of action is not fully understood, but it is believed to demonstrate some NSAID-like properties and block the production of prostaglandins. It has been proposed that there is a COX-3 enzyme that acetaminophen may inhibit to produce its clinical effects. Conversely, the hepatotoxicity that results as a side effect is well understood (see figure below). Primary Objective:Six formulas were developed utilizing the following ingredient quantities per tablet: Acetaminophen • 650mg – Quantity set to highest available OTC dose N-Acetylcysteine • 100mg – Quantity set for maximum theoretical dose per tablet (based upon a 1g tablet) Colloidal Silicon Dioxide • 3.75mg – Quantity set for anti-caking properties Croscarmellose Sodium • Factorial Dose Design: 15 – 25mg Hydroxypropyl Methylcellulose • 8.75mg – Quantity set for emulsification properties Magnesium Stearate • 1.25mg – Quantity set for tablet press lubrication properties Microcrystalline Cellulose • Factorial Dose Design: 45 – 54mg Starch • Factorial Dose Design: 35 – 54mg Purified Water • Quantity sufficient for wetting properties It stands to reason that combining acetaminophen and Nacetylcysteine (NAC) into a combination tablet may reduce the hepatotoxicity associated with excessive or long-term acetaminophen use. Therefore, it is a potential new combination drug that warrants further investigation and research. Secondary Objective: The untreated HepG2 cells in the control plate were still alive and replicating at 24 hours. The cells exposed to APAP only were dead and no longer replicating at 24 hours. Conversely, the cells exposed APAP + NAC cells were alive and replicating at 24 hours. Hypothesis & Objectives Hypothesis: A combination tablet with acetaminophen and N-acetylcysteine may reduce the hepatotoxicity associated with excessive or long-term acetaminophen use by promoting glutathione production and eliminating free radical oxidation of the liver cells. Primary Objective: To create a formula for a combination tablet with acetaminophen and N-acetylcysteine Secondary Objective: To confirm an efficacious reduction in acetaminophen’s toxic metabolite, NAPQI, with the use of the new combination tablet Methods Primary Objective: The formula for the APAP/NAC tablets was adapted from an existing formula for a combination acetaminophen tablet using Niazi Records. The dosage for the active pharmaceutical ingredients (API) and excipients were determined through a factorial design approach that supplied 30 tablets per batch. Secondary Objective: HepG2 liver cells were grown in vitro and utilized for preliminary testing of the active ingredients. These cells were grown in Dulbecco's Modified Eagle Medium (DMEM). The control plate contained only HepG2 cells in DMEM. The sample plates contained: (1) APAP only at a 10mM concentration and (2) APAP at a 10mM concentration + NAC at a 1.67mM concentration. These concentrations mimic the theoretical in vivo exposure to the API’s after ingestion of the new combination tablet. These plates were monitored for 24 hours and pictures were taken to record the effects of the ingredients on the HepG2 cells. Discussion & Future Studies Potential Impact: • Safe alternative therapy for acute and chronic mild pain • Safe alternative therapy for osteoarthritis • Safe alternative therapy for fever Potential Obstacles: • Risk of abuse • Risk of inadequate therapy • Risk of inaccurate exposure levels if taken in combination with other acetaminophen containing products Future Studies: • Stability Testing: Shelf Life, Thermostability, Friability, etc. • Bioequivalence Testing: Dissolution, Disintegration, Hardness, etc. • In Vivo Efficacy & Safety Testing: Phase I Clinical Trials Acknowledgements This research was supported by the Florida High Tech Corridor USFCoreRx Grant. References 1. 2. 3. 4. 5. 6. 7. 8. 9. Abebe A, Akseli I, Sprockel O, Kottala N, Cuitiño AM. “Review of Bilayer Tablet Technology”. Int J Pharm. 2014 Jan 30; 461(1-2): 549-58. “Acetaminophen”. Lexicomp Online. 2014. <http://online.lexi.com.ezproxy.hsc.usf.edu/lco/action/doc/retrieve/docid/patch_f/6264>. Acc: 7/11/14. “Acetylcysteine”. Lexicomp Online. 2014. <http://online.lexi.com.ezproxy.hsc.usf.edu/lco/action/doc/retrieve/docid/patch_f/6281#f_pharmacology-and-pharmacokinetics>. Accessed: 8/3/14. Chun BJ, Moon JM, Kim SH. Antidote for acetaminophen poisoning: N-acetylcysteine. J Korean Med Assoc. 2013 Dec;56(12):1067-1075. Dipiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM. “Chapter 71 – Osteoarthritis”. Pharmacotherapy: A Pathophysiological Approach - 9th Edition (Online Access). Niazi SK. Handbook of Pharmaceutical Manufacturing Formulations - 6 Volume Set. CRC Press; 2004. O’Malley GF. “Acetaminophen Poisoning”. The Merck Manual – Professional Edition (Online Access). 2013 Feb. <http://www.merckmanuals.com/professional/injuries_poisoning/poisoning/acetaminophen_poisoning.html>. Accessed: 6/26/14. Osteoarthritis”. Pharmacotherapy: A Pathophysiological Approach - 9th Edition (Online Access). <http://accesspharmacy.mhmedical.com.ezproxy.hsc.usf.edu/content.aspx?bookid=689§ionid=45310523>. Accessed: 6/26/14. Zelman D. “NSAIDs (Nonsteroidal Anti-infalmmatory Drugs) and Arthritis”. WebMD, LLC. 2014 Feb 11. <http://www.webmd.com/osteoarthritis/guide/anti-inflammatory-drugs?page=3>. Accessed: 7/11/14. Turning Research on Edge