Transcript USF Research Day Poster (Jeff Burgess)

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
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