(M1430-08-49) An In Vitro Model for Acetaminophen Dissolution from Overdosed Oral Formulations

Purpose: Acetaminophen, a popular analgesic and antipyretic drug, is safe within its therapeutic dose range. Yet, serious hepatotoxic effects may occur after ingestion of doses higher than those recommended, leading in severe cases to acute liver failure [1]. Several clinical trials of acetaminophen at higher doses in healthy volunteers have been published [2,3]; however, no in vitro model for acetaminophen dissolution after overdose has been presented to date.
Methods: Dissolution of acetaminophen oral formulations: immediate release (IR) tablets, extended release (ER) tablets, hard (HC) and soft capsules (SC), was tested in USP Apparatus 3 (Caleva, RRT 10). Each experiment was performed in a succession of buffers: FaSSGF (stomach), FaSSIF-V2 (upper small intestine), FaSSIF_midgut (mid-jejunum), SIF_ileum (ileum) and FeSSCoF (colon), each in a volume of 220 mL, to model the changes in physiology during transit through the gastrointestinal tract (Fig. 1). Acetaminophen dissolution from a single dose and from simulated overdoses, (ten and twenty doses, and additionally for IR tablets, fifty doses) was studied. All experiments were performed in triplicate. Analysis of the samples was performed using a validated HPLC method with UV detection at 240 nm.

Results: The results of all acetaminophen dissolution experiments are presented in Figure 2. Release from IR tablets was heavily dependent on the tablets studied, with release complete after testing in FaSSGF and FaSSIF-V2 buffers for a single tablet, but only after the tablets were subjected to FaSSIF_midgut for ten tablets, or, for twenty tablets, the FeSSCoF. When 50 IR tablets were tested, release was incomplete, with only 10 % release even after the tablets had been subjected to all buffers. The slowdown and (for 50 tablets) incomplete release were attributed to clumping and media flow disruption, which became progressively worse as the number of tablets was increased. Release from HC was already complete in FaSSGF from a single capsule, but slowed down and was incomplete for ten (76.9 ± 6.5 % in FaSSIF_midgut buffer) or twenty capsules (71.6 ± 2.0 % in SIF_ileum). Here too, the slowdown and incomplete release from ten and twenty capsules were attributed to clumping and media flow disruption. As all capsule material residues had penetrated into the outer vessel by the time they reached FaSSIF_midgut (for 10 HC), or SIF_ileum (for 20 HC), the HC experiments were stopped at that point. Release from a single SC was already complete after 10 minutes in FaSSGF and very rapid, but incomplete from ten capsules, reaching 90 % after 60 min in FaSSGF buffer. Release from twenty capsules was slower due to clumping and media flow disruption was observed in FaSSGF. This experiment was continued in FaSSIF-V2 buffer, where release was incomplete (72.5 ± 12.8 %), even though all capsule residues had penetrated into the outer vessel and were exposed to the media. As expected, release of the initial dose of a single ER tablet (approximately 50 %) was rapid, but much slower from the depot part of the ER tablet and therefore not complete (92.2 ± 2.0 %) after being subjected to all buffers. Release from ten or twenty ER tablets was slower, reaching 60.7 ± 12 % and 25.3 ± 12.7 % respectively in the last buffer, FeSSCoF. In these cases, dense clumping and media flow disruption were observed in all buffers and prevented the majority of the tablet residues from penetrating into the outer vessel.

Conclusion: A novel in vitro dissolution model for the release of overdosed acetaminophen is presented. Acetaminophen IR and ER tablets, hard and soft capsules at various doses were compared in the model. For all formulations, increased acetaminophen dose resulted in reduced dissolution, which is in line with the literature data obtained in acetaminophen clinical trials and a population pharmacokinetic model for overdosed acetaminophen [4]. The in vitro model was also able to model pharmacobezoar formation (clumping) reported in the literature in case studies of high dose ingestion [5]. The in vitro model may also be useful for testing other drugs that are frequently overdosed.

References: 1. Lee WM. Acetaminophen (APAP) hepatotoxicity – Isn’t it time for APAP to go away? J Hepatol. 2017;67(6):1324-1331. DOI:10.1016/j.jhep.2017.07.005
2. Gelotte CK, Auiler JF, Lynch JM, Temple AR, Slattery JT. Disposition of Acetaminophen at 4, 6, and 8 g/day for 3 Days in Healthy Young Adults. Clin Pharmacol Ther. 2007;81:840-848. DOI:10.1038/sj.clpt.6100121
3. Stork CM, Rees S, Howland MA, Kaplan L, Goldfrank L, Hoffman RS. Pharmacokinetics of extended relief vs regular release Tylenol in simulated human overdose. J Toxicol Clin Toxicol. 1996;34(2):157-62. DOI:10.3109/15563659609013764
4. Spyker DA, Dart RC, Yip L, Reynolds K, Brittain S, Yarema M. Population pharmacokinetic analysis of acetaminophen overdose with immediate release, extended release and modified release formulations. Clin Toxicol. 2022; 60(10):1113-1121. DOI:10.1080/15563650.2022.2114361
5. Yamaguchi J, Kinoshita K, Noda A, Furukawa M, Sakurai A. Delayed increase in serum acetaminophen concentration after ingestion of a combination medications: a case report. J Int Med Res. 2018;46(8):3435-3439. DOI:10.1177/0300060518777860

Acknowledgements: This work was funded by the Fraunhofer Internal Programs under Grant No. SME 840 046.

USP 3 dissolution testing set-up

Results for USP 3 dissolution testing of four acetaminophen commercial products: IR tablets, ER tablets, IR hard capsules and IR soft capsules