(M1430-05-33) Rapid Systemic Absorption of an Immediate-Release Ilaprazole-Sodium Bicarbonate Fixed Dose Formulation Comparable to a P-CAB: A Preclinical Pharmacokinetic Study

Purpose: Potassium-competitive acid blockers (P-CABs) are known as novel acid suppressive drugs with rapid onset of action and prolonged control of intragastric acidity compared to proton-pump inhibitors (PPIs) [1].  The gastric antisecretory effect of PPIs has been shown to correlate with total dose and AUC [2]. The purpose of this study was to investigate whether the newly developed immediate-release ilaprazole-sodium bicarbonate fixed-dose tablet (IR tablet, a PPI) and a P-CAB exhibit equivalent gastric acid secretion inhibitory effects and rapid onset of action through a pharmacokinetic approach in beagle dogs.

Methods: Sodium bicarbonate and excipients were wet-granulated, dried, blended with ilaprazole, and compressed into a single matrix tablet. Dissolution testing was performed using USP Apparatus Ⅱ (50 rpm, 37 °C). Noltec^® delayed-release tablet containing 10 mg of ilaprazole and immediate-release ilaprazole-sodium bicarbonate (10 mg/500 mg) fixed-dose tablets were evaluated in pH 6.8 buffer containing 1% polysorbate 80, while K-CAB^® tablets containing 50 mg of tegoprazan as the P-CAB agent were tested in pH 1.2, pH 4.0, and pH 6.8 buffers for 60 min. Pharmacokinetic (PK) evaluation was conducted in eight beagle dogs; after intramuscular pentagastrin administration, the three formulations were given orally, and blood samples were collected at predefined time points (0, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 h). Plasma ilaprazole and tegoprazan concentrations were analyzed by LC-MS/MS to calculate PK parameters.

Results: As shown in Figures 1 and 2, the dissolution similarity factor (f₂) between the immediate-release ilaprazole-sodium bicarbonate fixed-dose tablets and Noltec^® delayed-release tablets was 69.1, indicating similar dissolution profiles. K-CAB^® tablets released 95.7% ± 2.6% of the drug at 5 min in pH 1.2, but only 44.6% ± 1.3% at 60 min in pH 6.8, demonstrating pH dependence. Table 1 presents the PK parameters in beagle dogs. PK analysis showed that the T/R ratio between Noltec^® delayed-release tablets and immediate-release ilaprazole-sodium bicarbonate fixed-dose tablets was 1.2-fold higher for AUC and 1.48-fold higher for C_max. Compared to K-CAB^® tablets, the dose-adjusted AUC of the immediate-release ilaprazole-sodium bicarbonate fixed-dose tablets did not show a significant difference in the paired t-test (P > 0.05). T_max, indicative of the onset of action, was shortest for the IR tablet at 1 h (range 0.5–2.0), compared with 1 h for K-CAB^® tablet (0.5–4.0).

Conclusion: The sodium bicarbonate-layer matrix technology, formulated without an enteric coating, effectively achieved rapid absorption within 1 hour and demonstrated no statistically significant difference in dose-adjusted AUC compared to K-CAB^® (tegoprazan). Furthermore, the shortened T_max observed with the immediate-release formulation indicates a more rapid onset of pharmacodynamic action in terms of gastric acid suppression. These findings suggest that the newly developed immediate-release formulation of ilaprazole may provide a rapid and effective alternative for the treatment of acid-related disorders.

References: Shin, J.M., Kim, N., 2013. Pharmacokinetics and pharmacodynamics of the proton pump inhibitors. Journal of neurogastroenterology and motility 19, 25.
YJ Choi, 2022. Treatment of acid-related diseases using potassium-competitive acid blockers. The Korean Journal of Gastroenterology 80, 247-253.

Acknowledgements: This animal study was conducted in strict accordance with the Animal Welfare Act and the Guide for the Care and Use of Laboratory Animals. The study protocols were reviewed and approved by the Institutional Animal Care and Use Committee (IACUC) of Il-Yang Pharmaceutical Co., Ltd. Central Research Institute (approval number: IYNS-2024-10) to ensure compliance with ethical standards and the welfare of the animals involved in the study.

Figure 1. Dissolution profiles of Noltec® delayed-release tablets and immediate-release ilaprazole-sodium bicarbonate (10 mg/500 mg) fixed-dose tablets in pH 6.8 media containing 1% polysorbate 80 (USP Apparatus Ⅱ, 50 rpm, 37 ℃; n = 3)

Figure 2. Dissolution profiles of K-CAB 50 mg tablets in pH 1.2, pH 4.0, and pH 6.8 media (USP Apparatus Ⅱ, 50 rpm, 37 ℃; n = 3)

Table 1. Pharmacokinetic parameters of Noltec® delayed-release tablet, IR ilaprazole-sodium bicarbonate (10 mg/500 mg) tablet, and K-CAB® 50 mg after single oral administration to beagle dogs (n = 8)