(T1030-09-57) Formulation Development of Immediate Release Ilaprazole–Antacid Fixed-Dose Combination Tablets and Pharmacokinetic Evaluation in Beagle Dogs

Purpose: Proton pump inhibitors (PPIs) are commonly formulated as enteric-coated oral dosage forms to protect against degradation in the acidic environment of the stomach, which leads to delayed onset of action [1, 2]. Ilaprazole, a third-generation PPI, is used for the treatment of gastroesophageal reflux disease, duodenal ulcers, and gastric ulcers [3]. Therefore, an immediate-release formulation is required to overcome the delayed onset of initial drug effect due to enteric coating. The objective of this study was to investigate different combinations of antacids with ilaprazole to prevent gastric acid degradation and develop a rapid-onset oral formulation to replace conventional enteric-coated dosage forms.

Methods: The acid-neutralizing capacity (ANC) of five antacids (magnesium hydroxide, sodium bicarbonate, almagate, magnesium oxide, and calcium carbonate) was evaluated according to USP [301]. Drug-antacid compatibility and solubility studies were performed. For solubility testing, 10 mg of ilaprazole and 200–800 mg of various antacids were added to 30 mL of artificial gastric fluid and 150 mL of purified water, incubated at 37℃ ± 0.5°C for 2 hours, and then analyzed by HPLC after filtration through 0.45 μm membrane filters. Physical mixtures of ilaprazole and antacids (1:10 ratio) were subjected to accelerated stability conditions (40°C ± 0.5°C, 75% ± 5% RH) for 4 weeks to assess impurity formation. The pH-modulating effect of each antacid in artificial gastric fluid was evaluated. Fixed-dose combination tablets were manufactured, and dissolution studies were performed in pH 6.8 buffer containing 0.5% polysorbate using the USP Paddle method at 75 rpm. Noltec^® delayed-release tablets served as the reference product. In vivo pharmacokinetic studies of immediate-release formulations (sodium bicarbonate–ilaprazole fixed-dose matrix tablet and magnesium hydroxide–ilaprazole fixed-dose tablet-in-tablet) were conducted in beagle dogs. Plasma ilaprazole concentrations were analyzed by LC–MS/MS to calculate pharmacokinetic parameters.

Results: The acid-neutralizing capacities (mEq/g) were as follows: magnesium oxide, 42.8 ± 1.75; magnesium hydroxide, 35.8 ± 0.25; almagate, 28.8 ± 0.25; calcium carbonate, 21.4 ± 1.32; and sodium bicarbonate, 16.1 ± 1.01. After 4 weeks under accelerated conditions, total impurities were lowest with sodium bicarbonate (0.1%), followed by magnesium oxide (0.55%), magnesium hydroxide (0.65%), and almagate (1.1%). Ilaprazole solubility was lowest with almagate (5.0%) compared to other antacids (12.3%–18.7%). As shown in Figure 1, the ilaprazole release rate at 15 minutes was 81.0% for the sodium bicarbonate (500 mg)–ilaprazole (20 mg) matrix tablet, 67.5% for the magnesium hydroxide (300 mg)–ilaprazole (20 mg) tablet-in-tablet, and 52.8% for the Noltec^® delayed-release tablet as a reference product. Figure 2 presents the pharmacokinetic profiles in beagle dogs. Compared to the reference product, the sodium bicarbonate–ilaprazole fixed-dose matrix tablet demonstrated a 1.5-fold higher AUC, a 1.79-fold higher Cmax, and a shorter Tmax (1 vs 2 hours). The magnesium hydroxide–ilaprazole fixed-dose tablet-in-tablet showed a 1.1-fold higher AUC, similar Cmax (0.95-fold), and Tmax of 1.25 hours, indicating rapid onset of absorption for the immediate-release formulations.

Conclusion: Immediate-release ilaprazole formulations can be successfully developed using compatible antacids, eliminating the need for enteric coating. The sodium bicarbonate–ilaprazole fixed-dose combination (500 mg/20 mg) tablets effectively neutralized gastric acid and demonstrated superior pharmacokinetic properties with rapid onset compared to conventional enteric-coated formulations, representing a promising approach for improved PPI therapy.

References: 1. Al‐Matar, A.K., El‐Eswed, B., Tutunji, M.F., 2009. Kinetics of acid degradation of proton pump inhibitors in the presence of a thiol. International journal of chemical Kinetics 41, 498-506.
2. Srebro, J., Brniak, W., Mendyk, A., 2022. Formulation of dosage forms with proton pump inhibitors: state of the art, challenges and future perspectives. Pharmaceutics 14, 2043.
3. De Bortoli, N., Martinucci, I., Giacchino, M., Blandizzi, C., Marchi, S., Savarino, V., Savarino, E., 2013. The pharmacokinetics of ilaprazole for gastro-esophageal reflux treatment. Expert Opinion on Drug Metabolism & Toxicology 9, 1361-1369.

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-2022-06) to ensure compliance with ethical standards and the welfare of the animals involved in the study.

Figure 1. Comparative dissolution profiles of Noltec® Delayed-release tablet, Sodium bicarbonate-ilaprazole fixed-dose matrix tablet, and Magnesium hydroxide-ilaprazole fixed-dose tablet in tablet

Figure 2. Comparative pharmacokinetic profiles of Noltec® Delayed-release tablet, Sodium bicarbonate-ilaprazole fixed-dose matrix tablet, and Magnesium hydroxide-ilaprazole fixed-dose tablet in tablet