Release-modulating mechanism and comparative pharmacokinetics in beagle dogs of bethanechol-loaded oral dosage forms

Introduction

Bethanechol chloride (BTC) is a cholinergic agonist used to treat postoperative and postpartum non-obstructive functional urinary retention and neurogenic atony of the bladder (Finkbeiner, 1985). BTC is a polar quaternary ammonium derivative with a positive charge (Fig. 1), resulting in high water solubility and low gastrointestinal absorption (Rotival et al., 2013). However, the specific absorption site of BTC in the gastrointestinal tract remains unknown, necessitating further research.

Currently, BTC is orally administered in 10–25-mg doses three to four times daily as Mytonin® tablets (the reference drug product of BTC) effects appear within 30 min, peaking at 60 to 90 min. The duration of action is usually 1 h, although the effects can last up to 6 h at larger doses (300–400 mg). Pharmacokinetic studies using Mytonin® 25-mg tablets manufactured by Alvogen Korea revealed a 2.1-h time to peak plasma concentration (Tmax) of and approximately 4.6-h half-life for BTC.

These dosing regimens can be inconvenient to patients, reducing adherence. A review of 76 studies confirmed that the number of prescribed doses per day is inversely proportional to medication compliance (Claxton et al., 2001, Claxton et al., 2001). To improve patient compliance, there is an urgent need to develop more patient-friendly and advanced BTC dosage formulations. Four oral dosage formulations were designed: a gastro-retentive tablet (GRT), controlled-release tablet (CRT), bilayer tablet (BLT) with immediate and sustained drug release, and enteric-coated tablet-in-immediate release tablet (TIT).

Gastro-retentive drug delivery systems (GRDDSs) maintain drug release in the stomach, benefiting model drugs that are active at low pH or with gastric absorption windows (Ibrahim et al., 2019, Tripathi et al., 2019). Additionally, GRDDSs have the potential to achieve retention of the dosage form in the upper gastrointestinal tract, which can ensure complete solubilization of drugs in stomach fluids, followed by subsequent absorption in the stomach or proximal small intestine (Vrettos et al., 2021a). Although various gastric retention mechanisms exist (Tripathi et al., 2019), combining strategies, such as floating and swelling properties, effectively prevents pyloric passage and prolongs retention time in the stomach (Hou et al., 2023, Vrettos et al., 2021). In a study on brivaracetam GRT, a complex GRDDS with floating and swelling properties was designed (Hou et al., 2023). Hydrophilic polymers can be combined with effervescent agents, such as calcium carbonate, sodium bicarbonate, tartaric acid, and citric acid. Consequently, upon interaction with stomach fluid, CO2 is released and trapped in the hydrocolloid matrix, affecting drug release. (Kumar et al., 2024).

Controlled drug delivery systems with drug release throughout the gastrointestinal tract have been widely utilized to minimize dosing frequency and maintain plasma concentrations over a longer period. Hydrophilic or hydrophobic polymeric matrix systems offer advantages, such as simple manufacturing and predictable release kinetics (Sakkal et al., 2024). While hydrophilic matrices are widely used, they limit the long-term release of highly water-soluble drugs, such as BTC (Wen et al., 2010). Hydrophobic matrix polymeric systems can allow more precise controlled release of highly water-soluble drugs.

However, as a matrix tablet for sustained release (SR), SR systems cannot reach the minimum therapeutic systemic levels quickly. To overcome these problems, multilayer tablets, such as bilayer or three-layer tablets, with a dual-release mechanism have been developed (Han et al., 2022, Jun et al., 2018). This could be designed to ensure that the minimum effective concentration is achieved quickly with an immediate release layer, which is maintained by a SR layer to avoid repeated administration (Lopes et al., 2007). Tablet-in-tablet (TIT) technology can be used to develop a modified release product (e.g., a delayed release product) on the inner core. In addition, immediate and SR effects can be achieved by combining the same or different drugs (Gaikwad and Kshirsagar, 2020). To evaluate the absorption site of the drug, we designed a TIT tablet with an outer layer that immediately released the drug from the stomach and an inner core that delayed release of the drug in the small intestine at pH 6.0 or higher.

The aim of this study was to design four BTC-loaded dosage forms, and compare their release-modulating mechanisms and in vivo pharmacokinetics in beagle dogs. GRTs, CRTs, BLTs, and TITs were investigated. Dissolution studies of all formulations were conducted in pH 1.2 buffer solution. Release-modulating kinetics were investigated by comparing the swelling behavior, erosion, and water penetration using methylene blue staining. Drug release kinetic equation models were then compared to provide a deeper understanding of the release mechanisms. Additionally, BTC solubility in different media and the in vitro buoyancy behavior of GRTs for prolonged gastric residence were investigated. The physical appearance and cross-sectional morphology were evaluated as a function of time using field-emission scanning electron microscopy (FE-SEM). Fourier Transform-Infrared (FT-IR) spectroscopy was conducted to detect any potential molecular interactions between BTC and the pharmaceutical excipients in the formulations. The in vivo comparative pharmacokinetics in beagle dogs were evaluated by administering the optimized BTC-loaded dosage forms, along with the reference product, Mytonin® 25-mg tablet. The mechanistic understanding of the absorption behaviors and bioavailability of BTC-loaded formulations with differently designed BTC-loaded dosage forms was then discussed, aiming to achieve an appropriate dosage form that provides a promising option to effectively improve medication therapy and compliance by reducing the dosing frequency for patients with bladder dysfunction.

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Materials

BTC was purchased from Samjin Pharmaceutical Co., Ltd. (Cheong-Ju, Korea). Commercially available immediate-release Mytonin® tablets were manufactured by Alvogen (Seoul, Korea). Hydroxypropyl methylcellulose (HPMC)-100SR and HPMC-4000SR (viscosity 4,000 mPa·s) were supplied by Shin-Etsu (Tokyo, Japan). Kollidon SR, Povidone K90 (PVP K90), and Crospovidon CL were purchased from BASF Chemicals (Ludwigshafen, Germany). Hydroxypropyl methylcellulose (HPMC) K100M (viscosity 100,000 mPa·s), Opadry®.

Hyeong-Mo Jeong, Hansol Kim, Taeyeon Jang, Ayoung Choi, Jun-Bom Park, Chulhun Park, Beom-Jin Lee, Release-modulating mechanism and comparative pharmacokinetics in beagle dogs of bethanechol-loaded oral dosage forms, International Journal of Pharmaceutics, 2024, 125091, ISSN 0378-5173, https://doi.org/10.1016/j.ijpharm.2024.125091.

Read also our introduction article on Orally Disintegrating Tablets (ODTs) here: