Development of an oral bentonite-based modified-release freeze-dried powder of vactosertib: Pharmacokinetics and anti-colitis activity in rodent models of ulcerative colitis
Graphical abstract
Introduction
Vactosertib (TEW-7197) is a novel, orally bioavailable inhibitor of transforming growth factor-beta (TGF-β) receptor type 1 that specifically blocks the phosphorylation of Smad 2 or 3 (Jin et al., 2014, Son et al., 2014). TGF-β signaling via Smads plays a major role in a variety of pathological conditions such as inflammation, fibrosis and cancers; therefore, vactosertib is a promising candidate for the treatment of such conditions (Fabregat et al., 2014, Meng et al., 2016, Meulmeester et al., 2011, Neuzillet et al., 2015). Currently, vactosertib is under active development for the treatment of several types of cancers (NCT03724851, NCT03732274 and NCT03698825) after the safety aspect was evaluated in patients with advanced cancer in a phase 1 clinical trial (Keedy et al., 2018).
Ulcerative colitis is an inflammatory bowel disease characterized by relapsing inflammation and ulceration in the colon and rectum, resulting in serious complications such as perforation and fibrosis of the inflammatory lesion (Bilsborough et al., 2016, Gordon, 2018). Although the pathogenesis of inflammatory bowel disease has not been fully elucidated to date, dysregulated TGF-β signaling seems to be associated with the development of inflammation and fibrosis in the colon (Ihara et al., 2017, Marafini et al., 2013, Marek et al., 2002, Yun et al., 2019). Recently, the anti-inflammatory and anti-fibrotic effects of vactosertib have been demonstrated in a murine model of ulcerative colitis induced by dextran sulfate sodium (DSS) (Binabaj et al., 2019). The administration of vactosertib 5 mg/kg/day for eight consecutive days significantly reduced total histopathological scores in colitis mice compared to those in the positive control by attenuating colonic tissue inflammation, mucosal damage, and crypt loss. Furthermore the expression levels of pro-inflammatory and pro-fibrotic genes were significantly reduced.
In spite of the promising effects of vactosertib for the treatment of ulcerative colitis observed in animal models (Binabaj et al., 2019), the effects are not ensured in humans with conventional oral dosage forms because of the pharmacokinetic properties of vactosertib. Based on the analysis of pharmacokinetic data obtained from the phase 1 study, vactosertib administered as immediate-release tablets demonstrated a rapid rise and fast decline in plasma concentrations, with a median time to maximum concentration (tmax) of 1.2 h and a median terminal half-life (t1/2) of 3.2 h (Jung et al., 2019). These pharmacokinetic properties will likely result in a short duration of maintaining plasma concentrations above the therapeutically effective level and in potentially toxic peak concentrations (Ghiculescu, 2008). The pharmacokinetic properties appear to be associated with the physicochemical nature of the vactosertib molecule. Vactosertib is soluble only in strongly acidic conditions such as gastric pH and is insoluble in basic and even neutral conditions such as the intestinal pH, since vactosertib is a weakly basic and highly lipophilic drug (Jin et al., 2014). Hence, vactosertib administered as an immediate-release formulation appears to be dissolved and absorbed only in the upper gastrointestinal tract, which can make unfavorable pharmacokinetic properties mentioned above. Resolving such pharmacokinetic issues would be vital to the successful clinical development of vactosertib for the treatment of ulcerative colitis as well as various cancers.
Bentonite is a natural absorbent containing montmorillonite as a predominant component (Murray, 2006, Önal, 2006). Montmorillonite is a porous clay mineral compound composed of a 2:1-layer of two silica tetrahedral sheets sandwiching an alumina octahedral sheet containing exchangeable cations between the layers (Önal, 2006). This unique physical property of montmorillonite allows cationic drugs such as vactosertib to be adsorbed into the negatively-charged interlayer space by cationic exchange and electrostatic interactions (Hebbar et al., 2014, McGinity and Lach, 1976). Montmorillonite has been investigated as a drug carrier in modified-release drug delivery to enable the sustained release of drugs and avoid burst release (Bothiraja et al., 2014, Kaur et al., 2014). The pH of surrounding media is an important factor that primarily regulates the balance between drug absorption and release from montmorillonite (Joshi et al., 2009b, Karthikeyan et al., 2005). The application of a bentonite-based modified-release formulation to vactosertib delivery for the treatment of ulcerative colitis would enable a slower rate of vactosertib absorption, prolonging the therapeutic effect with lower peak concentrations for better safety. In addition, the application will likely allow substantial release of vactosertib not just in the upper gastrointestinal tract but also in the lower tract where the colitis lesions are present.
The objective of this study was to develop and characterize a bentonite-based, modified-release, freeze-dried powder formulation of vactosertib and evaluate the in vitro release profiles of vactosertib from the formulation in order to explore its potential in the treatment of ulcerative colitis. In addition, both the pharmacokinetic characteristics and the anti-colitis activities of vactosertib administered as the bentonite-based formulation were assessed using the experimental rodent models of ulcerative colitis.
Section snippets
Development of a bentonite-based modified-release formulation of vactosertib
Vactosertib was obtained as a pure powder form from MedPacto, Inc. (Seoul, Korea). Bentonite was obtained as a calcium-saturated form from the Korea Institute of Geoscience and Mineral Resources (Daejeon, Korea). The calcium-saturated bentonite is composed of silicon dioxide (59.92%), aluminum oxide (19.78%), magnesium oxide (1.53%), ferric oxide (2.96%), calcium oxide (0.64%), sodium oxide (2.06%), and potassium oxide (0.57%) (Rowe et al., 2009).
Development of bentonite-based modified-release formulation of vactosertib
The amount and efficiency of vactosertib adsorbed into the bentonite interlayer were influenced by the weight ratio of vactosertib to bentonite (Fig. 1A and 1B). The adsorbed amount of vactosertib per gram of bentonite was proportionally increased at the weight ratios of vactosertib to bentonite of 1:50, 1:20, 1:10 and 1:5, and the amount approached to the plateau near 200 mg at the range from 1:3.33 to 1:1 (Fig. 1A). The efficiency of vactosertib adsorbed to bentonite was greater than 80% at
Discussion
In the present study, a bentonite-based modified-release formulation was developed as an efficient oral delivery of vactosertib for the treatment of ulcerative colitis. The vactosertib/bentonite formulation demonstrated cationic vactosertib adsorption into the negatively-charged interlayer space of bentonite structure. The formulation was pharmacokinetically and histopathologically evaluated using experimental rodent models of ulcerative colitis induced by DSS.
The optimal adsorption ratio of
Conclusion
The novel bentonite-based modified-release formulation of vactosertib could alleviate the pharmacokinetic drawbacks of immediate-release vactosertib tablets in humans. The formulation appears to deliver vactosertib molecules to the lower gastrointestinal tract including the colon where colitis lesions are located, releasing these molecules slowly and steadily. Compared with the vactosertib oral solution, the formulation demonstrated 52.5% lower mean Cmax of vactosertib and three times longer
CRediT authorship contribution statement
Su Young Jung: Conceptualization, Methodology, Investigation, Writing - original draft. Ju-Hwan Park: Conceptualization, Methodology, Investigation, Writing - original draft. Min-Jun Baek: Methodology, Investigation, Visualization. Gyu-Ho Kim: Methodology, Investigation, Visualization. Jaehwan Kim: Resources, Project administration. Hong-Mei Zheng: Investigation, Resources. Jae-Min Kim: Investigation, Resources. Il-Mo Kang: Resources, Project administration. Dae-Duk Kim: Conceptualization,
Declaration of Competing Interest
The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: [The authors had two patents on design and utility of bentonite-based formulation of vactosertib.].
Acknowledgments
This study was supported by the Research Institute of Pharmaceutical Science in Seoul National University, and the basic research project of Korea Institute of Geoscience and Mineral Resources (KIGAM) funded by the Ministry of Science, ICT and Future Planning of Korea. The authors appreciate MedPacto, Inc. for providing vactosertib drug substance.
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Su Young Jung and Ju-Hwan Park contributed equally to this work.