Development of an oral bentonite-based modified-release freeze-dried powder of vactosertib: Pharmacokinetics and anti-colitis activity in rodent models of ulcerative colitis

Abstract

Vactosertib is a novel inhibitor of transforming growth factor-β signaling. Clinical applications of vactosertib have been challenging since conventional oral formulations such as immediate-release tablets demonstrate a rapid rise and fast decline in plasma concentrations. In this study, a novel bentonite-based, modified-release, freeze-dried powder of vactosertib was developed and evaluated to determine its potential in the treatment of ulcerative colitis. The formulation released vactosertib slowly and steadily in an in vitro drug release test. The extent of vactosertib released from the formulation was markedly low (18.0%) at pH 1.2 but considerably high (95.6%) at pH 7.4. Compared with vactosertib oral solution, the formulation demonstrated a 52.5% lower mean maximum concentration of vactosertib and three times longer median time to maximum concentration without a significant change in the extent of vactosertib absorption in a rodent colitis model. Furthermore, colitis mice administered with this formulation showed a significant reduction in the total histopathological score by 30% compared with those administered with the positive control, whereas the administration of vactosertib oral solution resulted in only a 10% reduction. Collectively, this novel formulation resolved the pharmacokinetic drawbacks of vactosertib and is expected to enhance its therapeutic effect by delivering vactosertib to the colitis lesions in the lower gastrointestinal tract.

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 (t_max) of 1.2 h and a median terminal half-life (t_1/2) 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.