The use of alkalizers in sodium caprate-based tablets for oligonucleotide oral delivery

Abstract

The oral delivery of biologics such as oligonucleotides may be enabled by the use of a chemical permeation enhancer such as sodium caprate (C10). However, C10 has low solubility under acidic gastric conditions which, often combined with poor drug stability, limits absorption when formulated in oral formulations. In this work, we investigated the use of alkalizers in immediate release C10-based formulations to enable the delivery of an oligonucleotide drug, RO7062931. Across the physiological pH range, C10 demonstrated low solubility and RO7062931 demonstrated poor chemical stability at pH values lower than 5, which together present significant obstacles to the oral delivery of the oligonucleotide. Screening alkalizers revealed that these pH-modifying components rapidly raised both the simulated gastric fluid bulk pH and microenvironmental pH when combined with C10, increasing the amount of C10 dissolving. Incorporating the most promising alkalizer, sodium carbonate, into C10-containing tablets of RO7062931 led to improved oligonucleotide chemical stability and C10 solubility under gastric conditions during in vitro testing, with the most effective formulation exhibiting complete RO7062931 stability and full C10 release. Alkalizer addition further contributed to oligonucleotide/C10 co-release, which is important for maximizing permeation enhancement activity at epithelial barriers. These findings offer insight into alkalizer incorporation as a promising strategy to improve the gastric delivery of oral formulations of oligonucleotide drugs and permeation enhancers.

Introduction

Since the watershed production of recombinant human insulin over three decades ago, biological therapeutics, or biologics, have been considered as a desirable alternative to traditional small molecule drugs [1]. The structural complexity of biologics, such as peptides and oligonucleotides, confers high specificities for in vivo targets, resulting in increased potencies and few off-target effects [2]. Despite these benefits, a major challenge facing the development of biologics is their poor oral bioavailability, requiring parenteral administration [3]. Barriers to the oral delivery of biologics include low enzymatic and chemical stabilities in gastrointestinal fluids and poor intrinsic permeabilities across physical barriers like the gastric and intestinal epithelia, typically resulting in oral bioavailabilities of 1–2 % or less [4].

Compared to parenteral administration, oral delivery provides increased patient convenience and compliance, particularly for chronic diseases [5]. As a result, developing drug delivery methods to improve the oral administration of biologics has become a burgeoning area of research within the pharmaceutical sector. Strategies have included the use of enteric-coatings, protease inhibitors, and nanoparticle-based delivery systems [6]. Currently, one of the most successful approaches is to co-formulate drugs with chemical permeation enhancers, which improve the ability of macromolecular drugs to penetrate the gastric and intestinal epithelia for absorption [7]. This mode of action is especially important for biologics, which are typically too hydrophilic to pass through epithelial cells by transcellular absorption and too large to infiltrate tight junctions between epithelial cells for paracellular absorption [8].

Different types of compounds have been studied as permeation enhancers, including bile salts [9], bacterial toxins [10], chelating agents [11], and medium-chain fatty acids [12]. These compounds transiently and reversibly affect transcellular and/or paracellular pathways of permeation by mechanisms such as decreasing epithelial cell membrane integrity and interfering with tight junction proteins. In particular, medium-chain fatty acid permeation enhancers have generated substantial interest recently with the regulatory approval of Rybelsus® and Mycapssa®, oral formulations of the peptides semaglutide and octreotide, respectively [13], [14]. Both formulations contain medium-chain fatty acids or derivatives such as salcaprozate sodium (SNAC) in Rybelsus® tablets, Wegovy® tablets and sodium caprylate in Mycappsa® as the primary permeation-enhancement component, resulting in oral bioavailability of 1–2 % [15], [16].

Among current medium-chain fatty acid permeation enhancers, one of the most promising is sodium caprate (C10). C10 has been incorporated into oral formulations of peptides and oligonucleotides for over two decades and has been clinically tested with a variety of macromolecular drugs [17], [18], [19], [20], [21]. It is thought that C10 can insert into epithelial cell membranes, decreasing membrane integrity and enhancing transcellular drug absorption [22]. C10 has additionally been shown to affect paracellular permeation pathways by inducing reorganization and internalization of tight junction proteins [23]. Before C10 can interact with epithelial barriers to improve permeation, however, it must first be released from its oral dosage form, such as the tablet or capsule, and dissolve in gastrointestinal fluids. Typically, permeation enhancer-based formulations, based on sodium caprate have been designed for intestinal delivery, thereby requiring an enteric coated dosage form to promote intestinal release [24], [25], [26]. However, enabling sufficient permeation enhancer dissolution in gastric fluids would bypass the need for an enteric coating, simplifying the formulation and decreasing overall manufacturing costs. As a result, recent formulations have focused on targeting gastric delivery, based on research by Buckley et al. [27] demonstrating gastric peptide absorption in an oral dosage form containing the permeation enhancer SNAC and sodium caprate [21], [27], [28]. Ensuring full release of permeation enhancers under gastric conditions is therefore important for effective permeation enhancement and drug absorption in these formulations.

The physicochemical properties of C10 heavily influence its gastric dissolution behaviour. C10 is a weak acid, with a pKa value of approximately 4.8, although aggregation of C10 molecules has been previously reported to increase its apparent pKa to around 7 [29]. At pH values above the pKa, C10 will be dominantly present in its ionized form, which readily dissolves in aqueous solution. However, at lower pH values, C10 molecules will exist in the poorly soluble neutral acid form. Consequently, poor C10 release in gastric fluids could pose a substantial obstacle to permeation enhancement in immediate release formulations. Moreover, many biologics suffer from low chemical stability under acidic conditions, another challenge that must be overcome for gastric delivery to be feasible [4]. Therefore, strategies that counteract the acidic pH of gastric fluids by increasing gastric pH to more neutral-to-alkaline levels could significantly improve the performance of C10-based formulations while providing protection to sensitive macromolecules.

Alkalizers are basic pH modifiers administered to increase the pH of gastric fluids. For example, alkalizers are routinely employed as over-the-counter medicines to treat acid reflux by neutralizing excess acid in gastric fluids and are used to treat kidney stones through urine alkalinization [30], [31]. Alkalizers have also been added as excipients to formulations containing ionizable small molecule drugs to improve release and chemical stability of acid-sensitive drugs. By modulating the surface – or microenvironmental – pH of a solid dosage form, alkalizers have been shown to enhance both drug solubility and dissolution rate [32], [33], [34]. Incorporating alkalizers into C10-based formulations therefore has the potential to improve permeation enhancer dissolution and drug stability in gastric fluids to increase gastric drug absorption.

Another important factor is the co-release of C10 and drug, as permeation enhancers act by transiently modulating the epithelial membrane to facilitate drug absorption. This effect is short-lived and localized, meaning that if the drug and permeation enhancer are not simultaneously released, the permeation enhancer may lose its activity before the drug is available, resulting in poor absorption. The co-release of sulpiride and C10 has been previously shown to significantly increase absorption in rats compared to a nonsynchronous control formulation [35]. Similarly, it was found that the use of a drug-coated beadlet dosage form that promoted SNAC/ibandronate co-release resulted in greater ibandronate absorption compared to granulate formulations with poor co-release [36]. Furthermore, the co-release of semaglutide and SNAC has been demonstrated to be critical for semaglutide gastric absorption [27]. The ability of alkalizers to neutralize gastric fluids and accelerate dissolution may therefore contribute to solid dosage forms achieving this crucial permeation enhancer/drug co-release, particularly in the case of drugs with good gastric solubility.

In this work, we developed an alkalizer screening setup to support the selection of the most promising alkalizers, and respective ratios, to improve C10 dissolution in fasted gastric media.

The work focuses on simulated fasted gastric media for screening of alkalizers as the ingestion of food triggers a substantial influx of gastrointestinal (GI) fluids, digestive enzymes, and lipids that rapidly dilutes the permeation enhancer below its effective threshold. Furthermore, this state accelerates GI motility and creates a physical food matrix barrier that structurally isolates the solid dosage form from the absorptive epithelium.

The most effective alkalizers were then used in formulation prototyping. An acid-sensitive oligonucleotide RO7062931 developed for treatment of hepatitis B [37] was chosen as a model drug to assess the impact of alkalizer on RO7062931 stability in simulated gastric fluid and C10/RO7062931 co-release under gastric conditions in vitro.

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Materials

The oligonucleotide RO7062931 is a GalNAc conjugated oligonucleotide with the structure (5′-GalNAc-C6O cO aO AS GS mCS gS aS aS gS tS gS cS aS cS AS mCS G -3′) LNA which was supplied by Roche (Basel, Switzerland) and is described in the literature [38], [39]. The permeation enhancer C10 was purchased from Combi-Blocks (San Diego, California, United States). For the alkalizers, sodium bicarbonate and TRIS were purchased from Merck (Darmstadt, Germany). Arginine and meglumine.

Sydney Marcy, Suleika Semling, Lasse Ingerslev Blaabjerg, Felipe Varum, Marc Lindenberg, The use of alkalizers in sodium caprate-based tablets for oligonucleotide oral delivery, European Journal of Pharmaceutics and Biopharmaceutics, Volume 227, 2026, 115208, ISSN 0939-6411, https://doi.org/10.1016/j.ejpb.2026.115208.

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