Oral capsule administration of biomacromolecules that achieves bioavailability and pharmacokinetics comparable to subcutaneous injection in dogs – the BIONDD® technology

Abstract

Biomacromolecules including peptides, proteins, antibodies, and gene medicines, comprise important classes of therapeutics in treating disease. A drawback of biologics is their inconvenient route of administration, as they are mostly injected. Most patients prefer the oral administration route over injections. To accommodate this need, we developed the BIONDD^® technology, which is an oral administration device for biomacromolecules contained in a standard 00 or 0-sized capsule. Upon ingestion and actuation in the stomach, the macromolecule is delivered from the cavity of the device’s spike into the gastric wall, from where it migrates to the blood vessels. Using 0.4 mg liraglutide as a model peptide, a short T_max and a relative oral bioavailability of 119% compared to subcutaneous administration were achieved over time after oral administration of the BIONDD^® capsule to dogs. The pharmacokinetic data from the large animal studies obtained provides proof-of-concept for a convenient oral delivery device for biologics.

Introduction

Peptides, proteins, monoclonal antibodies, RNAs, enzymes, hormones, and vaccines can be grouped as biomacromolecules (often referred to as biologics), which offer new opportunities for the effective treatment of and vaccination against multiple diseases [1,2,3,4]. These therapeutic classes include both biologically derived and synthetic molecules. Seven out of ten of the best-selling drugs in the US are biologics, and their overall sales are expected to overtake those of small molecules shortly [5]. An increasing proportion of biomacromolecules is in clinical development year-after-year [6]. While the focus has been on the benefits of biologics in treating diseases for which small molecules can be less than optimal, the limitations of large molecules have begun to attract attention [7]. An important drawback relates to their route of administration, as biologics are normally administered via injection or infusion, which can be a deterrent to medication adherence [7]. The current paper describes an effective approach for delivery of biologics via the oral route with potential to improve the clinical outcomes while making administration easier and more convenient for patients, thereby improving efficacy.

To many patients, needles signify pain, discomfort, the risk of needle injuries, and transmission of infectious diseases such as HIV, hepatitis B, and hepatitis C [7,8,9,10]. While the incidence of needle phobia across all ages is reported to be at least 10% [11], most children and up to 30% of young adults still fear needles, which makes some forgo treatments or skip vaccinations [12, 13]. Furthermore, having regular injections is time-consuming and can be a logistical challenge for patients, which is another reason why most patients prefer the oral treatment form [14,15,16]. Patient resistance to needles also affects clinicians’ views and results in lower-than-expected prescription rates for macromolecules [7]. From the healthcare system perspective, infusions are costly, time-consuming, labour-intensive, and carry a risk of needle stick injuries to healthcare workers, adding further to the costs [17,18,19]. Finally, from a sustainability perspective, the number of single-use syringes and needles for injections makes a total of 16 billion worldwide every year, according to the WHO, thereby contributing to a tremendous amount of medical waste [20, 21].

Biologics tend to degrade rapidly in the gastrointestinal (GI) tract and, due to their large size and hydrophilic nature, their absorption across gastric and small intestinal epithelia is negligible [22,23,24]. Still, the desire of patients to swallow a pill compared to having an injection has led to substantial efforts in developing methods for oral delivery of biomacromolecules [22, 23, 25,26,27,28]. Devices capable of effectively passing the mucosal barrier and getting into the GI wall while protecting the drug from degradation seem to be increasingly effective in obtaining high oral absorption of biologics [7]. To perform well, such devices must be easy and convenient to swallow, resist extreme pH values and gastric muscle contractions, and protect the active pharmaceutical ingredient (API) from degrading enzymes. In the case of an intra-wall (IW) delivery capsule targeted at the stomach, the device also needs to permeate mucus overlying the gastric epithelium before it can deliver the API into the stomach wall, from where it can move by passive diffusion to blood vessels to ultimately ensure systemic bioavailability that can be comparable to injections [7, 23, 24, 29].

Specific IW solutions under development include the self-orienting millimeter-scale applicator (SOMA) and its liquid-injecting version (L-SOMA), which inject a solid and a liquid drug-loaded needle, respectively, directly into the submucosal space of the stomach tissue [30, 31]. Also targeting the gastric wall is the omnidirectional adhesive microneedle (DOAM) system, which combines physical and chemical approaches [32]. An intra-wall delivery device with an operating principle of axial and radial microjets based on a cephalopod was also recently tested successfully for two 4 kDa peptides in large animals [28]. Other device-based solutions designed to transfer the API across the small intestinal wall include the RaniPill™ and the BioJet™ solutions [33,34,35]. Of these, the RaniPill™ is the most advanced and has been tested in humans [33]. Detailed and systematic comparison of these and other emerging oral macromolecule delivery devices, including their mechanisms, target sites, and development status, have been previously published [23, 36]. Importantly, these dosage forms are bigger than the generally acceptable pill size (00), making them difficult to swallow. Indeed, swallowability plays an important role when designing macro-devices, and the U.S. Food and Drug Administration (FDA) has provided guidelines for optimal size, shape, and physical characteristics for capsules and tablets [37, 38]. Therefore, further miniaturization may be needed before the above-mentioned solutions can be attractive alternatives to injections.

Agents included in hitherto approved oral peptide medications include sodium salcaprozate (SNAC) used in semaglutide tablets (Rybelsus®) and sodium caprylate (C8) used in octreotide capsules (Mycapssa®). SNAC and C8 belong to the category of medium-chain fatty acid derivative chemical permeation enhancers (PEs), which act by protecting the API from degradation and enhancing permeation across a particular epithelial region of the GI wall. While PEs are most efficient for macromolecules with relatively low molecular weight, long half-life, and high potency, their broader use is limited by the low oral bioavailability that they currently achieve, along with a requirement for large amounts of PE in the oral dosage form. The oral bioavailability of semaglutide (Rybelsus®) in humans, for instance, is 0.4–1.2%, and, to compensate for this low oral bioavailability, the amount of semaglutide used weekly for patients with type II diabetes (T2D, 14 mg x 7 days) is approximately 100 times higher than that in the injectable formulation (Ozempic®, 1 mg once weekly) [36, 39, 40]. Similarly, the recommended oral dose of octreotide (Mycapssa®) to treat acromegaly and neuroendocrine tumours is 20–40 mg twice daily, whereas the subcutaneous injectable version of octreotide requires only 0.1 mg 2–3 times a day [40].

Despite the considerable amounts of peptide required for the oral delivery of semaglutide, this administration route is as efficacious as a weekly injection in T2D patients under criteria including reduction in glycosylated haemoglobin and weight loss [41]. Cost-effectiveness improvement is anticipated for oral delivery devices offering a markedly higher oral bioavailability compared to Rybelsus®, especially if the device is also simple in construction with only a few sub-components, such as the device presented below. In sum, the same or higher oral bioavailability values as current marketed oral peptide dosage forms may be achieved using a lower dose of peptide, thereby allowing less waste of active substance than with PEs, while acceptable oral bioavailability can for the first time be achieved for biomacromolecules that have so far failed in traditional oral dosage form designs. This will expand the number of biomacromolecule candidates under consideration for oral delivery.

Here, we present proof-of-concept data for the BIONDD® technology. BIONDD® is an oral drug delivery device contained in a standard 00 or 0-sized capsule. Different capsule sizes are available to accommodate varying therapeutically-relevant doses of biologics and/or the needs of specific patient groups, e.g., the elderly and children. The capsule is orally ingested and dissolves in the stomach thereby releasing a spring mechanism to reveal a small spike containing the payload. Via the spike, the biomacromolecule is delivered directly into the gastric wall from where it migrates passively to gastric blood vessels. We selected liraglutide (Victoza®, Novo Nordisk, Måløv, Denmark), a once-daily injectable anti-T2D and anti-obesity glucagon-like peptide (GLP)-1 molecule (Mw 3751 Da), as a model biologic. It was dosed at a level of 0.4 mg (which is the dose tolerable to dogs). Here, we provide in vitro and in vivo data demonstrating the promising potential of the BIONDD® technology as a platform for oral administration of biomacromolecules.

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Materials

Device structure and units

The prototype device consists of six parts, including a detachment part and a rotor part (Fig. 1a-d). The spike has a length of 5.1 mm, and the active substance was located within the cavity of the spike, which was connected to the rotor part. The spring element is encased in the rotor part. The individual device parts were made of cut polyether ether ketone (PEEK) polymer (TEKAPEEK MT (medical grade), Ensinger, Nufringen, Germany), except for the tip of the spike and the spring component, which were comprised of stainless steel (grade 1.4310Mo) and an erodible element consisting of a dissolvable polymer, poly(ethylene oxide) (PEO, Mw 100 kDa, SENTRY™ POLYOX™ WSR N10, IFF, NY, USA), which was placed between the device body parts (shown in orange and green in Fig. 1b-d) and the detachment part, thereby temporarily locking these components until erosion enabled timely disengagement of the device from the tissue. The spike for the prototype device was fabricated from a 20G syringe needle (Spinocan^®, B Braun, Melsungen, Germany) by bending using a custom designed bending tool, and the cavity for the drug vehicle was cut using a 30w Fiber laser model PF-QB30 (JCZ Technology Co., Ltd, Beijing, China). The spring component was a torsion spring (0.14 mm thickness, 3 mm width, and 57.5 mm length) fabricated by cutting the end details and length using a 30w Fiber laser model PF-QB30. The torsion spring was attached at one end to the rotor axle and at the other end to the outer perimeter of the rotor part (Fig. 1d), where it was wound into an active configuration prior to encapsulation of the device. The device components were assembled as shown in Fig. 1d with the spring in active configuration, while the capsule keeps the device in the locked configuration (Fig. 1b). The prototype device was encapsulated in a hydroxypropyl methylcellulose (HPMC) capsule, size 00 (Vcaps^® Plus Capsules from Capsugel^®, Lonza) with a closed length of 23.30 ± 0.30 mm and an external cap diameter of 8.53 ± 0.07 mm. The size 0 capsule has a closed length of 21.70 ± mm and an external cap diameter of 7.64 ± 0.07 mm (Fig. 1e).

Formulation preparation

An excess of the solid liraglutide (Chengdu Shengnuo Biopharm Co., Chengdu, China) was gently ground into a fine powder in a mortar. The powdered liraglutide was weighed and mixed with polyethylene glycol (PEG) 6000 (Sigma-Aldrich, St. Louis, MO, USA) in a 5 mL glass beaker in amounts resulting in the desired liraglutide:PEG 6000%w/w ratio ± 1%w/w. The beaker was placed on a custom-made heating mantle to achieve uniform heating of the mixture to 67 °C. Upon melting of the PEG 6000, it was mixed with the solid liraglutide using a small spatula. The mixture was heated for no more than 60 min. The paste-like mixture was used in two ways: (i) direct loading into spikes for micro-dissolution testing, UV–Vis imaging release testing, and prototype device preparation, or (ii) cooling and solidification prior to preparation of samples (0.8–1.1 mg) for content uniformity and stability determination (n = 10) in screw-capped vials.

Skak, N., Mertz, N., Piwon, N. et al. Oral capsule administration of biomacromolecules that achieves bioavailability and pharmacokinetics comparable to subcutaneous injection in dogs – the BIONDD^® technology. Drug Deliv. and Transl. Res. (2026). https://doi.org/10.1007/s13346-026-02157-y

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