Following oral administration, gastric emptying is often a rate-limiting step in the absorption of drugs and is dependent on both physiological and pharmaceutical factors. To guide translation into humans, small animal imaging during pre-clinical studies has been increasingly used to localise the gastrointestinal transit of solid dosage forms. In contrast to humans, however, anaesthesia is usually required for effective imaging in animals which may have unintended effects on intestinal physiology. This study evaluated the effect of anaesthesia and capsule size on the gastric emptying rate of coated capsules in rats. Computed tomography (CT) imaging was used to track and locate the capsules through the gastrointestinal tract. Two commercial gelatine mini-capsules (size 9 and 9h) were filled with barium sulphate (contrast agent) and coated using Eudragit L. Under the effect of anaesthesia, none of the capsules emptied from the stomach. In non-anaesthetised rats, most of the size 9 capsules did not empty from the stomach, whereas the majority of the smaller size 9h capsules successfully emptied from the stomach and moved into the intestine. This study demonstrates that even with capsules designed to empty from the stomach in rats, the gastric emptying of such solid oral dosage forms is not guaranteed. In addition, the use of anaesthesia was found to abolish gastric emptying of both capsule sizes. The work herein further highlights the utility of CT imaging for the effective visualisation and location of solid dosage forms in the intestinal tract of rats without the use of anaesthesia.

Access to medicines, including their availability and affordability, is a major public health challenge worldwide. This research aimed to characterise rectal formulations containing amoxicillin for the treatment of pneumonia in children under five, as an accessible alternative to existing formulations. Lipophilic Suppocire (S-NA15) and hydrophilic polyethylene glycol (PEG; 80% PEG 1500 and 20% PEG 4000, w/w) suppositories containing 250 mg amoxicillin were prepared. Hardness, apparent viscosity, uniformity of mass, uniformity of content, disintegration and dissolution time were determined. Irritation potential was screened using a slug mucosal assay and antibacterial efficacy against Staphylococcus aureus determined by isothermal microcalorimetry. Both lipophilic and hydrophilic formulations met the European Pharmacopoeia standards for suppositories when tested in vitro. They disintegrated within 30 min with rapid amoxicillin release profiles (98.6 ± 0.9%, 94.9 ± 1.2% over 30 min, respectively). Over-encapsulation of S-NA15 suppositories with hydroxypropyl methylcellulose shells slowed drug release and improved stability over 2 months. S-NA15 suppositories were classified as non-irritant and PEG suppositories only mildly irritant. Antibacterial efficacy of formulations was equivalent to amoxicillin alone. Both PEG and over-encapsulated S-NA15 rectal formulations developed in the present work have shown promise based on pre-clinical screening, and further development is justified to develop a product with commercial potential.

Janus kinase (JAK) inhibitors, such as tofacitinib (Xeljanz) and filgotinib (Jyseleca), have been approved for treatment of ulcerative colitis with several other JAK inhibitors in late-stage clinical trials for inflammatory bowel disease (IBD). Despite their impressive efficacy, the risk of adverse effects accompanying the use of JAK inhibitors has brought the entire class under scrutiny, leading to them receiving an FDA black box warning. In this study we investigated whether ileocolonic-targeted delivery of a pan-JAK inhibitor, tofacitinib, can lead to increased tissue exposure and reduced systemic exposure compared to untargeted formulations. The stability of tofacitinib in the presence of rat colonic microbiota was first confirmed. Next, in vivo computed tomography imaging was performed in rats to determine the transit time and disintegration site of ileocolonic-targeted capsules compared to gastric release capsules. Pharmacokinetic studies demonstrated that systemic drug exposure was significantly decreased, and colonic tissue exposure increased at 10 mg/kg tofacitinib dosed in ileocolonic-targeted capsules compared to gastric release capsules and an oral solution. Finally, in a rat model of LPS-induced colonic inflammation, targeted tofacitinib capsules significantly reduced concentrations of proinflammatory interleukin 6 in colonic tissue compared to a vehicle-treated control (p = 0.0408), unlike gastric release tofacitinib capsules and orally administered dexamethasone. Overall, these results support further development of ileocolonic-targeted tofacitinib, and potentially other specific JAK inhibitors in pre-clinical and clinical development, for the treatment of IBD.

In the era of biologics where IBD treatment has been transformed by potent antibody-based therapeutics, a key challenge still remains, to develop orally administered antibody medicines for chronic GI inflammation. This is primarily due to the challenges in accurate oral targeted delivery of drugs to the lower GI tract and the inherent enzymatic instability of antibodies in these harsh luminal environment. As a result, all antibody therapeutics in clinical development and on the market are available only as an injection leading to undesired adverse effects due to high systemic exposure and suboptimal therapeutic response due to insufficient antibody levels at the inflamed tissue. We have developed a suite of delivery technologies that are designed to bypass the harsher stomach and small intestinal conditions of the GI tract and achieve accurate targeted release and enzymatic stabilization of the antibody therapeutics in the colon. The delivery platform comprises of a film coating which is applied on the outside of the pill. The coating is a clinically validated polymer coating comprising of a combination of pH sensitive polymer and polysaccharide that is designed to start releasing drugs only when exposed to the correct pH and/or colonic bacteria, dramatically improving on the inconsistent colonic release profiles of solely pH-based coatings. The second component is in the core of the pill, a cocktail of amino acid-based excipients that are mixed together with the antibody and protects the drug from pancreatic and bacterial origin protease enzymes, allowing high luminal antibody concentration build-up that leads to inflamed tissue/systemic uptake through a combination of active and passive diffusion. We demonstrated in an acute DSS mouse model of colitis the effective colonic delivery and stabilization of an anti-IL6 antibody leading to superior uptake into the tissue compared IP injection. The superior tissue level demonstrated higher downregulation of target IL6. We are working to leverage the delivery technology for oral delivery of a variety of anti-inflammatory and epithelial wound healing protein modalities such as monoclonal antibodies, fusion proteins, cytokines, VHHs and peptides to allow for broad therapeutic interventions in indications such as Crohn’s disease, ulcerative colitis, pouchitis and celiac disease. Mechanism of oral colon targeted delivery of therapeutic antibodies in local treatment of inflammatory bowel disease. In-vivo PK of anti-IL6 antibody in acute DSS colitis mouse model. A. Impact of stabilization on antibody levels in the colon lumen compared to naked antibody and injected antibody. B. Impact of stabilization on colon tissue uptake. C. Effect of tissue conc. on colon tissue IL6 target downregulation.

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