Double-coated semaglutide formulation for oral colon delivery

Diabetes mellitus is one of the most prevalent chronic diseases globally, with type 2 diabetes accounting for approximately 90% of all cases [1]. Glucagon-like peptide-1 (GLP-1) receptor agonists represent a major therapeutic advancement in the management of type 2 diabetes [2]. Beyond their glucose-lowering efficacy, these agents may help preserve pancreatic β-cell function and exert favorable effects on common comorbidities, such as hypertension, dyslipidemia and obesity. However, the need for subcutaneous administration represents an important barrier to long-term adherence to the therapy. Furthermore, gastrointestinal side effects including nausea, vomiting and abdominal discomfort- are frequently observed and constitute a leading cause of treatment discontinuation. The development of oral semaglutide (Rybelsus®) has overcome issues related to the injective route by offering a non-invasive delivery mode. Rybelsus® employs absorption enhancer sodium N-(8-[2-hydroxylbenzoyl]amino) caprylate (SNAC), which protects the drug from enzyme degradation by locally increasing pH, promotes drug dissolution and transiently modulates gut epithelial permeability [3]. Despite these advances, the oral bioavailability of the drug remains low because of enzymatic activity, variable pH and low responsiveness to promoters in the upper gastrointestinal tract. Thus, an alternative delivery strategy that may offer better chances of absorption while ensuring high patient compliance, such as colon targeting, could bring considerable benefits [4]. Moreover, delivery of semaglutide to the distal intestine may reduce nausea and vomiting associated with already available administration modes. To achieve colon delivery, a double coating technology has recently been developed for improved site selectivity of release. The outer layer comprises Eudragit®S -an enteric polymer with a pH-dependent dissolution threshold of 7- and guar gum, a natural polysaccharide degraded by the colon microbiota [5]. This layer protects the dosage form in the stomach and upper intestine and enables release into the colon. An inner low-viscosity hydroxypropyl methylcellulose (HPMC) coating introduces a lag phase, further delaying drug exposure in the event the outer coating is dissolved before colon arrival. In the present study, application of the above-mentioned oral delivery technology to semaglutide was explored aiming to achieve colon targeted delivery of the drug. Marketed Rybelsus® tablets were employed as the starting cores. For setup of the coating conditions, tablets comparable in shape and size to Rybelsus® ones were manufactured from a 27.77% paracetamol, 48.81% Emcompress®, 20.92% Avicel®PH200, 2.00% Explotab®CLV and 0.50% magnesium stearate powder mixture by a rotary press (AM-8S, Officine Ronchi, Italy) equipped with 14.5×7.5 mm oblong punches under 23 kN compression force. These tablets were also employed as the bulking substrate added to the commercial cores. The two sequential coating steps were carried out in a tangential-spray fluid bed processor (GPCG1.1, Glatt, D). The inner coating formulation consisted of an aqueous 8% w/w low-viscosity HPMC (Methocel™E50) solution, applied to a final nominal thickness of 300 µm. The outer coating formulation was a hydro-alcoholic dispersion of Eudragit®S and guar gum (7:3 solid weight ratio), applied up to 7 mg/cm² of polymethacrylate. The coated tablets were cured at 40 °C for 24 h. Following each coating step, the thickness (digital micrometer, Absolute, Mitutoyo, J; n= 15), weight gain and amount of Eudragit®S applied per surface area were recorded. The in vitro release performance of the double-coated systems was assessed by a USP paddle dissolution apparatus (Dissolution System 2100B, Distek, I) with UV/Vis detection, using 800 mL of 0.1 N HCl for 2 h followed by phosphate buffer pH 6.8 at 37±0.5°C. The two-step coating process was successfully adapted to the tablet cores, yielding consistent overlapping layers of uniform thickness. The release profiles showed that gastric resistance of semaglutide units was achieved according to compendial requirements. Moreover, a lag phase was observed after transition to intestinal pH fluid and dissolution of the outer coating, as needed to protect the drug-containing core in case of early in vivo failure of the enteric outer coating. The preliminary study performed indicates feasible application of the previously developed oral colon delivery technology to semaglutide and highlights a first attempt at distal intestinal release of this GLP-1 analog. References [1] Sharma D et al (2018). Life Sci 216, 265–273 [2] Prasad-Reddy L, Isaacs D (2015). Drugs in Context 4, 212283 [3] Overgaard RV et al (2021). Clin Pharmacokinet 60, 1335–1348 [4] Maroni A et al (2012). Adv Drug Deliv Rev 64, 540-556 [5] Moutaharrik S et al (2024). Drug Deliv Transl Res 14, 826-838.