Impact of sodium caprate dosed as a mini-tablet or suspension on insulin delivery and mucosa histomorphology

Abstract

Oral administration of solid dosage forms for delivery of therapeutic peptides is highly desired. Preclinical investigations on co-administration with permeation enhancers (PEs) to enable sufficient oral bioavailabilities are, however, predominantly done using liquid formulations despite the commercial end-goal being a solid dosage form. Given the amounts needed of PE, this will typically result in a compacted tablet with high amounts of the PE of choice. The aim of this study was to compare the pharmacokinetics (PK) and pharmacodynamics (PD) of insulin after co-formulation with a fixed dose of sodium caprate (C10) in solid dosage forms versus liquid dosage forms. PK/PD parameters in rats were evaluated after dosing mini-tablets and liquid formulations with different amounts of insulin and 26 mg/kg C10 after intestinal administration. Absorption of insulin was dose-dependent in the presence of the PE for both types of dosage forms, which was also reflected in the blood glucose levels. A significant absorption enhancing effect of C10 was found when dosing a 75 IU/kg insulin mini-tablet, resulting in a 26-fold increase in bioavailability. The effect of C10 on the rat intestinal tissue was investigated by histomorphological assessment evaluating erosion and villi height. Effects caused by the C10 mini-tablets and the liquid formulations were similar and shown to be transient. Overall, the findings in this study suggest that mini-tablets can be used to assess peptide bioavailability and the effect of PEs in rats as a preclinical model, and PK data may be nominally different from those obtained with liquid formulations.

Introduction

Peptide and protein therapeutics are increasingly used for treatment of chronic and acute diseases due to their high potency and specificity [1, 2]. Sufficient systemic bioavailability upon oral administration of peptides and proteins is, however, challenged by their physicochemical properties, resulting in low stability in the gastro-intestinal (GI) fluids and poor permeation across the intestinal mucosa. Administration by injection is, therefore, still the most employed method of administration for peptides and proteins, despite the poor patient compliance associated with repeated injections [3, 4]. Research suggests different approaches to improve both stability and permeation to achieve sufficient absorption of the fully functional therapeutic across the intestinal mucosa to the systemic circulation. A useful strategy is co-administration or co-formulation of functional excipients, such as permeation enhancers (PEs), with peptide and protein drugs [4, 5]. However, only a few such formulations have reached the market [4], including the peptide semaglutide formulated with the PE sodium N-(8-[2-hydroxybenzoyl]amino) caprylate (SNAC) as a tablet (Rybelsus®) used to improve glycemic control in adults with diabetes mellitus type 2. Rybelsus® contains 300 mg SNAC and only between 3 and 14 mg semaglutide resulting in an oral bioavailability of 0.4-1% in humans [6,7,8].

Another well-studied PE is C10, a sodium salt of the medium-chain fatty acid (MCFA) decanoic acid, which is believed to increase both the transcellular and paracellular permeation of co-formulated peptides and proteins [9,10,11]. C10 has been evaluated in clinical trials formulated as tablets in combination with either insulin or antisense oligonucleotides [12,13,14]. Further, studies have shown that co-administering C10 in liquid formulations can increase the intestinal absorption of peptides and of the macromolecule, fluorescein isothiocyanate-labelled dextran 4,000 Da (FD4) in rats following intra-intestinal administration [15,16,17]. This PE has also been shown to enhance the glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GIP/GLP-1) dual agonist peptide (LY) and the GLP1 receptor agonist drug candidate MEDI7219 absorption in mini-pigs when co-formulated into enteric-coated capsules administered into the small intestine [9, 18]. Furthermore, Berg et al. reported increased absorption after intestinal administration of the GLP-1 receptor agonist MEDI7219 in mini-pigs, when the drug was co-formulated with C10 into mini-tablets, which were subsequently loaded into an intestinal administration device [18].

In vivo evaluations of PEs for oral delivery of peptide drugs are most often done using liquid formulations, despite the end-goal being oral administration of a solid dosage form [19]. In vivo studies evaluating absorption of drugs, including biopharmaceuticals, are frequently (~ 80%) performed in rats dosed by oral gavage [19], and testing solid dosage forms such as tablets and capsules can be rather challenging. Indeed, studies investigating gastric capsule retention following oral gavage to rats, show that the dosage form does not consistently reach the intestinal lumen, thereby potentially affect the conclusions [20,21,22].

Administration by intestinal instillation/injection is a way to circumvent such problems with retention in the stomach but cannot be done in non-anesthetized animals. Bypassing the stomach gives the added benefit of avoiding the degradation of the peptide drug in the harsh gastric environment, and the approach allows for exclusive examination of intestinal absorption. A solid dosage form must disintegrate in the GI fluids to ensure the release and dissolution of both the active pharmaceutical ingredient (API) and the functional excipients, such as PEs. Disintegration of a compacted tablet is a complex process involving a series of physical phenomena, beginning with liquid penetration (wicking) into the pores of the powder compact, which is often the rate-limiting step. Once liquid penetrates into the compact, several mechanisms can be initiated, including swelling (omnidirectional expansion of particles), straining (unidirectional expansion of particles), and the dissolution of soluble excipients from the pore walls. These mechanisms, either individually or in combination, disrupt particle-particle bonds, ultimately leading to disintegration [23,24,25]. Following disintegration, both the API and the PE must dissolve to enable permeation enhancement and facilitate API absorption. It is thus crucial that a sufficient volume of fluid is present to dissolve the often high doses of PE. In the human small intestine, the total fluid volume is approximately 105 mL [26], whereas in the rat small intestine, it is lower (~ 1.9 mL) [27], which may present challenges for the disintegration process. Also, other conditions in the rat model such as the continuous bile secretion into the intestine may influence the outcome [16].

The aim of the study was to compare the efficacy and compatibility of compacted mini-tablets with insulin and a high dose of C10 to the corresponding doses administered as a liquid. Insulin was used as a model peptide allowing for a rapid pharmacological response and reliable detection of in vivo effects after intra-intestinal dosing of liquid formulations containing PEs [28]. The mini-tablets were produced by direct compression and administered to the rat small intestine via intestinal instillation. We evaluated the pharmacokinetics (PK) and pharmacodynamics (PD) readouts and performed histomorphological assessments of the mucosal tissue after exposure to the formulation for 20 and 120 min. Different doses of insulin were evaluated (25, 50, and 75 international units (IU)/kg) while maintaining the C10 dose (26 mg/kg).

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Materials

Human recombinant insulin (5808 g/mol, >27.5 IU/mg, < 1% zink, amorphous powder), barium sulfate (BaSO4, 99.99%, crystalline powder) was obtained from Merck (Darmstadt, Germany). Sodium decanoate (> 99.0%, crystalline powder) was purchased from TCI Europe (Zwijndrecht, Belgium). Crospovidone (Kollidon® CL-F) and copovidone (Kollidon® VA64 Fine) was kindly donated by BASF (Ludwigshafen, Germany). Magnesium stearate (Ph. Eur.) was from Alfa Aesar Pharma (Loughborough, UK). Microcrystalline cellulose (Avicel PH-101) and trifluoroacetic acid (TFA) was purchased from Merck (Darmstadt, Germany). Monohydrate lactose (Supertab® 11Sd) was purchased from DFE Pharma (Goch, Germany). Hank’s balanced salt solution (HBSS), bovine serum albumin (≥ 98%) (BSA), sodium phosphate dibasic heptahydrate (98.0-102.0%), sodium phosphate monobasic monohydrate (≥ 98%), formalin solution, neutral buffered 10%, Mayer’s hematoxylin solution, and eosin Y solution (alcoholic) were obtained from Merck (Darmstadt, Germany). 4-(2-hydroxyethyl)-1-piperazine-1-ethanesulfonic acid (HEPES) was purchased from PanReac AppliChem (Darmstadt, Germany). Hydrochloric acid (HCl) 5.0 N, sodium hydroxide (NaOH) 5.0 N in aqueous solution and sodium chloride (NaCl) (Ph. Eur.), Supelco® was purchased from VWR Chemicals BDH International (Leicestershire, UK). Midazolam 5 mg/mL was manufactured by Hameln Pharma (Gloucester, UK). Hypnorm containing fentanyl citrate 31.5 µg/mL and fluanisone 1 mg/mL was produced by Skanderborg Pharmacy (Skanderborg, Denmark). Euthasol® vet. containing pentobarbital 400 mg/mL was produced by Dechra Veterinary Products A/S (Uldum, Denmark). Ultrapure water was collected in-house (18.2 MΩ × cm by a PURELAB flex 4 system (ELGA, LabWater, High Wycombe, UK).

Fredholt, F., Heade, J., Rantanen, J. et al. Impact of sodium caprate dosed as a mini-tablet or suspension on insulin delivery and mucosa histomorphology. Drug Deliv. and Transl. Res. (2025). https://doi.org/10.1007/s13346-025-01977-8

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