(M1230-06-38) Improving Oral Bioavailability of Therapeutic Peptides with Lipid-Based Formulations and Ready-to-Use Enteric Capsules

Purpose: The oral bioavailability of therapeutic peptides is limited by several factors such as low stability in GI fluids, enzymatic degradation and poor permeability across the gastrointestinal (GI) walls. Lipid-Based Formulations (LBF) combined with Hydrophobic Ion Pairs (HIP) have shown promise in protecting peptides for proteolytic degradation and enhancing oral bioavailability [1–3]. Additionally, permeation enhancers such as sodium caprate (C10) can further boost intestinal absorption [4,5]. Protection from harsh gastric conditions can be achieved using enteric dosage forms. However, traditional post-filling coating methods may be detrimental to sensitive peptides due to solvent or heat. There is a need for a ready-to-use enteric capsule with polymer composition enabling compatibility with LBF. The aim of this study is (1) to develop a LBF of a model GLP-1 receptor agonist peptide, exenatide (EXE), loaded as a HIP and combined with C10, and (2) to manufacture an enteric capsule, compatible with the designed formulation.

Methods: EXE was paired with sodium lauryl sulfate (SLS) and sodium docusate (DOC) at various molar ratios. HIP formation efficiency was determined by measuring the unprecipitated exenatide content using HPLC. LogP measurements of the HIP with the highest precipitation efficiency (1:4 molar ratio) were used to select the combination leading to the highest lipophilicity increase. The solubility of native EXE and the selected HIP was evaluated in various lipid excipients. The best peptide solvents were combined to design the LBF, which homogeneity at room temperature and emulsification properties at 37°C were further assessed by Dynamic Light Scattering. C10 was added to the designed formulation in a solubilized form, and the solubility of the peptide in the final LBF was measured by HPLC. Ability of the design LBF to protect the loaded peptide from proteolytic degradation was assessed by incubating the designed formulation in an α-chymotrypsin solution and quantifying the amount of undegraded API at predetermined timepoints. Size #0 gelatin/HPMC-AS prototype capsules were produced on pilot-scale capsule manufacturing equipment using Lonza proprietary technology to manufacture bilayer capsules [6]. The enteric properties of the prototype capsules were evaluated with a two-stage dissolution test using Esomeprazole magnesium trihydrate (EMT), an acid-sensitive model compound, in USP Apparatus II (paddle) for 2 hours in 0.1N HCl followed by 1 hour pH 6.8 buffer. Enteric properties of the prototype capsules filled with designed LBF, was evaluated through disintegration test suing Apparatus B. The filled capsules were placed for 1 hour in 0.1N HCl followed by 1 hour in buffer pH 6.8.

Results: With both tested anionic counterions, the maximum formation efficiency was obtained for the 1:4 molar ratio, consistent with EXE’s four cationic sites in acidic pH. The highest log P increase (3 units) was obtain with EXE:DOC HIP. The solubility of this HIP in various lipid excipients guided LBF design, which composition and emulsification properties are detailed in Table 1. Incubation of EXE and EXE-loaded LBF (as HIP) with α-chymotrypsin confirmed the ability of LBF to protect incorporated peptide from proteolytic degradation, in accordance with published studies [1,7]. Customized size #0 gelatin/HPMC-AS bilayer capsules were successfully manufactured on pilot-scale capsule manufacturing equipment. Two-stage dissolution of the capsules filled with EMT have shown no release nor degradation of the acid-sensitive API in acid stage followed by a rapid release in pH 6.8 buffer, therefore confirming the enteric properties of the protype capsules, Figure 1. Disintegration tests performed on customized capsules filled with peptide-loaded LBF and C10 showed no opening of the capsules during the acid stage, Figure 2, followed by swift opening ( < 5 min) in pH 6.8 buffer for all capsules (n=6), proving that filled capsule retained their enteric properties.

Conclusion: This study presents a scalable strategy to enhance oral bioavailability of therapeutic peptides, combining Lipid-based Formulations, Hydrophobic Ion Pairs, permeation enhancers, and a compatible ready-to-use enteric capsules.

References: [1] G. Hetényi, J. Griesser, M. Moser, F. Demarne, V. Jannin, A. Bernkop-Schnürch, Comparison of the protective effect of self-emulsifying peptide drug delivery systems towards intestinal proteases and glutathione, International Journal of Pharmaceutics 523 (2017) 357–365. https://doi.org/10.1016/j.ijpharm.2017.03.027.
[2] J. Griesser, G. Hetényi, M. Moser, F. Demarne, V. Jannin, A. Bernkop-Schnürch, Hydrophobic ion pairing: Key to highly payloaded self-emulsifying peptide drug delivery systems, International Journal of Pharmaceutics 520 (2017) 267–274. https://doi.org/10.1016/j.ijpharm.2017.02.019.
[3] C. Menzel, T. Holzeisen, F. Laffleur, S. Zaichik, M. Abdulkarim, M. Gumbleton, A. Bernkop-Schnürch, In vivo evaluation of an oral self-emulsifying drug delivery system (SEDDS) for exenatide, Journal of Controlled Release 277 (2018) 165–172. https://doi.org/10.1016/j.jconrel.2018.03.018.
[4] C. Twarog, F. McCartney, S.M. Harrison, B. Illel, E. Fattal, D.J. Brayden, Comparison of the effects of the intestinal permeation enhancers, SNAC and sodium caprate (C10): Isolated rat intestinal mucosae and sacs, European Journal of Pharmaceutical Sciences 158 (2021) 105685. https://doi.org/10.1016/j.ejps.2020.105685.
[5] S. Maher, T.W. Leonard, J. Jacobsen, D.J. Brayden, Safety and efficacy of sodium caprate in promoting oral drug absorption: from in vitro to the clinic, Advanced Drug Delivery Reviews 61 (2009) 1427–1449. https://doi.org/10.1016/j.addr.2009.09.006.
[6] X. He, L. Palangetic, S. Vanquickenborne, J. Cuevas, Double layered delayed-release hard capsules, US20230414524A1, 2023. https://patents.google.com/patent/US20230414524A1/en (accessed March 17, 2025).
[7] R. Venkatasubramanian, P.M. Al-Maghrabi, O. Alavi, T. Lind, P.J. Sassene, J.J.K. Kirkensgaard, P. Mota-Santiago, T. Rades, A. Müllertz, Design, evaluation, and in vitro–in vivo correlation of self-nanoemulsifying drug delivery systems to improve the oral absorption of exenatide, Journal of Controlled Release 379 (2025) 440–451. https://doi.org/10.1016/j.jconrel.2025.01.013.


LBF prototype characteristics


EMT release profile from customized size #0 gelatin/HPMC-AS bilayer capsules , 2 h in 0.1N HCL followed by 1 h in pH 6.8 buffer, n=6


Exemplar image of customized size #0 gelatin/HPMC-AS capsules filled with T1, 6mg/g EXE:DOC HIP and 20 mg/g C10, after 1 h in HCl 0.1N