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Identification of a Multi-Component Formulation for Intestinal Delivery of a GLP-1/Glucagon Co-agonist Peptide

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Abstract

Purpose

Oral delivery of therapeutic peptides has been challenging due to multiple physiological factors and physicochemical properties of peptides. We report a systematic approach to identify formulation compositions combining a permeation enhancer and a peptidase inhibitor that minimize proteolytic degradation and increase absorption of a peptide across the small intestine.

Methods

An acylated glucagon-like peptide-1/glucagon co-agonist peptide (4.5 kDa) was selected as a model peptide. Proteolytic stability of the peptide was investigated in rat and pig SIF. Effective PEs and multiple component formulations were identified in rats. Relative bioavailability of the peptide was determined in minipigs via intraduodenal administration (ID) of enteric capsules.

Results

The peptide degraded rapidly in the rat and pig SIF. Citric acid, SBTI, and SBTCI inhibited the enzymatic degradation. The peptide self-associated into trimers in solution, however, addition of PEs monomerized the peptide. C10 was the most effective PE among tested PEs (DPC, LC, rhamnolipid, C12-maltosides, and SNAC) to improve intestinal absorption of the peptide in the rat IJ-closed loop model. A combination of C10 and SBTI or SBTCI increased the peptide exposure 5–tenfold compared to the exposure with the PE alone in the rat IJ-cannulated model, and achieved 1.06 ± 0.76% bioavailability in minipigs relative to subcutaneous via ID administration using enteric capsules.

Conclusion

We identified SBTI and C10 as an effective peptidase inhibitor and PE for intestinal absorption of the peptide. The combination of SBTI and C10 addressed the peptide physiochemical properties and provides a formulation strategy to achieve intestinal delivery of this peptide.

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Abbreviations

C12-maltoside:

Dodecyl maltosides

DPC:

Dodecyl phosphocholine

IJ:

Intrajejunal

LC:

Lauroyl L-carnitine

PE:

Permeation enhancer

SBTI:

Soybean trypsin chymotrypsin inhibitor

SBTI:

Soybean trypsin inhibitor

SIF:

Small intestinal fluid

SNAC:

Sodium N-(8-[2-hydroxybenzoyl] amino) caprylate

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Acknowledgements

We would like to thank Michele Lake and Donald Risley for the analytical support for the dissolution studies, Dr. Siyuan Huang for preparation of capsules, and Dr. Xianyin Lai for his LC/MS support of the proteolytic stability assay. The authors would like to thank Andrew Riley for editing and proofreading the manuscript.

Funding

Open Access funding enabled and organized by CAUL and its Member Institutions. This work was funded by Eli Lilly and Company.

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Authors and Affiliations

  1. Biotechnology Discovery Research, Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN, 46285, USA

    Huyen Tran & Mohamed E. H. ElSayed

  2. Synthetic Molecule Design and Development, Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN, 46285, USA

    Phenil J. Patel & Aktham Aburub

  3. Department of Drug Disposition, Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN, 46285, USA

    Andrea Sperry & Selina Estwick

  4. Exploratory Medicine and Pharmacology, Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN, 46285, USA

    Amita Datta –Mannan

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Correspondence to Huyen Tran or Amita Datta –Mannan.

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At the time the work in this publication was performed, all authors were employees of Eli Lilly and Company. The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. There are no other competing financial interests.

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Tran, H., Patel, P.J., Aburub, A. et al. Identification of a Multi-Component Formulation for Intestinal Delivery of a GLP-1/Glucagon Co-agonist Peptide. Pharm Res 39, 2555–2567 (2022). https://doi.org/10.1007/s11095-022-03372-1

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