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Design and Development of a New Glucagon-Like Peptide-1 Receptor Agonist to Obtain High Oral Bioavailability

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Abstract

Purpose

Semaglutide is the only oral GLP-1 RA in the market, but oral bioavailability is generally limited in range of 0.4–1%. In this study, a new GLP-1RA named SHR-2042 was developed to gain higher oral bioavailability than semaglutide.

Method

Self-association of SHR-2042, semaglutide and liraglutide were assessed using SEC-MALS. The intestinal perfusion test in SD rats was used to select permeation enhancers (PEs) including SNAC, C10 and LCC. ITC, CD and DLS were used to explore the interaction between SHR-2042 and SNAC. Gastric administrated test in SD rats was used to screen SHR-2042 granules with different SHR-2042/SNAC ratios. The oral bioavailability of SHR-2042 was studied in rats and monkeys.

Result

The designed GLP-1RA, SHR-2042, gives a better solubility and lipophilicity than semaglutide. While it forms a similar oligomer with that of semaglutide. During the selection of PEs, SNAC shows better exposure than the other competing PEs including C10 and LCC. SHR-2042 and SNAC bind quickly and exhibit hydrophobic interaction. SNAC could promote monomerization of SHR-2042 and form micelles to trap the monomerized SHR-2042. The oral bioavailability of SHR-2042 paired with SNAC is 0.041% (1:0, w/w), 0.083% (1:10, w/w), 0.32% (1:30, w/w) and 2.83% (1:60, w/w) in rats. And the oral bioavailability of SHR-2042 matched with SNAC is 3.39% (1:30, w/w) in monkeys, which is over 10 times higher than that of semaglutide.

Conclusion

We believe that the design and development of oral SHR-2042 will provide a new way to design more and more GLP-1RAs with high oral bioavailability in the future.

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Abbreviations

GLP-1:

Glucagon-like peptide-1

GLP-1RAs:

Glucagon-like peptide-1 receptor agonists

T2DM:

Type 2 diabetes mellitus

ADO:

Dioxaoctanoic acid

SEC-MALS:

Size-exclusion chromatography-multiangle laser scattering

ITC:

Isothermal titration calorimetry

CD:

Circular dichroism

DLS:

Dynamic Light Scattering

PEs:

Permeation enhancers

SNAC:

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

C10:

Sodium decanoate

LCC:

L-lauroylcarnitine chloride

SD rats:

Sprague-Dawley rats

RP-HPLC:

Reversed phase -high performance liquid chromatography

QC:

Quality control

NCA:

Non-compartmental model analysis

Tmax :

Peak time

Cmax :

Maximum concentration

AUC:

Area under the concentration–time curve

t1/2 :

Elimination half-life

Vd :

Apparent volume of distribution

Cl:

Plasma clearance

F:

Bioavailability

SD:

Standard deviation

CMC:

Critical micelle concentration

PBS:

Phosphate buffer solution

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ACKNOWLEDGEMENTS AND DISCLOSURES

Yadan Mao is gratefully thanked for correcting the manuscript.

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Authors and Affiliations

  1. School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, People’s Republic of China

    Hao Chen & Jianping Liu

  2. Jiangsu Hengrui Pharmaceuticals Co., Ltd., Lianyungang, 222000, People’s Republic of China

    Hao Chen, Yun Lu, Shuai Shi, Qiang Zhang, Xiaoli Cao, Lei Sun, Dong An, Xiaojie Zhang & Xianglin Kong

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  1. Hao Chen
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Correspondence to Jianping Liu.

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Hao Chen, Yun Lu, Shuai Shi, Qiang Zhang, Xiaoli Cao, Lei Sun, Dong An, Xiaojie Zhang, Xianglin Kong are employees of Jiangsu Hengrui Pharmaceuticals Co., Ltd.

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Chen, H., Lu, Y., Shi, S. et al. Design and Development of a New Glucagon-Like Peptide-1 Receptor Agonist to Obtain High Oral Bioavailability. Pharm Res 39, 1891–1906 (2022). https://doi.org/10.1007/s11095-022-03265-3

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  • DOI: https://doi.org/10.1007/s11095-022-03265-3

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