A Hydrogel-Microsphere Drug Delivery System That Supports Once-Monthly Administration of a GLP-1 Receptor Agonist

Abstract

We have developed a chemically controlled very long-acting delivery system to support once-monthly administration of a peptidic GLP-1R agonist. Initially, the prototypical GLP-1R agonist exenatide was covalently attached to hydrogel microspheres by a self-cleaving β-eliminative linker; after subcutaneous injection in rats, the peptide was slowly released into the systemic circulation. However, the short serum exenatide half-life suggested its degradation in the subcutaneous depot. We found that exenatide undergoes deamidation at Asn with an in vitro and in vivo half-life of approximately 2 weeks. The [Gln]exenatide variant and exenatide showed indistinguishable GLP-1R agonist activities as well as pharmacokinetic and pharmacodynamic effects in rodents; however, unlike exenatide, [Gln]exenatide is stable for long periods. Two different hydrogel-[Gln]exenatide conjugates were prepared using β-eliminative linkers with different cleavage rates. After subcutaneous injection in rodents, the serum half-lives for the released [Gln]exenatide from the two conjugates were about 2 weeks and one month. Two monthly injections of the latter in the Zucker diabetic fatty rat showed pharmacodynamic effects indistinguishable from two months of continuously infused exenatide. Pharmacokinetic simulations indicate that the delivery system should serve well as a once-monthly GLP-1R agonist for treatment of type 2 diabetes in humans.

High‐throughput, aseptic production of injectable Tetra‐PEG hydrogel microspheres for delivery of releasable covalently bound drugs

“…N α ‐(7‐Azido‐1‐cyano‐2‐heptyloxycarbonyl)‐[Gln 28 ]exenatide (N 3 ‐L(CN)‐[Gln 28 ]exenatide). In the present example, the drug is [Gln 28 ]exenatide, a stabilized analog of the GLP‐1R agonist exenatide 14 which contains an azido‐linker at the N‐terminus. [Gln 28 ]exenatide was synthesized by solid phase peptide synthesis using Fmoc/tBu chemistry and reacted on‐resin at the α ‐amine group with O ‐(7‐azido‐1‐cyanohept‐2‐yl)‐ O′ ‐succinimidyl carbonate in N,N dimethyl formamide containing N‐methyl morpholine.…”

“…Production of our injectable tetra‐PEG hydrogel MS‐drug conjugates is achieved in two stages (Scheme 2). 8,14 Stage 1 involves preparation of amine‐derivatized MSs (amino‐MS) by a unique droplet‐based microfluidic system that enables production under conditions of low bioburden. Here, equimolar amounts of a four‐arm PEG containing 4 amine and 4 azido‐linker end groups (LN 3 ) and a four‐arm PEG containing cyclooctyne end groups (CO) are mixed in a droplet forming microfluidic device.…”

Proglucagon-Derived Peptides as Therapeutics

“…Rapid discoveries followed of GLP-1 and GLP-2 (15,16), both of which have been successfully exploited by peptide chemistry approaches to generate fully approved medications. While innovation has witnessed the production of increasingly long-acting agents, multi-action unimolecular agonists and novel delivery methods (67,68,70,(73)(74)(75)(195)(196)(197), there is still a growing need for ever more effective agents to counter obesity, diabetes and a host of other degenerative diseases. Better understanding of the physiology of PGDPs and their various roles in the likes of cognition, bone turnover, cardiovascular function, fertility and liver function (157,174,185,334,368,369), may herald important future uses for proglucagon-derived therapeutics.…”

“…Additionally, the once weekly preparations albiglutide and dulaglutide employ covalent interactions to attach the peptide to human albumin or a tail fragment of an IgG 4 antibody respectively, which impedes clearance (67,68), while semaglutide achieves the same pharmacokinetic profile with non-covalent interaction with albumin (70). Such advancement has continued with a oncemonthly, hydrogel preparation utilising the analogue [Gln 28 ] exenatide currently undergoing development (75), while a novel osmotic minipump, termed Itca 650, is currently in phase III clinical trials (FREEDOM-1) (197). This pump administers a constant infusion of exenatide following subcutaneous implantation, reported to last for up to 12 months before requiring replacement (197).…”

Exendin‐4 from Heloderma suspectum venom: From discovery to its latest application as type II diabetes combatant

“…The biological half‐life of exendin‐4 is prolonged by substitution of its amino acid at position 20 or 38 through acylation of lysine residues with carboxylic acid. A residue substitution of Gln28 for Asn28 in exendin‐4 potentially increases its action without degradation after subcutaneous administration . This variant of exendin‐4 demonstrates a better stability and longer half‐life with no effects on its pharmacology in rodents, which is suitable for a once‐monthly regimen.…”