Hydrophobic ion pairing of a GLP-1 analogue for incorporating into lipid nanocarriers designed for oral delivery

Ismail, Ruba; Phan, Thi Nhu Quynh; Laffleur, Flavia; Csóka, Ildikó; Bernkop‐Schnürch, Andreas

doi:10.1016/j.ejpb.2020.04.025

Cited by 29 publications

(14 citation statements)

References 41 publications

(67 reference statements)

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“…One advantage of the HIP strategy is that it does not involve chemical modification of the peptide, which can affect its biological activity, and may lead to undesirable side effects. In addition, HIP is a simple and effective approach that has been shown to enhance the stability of a wide range of therapeutic peptides, including glucagon-like peptide-1 (GLP-1) and somatostatin analogs [ 199 , 200 ].…”

Section: Strategies To Optimize Peptide Stability In Aqueous Formulat...mentioning

confidence: 99%

Designing Formulation Strategies for Enhanced Stability of Therapeutic Peptides in Aqueous Solutions: A Review

et al. 2023

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Over the past few decades, there has been a tremendous increase in the utilization of therapeutic peptides. Therapeutic peptides are usually administered via the parenteral route, requiring an aqueous formulation. Unfortunately, peptides are often unstable in aqueous solutions, affecting stability and bioactivity. Although a stable and dry formulation for reconstitution might be designed, from a pharmaco-economic and practical convenience point of view, a peptide formulation in an aqueous liquid form is preferred. Designing formulation strategies that optimize peptide stability may improve bioavailability and increase therapeutic efficacy. This literature review provides an overview of various degradation pathways and formulation strategies to stabilize therapeutic peptides in aqueous solutions. First, we introduce the major peptide stability issues in liquid formulations and the degradation mechanisms. Then, we present a variety of known strategies to inhibit or slow down peptide degradation. Overall, the most practical approaches to peptide stabilization are pH optimization and selecting the appropriate type of buffer. Other practical strategies to reduce peptide degradation rates in solution are the application of co-solvency, air exclusion, viscosity enhancement, PEGylation, and using polyol excipients.

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Section: Strategies To Optimize Peptide Stability In Aqueous Formulat...mentioning

confidence: 99%

Designing Formulation Strategies for Enhanced Stability of Therapeutic Peptides in Aqueous Solutions: A Review

et al. 2023

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“…[ 111 ] Unsaturated, branched, and bulky structures as well as the presence of two or more hydrophobic tails increase the lipophilicity of the complex to a higher extent, presumably as due to an effective shielding of polar residues. [ 81a,112 ] Moreover, a high logP of the counterion correlates with a high logP of the resulting complex. [ 112b,113 ] Applied biodegradable counterions could already provide an up to 10 8 ‐fold increase in logP.…”

Section: Use As Complexing Agents For Drug Deliverymentioning

confidence: 99%

“…[ 81a,112 ] Moreover, a high logP of the counterion correlates with a high logP of the resulting complex. [ 112b,113 ] Applied biodegradable counterions could already provide an up to 10 8 ‐fold increase in logP. [ 6a,40c ] Still, these studies could not reach logP‐values that were achieved in studies using conventional counterions.…”

Section: Use As Complexing Agents For Drug Deliverymentioning

confidence: 99%

Biodegradable Cationic and Ionizable Cationic Lipids: A Roadmap for Safer Pharmaceutical Excipients

Jörgensen

Wibel

Bernkop‐Schnürch

2023

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The use of cationic and ionizable cationic lipids in pharmaceutical products, however, is a double-edged sword, as these excipients are of considerable safety concerns. Because of their permanent or pHdependent cationic nature, they perturbate cellular and nuclear membranes, trigger the release of degrading enzymes from lysosomes, cause mitochondrial permeabilization and dysfunction, generate reactive oxygen species (ROS), alter cytoplasmatic enzyme functions, and damage DNA. [3] To address this substantial shortcoming of cationic and ionizable cationic lipids, biodegradable alternatives have been introduced that are rapidly degraded in vivo to preferably endogenous metabolites. The design of such lipids is inspired by natural cationic or ionizable cationic compounds like arginine, lysine or betaine that are generally regarded as safe. Their conjugation to endogenous lipids like fatty acids or cholesterol results in amphiphilic lipids. As ester and amide bonds are cleaved in vivo by numerous enzymes such as lipases, esterases, and proteases, they are the preferred linkages between these natural building blocks.Since the FDA approved ethyl Nα-lauroyl-l-arginate as biodegradable food preservative being effective against a broad range of Gram-positive and Gram-negative bacteria, yeasts, and molds in 2005, [4] the potential use of biodegradable cationic and ionizable cationic lipids as pharmaceutical excipients has been evaluated by numerous research groups. As these excipients exhibit the same properties as their non-biodegradable counterparts but causing relatively low adverse effects, they will likely substitute currently used non-biodegradable lipids in the future. Within this review, we provide an overview on the different types of biodegradable cationic and ionizable cationic lipids, their synthesis and cleavage by endogenous enzymes. Applications in drug delivery systems and as antimicrobial agents are discussed. A guideline on their design and application is provided and an outlook on future developments is given. Building Blocks and Formation of Cationic and Ionizable Cationic LipidsGenerally, biodegradable cationic and ionizable cationic lipids are composed of biocompatible building blocks that are conjugated via a linkage such as an ester or amide bond. [5] Representative building blocks and linkages are depicted in Figure 1. Endogenous enzymes can break these linkages and degrade Cationic and ionizable cationic lipids are broadly applied as auxiliary agents, but their use is associated with adverse effects. If these excipients are rapidly degraded to endogenously occurring metabolites such as amino acids and fatty acids, their toxic potential can be minimized. So far, synthesized and evaluated biodegradable cationic and ionizable cationic lipids already showed promising results in terms of functionality and safety. Within this review, an overview about the different types of such biodegradable lipids, the available building blocks, their synthesis and cleavage by endogenous enzymes is provided. Moreover, ...

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“…Importantly, some of these GLP agonists have also been effective in attenuating neuroinflammation in a mouse model of MS [279,280]. Interestingly, several nanosystems containing incretin analogs have been developed [281][282][283][284][285][286][287] and they represent promising therapeutic strategies to be evaluated in different models of NI&NDD. Table 4 summarizes the described nanosystems containing regulators of mitochondrial energetic function in ND models.…”

Section: Restoring Production and Utilization Of Mitochondrial Energy In Niandnddsmentioning

confidence: 99%

Nanotechnology-Based Drug Delivery Strategies to Repair the Mitochondrial Function in Neuroinflammatory and Neurodegenerative Diseases

2021

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Mitochondria are vital organelles in eukaryotic cells that control diverse physiological processes related to energy production, calcium homeostasis, the generation of reactive oxygen species, and cell death. Several studies have demonstrated that structural and functional mitochondrial disturbances are involved in the development of different neuroinflammatory (NI) and neurodegenerative (ND) diseases (NI&NDDs) such as multiple sclerosis, Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and amyotrophic lateral sclerosis. Remarkably, counteracting mitochondrial impairment by genetic or pharmacologic treatment ameliorates neurodegeneration and clinical disability in animal models of these diseases. Therefore, the development of nanosystems enabling the sustained and selective delivery of mitochondria-targeted drugs is a novel and effective strategy to tackle NI&NDDs. In this review, we outline the impact of mitochondrial dysfunction associated with unbalanced mitochondrial dynamics, altered mitophagy, oxidative stress, energy deficit, and proteinopathies in NI&NDDs. In addition, we review different strategies for selective mitochondria-specific ligand targeting and discuss novel nanomaterials, nanozymes, and drug-loaded nanosystems developed to repair mitochondrial function and their therapeutic benefits protecting against oxidative stress, restoring cell energy production, preventing cell death, inhibiting protein aggregates, and improving motor and cognitive disability in cellular and animal models of different NI&NDDs.

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Hydrophobic ion pairing of a GLP-1 analogue for incorporating into lipid nanocarriers designed for oral delivery

Cited by 29 publications

References 41 publications

Designing Formulation Strategies for Enhanced Stability of Therapeutic Peptides in Aqueous Solutions: A Review

Designing Formulation Strategies for Enhanced Stability of Therapeutic Peptides in Aqueous Solutions: A Review

Biodegradable Cationic and Ionizable Cationic Lipids: A Roadmap for Safer Pharmaceutical Excipients

Nanotechnology-Based Drug Delivery Strategies to Repair the Mitochondrial Function in Neuroinflammatory and Neurodegenerative Diseases

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