Characterization and impact of peptide physicochemical properties on oral and subcutaneous delivery

Klepach, Alisa; Tran, Huyen; Mohammed, Faiz Ahmad; El-Sayed, Mohamed

doi:10.1016/j.addr.2022.114322

Cited by 25 publications

(8 citation statements)

References 187 publications

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“…Nonetheless, s.c. KK-103 was rapidly absorbed at a high bioavailability of ∼74%, which contrasts observations of slow absorbance with similar peptides . Physiological barriers and structural components in the s.c. space cause charge- or nonspecific interactions with peptides . These can result in slow absorption, low exposure, or variable PK, which were not encountered with KK-103.…”

Section: Results and Discussionmentioning

confidence: 99%

A Novel Leu-Enkephalin Prodrug Produces Pain-Relieving and Antidepressant Effects

Hohenwarter,

Puil,

Rouhollahi

et al. 2024

Mol. Pharmaceutics

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Persistent pain is a significant healthcare problem with limited treatment options. The high incidence of comorbid chronic pain and depression significantly reduces life quality and complicates the treatment of both conditions. Antidepressants are less effective for pain and depression than for depression alone and they induce severe side effects. Opioids are highly efficacious analgesics, but rapid development of tolerance, dependence, and debilitating side effects limit their efficacy and safe use. Leucineenkephalin (Leu-ENK), the endogenous delta opioid receptor agonist, controls pain and mood and produces potent analgesia with reduced adverse effects compared to conventional opioids. High proteolytic instability, however, makes Leu-ENK ineffective after systemic administration and limits its clinical usefulness. KK-103, a Leu-ENK prodrug, was developed to overcome these limitations of Leu-ENK via markedly increased plasma stability in mice. We showed rapid and substantially increased systemic adsorption and blood plasma exposure of KK-103 compared to Leu-ENK. We also observed brain uptake of radiolabeled KK-103 after systemic administration, indicating a central effect of KK-103. We then established KK-103's prolonged antinociceptive efficacy in the ramped hot plate and formalin test. In both models, KK-103 produced a comparable dose to the maximum antinociceptiveeffect relationship. The pain-alleviating effect of KK-103 primarily resulted from activating the delta opioid receptor after the likely conversion of KK-103 to Leu-ENK in vivo. Finally, KK-103 produced an antidepressant-like activity comparable to the antidepressant desipramine, but with minimal gastrointestinal inhibition and no incidence of sedation.

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Section: Results and Discussionmentioning

confidence: 99%

A Novel Leu-Enkephalin Prodrug Produces Pain-Relieving and Antidepressant Effects

Hohenwarter,

Puil,

Rouhollahi

et al. 2024

Mol. Pharmaceutics

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“…The molecular weight, flexibility, and hydrophilic nature of smaller peptide-based drugs provide them the advantage of paracellular passage in between cells [18]. This phenomenon was later confirmed by Foger et al [45] in a report that illustrated that the peptide permeability increases as the molecular weight decreases, but only for peptides with a molecular weight up to 1.4 kDa.…”

Section: Samplementioning

confidence: 86%

“…In contrast, the low intrinsic permeability of peptides is a bottleneck in the oral delivery of peptides. The oral absorption of peptides in the body occurs through three possible pathways: [18] i.…”

Section: Samplementioning

confidence: 99%

“…The oral delivery of peptides is influenced by food and water intake [17]. Further, the inherent physical and chemical properties of peptides, such as molecular size, proteolytic stability, hydrophilicity, and ionic charge, also influence their oral absorption [18]. Although oral peptides and proteins face barriers to delivery, the number of formulations that have been launched or are in clinical trials is steadily increasing.…”

Section: Introductionmentioning

confidence: 99%

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Experimental Elucidation of Templated Crystallization and Secondary Processing of Peptides

et al. 2023

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The crystallization of peptides offers a sustainable and inexpensive alternative to the purification process. In this study, diglycine was crystallised in porous silica, showing the porous templates’ positive yet discriminating effect. The diglycine induction time was reduced by five-fold and three-fold upon crystallising in the presence of silica with pore sizes of 6 nm and 10 nm, respectively. The diglycine induction time had a direct relationship with the silica pore size. The stable form (α-form) of diglycine was crystallised in the presence of porous silica, with the diglycine crystals obtained associated with the silica particles. Further, we studied the mechanical properties of diglycine tablets for their tabletability, compactability, and compressibility. The mechanical properties of the diglycine tablets were similar to those of pure MCC, even with the presence of diglycine crystals in the tablets. The diffusion studies of the tablets using the dialysis membrane presented an extended release of diglycine through the dialysis membrane, confirming that the peptide crystal can be used for oral formulation. Hence, the crystallization of peptides preserved their mechanical and pharmacological properties. More data on different peptides can help us produce oral formulation peptides faster than usual.

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“…The current roster of products falls into two classes: rapid-acting formulations designed for bolus injection before meals, or for use in insulin pumps and long-acting formulations meostatic insulin secretion pattern by pancreatic β cells. The fundamental concept initially realized in the 1930s via examinations of microcrystalline suspensions proposed that the physical chemistry of insulin, including its self-association equilibria, directly influences the stability of a subcutaneous (SC) depot and its absorption rate [70][71][72][73]. Below, we discuss the first-generation prandial and basal analogs, with an emphasis on structure-function relationships.…”

Section: Insulin and Insulin Derivatives: What Happens To Them?mentioning

confidence: 99%

Unraveling Light-Activated Insulin Action in Regulating Blood Glucose: New Photoactivatable Insight as a Novel Modality in Diabetes Management

Nurkolis,

Kurniawan,

Wiyarta

et al. 2024

Molecules

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Diabetes, particularly type 2 diabetes (T2D), is the main component of metabolic syndrome. It is highly prevalent and has drastically increased with sedentary lifestyles, notably behaviors linked to ease of access and minimal physical activity. Central to this condition is insulin, which plays a pivotal role in regulating glucose levels in the body by aiding glucose uptake and storage in cells, and what happens to diabetes? In diabetes, there is a disruption and malfunction in insulin regulation. Despite numerous efforts, effectively addressing diabetes remains a challenge. This article explores the potential of photoactivatable drugs in diabetes treatment, with a focus on light-activated insulin. We discuss its advantages and significant implications. This article is expected to enrich the existing literature substantially, offering a comprehensive analysis of potential strategies for improving diabetes management. With its minimal physical intrusion, light-activated insulin promises to improve patient comfort and treatment adherence. It offers precise regulation and localized impact, potentially mitigating the risks associated with conventional diabetes treatments. Additionally, light-activated insulin is capable of explicitly targeting RNA and epigenetic factors. This innovative approach may pave the way for more personalized and effective diabetes treatments, addressing not only the symptoms but also the underlying biological causes of the disease. The advancement of light-activated insulin could revolutionize diabetes management. This study represents a pioneering introduction to this novel modality for diabetes management.

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Characterization and impact of peptide physicochemical properties on oral and subcutaneous delivery

Cited by 25 publications

References 187 publications

A Novel Leu-Enkephalin Prodrug Produces Pain-Relieving and Antidepressant Effects

A Novel Leu-Enkephalin Prodrug Produces Pain-Relieving and Antidepressant Effects

Experimental Elucidation of Templated Crystallization and Secondary Processing of Peptides

Unraveling Light-Activated Insulin Action in Regulating Blood Glucose: New Photoactivatable Insight as a Novel Modality in Diabetes Management

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