Acylated Insulin Derivatives for Longer Action and Better Stability
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Solution Overview
Problem
Existing insulin derivatives, such as insulin degludec, have limitations in duration of action, frequency of administration, and physicochemical properties, necessitating frequent injections and discomfort for patients.
Innovation Solution
Development of novel insulin derivatives with specific hydrophilic linkers and albumin binding residues, such as fatty acids, linked to insulin parents via alkylene glycol-containing amino acid residues, enhancing binding to insulin receptors and extending duration of action.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Duration of action of moving object
If natural insulin or conventional insulin derivatives are used, then insulin can effectively treat diabetes and maintain metabolic regulation, but the duration of action is relatively short requiring frequent injections
Solution Approach 1:
The patent applies parameter changes by modifying the molecular structure of insulin through acylation at the N-terminus with fatty acid chains of specific lengths (C12-C24). This structural parameter change fundamentally alters the pharmacokinetic properties, extending the duration of action from hours to days while maintaining therapeutic efficacy. The systematic variation of fatty acid chain length allows optimization of both duration and injection frequency.
Solution Approach 2:
The invention creates a composite molecular structure by combining insulin with fatty acid chains through amide bonds. This composite structure (acylated insulin) integrates the biological activity of insulin with the extended circulation properties of lipid moieties, achieving prolonged duration of action and reduced injection frequency compared to native insulin.
2Reliability
If existing long-acting insulin derivatives like insulin degludec are used, then duration of action is extended, but physicochemical properties and drug effect are still insufficient
Solution Approach 1:
The patent systematically varies the fatty acid chain length (C12-C24) and composition to optimize both duration of action and drug effect. This parameter optimization reveals that specific chain lengths provide superior pharmacokinetic profiles compared to existing derivatives, achieving both extended duration and enhanced reliability of drug effect.
Solution Approach 2:
The invention modifies a specific local region of the insulin molecule (the N-terminus) through acylation, while preserving the overall insulin structure and its critical binding interfaces. This localized modification allows enhancement of pharmacokinetic properties without compromising the biological activity and reliability of drug effect.
3Ease of operation
If insulin derivatives with longer duration of action are developed, then injection frequency can be reduced, but physicochemical properties and stability may be compromised
Solution Approach 1:
The patent optimizes the fatty acid chain length parameter (C12-C24) to achieve the right balance between extended duration of action and maintained stability. This parameter optimization ensures that the acylated insulin derivatives remain sufficiently stable while achieving reduced injection frequency, overcoming the trade-off between duration and stability.
Data Source
AI summary
Disclosed is an acylated insulin, a pharmaceutical formulation thereof, a pharmaceutical composition thereof with a long-acting GLP-1 compound, and a medical use of the acylated insulin, the pharmaceutical formulation and the pharmaceutical composition. Compared with insulin degludec or other insulin derivatives, the acylated insulin has an unexpected, significantly increased drug effect, a longer duration of action, a longer in vivo half-life, an excellent bioavailability, as well as better physical and chemical stabilities.