Insulin Aspart Formulation pH Control for Chemical Stability
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Solution Overview
Problem
Existing insulin formulations face challenges in maintaining chemical and physical stability, particularly due to pH sensitivity and degradation issues, which affect their shelf life and efficacy in diabetes treatment.
Innovation Solution
A pharmaceutical formulation comprising 3.5 mg/mL insulin aspart, 31.62 mg/mL sorbitol, 1.72 mg/mL metacresol, 1.50 mg/mL phenol, 0.0196 mg/mL Zn(II), 0.58 mg/mL sodium chloride, 1.88 mg/mL Na2HPO4, and adjusted pH between 7.1 and 7.6, which provides excellent chemical and physical stability and is adaptable to specific osmolality ranges.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of operation
If insulin formulations are stored in aqueous media at physiological pH, then solubility and bioavailability are improved, but chemical stability deteriorates due to degradation
Solution Approach 1:
The patent applies parameter changes by carefully controlling pH within the narrow range of 7.2-7.4 and adjusting ionic strength through specific salt concentrations. This resolves the contradiction by finding the optimal parameter window where insulin maintains both solubility in aqueous media and chemical stability against degradation pathways.
Solution Approach 2:
The formulation uses a composite approach by combining insulin with multiple excipients including buffers (phosphate, acetate), preservatives (phenol, metacresol), and salts (sodium chloride, zinc). This composite formulation strategy allows the system to simultaneously achieve solubility through aqueous compatibility and stability through the protective effects of multiple components working synergistically.
2Ease of operation
If pH is adjusted to maintain solubility near isoelectric point, then solubility is improved, but chemical stability worsens due to acid or base degradation
Solution Approach 1:
The patent avoids the isoelectric point (pH 5.3-5.4) where solubility is lowest and instead operates at physiological pH 7.2-7.4. This parameter change resolves the contradiction by selecting a pH that provides adequate solubility while avoiding the harmful degradation effects associated with acidic or alkaline conditions.
Solution Approach 2:
Buffering agents (phosphate, acetate) act as intermediaries that maintain pH stability within the safe range. These buffers prevent pH excursions that would otherwise lead to acid or base-catalyzed degradation, while allowing the formulation to maintain solubility through controlled pH adjustment.
3Stability of the object's composition
If formulation components are added to enhance stability, then chemical stability is improved, but manufacturing complexity increases
Solution Approach 1:
The formulation employs multi-functional excipients that simultaneously address multiple requirements. For example, phosphate serves as both a buffer (controlling pH for stability) and an ionic strength adjustor (affecting solubility). Phenol and metacresol provide both preservative function and stabilization. This multi-functionality reduces the total number of components needed and simplifies manufacturing compared to using separate additives for each function.
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
The formulation ensures a stable insulin product with a defined shelf life, maintaining insulin activity and reducing degradation, thus effectively managing diabetes by providing a reliable and long-lasting therapeutic effect.
Implementation Method 1
The chemical and/or physical stability of insulin, insulin analogues and/or insulin derivatives strongly depends on the pharmaceutical formulation, e.g. the solvent, the pH value and the excipients
Implementation Method 2
The solubility of insulin, insulin analogues and/or insulin derivatives in aqueous media depends on the pH value. However, insulin suffers from degradation at strong acidic conditions and strong alkaline conditions. Therefore, most of the medicinal products containing insulin, insulin analogues and/or insulin derivatives have a pH value in the range of 7.2 to 7.4 and mostly buffering agents are used to achieve and maintain the pH within this range
Data Source
AI summary
Stabilized pharmaceutical formulations of insulin analogues and/or insulin derivatives are disclosed. In particular the application is directed to a pharmaceutical formulation comprising (a), at least one analogue and/or derivative of insulin; and (b). Zn(ll); and (c). sorbitol; and (d). optionally protamine.