Stabilizer System for Solid Drug Formulation Stability
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Solution Overview
Problem
Existing solid drug formulations containing [(1R,5S,6S)-6-(aminomethyl)-3-ethylbicyclo[3.2.0]hept-3-en-6-yl]acetic acid monobenzenesulfonate (compound I) face stability issues, requiring effective stabilizers to maintain the drug's efficacy.
Innovation Solution
Incorporating citric acid anhydride or citric acid hydrate and α-tocopherol in specific ratios within the drug formulation, along with compound I, to enhance stability, particularly in tablet form, using a combination of D-mannitol, carmellose calcium, and magnesium stearate, with citric acid anhydride or citric acid hydrate at 0.01 to 10% and α-tocopherol at 0.001 to 1.0% by weight.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional stabilizers are used in solid drug formulations containing compound (I), then the formulation can be produced, but the stability of compound (I) is insufficient and decomposition occurs
Solution Approach 1:
The patent applies composite stabilizing system by combining citric acid anhydride (or citric acid hydrate) with α-tocopherol in specific weight ratios (citric acid anhydride: 0.01-10% w/w, α-tocopherol: 0.001-1.0% w/w). This composite approach creates synergistic stabilization effect where citric acid provides chelation protection against metal-catalyzed decomposition while α-tocopherol provides radical scavenging protection, together preventing multiple degradation pathways of compound (I) more effectively than either stabilizer alone.
2Reliability
If higher amounts of stabilizers are added to improve stability, then decomposition is reduced, but the formulation complexity and manufacturing difficulty increase
Solution Approach 1:
The patent optimizes the weight ratio parameters of stabilizers to specific ranges (citric acid anhydride: 0.01-10% w/w, α-tocopherol: 0.001-1.0% w/w) to achieve effective stabilization at minimal concentrations. By carefully controlling these compositional parameters, the formulation achieves maximum stability with minimal stabilizer content, avoiding excessive formulation complexity while maintaining compound (I) stability under various storage conditions.
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 combination significantly stabilizes compound I, reducing decomposition products to below the reference level, ensuring the drug's stability and efficacy over time under open conditions of 25°C/75% RH/12 weeks.
Implementation Method 1
citric acid anhydride or citric acid hydrate... provides a particularly excellent stabilizing effect
Implementation Method 2
α-tocopherol... provides a particularly excellent stabilizing effect
Data Source
AI summary
An object of the present invention is to provide a solid drug formulation having excellent stability. The solution according to the present invention is a solid drug formulation containing:a compound having formula (I):(i) D-mannitol; (ii) carmellose calcium; (iii) citric acid hydrate or the like; and (iv) α-tocopherol.