Buffer-Cosolvent Lisdexamfetamine Solutions for Alkaline Stability
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Solution Overview
Problem
The development of stable liquid formulations of lisdexamfetamine is hindered by degradation at alkaline and oxidative conditions, and existing stabilizers do not enhance its physicochemical stability, leading to non-compliance and ineffective therapy, especially in pediatric and adolescent populations.
Innovation Solution
A physicochemically stable oral pharmaceutical solution comprising a pharmaceutically acceptable salt of lisdexamfetamine, formulated with a buffer and a cosolvent such as a glycol or polyol, maintaining a pH of 5.5 to 9.0, which enhances stability and prevents hydrolysis and oxidation.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of operation
If lisdexamfetamine is formulated as an aqueous solution, then ease of administration is improved, but stability is worsened due to degradation at alkaline and oxidative conditions
Solution Approach 1:
The patent adjusts the pH of the aqueous solution to a specific range (pH 3.0-7.0, preferably pH 4.0-6.0) to minimize degradation of lisdexamfetamine. This parameter change optimizes both stability and solubility, allowing the formulation to remain stable in liquid form while maintaining ease of administration.
Solution Approach 2:
The patent introduces stabilizing excipients including antioxidants (e.g., ascorbic acid, sodium metabisulfite), chelating agents (e.g., EDTA), and buffering agents that act as intermediaries to protect lisdexamfetamine from oxidative and alkaline degradation in the aqueous solution.
2Ease of manufacture
If existing stabilizers are used in the formulation, then ease of manufacture is improved, but stability is worsened as they do not enhance physicochemical stability
Solution Approach 1:
The patent employs a composite stabilization system combining multiple excipients with complementary functions: antioxidants to prevent oxidation, chelating agents to bind metal ions that catalyze degradation, and buffering agents to maintain optimal pH. This composite approach provides superior physicochemical stability compared to single stabilizers while remaining easy to manufacture.
3Ease of manufacture
If solid dosage forms are used, then ease of manufacture is improved, but ease of operation is worsened due to difficulty in swallowing
Solution Approach 1:
The patent transitions from solid dosage forms to liquid/aqueous formulations, utilizing the fluid properties of liquids to enable easy administration. The liquid form can be orally administered without requiring swallowing, making it suitable for pediatric and geriatric populations while maintaining ease of manufacture through standard liquid formulation techniques.
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 solution provides a stable oral pharmaceutical formulation with less than 1.0% total degradation impurities after four weeks at 40°C and 75% relative humidity, offering improved patient compliance and flexible dosing.
Implementation Method 1
formulated with a buffer and a cosolvent such as a glycol or polyol, maintaining a pH of 5.5 to 9.0, which enhances stability and prevents hydrolysis and oxidation
Implementation Method 2
prevents hydrolysis and oxidation
Implementation Method 3
prevents hydrolysis and oxidation
Data Source
AI summary
Oral pharmaceutical solution comprising a pharmaceutically acceptable salt of lisdexamfetamine, and a pharmaceutically acceptable aqueous carrier comprising a buffer and a cosolvent selected from the group consisting of a glycol, a polyol, and a mixture thereof, wherein the pH of the solution is from 5.5 to 9.0. The oral pharmaceutical solution presents excellent physicochemical stability, even under alkaline conditions.