Stable Amlodipine Oral Liquid Formulation for Accurate Dosing
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Solution Overview
Problem
Current amlodipine formulations, particularly tablets and refrigerated liquids, face issues with stability, dosing accuracy, and suitability for certain patient populations such as children and the elderly, leading to non-compliance and potential safety hazards from crushing tablets for liquid reconstitution.
Innovation Solution
Development of a stable oral liquid formulation comprising amlodipine benzoate or naphthalene sulfonate, citrate buffer, sodium benzoate, silicon dioxide, hydroxypropyl methylcellulose, simethicone, and polysorbate 80, with optional additives like sucralose and flavoring agents, maintaining stability between 5±5°C and 25±5°C for at least 12 months.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of operation
If amlodipine is administered as oral tablets, then dosing is convenient and storage is simple, but dosing accuracy deteriorates and suitability for certain patient populations deteriorates
Solution Approach 1:
The invention segments the dosage form from the dosage strength. Instead of fixed-strength tablets, the patent provides liquid concentrate that can be divided into precise aliquots corresponding to different dosage strengths (e.g., 2.5mg, 5mg, 10mg amlodipine). This allows the same convenient liquid form to provide both ease of administration and dosing precision through measurable volumes.
2Ease of operation
If amlodipine tablets are crushed for liquid reconstitution, then liquid administration is achieved, but safety deteriorates due to potential hazards from crushing
Solution Approach 1:
The invention performs the conversion to liquid form in advance during manufacturing, not at the point of use. The amlodipine is pre-dissolved in the liquid concentrate under controlled conditions, eliminating the need for patients or caregivers to crush tablets. This preliminary preparation ensures safety while maintaining the benefits of liquid administration.
3Stability of the object's composition
If refrigerated liquid formulation is used, then stability is improved, but ease of operation deteriorates due to storage requirements
Solution Approach 1:
The invention changes the chemical parameters of the formulation by using amlodipine benzoate or amlodipine naphthalene-2-sulfonate salts instead of the free base, and by adjusting the pH to acidic levels (3-6) using buffers like citrate or phosphate. These parameter changes enable the formulation to be stable at room temperature (20-25°C) without requiring refrigeration, thus improving storage convenience while maintaining stability.
4Adaptability or versatility
If oral liquid formulation is developed, then suitability for patient populations is improved, but manufacturing complexity increases
Solution Approach 1:
The invention simplifies manufacturing by selecting amlodipine benzoate or amlodipine naphthalene-2-sulfonate salts, which have favorable solubility characteristics that allow direct dissolution in aqueous buffers to achieve the desired concentration (0.5-2.0 mg/mL amlodipine equivalent). This avoids complex extraction or synthesis steps, making the liquid formulation easier to manufacture while providing versatility for various patient populations including children and the elderly.
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
Provides a safe, stable, and accurate oral liquid formulation for amlodipine, suitable for various patient populations, enhancing compliance and safety by maintaining formulation integrity and ease of administration.
Implementation Method 1
the amlodipine benzoate is formed by the reaction of a pharmaceutically acceptable salt of amlodipine that is more soluble in aqueous media than amlodipine benzoate with a molar excess of sodium benzoate
Implementation Method 2
about 3 mM of a citrate buffer
Implementation Method 3
about 1.0 mg/ml of polysorbate 80
Implementation Method 4
about 7.5 mg/ml of hydroxypropyl methylcellulose
Implementation Method 5
about 0.5 mg/ml of silicon dioxide
Implementation Method 6
about 0.15 mg/ml simethicone
Data Source
AI summary
Provided herein are stable amlodipine oral liquid formulations. Also provided herein are methods of using amlodipine oral liquid formulations for the treatment of certain diseases including hypertension and Coronary Artery Disease (CAD).