Fixed-Dose Triple-Drug Composition for Stability and Uniform Release
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Developing a stable, bioavailable, and cost-effective fixed-dose-combination pharmaceutical formulation of amlodipine, ramipril, and rosuvastatin that addresses incompatibilities and stability issues among these active ingredients, while ensuring similar release profiles and content uniformity, is challenging due to their differing sensitivities to environmental factors and manufacturing processes.
Innovation Solution
A pharmaceutical composition comprising a blend of ramipril granulate with intragranular polyvinyl alcohol and an extragranular phase with amlodipine, rosuvastatin, and an alkaline-environment producing stabilizing agent, prepared through a simplified wet granulation process, avoids physical separation and complex manufacturing steps.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of operation
If a fixed-dose-combination formulation containing amlodipine, ramipril and rosuvastatin is developed, then patient compliance and therapy simplification are improved, but formulation stability and purity are worsened due to incompatibilities between active ingredients
Solution Approach 1:
The formulation is segmented into two distinct phases: an intragranular phase containing ramipril and an extragranular phase containing amlodipine and rosuvastatin. This physical separation prevents direct contact and incompatibility reactions between the active ingredients while maintaining them in a single dosage form, thus preserving formulation stability without compromising patient compliance benefits
Solution Approach 2:
Excipients act as intermediary substances between the incompatible active ingredients. Specifically, the formulation uses buffered excipients to control pH and prevent degradation, and physical barriers (granulate structure) to separate ramipril from amlodipine and rosuvastatin, allowing them to coexist in the same dosage form without direct interaction
2Loss of energy
If a fixed-dose-combination formulation is developed, then therapy cost is reduced, but manufacturing complexity increases due to stability and purity requirements
Solution Approach 1:
The manufacturing process is segmented into separate preparation steps for the intragranular and extragranular phases, allowing each phase to be optimized independently for stability while maintaining a relatively simple overall process that avoids complex compatibility studies and processing requirements
Solution Approach 2:
The formulation controls pH parameters through buffered excipients to prevent degradation of the active ingredients. By maintaining specific pH ranges, the formulation achieves enhanced stability without requiring complex manufacturing controls or additional stabilization steps
3Stability of the object's composition
If physical separation of active ingredients is implemented, then formulation stability is improved, but content uniformity and release profile similarity become more difficult to achieve
Solution Approach 1:
Each phase (intragranular and extragranular) is formulated with specific local properties optimized for its contained active ingredients. The intragranular phase has properties optimized for ramipril stability, while the extragranular phase has properties optimized for amlodipine and rosuvastatin, allowing each component to maintain its required characteristics while achieving overall content uniformity through proper blending
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 composition achieves stabilization and purity of all active ingredients, maintains similar release profiles, and ensures bioavailability, while simplifying the manufacturing process and complying with regulatory requirements.
Implementation Method 1
a ramipril granulate comprising intragranular polyvinyl alcohol as a binder
Implementation Method 2
an extragranular phase, which is a powder blend comprising amlodipine or its pharmaceutically acceptable salt, rosuvastatin or its pharmaceutically acceptable salt, and an alkaline-environment producing organic or inorganic stabilizing agent
Data Source
AI summary
A solid pharmaceutical composition comprising amlodipine or its pharmaceutically acceptable salt, in particular amlodipine besylate, ramipril and rosuvastatin or its pharmaceutically acceptable salt, in particular rosuvastatin calcium, in a single dosage unit, a process for its preparation and a single dosage unit comprising it. The composition finds its use in the treatment of cardiovascular diseases.