Amorphous Solid Dispersion for Valsartan Sacubitril Stability
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Solution Overview
Problem
Existing formulations of valsartan and sacubitril, such as Entresto®, face challenges with physical and chemical instability, particularly due to hygroscopicity and deliquescence, leading to manufacturing issues like stickiness, clumping, and poor compressibility, which affect the stability and release of the active ingredients.
Innovation Solution
A solid dispersion of valsartan and sacubitril in a polymer matrix prepared by hot-melt extrusion, where the active ingredients are molecularly dissolved or present as amorphous particles, with a polymer such as polyvinylcaprolactam/polyvinylacetate/polyethylene glycol graft copolymer, and optionally mesoporous silica, to enhance stability and prevent moisture-induced degradation.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If valsartan and sacubitril are formulated as a cocrystal (LCZ696) for immediate-release tablets, then the drug combination achieves therapeutic efficacy, but the formulation exhibits physical and chemical instability due to hygroscopicity and deliquescence
Solution Approach 1:
The patent changes the physical state parameter of the active ingredients from crystalline (in the cocrystal form) to amorphous by using hot-melt extrusion processing. This parameter change eliminates the hygroscopicity and deliquescence issues associated with the crystalline cocrystal form while maintaining therapeutic efficacy.
Solution Approach 2:
The patent creates a composite material system where valsartan and sacubitril are dispersed in a polymer matrix (such as polyvinylcaprolactam/polyvinylacetate/polyethylene glycol graft copolymer) through hot-melt extrusion. This composite structure provides physical and chemical stability while maintaining the therapeutic benefits of the drug combination.
2Duration of action of moving object
If the cocrystal formulation is used in tablet form, then immediate-release therapeutic effect is achieved, but manufacturing issues arise due to stickiness, clumping, and poor compressibility
Solution Approach 1:
The patent applies hot-melt extrusion to transform the physical parameters of the drug mixture, creating an amorphous solid dispersion that exhibits improved flow and compressibility characteristics. This enables proper tablet manufacturing while maintaining the immediate-release property through appropriate polymer selection and formulation design.
Solution Approach 2:
The polymer matrix acts as an intermediary material that facilitates manufacturing by providing suitable rheological properties during tablet compression. The polymer prevents stickiness and clumping while allowing the active ingredients to be properly incorporated and compressed into tablets.
3Stability of the object's composition
If moisture is present during storage or processing, then the cocrystal formulation degrades through hygroscopicity and deliquescence, but protective packaging increases complexity
Solution Approach 1:
The patent converts the harmful hygroscopic and deliquescent properties of the crystalline cocrystal into a beneficial amorphous state that is inherently more moisture-resistant. The hot-melt extrusion process creates a homogeneous amorphous dispersion where the polymer matrix protects the active ingredients from moisture, reducing the need for complex packaging.
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 solid dispersion achieves high physical and chemical stability, maintaining the active ingredients in a non-crystalline state, improving compressibility and preventing degradation, resulting in a stable and effective oral dosage form with enhanced hygroscopic stability.
Implementation Method 1
The solid dispersion is prepared by hot-melt extrusion
Implementation Method 2
The active ingredients are in a non-crystalline state (i.e. molecularly dissolved or in the form of amorphous particles)
Implementation Method 3
The solid dispersion achieves high physical and chemical stability, maintaining the active ingredients in a non-crystalline state, improving compressibility and preventing degradation, resulting in a stable and effective oral dosage form with enhanced hygroscopic stability
Data Source
AI summary
The present invention relates to a solid unit dosage form for oral administration (tablet or granules) containing a solid dispersion of valsartan and sacubitril in a polymeric matrix. The solid dispersion is prepared by hot-melt extrusion and may contain the active ingredients preferably in a non-crystalline state. LCZ696, (pseudo)polymorphic forms thereof as well as the individual drugs, e.g. valsartan disodium and sacubitril monosodium, may be subjected to the hot-melt extrusion process.