Dual-Phase Ezetimibe-Pitavastatin Tablet for Stability and Dissolution
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Solution Overview
Problem
Existing combination products of ezetimibe and pitavastatin do not achieve satisfactory pharmacologic efficacy, physical and chemical stability, and dissolution profiles, and their manufacturing processes are complex and costly.
Innovation Solution
A solid oral dosage form comprising ezetimibe and pitavastatin in separate phases with specific excipients, allowing for a common blend that is physically separated but present in a single layer, enabling fast dissolution and stability, manufactured through a conventional and economical process.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If ezetimibe and pitavastatin are combined in a single pharmaceutical composition, then pharmacologic efficacy is improved through complementary action, but physical and chemical stability deteriorates due to incompatibility between the two active ingredients
Solution Approach 1:
The pharmaceutical composition is divided into two distinct granulate phases: a first granulate containing ezetimibe and a second granulate containing pitavastatin. This segmentation physically separates the two incompatible active ingredients while maintaining them in a single combined composition, thereby preserving both the pharmacologic efficacy of the combination and the individual stability of each ingredient.
2Reliability
If ezetimibe and pitavastatin are formulated together, then therapeutic benefit is enhanced, but dissolution profile becomes unsatisfactory due to interference between components
Solution Approach 1:
The composition separates ezetimibe and pitavastatin into different granulate phases, allowing each ingredient to dissolve independently according to its own characteristics. The first granulate dissolves to release ezetimibe while the second granulate dissolves to release pitavastatin, ensuring both achieve satisfactory dissolution profiles without mutual interference.
Solution Approach 2:
Each granulate phase is formulated with excipients optimized for its specific active ingredient. The first granulate contains excipients suitable for ezetimibe dissolution, while the second granulate contains excipients optimized for pitavastatin dissolution. This local optimization ensures each component achieves its desired dissolution profile in the combined composition.
3Reliability
If complex manufacturing processes are used to achieve stability and efficacy, then product quality is improved, but manufacturing cost and complexity increase
Solution Approach 1:
The manufacturing process is segmented into two independent granulation processes, each optimized for a specific active ingredient. These can be performed separately and then combined, allowing for simplified individual process optimization rather than attempting to manage a single complex co-formulation process. This reduces overall manufacturing complexity while maintaining product quality.
Data Source
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AI summary
The invention relates to solid pharmaceutical compositions comprising or essentially consisting of (A) an intragranular phase comprising or essentially consisting of (i) ezetimibe, a pharmaceutically acceptable salt and/or solvate thereof; (ii) one or more intragranular diluents; (iii) one or more intragranular binders; (iv) optionally, one or more intragranular disintegrants; and (v) optionally, one or more intragranular surfactants; and (B) an extragranular phase comprising or essentially consisting of (vi) pitavas-tatin, a pharmaceutically acceptable salt and/or solvate thereof; (vii) one or more extragranular diluents; (viii) optionally, one or more extragranular disintegrants; and (ix) optionally, one or more extragranular lubricants. The invention further relates to an oral dosage form comprising the solid pharmaceutical composition suitable for oral administration.