Ticagrelor Composition with Water-Insoluble Fillers for Robust Dissolution
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Solution Overview
Problem
Existing pharmaceutical compositions of ticagrelor rely on water-soluble fillers like mannitol, which can cause adverse effects in patients and are costly, and the formulation is sensitive to variations in processing parameters, affecting clinical performance and stability.
Innovation Solution
A pharmaceutical formulation comprising ticagrelor with a mixture of water-insoluble fillers, such as microcrystalline cellulose and calcium hydrogen phosphate, and excipients like hydroxypropyl cellulose and croscarmellose sodium, without water-soluble fillers, using a wet granulation process.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of manufacture
If water-soluble fillers like mannitol are used in ticagrelor formulation, then processability and dissolution are improved, but adverse effects in patients and cost increase
Solution Approach 1:
The patent changes the solubility parameter of the filler from water-soluble to water-insoluble. By selecting water-insoluble fillers like microcrystalline cellulose and calcium hydrogen phosphate, the formulation eliminates adverse effects associated with water-soluble fillers while maintaining processability through optimized granulation parameters and binder selection.
Solution Approach 2:
The patent uses a composite filler system combining water-insoluble materials (microcrystalline cellulose and calcium hydrogen phosphate) with specific binders (hydroxypropyl cellulose) and disintegrants (croscarmellose sodium). This composite approach compensates for the lack of water solubility by creating a synergistic system that achieves both processability and safe patient use.
2Ease of manufacture
If water-soluble fillers are used in ticagrelor formulation, then dissolution profile is achieved, but formulation stability and robustness against processing variations deteriorate
Solution Approach 1:
The patent changes the solubility parameter of fillers to water-insoluble, which inherently improves formulation stability and robustness. The dissolution profile is maintained through careful selection of particle sizes, binder types, and disintegrant combinations that work effectively with water-insoluble fillers during the wet granulation process.
Solution Approach 2:
The patent employs readily available water-insoluble fillers like microcrystalline cellulose and calcium hydrogen phosphate that provide stable, reproducible formulation performance. These materials offer consistent results across manufacturing batches without the stability issues associated with water-soluble alternatives.
3Object-affected harmful factors
If water-insoluble fillers are used in ticagrelor formulation, then adverse effects are eliminated and cost is reduced, but processability and uniform drug release may deteriorate
Solution Approach 1:
The patent uses hydroxypropyl cellulose as a binder intermediary that bridges the water-insoluble fillers (microcrystalline cellulose and calcium hydrogen phosphate) to achieve uniform granulation and tablet formation. The binder acts as a mediating substance that enables processability without requiring water-soluble fillers.
Solution Approach 2:
The patent creates a composite formulation system combining water-insoluble fillers with specific binders and disintegrants. This composite approach ensures uniform drug release by creating a granulate structure that maintains porosity and allows controlled drug dissolution, compensating for the water-insolubility of the fillers.
4Stability of the object's composition
If water-insoluble fillers are used in ticagrelor formulation, then formulation robustness against processing variations is improved, but dissolution profile may deteriorate
Solution Approach 1:
The patent optimizes granulation parameters (liquid-to-powder ratio, granulation time, drying conditions) specifically for water-insoluble fillers to maintain good dissolution profiles. The robustness against processing variations is achieved through the inherent stability of water-insoluble fillers, while dissolution is maintained through proper binder and disintegrant selection.
Solution Approach 2:
The patent creates local quality variations within the granulate structure through controlled granulation, ensuring that drug particles are distributed in regions with appropriate porosity and binder content. This local optimization ensures uniform drug release and good dissolution profile even with water-insoluble fillers providing overall formulation robustness.
Data Source
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AI summary
The present invention provides solid pharmaceutical formulations and methods for making the same, wherein the pharmaceutical formulations comprise ticagrelor and is free of water soluble fillers. The pharmaceutical formulations of the present invention exhibit desirable dissolution profiles and are bioequivalent to the marketed composition.