Dimethyl Fumarate Granulate Disintegrant Addition
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Solution Overview
Problem
The effectiveness of disintegrants in pharmaceutical granulation processes is compromised by wetting and drying in wet granulation, leading to reduced disintegration activity, while in dry granulation, the disintegrant's activity remains intact but is not optimally utilized, suggesting a need for a more efficient method to achieve desired drug release profiles.
Innovation Solution
A dry granulation process where dimethyl fumarate is blended with excipients like microcrystalline cellulose, mannitol, and anhydrous dibasic calcium phosphate, followed by a second mixing step with a disintegrant, without including disintegrants in the initial blend, and optionally coated with enteric layers, to enhance drug release.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If wet granulation process is used, then granulation efficiency is improved, but disintegrant activity is reduced due to wetting and drying
Solution Approach 1:
The patent changes the granulation method from wet to dry granulation, fundamentally altering the process parameters to eliminate moisture exposure. This parameter change preserves disintegrant activity while still achieving effective granulation through compression and mechanical force alone.
Solution Approach 2:
The patent extracts the harmful element (moisture/wetting agent) from the granulation process by using dry granulation instead of wet granulation. This removes the cause of disintegrant degradation while maintaining the granulation function through alternative mechanisms.
2Ease of manufacture
If disintegrant is added intragranularly in wet granulation, then granule formation is improved, but disintegration effectiveness is compromised
Solution Approach 1:
The patent inverts the conventional approach by adding disintegrant extragranularly after dry granulation rather than intragranularly during granulation. This reversal preserves disintegrant activity while still achieving effective disintegration, as the disintegrant remains intact and functional when added to the already-formed granules.
Solution Approach 2:
The patent segments the granulation and disintegrant addition processes into separate steps: first forming granules through dry granulation, then adding disintegrant in a subsequent mixing step. This segmentation prevents the disintegrant from being exposed to degrading conditions during granulation.
3Reliability
If two-step disintegrant addition is implemented, then drug release profile is optimized, but process complexity increases
Solution Approach 1:
The patent uses partial action by adding disintegrant only extragranularly rather than both intragranularly and extragranularly. This partial approach achieves adequate drug release profiles while simplifying the process, demonstrating that full two-step addition is not necessary when using dry granulation.
Data Source
AI summary
The present invention relates to a process for the manufacture of a pharmaceutical preparation in the form of a granulate comprising dimethyl fumarate and pharmaceutically acceptable excipients. The invention also relates to a pharmaceutical preparation in the form of granulate obtained by the process of the present invention and to use of the preparation in the treatment of multiple sclerosis.