Tacrolimus Stabilized Composition Using Tartaric Acid
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Solution Overview
Problem
Tacrolimus pharmaceutical compositions face challenges with degradation products, particularly 8-epitacrolimus, which affect bioavailability and regulatory compliance due to their formation during storage and manufacturing, and existing formulations often require solvents that are costly and undesirable.
Innovation Solution
A stabilized pharmaceutical composition of tacrolimus or its analogue dissolved or dispersed in a vehicle with a stabilizing agent, such as tartaric acid, that maintains a pH below 7, effectively reducing the formation of degradation products like 8-epitacrolimus, thereby enhancing stability and compliance.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of manufacture
If tacrolimus is formulated in conventional crystalline form, then manufacturing is simpler, but bioavailability is very low due to poor solubility
Solution Approach 1:
The patent changes the physical state of tacrolimus from crystalline to amorphous form, fundamentally altering its dissolution properties. The amorphous solid dispersion increases solubility and bioavailability by eliminating the crystal lattice structure that limits dissolution rate, while maintaining manufacturing feasibility through spray drying and other dispersion techniques
Solution Approach 2:
The patent creates composite materials by dispersing amorphous tacrolimus in carrier materials such as polymers (HPMC, PEG), sugars, or starches. These composite solid dispersions combine the poor solubility of crystalline tacrolimus with the solubility-enhancing properties of the amorphous state and carrier materials, achieving both improved bioavailability and manufacturing practicality
2Duration of action of stationary object
If tacrolimus compositions are stored during shelf-life, then distribution and use are enabled, but degradation products form which reduce reliability
Solution Approach 1:
The patent performs preliminary stabilization by incorporating antioxidants (vitamin E, vitamin C), chelating agents (EDTA), and pH buffers into the formulation before storage. These agents preemptively prevent or slow degradation reactions during shelf-life, maintaining tacrolimus stability without requiring complex post-manufacturing interventions
Solution Approach 2:
The patent introduces intermediary substances such as antioxidants and chelating agents that act as mediators between tacrolimus and environmental factors (oxygen, moisture, light). These intermediaries sacrifice themselves to protect tacrolimus from degradation, extending shelf-life while maintaining product reliability through mechanisms like radical scavenging and metal ion chelation
3Reliability
If solvents are used to improve tacrolimus solubility, then bioavailability increases, but manufacturing cost and complexity increase
Solution Approach 1:
The patent extracts or eliminates organic solvents from the formulation by using amorphous solid dispersions that achieve solubility enhancement through physical state change rather than solvent action. This removes the need for solvent removal steps, reduces manufacturing complexity, and eliminates solvent-related safety and cost issues while maintaining bioavailability improvements
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 use of tartaric acid as a stabilizing agent in the composition significantly reduces the formation of 8-epitacrolimus, ensuring the stability of tacrolimus formulations during storage and manufacturing, improving bioavailability and compliance with regulatory standards.
Implementation Method 1
a stabilizing agent, such as tartaric acid, that maintains a pH below 7, effectively reducing the formation of degradation products like 8-epitacrolimus
Data Source
AI summary
The invention relates to a stable pharmaceutical composition comprising comprising a solid dispersion of tacrolimus in a vehicle further comprising a stabilizing agent capable of providing a pH below 7 in the composition, as measured after re-dispersion in water, and preventing or reducing the formation upon storage of major degradation products of tacrolimus, in particular the 8-epitacrolimus.