Amorphous Sirolimus Formulation with Fatty Acid Ester
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Solution Overview
Problem
Sirolimus has low solubility in water, leading to inadequate dissolution in gastrointestinal fluid, which complicates its oral administration and results in batch-to-batch variations in dissolution from tablets, necessitating an alternative approach to enhance solubility and stability.
Innovation Solution
A pharmaceutical composition comprising sirolimus in the amorphous form, combined with a fatty acid ester and a pharmaceutically acceptable polymer, where the fatty acid ester is present at a concentration less than 10% of the total weight, enhancing stability and release properties without adversely affecting the release rate.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If sirolimus is formulated as nanosized particles or oral solution to enhance solubility, then dissolution is improved, but preparation complexity and batch-to-batch variations increase
Solution Approach 1:
The patent transforms sirolimus from crystalline to amorphous form, fundamentally changing its physical state and dissolution behavior. This parameter change enables significantly enhanced solubility without requiring nanosization or special preparation procedures, thereby improving dissolution reliability while avoiding preparation complexity
Solution Approach 2:
The patent creates a composite system by combining amorphous sirolimus with specific carriers (mannitol, sucrose, lactose) and hydrophilic polymers (HPMC, PVP, carbopol). This composite approach stabilizes the amorphous form and maintains consistent dissolution performance across batches without requiring complex nanosized particle preparation
2Reliability
If crystalline sirolimus is transformed to amorphous form to increase solubility, then dissolution is enhanced, but chemical stability deteriorates
Solution Approach 1:
The patent introduces hydrophilic polymers (HPMC, PVP, carbopol) as intermediary substances that interact with amorphous sirolimus to form stable complexes. These polymers act as mediators that prevent molecular rearrangement and degradation of the amorphous form, thereby maintaining chemical stability while preserving enhanced dissolution performance
Solution Approach 2:
The patent formulates amorphous sirolimus as a composite material with stabilizing carriers and hydrophilic polymers. This composite structure physically protects the unstable amorphous sirolimus from degradation while maintaining its high solubility advantage, effectively resolving the stability-dissolution contradiction
3Reliability
If high concentration of fatty acid ester is used to improve release rate, then dissolution is enhanced, but stability deteriorates
Solution Approach 1:
The patent optimizes the concentration parameter of fatty acid ester to a specific range (2-10% w/w) rather than using high concentrations. This parameter optimization achieves sufficient release rate enhancement while preventing the stability deterioration that occurs at higher concentrations, resolving the contradiction between release and stability
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 composition significantly improves the stability and solubility of sirolimus, reducing degradation and maintaining effective release rates, as demonstrated by stability testing compared to commercially available formulations.
Implementation Method 1
it has a very low solubility in water (only 2.6 μg/ml)... the transformation of the crystalline form of a low solubility drug to the amorphous form can significantly increase the solubility thereof
Implementation Method 2
sirolimus in the amorphous form combined with a fatty acid ester and a pharmaceutically acceptable polymer... significantly improves the stability and solubility of sirolimus, reducing degradation
Data Source
AI summary
The present invention relates to a stable pharmaceutical composition comprising sirolimus. The pharmaceutical composition comprises sirolimus in the amorphous form, a fatty acid ester and a pharmaceutically acceptable polymer wherein the fatty acid ester is present at a concentration of less than 10 % w/w compared to the total weight of the composition.