Fulvestrant Pharmaceutical Composition Solubility and Precipitation Control
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Solution Overview
Problem
Pharmaceutical compositions containing high concentrations of fulvestrant for intramuscular injection often result in precipitation at the injection site, leading to tissue irritation and inflammation due to interaction with body fluids, despite efforts to increase concentration for reduced injection burden on patients.
Innovation Solution
A pharmaceutical composition with fulvestrant concentrations between 8% to 14% by mass, incorporating an aqueous solvent with ethanol and polyhydric alcohols, and a nonaqueous carrier like castor oil or its mixtures, which maintains solubility and prevents precipitation when exposed to body fluids.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of operation
If fulvestrant concentration is increased to reduce injection burden, then fewer injection sites are needed, but precipitation occurs at injection site causing tissue irritation
Solution Approach 1:
The patent changes the chemical composition parameters of the vehicle system by introducing specific polyhydric alcohols (propylene glycol, 1,3-butylene glycol) and controlling the ratio of alcoholic solvent to castor oil. This parameter optimization enables high fulvestrant concentration (≥100 mg/mL) while preventing precipitation and tissue irritation through improved solubility characteristics.
Solution Approach 2:
The patent creates a composite vehicle system combining multiple components: castor oil, polyhydric alcohols, and alcoholic solvents in specific ratios. This composite formulation synergistically prevents fulvestrant precipitation while maintaining high concentration, resolving the contradiction between concentration and tissue irritation.
2Quantity of substance
If fulvestrant concentration is increased to 100 mg/mL or higher, then injection volume is reduced, but fulvestrant precipitates when contacted with body fluid
Solution Approach 1:
The patent optimizes the vehicle composition parameters including the addition of polyhydric alcohols and controlled solvent ratios, which fundamentally changes the solubility parameters of fulvestrant. This enables the formulation to maintain stability ≥100 mg/mL concentration without precipitation upon contact with body fluids.
Solution Approach 2:
The patent introduces polyhydric alcohols as intermediary substances that mediate between fulvestrant and body fluids. These intermediaries prevent direct interaction that would cause precipitation, allowing high concentration formulation while maintaining stability in physiological conditions.
3Device complexity
If conventional vehicle composition is used, then formulation is simple, but fulvestrant precipitates at high concentration
Solution Approach 1:
The patent modifies the vehicle composition parameters by adding specific polyhydric alcohols and optimizing solvent ratios. While this increases formulation complexity slightly, it enables achieving ≥100 mg/mL fulvestrant concentration, which is the primary goal. The complexity increase is minimal and justified by the significant concentration improvement.
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 effectively maintains fulvestrant solubility and prevents precipitation upon contact with body fluids, reducing tissue irritation and allowing for higher concentration administration with fewer injection sites, thus alleviating patient burden while ensuring stable ingredient mixing and storage properties.
Implementation Method 1
A pharmaceutical composition with fulvestrant concentrations between 8% to 14% by mass, incorporating an aqueous solvent with ethanol and polyhydric alcohols, and a nonaqueous carrier like castor oil or its mixtures, which maintains solubility and prevents precipitation when exposed to body fluids
Data Source
AI summary
Provided is a pharmaceutical composition which contains fulvestrant in an amount of equal to or greater than 8% by mass with respect to the entire mass of the pharmaceutical composition, an aqueous solvent satisfying (1) to (4), and a pharmaceutically acceptable nonaqueous carrier satisfying (A) and (B). (1) Ethanol is contained in an amount of equal to or greater than 8% by mass with respect to the entire mass of the pharmaceutical composition. (2) At least one kind of polyhydric alcohol selected from propylene glycol or 1,3-butylene glycol is contained in an amount of equal to or greater than 3% by mass with respect to the entire mass of the pharmaceutical composition. (3) A content of benzyl alcohol is less than 5% by mass with respect to the entire mass of the pharmaceutical composition. (4) A content of the aqueous solvent is 15% to 50% by mass with respect to the entire mass of the pharmaceutical composition. (A) A content of benzyl benzoate is less than 1% by mass with respect to the entire mass of the pharmaceutical composition. (B) A content of the nonaqueous carrier is 40% to 75% by mass with respect to the entire mass of the pharmaceutical composition.