Fulvestrant Aqueous Particle Suspensions for Lower-Pain Injection Delivery
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Solution Overview
Problem
Fulvestrant, a selective estrogen receptor degrader for treating hormone receptor positive metastatic breast cancer, has poor solubility and oral bioavailability, leading to painful and inefficient intramuscular injections due to its lipophilic nature and low aqueous solubility, with existing formulations causing local tissue irritation and poor release profiles.
Innovation Solution
Development of fulvestrant formulations comprising particles with specific size distributions and a non-oil vehicle, such as aqueous suspensions with concentrations ranging from 40 to 125 mg/mL, to improve dosing properties and pharmacokinetic profiles, reducing injection pain and improving release rates.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Quantity of substance
If fulvestrant is formulated in oil-based vehicle to improve solubility, then solubility is improved, but injection pain and viscosity increase
Solution Approach 1:
The patent changes the physical state of fulvestrant from dissolved state in oil to suspended state as particles in aqueous vehicle. This parameter change from dissolution to suspension allows the use of water-based vehicles with lower viscosity, thereby reducing injection pain while maintaining adequate drug delivery through controlled particle suspension.
Solution Approach 2:
The patent introduces surfactants and suspending agents as intermediary substances to stabilize fulvestrant particles in aqueous vehicle. These intermediaries prevent particle aggregation and ensure stable suspension, enabling the use of non-oil vehicles while maintaining drug solubility and delivery effectiveness.
2Object-affected harmful factors
If fulvestrant is formulated as aqueous suspension to reduce viscosity, then injection comfort is improved, but release rate decreases
Solution Approach 1:
The patent optimizes particle size parameters of fulvestrant, controlling Dv(10), Dv(50), and Dv(90) within specific ranges. This parameter control balances suspension stability with release rate, ensuring particles are small enough to dissolve at clinically significant rates but large enough to maintain stable suspension and reduce injection pain.
Solution Approach 2:
The patent creates local quality variations in the formulation by using specific suspending agents and surfactants that provide different functions at different stages: initial suspension stability for injection comfort, and controlled dissolution for release rate. The formulation has optimized local properties at particle surface, suspension medium, and injection site.
Data Source
AI summary
The disclosure is directed to fulvestrant formulations including suspensions of fulvestrant particles suitable for injection. The formulations can comprise fulvestrant particles having an LD Dv(10) less than about 3 microns, for example, between about 1 micron to about 3 microns, an LD Dv(50) less than about 35 microns, for example, between about 2 microns and about 35 microns, and an LD Dv(90) less than about 120 microns, for example, between about 4 microns and about 120 microns. The formulations can comprise fulvestrant particles having a CE Dv(90) less than about 200 microns, for example, between about 10 microns and about 200 microns, a CE Dv(50) less than about 60 microns, for example, between about 5 microns and about 60 microns, and a CE Dv(10) less than about 25 microns, for example, between about 1 microns and about 25 microns.