Dasatinib Amorphous Solid Dispersion for pH-Independent Delivery
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Solution Overview
Problem
Current dasatinib formulations, such as SPRYCEL, are affected by co-administration with gastric acid-reducing agents, leading to reduced efficacy and significant inter- and intra-patient variability in pharmacokinetic parameters, necessitating restrictive usage guidelines that burden patients and may lead to poor adherence.
Innovation Solution
Development of amorphous solid dispersions (ASDs) of dasatinib with polymers that enhance solubility and stability, allowing administration without regard to gastric acid-reducing agents and reducing variability.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If crystalline dasatinib monohydrate is used as the formulation, then the drug can be manufactured and administered, but the oral bioavailability is strongly affected by gastric acid-reducing agents leading to reduced efficacy
Solution Approach 1:
The patent transforms dasatinib from its crystalline form to an amorphous solid dispersion form, changing the physical state parameter of the drug. This parameter change eliminates the pH-dependent solubility issue that caused the contradiction, allowing the drug to maintain consistent bioavailability regardless of gastric pH conditions created by acid-reducing agents.
Solution Approach 2:
The patent creates a composite material system by dispersing dasatinib within a polymer matrix (such as HPMC, PVP, or Eudragit). This composite amorphous solid dispersion combines the drug with excipients that stabilize the amorphous state and enhance solubility, resolving the contradiction between maintaining efficacy and compatibility with gastric acid-reducing agents.
2Stability of the object's composition
If crystalline dasatinib monohydrate is used, then the formulation is stable, but there is significant inter- and intra-patient variability in pharmacokinetic parameters
Solution Approach 1:
The patent changes the physical state parameter from crystalline to amorphous, which fundamentally alters the dissolution behavior. The amorphous state provides more consistent and predictable dissolution rates across different patients and conditions, reducing pharmacokinetic variability while maintaining formulation stability through the polymer matrix.
Solution Approach 2:
The polymer matrix acts as an intermediary that controls and standardizes the dissolution process. Materials like HPMC, PVP, or Eudragit serve as mediators between the drug and the gastrointestinal environment, providing consistent dissolution rates that reduce patient-to-patient and intra-patient variability in pharmacokinetic parameters.
3Reliability
If amorphous solid dispersion is used, then solubility and bioavailability are improved, but the formulation complexity increases
Solution Approach 1:
The patent applies parameter changes by transforming the physical state of dasatinib from crystalline to amorphous within a polymer matrix. This single parameter change (crystalline to amorphous) provides significant improvements in solubility and bioavailability without requiring complex multi-component systems or sophisticated delivery mechanisms.
Solution Approach 2:
The patent uses composite materials by combining dasatinib with well-established polymer excipients (HPMC, PVP, Eudragit) that are already widely used in pharmaceutical formulations. This approach improves bioavailability through the amorphous solid dispersion mechanism while minimizing formulation complexity by using proven, commercially available materials rather than novel complex systems.
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 ASDs provide stable and effective dasatinib delivery, maintaining efficacy regardless of gastric pH and co-administration with gastric acid-reducing agents, and reduce inter- and intra-patient variability.
Implementation Method 1
amorphous solid dispersions (ASDs) of dasatinib with polymers that enhance solubility and stability
Implementation Method 2
amorphous solid dispersions (ASDs) of dasatinib with polymers that enhance solubility and stability
Data Source
AI summary
Amorphous solid dispersions and pharmaceutical compositions of the protein kinase inhibitor dasatinib. The pharmaceutical compositions may be used in methods of treating a proliferative disorder such as cancer, or in methods of delivering dasatinib to patients without regard to whether the patient is concurrently administered a gastric acid-reducing agent, or without regard to whether the patient has an elevated gastric pH. The compositions may be particularly suitable for patients afflicted by achlorhydria or hypochlorhydria, or Helicobacter pylori infection.