Dasatinib Amorphous Solid Dispersion for pH-Independent Oral Delivery
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Current dasatinib formulations, such as SPRYCEL, are adversely affected by co-administration with gastric acid-reducing agents, leading to reduced efficacy and significant pharmacokinetic variability, necessitating restrictive patient treatment protocols.
Innovation Solution
Development of amorphous solid dispersions (ASDs) of dasatinib with specific polymers that maintain efficacy and stability even when co-administered with gastric acid-reducing agents, reducing inter- and intra-patient variability.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If crystalline dasatinib monohydrate is used in immediate-release formulation, then the formulation is simple and stable, but oral bioavailability is strongly affected by co-administration with gastric acid-reducing agents
Solution Approach 1:
The patent transforms dasatinib from its crystalline monohydrate form to an amorphous solid dispersion form, fundamentally changing the physical state and dissolution characteristics of the drug. This parameter change enables the drug to maintain solubility and bioavailability across a broader pH range, eliminating the interaction problem with gastric acid-reducing agents
Solution Approach 2:
The patent creates composite materials by dispersing dasatinib within polymer matrices (such as HPMC, Eudragit, or other excipients). This composite structure provides both the therapeutic activity of dasatinib and the pH-independent dissolution properties of the polymer matrix, resolving the contradiction between stability and compatibility
2Ease of operation
If dasatinib is administered with gastric acid-reducing agents, then patient compliance improves, but dasatinib concentrations decrease and efficacy is reduced
Solution Approach 1:
The amorphous solid dispersion formulation changes the dissolution parameter of dasatinib from pH-dependent to pH-independent. This allows the drug to be administered with gastric acid-reducing agents without compromising bioavailability, thereby improving patient compliance while maintaining therapeutic concentrations
Solution Approach 2:
The polymer matrix acts as an intermediary that protects dasatinib from pH variations in the gastrointestinal tract. This mediator enables co-administration with acid-reducing agents by buffering the microenvironment around the drug particles, ensuring consistent dissolution and absorption
3Ease of manufacture
If crystalline dasatinib formulation is used, then manufacturing is straightforward, but inter- and intra-patient variability in pharmacokinetic parameters is considerable
Solution Approach 1:
The transition from crystalline to amorphous form changes the dissolution rate parameter, creating more predictable and consistent absorption profiles. This reduces both inter-patient and intra-patient variability while maintaining manufacturing feasibility through established spray-drying and extrusion technologies
Solution Approach 2:
The patent applies local quality control by optimizing the micro-structure of the amorphous dispersion within the dosage form. By controlling polymer-to-drug ratios, particle size distribution, and dispersion homogeneity, the formulation achieves consistent performance across patients while using straightforward manufacturing processes
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 allowing co-administration with gastric acid-reducing agents, thus enhancing patient compliance and reducing variability.
Implementation Method 1
amorphous solid dispersions (ASDs) of dasatinib with specific polymers that maintain efficacy and stability even when co-administered with gastric acid-reducing agents
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.