Crushable Dasatinib Amorphous Dispersions for pH-Stable Oral Dosing
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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 bioavailability, and cannot be crushed for patients with swallowing difficulties, resulting in sub-therapeutic doses and high variability in pharmacokinetic parameters.
Innovation Solution
Development of amorphous solid dispersions (ASDs) of dasatinib with polymers that enhance solubility and stability, allowing co-administration with gastric acid-reducing agents and enabling crushing for alternative dosing methods.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of operation
If crystalline dasatinib monohydrate is used in immediate-release formulation, then the drug can be administered orally, but co-administration with gastric acid-reducing agents reduces bioavailability and efficacy
Solution Approach 1:
The patent changes the physical state parameter of dasatinib from crystalline to amorphous form, and modifies the formulation pH characteristics to be less sensitive to gastric acid-reducing agents. This parameter change allows the drug to maintain bioavailability despite co-administration with H2 blockers or proton pump inhibitors, resolving the contradiction between ease of oral administration and reliability of bioavailability.
2Stability of the object's composition
If crystalline dasatinib tablets are used, then the formulation is stable, but the tablets cannot be crushed for patients with swallowing difficulties
Solution Approach 1:
The patent changes the physical form from intact crystalline tablets to amorphous solid dispersion particles that can be crushed into powder. This parameter change maintains formulation stability through controlled amorphous structure while enabling dosing flexibility for patients with swallowing difficulties who can receive the crushed powder dispersed in food or fluid.
Solution Approach 2:
The patent segments the tablet form into crushable particles or powder form, allowing the dosage form to be divided and adapted for different patient needs. The amorphous solid dispersion can be crushed and dispersed in food or liquid, providing segmentation that maintains stability while enabling versatility in administration methods.
3Reliability
If strict administration restrictions are imposed on dasatinib formulation, then pharmacokinetic variability is reduced, but patient adherence becomes difficult
Solution Approach 1:
The patent changes the formulation to amorphous solid dispersion with modified pH characteristics, reducing sensitivity to gastric acid-reducing agents. This parameter change decreases pharmacokinetic variability without requiring strict administration restrictions, thereby improving patient adherence while maintaining reliability of pharmacokinetic consistency.
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, high drug load formulations with reduced variability and improved bioavailability, enabling effective dosing regardless of gastric pH and swallowing abilities, and eliminating the need for strict administration restrictions.
Implementation Method 1
amorphous solid dispersions (ASDs) of dasatinib with polymers that enhance solubility and stability
Implementation Method 2
The aqueous solubility of dasatinib is pH-dependent. As a result, upon administration the exposure (expressed as area-under-the-curve, or 'AUC') achieved by oral dosage of SPRYCEL can be reduced significantly
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. The compositions may be administered intact, or may be crushed prior to administration.