Anagrelide Sustained-Release Formulation for Platelet Control
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Solution Overview
Problem
Current treatments for essential thrombocythemia, such as hydroxyurea and Alpha-Interferon, have limitations including non-selective platelet reduction, severe side effects, and intolerance issues, necessitating a more effective and tolerable therapeutic option.
Innovation Solution
A novel pharmaceutical composition of micronized anagrelide hydrochloride combined with lactose monohydrate, microcristalline cellulose, and pyrrolidones, which provides non-immediate and consistent release properties, reducing the peak plasma levels of anagrelide and its metabolite 3-hydroxyanagrelide, thereby minimizing side effects and improving tolerability.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If anagrelide is administered to reduce platelet counts in essential thrombocythemia, then platelet reduction efficacy is improved, but peak plasma levels cause increased side effects such as headache and dizziness
Solution Approach 1:
The patent employs sustained-release technology to transform immediate-release anagrelide into a formulation that releases the drug periodically over time. This maintains platelet reduction efficacy while avoiding peak plasma concentration spikes that cause side effects like headache and dizziness.
Solution Approach 2:
The patent modifies the release rate parameter of anagrelide from immediate to sustained release. By changing the temporal distribution of drug delivery, it maintains therapeutic efficacy while reducing the intensity of peak concentrations that trigger adverse events.
2Reliability
If hydroxyurea is used for platelet reduction, then platelet counts are reduced, but severe side effects including leukemia risk occur
Solution Approach 1:
The patent positions anagrelide as a safer alternative to hydroxyurea, particularly for young patients and those at risk of leukemic transformation. While anagrelide requires more frequent dosing due to its shorter half-life, it avoids the severe long-term risks associated with hydroxyurea.
3Reliability
If Alpha-Interferon is administered for treatment, then platelet counts are reduced, but patient tolerability deteriorates due to multiple effects on other cell lineages
Solution Approach 1:
The patent highlights anagrelide's selective action on megakaryocytes and platelets compared to Alpha-Interferon's broad effects on multiple cell lineages. This localized specificity improves patient tolerability by avoiding off-target effects while maintaining platelet reduction efficacy.
4Reliability
If anagrelide is given to young patients for long periods, then platelet control is achieved, but potential leukemogenic risk increases
Solution Approach 1:
The patent positions anagrelide as a safer alternative to hydroxyurea for young patients, despite requiring longer treatment duration. The sustained-release formulation enhances safety by avoiding peak concentrations, making it suitable for prolonged use in patients where leukemogenic risk is a concern.
Data Source
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AI summary
The invention relates to novel formulations of anagrelide resulting in a non- immediate release of the active ingredient of anagrelide. The inventors have shown that pharmaceutical compositions comprising anagrelide particles, wherein at least 90% of said anagrelide particles are smaller than 10μm, in combination with lactose monohydrate provide a formulation with reduced release characteristics when administered to a patient. Optionally, the pharmaceutical composition can further comprise povidone, crospovidone, microcristalline cellulose and/or magnesium stearate.