Anagrelide Hydrochloride Monohydrate Granulate for Thrombocythemia
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Solution Overview
Problem
Current treatments for essential thrombocythemia do not effectively reduce platelet counts to normal levels, leading to ongoing thromboembolic complications, and existing anagrelide formulations have issues with stability and bioavailability.
Innovation Solution
A stable pharmaceutical composition of anagrelide hydrochloride monohydrate with a fast onset and high bioavailability is developed, featuring a granulate with specific particle size distribution and a low content of impurities, allowing for immediate release and easy encapsulation in hard capsules.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If existing anagrelide formulations are used, then platelet count reduction is achieved, but stability and bioavailability are insufficient
Solution Approach 1:
The patent changes the particle size parameter of anagrelide hydrochloride monohydrate to D50 between 0.4 and 10 microns and D90 between 3 and 20 microns. This parameter change improves both stability by reducing decomposition impurities and bioavailability through enhanced dissolution rate, with at least 85% dissolving in 15 minutes.
Solution Approach 2:
The patent creates a composite granulate formulation combining anagrelide hydrochloride monohydrate with specific excipients including lactose, microcrystalline cellulose, and magnesium stearate. This composite structure maintains stability while improving bioavailability through the immediate release profile enabled by the fine particle size distribution.
2Productivity
If particle size is reduced to improve dissolution, then bioavailability increases, but manufacturing complexity increases
Solution Approach 1:
The patent performs preliminary size reduction and classification of anagrelide hydrochloride monohydrate to achieve the target particle size distribution (D50: 0.4-10 microns, D90: 3-20 microns) before formulation. This preliminary action simplifies subsequent manufacturing steps while ensuring the dissolution rate requirement of at least 85% in 15 minutes is met.
Solution Approach 2:
The patent specifies precise particle size parameters (D50 between 0.4 and 10 microns, D90 between 3 and 20 microns) that optimize both dissolution rate and manufacturability. These parameter changes enable immediate release profile while maintaining ease of encapsulation in hard capsules.
3Productivity
If particle size is reduced to improve dissolution, then bioavailability increases, but impurity formation increases
Solution Approach 1:
The patent optimizes the particle size parameters to a specific range (D50: 0.4-10 microns, D90: 3-20 microns) that balances dissolution rate improvement with stability maintenance. This parameter optimization achieves at least 85% dissolution in 15 minutes while minimizing decomposition impurities through controlled particle size reduction.
Solution Approach 2:
The patent uses protective excipients including magnesium stearate (0.3-1.2% w/w) and antioxidants in the granulate formulation to prevent oxidation and decomposition of the fine particle anagrelide. This beforehand cushioning protects against impurity formation that would otherwise result from the increased surface area of reduced particles.
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 composition achieves high bioavailability and stability, with at least 85% of anagrelide dissolving in 15 minutes, reducing impurities and improving treatment efficacy for essential thrombocythemia by effectively lowering platelet counts.
Implementation Method 1
at least 85 % of the active agent of the pharmaceutical granulate dissolves in 15 minutes in a paddle dissolution test apparatus
Implementation Method 2
The active agent has a particle size volume distribution with D50 between 0.4 and 10 microns, and a D90 between 3 and 20 microns
Data Source
Figure 1
AI summary
The present invention relates to pharmaceutical compositions comprising anagrelide hydrochloride monohydrate, as well as to a process for the manufacture of said pharmaceutical compositions and to the use of said pharmaceutical compositions for the treatment of essential thrombocythemia.