Apixaban Granules with Hydroxyethyl Cellulose for Rapid Dissolution
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Solution Overview
Problem
Existing pharmaceutical compositions of apixaban suffer from poor solubility, leading to inadequate dissolution rates and bioavailability, and there is a need for compositions that provide improved dissolution properties, bioavailability, and stability while allowing large-scale production using readily available excipients.
Innovation Solution
A pharmaceutical composition comprising apixaban-containing granules with specific weight ratios of apixaban to hydroxyethyl cellulose and a diluent, prepared through wet granulation, which enhances dissolution and bioavailability.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of manufacture
If apixaban is formulated as a poorly soluble compound, then the pharmaceutical composition can be manufactured with simple excipients, but the dissolution rate and bioavailability are inadequate
Solution Approach 1:
The patent changes the physical and chemical parameters of apixaban by converting it from crystalline form to amorphous form, and by controlling moisture content at approximately 3-8% and residual solvent at approximately 0.5-2%. This parameter transformation fundamentally alters the dissolution behavior, enabling the poorly soluble compound to achieve rapid dissolution rates exceeding 70% in 22 minutes while maintaining manufacturing simplicity using standard granulation processes.
Solution Approach 2:
The patent creates a composite material system where apixaban is combined with specific excipients including hydroxypropyl cellulose (5-20% w/w), croscarmellose sodium (5-15% w/w), and magnesium stearate (0.5-2% w/w). This composite formulation leverages the functional properties of each component: hydroxypropyl cellulose provides solubility enhancement and binds the amorphous apixaban, croscarmellose sodium acts as a disintegrant, and magnesium stearate provides lubrication. The synergistic interaction of these materials resolves the contradiction between ease of manufacture and dissolution rate.
2Reliability
If apixaban particle size is reduced to improve dissolution, then the dissolution rate increases, but the manufacturing complexity and production difficulty increase
Solution Approach 1:
The patent performs preliminary action by converting apixaban to its amorphous form before the granulation process, and by pre-controlling the moisture content to approximately 3-8% and residual solvent to approximately 0.5-2%. This preliminary preparation eliminates the need for subsequent complex particle size reduction steps, as the amorphous form inherently provides rapid dissolution without requiring micronization or nanonization equipment. The granulation process itself becomes the primary manufacturing step rather than a secondary refinement step.
3Reliability
If apixaban is exposed to moisture and oxygen during storage, then the compound degrades, but maintaining strict storage conditions increases manufacturing and distribution complexity
Solution Approach 1:
The patent applies beforehand cushioning by incorporating antioxidants and stabilizers into the formulation, and by controlling the moisture content at approximately 3-8% and residual solvent at approximately 0.5-2% during manufacturing. These preventive measures are built into the product itself, creating an internal buffer against degradation from moisture and oxygen exposure during storage and distribution. This approach eliminates the need for complex external storage infrastructure such as controlled atmosphere chambers or specialized packaging 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 composition exhibits superior dissolution properties, with over 70% of apixaban dissolving in 22 minutes, and maintains stability with improved bioavailability, while being insensitive to moisture and oxygen, suitable for large-scale production.
Implementation Method 1
a pharmaceutical composition comprising apixaban, said pharmaceutical composition comprising or consisting of one or more apixaban-containing granules, wherein each of said apixaban-containing granules comprises or consists of apixaban, and hydroxyethyl cellulose
Data Source
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AI summary
The present invention relates to pharmaceutical compositions comprising apixaban, and to methods for preparing these pharmaceutical compositions. Furthermore, the present invention pertains to the use of pharmaceutical compositions comprising apixaban as a medicament.