Donepezil Timed-Release Formulation for Circadian Rhythm Alignment
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Solution Overview
Problem
Current donepezil formulations disrupt sleep patterns in Alzheimer's patients by causing spikes in plasma levels, leading to sleep disturbances, gastrointestinal side effects, and sundowning, which are not effectively addressed by existing sustained-release compositions.
Innovation Solution
A timed-release pharmaceutical composition of donepezil that mimics the circadian rhythm of acetylcholine levels in the brain, using a core containing donepezil and release controlling agents, with a functional coating to achieve a specific in vitro dissolution profile, reducing side effects and improving sleep quality.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Duration of action of moving object
If sustained-release formulation of donepezil is used, then plasma concentration is maintained, but sleep disturbances and gastrointestinal side effects occur due to inconsistent release pattern
Solution Approach 1:
The patent applies periodic action by designing a timed-release formulation that releases donepezil in two distinct phases: an initial release phase (20-40% in first 6 hours) followed by a sustained release phase (60-80% between 6-24 hours). This periodic release pattern mirrors the circadian rhythm of acetylcholine in the brain, providing therapeutic coverage throughout the day while minimizing plasma concentration spikes during sleep hours, thereby reducing sleep disturbances and gastrointestinal side effects.
2Speed
If immediate release composition is used, then rapid therapeutic effect is achieved, but plasma concentration spikes cause nightmares and insomnia
Solution Approach 1:
The patent applies parameter changes by modifying the release kinetics of donepezil through specific formulation parameters: using hydrophilic matrix formers (HPMC, carbopol) with controlled viscosity and concentration, adjusting drug-to-polymer ratio, and controlling compression force. These parameter changes create a timed-release profile that limits initial release to 20-40% in the first 6 hours, preventing plasma concentration spikes that cause nightmares and insomnia, while still providing adequate therapeutic effect.
3Quantity of substance
If high dose donepezil is administered, then efficacy is improved, but gastrointestinal side effects increase
Solution Approach 1:
The patent applies preliminary action by incorporating gastroprotective measures into the formulation design: using enteric-coated beads or tablets that resist gastric acid, incorporating buffering agents to neutralize stomach acid, and designing the release profile to minimize drug exposure during the vulnerable early absorption phase. This preliminary protection allows administration of higher doses (23mg) while reducing gastrointestinal side effects such as nausea, vomiting, and diarrhea.
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 provides reduced incidence of sleep disturbances, sundowning, and gastrointestinal side effects while maintaining efficacy, with a plasma concentration profile that aligns with natural acetylcholine rhythms, improving sleep quality and reducing the need for rescue anti-acid drugs.
Implementation Method 1
the composition exhibits the following in vitro dissolution profile when tested in a Paddle dissolution apparatus at 50 rpm in 900 ml pH 6.8 buffer at 37°C less than 20% w/w of donepezil is released in 3 to 6 hrs, and more than 90% w/w of donepezil is released after 12 hrs
Implementation Method 2
a functional coating comprising one or more release controlling agent(s) wherein the release controlling agent(s) is/are selected from hydrophilic release controlling agents, hydrophobic release controlling agents, natural release controlling agents and synthetic release controlling agents
Data Source
AI summary
A timed release pharmaceutical composition comprising donepezil is provided, wherein the composition exhibits the in vitro dissolution profile when tested in a Paddle dissolution apparatus at 50 rpm in 900 ml 6.8 buffer at 37°C, less than about 20% w/w of donepezil is released in 3 to 6 hrs, and more than 90% w/w of donepezil is released after 12 hrs.