Microparticulate Solid Oral Form with pH-Dependent Release
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Solution Overview
Problem
Conventional enteric formulations for oral administration have high variability in release due to unpredictable gastric emptying times, leading to inconsistent drug delivery, especially for active ingredients with a low therapeutic index, as they often retain the active ingredient in the stomach for longer than expected, causing either under or over-dosing.
Innovation Solution
A solid oral form comprising microparticles with a specific three-phase release profile, where the active ingredient is coated with a polymer blend of ethylcellulose and pH-sensitive polymers, ensuring delayed release in the stomach and immediate release in the intestine, maintaining therapeutic levels with reduced variability.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional enteric formulations are used for oral administration, then the active ingredient can be delivered to the intestine, but the release time and plasma concentration vary significantly due to unpredictable gastric emptying times
Solution Approach 1:
The patent changes the release mechanism from being time-dependent (gastric emptying controlled) to being pH-dependent (polymer dissolution controlled). The enteric coating polymers are designed to dissolve at specific pH ranges encountered in the gastrointestinal tract, making the release profile independent of gastric retention time and predictable based on physiological pH gradients.
Solution Approach 2:
The patent replaces the mechanical/physiological control mechanism (gastric emptying) with a chemical control mechanism (pH-sensitive polymer dissolution). This substitution eliminates the variability introduced by physiological processes and provides reliable, predictable drug release based on the well-characterized pH environment of different gastrointestinal regions.
2Reliability
If the active ingredient is retained in the stomach for longer than expected, then gastric retention increases, but this causes under-dosing or over-dosing due to inconsistent release
Solution Approach 1:
The patent changes the release trigger from time-based (duration of gastric retention) to pH-based (environmental acidity). The enteric coating remains intact during gastric retention regardless of duration, and releases the drug predictably when the pH threshold is reached in the intestine, ensuring accurate dosing independent of how long the formulation remains in the stomach.
3Reliability
If a single release profile is used, then the formulation is simple, but it cannot maintain constant plasma concentration for active ingredients with low therapeutic index
Solution Approach 1:
The patent segments the release function into multiple independent components with different pH sensitivity. By using blends of enteric polymers with different dissolution pH ranges (e.g., Eudragit L100 dissolving at pH 6, Eudragit S100 at pH 7), the formulation creates a multi-phase release profile that maintains stable plasma concentrations through staggered drug release, while each polymer component remains a simple, well-characterized material.
Solution Approach 2:
The patent uses composite enteric coating formulations combining multiple pH-sensitive polymers. This composite approach allows the coating to exhibit a broader, more gradual dissolution profile across the pH range encountered in the gastrointestinal tract, enabling sustained and stable drug release without requiring complex multi-layer structures or novel materials.
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 solid form achieves a consistent three-phase release profile, ensuring prolonged and controlled drug delivery, minimizing hepatic metabolism and maintaining bioavailability, even for active ingredients with low therapeutic indices, by using a polymer blend that adjusts release based on time and pH changes.
Implementation Method 1
a polymer B having a solubilization pH value varying in the pH range from 5 to 7
Data Source
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AI summary
The invention relates to a solid form intended for the oral administration of at least one active agent and capable of ensuring a dual mechanism for the release of said active agent, whereby the first release is conditioned by time and the second release is conditioned by pH. The invention is characterised in that the active agent is present in the form of a microparticulate system, the microparticulates of which include a core which is made up entirely or partly of said active agent and coated with at least one layer which conditions the release profile of the active agent and which is formed by a material containing at least: (i) 25% to 75% by weight, relative to the total weight of the coating, of at least a polymer A that is insoluble in the gastrointestinal fluids, (ii) 25% to 75% by weight, relative to the total weight of the coating, of at least a polymer B that has a solubilisation pH value in the pH range of from 5 to 7, and (iii) 0 to 25% by weight, relative to the total weight of the coating, of at least one plasticiser, said polymers A and B being present in a polymer(s) B/polymer(s) A weight ratio that is at least equal to 0.25. The invention also relates to a method for preparing this solid form and the corresponding microparticulates.