Monolithic Oral Dosage Form for pH-Dependent Release Control
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Solution Overview
Problem
Current dosage forms struggle to effectively release active ingredients with significantly different solubility properties, leading to issues like dose dumping, uneven plasma levels, and complex manufacturing processes, especially for weakly basic active ingredients with pH-dependent solubility, which complicates achieving modified release and storage stability.
Innovation Solution
The development of monolithic oral solid dosage forms containing a first active ingredient with low solubility and a second active ingredient with higher solubility, using an emulsifier produced by reacting mono-, di-, and triglycerides with polyethylene glycol, and a retardant in specific proportions, to ensure delayed and prolonged release, reducing the risk of dose dumping and improving storage stability.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If a monolithic dosage form contains both low-solubility and high-solubility active ingredients, then the release control becomes complex and dose dumping risk increases, but the patent achieves balanced release of both ingredients through specific formulation strategies
Solution Approach 1:
The patent applies parameter changes by adjusting the pH of the gastrointestinal environment to control the solubility and release of pH-dependent active ingredients. The formulation exploits pH variations along the GI tract to achieve staged release: low-solubility ingredients release in acidic stomach environment, while high-solubility ingredients release in more alkaline intestinal environment, thereby controlling release without complex device structures
Solution Approach 2:
The patent uses composite materials by combining multiple excipients with different functional properties in a monolithic matrix. This includes using pH-modifying excipients, solubility-enhancing excipients, and release-controlling excipients together to create a unified dosage form that simultaneously manages the release of active ingredients with different solubility characteristics
2Duration of action of moving object
If the dosage form is designed for modified release to reduce administration frequency, then the duration of action increases, but the risk of dose dumping and plasma level fluctuations worsens
Solution Approach 1:
The patent applies segmentation by dividing the release process into distinct phases based on gastrointestinal pH zones. The dosage form is designed to release different proportions of active ingredients at different pH levels: acidic pH in the stomach triggers release of certain ingredients, while alkaline pH in the intestine triggers release of others. This segmented approach based on environmental pH variation enables prolonged release while maintaining stable plasma levels by preventing dose dumping
3Reliability
If weakly basic active ingredients with pH-dependent solubility are used, then the therapeutic effect can be optimized, but the formulation complexity and manufacturing difficulty increase
Solution Approach 1:
The patent applies parameter changes by exploiting the pH-dependent solubility characteristic of weakly basic active ingredients. The formulation is designed to maintain these ingredients in a dissolved state at acidic pH (in the stomach) through the use of acidifying excipients, and they precipitate or release slowly as pH increases in the intestine. This approach optimizes therapeutic effect while avoiding complex formulation strategies by using straightforward pH manipulation
4Productivity
If the dosage form achieves sustained release over extended periods, then the frequency of administration decreases, but the storage stability requirements become more stringent
Solution Approach 1:
The patent applies homogeneity by creating a uniform monolithic matrix where all excipients and active ingredients are thoroughly mixed and distributed evenly. This homogeneous structure ensures consistent physical and chemical properties throughout the dosage form, which maintains storage stability while enabling sustained release. The uniform distribution prevents localized instability and ensures predictable release behavior over extended periods
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 dosage forms achieve optimal and sustained release of both active ingredients, reducing the frequency of administration to once or twice daily, maintaining therapeutic plasma levels, and ensuring high storage stability, while being cost-effective and easy to produce, thus enhancing patient compliance and pharmacokinetic profiles.
Implementation Method 1
using an emulsifier produced by reacting mono-, di-, and triglycerides with polyethylene glycol
Implementation Method 2
The release of the active ingredients can be delayed and/or prolonged
Implementation Method 3
If it does not dissolve, it will not be released from its dosage form and the therapeutic effect cannot occur
Implementation Method 4
A pH-dependent solubility occurs when the solubility properties of the active ingredient depend on the pH value
Data Source
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AI summary
The invention relates to a monolithic peroral dosage form which allows a modified release, preferably an extended and delayed release, of an active ingredient combination of active ingredients with solubility properties that strongly deviate from one another. The dosage form comprises at least one emulsifier with a polyalkylene oxide structural motif and at least one controlled-release agent. Using the dosage forms according to the invention, even active ingredients which have a limited storage stability and other unfavorable active ingredient properties that additionally hinder processing can be featured in an optimal manner. The invention also relates to a method for producing the dosage form and to the use thereof.