Flibanserin Extended Release System pH-Independent Polymers
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Solution Overview
Problem
Developing an extended release system for flibanserin that provides pH-independent bioavailability is challenging due to its pH-dependent water solubility, as conventional systems either release the drug too quickly in the stomach or not at all in the small intestine and colon, and existing formulations have limitations such as requiring exclusion of calcium ions and being specific to zwitterionic drugs.
Innovation Solution
A combination of pH-dependent and pH-independent polymers with organic acids creates a micro-environment that maintains slow drug release across the gastrointestinal tract, ensuring pH-independent release profiles by using flibanserin, pH-dependent polymers, pH-independent polymers, and organic acids in specific proportions within the extended release system.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Speed
If conventional pH-independent swelling polymers are used for extended release, then drug release is faster in the stomach, but drug release is slower or incomplete in the small intestine and colon
Solution Approach 1:
The patent applies local quality by using pH-dependent polymers that change their properties at different pH locations in the gastrointestinal tract. The polymers remain insoluble in acidic stomach environment to maintain slow release, then become soluble in the higher pH environment of the small intestine to enhance release, creating location-specific release behavior that resolves the contradiction between fast stomach release and slow intestine release
Solution Approach 2:
The patent utilizes parameter changes by exploiting the pH-dependent solubility characteristics of specific polymers. The polymers undergo a solubility transition based on pH changes along the gastrointestinal tract, allowing the formulation to automatically adjust its release rate according to the local pH environment, thereby achieving consistent drug release across different gastrointestinal regions
2Duration of action of moving object
If pH-dependent retarding polymers are used to slow drug release, then drug release is slower in the stomach, but these polymers lose their retarding effect above a certain pH
Solution Approach 1:
The patent applies local quality by selecting polymers with specific pH transition points that match the gastrointestinal pH gradient. The polymers provide retarding effect in the acidic stomach environment and then transition to a soluble state in the higher pH intestine, creating locally optimized release control that maintains duration while ensuring reliability across different pH zones
Solution Approach 2:
The patent uses composite materials by combining pH-dependent polymers with specific solubility characteristics with flibanserin. This composite formulation leverages the pH-responsive behavior of the polymers to maintain stable release control throughout the gastrointestinal tract, resolving the contradiction between extended duration and reliable pH-dependent control
3Reliability
If alginates are used to form insoluble gel layer in the stomach, then calcium ions must be excluded, but this provides very limited usability of the formulation
Solution Approach 1:
The patent applies the taking out principle by removing calcium ions from the formulation entirely, eliminating the need for calcium-dependent gel formation. This extraction of the problematic component allows the use of alternative pH-dependent polymers that do not require calcium, thereby maintaining reliable gel layer formation while significantly improving formulation usability and flexibility
Solution Approach 2:
The patent uses intermediary substances (alternative pH-dependent polymers) that can form gel layers without requiring calcium ions. These intermediary polymers mediate between the need for reliable gel formation and the desire for broad formulation usability, allowing the system to function reliably across different gastrointestinal conditions without the limitations of calcium dependency
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 system achieves a pH-independent drug release profile from pH 1-5, enhancing bioavailability and allowing for reduced dosing frequency by maintaining slow drug release across different pH environments in the gastrointestinal tract.
Implementation Method 1
Flibanserin shows a solubility of 6.2 mg/ml in 0.1 N HCl and a solubility of 0.002 mg/ml in 0.05 M phosphate buffer pH 6.8. These physicochemical properties of basic compounds make it difficult to develop extended release dosage forms.
Implementation Method 2
The drug release of flibanserin from conventional systems containing only pH-independent swelling polymers would be much faster in the stomach compared to the slower or even incomplete drug release in the small intestine and the colon.
Implementation Method 3
There is a natural pH gradient from the acidity of the stomach where the pH of physiological fluids are typically around 1-2, through the weakly acidic duodenum to the virtually neutral environment of the small intestine where the pH is in the range of 5-8.
Data Source
AI summary
The invention is directed to a Pharmaceutical extended release system, particularly for oral administration, of a pH-dependent water-soluble active substance, comprising or essentially consisting ofa) flibanserin or a pharmaceutically acceptable derivative thereof as active substance;b) one or more pharmaceutically acceptable pH-dependent polymers;c) one or more pharmaceutically acceptable pH-independent polymers;d) one or more pharmaceutically acceptable acids; ande) optionally one or more additives.The present invention provides a release profile of flibanserin which is independent on the pH in the gastrointestinal tract when administered orally resulting in a significantly improved bioavailability.