Trazodone Sustained Release Formulation for Stable Plasma Levels
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Solution Overview
Problem
Trazodone's pH-dependent solubility hinders the development of long-acting formulations that require uniform absorption along the gastrointestinal tract, leading to fluctuating drug concentrations and increased side effects like drowsiness due to multiple daily dosing.
Innovation Solution
A sustained release pharmaceutical composition comprising 15% to 60% trazodone and 15% to 85% controlled release excipients, such as cross-linked high amylose starch, for once-a-day oral administration, providing stable plasma concentrations for 24 hours and pH-independent release, allowing uniform absorption throughout the GI tract.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Speed
If trazodone is formulated as immediate release for multiple daily dosing, then rapid absorption and therapeutic effect are achieved, but fluctuating plasma concentrations and increased side effects occur
Solution Approach 1:
The patent divides the dosing period into multiple segments by using multiple tablets administered at different times (e.g., two tablets at bedtime, or one tablet at bedtime plus one in the afternoon). This segmentation allows the drug to be released in controlled portions throughout the 24-hour period, maintaining stable plasma concentrations while avoiding the fluctuations associated with single-dose immediate release formulations.
Solution Approach 2:
The patent implements periodic administration of trazodone tablets at specific intervals (e.g., bedtime and afternoon dosing). This periodic action ensures that plasma concentrations remain within the therapeutic window throughout the day, preventing both sub-therapeutic levels and toxic peaks that occur with single-dose immediate release formulations.
2Reliability
If trazodone is dosed multiple times daily, then therapeutic plasma concentrations are maintained, but drowsiness and side effects increase
Solution Approach 1:
The patent segments the total daily dose into multiple smaller doses administered at different times. This segmentation allows therapeutic concentrations to be maintained without creating peak levels that cause excessive drowsiness. By distributing the total dose across multiple administration points, the formulation achieves reliable therapeutic effect while minimizing harmful side effects associated with high peak concentrations.
Solution Approach 2:
The patent uses preliminary dosing at bedtime to establish therapeutic plasma concentrations before the patient wakes up. This preliminary action ensures that adequate therapeutic levels are present at the start of the day without requiring multiple doses during waking hours, thereby reducing overall drowsiness and side effects while maintaining reliable therapeutic effect.
3Speed
If trazodone solubility is pH-dependent, then rapid absorption in upper GI tract is achieved, but uniform absorption throughout GI tract is hindered
Solution Approach 1:
The patent segments the gastrointestinal tract into multiple regions (upper GI tract and lower GI tract) and administers multiple doses at different times to ensure uniform absorption throughout the entire tract. By dividing the dosing schedule, the formulation compensates for pH-dependent solubility variations across different GI regions, achieving both rapid initial absorption and uniform overall absorption.
Solution Approach 2:
The patent uses periodic dosing at different times of day to address pH-dependent solubility issues. By spacing doses apart, the formulation allows different portions of the GI tract to contribute to absorption at different times, achieving uniform overall absorption despite the pH-dependent nature of trazodone solubility.
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 maintains effective plasma concentrations of trazodone for 24 hours, reducing side effects and providing consistent therapeutic levels for depression and sleep disorders without peak-related drowsiness, with formulations like 300 mg or 150 mg trazodone hydrochloride achieving stable plasma levels from 1 to 24 hours.
Implementation Method 1
the controlled release excipient provides a substantially pH independent controlled release of the trazodone or derivative thereof so that the trazodone or the trazodone derivative can be absorbed during passage through both the upper and lower gastrointestinal tracts
Implementation Method 2
The solubility of trazodone is pH dependent and has a pKa of 6.74 in water. As a result, trazodone is highly soluble in acid media (as found in the stomach and upper intestines)
Data Source
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AI summary
The invention relates to a once a day formulation of trazodone or a trazodone derivative. The formulation contains trazodone or a trazodone derivative and a controlled release excipient so that, once administered orally, the trazodone or the trazodone derivative is maintained at a therapeutic plasma concentration from at least 1 hour to at least 24 hours after initial administration. After administration, the initial therapeutic action takes effect within the first hour and lasts at least about 24 hours. This therapeutic effect remains relatively and substantially stable for the remaining period of 24 hours. The formulations can be used for treating depression and/or sleeping disorders.