Pregabalin Solid Composition for Once Daily Dosing
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Solution Overview
Problem
Conventional extended release pharmaceutical compositions for pregabalin are ineffective for once daily dosing due to non-uniform absorption in the gastrointestinal tract and potential intramolecular cyclization issues, leading to wasted drug release and stability concerns.
Innovation Solution
A stable pharmaceutical composition comprising pregabalin, polyvinyl acetate, and cross-linked polyvinylpyrrolidone, which swells in gastric fluid to prolong drug release in the stomach, extending the absorption window and preventing undesirable lactam formation.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of operation
If conventional extended release compositions are used for once daily dosing, then the dosing frequency is reduced to once daily, but the drug is not absorbed uniformly in the gastrointestinal tract and drug release beyond six hours is wasted
Solution Approach 1:
The patent segments the drug release process into two distinct phases: gastric phase (0-6 hours) and intestinal phase (6-24 hours). This is achieved by using a multi-component matrix system with different erosion rates, where the first component erodes primarily in the stomach and the second component erodes in the intestine, ensuring uniform absorption across different GI locations.
Solution Approach 2:
The patent applies local quality by creating spatially differentiated release characteristics within the dosage form. The matrix contains regions with different compositions and erosion properties, allowing the drug to be released at different rates in different parts of the GI tract, matching the absorption characteristics of each location.
2Ease of operation
If conventional extended release compositions are used for once daily dosing, then the dosing frequency is reduced to once daily, but the drug release extends beyond the absorption window and is wasted
Solution Approach 1:
The patent employs preliminary action by pre-planning the drug release profile to match the absorption window. The matrix is designed with specific erosion kinetics that ensure complete drug release occurs within 6-8 hours, aligning with the gastric residence time and absorption window, preventing any drug from being released after the hepatic flexure is passed.
Solution Approach 2:
The patent changes the release time parameter by using a matrix system with controlled erosion rates. The combination of hydrophilic and hydrophobic components creates a release profile that extends drug release from the typical 4-6 hours of immediate release formulations to 8-24 hours, matching the extended gastric retention time needed for once-daily dosing.
3Ease of manufacture
If pregabalin is stored under normal conditions, then the storage is simple, but intramolecular cyclization occurs to form lactam
Solution Approach 1:
The patent introduces excipients as intermediaries that interact with pregabalin to prevent cyclization. Specifically, hydrophilic excipients form hydrogen bonding networks with the carboxylic acid group of pregabalin, blocking the intramolecular reaction that would form the lactam. This allows stable storage under simple conditions without requiring complex protective measures.
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 allows for sustained release of pregabalin over an extended period, achieving a steady-state maximum and minimum plasma concentration suitable for once daily dosing while maintaining stability and preventing lactam formation.
Implementation Method 1
cross-linked polyvinylpyrrolidone, which swells in gastric fluid to prolong drug release in the stomach
Implementation Method 2
pregabalin is a γ-amino acid which under normal storage conditions may undergo intramolecular cyclization to form a lactam
Data Source
AI summary
A solid pharmaceutical composition containing pregabalin is described. The composition includes a matrix forming agent and a swelling agent and is suitable for once daily oral administration. Exemplary matrix forming agents include mixtures of polyvinyl acetate and polyvinylpyrrolidone, and exemplary swelling agents include cross-linked polymers of polyvinylpyrrolidone.