Epalrestat Modified Release Formulation for Once-Daily Dosing
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Solution Overview
Problem
Epalrestat, an aldose reductase inhibitor, is currently prescribed as an immediate release formulation requiring three times a day administration, which is inconvenient and may lead to undesired side effects, necessitating a modified release formulation for once-a-day administration that maintains therapeutic effects while minimizing side effects.
Innovation Solution
A modified release pharmaceutical composition of epalrestat or its derivatives, including sustained, controlled, bi-modal, or delayed release forms, such as choline hydrogen diepalrestat or crystalline salts, to provide steady state plasma concentrations and maintain therapeutic efficacy with reduced frequency of administration.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of operation
If immediate release formulation is used, then therapeutic effect is achieved, but administration frequency must be three times a day which reduces patient compliance
Solution Approach 1:
The patent applies dynamics by transitioning from static immediate release to dynamic modified release formulation. The composition uses pH-dependent solubility characteristics of epalrestat to create time-varying drug release profiles, where the drug dissolves and releases at different rates depending on gastrointestinal pH conditions encountered during transit through the digestive system, thereby extending duration of action while maintaining therapeutic efficacy
Solution Approach 2:
The patent utilizes parameter changes by exploiting the pH-dependent solubility parameter of epalrestat. The drug's solubility changes dramatically with pH, being insoluble at gastric pH but soluble at intestinal pH. This natural parameter change is harnessed to create extended release without requiring complex formulation systems, allowing once-daily administration while maintaining therapeutic blood concentrations
2Object-affected harmful factors
If immediate release formulation is administered three times a day, then therapeutic coverage is maintained, but undesired side effects increase
Solution Approach 1:
The patent applies periodic action through the natural cyclic pH changes in the gastrointestinal tract. As the formulation moves through different regions of the GI system, it encounters periodic pH variations that trigger controlled drug release. This periodic exposure to different pH environments creates a sustained, rhythmic release pattern that maintains therapeutic coverage while avoiding the peaks and troughs associated with multiple daily dosing
Solution Approach 2:
The patent uses gastrointestinal pH as an intermediary mechanism to control drug release. Rather than direct contact with digestive enzymes or mechanical breakdown, the pH environment acts as an intermediary that modulates drug solubility and release rate. This intermediary control system provides more predictable and sustained release compared to immediate release formulations, reducing side effects while maintaining reliability
Data Source
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AI summary
Modified release pharmaceutical compositions of epalrestat are provided. Methods of manufacturing the tablets and treating various diseases and conditions, including diabetes and diabetic complications, by administering the modified release compositions to patients in need thereof. A modified release formulation of epalrestat or a pharmaceutically acceptable derivative thereof, which maintains an adequate epalrestat plasma concentration-time profile to effectively treat a patient in need thereof, using once-a-day administration. The modified release composition, in one embodiment, is a sustained release, controlled release, bi-modal release or delayed release composition. The modified release epalrestat pharmaceutical composition comprises a pharmaceutically acceptable epalrestat derivative, such as choline hydrogen diepalrestat or betaine hydrogen diepalrestat.