Ibudilast Pellet Formulation for Once-Daily Release and GI Tolerability
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Solution Overview
Problem
Existing ibudilast formulations require multiple daily doses and cause significant gastrointestinal side effects due to steep blood concentration increases, necessitating improved oral delivery systems for better patient compliance and tolerance.
Innovation Solution
A pharmaceutical composition comprising extended-release and optionally delayed-release pellets with specific coatings, allowing for fewer daily doses and maintaining similar AUC values while reducing side effects by adjusting active agent loading and optimizing release profiles.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If multiple capsules are administered daily to achieve expected efficacy exposure, then therapeutic effectiveness is improved, but patient compliance and tolerability deteriorate due to frequent dosing and gastrointestinal side effects
Solution Approach 1:
The formulation divides the daily dose into multiple pellets with different release characteristics (immediate, extended-release, delayed-release) that can be combined in a single capsule. This segmentation allows the drug to be released in controlled stages throughout the day, maintaining therapeutic effectiveness while reducing the number of dosing events from 2-3 times daily to once daily.
Solution Approach 2:
The patent modifies the release rate parameters of the formulation by incorporating pellets with different coating formulations and release characteristics. By adjusting the ratio and composition of immediate-release, extended-release, and delayed-release pellets, the formulation achieves sustained plasma concentrations that maintain therapeutic effectiveness while improving patient compliance through once-daily dosing.
2Reliability
If multiple capsules are administered daily to achieve expected efficacy exposure, then therapeutic effectiveness is improved, but patient tolerability deteriorates due to gastrointestinal side effects
Solution Approach 1:
The formulation ensures continuous therapeutic action by combining immediate-release, extended-release, and delayed-release pellets in a single capsule. This continuous release pattern maintains stable plasma concentrations throughout the day, avoiding the steep concentration increases that cause gastrointestinal side effects while maintaining therapeutic effectiveness.
Solution Approach 2:
The patent changes the plasma concentration profile parameters by optimizing the release characteristics of different pellet types. The extended-release and delayed-release components flatten the concentration curve, preventing steep increases that trigger gastrointestinal adverse effects, while the combined dose maintains therapeutic effectiveness.
3Device complexity
If intermediate release formulation is used, then drug delivery is simplified, but side effects increase due to steep blood concentration increases
Solution Approach 1:
The formulation segments the release profile into three distinct components (immediate-release, extended-release, delayed-release) within a single capsule system. This segmentation creates a more gradual and sustained plasma concentration profile compared to conventional intermediate-release formulations, reducing steep concentration increases that cause side effects while maintaining reasonable formulation complexity.
Solution Approach 2:
The patent uses a composite formulation combining different types of pellets with distinct release characteristics and coating formulations. This composite approach creates a synergistic release pattern that flattens plasma concentration curves, reducing side effects associated with steep increases, while the unified capsule design maintains formulation simplicity for the end user.
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 achieves higher Tmax values when administered with food, diminishing side effects and ensuring effective drug exposure with fewer capsules per day, thus improving patient compliance and tolerability.
Implementation Method 1
each of the extended-release pellets and each of the delayed release pellets comprises a drug pellet and an outer coating; the outer coating of the extended-release pellets is an extended-release outer coating
Implementation Method 2
the outer coating of the delayed release pellets is a delayed release outer coating
Data Source
AI summary
Described herein are pharmaceutical compositions comprising extended-release pellets and optionally delayed release pellets, wherein each of the extended-release pellets and each of the delayed release pellets comprises a drug pellet and an outer coating; the outer coating of the extended-release pellets is an extended-release outer coating; the outer coating of the delayed release pellets is a delayed release outer coating; the outer coating of the extended-release pellets is an extended-release outer coating; the outer coating of the delayed release pellets is a delayed release outer coating; the drug pellet comprises about 15 wt. % to about 25 wt. % ibudilast, about 60 wt. % to about 70 wt. % sugar sphere, about 5 wt. % to about 10 wt. % hydroxypropyl methylcellulose, and about 4 wt. % to about 8 wt. % silicon dioxide; the extended-release outer coating comprises about 20 wt. % to about 55 wt. % ethyl cellulose, about 20 wt. % to about 55 wt. % hydroxypropyl methylcellulose, about 1 wt. % to about 4 wt. % triethyl citrate, and about 20 wt. % to about 25 wt. % talc, wherein the weight percentages of ethyl cellulose, hydroxypropyl methylcellulose, triethyl citrate, and talc are based on total weight of the extended-release outer coating; and the delayed release outer coating comprises about 55 wt. % to about 65 wt. % copolymer of methacrylic acid and ethyl acrylate, about 3 wt. % to about 9 wt. % triethyl citrate, and about 25 wt. % to about 35 wt. % talc, wherein the weight percentages of the copolymer of methacrylic acid and ethyl acrylate, triethyl citrate, and talc are based on total weight of the delayed release outer coating.