Pediatric ASBTI Formulations for Local Bile Acid Control
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Solution Overview
Problem
Pediatric cholestatic liver diseases require invasive and costly treatments, and existing medications pose challenges such as unpleasant taste, swallowing difficulties, and side effects like diarrhea and intestinal discomfort, necessitating a safer and more effective treatment form for children.
Innovation Solution
Non-systemic administration of therapeutic compositions containing Apical Sodium-dependent Bile Transporter Inhibitors (ASBTIs) or their pharmaceutically acceptable salts, formulated as pediatric dosage forms to target the distal ileum, colon, and rectum, reducing systemic absorption and addressing symptoms like pruritis, hypercholemia, and bile acid-related issues.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of operation
If adult solid dosage forms are used for pediatric patients, then medication can be administered, but the medication causes swallowing difficulties, unpleasant taste, and gastrointestinal side effects
Solution Approach 1:
The patent changes the physical and chemical parameters of the medication by using liquid formulations instead of solid dosage forms, and by modifying the pH and composition to match pediatric physiological parameters, thereby eliminating swallowing difficulties and unpleasant taste while reducing gastrointestinal side effects
Solution Approach 2:
The patent employs single-use liquid dosage forms that are discarded after administration, eliminating the need for complex packaging and storage required for solid dosage forms, and allowing for optimized formulation without concern for long-term stability in the product
2Quantity of substance
If systemic administration of bile acid sequestrants is used, then bile acid levels can be reduced, but the medication causes diarrhea and intestinal discomfort
Solution Approach 1:
The patent applies local quality by formulating the medication to act locally in the intestine rather than systemically, using pH-dependent solubility to ensure the active ingredient is released and acts only in the distal intestine where bile acid recycling occurs, thereby reducing bile acid levels without causing systemic gastrointestinal side effects
Solution Approach 2:
The patent uses pH as an intermediary mechanism to control the release and activation of the bile acid sequestrant, with the medication remaining inactive in the stomach and proximal intestine (acidic pH) and becoming active only in the distal intestine (higher pH), thereby mediating between systemic administration and local action
3Reliability
If invasive treatments like liver transplantation are used, then treatment effectiveness is improved, but treatment cost and invasiveness increase significantly
Solution Approach 1:
The patent extracts the essential therapeutic function from complex invasive procedures by identifying and targeting the specific physiological mechanism of bile acid recycling in the distal intestine, thereby treating the underlying cause of pediatric cholestatic liver diseases through a simple oral medication rather than invasive surgery
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 methods significantly decrease serum and hepatic bile acid levels by at least 15-50%, ameliorate pruritis, and protect liver and intestinal integrity by increasing intraluminal bile acid concentrations, providing a safer and more effective treatment for pediatric cholestatic liver diseases.
Implementation Method 1
administration of a composition comprising an Apical Sodium-dependent Bile Transporter Inhibitor (ASBTI)
Data Source
AI summary
Provided herein are methods of treating or ameliorating a pediatric cholestatic liver disease by non-systemically administering to an individual in need thereof a therapeutically effective amount of a pediatric formulation comprising an Apical Sodium-dependent Bile Acid Transporter Inhibitor (ASBTI) or a pharmaceutically acceptable salt thereof. Also provided are methods for treating or ameliorating a pediatric liver disease, decreasing the levels of serum bile acids or hepatic bile acids, treating or ameliorating pruritis, reducing liver enzymes, or reducing bilirubin comprising non-systemically administering to an individual in need thereof a therapeutically effective amount of a pediatric formulation comprising an ASBTI or a pharmaceutically acceptable salt thereof.