Enteric Coated Ileum-Targeted Kinase Inhibitor Dosage
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Solution Overview
Problem
Reversible and irreversible covalent drug molecules with a Michael acceptor moiety face challenges in bioavailability due to reactivity in the stomach, leading to low plasma AUC and C max values, and adverse side effects such as diarrhea, nausea, and emesis, as they react with thiols and enzymes, reducing their therapeutic efficacy.
Innovation Solution
A solid oral dosage form is developed with an enteric coating that protects the drug until it reaches the ileo-jejunal region of the small intestine, using a core covered by a water-soluble or water-insoluble subcoat that releases the drug as a bolus, enhancing bioavailability and minimizing exposure to the stomach's acidic environment.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If covalent drug molecules with Michael acceptor moiety are administered orally, then they can achieve high selectivity and prolonged inhibition, but they react with thiols and enzymes in the stomach leading to low bioavailability and adverse side effects
Solution Approach 1:
The dosage form is segmented into multiple layers: an enteric coating layer that resists stomach acid, a subcoat layer with controlled erosion properties, and a core layer containing the drug. This segmentation allows the drug to be protected during gastric passage and released specifically in the ileo-jejunal region, resolving the contradiction between maintaining drug stability and achieving targeted release
Solution Approach 2:
The enteric coating and subcoat act as intermediary layers that protect the Michael acceptor drug from reacting with gastric thiols and enzymes. These intermediaries allow the drug to pass through the stomach intact and release it in the intestine where absorption is optimal, thereby eliminating stomach-related side effects while maintaining drug efficacy
2Length of moving object
If the drug is released in the stomach, then absorption path length is maximized, but bioavailability is reduced due to chemical and metabolic transformation
Solution Approach 1:
The enteric coating is applied in advance to protect the drug during gastric transit. The subcoat is designed with specific erosion characteristics that control the timing of drug release. These preliminary actions ensure the drug reaches the ileo-jejunal region intact, where it can be released and absorbed without undergoing stomach-related degradation, thus maximizing bioavailability
3Quantity of substance
If the drug exposure to stomach is increased, then therapeutic effect may be enhanced, but adverse side effects such as diarrhea, nausea, and emesis are exacerbated
Solution Approach 1:
The invention extracts the harmful interaction between the Michael acceptor drug and gastric environment by using the enteric coating and subcoat system. This allows the drug to be delivered to the intestine where absorption occurs without exposing it to stomach thiols and enzymes, thereby eliminating side effects like diarrhea, nausea, and emesis while maintaining adequate drug exposure for therapeutic effect
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 dosage form achieves a significant increase in drug absorption and bioavailability in the ileum and jejunum, reducing adverse side effects and improving therapeutic efficacy by delaying drug release until the small intestine, where it can be effectively absorbed.
Implementation Method 1
an enteric coating that protects the drug until it reaches the ileo-jejunal region of the small intestine
Implementation Method 2
a core covered by a water-soluble or water-insoluble subcoat that releases the drug as a bolus
Implementation Method 3
The dosage form achieves a significant increase in drug absorption and bioavailability in the ileum and jejunum
Data Source
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AI summary
The current invention affords new formulations which deliver reversible and irreversible covalent kinase inhibitors, in particular BTK inhibitors, into the small intestine and specifically into the ileum and jejunum of the small intestine.