Enteric-Coated BTK Inhibitor Tablets for Stable Intestinal Release
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Solution Overview
Problem
Oral administration of covalent kinase inhibitors like Compound (I) faces challenges with poor aqueous solubility, slow dissolution, poor stability at physiological pH, and variable systemic absorption, leading to inconsistent drug exposure and adverse side effects.
Innovation Solution
A modified release solid oral dosage form comprising a core composition of Compound (I) with a sub-coating layer of polyvinyl alcohol or hydroxypropyl methyl cellulose and an enteric coating layer of acrylic/methacrylic polymers, designed to release the drug effectively in the small intestine, avoiding stomach exposure.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of operation
If oral administration is used to deliver the drug, then patient compliance and ease of self-administration are improved, but consistent and adequate circulating levels of drug are difficult to obtain due to poor aqueous solubility, slow dissolution rate, and variable absorption
Solution Approach 1:
The drug is pre-processed into a specific solid state form (amorphous or crystalline) before administration, and formulated with specific excipients and coating layers to prepare the dosage form for optimal dissolution and absorption in the gastrointestinal tract, thereby ensuring reliable drug circulation levels
Solution Approach 2:
The patent utilizes enteric coating materials that change their properties based on pH conditions - remaining intact in the acidic stomach environment and dissolving in the higher pH environment of the small intestine, thereby controlling where and how the drug is released to ensure consistent absorption
2Productivity
If the drug is released in the stomach, then absorption can occur, but the drug is exposed to low pH and digestive enzymes that cause poor stability and extensive presystemic metabolism
Solution Approach 1:
An enteric coating layer acts as an intermediary barrier between the drug and the harsh stomach environment (low pH and digestive enzymes). This coating protects the drug from degradation and presystemic metabolism while allowing controlled release in the more favorable environment of the small intestine
Solution Approach 2:
The dosage form is segmented into distinct layers with different functions: a core composition containing the drug, a sub-coating layer, and an enteric coating layer. This segmentation allows the drug to be protected during gastric transit and then released in the appropriate location for optimal absorption and stability
3Reliability
If covalent drugs are used to achieve high selectivity and prolonged inhibition, then therapeutic efficacy is improved, but poor oral bioavailability and delayed systemic absorption occur due to reactivity of Michael acceptor moieties
Solution Approach 1:
The enteric coating is applied in advance to protect the reactive covalent drug moieties from premature reaction in the stomach. This preliminary protective action allows the drug to reach the small intestine in an intact, active form, enabling both high bioavailability and maintained therapeutic efficacy
Solution Approach 2:
The patent converts the potential harm of reactive Michael acceptor moieties (which cause poor bioavailability through premature reaction) into a benefit by using the enteric coating to control where the reactivity occurs - only after the coating dissolves in the small intestine does the drug become reactive, ensuring it reaches systemic circulation first and then exerts its covalent inhibitory 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
Enhances systemic exposure and reduces adverse side effects by ensuring consistent drug release and absorption in the small intestine, improving bioavailability and therapeutic efficacy.
Implementation Method 1
an enteric coating layer encapsulating the sub-coating layer and the core composition, said enteric coating layer comprising at least one polymer selected from an acrylic/methacrylic/ethacrylic acid homopolymer and copolymer
Implementation Method 2
a sub-coating layer coating the core composition, said sub-coating layer comprising a polyvinyl alcohol and/or hydroxypropyl methyl cellulose
Data Source
AI summary
Modified release formulations, such as solid oral dosage forms comprising a core composition comprising Compound (I) and/or a pharmaceutically acceptable salt thereof; a sub-coating layer coating the core composition, said sub-coating layer comprising a polyvinyl alcohol and/or a hydroxypropyl methyl cellulose; and an enteric coating layer encapsulating the sub-coating layer and the core composition, said enteric coating layer comprising at least one polymer selected from an acrylic/methacrylic/ethacrylic acid homopolymer and copolymers thereof, a cellulose derivative, and a polyvinylpyrrolidone, and methods of administration of a Bruton's tyrosine kinase (BTK) inhibitor using said formulations.