High-Dose Endoxifen Formulations for Acid-Stable Intestinal Release

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Solution Overview

Problem

Existing oral drug delivery systems for high doses of endoxifen face challenges due to interconversion between the pharmaceutically active (Z)-form and less active (E)-form under acidic conditions, leading to poor dissolution and drug delivery, particularly in the stomach, and crosslinking issues with enteric-resistant delayed release capsules.

Innovation Solution

Formulations comprising not less than 4% (Z)-endoxifen and not less than 1% croscarmellose sodium, encapsulated in enteric-resistant delayed release capsules, designed to minimize dissolution in the stomach and maximize release in the intestines, preventing interconversion and crosslinking.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If high dose endoxifen is formulated in enteric-resistant delayed release capsules, then drug delivery to intestines is improved, but crosslinking issues occur with the capsule material

Engineering Contradiction:

Improvedrug deliveryVSAvoidcrosslinking

Core Design Contradiction:

ReliabilityVSObject-generated harmful factors

Solution Approach 1:

Croscarmellose sodium serves as an intermediary substance that prevents direct crosslinking between endoxifen and the capsule material. It acts as a protective agent that allows the endoxifen to maintain its structural integrity while still enabling the enteric-resistant delayed release functionality.

Inventive Principle:

Principle #24Intermediary (Mediator)

Solution Approach 2:

The formulation changes the chemical parameters by incorporating croscarmellose sodium at specific concentrations (1-5% by weight), which alters the interaction between endoxifen and the capsule material, preventing crosslinking while maintaining drug delivery properties.

Inventive Principle:

Principle #35Parameter changes

2Productivity

If endoxifen is exposed to acidic conditions in the stomach, then dissolution occurs, but interconversion between (Z)-form and (E)-form reduces pharmacological activity

Engineering Contradiction:

Improvedissolution rateVSAvoidpharmacological activity

Core Design Contradiction:

ProductivityVSReliability

Solution Approach 1:

The enteric-resistant coating provides preliminary protection against acidic conditions in the stomach, preventing the interconversion reaction before it can occur. This anti-action against acid exposure maintains the (Z)-form integrity during gastric passage.

Inventive Principle:

Principle #9Preliminary anti-action

Solution Approach 2:

The formulation design allows the endoxifen to skip the acidic stomach environment entirely by using enteric-resistant capsules that resist dissolution in acid, rushing through the gastric phase without undergoing unwanted interconversion, and only dissolving in the neutral intestinal environment.

Inventive Principle:

Principle #21Skipping (Rushing through)

3Reliability

If minimal release is achieved in the stomach, then bioavailability is improved, but dissolution control becomes difficult

Engineering Contradiction:

ImprovebioavailabilityVSAvoiddissolution control

Core Design Contradiction:

ReliabilityVSDevice complexity

Solution Approach 1:

The formulation uses specific parameter changes in the capsule material composition and coating properties to achieve minimal release in the stomach. The enteric-resistant properties are engineered through specific material selection and formulation parameters that provide automatic pH-dependent release behavior.

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The capsule system provides self-service dissolution control by automatically responding to pH changes in the gastrointestinal tract. The enteric-resistant coating self-regulates release based on the environmental conditions, eliminating the need for complex external control mechanisms.

Inventive Principle:

Principle #25Self-service

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 formulations effectively deliver bioavailable (Z)-endoxifen in its pharmaceutically active form by ensuring minimal release in the stomach and optimal release in the intestines, overcoming drug delivery inefficiencies.

Implementation Method 1

crosslinking issues with enteric-resistant delayed release capsules

Methodology Applied

Scientific EffectCrosslinking prevention:

Implementation Method 2

enteric-resistant delayed release capsule encapsulating the drug formulation

Methodology Applied

Scientific EffectEnteric resistance:

Implementation Method 3

enteric-resistant delayed release capsule encapsulating the drug formulation

Methodology Applied

Scientific EffectDelayed release:

Implementation Method 4

interconversion between the pharmaceutically active (Z)-form and less active (E)-form under acidic conditions

Methodology Applied

Scientific EffectIsomer stability:

Data Source

PatentUS20250281414A1High dose endoxifen formulations and methods of use

Publication Date: 2025.09.11 ATOSSA THERAPEUTICS INC

AI summary

Described herein are pharmaceutical compositions comprising high doses of (Z)-endoxifen. A high dose endoxifen composition may be formulated to prevent crosslinking between the endoxifen active pharmaceutical ingredient and a surrounding layer, such as a capsule. The compositions may be further formulated as enteric resistant compositions for oral administration and delivery to an intestine of a subject. Also described herein are methods of treatment using high dose endoxifen compositions.