Cedazuridine-Azacitidine Oral Formulation With Enteric Azacitidine Release

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Solution Overview

Problem

Cytidine analog drugs like azacitidine have poor oral bioavailability due to degradation by cytidine deaminases and chemical instability in the acidic gastric environment, leading to resistance in cancer treatment and the need for improved formulations to enhance absorption.

Innovation Solution

A fixed dose combination formulation with cedazuridine, a CDA inhibitor, and azacitidine, where cedazuridine is formulated for immediate release and at least a portion of azacitidine is formulated for enteric release, allowing for enhanced bioavailability by releasing azacitidine outside the stomach.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If azacitidine is orally administered, then it provides cancer treatment, but bioavailability is poor due to degradation by cytidine deaminases and chemical instability in acidic gastric environment

Engineering Contradiction:

ImprovebioavailabilityVSAvoiddegradation by cytidine deaminases and chemical instability

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent divides the azacitidine dosage into multiple separate tablets, each containing a specific amount of azacitidine. This segmentation allows for controlled release of the drug in the intestine, preventing degradation by cytidine deaminases and chemical instability in the acidic gastric environment, thereby improving bioavailability while maintaining cancer treatment efficacy

Inventive Principle:

Principle #1Segmentation

Solution Approach 2:

The patent introduces an intermediary substance that protects azacitidine from degradation by cytidine deaminases and chemical instability in the acidic gastric environment. This intermediary allows the drug to reach the intestine intact, where it can be properly absorbed and exert its cancer treatment effect, thus improving bioavailability

Inventive Principle:

Principle #24Intermediary (Mediator)

2Reliability

If enteric coating is applied to azacitidine, then bioavailability increases by releasing drug outside the stomach, but manufacturing complexity increases

Engineering Contradiction:

ImprovebioavailabilityVSAvoidformulation complexity

Core Design Contradiction:

ReliabilityVSDevice complexity

Solution Approach 1:

The patent segments the azacitidine dosage into multiple separate tablets, each containing a specific amount of azacitidine. This segmentation simplifies the enteric coating process compared to coating a single large tablet, while still achieving the goal of releasing the drug outside the stomach to improve bioavailability

Inventive Principle:

Principle #1Segmentation

Solution Approach 2:

The patent changes the physical and chemical parameters of the azacitidine formulation, including the use of specific excipients and the segmentation into multiple tablets. These parameter changes enable the drug to be released outside the stomach while simplifying the manufacturing process and reducing formulation complexity

Inventive Principle:

Principle #35Parameter changes

3Ease of operation

If fixed dose combination formulation is used with cedazuridine and azacitidine, then pill burden is reduced and patient compliance improves, but manufacturing precision requirements increase

Engineering Contradiction:

Improvepatient complianceVSAvoiddosage formulation precision

Core Design Contradiction:

Ease of operationVSManufacturing precision

Solution Approach 1:

The patent segments the combination formulation into multiple separate tablets, each containing a specific amount of azacitidine and cedazuridine. This segmentation allows for precise control of the dosage in each tablet, meeting manufacturing precision requirements while still reducing the overall pill burden and improving patient compliance through the fixed dose combination

Inventive Principle:

Principle #1Segmentation

Solution Approach 2:

The patent changes the formulation parameters of the combination product, including the specific amounts of azacitidine and cedazuridine in each tablet. These parameter changes enable precise dosage control to meet manufacturing precision requirements while maintaining the benefits of fixed dose combination therapy for improved patient compliance

Inventive Principle:

Principle #35Parameter changes

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 formulation significantly increases azacitidine bioavailability and reduces variability in drug exposure, improving cancer treatment efficacy by enhancing absorption and reducing the amount of azacitidine required.

Implementation Method 1

cedazuridine, a CDA inhibitor, further increases bioavailability of azacitidine

Methodology Applied

Scientific EffectEnzyme inhibition: Enzyme

Implementation Method 2

enteric release of azacitidine increases bioavailability of azacitidine

Methodology Applied

Scientific EffectEnteric coating: Coatings

Implementation Method 3

enteric release of azacitidine increases bioavailability of azacitidine

Methodology Applied

Scientific EffectAbsorption: Absorption (physical)

Data Source

PatentUS20260000697A1Combination formulation of cedazuridine

Publication Date: 2026.01.01 OTSUKA PHARM CO LTD

AI summary

The present disclosure relates generally to pharmaceutical dosage forms comprising azacitidine and cedazuridine.