Combined Oral GnRH Antagonist Tablets With Hormone Add-Back

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Solution Overview

Problem

Existing treatments for hormone-sensitive conditions like uterine fibroids and endometriosis using GnRH antagonists face challenges in balancing hormone levels to alleviate symptoms while minimizing side effects such as bone mineral density loss and endometrial hyperplasia, and ensuring consistent patient compliance and stability of active ingredients in oral formulations.

Innovation Solution

A combination solid oral dosage form comprising N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea (Compound 1) and hormone replacement medicaments like estradiol and norethindrone acetate, with specific excipient ratios and formulation processes to maintain stability and bioequivalence, ensuring minimal side effects and optimal hormone balance.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If GnRH antagonist is used to treat hormone-sensitive conditions, then symptoms are alleviated, but bone mineral density loss occurs

Engineering Contradiction:

Improvesymptom alleviationVSAvoidbone mineral density loss

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent combines a GnRH antagonist with hormone replacement medicaments (estradiol and/or progesterone) in a single oral dosage form. This merging allows the simultaneous achievement of symptom alleviation through GnRH antagonist activity while preventing bone mineral density loss through hormone replacement, thereby resolving the contradiction between therapeutic efficacy and harmful side effects.

Inventive Principle:

Principle #5Merging (Combining)

Solution Approach 2:

The hormone replacement medicaments act as intermediaries that mitigate the harmful effects of the GnRH antagonist. Specifically, estradiol and progesterone replace the hormones suppressed by the GnRH antagonist, preventing bone mineral density loss and endometrial hyperplasia while allowing the GnRH antagonist to continue providing symptom relief.

Inventive Principle:

Principle #24Intermediary (Mediator)

2Reliability

If GnRH antagonist suppresses estrogen and progesterone, then hormone-sensitive symptoms are reduced, but endometrial hyperplasia risk increases

Engineering Contradiction:

Improvesymptom reductionVSAvoidendometrialhyperplasia

Core Design Contradiction:

ReliabilityVSObject-generated harmful factors

Solution Approach 1:

The combination dosage form merges the GnRH antagonist with progesterone replacement medicament, enabling simultaneous suppression of hormone-sensitive symptoms while providing progesterone to prevent endometrial hyperplasia. This resolves the contradiction by addressing both the therapeutic effect and the harmful side effect within a single formulation.

Inventive Principle:

Principle #5Merging (Combining)

Solution Approach 2:

The progesterone medicament serves as an intermediary that counteracts the endometrial hyperplasia risk caused by unopposed estrogen suppression. By providing concurrent progesterone replacement, the formulation prevents endometrial hyperplasia while maintaining the symptom-relieving effects of GnRH antagonist therapy.

Inventive Principle:

Principle #24Intermediary (Mediator)

3Adaptability or versatility

If separate dosage forms are used for GnRH antagonist and hormone replacement, then dosing flexibility is maintained, but patient compliance decreases

Engineering Contradiction:

Improvedosing flexibilityVSAvoidpatient compliance

Core Design Contradiction:

Adaptability or versatilityVSEase of operation

Solution Approach 1:

The patent merges multiple medications (GnRH antagonist and hormone replacement medicaments) into a single oral dosage form. This combination simplifies the patient regimen by reducing the number of separate pills to take, thereby improving compliance while maintaining the therapeutic benefits of each individual medication.

Inventive Principle:

Principle #5Merging (Combining)

Solution Approach 2:

The single oral dosage form performs multiple functions simultaneously: it provides GnRH antagonist activity for symptom relief and hormone replacement for side effect prevention. This multi-functionality in a single formulation improves ease of operation and patient compliance while preserving dosing flexibility through controlled release mechanisms.

Inventive Principle:

Principle #6Universality (Multi-functionality)

4Reliability

If stable oral formulation is achieved, then bioequivalence is maintained, but formulation complexity increases

Engineering Contradiction:

ImprovebioequivalenceVSAvoidformulation complexity

Core Design Contradiction:

ReliabilityVSDevice complexity

Solution Approach 1:

The patent employs composite material principles in the formulation, combining multiple active ingredients (GnRH antagonist and hormone replacement medicaments) with specific excipients in controlled ratios. This composite approach ensures stable oral formulation and bioequivalence while managing formulation complexity through systematic design of the composite dosage form.

Inventive Principle:

Principle #40Composite materials

Data Source

PatentUS12551447B2Combination solid oral dosage forms of gonadotropin-releasing hormone antagonists

Publication Date: 2026.02.17 SUMITOMO PHARMA CO LTD

AI summary

The present disclosure includes combination solid oral dosage forms having 40 mg of N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea, or a corresponding amount of a pharmaceutically acceptable salt thereof, and hormone replacement medicaments. Also provided are processes for making and using the solid oral dosage forms.