GnRH Antagonist Melt-Processed Solid Formulations for High Drug Loading
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Solution Overview
Problem
There is a need for new orally administered treatments for endometriosis, uterine fibroids, polycystic ovary syndrome (PCOS), and adenomyosis, particularly for managing pain and heavy menstrual bleeding associated with these conditions, and there is a challenge in developing orally bioavailable dosage forms with high drug loads that maintain compressibility and patient compliance.
Innovation Solution
The development of solid pharmaceutical compositions comprising Compound A or its pharmaceutically acceptable salts, utilizing melt-processing techniques to achieve high drug loads with less than 10% meltable binder, allowing for amorphous sodium 4-((R)-2-[5-(2-fluoro-3-methoxy-phenyl)-3-(2-fluoro-6-trifluoromethyl-benzyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl]-1-phenyl-ethylamino) butanoate to be miscible with polyethylene glycol, resulting in single-phase or multi-phase systems with improved compressibility and flow properties.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Quantity of substance
If conventional melt-processing is used with at least 10% binder, then the composition can be manufactured with standard processing, but the drug load is limited and the dosage form size increases
Solution Approach 1:
The patent changes the binder content parameter from conventional levels (≥10%) to reduced levels (<10%), and modifies the processing parameters (temperature, mixing time) to achieve homogeneous distribution of Compound A at high concentrations without compromising manufacturability
Solution Approach 2:
The patent creates a composite formulation system combining Compound A with specific excipients (binders, fillers, lubricants) in optimized ratios, where the composite properties enable both high drug load and adequate compressibility for tablet formation
2Quantity of substance
If high drug load compositions are developed, then the therapeutic efficacy is improved, but the compressibility and patient compliance may deteriorate
Solution Approach 1:
The patent optimizes physical parameters including particle size distribution, bulk density, and flow properties of the high drug load composition to maintain compressibility and produce patient-compliant dosage forms (appropriate size, weight, and disintegration characteristics)
Solution Approach 2:
The patent uses composite material design with multiple excipients serving different functions: binders for compression, fillers for volume, lubricants for ejection, creating a balanced formulation that maintains manufacturability and patient compliance despite high API content
3Volume of moving object
If the binder content is reduced to increase drug load, then the dosage form size is reduced, but the compressibility and structural integrity may worsen
Solution Approach 1:
The patent carefully controls the binder content parameter within the <10% range and adjusts other formulation parameters (excipient types, particle size, moisture content) to compensate for reduced binder, maintaining adequate compressibility and structural integrity
Solution Approach 2:
The patent employs composite formulations where alternative excipients provide binding and structural functions, creating a multi-component system that achieves both reduced dosage form size and maintained compressibility through synergistic interactions among components
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 compositions provide high drug loads in a suitable dosage form, maintaining compressibility and patient compliance, with rapid dissolution and effective suppression of hormones, addressing the therapeutic needs for endometriosis, uterine fibroids, PCOS, and adenomyosis.
Implementation Method 1
conventional melt-processing utilizes compositions comprising at least 10% (w/w) of a binder
Implementation Method 2
amorphous sodium 4-((R)-2-[5-(2-fluoro-3-methoxy-phenyl)-3-(2-fluoro-6-trifluoromethyl-benzyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl]-1-phenyl-ethylamino) butanoate miscible with polyethylene glycol
Data Source
AI summary
The present disclosure relates to pharmaceutical compositions comprising a gonadotropin-releasing hormone (GnRH) antagonist and methods of preparing and using such compositions. The disclosure also relates to methods of facilitating release of a GnRH antagonist from a pharmaceutical composition.