Solid Pharmaceutical Formulations with High Drug Load and Compressibility
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Solution Overview
Problem
There is a need for new orally administered treatments for endometriosis, uterine fibroids, and polycystic ovary syndrome (PCOS), particularly for managing pain and heavy menstrual bleeding associated with these conditions, and there is a challenge in developing high drug load pharmaceutical compositions that maintain sufficient compressibility for effective dosage forms.
Innovation Solution
The development of solid pharmaceutical compositions comprising Compound A or its pharmaceutically acceptable salt, utilizing melt-processing techniques with a miscible binder like polyethylene glycol, allowing for high drug load formulations with reduced polymer usage and maintaining compressibility, enabling the creation of suitable dosage forms such as tablets with improved flow properties.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Quantity of substance
If conventional melt-processing is used with at least 10% (w/w) binder, then the composition can be manufactured with sufficient compressibility, but the drug load is limited and the amount of API that can be included is reduced
Solution Approach 1:
The patent reduces the binder content from the conventional minimum of 10% (w/w) to less than 10% (w/w), specifically achieving high drug load formulations with 5-8% (w/w) binder. This parameter change in binder concentration enables increased API content while maintaining sufficient compressibility for tablet formation through the melt-processing method
Solution Approach 2:
The patent creates a composite formulation system combining API, meltable binder, and optional excipients in a specific composition ratio. This composite approach allows the formulation to achieve both high drug load and adequate compressibility by optimizing the interaction between components in the melt-processed solid dispersion
2Quantity of substance
If high drug load compositions are developed with less than 10% (w/w) binder, then the API content is increased, but the compressibility and suitability for dosage form production becomes challenging
Solution Approach 1:
The patent optimizes the binder content parameter to a specific range of 5-8% (w/w), which is less than the conventional 10% minimum but sufficient to maintain compressibility. This precise parameter control enables high API content (greater than 90% of total formulation weight) while ensuring the formulation remains manufacturable as a dosage form
Solution Approach 2:
The patent uses melt-processing to create a solid dispersion that replicates the functional properties of conventional formulations with higher binder content. The melt-processed solid dispersion copies the compressibility and flow properties needed for tablet formation, but achieves this with reduced binder content through the amorphous solid state structure
3Productivity
If melt-processing is used to achieve high drug load, then the formulation efficiency is improved, but the process requires precise control of miscibility between API and binder
Solution Approach 1:
The patent uses a meltable binder as an intermediary substance that facilitates the melt-processing of API. The binder's ability to melt and mix with API at elevated temperatures, then solidify upon cooling, enables the high drug load formulation process. Examples include PEG 3350, PEG 4000, and PEG 6000 as intermediary materials that control the miscibility and phase behavior during processing
Solution Approach 2:
The patent exploits phase transitions of the meltable binder during the melt-processing procedure. The binder transitions from solid to liquid state during mixing with API, enables homogeneous distribution, then transitions back to solid state upon cooling to form the final dosage form. This phase change mechanism simplifies the processing of high drug load formulations while maintaining control over miscibility
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 achieve a high drug load while ensuring compressibility, facilitating the production of effective tablets with enhanced bioavailability and patient compliance, addressing the limitations of existing treatments in managing pain and heavy menstrual bleeding.
Implementation Method 1
Compound A or a pharmaceutically acceptable salt thereof and, in particular, 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 is miscible with a pharmaceutically acceptable meltable binder, such as polyethylene glycol (PEG)
Implementation Method 2
conventional melt-processing utilizes compositions comprising at least 10% (w/w) of a binder
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.