Thromboxane Antagonist Drug-in-Capsule Formulations for Bioavailability
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Solution Overview
Problem
Existing formulations of thromboxane receptor antagonists face challenges in achieving oral bioavailability, stability, and efficient release of active ingredients, particularly for conditions like pulmonary arterial hypertension and interstitial lung diseases, due to issues such as crystallization and poor compatibility with excipients.
Innovation Solution
Formulations of substituted biphenyl benzenesulfonyl urea compounds in amorphous solid dispersion (ASD) with copovidone, mannitol, crospovidone, and magnesium stearate, encapsulated in capsules, ensuring controlled release and stability, suitable for industrial processes.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If the active ingredient is formulated in conventional crystalline form, then manufacturing is simpler, but oral bioavailability and absorption are poor
Solution Approach 1:
The patent transforms the active ingredient from crystalline form to amorphous form, fundamentally changing its physical state and dissolution properties. This parameter change enables significantly improved oral bioavailability and absorption while maintaining formulation stability through the use of amorphous solid dispersion technology with copovidone as a carrier polymer.
Solution Approach 2:
The patent creates a composite material system consisting of the active ingredient dispersed within copovidone polymer matrix. This composite amorphous solid dispersion combines the therapeutic benefits of the active ingredient with the stabilizing and solubility-enhancing properties of the polymer carrier, resolving the contradiction between improved bioavailability and formulation complexity.
2Reliability
If the active ingredient is formulated to release rapidly, then absorption is improved, but stability and controlled release are compromised
Solution Approach 1:
By changing the physical state of the active ingredient to amorphous form within the copovidone matrix, the formulation achieves rapid dissolution and absorption upon contact with gastrointestinal fluids, while the amorphous solid dispersion structure itself provides long-term stability during storage, preventing premature release or degradation.
Solution Approach 2:
The copovidone polymer acts as an intermediary carrier that stabilizes the amorphous active ingredient during storage and transport, then facilitates rapid release and absorption when the formulation encounters gastrointestinal conditions. This mediator resolves the contradiction between stability and rapid absorption.
3Ease of manufacture
If excipients are added to improve formulation properties, then manufacturing and delivery are enhanced, but compatibility issues and adverse effects may arise
Solution Approach 1:
The patent uses a minimal excipient approach with copovidone as the primary carrier, eliminating the need for multiple traditional excipients. This parameter change in formulation composition reduces the risk of excipient-drug interactions and adverse events while maintaining ease of manufacture through the robust amorphous solid dispersion process.
Solution Approach 2:
The patent extracts and eliminates unnecessary excipients from the formulation, using only copovidone as the essential carrier polymer. This reduction in formulation complexity minimizes potential compatibility issues and adverse events associated with multiple excipients, while still achieving excellent manufacturing properties.
4Reliability
If the formulation is optimized for bioavailability, then therapeutic effect is improved, but manufacturing scalability and industrial process compatibility are reduced
Solution Approach 1:
The amorphous solid dispersion formulation uses parameter changes in the physical state of the active ingredient and the polymer-carrier ratio to achieve high bioavailability. These same parameters are optimized to ensure the formulation can be manufactured at scale using conventional pharmaceutical processing equipment and techniques, enabling industrial scalability.
Solution Approach 2:
The composite amorphous solid dispersion structure combines the high bioavailability benefits of amorphous formulation with the manufacturing robustness of solid dispersion technology. This composite approach enables both optimized therapeutic delivery and scalable industrial manufacturing processes.
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 provide rapid and controlled absorption of the active ingredients, maintaining stability and bioavailability, suitable for large-scale manufacturing and safe oral administration, with no adverse events, and effective target engagement.
Implementation Method 1
an amorphous solid dispersion (ASD) comprising an active ingredient and copovidone
Implementation Method 2
The active ingredient may be present in an amorphous solid dispersion (ASD) with copovidone
Implementation Method 3
compositions of the invention are contained in a capsule
Data Source
AI summary
The invention provides formulations of certain substituted biphenyl benzenesulfonyl urea compounds, as thromboxane receptor antagonists, in capsules that provide for oral delivery of those drugs with good bioavailability. In particular, compositions of the invention provide certain substituted biphenyl benzenesulfonyl urea compounds (such as N-(tert-butylcarbamoyl)-5-cyano-2-((4′-(trifluoromethoxy)-[1,1′-biphenyl]-3-yl)oxy)benzenesulfonamide) as an active ingredient in an amorphous solid dispersion (ASD) with copovidone. The ASD with a filler, disintegrant and lubricant make up an intragranular blend that, along with an extragranular disintegrant/lubricant blend are encapsulated, making a drug-in-capsule (DiC) formulation.