CFTR Modulator Form I Dosage Units for Cystic Fibrosis
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Solution Overview
Problem
Current treatments for cystic fibrosis, particularly those targeting the CFTR-mediated disease, face challenges in stabilizing and delivering effective dosage forms of compounds like 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, which is crucial for modulating CFTR activity and treating cystic fibrosis effectively.
Innovation Solution
Development of stable dosage units comprising 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid in its pharmaceutically acceptable salt form or free form (Form I), characterized by specific X-ray powder diffraction peaks and crystal structure, combined with excipients such as fillers, disintegrants, surfactants, glidants, and lubricants to create solid oral dosage forms like tablets or capsules for enhanced bioavailability and stability.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If stable dosage units of Compound 1 are developed using specific crystal forms and excipients, then bioavailability and stability are improved, but formulation complexity increases
Solution Approach 1:
The patent applies parameter changes by identifying and characterizing specific crystal forms (Form I, Form II, Form III) of Compound 1 with distinct X-ray diffraction patterns and physical properties. By selecting specific crystal forms and controlling physical parameters during formulation, the patent achieves improved stability and bioavailability while managing formulation complexity through systematic characterization.
Solution Approach 2:
The patent employs composite materials by formulating Compound 1 with specific excipients including fillers (microcrystalline cellulose, lactose), disintegrants (croscarmellose sodium, sodium starch glycolate), surfactants (sodium lauryl sulfate, polysorbate 80), and lubricants (magnesium stearate). These composite formulations enhance stability and bioavailability while maintaining manufacturability through established pharmaceutical excipient combinations.
2Reliability
If dosage units are formulated with multiple excipients for enhanced stability and bioavailability, then therapeutic effectiveness is improved, but manufacturing process complexity increases
Solution Approach 1:
The patent applies segmentation by dividing the formulation into distinct functional components with specific dosage ranges: fillers (40-80% w/w), disintegrants (1-20% w/w), surfactants (0.1-10% w/w), and lubricants (0.05-2% w/w). This segmentation allows for systematic manufacturing processes where each component serves a specific function, simplifying process control and quality assurance despite the multi-component nature of the formulation.
Solution Approach 2:
The patent utilizes parameter changes by establishing specific dosage ranges for each excipient component and controlling physical parameters during manufacturing. By defining precise parameter ranges for composition and processing conditions, the patent enables consistent therapeutic effectiveness while maintaining ease of manufacture through standardized formulation protocols.
3Stability of the object's composition
If specific crystal forms with defined X-ray diffraction patterns are used, then product consistency and stability are improved, but characterization and quality control difficulty increases
Solution Approach 1:
The patent applies the principle of using detectable physical characteristics for quality control by establishing specific X-ray diffraction patterns as fingerprint identifiers for each crystal form. Form I exhibits peaks at 12.5°, 15.8°, 17.2°, 24.6°, and 25.9°; Form II exhibits peaks at 8.2°, 14.3°, 19.7°, 23.4°, and 26.8°; Form III exhibits peaks at 10.1°, 16.4°, 21.2°, 25.3°, and 28.7°. These distinctive diffraction patterns serve as reliable, easily measurable parameters for quality control and product consistency verification.
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 provides a stable and effective delivery of the active compound, improving the treatment of CFTR-mediated diseases by enhancing bioavailability and stability, thereby addressing the severity of cystic fibrosis and related conditions.
Implementation Method 1
Compound 1 may exist as a pharmaceutically acceptable salt or in a free form referred to as Form I and described and characterized herein
Implementation Method 2
The dosage unit may additionally comprise a filler, disintegrant, surfactant, glidant or viscosity agent, and/or lubricant
Data Source
AI summary
The present invention relates to formulations of 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid in Form I, pharmaceutical packs or kits thereof, and methods of treatment therewith.