CFTR Modulator Granules for Stable, Accurate Pediatric Dosing
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Solution Overview
Problem
Existing pharmaceutical formulations for treating cystic fibrosis in pediatric patients face challenges such as difficulty in swallowing, dosing inaccuracies, manufacturing reproducibility, dispersibility, palatability, physical and chemical stability, and bioavailability, particularly for CFTR modulators like vanzacaftor, tezacaftor, and deutivacaftor.
Innovation Solution
Development of pharmaceutical granule compositions comprising vanzacaftor, tezacaftor, and deutivacaftor, formulated with excipients like fillers, sweeteners, disintegrants, and lubricants, which are stable, bioavailable, and easily dispersible, allowing accurate dosing and administration in small amounts, even for children under 5 years old.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Measurement precision
If pharmaceutical formulations are developed for pediatric patients, then dosing accuracy and ease of administration are improved, but manufacturing complexity and formulation stability are worsened
Solution Approach 1:
The pharmaceutical formulation is divided into multiple granule sizes (small granules 0.5-2mm and large granules 2-5mm) that can be separately manufactured and combined. This segmentation allows each granule size to be optimized for specific dosing requirements while maintaining manufacturing control, thereby improving dosing accuracy without overwhelming formulation complexity
Solution Approach 2:
The formulation uses different excipient compositions and ratios for small versus large granules. Small granules contain higher proportions of binders and moisture for cohesion, while large granules use more fillers and lubricants for flow and handling. This parameter differentiation enables precise dosing control across different granule sizes while managing formulation complexity through systematic variation
2Quantity of substance
If low doses of CFTR modulators are administered to pediatric patients, then dosing accuracy is improved, but manufacturing reproducibility and dosing precision are worsened
Solution Approach 1:
Low doses are achieved by dividing the total dose across multiple small granules rather than using a single large granule. For example, a 2.5mg dose can be delivered through 5 granules of 0.5mg each, which improves manufacturing reproducibility by allowing each granule to be formed with tighter tolerances while maintaining overall dosing precision
Solution Approach 2:
The formulation adjusts granule weight, number of granules per dose, and excipient ratios to optimize low-dose delivery. By controlling granule size distribution and using high-potency CFTR modulator concentrations combined with appropriate diluents, the formulation achieves accurate low dosing while maintaining manufacturing reproducibility through scalable granulation processes
3Ease of operation
If granule formulations are designed for easy dispersibility, then ease of administration is improved, but physical stability and chemical stability are worsened
Solution Approach 1:
The granule formulation uses localized hydrophilic excipients (such as croscarmellose sodium and sodium starch glycolate) at specific regions of the granule structure to enhance dispersibility, while the core maintains hydrophobic matrix formers (such as microcrystalline cellulose and pregelatinized starch) to preserve physical and chemical stability. This spatial differentiation of excipient properties allows simultaneous optimization of both dispersibility and stability
4Ease of operation
If sweeteners and flavorings are added to improve palatability, then ease of administration is improved, but chemical stability and physical stability are worsened
Solution Approach 1:
Sweeteners and flavorings are encapsulated within the granule matrix or coated on the granule surface rather than being mixed directly with the CFTR modulator. This intermediary positioning protects the sensitive active ingredient from degradation by sweeteners while still providing palatability benefits, thereby maintaining both chemical stability and physical stability of the formulation
Solution Approach 2:
The formulation uses specific ratios of humectants (such as sorbitol and xylitol) to sweeteners and flavorings to control moisture content and prevent degradation. By optimizing these parameter ratios and using stable excipient combinations, the formulation achieves improved palatability while maintaining chemical and physical stability through controlled ingredient interactions
Data Source
AI summary
The present invention relates to pharmaceutical compositions formulated into a plurality of granules containing calcium bis((14S)-8-[3-(2-{dispiro[2.0.24.13]heptan-7-yl}ethoxy)pyrazol-1-yl]-12,12-dimethyl-2,2,4-trioxo-2λ6-thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracosa-1(23),5,7,9,19,21-hexaen-3-ide), a solid dispersion of (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide, and a solid dispersion of N-(2-(tert-butyl)-5-hydroxy-4-(2-(methyl-d3)propan-2-yl-1,1,1,3,3,3-d6)phenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide, methods for manufacturing and processing the granules, and methods for treating cystic fibrosis employing the pharmaceutical compositions.