CFTR Modulator Mini-Tablet Composition for Accurate Pediatric Dosing
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Solution Overview
Problem
Existing pharmaceutical compositions for treating cystic fibrosis, particularly in pediatric patients, face challenges with swallowing difficulties, dosing inaccuracies, and absorption issues due to the use of crushed tablets and powders, leading to therapeutic failures and dosage errors.
Innovation Solution
Development of stable, bioavailable pharmaceutical compositions in the form of mini-tablets, granules, and other solid dosage forms containing CFTR modulators, such as Compound I, II, and III, with excipients like fillers, sweeteners, disintegrants, and lubricants, which can be administered in unit doses within capsules, sachets, or sprinkled into food or liquids, ensuring accurate and flexible dosing.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Adaptability or versatility
If crushed tablets or powders are used for pediatric patients, then dosing flexibility is improved, but dosing accuracy deteriorates due to incomplete absorption and dosage errors
Solution Approach 1:
The patent divides the pharmaceutical composition into multiple granules within a single capsule, where each granule contains a precise amount of active ingredient. This segmentation allows the entire capsule to be crushed and mixed with food for pediatric patients (maintaining flexibility) while each granule ensures precise dosing (improving accuracy) because the granules can be individually counted and verified before administration.
Solution Approach 2:
The patent introduces an intermediary formulation approach where the medication is provided as encapsulated granules that serve as a middle ground between whole tablets and loose powders. The granules can be crushed like powders for mixing with food, but their structured formulation within the capsule ensures precise dosing, acting as an intermediary solution that combines the benefits of both approaches while eliminating their drawbacks.
2Measurement precision
If whole tablets are used for pediatric patients, then dosing accuracy is improved, but ease of administration deteriorates due to swallowing difficulties
Solution Approach 1:
The patent segments the tablet formulation into smaller granules that can be easily crushed and mixed with food or liquid for pediatric patients. This segmentation maintains dosing accuracy because the granules are formulated to contain precise amounts of active ingredient, while simultaneously improving ease of administration as the granules can be conveniently mixed into small amounts of food without requiring the child to swallow a whole tablet.
Solution Approach 2:
The patent changes the physical parameter of the dosage form from whole tablets to crushable granules within capsules. This parameter change allows the medication to be administered in a form that pediatric patients can easily consume (mixed with food) while maintaining the precise dosing characteristics of tablet formulations through controlled granule composition and sizing.
3Ease of operation
If powders are used for pediatric patients, then ease of administration is improved, but reliability deteriorates due to incomplete absorption and therapeutic failure
Solution Approach 1:
The patent introduces encapsulated granules as an intermediary formulation between loose powders and whole tablets. The granules maintain the ease of administration of powders by being crushable and mixable with food, while their structured formulation within the capsule ensures reliable drug delivery and complete absorption, thereby improving therapeutic efficacy and reliability compared to loose powder formulations.
Solution Approach 2:
The patent changes the physical and structural parameters of the powder formulation by enclosing granules within capsules. This parameter change improves reliability by ensuring that the active ingredient is delivered in a controlled, stable format that promotes complete absorption, while still allowing the granules to be crushed and mixed with food for easy administration to pediatric patients.
Data Source
AI summary
The present invention relates to pharmaceutical compositions containing N-(1,3-dimethylpyrazol-4-yl)sulfonyl-6-[3-(3,3, 3-trifluoro-2,2-dimethyl-propoxy)pyrazol-1-yl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide, a solid dispersion of (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-7V-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-en indol-5-yl)cyclopropanecarboxamide, and a solid dispersion of N-[2,4-Bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxo-quinoline-3-carboxamide, including formulations of the solid dispersions into powders, granules and mini-tablets, methods for manufacturing and processing the powders, granules and mini-tablets, and methods for treating cystic fibrosis employing the pharmaceutical compositions.