Capsule Inhaler Formulation Without Ternary Agents for PDE4 Delivery
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Solution Overview
Problem
Existing PDE4 inhibitor formulations for respiratory diseases, such as tanimilast, face challenges due to systemic side effects and the regulatory burden of using ternary agents, which are necessary for achieving optimal inhalatory performance.
Innovation Solution
A single-dose dry powder inhalation device and composition using micronized particles of formula (I) with a specific carrier mixture of coarse and fine lactose particles, without ternary agents, optimized for inspiratory flow rates between 30 l/min and 65 l/min, ensuring similar inhalatory performance to reference products.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If ternary agents are used in the composition, then inhalatory performance is improved, but regulatory burden increases
Solution Approach 1:
The invention extracts and removes the ternary agent (magnesium stearate) from the composition while maintaining the essential binary components (coarse lactose and fine lactose). This extraction eliminates the regulatory burden associated with ternary agents while preserving the core inhalatory performance through optimized binary carrier ratios and particle size distributions.
Solution Approach 2:
The invention changes the parameters of the carrier particles by specifying precise size ranges for coarse lactose (200-500 μm) and fine lactose (with dv(0.1) 1-5 μm, dv(0.5) 18-30 μm, dv(0.9) 65-95 μm), and optimizing their ratio (70:30 to 95:5). These parameter changes enable the binary mixture to achieve the same inhalatory performance previously requiring ternary agents.
2Reliability
If PDE4 inhibitors are administered systemically, then therapeutic effect is achieved, but systemic side effects occur
Solution Approach 1:
The invention uses an inhalation device as an intermediary delivery system that transports the PDE4 inhibitor directly to the respiratory tract. The micronized particles (0.1-15 μm) act as carriers that facilitate direct deposition in the lungs, bypassing systemic circulation and achieving localized therapeutic effect while minimizing systemic side effects.
3Reliability
If micronized particles are used, then respirable fraction is improved, but manufacturing complexity increases
Solution Approach 1:
The invention segments the carrier particles into distinct size categories (coarse lactose 200-500 μm and fine lactose with specific dv values) with clear size boundaries. This segmentation approach simplifies manufacturing by providing well-defined particle size ranges that can be achieved through standard micronization and classification techniques, while ensuring optimal respirable fraction.
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 new formulation achieves comparable respirable fractions and extrafine particle delivery to existing products, reducing systemic absorption and regulatory hurdles while maintaining bioequivalence, as demonstrated by in vitro and IVIVC models.
Implementation Method 1
a pharmaceutical composition to be inhaled... micronized particles having a size comprised between 0.1 and 15 micron of the compound of formula (I)
Implementation Method 2
a carrier consisting of a mixture of coarse and fine particles of pharmaceutically inert acceptable excipient, wherein the coarse particles having an equivalent volume diameter comprised between 200 and 500 micron, while the fine particles having the dv(0.1) comprised between 1 and 5 μm
Data Source
AI summary
The present invention relates to a drug product comprising a single-dose dry powder inhalation device and a pharmaceutical composition filled in a capsule, the pharmaceutical composition comprising micronized particles of the compound of formula (I) and a carrier. The present invention also relates to a drug product or a pharmaceutical composition for use for the treatment of a respiratory disease and to a method for the treatment of a respiratory disease.