Micronized MTP and Apo-B Inhibitor Compositions for Stable Dispersion
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Solution Overview
Problem
Compounds represented by Formula 1 exhibit low solubility and permeability, and a tendency to cluster and aggregate, necessitating additional processing to achieve optimal efficacy and safety in pharmaceutical formulations.
Innovation Solution
The development of micronized particles comprising compounds of Formula 1, characterized by a volume particle fraction of less than 30 μm, preferably less than 10 μm, with at least 50% of particles under 5 μm, to enhance therapeutic effect and safety.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If compounds of Formula 1 are synthesized in bulk, then production efficiency is improved, but particle size becomes uncontrolled and physicochemical properties deteriorate
Solution Approach 1:
The bulk synthesized compound is segmented into microparticles with controlled size distribution (50% or more by volume having a volume particle fraction of less than 30 μm). This segmentation transforms the uncontrolled bulk material into discrete, size-controlled particles that maintain therapeutic efficacy while improving physicochemical properties.
Solution Approach 2:
The particle size parameter is changed and controlled to resolve the contradiction. By specifying that at least 50% of particles have a volume particle fraction less than 30 μm (preferably less than 10 μm, more preferably less than 5 μm), the invention achieves both productive bulk synthesis and controlled particle characteristics for optimal therapeutic effect.
2Device complexity
If compounds of Formula 1 are used without additional processing, then manufacturing complexity is reduced, but therapeutic efficacy and safety are suboptimal
Solution Approach 1:
The micronization process is performed as a preliminary action during manufacturing to prepare the compound in its optimal physical form before final formulation. This preliminary particle size control ensures that the compound exhibits improved solubility, reduced aggregation, and enhanced therapeutic efficacy without requiring complex post-processing steps.
3Reliability
If particle size is reduced to improve dispersion and solubility, then therapeutic efficacy is improved, but manufacturing precision requirements increase
Solution Approach 1:
Rather than requiring complete micronization of all particles, the invention applies partial action by specifying that at least 50% of the particle volume should have a fraction less than 30 μm. This partial requirement achieves sufficient dispersion and solubility improvement for therapeutic efficacy while being more manufacturable than requiring 100% of particles to meet the size criterion.
Data Source
AI summary
The present invention relates to pharmaceutical composition(s) comprising particles comprising one or more compounds which are inhibitors of microsomal triglyceride transfer protein and/or apolipoprotein B (Apo B) secretion, wherein at least 50% of the particles are characterized by a volume particle fraction less than 10 μm, more preferably less than 5 μm, more preferably less than 2.5 μm. The pharmaceutical composition can be useful for the prevention and treatment of various diseases, particularly atherosclerosis and its clinical sequelae, for lowering serum lipids, and related ailments. The invention further relates to methods of treating diseases, such as hypertriglyceridemia, hyperchylomicronemia, atherosclerosis, obesity, and related conditions using the compounds. A method for decreasing apolipoprotein B (apo B) secretion is also provided.