TQS-168 Solid Dosage Forms for Therapeutic Brain Exposure
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Solution Overview
Problem
The 2-arylbenzimidazole compound TQS-168, known for its therapeutic effects in neurodegenerative diseases, has low solubility and lacks pharmacokinetic data on plasma and brain concentrations for effective oral dosing in humans.
Innovation Solution
Oral administration of TQS-168 or its pharmaceutically acceptable salts at specific concentrations and formulations to achieve plasma and brain concentrations within the range of 0.3 μM to 20 μM, targeting neuroinflammation and neurodegenerative diseases, with formulations including liquid suspensions and solid forms like crystalline, amorphous, spray-dried dispersion, and hot melt extrusion.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of operation
If TQS-168 is administered as an oral suspension, then the compound can be delivered to experimental animals, but plasma and brain concentrations are not achieved and pharmacokinetic information is not obtained
Solution Approach 1:
The patent applies parameter changes by transitioning from oral suspension to multiple solid dosage forms (crystalline, amorphous, spray-dried dispersion, hot melt extrusion) with different physical and chemical parameters. This enables achieving therapeutic plasma concentrations (0.3-20 μM) and proper pharmacokinetic profiles while maintaining ease of oral administration.
Solution Approach 2:
The patent employs composite materials by formulating TQS-168 with various excipients and using multiple formulation approaches (spray-dried dispersion, hot melt extrusion) to create complex dosage forms that improve solubility and bioavailability while maintaining oral administrability.
2Reliability
If TQS-168 is administered at high doses to achieve therapeutic concentrations, then neuroinflammation suppression is achieved, but the compound's low solubility limits effective dosing
Solution Approach 1:
The patent changes the physical state and dissolution parameters of TQS-168 by developing amorphous and spray-dried dispersion formulations. These formulations have enhanced solubility and dissolution rates compared to crystalline forms, enabling achievement of therapeutic plasma concentrations (0.3-20 μM) without requiring excessively high doses.
Solution Approach 2:
The patent utilizes phase transitions by converting TQS-168 from crystalline to amorphous state and creating spray-dried dispersions. These phase changes improve the compound's apparent solubility and bioavailability, allowing effective dosing despite the compound's inherently low solubility.
3Reliability
If multiple formulation types are developed to improve solubility, then pharmacokinetic performance is enhanced, but formulation complexity increases
Solution Approach 1:
The patent applies segmentation by dividing the formulation development into distinct approaches (crystalline, amorphous, spray-dried dispersion, hot melt extrusion), each with its own manufacturing process and excipient requirements. This allows selection of the most appropriate formulation type based on specific product requirements while maintaining clear development pathways.
Data Source
AI summary
Methods are provided for reducing neuroinflammation and/or treating a neurodegenerative disease in a subject. The methods comprise orally administering to a subject with neuroinflammation and/or a neurogenerative disease a pharmaceutical composition comprising the compound of formula (I)(TQS-168), or a pharmaceutically acceptable salt thereof, in amount that provides defined plasma and brain exposures of TQS-168 and/or an active metabolite following administration.