Transmucosal Formulations to Minimize Hepatic First-Pass Metabolism
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Existing formulations of ITI-007 and its deuterated variants suffer from high first-pass metabolism in the liver, necessitating higher oral doses and increased liver burden, manufacturing challenges, and patient-to-patient variability in dose response, which traditional routes like parenteral and oral dosing fail to address effectively.
Innovation Solution
Development of novel transmucosal and subcutaneous pharmaceutical formulations, including oral, nasal, and vaginal delivery systems in liquid, solid, and aerosol forms, such as sublingual tablets, films, sprays, and gels, to minimize first-pass metabolism and optimize drug absorption.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of operation
If oral dosing is used for ITI-007, then the drug can be administered easily by patients, but high first-pass metabolism occurs resulting in higher dosing requirements and increased liver burden
Solution Approach 1:
The patent introduces transmucosal delivery systems (sublingual, buccal, intranasal) as intermediary routes that bypass the hepatic first-pass metabolism. These delivery systems utilize the rich vascular network of the mucosal membranes to transport the drug directly into the systemic circulation, thereby reducing first-pass metabolism while maintaining ease of patient self-administration.
Solution Approach 2:
The patent transitions from oral administration (gastrointestinal tract) to transmucosal administration (oral cavity, nasal cavity, buccal cavity). This dimensional change in the delivery route allows the drug to enter the bloodstream through highly vascularized mucosal surfaces rather than undergoing hepatic metabolism, thus resolving the contradiction between ease of administration and first-pass metabolism.
2Device complexity
If oral dosing is used for ITI-007, then the formulation can be simple, but patient-to-patient variability in dose response increases
Solution Approach 1:
The transmucosal delivery system acts as a controlled intermediary that provides more consistent and predictable drug absorption compared to oral dosing. The mucosal membranes provide a controlled interface for drug absorption that reduces variability between patients, while the formulation itself remains relatively simple (tablets, films, sprays, gels).
3Loss of energy
If parenteral dosing is used to avoid first-pass metabolism, then drug absorption is effective, but administration requires trained professionals and clinical environment
Solution Approach 1:
The patent employs transmucosal membranes as an intermediary delivery interface that combines the advantages of parenteral dosing (bypassing first-pass metabolism) with the advantages of oral dosing (patient self-administration). The mucosal membranes provide a accessible, non-invasive route that patients can use independently without requiring trained professionals or clinical settings.
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
These formulations enable rapid drug absorption with minimal first-pass metabolism, reducing dosing requirements and liver burden, and providing consistent patient responses.
Implementation Method 1
These formulations enable rapid drug absorption with minimal first-pass metabolism
Implementation Method 2
Subcutaneous delivery similarly provides highly effective drug absorption with minimal first-pass metabolism, while also providing the potential for delayed or extended release
Data Source
AI summary
The disclosure provides new transmucosal and subcutaneous pharmaceutical compositions comprising 1-(4-fluoro-phenyl)-4-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H,7H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxalin-8-yl)-butan-1-one or 1-(4-fluoro-phenyl)-4-((6bR,10aS)-2,2-d2-3-methyl-2,3,6b,9,10,10a-hexahydro-1H,7H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxalin-8-yl)-butan-1-one or comprising-(4-fluoro-phenyl)-4-((6bR,10aS)-1,1,2,2-d4-3-methyl-2,3,6b,9,10,10a-hexahydro-1H,7H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxalin-8-yl)-butan-1-one, in free base, co-crystal or salt form, together with methods of making and using them.