Catecholamine Prodrug Solid Forms for Stable Parkinson's Exposure
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Solution Overview
Problem
Current treatments for Parkinson's disease, such as L-DOPA and apomorphine, suffer from complications like dyskinesia, off fluctuations, and low oral bioavailability, necessitating the development of efficient, well-tolerated, and orally active dopamine receptor agonists with a stable pharmacokinetic profile.
Innovation Solution
The development of novel solid forms of (2S,3S,4S,5R,6S)-3,4,5-trihydroxy-6-(((4aR,10aR)-7-hydroxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-yl)oxy)tetrahydro-2H-pyran-2-carboxylic acid, particularly the dihydrate of the zwitterion and potassium salt, which act as prodrugs converting to the active compound (I) in vivo, providing stable plasma exposure and reduced side effects.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If L-DOPA is used as treatment, then motor symptoms are effectively controlled, but dyskinesia and off fluctuations occur
Solution Approach 1:
The patent introduces a prodrug compound (compound I) as an intermediary that converts to active dopamine agonist in vivo. This prodrug approach mediates between the need for effective dopamine receptor activation and the need to avoid direct administration side effects, thereby controlling motor symptoms while reducing dyskinesia and off fluctuations
Solution Approach 2:
The patent modifies the pharmacokinetic parameters of dopamine agonist delivery by using a prodrug formulation. This changes the absorption, distribution, metabolism, and excretion profile, leading to smoother plasma concentration levels that prevent peak-related dyskinesia and trough-related off fluctuations
2Reliability
If apomorphine is administered, then dopamine receptor activation is achieved, but oral bioavailability is low
Solution Approach 1:
The patent uses a prodrug compound as an intermediary delivery system that facilitates oral administration. The prodrug is designed to be orally bioavailable and then convert to the active dopamine agonist in the body, serving as a mediator between oral administration and effective receptor activation
Solution Approach 2:
The patent changes the chemical structure parameters by creating a prodrug derivative that improves oral bioavailability while maintaining the core pharmacophore necessary for dopamine receptor activation. This structural modification enables effective oral delivery
3Speed
If high peak concentrations are achieved, then rapid therapeutic effect is obtained, but side effects increase
Solution Approach 1:
The patent employs a prodrug formulation that provides periodic or sustained release of the active compound through controlled conversion in vivo. This creates a more gradual and sustained therapeutic effect rather than sharp peaks, reducing side effects while maintaining efficacy
Solution Approach 2:
The patent modifies the concentration-time profile parameters by using a prodrug that converts to active compound at a controlled rate. This changes the pharmacokinetic parameters to achieve sustained moderate concentrations rather than high peak concentrations, reducing side effects
Data Source
AI summary
The present invention relates to new solid forms of the compound (2S,3S,4S,5R,6S)-3,4,5-trihydroxy-6-(((4aR,10aR)-7-hydroxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-yl)oxy)tetrahydro-2H-pyran-2-carboxylic acid with the formula (Id) below.The compound of formula (Id) is a prodrug of a catecholamine for use in treatment of neurodegenerative diseases and disorders such as Parkinson's Disease.