Solid Forms of a Catecholamine Prodrug for Sustained Plasma 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, specifically 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 avoiding rapid peak concentrations.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If L-DOPA is administered chronically to treat Parkinson's disease, then motor symptoms are controlled effectively, but dyskinesia and off fluctuations occur as complications
Solution Approach 1:
The patent applies preliminary action by developing a prodrug formulation (compound of formula I) that is converted to the active dopamine agonist in vivo. This preliminary conversion allows the active compound to be released gradually at the target site, avoiding the rapid peak concentrations that cause dyskinesia while maintaining therapeutic efficacy. The prodrug structure enables controlled transformation to the active form, thereby preventing harmful fluctuations before they occur.
Solution Approach 2:
The patent uses an intermediary approach by introducing a prodrug molecule as a mediator between the administered form and the active dopamine agonist. This intermediary compound (formula I) serves as a carrier that transports the active principle to the target site and releases it through metabolic conversion, thereby smoothing out concentration fluctuations and reducing dyskinesia while maintaining reliable therapeutic effect.
2Reliability
If apomorphine is administered as a dopamine receptor agonist, then motor relief is achieved, but oral bioavailability is low
Solution Approach 1:
The patent applies parameter changes by modifying the chemical parameters of the dopamine agonist through prodrug design. The compound of formula I has different physicochemical properties compared to apomorphine, particularly in terms of oral absorption. This parameter modification enables the compound to be orally active with improved bioavailability while maintaining the desired dopamine agonist activity and therapeutic effect.
3Ease of manufacture
If existing prodrugs are used to improve oral bioavailability, then absorption is enhanced, but rapid peak concentrations still occur causing side effects
Solution Approach 1:
The patent applies preliminary action by designing a prodrug structure that undergoes gradual in vivo conversion to the active compound. This preliminary transformation occurs through metabolic processes that release the active dopamine agonist slowly, preventing rapid peak concentrations in plasma. The prodrug formulation thus achieves both improved oral absorption and controlled release kinetics, eliminating side effects associated with sudden high concentrations.
Solution Approach 2:
The patent uses an intermediary approach where the prodrug molecule acts as a mediator that controls the release kinetics of the active compound. This intermediary structure ensures that the active dopamine agonist is released gradually after absorption, smoothing out concentration peaks while maintaining sustained therapeutic levels. The mediator thus simultaneously improves bioavailability and prevents harmful rapid concentration spikes.
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.