Phenolic Hydroxyl Dimerization for Localized GI Action

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Solution Overview

Problem

Current treatments for diarrhea-predominant irritable bowel syndrome (IBS-D) fail to effectively decrease intestinal motility, are associated with pancreatitis risk, and do not address underlying hypersensitivity and hyperalgesia, while pharmaceutical agents with phenolic hydroxyl groups face issues with photo instability, rapid metabolism, and central nervous system absorption leading to adverse effects.

Innovation Solution

Dimerization of pharmaceutical agents through their phenolic hydroxyl groups using an ethylene linker, creating stable homo-dimers that resist presystemic metabolism, avoid central nervous system absorption, and maintain receptor pharmacology, thereby addressing IBS-D symptoms without pancreatitis risk.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If phenolic hydroxyl groups are used in pharmaceutical agents, then receptor pharmacology is achieved, but photo instability and rapid presystemic metabolism occur

Engineering Contradiction:

Improvereceptor pharmacologyVSAvoidphoto instability

Core Design Contradiction:

ReliabilityVSStability of the object's composition

Solution Approach 1:

Two phenolic compound molecules are merged through covalent bonding of their phenolic hydroxyl groups to form a dimer. This merging preserves the pharmacologically active phenolic structure while eliminating the instability and metabolism issues of individual phenolic groups, as the bonded phenolics are no longer available for rapid presystemic metabolism.

Inventive Principle:

Principle #5Merging (Combining)

Solution Approach 2:

The patent creates a composite molecular structure where two phenolic units are combined through a linker group. This composite dimer structure integrates the beneficial pharmacological properties of phenolic compounds while mitigating their detrimental photo-instability and metabolic susceptibility through the protective effect of covalent bonding.

Inventive Principle:

Principle #40Composite materials

2Reliability

If phenolic hydroxyl groups are used in pharmaceutical agents, then receptor pharmacology is achieved, but rapid presystemic metabolism occurs

Engineering Contradiction:

Improvereceptor pharmacologyVSAvoidpresystemic metabolism rate

Core Design Contradiction:

ReliabilityVSDuration of action of moving object

Solution Approach 1:

Inventive Principle:

Principle #5Merging (Combining)

Solution Approach 2:

The patent fundamentally changes the chemical state of the phenolic hydroxyl groups from free/reactive to covalently bonded/inactive. By transforming the phenolic groups into bonded linkages, the molecule's susceptibility to presystemic metabolism is dramatically reduced, extending the drug's duration of action and bioavailability.

Inventive Principle:

Principle #35Parameter changes

3Reliability

If phenolic hydroxyl groups are used in pharmaceutical agents, then receptor pharmacology is achieved, but central nervous system absorption occurs leading to adverse effects

Engineering Contradiction:

Improvereceptor pharmacologyVSAvoidcentral nervous system absorption

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent creates a molecule with differentiated properties: the dimer structure provides localized action in the gastrointestinal tract while preventing systemic absorption. The covalently bonded phenolic groups create a molecule that is too large and polar to cross the blood-brain barrier, thus achieving local therapeutic effect without central nervous system adverse effects.

Inventive Principle:

Principle #3Local quality

Solution Approach 2:

The patent segments the pharmacological action from systemic absorption by creating a dimer structure that remains in the gastrointestinal lumen. The segmented dimer molecules exert their effect locally on gastrointestinal receptors without entering the bloodstream and crossing into the central nervous system, separating therapeutic action from harmful systemic effects.

Inventive Principle:

Principle #1Segmentation

4Quantity of substance

If monomeric phenolic compounds are used, then bioavailability is reduced due to metabolism, but dimerization increases molecular size

Engineering Contradiction:

ImprovebioavailabilityVSAvoidmolecular size

Core Design Contradiction:

Quantity of substanceVSLength of moving object

Solution Approach 1:

Inventive Principle:

Principle #35Parameter changes

Data Source

PatentEP3137080B1Pharmaceutically active dimers linked through phenolic hydroxyl groups

Publication Date: 2019.09.04 ORPHOMED INC

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AI summary

Pharmaceutically active homo-dimers of opioid and other pharmaceutically active agents characterized by a single phenolic hydroxyl group wherein the respective monomers are ether-linked through such groups by an ethylene residue. The dimers share the receptor pharmacology of the corresponding monomer, in particular cases are non-absorbed, and the ether link of the dimers is particularly resistant to metabolism when administered to a subject, all conferring divers advantages relative to the corresponding monomers. Exemplary of the dimers are those of buprenorphine, naloxone, naltrexone, des-venlafaxine, albuterol and acetaminophen.