Amidine Derivative Oral Formulation for Hereditary Angioedema
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Solution Overview
Problem
Current treatments for hereditary angioedema (HAE) lack a specific targeted oral chronic therapy, and existing pharmaceutical compounds like 3-[2-(4-carbamimidoyl-phenylcarbamoyl)-5-methoxy-4-vinyl-phenyl]-6-(cyclopropylmethyl-carbamoyl)-pyridine-2-carboxylic acid face challenges due to poor solubility, permeability, and stability, making oral administration difficult.
Innovation Solution
Development of an oral formulation of 3-[2-(4-carbamimidoyl-phenylcarbamoyl)-5-methoxy-4-vinyl-phenyl]-6-(cyclopropylmethyl-carbamoyl)-pyridine-2-carboxylic acid in a specific crystal form (Form A) that overcomes solubility, permeability, and stability issues, enabling effective oral delivery and treatment of HAE.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of operation
If the compound is administered orally, then patient convenience and flexibility are improved, but the compound cannot be effectively administered due to poor solubility, permeability, and stability
Solution Approach 1:
The patent applies parameter changes by modifying the physical and chemical properties of the compound through salt formation (converting to hydrochloride salt) and crystal form selection (Form A). These parameter changes improve solubility and stability while maintaining the compound's biological activity, enabling effective oral delivery
Solution Approach 2:
The patent uses an intermediary approach by employing specific excipients and formulation components that facilitate the delivery of the compound. The formulation includes intermediaries such as solvents, stabilizers, and delivery vehicles that protect the compound from degradation and enhance its solubility and permeability in the gastrointestinal tract
2Reliability
If non-oral routes are used, then effective delivery is improved, but patient convenience and invasiveness are worsened
Solution Approach 1:
The patent changes the parameters of the compound (solubility, stability, permeability) through salt formation and crystal form selection, transforming it from a compound suitable only for non-oral administration to one that can be effectively delivered orally, thereby improving patient convenience without sacrificing reliability
3Ease of operation
If the compound is formulated for oral administration, then patient convenience is improved, but formulation complexity increases due to solubility and stability challenges
Solution Approach 1:
The patent simplifies the formulation complexity by making fundamental parameter changes to the compound itself through salt formation and crystal form selection. These changes inherently improve solubility and stability, reducing the need for complex formulation strategies and making the oral formulation more straightforward to develop and manufacture
Data Source
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AI summary
Use of a compound of formula (I): wherein A, X, Y, R1 and R2 as defined herein, in treating hereditary angioedema is disclosed. A composition containing the compounds, a polar organic solvent or a mixture thereof; and optionally a co-solvent, is also disclosed.