Treprostinil Prodrug Compositions for Lower-Toxicity PH Dosing
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Solution Overview
Problem
Current prostacyclin therapies for pulmonary hypertension (PH) are associated with severe toxicity and tolerability issues, as well as inconvenient dosing schedules.
Innovation Solution
Development of novel prostacyclin compounds and compositions, including specific alkyl esters of treprostinil, formulated with hydrophobic additives and amphiphilic agents, for convenient pulmonary administration via inhalers, reducing toxicity and improving tolerability.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If current prostacyclin therapies are used for pulmonary hypertension, then the disease can be treated, but severe toxicity and tolerability issues occur
Solution Approach 1:
The patent modifies the chemical structure of prostacyclin compounds by changing parameters such as the alkyl chain length (C5-C18), branching patterns, and functional groups at positions R2, R5, and R6. These structural parameter changes result in compounds with improved safety profiles while maintaining therapeutic efficacy for pulmonary hypertension
Solution Approach 2:
The invention creates composite molecular structures combining the prostacyclin core with various alkyl, alkenyl, aryl, amino acid, or peptide substituents. These composite structures allow optimization of both efficacy and tolerability by selecting appropriate combinations of structural elements
2Reliability
If current prostacyclin therapies are used for pulmonary hypertension, then the disease can be treated, but inconvenient dosing schedules are required
Solution Approach 1:
The patent describes compounds with extended half-lives that allow treatment with less frequent dosing than current therapies. By achieving sufficient therapeutic effect with partial dosing frequency, the invention improves patient convenience while maintaining efficacy
Solution Approach 2:
Modifications to the prostacyclin molecular structure, particularly the addition of specific alkyl chains and functional groups, alter the pharmacokinetic parameters including half-life and metabolism rate, enabling more convenient dosing schedules
3Object-affected harmful factors
If novel prostacyclin compounds with modified structures are developed, then toxicity is reduced and tolerability is improved, but compound complexity increases
Solution Approach 1:
The prostacyclin molecule is segmented into distinct functional regions: the core prostacyclin structure, the variable R2 alkyl/alkenyl chain, the R5 and R6 substituents, and optional functional groups. This segmentation allows independent optimization of each region to reduce toxicity while managing overall complexity
Solution Approach 2:
Specific local modifications are made at key positions (R2, R5, R6) to achieve toxicity reduction. For example, adding specific alkyl chains at R2 or modifying groups at R5/R6 provides localized structural changes that improve safety without requiring complete redesign of the entire molecule
Data Source
AI summary
Prostacyclin compounds and compositions comprising the same are provided herein. Specifically, prostacyclin compounds comprising treprostinil covalently linked to a linear C5-C18 alkyl, branched C5-C18 alkyl, linear C2-C18 alkenyl, branched C3-C18 alkenyl, aryl, aryl-C1-C18 alkyl or an amino acid or a peptide (e.g., dipeptide, tripeptide, tetrapeptide) are described. The linkage, in one embodiment, is via a carbamate, amide or ester bond. Prostacyclin compounds provided herein can also include at least one hydrogen atom substituted with at least one deuterium atom. Methods for treating pulmonary hypertension (e.g., pulmonary arterial hypertension) and portopulmonary hypertension are also provided.