Treprostinil derivative compounds and methods of using same
Inventors
BECKER, Cyrus K. • Venkatraman, Meenakshi S. • Zhang, Xiaoming
Assignees
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Publication Number
US-11505535-B2
Publication Date
2022-11-22
Expiration Date
Abstract
Compounds represented by formulae I, II, III, and IV including pro-drugs for treprostinil and prostacyclin analogs. Uses include treatment of pulmonary hypertension (PH) or pulmonary arterial hypertension (PAH). The structures of the compounds can be adapted to the particular application for a suitable treatment dosage. Transdermal applications can be used.
Core Innovation
The invention relates to pharmaceutical formulation strategies for treprostinil derivatives, including transdermal delivery by means of a transdermal patch. A topical composition includes a compound of Formula (I), or a pharmaceutically acceptable salt, polymorph, or stereoisomer thereof, incorporated into the patch format for application to a subject. The disclosed compounds are described as treprostinil and prostacyclin-analog pro-drug derivative compounds in broad structural Formulae I to IV, with pharmaceutically acceptable salts, solvates, polymorphs and enantiomers.
The compounds of Formula (I) are defined by extensive structural substituent variability, including R20 through R36, each independently H or deuterium, and functional group Z selected from —OH, —OR11, —N(R11)R12, —SR11, or P1. The formulation concepts include matrix form and release-system concepts for controlled release such as pulsatile, continuous, or digital release, together with permeation-enhancer composition embodiments and related excipient options.
The topical compositions are described for therapeutic use in treating pulmonary hypertension, including pulmonary arterial hypertension (PAH) and pulmonary venous hypertension (PVH) within WHO Group I-V. The invention further provides compositions for transdermal delivery, including optional transdermal patch formulations, and is described in connection with systemic availability and bioavailability considerations.
Claims Coverage
The consolidated material provides one independent claim focused on a transdermal patch. The claim centers on a topical composition containing a Formula (I) compound or a pharmaceutically acceptable salt, polymorph or stereoisomer, with extensive structural constraints across R20 to R36, Z, P1, P2, and the associated substituent and ring-forming definitions.
Transdermal patch with Formula (I) topical composition
A transdermal patch comprising a topical composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt, polymorph or stereoisomer thereof.
Hydrogen/deuterium selection across R20-R36
R20, R21, R22, R23, R24, R25, R26, R27, R28, R29, R30, R31, R32, R33, R34, R35 and R36 are independently H or deuterium.
Defined Z substituent
Z is —OH, —OR11, —N(R11)R12, —SR11 or P1, with R11 and R12 defined by enumerated substituent classes.
P1 sub-structure with m and ring-forming options
P1 is selected from a defined set wherein m is 1, 2, 3 or 4, and wherein R14 and R15 are independently selected from enumerated substituent types or optionally together form a 5- to 7-membered ring incorporating two ring heteroatoms chosen from N, O and S, unsubstituted or substituted with halo, methyl and methoxy.
R18 and R19 definition with optional ring formation
R18 and R19 are independently hydrogen or alkyl with optional substitution, and R14 and R18, R14 and R19, R15 and R18, and R15 and R19 optionally form a 5- to 7-membered ring.
P2 assignment for R1 and R2
R1 and R2 are independently H or P2, wherein at least one of R1 and R2 is P2, and P2 is selected from a defined set with m being 1, 2, 3 or 4 and R14 independently selected from enumerated substituent types.
The independent claim is directed to a transdermal patch whose topical composition contains a Formula (I) compound defined by extensive substituent constraints, including hydrogen/deuterium assignment for R20 to R36, Z selection, and two sub-structure families P1 and P2 with m and enumerated R14/R15 and optional ring-forming definitions.
Stated Advantages
Tailoring chemical motifs to optimize drug delivery/bioavailability.
Improved bioavailability via transdermal delivery.
Improving systemic availability versus oral treprostinil constraints.
Tailoring structure for PH/PAH treatment.
Documented Applications
Treatment of pulmonary hypertension (PH), including pulmonary arterial hypertension (PAH), using a transdermal patch topical composition containing a compound of Formula (I) or a pharmaceutically acceptable salt, polymorph or stereoisomer.
Transdermal delivery for pulmonary hypertension (PH), including pulmonary arterial hypertension (PAH).
Topical administration via a transdermal patch for treating pulmonary hypertension, including pulmonary arterial hypertension (PAH) and pulmonary venous hypertension (PVH) within WHO Group I-V.
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