Delving into the Latest Updates on Revaprazan Hydrochloride with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

Revanex, Revaprazan, Revaprazan hydrochloride (USAN)

+ [9]

Target

H+/K+ ATPase x Proton pump

Mechanism

P-CAB(Potassium-competitive acid blockers), Proton pump inhibitors

Therapeutic Areas

Digestive System Disorders

Active Indication

Duodenal UlcerGastritisStomach Ulcer

Inactive Indication

Non-erosive gastro-esophageal reflux diseaseNon-erosive reflux disease

Originator Organization

Yuhan Corp.

Active Organization

Yuhan Corp.

Inactive Organization-

Drug Highest PhaseApproved

First Approval Date

KR (15 Sep 2005),

Duodenal UlcerGastritisStomach Ulcer

Regulation-

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Structure

Molecular FormulaC22H24ClFN4

InChIKeyMALPZYQJEDBIAK-UHFFFAOYSA-N

CAS Registry178307-42-1

A cochleate formulation was developed to enhance the oral bioavailability of revaprazan (RVP). Dimyristoyl phosphatidylcholine (DMPC) liposome containing dicetyl phosphate (DCP) successfully formed a cochleate after treatment with CaCl₂, whereas that containing sodium deoxycholate did not. Cochleate was optimised using a D-optimal mixture design with three independent variables-DMPC (X₁, 70.58 mol%), cholesterol (X₂, 22.54 mol%), and DCP (X₃, 6.88 mol%)-and three response variables: encapsulation efficiency (Y_1, 76.92%), released amount of free fatty acid at 2 h (Y₂, 39.82%), and released amount of RVP at 6 h (Y₃, 73.72%). The desirability function was 0.616, showing an excellent agreement between the predicted and experimental values. The cylindrical morphology of the optimised cochleate was visualised, and laurdan spectroscopy confirmed the dehydrated membrane interface, showing an increased generalised polarisation value (approximately 0.5) over small unilamellar vesicle of RVP (RVP-SUV; approximately 0.1). The optimised cochleate showed greater resistance to pancreatic enzyme than RVP-SUV. RVP was released in a controlled manner, achieving approximately 94% release in 12 h. Following oral administration in rats, the optimised cochleate improved the relative bioavailability of RVP by approximately 274%, 255%, and 172% compared to RVP suspension, a physical mixture of RVP and the cochleate, and RVP-SUV, respectively. Thus, the optimised cochleate formulation might be a good candidate for the practical development of RVP.

01 Dec 2023·International journal of biological macromolecules

Sodium alginate-based smart gastro-retentive drug delivery system of revaprazan loaded SLNs; Formulation and characterization

Article

Author: Alamri, Ali H ; Al Awadh, Ahmed Abdullah ; Lahiq, Ahmed A ; Khan, Salman ; Raja, Hadiqa Nazish ; Alasiri, Ali ; Din, Fakhar Ud ; Shabbir, Kanwal

Revaprazan (REV), a novel reversible Proton Pump Inhibitor (PPI) used to treat peptic ulcers, faces challenges in therapeutic efficacy due to its poor dissolution properties and a short half-life. Solid lipid nanoparticles (SLNs) have emerged as a drug delivery system capable of enhancing dissolution and bioavailability of lipid soluble drugs. Here, we report on the development and optimization of a smart gastro-retentive raft system of REV-loaded SLNs (GRS/REV-SLNs) to enhance drug bioavailability and gastric retention. The optimized REV-SLNs had a particle size of 120 nm, a Polydispersity Index (PDI) of 0.313, a zeta potential of -20.7 mV, and efficient drug incorporation of 88 %. Transmission Electron Microscopy (TEM) affirmed the spherical morphology of these REV-SLNs, while Fourier Transform Infrared Spectroscopy (FTIR) revealed no chemical interactions among components. In-vitro assessment of the final GRS/REV-SLNs demonstrated sustained gelation and buoyancy for over 12 h, which would significantly enhance REV retention and its release within the stomach. Further assessments in rats confirmed successful gel transformation within the stomach, resulting in the improved bioavailability of REV. Thus, the development of GRS/REV-SLNs significantly improved the delivery and bioavailability of REV within the stomach, and offers a potentially improved method of treating peptic ulcers.

09 Jun 2022·Journal of medicinal chemistryQ1 · MEDICINE

Structural Basis for Binding of Potassium-Competitive Acid Blockers to the Gastric Proton Pump

Q1 · MEDICINE

Article

Author: Shigematsu, Hideki ; Hayashida, Kenichi ; Gerle, Christoph ; Tanaka, Saki ; Madapally, Hridya Valia ; Yamagishi, Tatsuya ; Khandelia, Himanshu ; Morita, Mikio ; Abe, Kazuhiro ; Oshima, Atsunori

As specific inhibitors of the gastric proton pump, responsible for gastric acidification, K⁺-competitive acid blockers (P-CABs) have recently been utilized in the clinical treatment of gastric acid-related diseases in Asia. However, as these compounds have been developed based on phenotypic screening, their detailed binding poses are unknown. We show crystal and cryo-EM structures of the gastric proton pump in complex with four different P-CABs, tegoprazan, soraprazan, PF-03716556 and revaprazan, at resolutions reaching 2.8 Å. The structures describe molecular details of their interactions and are supported by functional analyses of mutations and molecular dynamics simulations. We reveal that revaprazan has a novel binding mode in which its tetrahydroisoquinoline moiety binds deep in the cation transport conduit. The mechanism of action of these P-CABs can now be evaluated at the molecular level, which will facilitate the rational development and improvement of currently available P-CABs to provide better treatment of acid-related gastrointestinal diseases.

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