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brimonidine + ripasudil (gra alfa / Graalfa / K232)

✓ Approved

Kowa · ADRA2A · Small Molecule

What is brimonidine + ripasudil?

brimonidine + ripasudil is a small molecule developed by Kowa. It is approved for therapeutic indications via others or topical.

Drug Profile

Brand Namesgra alfa, Graalfa, K232
CompanyKowa
Drug ClassSmall Molecule
Molecular TargetADRA2A, ROCK1
RouteOthers, Topical
StatusApproved
Sources: ClinicalTrials.gov, Kowa

Mechanism of Action

Molecular Targets

brimonidine + ripasudil acts on 2 molecular targets:

ADRA2Aadrenoceptor alpha 2A (ADRAR, ADRA2R)
ROCK1Rho associated coiled-coil containing protein kinase 1 (ROCK-I, P160ROCK)
Want deeper analysis?Noah AI can explain complex mechanisms and compare to similar drugs.

Therapeutic Indications

brimonidine + ripasudil is developed for 1 unique indication across 1 therapeutic area.

Therapeutic AreaConditionPhase
Eye disordersGlaucoma✓ Approved

Related Research Articles

PubMedBiomacromolecules2026-09-14

Mucoadhesive Carboxymethyl Chitosan Hydrogel Eyedrops via Dual Dynamic Covalent Chemistry for Long-Acting Glaucoma Therapy.

Pan Jin J, Gong Huangkun H, Shao Qiuyun Q, Zhang Xuehan X et al.

Glaucoma, a leading cause of irreversible blindness, is commonly treated with topical eye drops that reduce intraocular pressure (IOP), but their efficacy is limited by rapid precorneal clearance. To address this, we developed a dynamic hydrogel (CSFP) via Schiff base bonding between carboxymethyl chitosan (CMCS) and 4-formylphenylboronic acid (FPBA) as an advanced delivery vehicle for brimonidine (BRI) and timolol (TIM), two common IOP-lowering agents. The mechanical properties were tunable by adjusting CMCS and FPBA concentrations. The optimized hydrogel exhibited a storage modulus of ∼38.8 Pa (at 1 Hz, 1% strain), excellent self-healing ability, and shear-thinning behavior, facilitating easy administration and resistance to blink-induced clearance. It also achieved near 100% transmittance and a refractive index of 1.339, ensuring optical clarity. Notably, the incorporated phenylboronic acid (PBA) groups enabled selective binding to sialic acid residues on ocular mucins via dynamic phenylboronic ester bonding, prolonging precorneal retention beyond 30 min compared to less than 5 min for the solution control. In a magnetic bead-induced ocular hypertensive rat model, CSFP hydrogel loaded with either BRI or TIM induced greater and long-lasting IOP reduction than the free drug solutions. This work highlights the potential of mucoadhesive dynamic covalent hydrogels for advanced ocular drug delivery.

PMID 42734286
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PubMedMolecules (Basel, Switzerland)2026-08-27

Latanoprost Acid-Brimonidine, a New Amide Prodrug for Glaucoma Management Based on the Concept of Sustained Release.

Lin Hong-Jia HJ, Su Shih-Horng SH, Wu Wen-Chung WC

Glaucoma is an ocular disease caused by the improper management of elevated intraocular pressure (IOP). IOP-lowering via topical administration is the first choice to prevent further progression. However, patients may forget to administer their medication, compromising IOP control. To address this problem, a prolonged active pharmaceutical ingredient (API) release system is proposed. A new prodrug (latanoprost acid-brimonidine conjugate, LBJ) was designed and expected to achieve potential long-lasting release of APIs. LBJ was synthesized by two methods. First, Steglich esterification without protecting the hydroxyl group led to a yield of 34.24%. However, the integral ratio between LPA and BM obtained from NMR was 1.25:1, indicating a potential side product resulting from further coupling through the unprotected hydroxyl group in LBJ. As an alternative route, Steglich esterification with a protecting agent, tert-butyldimethylchlorosilane (TBDMSCl), resulted in a yield of 39.35%, and the integral ratio between LPA and BM obtained from NMR was 1:1. The hydrolysis time of LBJ was investigated and compared with that of latanoprost (LP). In the presence of esterase (0.4 U/mL), the hydrolysis times of LP and LBJ were 4 h and 28 days, respectively. The prolonged hydrolysis time results in sustained APIs release, which is beneficial for the development of a sustained drug release system.

PMID 42653864
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PubMedInvestigative ophthalmology & visual science2026-08-13

Targeting RhoA/ROCK Signaling to Modulate Extracellular Matrix Remodeling in Corneal Endothelial Dystrophies.

Schlötzer-Schrehardt Ursula U, Zenkel Matthias M, Pulasani Sai S, Strunz Maria M et al.

Fuchs endothelial corneal dystrophy (FECD) involves pathological extracellular matrix (ECM) accumulation within Descemet's membrane, leading to guttae formation, endothelial dysfunction, and vision impairment. As current treatment is primarily surgical, we investigated whether Rho-associated protein kinase (ROCK) inhibition can reduce fibrotic ECM remodeling in FECD and related corneal endothelial diseases. Endothelial cell-Descemet membrane specimens from FECD, pseudophakous bullous keratopathy (PBK), pseudoexfoliation keratopathy (PEX-K), and normal donor corneas were treated ex vivo with ripasudil or comparator ROCK inhibitors (netarsudil, Y-27632). Complementary in vitro studies used human corneal endothelial cells. ROCK activity, ECM expression, matrix metalloproteinase (MMP) activity, and TGF-β/Smad signaling were analyzed using molecular and imaging techniques. Relative to controls, FECD samples showed constitutive ROCK and TGF-β signaling activation. Ripasudil suppressed ROCK activity and downregulated fibrosis-associated ECM components (including collagens I/III, fibronectin, agrin, TGFBI, clusterin, and tenascin-C), while shifting the MMP-tissue inhibitor of metalloproteinases (TIMP) balance to enhance ECM turnover. These effects were accompanied by reduced ECM deposition and attenuation of TGF-β/Smad signaling, alongside broad transcriptional reprogramming related to fibrosis, inflammation, and cytoskeletal dynamics. Similar ECM-modulating effects were observed in PBK and PEX-K, with ripasudil showing the most pronounced effects among tested inhibitors. ROCK activation contributes to pathological ECM alterations in FECD, and its pharmacologic inhibition with ripasudil suppresses pro-fibrotic ECM production, promotes ECM-remodeling pathways, and supports restoration of ECM homeostasis. These findings suggest ROCK inhibition as a promising non-surgical therapeutic strategy for FECD and related corneal endothelial disorders, warranting further validation in preclinical studies.

PMID 42593179
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PubMedSeminars in ophthalmology2026-08-10

Efficacy and Safety of Aceclidine in Presbyopia, a Systematic Review and Meta -Analysis.

Ibrahim Taha T, Burhan Muhammad M, Bin Shafiq Shaheer S, Razzak Muhammad Junaid MJ et al.

Presbyopia is a prevalent age-related visual disorder affecting approximately 1.8 billion individuals worldwide, with many lacking access to effective correction. Topical pharmacologic therapies such as aceclidine have emerged as potential noninvasive treatments, though their efficacy and safety remain incompletely established. A systematic review and meta-analysis of randomized controlled trials was conducted in accordance with PRISMA guidelines (PROSPERO: CRD420261353653). Databases were searched till March 2026. Adults with presbyopia treated with topical aceclidine, alone or in combination, were included. The primary outcome was ≥ 3-line improvement in distance-corrected near visual acuity (DCNVA). Random-effects models were used to calculate pooled risk ratios (RR) with 95% confidence intervals (CI). Five trials involving 883 randomized participants were included. In the primary analysis of parallel-group trials, aceclidine significantly increased the likelihood of achieving a ≥ 3-line improvement in distance-corrected near visual acuity compared with placebo (RR 6.28, 95% CI 4.22-9.35; I2 = 2.4%) and compared with aceclidine plus brimonidine (RR 5.05, 95% CI 3.04-8.38; I2 = 28.2%). Secondary analyses of crossover trials demonstrated similar superiority over placebo (RR 14.92, 95% CI 6.77-32.86; I2 = 0%), whereas no significant difference was observed versus combination therapy (RR 1.11, 95% CI 0.90-1.38; I2 = 24.6%). Aceclidine was associated with a higher incidence of treatment-emergent adverse events than placebo (RR 2.23, 95% CI 1.61-3.09). No significant differences were observed in serious adverse events. Aceclidine provides significant short-term improvement in near vision with an acceptable safety profile. Monotherapy may offer slight efficacy benefits over combination regimens. However, limited study numbers and short follow-up necessitate further large-scale, long-term trials.

PMID 42574210
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PubMedAdvanced materials (Deerfield Beach, Fla.)2026-08-03

An E-interwoven Therapeutic Contact Lens System for Rapid Drug Delivery and Precision Dose Monitoring.

Yang Huan H, Zhu Hengtian H, Teng Wenyu W, Huang Heyu H et al.

Precise intraocular pressure (IOP) management and rapid intervention preserve glaucoma vision, yet current ocular delivery systems lack in situ dosage verification, causing treatment blind spots. Here, we develop a wireless therapeutic smart contact lens (SCL) containing a rapid voltage-triggered drug delivery system with a real-time dosage monitoring sensor. The e-interwoven design integrates drug delivery and sensing electrodes in an ultra-thin (17.4 µm) tri-interdigital configuration, which enables the electric field to interact with the drug-loaded hydrogel in the same spatial region. A frequency-matching strategy boosts voltage coupling to drive a brimonidine tartrate-loaded hydrogel to achieve high concentrations in the aqueous humor in 20 min, significantly faster than topical eye drops. The built-in drug dose sensor has a high accuracy <2.8 µg, benefiting from the great linear correlation between wireless frequency drift and release dosage. In acute glaucoma rabbit models, this SCL suppresses peak IOP elevation by 85.7% compared to eye drops. This SCL presents a highly integrated therapeutic platform demonstrating potential for rapid and precise glaucoma treatment.

PMID 42544728
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PubMedJapanese journal of ophthalmology2026-07-18

Real-world effectiveness and safety of a fixed-dose combination of 0.4% ripasudil and 0.1% brimonidine in the management of uveitic glaucoma.

Kusuhara Sentaro S, Matsumiya Wataru W, Mori Sotaro S, Sakamoto Mari M et al.

To evaluate the real-world use, treatment outcomes, and tolerability of the fixed-dose combination of ripasudil 0.4% and brimonidine 0.1% (RBFC) eye drops in patients with uveitic glaucoma (UG). Single-center retrospective case series. Medical records of 39 eyes with open-angle UG treated with RBFC were reviewed. The outcome measures included changes in intraocular pressure (IOP) and glaucoma drug score (GDS) at 12 months, the proportion of eyes with an IOP reduction of ≥2 mmHg at 12 months, the relationship between the duration of UG and the change in IOP at 12 months, changes in IOP in eyes switched from ripasudil plus brimonidine, and adverse events. The median IOP significantly decreased from 19 mmHg at baseline to 14 mmHg at 12 months (p < 0.001), while the median GDS showed no significant change, from 3 at baseline to 4 at 12 months (p = 0.562). At 12 months, 64% of eyes achieved an IOP reduction of ≥2 mmHg. A positive correlation was observed between the duration of UG and the change in IOP at 12 months (rho = 0.539, p < 0.01). In the subgroup analysis restricted to eyes switched from ripasudil plus brimonidine eye drops to RBFC, IOP showed a decreasing trend (p = 0.057). No drug-related adverse events were observed, except for transient conjunctival hyperemia. This real-world study in patients with UG showed that RBFC achieves effective IOP control while reducing treatment burden, with good tolerability, supporting its continued use in UG management.

PMID 42469566
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