A robust, rapid, and reproducible reversed-phase high-performance liquid chromatography (RP-HPLC) method was developed and validated for the simultaneous quantification of Brimonidine Tartrate and Timolol Maleate (Combigan) in ophthalmic dosage forms. Chromatographic separation was achieved on a Supelco Discovery C18 column (25cm × 4.6mm, 5μm) maintained at ambient temperature, employing isocratic elution with two mobile phases: phase A (buffer at pH 7.0 containing 30 mM triethylamine) and phase B (acetonitrile) in a ratio of 80:20. The flow rate was set at 1.0 mL/min, and detection was performed at 245nm and 295nm using a diode array detector (DAD). Method validation, conducted in accordance with ICH Q2(R1), USP, and FDA guidelines, confirmed excellent linearity over the ranges of 0.24-500 ppm for Brimonidine Tartrate and 0.60-1250 ppm for Timolol Maleate. Accuracy results ranged from 99.42% to 99.82% for Brimonidine Tartrate and from 98.71% to 101.10% for Timolol Maleate. Relative standard deviations (RSDs) for precision, specificity, and robustness were all below 2%, demonstrating the method's consistency and reliability. Additionally, the limits of detection (LOD) were determined to be 0.08 ppm for Brimonidine Tartrate and 0.20 ppm for Timolol Maleate, while the limits of quantification (LOQ) were 0.24 ppm and 0.60 ppm, respectively. Forced degradation studies under various stress conditions, including acid and base hydrolysis and hydrogen peroxide oxidation, demonstrated that the method successfully separated Brimonidine Tartrate and Timolol Maleate from their degradation products, confirming its stability-indicating capability. Notably, both drugs remained stable under thermal and photolytic stress; however, Timolol Maleate was significantly more prone to degradation under strong hydrolytic and oxidative conditions, underscoring the need for stringent control during formulation and storage. Additionally, the three complementary green analytical chemistry (GAC) metrics were evaluated. The method achieved an Eco-Scale score of approximately 75. The GAPI pictogram for this method showed a mixture of green and yellow zones. The AGREE evaluation yielded a score of 0.57 (out of 1.0), indicating moderate greenness. Overall, this method effectively quantified both active pharmaceutical ingredients without interference from excipients or degradation products, supporting its suitability for routine quality control and stability testing of combined ophthalmic formulations.

In this study, we developed multifunctional nanoparticles based on polyamidoamine (PAMAM) dendrimers functionalized with caffeic acid (CA) and poly(ethylene glycol) maleimide (PEGM) for the topical delivery of hydrophobic antiglaucoma drugs brimonidine (BM) and betaxolol (BX). The PAMAM-CA and PAMAM-CA-PEGM conjugates exhibited antioxidant and iron-chelating activities in a dose-dependent manner. BM- and BX-loaded dendrimer nanoparticles produced using a multi-inlet vortex mixer showed uniform spherical morphology (∼80 nm by TEM) and hydrated sizes of ∼135-144 nm by DLS. Both nanoformulations demonstrated high cytocompatibility with human corneal epithelial cells and were nonirritant in the HET-CAM assay, with PEGM further improving cytocompatibility. Drug release was sustained for 8 h. Ex vivo corneal permeation studies revealed significantly enhanced drug transport, with PAMAM-CA and PAMAM-CA-PEGM nanoparticles achieving approximately 2- and 3-fold higher permeation, respectively, compared to commercial formulations. Conjugation of CA within our formulations effectively promoted the removal of ferric ions from the surrounding environment. Both PAMAM-CA and PAMAM-CA-PEGM nanoparticles exhibited concentration-dependent antioxidant activity comparable to that of CA. These findings suggest the potential of this multifunctional dendrimer-based nanoparticle system as an innovative strategy for glaucoma medication.

This retrospective observational study describes the clinical outcomes and examines the association between refractive regression and corneal epithelial remodeling in patients treated with combined fluorometholone and intraocular pressure (IOP)-lowering eye drops after corneal laser surgery. Patients with refractive regression following corneal laser surgery who were treated with fluorometholone combined with either timolol maleate or brimonidine tartrate were included. Changes in uncorrected visual acuity (UCVA), spherical equivalent (SE), and central corneal epithelial thickness were recorded over time. Statistical analyses, including normality testing with the Shapiro–Wilk test and correlation analysis, were performed to evaluate the relationship between refractive outcomes and epithelial remodeling. Mean UCVA improved from 0.28 ± 0.10 to 0.08 ± 0.08 LogMAR, SE from − 1.49 ± 0.37 days to − 0.77 ± 0.29 days, and epithelial thickness from 68.22 ± 4.40 μm to 59.63 ± 4.99 μm (all P <.001). △ET was positively correlated with improvements in SE (R = 0.742, P <.001) and UCVA (R = 0.446). A linear relationship (y = 0.0559x + 0.1522) suggested that a 15 μm decrease in epithelial thickness corresponded to a 1 day improvement in SE. Patients with refractive regression after corneal laser surgery showed improvements in UCVA and SE, accompanied by reductions in central corneal epithelial thickness. These findings suggest that corneal epithelial remodeling may contribute to refractive outcomes in this setting. However, as this was an observational study without a control group, causality cannot be inferred. Further controlled studies are needed to validate these findings.

To investigate and compare the effectiveness and safety of pulsed dye laser (PDL), topical brimonidine tartrate, and their combined use in post-acne erythema (PAE) treatment. In this randomized clinical comparative trial, 60 patients who had PAE on both sides of the face were equally divided into 2 groups. According to a split-face design, the PAE lesions in each participant of group A were randomly treated with PDL followed by brimonidine tartrate on one side and PDL alone on the other one. Alternatively, PAE lesions on each face side in group B were treated with a single-treatment modality, either brimonidine or PDL. The efficiency of treatments was assessed by the Global Assessment of Improvement scores, by the clinical assessment of PAE lesion count, and patient satisfaction, as well as objective morphometric analysis of the patient photographs. Significant improvement was noticed subjectively and objectively after treatment with PDL alone, brimonidine alone, and PDL+brimonidine compared with baseline. In group A, PDL+brimonidine achieved superior improvement with regard to global assessment of improvement, percentage of lesion count reduced, erythema index, and patient satisfaction. Pulsed dye laser and topical brimonidine separately proved to be effective and safe in the treatment of PAE. Their combination can have an additively positive therapeutic outcome.

Glaucoma causes irreversible blindness, with poor adherence driven by frequent dosing and low eye drop bioavailability. Brimonidine tartrate (BRT) requires multiple daily doses due to rapid elimination and limited corneal permeability. To address these limitations, this study aimed to develop a long-acting, mucoadhesive ocular delivery system using hyaluronic acid-coated cubosomes (HA-BRT-CUB), further incorporated into a thermoresponsive in situ gel (HA-BRT-CUB-ISG). The HA-BRT-CUB formulation was optimized using a Design of Experiments (DoE) approach, resulting in a particle size of 189.24 ± 2.05 nm, zeta potential of −25.45 ± 0.88 mV, and entrapment efficiency of 78.86 ± 2.42%. Incorporation into a poloxamer-based ISG system enhanced precorneal retention and sustained delivery. In vitro release from HA-BRT-CUB-ISG was extended over 24 h (h), best fitting the Korsmeyer–Peppas model (R 2 = 0.981). Ex vivo permeation studies revealed a flux (J) of 2.89 µg/cm2/h and a 3.92-fold enhancement ratio (ER) compared to the BRT solution. In normotensive New Zealand rabbits, HA-BRT-CUB-ISG achieved a 30.31% IOP reduction at 24 h (17.05 ± 0.35 mmHg), compared to 29.91% with HA-BRT-CUB and only 20.75% with Alphagan®. Pharmacokinetic analysis revealed that HA-BRT-CUB-ISG attained a Cmax of 7.35 ± 0.82 μg/mL and an AUC0–∞ of 70.22 ± 3.56 µg/mL* h, representing a 4.5- and 12-fold improvement, respectively, over Alphagan®. The half-life extended to 8.75 ± 1.34 h with minimal clearance (Cl/F = 1.42 ± 0.59). Stability studies confirmed HA-BRT-CUB formulation integrity under refrigerated conditions over 90 days. Overall, HA-BRT-CUB-ISG presents a promising once-daily nanocarrier system for sustained glaucoma management.

PurposeResidual myopia following Laser-assisted in situ keratomileusis (LASIK) surgery poses a significant concern, with existing literature extensively detailing the use of timolol for treatment. This study aims to assess prediction factors for brimonidine tartrate 0.15% (Alphagan-P) response on post-LASIK residual myopic refraction reduction.MethodsThe study included consecutive patients who received Alphagan-P during their follow-up for post-LASIK residual myopia.ResultsWe included 61 patients (55% male) with a mean age of 35.18 ± 10.13 Alphagan-P Treatment started at a mean of 4.94 ± 5.64 months after surgery for residual myopia of −0.53 ± 0.71D. Comparison analysis of patients who responded (n = 32, 51.6%) to patients who did not (n = 30, 48.4%) shows that responders were older (38.1 ± 9.1 vs. 32.3 ± 10.3, p = 0.03), had higher baseline myopic Spherical equivalent (SE, −0.82 ± 0.65 vs. −0.26 ± 0.66 p < 0.01), and lower uncorrected visual acuity (Uncorrected visual acuity [UCVA], 0.14 ± 0.2 vs. −0.003 ± 0.12 p = 0.01). Multiple Binary logistic regression confirmed these predictors for response (UCVA (OR=70.6, P = .006), larger SE (OR=3.8, P = .004,) and older age (OR=1.06, P = .03)).ConclusionsAlphagan-P can reduce up to 0.5D of post-LASIK residual myopia in roughly 50% of subjects. This treatment might be recommended to fine-tune outcomes for low residual myopia.

Ocular redness is common, can affect quality of life, and can be relieved by short-term use of topical adrenergic receptor (AR) agonists. Brimonidine tartrate ophthalmic solution 0.025% (LUMIFY® 0.025%) is the first α2-AR-selective agonist approved for ocular redness. The preservative benzalkonium chloride (BAK) maintains ophthalmic solution sterility, reducing the risk of ocular infections, but may cause symptoms of ocular surface disease (OSD) in some patients. A BAK-free formulation of LUMIFY 0.025% (BTOS-PF 0.025%) could offer a solution for BAK-sensitive patients. This randomized, active-controlled, multicenter study aimed to establish non-inferior efficacy of BTOS-PF 0.025% to LUMIFY 0.025% and compare safety. Randomized participants received either formulation instilled as a single drop four times daily, for 4weeks. The primary endpoint was investigator-assessed ocular redness at 5, 15, 30, 60, 90, 120, 180, and 240min post-instillation at visit1 (day 1). Eight hierarchical secondary endpoints included additional post-instillation timepoints at visit 1 and visits 2 and 3 (days 14 and 28), and participant-assessed redness. BTOS-PF 0.025% was statistically non-inferior to LUMIFY 0.025% for ocular redness reduction across the eight timepoints at visit 1. Efficacy for both formulations was seen as early as 1min and up to 8h post-instillation. BTOS-PF 0.025% performed similarly to LUMIFY 0.025% after 14 and 28days, rebound redness rates were low and similar, and total clearance of ocular redness and participant-evaluated redness were similar. The safety profile of both formulations was similar, with no severe or serious ocular events. BTOS-PF 0.025% was non-inferior to LUMIFY 0.025% in reducing ocular redness in adults, was well-tolerated, and offers an alternative topical solution, without loss of efficacy or compromised safety, for patients who prefer a preservative-free formulation or are at increased risk of OSD. ClinicalTrials.gov identifier: NCT05360784. Date of registration: 29 April2022.

Background:This study aimed to assess pupillometry changes and alterations in clinical headache severity following brimonidine tartrate 0.15% administration in patients with acute migraine attacks.Methods:A randomized controlled prospective study was conducted involving 42 patients with acute migraine attacks and 48 healthy individuals in the control group. Infrared pupillometry and Visual Analog Scale measurements were assessed before and after ocular instillation of brimonidine tartrate 0.15%.Results:In patients with acute migraine attacks, the mean latency was 156 ms compared with 173 ms in the control group (P = .042). Pupillary amplitude was 2.45 mm in the acute migraine group and 2.91 mm in the control group (P = .041). Both groups exhibited a statistically significant decrease in pupillary diameter after the administration of brimonidine tartrate 0.15% in dynamic and static pupillometry. However, latency was significantly prolonged in the acute migraine group (P = .009), whereas no significant change was observed in the control group (P > .05). Although there was a statistically significant decrease in the anterior chamber depth in the migraine group after brimonidine tartrate 0.15% (P = .005), the decrease in the control group was not significant (P = .052). Visual Analog Scale scores significantly decreased in patients with acute migraine patients after brimonidine (P < .001).Conclusion:The study findings suggest that patients experiencing acute migraine attacks demonstrate shorter pupillary constriction latencies, indicating the presence of accompanying sympathetic hypoactivity in migraine patients. Latency prolongation after brimonidine suggests sympathetic hyperfunction secondary to chronic sympathetic hypofunction in migraine patients. Brimonidine, with its ability to cross the blood–brain barrier, may provide pain relief through a mechanism similar to that of latency prolongation. This study sheds light on the potential role of brimonidine tartrate in the management of acute migraine attacks, and highlights its effects on pupillometric parameters, thereby contributing to our understanding of migraine pathophysiology and potential treatment avenues.

Background. Neurovascular disorders and an imbalance of immune regulation are the leading links in the pathogenesis of rosacea. However, the basic therapeutic goal underlying the formation of clinical manifestations of rosacea has not been determined, so most treatment methods do not give the desired result. One of the “sniper” drugs is a highly selective α2-adrenergic receptor agonist with powerful vasoconstrictive activity brimonidine tartrate. Promising topical drugs are β-blockers. The mechanism of their action consists not only in vasoconstriction, but also in slowing the growth of vascular epithelial cells and reducing their ability to divide and reduce erythema. Hardware methods of cosmetic correction, such as laser therapy, help to significantly improve skin color and the quality of fibrous tissue. Aim. To determine the diagnostic value of interleukin-17 (IL-17) and human β-defensin-2 (HBD-2) in the pathogenesis of rosacea and to study the clinical efficacy of the β-adrenoblocker Propranolol in the form of 10% ointment in mono- and combination therapy of rosacea. Materials and methods. The study included patients aged 20 to 72 years with a diagnosis of Rosacea. The concentration of IL-17 in blood serum was measured by enzyme immunoassay using ELISA (Enzyme-Linked Immunosorbent Assay) Kit for Interleukin 17 (IL17) Cloud Clone Corp. Sensitivity: 5.5 pg/ml. Detection range: 15.6–1000 pg/ml. The patients were divided into two experimental groups. In the first group, monotherapy with 10% Propranolol ointment was performed. The patients of the second group underwent combination therapy: 10% Propranolol ointment, as well as Nd:Yag/Ktp-Qsw laser scanning. Results. The levels of HBD-2 and IL-17 were significantly increased in patients with rosacea compared with controls. The level of HBD-2 had no significant differences depending on gender, subtype, severity of rosacea and duration of the pathological process, the level of cytokine IL-17 had no significant differences depending on gender, subtype, severity of rosacea, but it significantly increased depending on the duration of the pathological process. In both groups, there was a statistically significant decrease in erythema intensity after treatment. Increased skin vascularization decreased more significantly in the second group 2 weeks after the last visit. The number of inflammatory elements regressed 2 weeks after the start of treatment and was completely resolved by the end of therapy in both groups. Conclusion. The use of laser therapy in combination with local rosacea treatments provides a comprehensive, personalized approach.

Purpose To assess the effects of topical latanoprost 0.005% versus brimonidine tartrate 0.2% on perfusion of optic nerve head in patients with POAG using optical coherence tomography angiography. Patients and methods This study included 56 patients with bilateral POAG divided into two groups, 28 patients in each (nine patients, five in group I and four in group II were excluded). Group I included 23 patients (46 eyes) treated with latanoprost 0.005% eye drops, while 24 patients (48 eyes) received treatment with brimonidine tartrate 0.2% eye drops in group II. All patients underwent radial peripapillary capillary vessel density (VD) measurement using optical coherence tomography angiography, intra ocular pressure (IOP) measurement and mean ocular perfusion pressure (MOPP) calculation before starting treatment, one and three months after treatment. Results A total of 12 males were included in group I while group II included 14 males. The mean presenting initial IOP was 27.4±1.9 mmHg and 26.3±1.8 mmHg that decreased after 3 months, at the end of follow-up, to 13.8±0.8 mmHg and 13.5±0.7 in group I and group II, respectively, which was statistically significant (P&lt;0.005), with no significant difference in post treatment IOP between both groups. The whole VD was improved from 35.3±1.2% and 32.1±1.1 before treatment to 47.6±0.9% and 40.8±0.6% 3 months after treatment in group I and group II, respectively, with percentage increase 34.8% and 27.1% that was statistically significant. The difference in percentage change between both groups was also significant (P&lt;0.005) with superior improvement in group I. The VD increased significantly in all quadrants compared with the initial VD in both groups, with superior improvement in group I in comparison to group II (P&lt;0.005). The mean ocular perfusion pressure was significantly improved in both groups after treatment in both groups. Conclusion Both latanoprost and brimonidine eye drops improved the optic head perfusion in POAG with superior effect of latanoprost.

Abstract Facial erythema is a common and debilitating symptom in rosacea. Brimonidine tartrate gel 0.33% (Mirvaso) is an α2-receptor agonist that targets superficial cutaneous blood vessels causing vasoconstriction. It is approved for the treatment of persistent facial erythema in rosacea and is included in the British Association of Dermatologists rosacea guidelines. Recognized adverse effects including flushing, worsening of erythema and rosacea, and in 2.2% of cases, either irritant or allergic contact dermatitis (ACD) (Moore A, Kempers S, Murakawa G et al. Long-term safety and efficacy of once-daily topical brimonidine tartrate gel 0.5%. J Drugs Dermatol 2014; 13: 56–61). Allergic contact blepharitis to brimonidine eye drops is recognized and, more recently, case reports have described patients developing ACD to topical brimonidine gel [Bangsgaard N, Fischer LAN, Zachariae C. Sensitization to and allergic contact dermatitis caused by Mirvaso® (brimonidine tartrate) for treatment of rosacea – 2 cases. Contact Dermatitis 2016; 74: 378–9]. Here we report two cases of ACD to Mirvaso gel used as a treatment for rosacea. A 27-year-old man presented with a 4-year history of facial redness with associated papules and pustules. He had been using topical Elocon cream daily (mometasone furoate 0.1%) and was diagnosed with steroid-induced rosacea. He was prescribed oral doxycycline, ivermectin cream and brimonidine gel. There was initially an improvement in his symptoms but 6 weeks later he developed a florid, facial inflammatory rash across the bridge of his nose and eyelids. Patch testing to the British Society for Cutaneous Allergy (BSCA) standard, facial and medicaments series, as well as the patient’s own products, showed a positive reaction to Mirvaso gel only (day 2 +, day 4 ++). To complicate matters he developed abnormal liver function tests while on doxycycline and on questioning reported regular use of anabolic steroid and testosterone injections purchased online for bodybuilding purposes. On stopping these his liver tests reassuringly normalized. With avoidance of Mirvaso gel he is now managing his symptoms well. A 45-year-old woman presented to dermatology with erythema on the nose and cheeks, typical for rosacea, and at her request was prescribed Mirvaso gel. One year later she represented with a florid periorbital rash and oedema requiring prednisolone. Occupational ACD linked with her job in a paint mixing factory was initially suspected. Patch testing to the BSCA standard, medicaments and facial series showed a positive reaction on day 4 to brimonidine gel only. Since avoidance her skin has been clear. Individual constituents of the gel were not sent to us after we contacted the manufacturer. We would like to raise awareness that in addition to rebound erythema, topical brimonidine gel is also a cause of severe facial ACD. Patch testing to the patient’s own medicaments should be performed in suspected cases.

Formulation and In Vitro Evaluation of Brimonidine Tartrate Microemulgel for Topical Delivery

To investigate the predictive factors for intraocular pressure (IOP) after microhook ab interno trabeculotomy (TLO). We included 147 eyes of 97 glaucoma patients who underwent TLO. We recorded the following preoperative parameters: systemic parameters (age, height, body mass index, systolic blood pressure, diastolic blood pressure, and history of smoking), blood examination scores, ocular parameters (preoperative Goldmann applanation tonometry [GAT]-IOP, central corneal thickness, type of glaucoma, and preoperative use of anti-glaucoma eyedrops), and Ocular Response Analyzer (ORA) parameters (corneal resistance factor [CRF], corneal hysteresis, corneal-compensated intraocular pressure). We analyzed the preoperative parameters associated with postoperative GAT-IOP. Subsequently, similar analysis was performed using a corneal visualization Scheimpflug technology instrument (Corvis ST) parameters, instead of the ORA parameters. Postoperative GAT-IOP was measured after 12 months from TLO. When ORA parameters were used, preoperative high hemoglobin (Hb), high C-reactive protein (CRP), use of brimonidine tartrate, and high CRF were significant risk factors for postoperative high GAT-IOP, in addition to type of glaucoma. When Corvis ST parameters were used, preoperative high serum Hb, high serum CRP, usage of brimonidine tartrate, high biomechanical intraocular pressure, high stress-strain index, and low time to maximal displacement of whole eye movement were significant risk factors for postoperative high GAT-IOP. ORA and Corvis ST measurements suggested that stiff cornea was a risk factor for high postoperative GAT-IOP after TLO, in addition to preoperative high Hb, high CRP, and the use of brimonidine tartrate. Stiff cornea is a risk factor for high postoperative intraocular pressure after trabeculotomy.

Abstract The eye is a highly sensitive organ with multiple physiological barriers that limit drug bioavailability and reduce patient compliance. Research studies are still going on to discover a novel drug delivery system for ocular delivery. The current research aims to develop and compare the PLGA ocuserts of brimonidine tartrate (BT) by different methods. These BT-loaded PLGA ocuserts offer a promising alternative to commercially available BT eye drops. Ocuserts could significantly minimize the challenges encountered with eye drops like lacrimation, blinking-induced washout, dosing frequency, penetration, stability, and controlled release issues. The BT-loaded PLGA ocuserts were prepared using two methods: solvent casting method (SCM) and glass substrate method (GSM). Both SCM and GSM formulations exhibited smooth texture, pH levels within the range of 6.88±0.24 to 6.90±0.28, uniform thickness (SCM: 0.47±0.10 mm; GSM: 0.29±0.03 mm), minimal weight variation (SCM: 7.83±0.38 mg; GSM: 6.55±0.76 mg), sterility, and appropriate swelling indices (SCM: 6.69±0.33%; GSM: 5.40±0.27%). The evaluation results of SCM and GSM ocuserts revealed positive attributes for ophthalmic use. Noteworthy distinctions emerged in folding endurance, with SCM ocuserts demonstrating significantly higher endurance (87.17±4.34 folds) than GSM ocuserts (71.33±4.82 folds). Moreover, SCM ocuserts exhibited superior drug entrapment efficiency (88.26±3.33 %) to GSM ocuserts (74.91±4.39 %). Stability studies confirmed good stability over a 6-month period, while in vitro (italics) drug release study indicated better controlled release properties for SCM than GSM. Findings demonstrate that SCM emerged as an effective method for preparation of polymeric films in various pharmaceutical industries, including transdermal patches, scaffolds in tissue engineering, flexible wound healing films, biodegradable drug delivery systems, and pharmaceutical packaging as well.

The corneal permeability of an eye drop is crucial in drug delivery into the eye, but our understanding of drug migration through the cornea and drug distribution within the anterior chamber still requires improvement. To this end, we developed an electrochemical method using boron-doped diamond (BDD) to monitor real-time changes in the drug concentration in the anterior chamber. A needle-shaped BDD microelectrode, with a respective length and tip diameter of ∼200 and ∼40 μm, was used in the in vivo detection of brimonidine tartrate (BRM), which is a widely used antiglaucoma drug. We inserted the tip of the electrode into the right cornea of an anesthetized mouse. BRM was then administered to the right eye, resulting in the successful real-time monitoring of the changes in current. The recorded current reflected the combined reduction of BRM and dissolved oxygen within the anterior chamber. Based on the subtraction of the contribution of the oxygen, the BRM-specific reduction current increased immediately after administration, corresponding to 4.1 μM. Validation via liquid chromatography-tandem mass spectrometry confirmed the accuracy of this approach. Notably, the pharmacological effect of BRM, i.e., a reduced intraocular pressure, was observed 30 min after administration, lagging behind drug migration. These findings may provide valuable insights into the ocular pharmacokinetics of novel drugs and facilitate the development of more effective therapeutic approaches.

This study evaluated the effects of α2-adrenergic agonist, prostaglandin F2α analog, and EP2 receptor agonist on tunicamycin-induced endoplasmic reticulum (ER) stress and fibrosis in human trabecular meshwork (TM) cells. Human TM cells were treated with tunicamycin for 24 h, followed by cotreatment with brimonidine (BRI), latanoprost (LAT), or omidenepag (OMD). Immunocytochemistry was used to assess expressions of collagen type I alpha 1 chain (COL1A1), fibronectin, F-actin, and alpha-smooth muscle actin (α-SMA). Western blotting was performed to evaluate levels of C/EBP homologous protein (CHOP), 78-kDa glucose-regulated protein (GRP78), and splicing X-box binding protein-1 (sXBP-1). Real-time qPCR was used to examine the mRNA expressions of COL1A1, connective tissue growth factor (CTGF), fibronectin, α-SMA, CHOP, GRP78, and sXBP-1. Expressions of COL1A1, CTGF, F-actin, fibronectin, α-SMA, CHOP, GRP78, and sXBP-1 significantly increased after tunicamycin treatment. BRI cotreatment significantly downregulated the mRNA and protein expressions of GRP78, and LAT or OMD cotreatment significantly reduced the CHOP and sXBP-1 expressions compared to the tunicamycin-treated group. BRI, LAT, or OMD cotreatment significantly attenuated cellular cytoskeletal changes and the increase of fibrosis markers such as COL1A1, CTGF, fibronectin, and α-SMA. In addition, COL1A1 mRNA expression was significantly lowered with LAT or OMD cotreatment compared to the BRI-cotreated group. Cotreatment with α2-adrenergic agonist, prostaglandin F2α analog, or EP2 receptor agonist alleviates tunicamycin-induced ER stress in human TM cells.

Senjam SS. Glaucoma blindness–A rapidly emerging non-communicable ocular disease in India: Addressing the issue with advocacy. Journal of Family Medicine and Primary Care. 2020; May; 9(5): 2200. Weinreb RN, Aung T, Medeiros FA. The pathophysiology and treatment of glaucoma: a review. JAMA. 2014; May 14; 311(18): 1901-11. Feng KM, Tsung TH, Chen YH, Lu DW. The Role of Retinal Ganglion Cell Structure and Function in Glaucoma. Cells. 2023; Dec 8; 12(24): 2797. Wagner IV, Stewart MW, Dorairaj SK. Updates on the Diagnosis and Management of Glaucoma. Mayo Clinic Proceedings: Innovations, Quality and Outcomes. 2022; Dec 1; 6(6): 618-35. Toris CB, Gagrani M, Ghate D. Current methods and new approaches to assess aqueous humor dynamics. Expert Review of Ophthalmology. 2021; May 4; 16(3): 139-60. Lee DA, Higginbotham EJ. Glaucoma and its treatment: a review. American Journal of Health-System Pharmacy. 2005; Apr 1; 62(7): 691-9. Hu CX, Zangalli C, Hsieh M, Gupta L, Williams AL, Richman J, Spaeth GL. What do patients with glaucoma see? Visual symptoms reported by patients with glaucoma. The American Journal of The Medical Sciences. 2014; Nov 1; 348(5): 403-9. Schuster AK, Erb C, Hoffmann EM, Dietlein T, Pfeiffer N. The diagnosis and treatment of glaucoma. Deutsches Ärzteblatt International. 2020; Mar; 117(13): 225. Juliana FR, Kesse S, Boakye-Yiadom KO, Veroniaina H, Wang H, Sun M. Promising approach in the treatment of glaucoma using nanotechnology and nanomedicine-based systems. Molecules. 2019; Oct 22; 24(20): 3805 Cvenkel B, Kolko M. Current medical therapy and future trends in the management of glaucoma treatment. Journal of Ophthalmology. 2020; Jul 21; 2020. Anjum S, Ishaque S, Fatima H, Farooq W, Hano C, Abbasi BH, Anjum I. Emerging applications of nanotechnology in healthcare systems: Grand challenges and perspectives. Pharmaceuticals. 2021; Jul 21; 14(8): 707. Li S, Chen L, Fu Y. Nanotechnology-based ocular drug delivery systems: recent advances and future prospects. Journal of Nanobiotechnology. 2023; Jul 22; 21(1): 232. Guimarães D, Cavaco-Paulo A, Nogueira E. Design of liposomes as drug delivery system for therapeutic applications. International Journal of Pharmaceutics. 2021; May 15; 601: 120571. Mishra GP, Bagui M, Tamboli V, Mitra AK. Recent applications of liposomes in ophthalmic drug delivery. Journal of Drug Delivery. 2011; 2011. Hathout RM, Gad HA, Abdel-Hafez SM, Nasser N, Khalil N, Ateyya T, Amr A, Yasser N, Nasr S, Metwally AA. Gelatinized core liposomes: A new Trojan horse for the development of a novel timolol maleate glaucoma medication. International Journal of Pharmaceutics. 2019; Feb 10; 556: 192-9. Bose A, Roy Burman D, Sikdar B, Patra P. Nanomicelles: Types, properties and applications in drug delivery. IET Nanobiotechnology. 2021; Feb; 15(1): 19-27. Cholkar K, Patel A, Dutt Vadlapudi A, K Mitra A. Novel nanomicellar formulation approaches for anterior and posterior segment ocular drug delivery. Recent Patents on Nanomedicine. 2012; Oct 1; 2(2): 82-95. Vaishya RD, Khurana V, Patel S, Mitra AK. Controlled ocular drug delivery with nanomicelles. Wiley Interdisciplinary Reviews: Nanomedicine and Nanobiotechnology. 2014; Sep; 6(5): 422-37. Ozturk MR, Popa M, Rata DM, Cadinoiu AN, Parfait F, Delaite C, Atanase LI, Solcan C, Daraba OM. Drug-Loaded Polymeric Micelles Based on Smart Biocompatible Graft Copolymers with Potential Applications for the Treatment of Glaucoma. International Journal of Molecular Sciences. 2022; Aug 19; 23(16): 9382. Zhou HY, Hao JL, Wang S, Zheng Y, Zhang WS. Nanoparticles in the ocular drug delivery. International Journal of Ophthalmology. 2013; 6(3): 390 Zielińska A, Carreiró F, Oliveira AM, Neves A, Pires B, Venkatesh DN, Durazzo A, Lucarini M, Eder P, Silva AM, Santini A. Polymeric nanoparticles: production, characterization, toxicology and ecotoxicology. Molecules. 2020; Aug 15; 25(16): 3731. Salama HA, Ghorab M, Mahmoud AA, Abdel Hady M. PLGA nanoparticles as subconjunctival injection for management of glaucoma. Aaps Pharmscitech. 2017; Oct; 18: 2517-28. Saroha A, Pandey P, Kaushik D. Development of Timolol Maleate Loaded Chitosan Nanoparticles for Improved Ocular Delivery. Pharmaceutical Nanotechnology. 2017; Jan 1; 5(4): 310-6. Müller RH, Mäder K, Gohla S. Solid lipid nanoparticles (SLN) for controlled drug delivery–a review of the state of the art. European Journal of Pharmaceutics and Biopharmaceutics. 2000; Jul 3; 50(1): 161-77. Ghasemiyeh P, Mohammadi-Samani S. Solid lipid nanoparticles and nanostructured lipid carriers as novel drug delivery systems: Applications, advantages and disadvantages. Research in Pharmaceutical Sciences. 2018; Aug 1; 13(4): 288-303. Satyanarayana SD, Abu Lila AS, Moin A, Moglad EH, Khafagy ES, Alotaibi HF, Obaidullah AJ, Charyulu RN. Ocular delivery of bimatoprost-loaded solid lipid nanoparticles for effective management of glaucoma. Pharmaceuticals. 2023; Jul 13; 16(7): 1001. Ge X, Wei M, He S, Yuan WE. Advances of non-ionic surfactant vesicles (niosomes) and their application in drug delivery. Pharmaceutics. 2019; Jan 29; 11(2): 55. Allam A, Elsabahy M, El Badry M, Eleraky NE. Betaxolol‐loaded niosomes integrated within pH‐sensitive in situ forming gel for management of glaucoma. International Journal of Pharmaceutics. 2021; Apr 1; 598: 120380. Jacob S, Nair AB, Shah J. Emerging role of nanosuspensions in drug delivery systems. Biomaterials research. 2020; Dec; 24: 1-6. Pignatello R, Bucolo C, Spedalieri G, Maltese A, Puglisi G. Flurbiprofen-loaded acrylate polymer nanosuspensions for ophthalmic application. Biomaterials. 2002; Aug 1; 23(15): 3247-55. Hanagandi V, Patil AS, Masareddy RS, Dandagi PM, Bolmal UB. Development and Evaluation of Nanosuspension Incorporated in situ gel of Brimonidine Tartarate for Ocular Drug Delivery. Indian J. Pharm. Educ. Res. 2022; Jan 1; 56: 94-102. Tiwari K, Bhattacharya S. The ascension of nanosponges as a drug delivery carrier: Preparation, characterization, and applications. Journal of Materials Science: Materials in Medicine. 2022; Mar; 33(3): 28. Arshad K, Khan A, Bhargav E, Reddy K, Sowmya C. Nanosponges: a new approach for drug targeting. International Journal of Advances in Pharmaceutical Research. 2016; 7(3): 381-96. Pillai MK, Jain P, Pillai S. Fabrication and evaluation of nanosponges of besifloxacin hydrochloride for ocular drug delivery. J Med Pharm Allied Sci. 2022; Mar 30; 11(2): 4657-60. Bagul US, Nazirkar MV, Mane AK, Khot SV, Tagalpallewar AA, Kokare CR. Fabrication of architectonic nanosponges for intraocular delivery of Brinzolamide: An insight into QbD driven optimization, in vitro characterization, and pharmacodynamics. International Journal of Pharmaceutics. 2024; Jan 25; 650: 123746. Mittal P, Saharan A, Verma R, Altalbawy F, Alfaidi MA, Batiha GE, Akter W, Gautam RK, Uddin MS, Rahman MS. Dendrimers: a new race of pharmaceutical nanocarriers. BioMed Research International. 2021; Feb 15; 2021. Tsung TH, Tsai YC, Lee HP, Chen YH, Lu DW. Biodegradable Polymer-Based Drug-Delivery Systems for Ocular Diseases. International Journal of Molecular Sciences. 2023; Aug 19; 24(16): 12976. Lyu Z, Ding L, Huang AT, Kao CL, Peng L. Poly (amidoamine) dendrimers: Covalent and supramolecular synthesis. Materials Today Chemistry. 2019; Sep 1; 13: 34-48. El-Moslamy SH, Kamoun EA. Novel long-acting brimonidine tartrate loaded-PCL/PVP nanofibers for versatile biomedical applications: fabrication, characterization and antimicrobial evaluation. Thang NH, Chien TB, Cuong DX. Polymer-based hydrogels applied in drug delivery: An overview. Gels. 2023; Jun 27; 9(7): 523. Chen J, Zhou R, Li L, Li B, Zhang X, Su J. Mechanical, rheological and release behaviors of a poloxamer 407/poloxamer 188/carbopol 940 thermosensitive composite hydrogel. Molecules. 2013; Oct 8; 18(10): 12415-25. Fea AM, Novarese C, Caselgrandi P, Boscia G. Glaucoma Treatment and Hydrogel: Current Insights and State of the Art. Gels. 2022; Aug 17; 8(8): 510. Dhumal N, Yadav V, Borkar S. Nanoemulsion as Novel Drug Delivery System: Development, Characterization and Application. Asian Journal of Pharmaceutical Research and Development. 2022; Dec 14; 10(6): 120-7. Mahboobian MM, Seyfoddin A, Aboofazeli R, Foroutan SM, Rupenthal ID. Brinzolamide–loaded nanoemulsions: ex vivo transcorneal permeation, cell viability and ocular irritation tests. Pharmaceutical Development and Technology. 2019; May 28; 24(5): 600-6. Avcil M, Çelik A. Microneedles in drug delivery: progress and challenges. Micromachines. 2021; Oct 28; 12(11): 1321. Roy G, Galigama RD, Thorat VS, Garg P, Venuganti VV. Microneedle ocular patch: Fabrication, characterization, and ex-vivo evaluation using pilocarpine as model drug. Drug Development and Industrial Pharmacy. 2020; Jul 2; 46(7): 1114-22. Jiang J, Gill HS, Ghate D, McCarey BE, Patel SR, Edelhauser HF, Prausnitz MR. Coated microneedles for drug delivery to the eye. Investigative Ophthalmology and Visual Science. 2007; Sep 1; 48(9): 4038-43. Sakpal D, Gharat S, Momin M. Recent advancements in polymeric nanofibers for ophthalmic drug delivery and ophthalmic tissue engineering. Biomaterials Advances. 2022; Sep 17: 213124. Li S, Chen L, Fu Y. Nanotechnology-based ocular drug delivery systems: recent advances and future prospects. Journal of Nanobiotechnology. 2023; Jul 22; 21(1): 232. Ahmad W, Jawed R. An updated review on preparation and characterization of solid lipid nanoparticles. Asian Journal of Pharmacy and Technology. 2022; 12(4): 313-9. Deshmukh S, Chaudhari B, Velhal A, Redasani V. A compendious review on biodegradable polymeric nanoparticles. Asian Journal of Pharmacy and Technology. 2022; 12(4): 371-81. Pravin P, Adhikrao Y, Varsha G. Ocular Drug Delivery and Novel Formulations: A Review. Asian Journal of Pharmacy and Technology. 2018; 8(4): 248-54. Khandbahale SV. A review-Nanosuspension technology in drug delivery system. Asian Journal of Pharmaceutical Research. 2019; 9(2): 130-8. Banu S, Farheen SA. Ocular Drug Delivery System: A Novel Approach. Asian Journal of Research in Pharmaceutical Science. 2019; 9(2): 97-106. Brahamdutt VK, Kumar A, Hooda MS, Sangwan P. Nanotechnology: Various methods used for preparation of Nanomaterials. Asian Journal of Pharmacy and Pharmacology. 2018; 4(4): 386-93.

Glaucoma is a chronic ocular disease requiring sustained drug delivery for effective treatment. This study presents the formulation and evaluation of a novel ocular drug delivery system using Poly(lactic-co-glycolic acid) (PLGA) nanoparticles for the combined glaucoma treatment with brinzolamide and brimonidine tartrate, as found in the drug Simbrinza. The PLGA nanoparticles exhibited an average hydrodynamic diameter of 178 ± 5 nm and a low Polydispersity Index (PDI) of 0.15 ± 0.03, ensuring uniform size distribution and efficient drug penetration. Zeta potential measurements revealed a stable surface charge of -27 ± 2 mV, enhancing colloidal stability. High drug loading efficiencies of 20% w/w for brinzolamide and 15% w/w for brimonidine tartrate were achieved, indicating effective drug encapsulation. Scanning and transmission electron microscopy confirmed uniform spherical morphology and a core-shell structure, ensuring structural integrity. In vitro drug release studies demonstrated sustained release profiles over 72 hours, following a diffusion-controlled mechanism with high correlation coefficients (R²) of 0.98 for brinzolamide and 0.97 for brimonidine tartrate. These findings suggest the potential of this PLGA nanoparticle-based delivery system for efficient and prolonged glaucoma therapy, promising improved patient compliance and therapeutic efficacy.

To assess the efficacy of 2% dorzolamide/0.5% timolol/0.2% brimonidine tartrate fixed combination (DTB-FC) eye drops in patients with intermediate glaucoma stage. A retrospective case series study was performed, including eyes diagnosed with primary open-angle (POAG) or chronic angle-closure glaucoma (CACG), which were at intermediate stage of the illness according to the Brusini grading system and were initially treated with 2% dorzolamide/0.5% timolol fixed combination (DT-FC), and switched at baseline to DTB-FC. Main outcome was intraocular pressure (IOP) baseline measured, as well as at weeks 1 and 2, months 1, 3, and 6, and 1 year after switching. IOP differences were analyzed using analysis of variance (ANOVA) repeated measures. A total of 36 eyes from 22 patients were included in the study. The median age of the participants was 61 years [interquartile range (IQR) 53-71], with 59.1% (n = 13) being female. At baseline, 1, 2 weeks, 1, 3, 6 months, and 1 year after switching to DTB-FC, the mean IOP values were 20.3 (95% CI, 19.5-21.1), 15.3 (95% CI, 14.5-16.1), 15.5 (95% CI, 14.7-16.2), 15.5 (95% CI, 14.8-16.0), 15.5 (95% CI, 14.9-16.2), 15.5 (95% CI, 14.8-16.2) and 15.3 (95% CI, 14.7-15.9) mm Hg, respectively (p > 0.001). The mean IOP reduction after 1 year of treatment was -5.0 ± (4.2-5.8) mm Hg. Treatment success rates were 86.1, 80.6, 80.6, 77.8, 72.2, and 66.7%, respectively. When stratified by diagnosis, there were no statistically significant differences in the treatment success rates between POAG and CACG (p > 0.05). Therapy switching from DT-FC to DTB-FC was shown to be effective in reducing IOP of eyes with POAG or CACG during 6-12 months. The DTB-FC therapy improved the therapeutic management of POAG or CACG previously treated with DT-FC therapy, which may be relevant to prevent its progression in the future. Justiniano JM, Rodríguez GM, Passerini MS. Triple-fixed Combination of Dorzolamide/Timolol/Brimonidine: Efficacy Study in Bolivian Population. J Curr Glaucoma Pract 2024;18(4):137-141.

Review of the Synthesis of Timolol Maleate and Brimonidine Tartrate Drug Substances Used for the Treatment of Open-Angle Glaucoma