Topical Timolol Maleate as An Adjuvant for Microneedling in The Treatment of Post-Acne Scars

Infantile hemangiomas (IHs) can lead to significant complications during the proliferative phase, particularly in thick lesions that are not adequately controlled by topical timolol due to its limited skin penetration. Oral propranolol is effective but limited by systemic side effects and resistance. To overcome these challenges, we developed a novel barbed microneedle (MN) system for depth-specific dual-drug delivery. Bleomycin (BLM) is loaded in the needle tips for deep ablation, while timolol (TM) is incorporated in the base hydrogel for superficial vasoconstriction, enabling synergistic therapy (TM-BLM@MN). The barbed structure secured prolonged retention in vivo. In vitro, the TM-BLM@MN significantly inhibited hemangioma stem cell proliferation, migration, and tube formation. In vivo, treatment of TM-BLM@MN achieved a 1.93-fold greater reduction in tumor volume compared to controls and markedly suppressed pathological angiogenesis by histology. TM-BLM@MN as a minimally invasive platform demonstrates high efficacy for thick IH and holds strong potential for clinical translation and home-based therapy.

Corchorus olitorius-derived green carbon dots: A single nanomaterial for multiplexed applications in sensing, catalysis, and critical micelle concentration analysis.

IntroductionInfantile hemangiomas, the commonest benign vascular tumors of infancy, often cluster on the head and neck where early treatment can avert permanent disfigurement, prompting us to evaluate 0.5% timolol maleate wet compresses as a non-invasive alternative to oral propranolol.MethodsWe conducted a study of 359 consecutive infants treated at Sichuan Provincial People's Hospital between December 2018 and January 2024. Baseline demographics, lesion site and size, age at initial treatment, treatment duration, and follow-up period were recorded. Treatment outcomes were graded as excellent (complete regression), good (≥50% shrinkage), fair (<50% shrinkage), or poor (no change/growth). Eexcellent/good outcomes were defined as a positive therapeutic effect, while fair/poor outcomes were classified as negative therapeutic effect.Results267 infants (74.37%) achieved positive therapeutic effect, with 117 excellent and 150 good, whereas 92 infants (25.63%) achieved negative therapeutic effect including 53 were fair and 39 poor. Treatment outcomes were significantly better when therapy began before 3 months (early age) (U = 9954, Z = − 3.256, P = 0.001) and for lesions ≤3 cm diameter (small size) (U = 2,869.5, Z = − 13.952, P < 0.001), and multivariate analysis confirmed early age (OR = 0.784, P = 0.024) and small size (OR = 0.113, P < 0.001) as independent predictors of positive therapeutic effect. Adverse events were mild: 24 (6.69%) local irritation, 41 (11.42%) transient systemic symptoms. Skin sequelae were observed in 12 (3.34%) cases.DiscussionTopical timolol compresses offer a safe, effective first-line option for superficial head-and-neck infantile hemangiomas, especially when started early and directed at smaller lesions.

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.

Amino-functionalized poloxamer-hyaluronate in situ gels for sustained delivery of timolol maleate in glaucoma therapy.

ObjectiveThis study aimed to develop and validate a nomogram prediction model based on the clinical characteristics, optic nerve status, and visual function to predict treatment outcomes after primary glaucoma surgery, providing a tool for clinical decision-making.MethodsClinical data from patients who underwent primary glaucoma surgery and received timolol maleate eye drops between January 2021 and March 2024 were retrospectively analyzed. Univariate and multivariate Logistic regression analyses were used to identify independent predictors. A nomogram was constructed based on regression coefficients. Model performance was assessed using the concordance index (C-index) and calibration curves.ResultsAmong 220 enrolled patients, 154 were assigned to the training set and 66 to the validation set. Poor treatment outcomes occurred in 27.27% and 25.76% of each group, respectively. Multivariate analysis identified cup-to-disc ratio, vascular resistance index, distant visual acuity, mean visual field level, central visual field sensitivity, and frequency contrast sensitivity (low, medium and high) as independent predictors of poor outcomes (all P < 0.05). The nomogram demonstrated high predictive accuracy, with area under the curve values of 0.928 (95% CI 0.879–0.978) in the training set and 0.823 (95% CI 0.640–1.000) in the validation set. Sensitivity and specificity were 0.879 and 0.827 in the training set, and 0.778 and 0.919 in the validation set, respectively. Calibration curves indicated good model fit.ConclusionThe nomogram model accurately predicts treatment outcomes after primary glaucoma surgery, showing strong discriminative ability and calibration. It may assist clinicians in personalizing postoperative treatment strategies. Further large-sample, multicenter studies are warranted for validation and broader application.

IntroductionThe simultaneous quantification of Brimonidine Tartrate and Timolol Maleate in ophthalmic formulations is essential for ensuring product quality, efficacy, and stability. However, few methods provide adequate selectivity, sensitivity, and environmental sustainability. This study aimed to develop and validate a robust, rapid, and reproducible reversed‐phase high‐performance liquid chromatography (RP‐HPLC) method with stability-indicating and green chemistry attributes.MethodsChromatographic separation was performed on a Supelco Discovery C18 column (25 cm × 4.6 mm, 5 μm) using isocratic elution with phase A (30 mM triethylamine buffer, pH 7.0) and phase B (acetonitrile) in a ratio of 80:20. The flow rate was 1.0 mL/min, and analytes were detected at 245 nm and 295 nm using a diode array detector. Method validation followed ICH Q2 (R1), USP, and FDA guidelines, evaluating linearity, accuracy, precision, specificity, robustness, and sensitivity. Forced degradation under acid, base, oxidative, thermal, and photolytic conditions was conducted to assess stability-indicating capability. Green analytical chemistry (GAC) metrics were calculated using Eco-Scale, GAPI, and AGREE tools.ResultsThe method exhibited excellent linearity over 100–500 ppm for Brimonidine Tartrate and 250–1,250 ppm for Timolol Maleate. Accuracy ranged from 99.42% to 99.82% for Brimonidine Tartrate and 98.71% to 101.10% for Timolol Maleate. Precision, specificity, and robustness results showed relative standard deviations below 2%. The LODs were 0.08 ppm for Brimonidine Tartrate and 0.20 ppm for Timolol Maleate, while LOQs were 0.24 ppm and 0.60 ppm, respectively. Forced degradation confirmed the method’s ability to separate both drugs from their degradation products. Brimonidine Tartrate remained stable under all stress conditions, whereas Timolol Maleate was susceptible to hydrolytic and oxidative degradation. The method demonstrated moderate greenness with an Eco‐Scale score of ~75, a GAPI pictogram with mixed green/yellow zones, and an AGREE score of 0.57.DiscussionThe validated RP-HPLC method proved accurate, precise, sensitive, and stability‐indicating for the simultaneous determination of Brimonidine Tartrate and Timolol Maleate. Its moderate GAC performance supports a balance between analytical rigor and sustainability. These findings establish the method as suitable for routine quality control and stability testing of ophthalmic formulations containing both drugs.

Eye drops suffer from challenges primarily associated with fast tear clearance, resulting in poor drug bioavailability. We developed a drug-eluting intraocular lens (IOL) that ensures a sustained release of timolol (maleate) as an antiglaucoma agent, for extended periods. Biodegradable poly(lactic-co-glycolic acid) (PLGA) microspheres encapsulated with timolol are first synthesized using the water-in-oil-in-water (w/o/w) double emulsion method. These drug-loaded microspheres are incorporated into poly(acrylamide-sodium acrylate) hydrogel (PAH) IOL cast from a 3D-printed mold, which is then monitored for sustained drug release for an extended period. Developed drug-loaded IOLs are transparent and flexible and demonstrate sustained release of timolol for over 7 weeks. This release duration is drastically higher than direct drug loading in the PAH film, i.e., the degradation control of drug release is much more efficient than drug transport by diffusion alone. Moreover, the incorporation of PLGA microspheres into the PAH film slows PLGA degradation, resulting in a 3-fold increase in release duration when compared to that of standalone microspheres. The resulting system ensures a long-term, patient-friendly approach to glaucoma treatment.

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.

A novel stability indicating RP-HPLC method of related substances for dorzolamide hydrochloride and timolol maleate in glaucoma treatment ophthalmic formulation

Objectives To evaluate the clinical characteristics and therapeutic outcomes of ulcerated infantile hemangioma (IH) and identify prognostic factors of ulcerated IH. Methods A single-center retrospective study recruiting patients with ulcerated IH between 2008 and 2023 was conducted. Clinical features and treatment response were analyzed to identify prognostic factors of ulcerated IH and differences in outcomes between early versus late pediatric dermatology referral. Results A total of 85 patients with ulcerated IH were included. Hemangiomas in the head and neck (H&N) and anogenital regions had an earlier presentation and occurrence of ulceration. Large hemangiomas or ulcers, combined/mixed IH, lip hemangiomas, and positive microbial growth were significant prognostic indicators for longer healing time, more complications and recurrence of ulceration. Cheek hemangiomas, focal IH and later onset ulceration were associated with less scarring and complications. Early referrals before ulceration had less ulcer recurrence (odds ratio [OR] = 0.139; 95% confidence interval [CI]: 0.028–0.693] and secondary complications (OR = 0.081 [95% CI: 0.019–0.348]). Prophylactic topical timolol maleate 0.5% was effective in reducing scar formation (OR = 0.06 [95% CI: 0.005–0.75]) and shortening follow-up duration (P = 0.044). Combination therapy with oral propranolol and pulsed dye laser was the mainstay of treatment (74%). Maintenance laser after ulcer resolution was associated with less ulcer recurrence (OR = 0.27 [95% CI: 0.075–0.96]). Conclusion Early referral of high-risk cases to a pediatric dermatology center before ulceration is crucial. Prophylactic topical timolol before ulceration and maintenance laser therapy after ulcer resolution can improve outcomes.

Extend Phase 2A study to evaluate additional concentrations of H-1337 and dosing frequencies, and to compare them with a positive control. Phase 2B, randomized, double-masked, active-controlled, dose-response study of 28 days of four treatments: H-1337 0.6% b.i.d., 1.0% b.i.d., or 1.0% q.d. (1.0% in the morning with H-1337 vehicle in the evening), and timolol maleate 0.5% b.i.d. Two hundred one subjects with open-angle glaucoma or ocular hypertension at eight private practice sites in the United States. Diurnal intraocular pressure (IOP) over 28 days of dosing. Non-inferiority to timolol in change from baseline in IOP at Day 1 and Day 28. Mean reduction in IOP was 4-7 mmHg for the H-1337 groups and 5-8 mmHg for the timolol group. Non-inferiority to timolol for H-1337 1.0% b.i.d. [upper limit of 95% confidence interval (CI) strictly lower than 1.5 mmHg] was met at 6/9 time points (Day 1: h 8 and 12; Day 28: h 2, 4, 8, and 12). Similar comparative efficacy was seen for the other H-1337 treatment groups. The most common adverse event observed was hyperemia, reported in 54.0% (27/50) for H-1337 1.0% q.d., 33.3% (17/51) for H-1337 0.6% b.i.d., 41.2% (21/51) for H-1337 1.0% b.i.d., and 8.2% (4/49) for timolol. H-1337 in doses of 0.6% b.i.d., 1.0% q.d., and 1.0% b.i.d. had ocular hypotensive efficacy in the range of timolol, although not within the strict Phase 3 non-inferiority margins, which would have required a larger sample size.

Comparing the intraocular pressure lowering (IOP-L) of microdrops (MD) dispensed with the Nanodropper to conventional drops (CD) in patients on IOP-L monotherapy. Outpatient clinic. Prospective, crossover, examiner-masked, active-controlled, randomized trial conducted at a single center. We enrolled adults with stable primary glaucoma or ocular hypertension on monotherapy with either latanoprost 0.005% or timolol maleate 0.5%. Subjects self-administered either CD or MD for 12 weeks, then crossed over to the alternate treatment for an additional 12 weeks. The primary outcome was IOP at 12 weeks compared to baseline at enrollment. Secondary outcomes included running out of drops (premature bottle exhaustion or PBE), adverse effects (AEs), and subjective evaluations of the device's usability. Twenty-nine subjects completed the study. MD significantly decreased IOP from baseline by 1.6 mm Hg (95% CI: 0.88 to 2.29), compared to a CD (0.13 mm Hg, 95% CI: -0.26 to 0.52). Incidence of PBE decreased from 83% with CD to 17% with MD. AEs were reduced from 83% of subjects reporting at least one AE with CD versus 62% with MD. Most found MD easy to administer and believed it helped prevent eyedrop waste. MD delivered with the Nanodropper adaptor provided additional IOP-L, significantly reduced PBE, and decreased the occurrence and severity of non-systemic AEs compared to CD in this cohort of stable POAG/OHT subjects. MD use among glaucoma subjects may enhance tolerability, improve adherence, and long-term IOP control.

Background/Objectives: Glaucoma is a multifactorial eye disease that can cause optic nerve damage and irreversible blindness. It is considered a significant public health problem worldwide. Topical intraocular pressure (IOP)-lowering eye preparations are used to prevent or slow further damage. Previously, we demonstrated that nimodipine (NMD), a calcium channel blocker, significantly reduced IOP after a single drop of NMD/HPMC suspension. The current study was designed to develop NMD chitosan nanoparticles (NMD-CS NPs) to improve the NMD IOP-lowering efficacy. Methods: NMD-CS NPs were prepared using the spontaneous-emulsification solvent diffusion method. Three different types of chitosan, carboxymethyl CS (CMCS), low molecular weight CS (LCS), and medium molecular weight CS (MCS), were used. Different concentrations of polymers, various stabilizers, and two pHs were used for formulation optimization. NMD-CS NPs were characterized regarding their particle size, polydispersity index (PDI), zeta potential, DSC, FTIR, and encapsulation efficiency. NMD-CS NPs were incorporated into eye drops and characterized in terms of their in vitro release, cytotoxicity, transcorneal permeability, and in vivo efficacy. Results: The optimized NMD-CS NPs demonstrate a small particle size with a narrow size distribution and acceptable zeta potential values. DSC and FTIR results confirmed the complete entrapment of NMD inside the NPs. NMD-CS NP eye drops successfully sustained NMD release without any burst effect. These NPs demonstrated a Higuchi non-Fickian diffusion mechanism and 79.41% improved corneal permeability. Cytotoxicity studies revealed that NMD formulations are nontoxic. After a single topical ocular application, NMD-MCS NP eye drops induced a significantly superior effect to Timolol maleate eye drops with regard to the %IOP reduction and duration of action. Conclusions: Evaluation results of NMD-CS NP eye drops show their positive effect in a preclinical animal model as a promising glaucoma therapy.

It was previously demonstrated that timolol (TIM), naphazoline (NAPH), and diflunisal (DIF) are susceptible to degradation when exposed to extreme pH conditions and UV/Vis light. However, their stability in the presence of pharmaceutical excipients remains largely unexplored. Thus, their binary mixtures (1:1 ratio, w/w) with five excipients, hydroxyethyl cellulose (HCA), mannitol (MAN), poly(vinyl alcohol) (PVA), poly(vinylpyrrolidone) (PVP), and Tris HCl (TRIS), were subjected to forced degradation (70 °C/80% RH and UV/Vis light in the dose 94.510 kJ/m2). Forced degradation was designed to accelerate potential interactions between these compounds, allowing the earlier identification of degradation risk compared to formal stability studies. FT-IR/ATR and NIR spectroscopy, along with chemometric evaluation using Principal Component Analysis (PCA) and Hierarchical Cluster Analysis (HCA), was applied to assess changes in the spectra, compared to individual compounds and the non-stressed mixtures. A hybrid approach, combining visual assessment with chemometric evaluation of the spectral data, enabled the detection of changes that were not clearly observable using a single analytical method. In particular, interactions of TIM, NAPH, and DIF with MAN and TRIS were clearly identified, while the mixtures of NAPH with excipients proved to be the least sensitive to forced degradation.

Glaucoma, a major global health issue, is the second leading cause of blindness. Topical eye drops are commonly used due to their simplicity, but the eye's protective barriers hinder optimal drug concentration at the target site. This study addresses these challenges by developing a novel dual-drug delivery system, integrating polycaprolactone microparticles loaded with latanoprost(hydrophobic) and timolol maleate(hydrophilic) antiglaucoma drugs into a gelatin-alginate hydrogel matrix. There is a fundamental challenge to combine both drugs in the same delivery system with a controlled release profile. Hydrogel-microparticles(HMPs) were assessed via in vitro drug-release and cell culture for biocompatibility with Raman analysis for chemical compatibility and drug diffusivity. Results showed that the hydrogel-microparticle system has prolonged drug release for up to 32 days. Raman analysis confirmed the chemical compatibility of the formulation components, and in vitro biocompatibility studies demonstrate that the HMPs system is biocompatible and exhibits minimal toxicity to the cells. This novel HMPs system can serve as a flexible, controlled release platform modulating the release profile. Our study highlights that the polymer and drug properties, along with the external matrix, were key factors influencing the drug release behavior of the formulations, and the proposed HMPs system can potentially be considered for glaucoma therapy.

Timolol maleate (TM), a beta-blocker drug, is used in treating conditions related to arterial hypertension. Exploring the possible interaction between TM and plasma proteins is crucial for enhancing the drug potency. This interaction study is done to examine the impact of TM on the comportment of bovine plasma Fibrinogen (FB) by utilizing spectroscopic and computational techniques such as fluorescence spectroscopy, circular dichroism (CD), and molecular docking. Employing fluorescence spectroscopy at temperatures 290 K, 298 K, and 308 K disclosed that TM used hydrophobic interactions to quench the intrinsic fluorescence of FB and show a hypochromic shift. The values of the binding and quenching rate constant specify the strong interaction between the TM and FB. The thermodynamic parameters such as ΔH and ΔG unveil the existence of hydrophobic forces. The CD demonstrates the influence of TM on the secondary structure of FB. Molecular docking revealed the theoretical evaluation of FB and TM binding. The investigation provides insightful information on stability, pharmacokinetics and bioavailability of TM, which is crucial for maximizing its therapeutic value.

Glaucoma, a leading cause of irreversible blindness, is characterized by retinal ganglion cell (RGC) degeneration due to elevated intraocular pressure (IOP) and apoptosis. While timolol maleate effectively lowers IOP, it does not prevent RGC loss and suffers from poor corneal permeability and rapid clearance. This study introduces a novel dual-delivery nanovesicular system employing multifunctional spanlastics to simultaneously lower IOP and inhibit RGC apoptosis via caspase-2 gene silencing. The system comprises two distinct nanovesicle populations: (i) timolol-loaded vesicles conjugated with peptide dendrimers to enhance corneal penetration and anterior segment delivery; and (ii) siRNA-loaded vesicles targeting Caspase-2, coated with hyaluronic acid for posterior segment delivery and gene silencing. This is the first approach integrating IOP reduction with targeted genetic intervention to protect RGCs. Formulations were optimized using a Design of Experiments approach and showed desirable physicochemical properties, sustained release, improved transcorneal permeability, and 1-month stability at 4 °C. In vitro studies confirmed Caspase-2 silencing and apoptosis reduction in RGC-5 cells, while in vivo results demonstrated prolonged IOP control. Safety was confirmed via histopathological and ocular irritation assessments. This targeted, non-invasive dual-delivery platform offers a promising therapeutic strategy for comprehensive glaucoma management.Supplementary InformationThe online version contains supplementary material available at 10.1038/s41598-025-10960-9.

Efficacy and safety of topical 0.5% timolol maleate enhanced by microneedling for treatment of post-acne scars