Timolol Research Articles

Doing the math: A simple approach to topical timolol dosing for infantile hemangiomas.

Topical timolol maleate has recently gained popularity as a treatment for superficial infantile hemangiomas, but calculating a safe dose of timolol can be time consuming, which may limit the medication's use in fast-paced clinical environments. This report offers a simplified calculation of the maximum daily safe dosage as 1 drop of medication per kilogram of body weight.

Synchronized Separation of Timolol from Some Prostaglandin Analogs (Bimatoprost, Latanoprost and Travoprost) for Determination in their Combined Pharmaceutical Formulations Using RP-HPLC

A rapid, precise and selective RP-LC method was developed for the simultaneous determination of the well-known beta blocker, Timolol (TIM), along with some of the most commonly prescribed prostaglandin analogues, namely; Bimatoprost (BIM), Latanoprost (LAT) and Travoprost (TRV), in laboratory prepared mixtures and in their combined pharmaceutical formulations. The chromatographic separation was carried out using gradient elution mode with a mobile phase consisting of 25 mM phosphate buffer (pH 3 ± 0.1), acetonitrile and methanol at a flow rate of 1 mL/min on a stationary phase composed of Thermo Hypersil BDS C18 (4.6×250 mm, 5 μm) column. UV detection was carried out at 295 nm and 210 nm wavelength gradient at 25°C. The method was validated according to ICH guidelines. Linearity, accuracy and precision results were satisfactory over the concentration ranges of 10.00-600.00 μg/ml for TIM and 1.00-60.00 μg/ml for BIM, LAT and TRV. The correlation coefficients (r2 values) were 0.9965 for TIM, 0.99995 for BIM, 0.99998 for LAT and 0.99996 for TRV. The method was successfully applied for the determination of TIM in its synthetic mixture and co-formulated eye drops with each of the three prostaglandin analogues BIM, LAT or TRV. The developed method is specific and accurate for the quality control and routine analysis of the cited drugs in their pharmaceutical preparations. This method is considered global and can be applied to all prostaglandin analog combinations with TIM.

DEVELOPMENT AND CHARACTERIZATION OF MUCOADHESIVE BUCCAL PATCH OF TIMOLOL MALEATE

The oral transmucosal Timolol maleate delivery bypasses liver and avoids presystemic elimination in the gastro intestinal tract andliver which enhance the bioavailability as well decreases the adverse effect. Objective: The present investigation highlights the formulation andevaluation of mucoadhesive buccal patch of Timolol maleate because Timolol maleate has biphasic solubility hence relatively permeated throughbuccal mucosa, which is well supplied with both vascular and lymphatic drainage. Material and Method: The mucoadhesive buccal patches ofTimolol maleate were prepared by solvent casting technique using polymers like Hydroxypropylmethyl cellulose-15cps and Polyvinylpyrrolidone. The formulated films were evaluated for their physiochemical parameters like surface pH, percentage moisture absorption, swellingpercentage, thickness, folding endurance and drug content. In vitro permeation and in vitro release studies were performed with pH 6.8 phosphatebuffer solution. Result and Discussion: The patches exhibited controlled release for more than 12 h. The in vitro release data were fit to differentequations and kinetic models to explain release profiles. The kinetic models used were zero order, first order higuchi’s and peppa’s. The bestmucoadhesive performance and matrix controlled release was exhibited by the formulation CK2 (3 % HPMC and 1 % PVP). Conclusion: Goodresults were obtained both in physico chemical characteristics and in vitro studies in formulation CK2. Hence the formulations of Timololmaleate bioadhesive buccal patch is a promising one as the controlled drug delivery with improved bioavailability.

Oral Propranolol Combined with Topical Timolol Maleate for the Treatment of Compound Infantile Hemangioma in Parotid Region

Oral Propranolol Combined with Topical Timolol Maleate for the Treatment of Compound Infantile Hemangioma in Parotid Region

Effect of benzalkonium chloride–preserved timolol maleate on dry eye disease in a black African population, southwestern Nigeria

Objective: Benzalkonium chloride, a commonly used preservative in many ophthalmic preparations, has been postulated as a cause of ocular surface toxicity, resulting in dry eye disease in patients on long-term treatment with topical medications. This study aims to determine the effect of benzalkonium chloride–preserved timolol maleate on dry eye disease in an African population. Materials and Methods: Information was retrieved from the data generated at a cross-sectional study on the prevalence of dry eye disease conducted in a randomly selected local government area, southwestern Nigeria, and analysis was conducted on participants with glaucoma and using benzalkonium chloride–preserved timolol maleate (cases), and age- and sex-matched controls. Results: One hundred and seventy-four participants were included in this study with a mean age of 65.05 ± 11.65 years. There was no significant association (P > 0.05) between the use of benzalkonium chloride–preserved timolol maleate and tear-film break-up time, Schirmer 1 test, fluorescein staining score, and overall diagnosis of dry eye disease in the patients. Conclusion: Benzalkonium chloride–preserved timolol maleate did not contribute significantly to dry eye disease in the studied population.

Vascular Anomalies of the Orbit--A Reappraisal.

The recent International Society for the Study of Vascular Anomalies (ISSVA) classification of vascular anomalies can be applied to orbital lesions, dividing them into vascular tumors and vascular malformations. Orbital cavernous hemangiomas are probably best considered cavernous venous malformations under this classification. Management of symptomatic lesions can be with surgical excision or stereotactic fractionated radiotherapy in selected cases. Beta-blockers including propranolol and topical timolol maleate represent first-line therapy for infantile hemangiomas, although surgery has a role in selected cases. Orbital venous-lymphatic malformations are problematic but with improved imaging, neuroradiological intervention, and a multidisciplinary approach to management, outcomes are improving.

NON-IONIC SURFACTANT VESICLES (NIOSOMES) BASED NOVEL OPHTHALMIC FORMULATION OF TIMOLOL MALEATE

The objective of the present work was to develop drug loaded niosomal ophthalmic formulation of timolol maleate (an antiglaucomal drug) for enhanced trans-corneal drug permeation and better ocular bioavailability. Timolol loaded niosomes were prepared by thin film hydration method using rotary evapoarator and ultra-sonicated for size reducation using probe sonicator. The nano-vesicle (niosomal) formulation was optimized by selecting surfactant content, cholesterol content and sonication time as independent variables and particle (vesicle) size, drug entrapment efficiency and % drug release as response variables for optimization studies. The timolol maleate niosomal (TMN) formulation was evaluated for particle size, pH and osmolality and was found to possess the desired properties. The developed TMN formulation was studied for % cumulative in-vitro drug release using bottle rotating apparatus (electrolab) and was found to be 79.98% over 8 hr period exhibiting sustained drug release profile. The ex-vivo trans-corneal drug permeation profile of developed TMN was studied using modified franz-diffusion cell apparatus (Permegear) and the % cumulative drug permeation across freshly excised goat cornea was found to be 65.90 % in 8 hrs duration, which was approximately 1.5 times higher than the conventional eye drop formulation. The developed TMN was also proved to be isotonic and non-irritant in HET-CAM ocular irritancy test. It was therefore, concluded from above studies, that the developed timolol maleate niosomal (TMN) formulation is better than conventional eye drops due to longer corneal retention, sustained drug release and better trans-corneal drug permeation and thereby higher ocular bioavailability, hence, would need less frequent administration.Â

ENHANCEMENT OF TRANSCORNEAL PERMEATION AND SUSTAIN RELEASE OF TIMOLOL MALEATE FROM DEVELOPED AND OPTIMIZED IN SITU GEL WITH BETTER SAFETY PROFILE

Glaucoma is a chronic disease that causes irreversible blindness. Timolol Maleate is used as first line drug in treatment of glaucoma. Poor ocular bioavailability and therapeutic response shown by conventional ophthalmic system can be overcome by use of in situ gelling system which undergoes reversible sol to gel transition in cul-de-sac by physical stimulation. Present work describes formulation and evaluation of pH sensitive in situ gel system of Timolol Maleate. Carbopol 974P was used as pH sensitive polymer with HPMC K15M as viscosity modifier. 32 factorial design was used to study the effect of independent variables viz. concentrations of Carbopol 974P and HPMC K15M on dependent variables like in vitro drug diffusion and viscosity. Optimized batch showed 88.48% drug diffusion upto 8h. Optimized formulation was evaluated for various parameters such as drug release study, isotonicity, texture analysis, preservative efficacy studies, sterility testing as per IP 2010, accelerated stability studies. Ex vivo transcorneal permeability study was carried out on goat eye cornea which showed that EDTA (0.5%) increases drug penetration by 1.90 fold and showed no corneal damage after histological study. In conclusion, prepared formulation is stable and non-irritant.

The application of artificial neural networks and support vector regression for simultaneous spectrophotometric determination of commercial eye drop contents

In the present study, artificial neural networks (ANNs) and support vector regression (SVR) as intelligent methods coupled with UV spectroscopy for simultaneous quantitative determination of Dorzolamide (DOR) and Timolol (TIM) in eye drop. Several synthetic mixtures were analyzed for validating the proposed methods. At first, neural network time series, which one type of network from the artificial neural network was employed and its efficiency was evaluated. Afterwards, the radial basis network was applied as another neural network. Results showed that the performance of this method is suitable for predicting. Finally, support vector regression was proposed to construct the Zilomole prediction model. Also, root mean square error (RMSE) and mean recovery (%) were calculated for SVR method. Moreover, the proposed methods were compared to the high-performance liquid chromatography (HPLC) as a reference method. One way analysis of variance (ANOVA) test at the 95% confidence level applied to the comparison results of suggested and reference methods that there were no significant differences between them. Also, the effect of interferences was investigated in spike solutions.

Self-Assembling Elastin-Like Hydrogels for Timolol Delivery: Development of an Ophthalmic Formulation Against Glaucoma.

This work focuses on improving the effectiveness of current therapies against glaucoma by incorporating self-assembled polymers into the ophthalmic formulation. To that end, we first studied the influence of the dispersing medium on the mechanical performance of self-assembling elastin-like (EL) and silk-elastin-like (SEL) hydrogels by conducting rheological tests. These polymers were subsequently incorporated into the antiglaucoma formulation, which contains timolol maleate (TM) as active ingredient, and in vivo tests, namely adhesion tests and intraocular pressure measurements (IOP), were performed in New Zealand rabbits. An enhanced reduction in IOP due to the presence of the polymers was observed. Moreover, differences in the effectiveness between both EL- and SEL-hydrogels, which can be explained on the basis of the different rheological properties displayed by these two systems, were also encountered. The results point to the potential of this system as a basis for the development of an ophthalmic formulation against glaucoma.

Self-Assembling Peptide Nanofiber Hydrogels for Controlled Ocular Delivery of Timolol Maleate.

The self-assembling peptides Ac-(RADA)4-CONH2 and Ac-(IEIK)3I-CONH2, which form hydrogels in physiological conditions, were evaluated as carriers for ocular delivery of the β-blocker timolol maleate. Electron microscopy studies revealed that hydrogels contain nanofibers, whereas rheological studies showed that the Ac-(IEIK)3I-CONH2 self-assembles in a stiffer hydrogel compared with the Ac-(RADA)4-CONH2 peptide. The in vitro release and ex vivo permeation studies demonstrated controlled release and transport of the drug through the cornea, which depended on the self-assembling peptide sequence. In vivo studies in rabbits showed significant increase in the area under the concentration-time curve (AUC) after administration of the drug through the Ac-(RADA)4-CONH2 hydrogel compared to drug solution, whereas a sustained reduction of intraocular pressure for up to 24 h after instillation was achieved for both drug-loaded hydrogels. Histological studies revealed good ocular tolerability upon application of the formulations, suggesting that self-assembling peptide hydrogels are promising systems for sustained ocular drug delivery.

Nanogel-based natural polymers as smart carriers for the controlled delivery of Timolol Maleate through the cornea for glaucoma

Despite frequent scientific efforts, efficient ocular drug delivery is a major challenge for pharmaceutical scientists. Poor bioavailability of ophthalmic solutions can be overcome by using smart ophthalmic drug-delivery systems. In this research, loading and delivery of Timolol Maleate (TM) through the cornea by synthesized nanoparticles based on biopolymers (chitosan-alginate) were studied. The physico-chemical properties of these nanoparticles were characterized using scanning electron microscopy (SEM), transmission electron microscopy (TEM) and dynamic light scattering (DLS). Loading and release were evaluated by a UV–vis spectrometer and the ex vivo permeation study was carried out using the Franz Diffusion Cell and fluorescent microscopy studies. The results indicated that morphology and size of nanoparticles were spherical and in the range of 80–100nm. The loading capacity and encapsulation efficiency were about 42% and 94% respectively. They illustrated a burst release in the first hour followed by a slower and more sustained drug release during the next 24h. Also, the results indicated that the cornea penetration of TM loaded in nanoparticles was twice than that of TM. Hence, this nanocarrier can be considered as a suitable candidate for controlled TM delivery and release through the cornea.

Changes in Ocular Hemodynamics after Carotid Artery Angioplasty and Stenting (CAAS) in Patients with Different Severity of Ocular Ischemic Syndrome

ABSTRACTPurpose: To evaluate the effects of carotid artery angioplasty and stenting (CAAS) on patients who were diagnosed with ocular ischemic syndrome (OIS).Methods: Sixty-four eyes of 64 OIS patients with ipsilateral internal carotid artery stenosis ≥70% were included in the study. The study eyes were divided into two groups according to the presence of iris neovascularization: NVI-absent group and NVI-present group, with 32 eyes, respectively. All patients received ocular treatment modality according to the presence of non-perfusion area (pan-retinal photocoagulation) and intraocular pressure (medical treatment included timolol maleate eye drops combined with brinzolamide eye drop; trabeculectomy and cyclophotocoagulation). All patients went through CAAS surgery for treatment of internal carotid artery stenosis. Best-corrected visual acuity (BCVA); intraocular pressure (IOP), slit lamp examination, iris fluorescence angiography, fundus fluorescein angiography and color Doppler ultrasound of the internal carotid artery (ICA), ophthalmic artery (OA), central retinal artery (CRA), and short posterior ciliary arteries (PCA) were performed pre-operatively and 1 month, 3 months, 6 months, and 12 months post-operatively.Results: There was no significant BCVA change postoperatively in the NVI-absent group, while postoperative BCVA in the INV-present group decreased significantly. There was no significant BCVA difference at pre-operative and 1month post-operative follow-up between the two groups. However, post-operative BCVA of NVI-present group starting from 3-months follow-up was significantly worse than NVI-absent group. Arm-retinal artery circulation time and arteriovenous circulation time decreased significantly in NVI-absent group, while showed no statistical difference in NVI-present group during the 12-months follow-up. Postoperative peak systolic velocity (PSV) of the ophthalmic artery, the central retinal artery, and short posterior ciliary artery showed significant increases at 1 month, 3 months, 6 months and 12 months follow-up in both groups.Conclusion: CAAS can greatly improve ocular blood in OIS patients with and without iris neovascularization. However, CAAS improved BCVA only in patients without iris neovascularization.

Validated TLC-Densitometry Method for Simultanouse Determination of Brinzolamide and Timolol in Their Ophthalmic Preparation

Sensitive, simple and accurate thin-layer chromatography (TLC) - densitometry method for simultaneous determination of brinzolamide (BRZ) and timolol maleate (TML) in their pharmaceutical formulations was developed and validated, where separation was occurred using a mobile phase composed of chloroform: methanol: ammonia (9:0.5:0.1 by volume) on silica gel 60 F254 plates, densitometric detection was done at 254 nm for brinzolamide and 298 nm for timolol. The calibration curves are linear over the concentration range of 3-16 μg/spot for BRZ and 4-14 μg/spot for TML. The obtained results were statistically compared with those obtained by the reported methods, showing no significant difference. The developed method was validated according to the ICH guidelines and was successfully applied for simultaneous determination of brinzolamide and timolol maleate in bulk drug and in their ophthalmic preparation.

Combined Oral and Topical Beta Blockers for the Treatment of Early Proliferative Superficial Periocular Infantile Capillary Hemangioma.

To evaluate the safety and efficacy of combined oral and topical beta blockers for the treatment of superficial periocular infantile hemangioma at the early proliferative stage. This was a randomized, controlled comparison trial involving 25 patients. Patients were randomly enrolled into two groups: the topical and systemic treatment and systemic treatment only groups. The topical and systemic treatment group was treated with oral propranolol (1 mg/kg per day initially, increased to 2 mg/kg per day gradually in 2 weeks) and timolol maleate 0.5% gel. The systemic treatment only group received oral propranolol (1 mg/kg per day initially, increased to 2 mg/kg per day gradually in 2 weeks) and simple eye ointment to be applied to the lesion. The Hemangioma Activity Score was used to record the proliferative activity of the hemangioma. The main outcomes of the study were the change in the hemangioma size, the proliferative activity, and the treatment side effects. At the end of the treatment period, the Hemangioma Activity Score was significantly improved in both groups from their values before treatment. However, the score obtained after treatment was significantly better in the topical and systemic treatment group (P < .05). Regarding the response to treatment, 10 and 3 cases in the topical and systemic treatment and systemic treatment only groups, respectively, showed a good response, with a significant difference between the two groups (P < .50). There were no recorded serious local or systemic complications during treatment in either group. The results from combining topical with oral beta blockers showed that topical beta blockers are of additive value in treating superficial periocular infantile hemangioma in the early proliferative stage. [J Pediatr Ophthalmol Strabismus. 2018;55(1):37-42.].

Co-instillation of nano-solid magnesium hydroxide enhances corneal permeability of dissolved timolol

We prepared magnesium hydroxide (MH) nanoparticles by a bead mill method, and investigated whether the co-instillation of MH nanoparticles improves the low transcorneal penetration of water-soluble drugs, such as the anti-glaucoma eye drug timolol maleate (TM). MH particle size was decreased by the bead mill treatment to a mean particle size of 71 nm. In addition, the MH nanoparticles were highly stable. Next, we demonstrated the effect of MH nanoparticles on the corneal surface. MH shows only slight solubility in lacrimal fluid, and the instillation of MH nanoparticles for 14 days did not affect the behavior (balance of secretion and excretion) of the lacrimal fluid in rabbit corneas. Moreover, there was no observable corneal toxicity of MH nanoparticles, and treatment with MH nanoparticles enhanced the intercellular space ratio in the eyes of rats. MH alone did not permeate into the cornea; however, the co-instillation of MH nanoparticles and dissolved TM (nMTFC) enhanced the corneal penetration of TM. In addition, the intraocular pressure (IOP)-reducing effect of nMTFC was significantly higher than those of the TM solution or the co-instillation of MH microparticles and TM. In conclusion, we found that MH nanoparticles enhance the corneal penetration of dissolved TM with no observable corneal stimulation or obstruction of the nasolacrimal duct by the MH nanoparticles. It is possible that the co-instillation of MH nanoparticles may provide a useful way to improve the bioavailability of water-soluble drugs in the ophthalmic field. These findings provide significant information that can be used to design further studies aimed at developing anti-glaucoma eye drugs.

Ophthalmic administration of a 10-fold-lower dose of conventional nanoliposome formulations caused levels of intraocular pressure similar to those induced by marketed eye drops

The purpose of this study was to compare the in vivo efficacy of several timolol (TM)-loaded liposomal formulations with current TM antiglaucoma treatment (aqueous 0.5% w/v eye drops).In this study, conventional liposomes (CL) and deformable liposomes, without (DL1) and with ethanol (DL2) were prepared and characterized. In addition, in vitro release and permeation studies, as well as in vivo lowering intraocular pressure (IOP) and biocompatibility studies were performed.It was found that the quali and quantitative lipid bilayer composition played a significant role in modifying the physical properties of vesicles. The deformability study and electronic microscopy images revealed that membrane elasticity of DL1 and DL2 was much higher than CL. However, in vitro permeation results showed that the flux and permeability coefficient were significantly higher in CL compared to DL.The IOP study revealed that TM-loaded CL showed the best pharmacological activity, in comparison to deformable vesicles. Compared to the eye drops, CL formulation could equally reduce the IOP but using a concentration 10-fold lower, whereas the effective time was significantly longer. In addition, the formulations showed no irritant effects after instillation on the ocular surface.

Development and characterisation of electrospun timolol maleate-loaded polymeric contact lens coatings containing various permeation enhancers

Despite exponential growth in research relating to sustained and controlled ocular drug delivery, anatomical and chemical barriers of the eye still pose formulation challenges. Nanotechnology integration into the pharmaceutical industry has aided efforts in potential ocular drug device development. Here, the integration and in vitro effect of four different permeation enhancers (PEs) on the release of anti-glaucoma drug timolol maleate (TM) from polymeric nanofiber formulations is explored. Electrohydrodynamic (EHD) engineering, more specifically electrospinning, was used to engineer nanofibers (NFs) which coated the exterior of contact lenses. Parameters used for engineering included flow rates ranging from 8 to 15μL/min and a novel EHD deposition system was used; capable of hosting four lenses, masked template and a ground electrode to direct charged atomised structures. SEM analysis of the electrospun structures confirmed the presence of smooth nano-fibers; whilst thermal analysis confirmed the stability of all formulations. In vitro release studies demonstrated a triphasic release; initial burst release with two subsequent sustained release phases with most of the drug being released after 24h (86.7%) Biological evaluation studies confirmed the tolerability of all formulations tested with release kinetics modelling results showing drug release was via quasi-Fickian or Fickian diffusion. There were evident differences (p<0.05) in TM release dependant on permeation enhancer.

Dorzolamide Hydrochloride %2 and Timolol Maleate %0.5 FixedCombination in Lowering Intraocular Pressure after Phacoemulsification Cataract Surgery

Background and objectives: To evaluate the role of dorzolamide –timolol fixed combination in lowering intraocular pressure (IOP) after cataract surgery. Methods: The study included 94 eyes of 89 patients who underwent cataract surgery and intraocular lens implantation. Patients planed for phacoemulsification were assigned to 1 of 2 groups. The treatment group received 1 drop of dorzolamide-timolol fixed combination immediately after surgery, and the control group received no treatment. The IOP was measured preoperatively and at 6 hours and 24 hours post- operatively. Results: The mean IOP change was lower in the treatment group than in the control group at 6 hours postoperatively. The difference between the mean IOP a value of the two groups at 6 hours postoperatively was found to be statistically significant. Twenty-four hours after the surgery, the mean IOP change was still higher in the control group when compared to the treatment group. Conclusions: The fixed combination dorzolamide-timolol can effectively lower IOP after phacoemulsification cataract surgery.

Topical timolol maleate for the treatment of infantile hemangiomas works, but referral is still the standard of care

Topical timolol maleate for the treatment of infantile hemangiomas works, but referral is still the standard of care