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For partial responder patients (timolol group and one patient of propranolol group), we decided to start therapy with elastic stocking. Patients were randomly divided into two treatment groups; six patients were treated with timolol maleate 0.5% gel (available for ophthalmic use), while the remaining patients were treated with 2% propranolol cream (galenic preparation). [Extracted from the article]

Overall, 19 patients completed the treatment and follow-up, as one patient in the PDL group lost to follow-up after the first treatment (Table 1). Infantile haemangioma (IH) is the most common benign vascular tumour of infancy, and approximately 10-15% of patients with IH develop complications, among which ulceration is the most frequent.1 To date, oral propranolol has been most widely used in ulcerated IHs.2 Nevertheless, for relatively small ulcers, the topical application of timolol was proposed as an alternative method.3 Meanwhile, pulsed dye laser (PDL) may also promote the resolution of ulcerated IHs.4 However, there are no clinical studies comparing the efficacy of these two localized therapies in promoting ulcer healing in IHs. [Extracted from the article]

Glaucoma is a group of irreversible ocular diseases which result in damage to the optic nerve and vision loss. The objective of the present work was to develop micelles-laden contact lenses (CLs-M) that could achieve the sustained release of timolol and latanoprost simultaneously for the treatment of glaucoma. CLs-M were obtained by free radical polymerization of HEMA monomer with timolol and latanoprost loaded mPEG-PLA micelles. The prepared CLs-M had a minimal impact on critical CLs properties, and could release timolol and latanoprost in simulated tear fluid for 144 h and 120 h individually, which is promising for extended drugs release applications. The in vivo PK study on rabbit eyes showed sustained timolol and latanoprost release for up to 120 h and 96 h in tear fluid, respectively. There was significant improvement of the mean residence time (79.6-fold and 122.2-fold) and bioavailability (2.2-fold and 7.3-fold) for both timolol and latanoprost delivered by CLs-M compared with eye drops. An in vivo PD study in a rabbit model with high IOP showed sustained reduction in the IOP for over 168 h. The relative pharmacological availability (PA) of CLs-M was 9.8 times as high as the eye drops. The protein adsorption, ocular irritation study and histological examination study indicated the safety of CLs-M. Therefore, this work has demonstrated the promising potential of micelles-laden CLs to co-deliver timolol and latanoprost for an extended period of time to treat glaucoma. Unlabelled Image [ABSTRACT FROM AUTHOR]

Background Although infantile hemangioma is a common benign childhood tumor, it is still one of the challenging problems. Aim The current prospective study aimed to evaluate the effect of local propranolol gel in the treatment of infantile periorbital hemangioma. Patients and methods A prospective study in the period of 4 years from January 2012 to December 2016 was carried out on infants with periorbital hemangioma with a follow-up period of a minimum of 1 year. All infants underwent a fine-needle histopathological sample. All patients who proved to be capillary hemangioma were divided into two groups. Group I included those patients who were treated with topical timolol maleate gel from 4 to 30 weeks. On the other hand, group II included those patients who underwent a local corticosteroid therapy in the form of clobetasol 0.05% gel for a similar period. Posttherapy clinical and histopathological assessment took place in both groups. The obtained data were statistically analyzed. Results Twenty-eight patients were enrolled in the study. They were 18 women and 10 men with the ratio of women to men being about 2 : 1. In 21 infants, the tumor shrank in a period of 4–10 weeks after topical timolol administration. On the other hand, those who underwent local corticosteroid therapy showed a longer period for the shrinkage of the tumor; the P value is less than 0.003. Conclusion Local timolol gel therapy is superior to topical corticosteroid therapy with a wide range of safety and less side effects. Moreover, its cost-effectiveness is acceptable compared with other modalities such as laser therapy. The number of the study materials are limited; yet, it may be an indicator for a road map of managing infantile periorbital hemangiomas. Further studies with a larger population may be needed, as the problem deserves a full citizenship in the world of pediatric research. [ABSTRACT FROM AUTHOR]

In the present investigation, an attempt was made to formulate timolol maleate (TML) loaded polymeric nanoparticles of flax seed gum (FX) and chitosan (CH) for ocular delivery using ionic gelation method. The process of nanoparticle preparation was optimized using 2-factor, 3-level central composite experimental design. The optimal concentration of FX and CH that yielded nanoparticles with minimum particle size (267.06 ± 8.65 nm) and maximum encapsulation efficiency (74.96 ± 4.78%) was found to be 0.10% w/v and 0.08% w/v, respectively. The formulated nanoparticles revealed considerable bioadhesive strength and exhibited sustained release of drug in in vitro diffusion studies. The ex vivo transcorneal penetration study revealed higher corneal penetration of TML compared to marketed eye drops. The confocal scanning laser microscopy (CSLM) studies also confirmed the ability of nanoparticles to penetrate into deeper layers of cornea. The histopathological studies revealed corneal biocompatibility of nanoparticles. The nanoparticles were found to reduce the intra ocular pressure (IOP) in rabbits for prolonged period when compared to conventional eye drops. The results of the present study suggested a promising role of polymeric nanoparticles for ocular drug delivery in treatment of glaucoma. [ABSTRACT FROM AUTHOR]

Glaucoma is a progressive, chronic optic neuropathy characterized by a typical visual field defects. Four main classes of topical medication are actually available on the market: beta-blockers, prostaglandins, alpha2-agonists, and topical carbonic anhydrase inhibitor to treat intraocular pressure (IOP). The aim of this review is to outline the efficacy of timolol and to evaluate the impact of this treatment on patients' quality of life. Among beta-blockers, timolol is most used at three different concentrations: 0.1%, 0.25%, and 0.5%. While the first one is a gel, the other two products are solution. Timolol has few topical side effects, while it has some important systemic side effects on the cardiac and respiratory systems. The balance between efficacy and safety is always the main aspect to care patients. Because of the less efficacy of timolol 0.1% solution, the possibility to use carbomers as vehicle in the gel drops helped timolol 0.1 to be used in clinics, extending the time contact between the active ingredient and the surface of the cornea. Using preservative-free timolol 0.1 for treatment, IOP was at the same level of the other beta-blockers at higher concentration, but it was better tolerated. Preservative-free treatment improved the quality of life reducing dry-eye like symptoms; furthermore, the presence of an artificial tear in the medication bottle could help adherence. The once daily dosing improves compliance. [ABSTRACT FROM AUTHOR]

Objective: The clinical, demographic and treatment characheristics of patients with Kaposi's sarcoma (KS) are not well-defined. There is lack of consensus on treatment modalities. Thus, we aimed to define demographic, clinical characteristics and treatment outcomes in our cohort of patients with KS. Patients and Methods: A retrospective cohort study was done and all patients who were followed up in our specialized cutaneous tumors outpatient clinic with a diagnosis of KS between 2006 and 2018 were included in the study. Results: A total of 25 patients were included in the study. The mean age of the patients was 66 and 80% were male. The most common form of KS was classic type (80%). During a mean follow-up of 43 months, the most frequently administered treatments were cryotherapy, interferons, radiotherapy, topical imiquimod and topical timolol. Overall a complete response was observed in 9 (36%) patients. Conclusion: The clinical and demographic characteristics of our cohort match those observed in existing literature. We think that the use of local treatments such as cryotherapy, topical imiquimod should be used more frequently in patients with limited disease. Considering the efficacy of timolol in other vascular tumors, future prospective studies investigating the effects of timolol in KS are highly warranted. [ABSTRACT FROM AUTHOR]

Background/Objectives: First‐line therapy for infantile hemangiomas (IH) is oral propranolol, a systemic beta‐blocker with the risk of rare but serious adverse effects. Topical timolol presents an attractive off‐label alternative with good tolerability, but sequential therapy with propranolol followed by timolol is not well studied. Here, we report effects of topical timolol preceding or following oral propranolol as adjunct therapy for IH. Methods: A retrospective chart review of 559 patients with IH seen at the pediatric dermatology clinic of a tertiary care center between December 2008 and January 2018. Children were grouped by treatment received: propranolol only, timolol only, propranolol to timolol, timolol to propranolol to timolol, and timolol to propranolol. Patient demographics, clinical/treatment characteristics, and pairwise differences were explored between groups. Results: Among all patients treated with propranolol, those who received propranolol followed by timolol received the shortest duration of oral propranolol and were the youngest at the time of propranolol completion. These patients received propranolol for a median of 2.2 months duration (P = 0.006) and were a median of 1.7 months younger (P = 0.007) compared with patients who received oral propranolol only. None had treatment failure defined as requiring propranolol reinitiation, compared with 13% of patients in the propranolol only group (P = 0.036). Conclusions: Sequential therapy with oral propranolol followed by topical timolol for IH may help minimize potential adverse effects of systemic beta‐blockers by reducing the duration of propranolol therapy and facilitating successful taper at a younger age without an increase in treatment failures. [ABSTRACT FROM AUTHOR]

PURPOSE: The purpose of the study is to evaluate the changes in contrast sensitivity (CS) after using the four different types of antiglaucoma eye drops in patients with primary open-angle glaucoma (POAG) by OPTEC-functional vision analyzer (FVA). METHODS: In this prospective study, eighty patients (80 eyes) with POAG were randomly divided into four groups. The groups were randomly received timolol maleate 0.5%, travoprost 0.004%, dorzolamide 2%, and brimonidine tartrate 0.2%. The medications were used in the eye that was randomly selected. The CS was assessed before and 15 min after the intervention by the FVA. The paired t-test was used to compare the difference between before and after the intervention. P< 0.05 was considered statistically significant. RESULTS: Fifteen minutes after the instillation of timolol maleate (Group A), the CS in three out of twenty patients at the spatial frequencies of 1.5, and 3 cycles per degree (cpd) was significantly decreased (P = 0.015). However, using travoprost (Group B) and dorzolamide (Group C), the CS in one out of twenty patients at low spatial frequencies (1.5 and 3 cpd) was decreased in the two groups, which was not statistically significant for these medications (P > 0.05). In Group D, after applying brimonidine tartrate, the CS in two out of twenty patients at the spatial frequency of 18 cpd was significantly decreased (P = 0.042). CONCLUSION: Our study showed that CS values at low and high spatial frequencies after applying timolol and brimonidine eye drops are temporarily reduced in patients with POAG. [ABSTRACT FROM AUTHOR]

Abstract This article reports on electrohydrodynamic atomization to engineer on-demand novel coatings for ocular contact lenses. A formulation approach was adopted to modulate the release of timolol maleate (TM) using chitosan and borneol. Polymers polyvinylpyrrolidone and poly (N-isopropylacrylamide) were utilized to encapsulate TM and were electrically atomized to produce optimized, stationary contact lens coatings. The particle and fiber diameter, thermal stability, material compatibility of the formed coatings, their in vitro release-modulating effect, and ocular tolerability were investigated. Results demonstrated highly stable nanomatrices with advantageous morphology and size. All formulations yielded coatings with high TM encapsulation (>88%) and excellent ocular biocompatibility. Coatings yielded biphasic and triphasic release, depending on composition. Kinetic modeling revealed a noticeable effect of chitosan; the higher the concentration, the more the release of TM because of chitosan swelling, with the mechanism changing from Fickian diffusion (1% w/v; n = 0.5) to non-Fickian (5% w/v, 0.45 < n < 0.89). The use of electrohydrodynamic atomization has not yet been explored in depth within the ocular research remit, engineering on-demand lens coatings capable of sustaining TM release. This is likely to offer an alternative dosage form for management of glaucoma with particular emphasis on improving poor patient compliance. [ABSTRACT FROM AUTHOR]

Purpose: To perform patient preference-based comparative effectiveness and cost-utility (cost-effectiveness) analyses to evaluate topical bimatoprost 0.01%, latanoprost 0.005%, travoprost 0.004%, tafluprost 0.0015%, and timolol 0.5% for the treatment of open-angle glaucoma (OAG).Methods: Value-Based Medicine®, incremental cost-utility analysis, and average cost-utility analysis were performed using published systematic review and network meta-analyses with 3-month clinical data for a base case of OAG with an untreated intraocular pressure of 26 mm Hg. Visual acuity and visual field changes were converted to time tradeoff utility format. A 20-year model was undertaken; bilateral therapy was presumed; a national average Medicare Fee Schedule was used; and ophthalmic, third party insurer, and societal cost perspectives were utilized. Patient value outcomes (QALYs or quality-adjusted life-years) and costs were discounted at 3% annually.Results: Bimatoprost conferred a mean 2.56 QALY gain (22.9% patient quality-of-life gain) for the average OAG patient, while latanoprost for the average OAG patient, while latanoprost conferred a 2.00 QALY gain (17.8% quality-of-life gain), tafluprost a 1.99 QALY gain (17.9% quality-of-life gain), travoprost a l.92 QALY gain (17.2% quality-of-life gain), and timolol a 1.42 QALY gain (12.8% quality-of-life gain). The ophthalmic cost-perspective, incremental cost-utility ratio of bimatoprost referent to travoprost was $6,034/QALY, to latanoprost was $27,973/QALY, and to timolol was $16,063/QALY. Bimatoprost dominated tafluprost, meaning that it conferred greater patient value for lesser cost than tafluprost.Conclusions: Topical bimatoprost delivers greater patient value than the other prostamides and topical timolol for the treatment of OAG. Bimatoprost is incrementally cost-effective referent to the other prostamides and timolol. [ABSTRACT FROM AUTHOR]

Abstract A carbon paste electrode modified with iron (III) oxide nanoparticles (MCPE) was fabricated for the simultaneous quantitative voltammetric determination of timolol maleate (TM) and brimonidine tartrate (BT) using chemometrics analysis. In this paper, for the first time, a novel voltammetric method was developed for a rapid, sensitive and efficient simultaneous determination of TM and BT in the marketed ophthalmic formulation. This method is based on the incorporation of iron (III) oxide nanoparticles into the carbon paste electrode which improves the characteristics of the electrode and increases its sensitivity. The electrochemical oxidation of the two drugs was established using cyclic voltammetry (CV), differential pulse voltammetry (DPV) and square wave voltammetry (SWV) techniques. DPV and SWV techniques were developed for the quantitative voltammetric determination of TM and BT in their pure forms and pharmaceutical formulations. The method revealed a minimum detectability (LOD) of 1.31 × 10−6 μg/mL for BT and 1.37 × 10−5 μg/mL for TM and a limit of quantitation (LOQ) of 3.97 × 10−6 μg/mL for BT and 4.16 × 10−5 μg/mL for TM for SWV. Different chemometric methods (PCR and PLS) were tested for the resolution of the overlapped peaks of both compounds and their determination in mixtures. The best results were obtained with the PLS method. The proposed method was validated and compared with the reported HPLC method, revealing the good accuracy, precision and reproducible results of this method. Highlights • In this study, TM and BT are both determined using chemometrics. • we reached very low detection limits. • Robust process (less affected by the variation of inputs) [ABSTRACT FROM AUTHOR]

Graphical abstract Gelatinized-core liposomes as a new Trojan horse for the development of a novel glaucoma medication. Abstract Glaucoma treatment with ocular medications requires overcoming the corneal barrier to drug penetration. Liposomes have a great corneal penetration ability and affinity while suffering from poor stability and low entrapment of hydrophilic drugs accompanied by rapid drug release. This work aims to develop a new, effective and stable glaucoma medication with sustained drug release properties; Timolol maleate gelatinized core liposomes. A full factorial design was utilized to study the effects of three formulation variables on drug loading and vesicle particle size. Vesicles were prepared by the thin-film hydration method, and characterized for in-vitro drug release and stability. Intra-ocular pressure (IOP) reduction was evaluated in-vivo on glaucomatous rabbit's eyes. The safety profile was assessed using histopathological examinations. Gelatin significantly increased the drug entrapment percentage reaching 50% with a particle size of 38.81 µm. Sustained drug release was recorded compared to a marketed product and to a conventional liposomal formulation. The prepared vesicles caused the highest reduction in IOP accompanied by safe histological findings. This work provided a new, safe and effective ocular glaucoma medication; Timolol maleate gelatinized core liposomes, solving the main problems of ocular liposomal formulations of hydrophilic drugs, suitable for the pharmaceutical industry and comprising abundant and relatively cheap components. [ABSTRACT FROM AUTHOR]

Timolol is a medication used widely to treat glaucoma. Regarding Ca2+ signaling, timolol was shown to modulate Ca2+-related physiology in various cell types, however, the effect of timolol on Ca2+ homeostasis and cell viability has not been explored in human prostate cancer cells. The aim of this study was to explore the effect of timolol on intracellular Ca2+ concentrations ([Ca2+]i) and viability in PC3 human prostate cancer cells. Timolol at concentrations of 100-1000 μM induced [Ca2+]i rises. The Ca2+ signal in Ca2+-containing medium was reduced by removal of extracellular Ca2+ by approximately 75%. Timolol (1000 μM) induced Mn2+ influx suggesting of Ca2+ entry. Timolol-induced Ca2+ entry was partially inhibited by three inhibitors of store-operated Ca2+ channels: nifedipine, econoazole and SKF96365, and by a protein kinase C (PKC) activator (phorbol 12-myristate 13 acetate [PMA]) or an inhibitor (GF109203X). In Ca2+-free medium, treatment with the endoplasmic reticulum Ca2+ pump inhibitor thapsigargin abolished timolol-evoked [Ca2+]i rises. Conversely, treatment with timolol abolished thapsigargin-evoked [Ca2+]i rises. Inhibition of phospholipase C (PLC) with U73122 abolished timolol-induced [Ca2+]i rises. Timolol at concentrations between 200 and 600 μM killed cells in a concentration-dependent fashion. Chelation of cytosolic Ca2+ with 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid/AM (BAPTA/AM) did not reverse cytotoxicity of timolol. Together, in PC3 cells, timolol induced [Ca2+]i rises by evoking Ca2+release from the endoplasmic reticulum in a PLC-dependent manner, and Ca2+ influx via PKC-regulated store-operated Ca2+ entry. Timolol also caused cell death that was not linked to preceding [Ca2+]i rises. [ABSTRACT FROM AUTHOR]

Abstract In this study, the simultaneous spectrochromatographic determination of dorzolamide hydrochloride (DOR) and timolol maleate (TMM) in an ophthalmic formulation was performed by applying multiway resolution methods, parallel factor analysis (PARAFAC) and three way partial least squares (3W-PLS) models. In similar manner, unfolded partial least squares (U-PLS) approach was applied to the UPLC analysis of the related drugs. For the three-way resolutions, the ultra-performance liquid chromatography–photodiode array (UPLC-PDA) data array of the calibration samples and others (validation and commercial samples) containing the analyzed drugs (DOR and TMM) and thiamine hydrochloride as an internal standard (IS) was decomposed into triads or trilinear components. These three different calibration models were employed for the spectrochromatographic resolution of a commercial ophthalmic formulation of DOR and TMM and then successful quantitation results were obtained. Analysis results provided by applying three-way and two-way resolutions were statistically compared to those obtained by the newly developed standard UPLC approach. It was observed that the proposed methods gave comparable determination results for analysis of the DOR-TMM ophthalmic formulation. Graphical abstract fx1 Highlights • This research study is the first application of three-way analysis methods (PARAFAC and 3W-PLS) to the overlapping spectrochromatograms for the analysis of DOR-TMM ophthalmic solution. • The application of PARAFAC and 3W-PLS analysis provided good results, short runtime and low cost. • In comparison, ordinary two-way partial least squares (U-PLS) and standard UPLC method were used for the same analysis problem. Comparable results were obtained for the quantification of the related drugs. [ABSTRACT FROM AUTHOR]

Abstract A sensitive and selective differential pulse-adsorptive anodic stripping voltammetry (DP ASV) method has been developed for trace determination of timolol maleate drug in complex matrices. The established method is first of its kind for timolol maleate (TM) determination with a wide linear dynamic range (1.0 × 10−9–2.0 × 10−5 mol L−1) coupled with limits of detection and quantification of 7.1 × 10−10 mol L−1 (0.31 μg L−1) and 2.4 × 10−9 mol L−1 (1.04 μg L−1), respectively. A relative standard deviation (±0.565%, n = 5) at 2.0 × 10−6 mol L−1 concentration of the drug was obtained. The method was validated by comparison with standard HPLC method. Statistical treatment of data using Student t and F tests at P = 0.05 revealed no significant differences between experimental and tabulated t and F values. Due to high selectivity towards TM and minimum interference from common organic and inorganic compounds the developed probe was successfully applied for trace analysis of TM in an eye drop, urine and water samples. The established method has a unique advantage to be quantitatively applied to a variety of samples due to rapid response, short analytical time and high sensitivity, and excellent selectivity with good reproducibility. The figures of merits were compared successfully with some reported electrochemical, chromatographic and spectrochemical methods. The interfacial properties of the modified Nafion/c-MWCNTs/GCE were explored by electrochemical impedance spectroscopy (EIS). Highlights • A novel electrochemical sensor for sensing timolol maleate drug is proposed. • Good linear dynamic range (1.0×10-9 - 2.0×10-5 mol L-1) with LOD and LOQ of 7.1×10-10 mol L-1 (0.31 μg L-1) was achieved. • DP ASV was applied in residue analysis for melamine in milk, milk powder and water. • The proposed DP ASV provides simple probe with good precision, robustness, and short analytical time. • The newly developed DP ASV method is rapid, economical, convenient and sensitive [ABSTRACT FROM AUTHOR]

Abstract Ocular hypertension due to increased intraocular pressure is a major risk factor for the development of glaucoma. Rapid clearance and low ocular bioavailability are drawbacks of conventional ocular treatments. This requires frequent and long-term application of antiglaucoma drugs which in turn cause local side effects and are a major cause of therapeutic failure due to loss of persistence in using glaucoma therapy. In this study, a semisynthetic, biocompatible, oxidized sucrose crosslinker was developed and used in the formulation of chitosan-gelatin hydrogel for the sustained release of timolol to control ocular hypertension. The swelling properties of the hydrogel showed a strong relationship with the oxidized sucrose concentration. Mucoadhesive properties of the hydrogel were studied and the in vitro release profiles demonstrated that crosslinking with oxidized sucrose reduced the release rate of the entrapped timolol. The results of both in vitro and in vivo studies supported that the formulated hydrogel maintained the release and in turn the efficacy of timolol for a longer period of time compared to the conventional eye drops. This is expected to reduce the frequency of drug application onto the eye surface and in turn enhances patients' convenience. In conclusion, the developed formulation represents a promising platform for an effective and compliant treatment of ocular hypertension. [ABSTRACT FROM AUTHOR]

Purpose: To compare the hypotensive effect of travoprost 0.004%/timolol 0.5% fixed combination (TTFC) to the concomitant use of travoprost and timolol 0.1% gel formulation (Trav + Geltim). Materials and methods: Thirty-three patients (62 eyes) were enrolled and divided into two groups. Patients in group 1 (31 eyes) received the TTFC and patients in group 2 (31 eyes) received the concomitant treatment with Trav + Geltim. Patients on previous antiglaucoma treatment discontinued their drops for 2–4 weeks before starting their new treatment (TTFC or Trav + Geltim). The drops were instilled in the evening in group 1 and in group 2, the prostaglandin was installed in the evening, and timolol in the morning. IOP was measured at 1 and 3 months after the initiation of treatment at four time points during the day (09:00, 12:00, 15:00, and 18:00). Results: Both groups showed significant IOP reduction from baseline at all time points at 1 and 3 months. When the two groups were compared, group 2 showed slightly better hypotensive effect that reached statistical significance only at the 18:00 time point at both 1 and 3 months. Conclusion: Both the TTFC and the concomitant use of the travoprost/timolol gel showed similar hypotensive effect with the latter being slightly more potent in reducing the IOP. [ABSTRACT FROM AUTHOR]

Purpose: To test the hypothesis that the use of refrigerated fixed combination of dorzolamide 2% plus timolol 0.5% solution (COSOPT®) is associated with less ocular discomfort compared with the use of this solution kept at room temperature.Methods: In this prospective comparative study, 30 primary open-angle patients and 30 healthy subjects filled in the questionnaire on symptoms (Ocular Surface Disease Index) and subjective stinging feeling scale (1-10), at the start of study and 30 days after continuous use of refrigerated fixed combination or placebo eye drops. Results were processed by applying the methods of descriptive (arithmetical mean, standard deviation) and analytical statistics for evaluation of significance of the difference (Student's t-test).Results: Ocular discomfort parameters were significantly lower after the use of refrigerated fixed combination of dorzolamide 2% plus timolol 0.5% solution (t-test, P < 0.0001). Breakup time, Schirmer 1 test, and intraocular pressure values did not differ.Conclusions: The use of refrigerated fixed combination of dorzolamide 2% plus timolol 0.5% (COSOPT) solution is associated with less ocular discomfort than the use of the same fixed combination at room temperature. [ABSTRACT FROM AUTHOR]

Abstract Aims Glaucoma is a chronic ophthalmic disease, which has become one of the leading causes to progressive and irreversible blindness. Current ophthalmic drug delivery to treat glaucoma is mostly eyedrop, whose rapid elimination on corneal surface can lead to poor bioavailability. The present study was aimed to develop a timolol maleate loaded thermo-sensitive gel (TM-TSG) with improved bioavailability to treat glaucoma. Main methods TM-TSG was prepared by homogeneously dispersing 0.3% (w / v) timolol maleate, 24.25% (w/v) poloxamer 407 (P407) and 1.56% (w/v) poloxamer 188 (P188) into phosphate buffer solution (pH = 7.4) and the formulated TM-TSG was characterized. Key findings TM-TSG was stored in liquid form at room temperature (25 °C) and transited to semisolid gel at physiological temperature (32 °C). The rheological property of TM-TSG was in favor of uniform distribution of drug. TM-TSG showed good stability at different conditions including centrifugation, autoclaving and different temperature. In vivo pharmacokinetic studies indicated that TM-TSG could enhance absorption of TM in aqueous humor and improve the ocular bioavailability in comparison of commercial TM eyedrops. In vivo experiment result showed that TM-TSG had greater effect in treating glaucoma than TM eyedrops by sustainably lowering intraocular pressure (IOP) for a week. Moreover, slit lamp test and histopathological analysis demonstrated that TM-TSG had excellent biocompatibility. Significance TM-TSG could be a promising ophthalmic delivery system for glaucoma therapy. Graphical abstract Unlabelled Image Highlights • The liquid-solid phase transition of thermo-sensitive gel facilitates administration and prolongs the drug retention time. • Enhanced bioavailability is achieved by the prolonged retention and drug release compared with TM commercial eyedrops. [ABSTRACT FROM AUTHOR]

Abstract A novel UPLC-UV method was developed for analysis of timolol in human plasma using a simple, fast, and cost effective ion-exchange SPE procedure, followed by separation on a C 18 UPLC column with a mobile phase consisting of acetonitrile, phosphate buffer, and sodium 1-octane sulfonate as an ion pairing agent. The method was fully validated according to US-FDA guidelines, and was found to be sufficiently accurate and precise for analysis of timolol in human plasma for clinical pharmacokinetic studies. The application of ion-exchange SPE cartridges for purification of timolol in plasma produced excellent percent recoveries and good sample clean-up, while the ion-pairing separation described here allowed quantitation of timolol without interference from endogenous sample components. The method lower limit of detection was 1.7 ng/mL and the lower limit of quantitation was 5.0 ng/mL, allowing for analysis of therapeutic concentrations of timolol in plasma. Highlights • We developed an ion-pairing chromatography method for analysis of timolol in plasma. • Cation-exchange solid phase extraction is simple and selective for timolol. • Ion-pairing chromatography enhances selectivity for beta-blockers on c18 phases. • The developed method was successfully validated according to US-FDA guidelines. [ABSTRACT FROM AUTHOR]

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