Ocular Cubosome Drug Delivery System for Timolol Maleate: Preparation, Characterization, Cytotoxicity, Ex Vivo, and In Vivo Evaluation.

Glaucoma is an ocular disease featuring increased intraocular pressure (IOP) and its primary treatment strategy is to lower IOP by medication. Current ocular drug delivery in treating glaucoma is confronting a variety of challenges, such as low corneal permeability and bioavailability due to the unique anatomical structure of the human eye. To tackle these challenges, a cubosome drug delivery system for glaucoma treatment was constructed for timolol maleate (TM) in this study. The TM cubosomes (liquid crystalline nanoparticles) were prepared using glycerol monooleate and poloxamer 407 via high-pressure homogenization. These constructed nanoparticles appeared spherical using transmission electron microscopy and had an average particle size of 142 nm, zeta potential of -6.27 mV, and over 85% encapsulation efficiency. Moreover, using polarized light microscopy and small-angle X-ray scattering (SAXS), it was shown that the TM cubosomes have cubic liquid crystalline D-type (Pn3m) structure, which provides good physicochemical stability and high encapsulation efficiency. Ex vivo corneal permeability experiments showed that the total amount of TM cubosomes penetrated was higher than the commercially available eye drops. In addition, in vivo studies revealed that TM cubosomes reduced the IOP in rabbits from 27.8∼39.7 to 21.4∼32.6 mmHg after 1-week administration and had a longer retention time and better lower-IOP effect than the commercial TM eye drops. Furthermore, neither cytotoxicity nor histological impairment in the rabbit corneas was observed. This study suggests that cubosomes are capable of increasing the corneal permeability and bioavailability of TM and have great potential for ocular disease treatment.

Preparation and evaluation of a timolol maleate drug-resin ophthalmic suspension as a sustained-release formulation in vitro and in vivo.

The aim of this work was to assess the performance of resin as an ocular delivery system. Timolol maleate (TM) was chosen as the model drug and an ion exchange resin (IER) as the carrier. The drug-resin complex was prepared using an oscillation method and then characterized regarding particle size, zeta potential, morphology, and drug content. After in vitro drug release study and corneal permeation study were performed, in vivo studies were performed in New Zealand albino rabbits using a suspension with particles sized 4.8 ± 1.2 µm and drug loading at 43.00 ± 0.09%. The results indicate that drug released from the drug-resin ophthalmic suspension permeated the cornea and displayed a sustained-release behavior. Drug levels in the ocular tissues after administration of the drug-resin ophthalmic suspension were significantly higher than after treatment with an eye drop formulation but were lower in body tissues and in the plasma. In conclusion, resins have great potential as effective ocular drug delivery carriers to increase ocular bioavailability of timolol while simultaneously reducing systemic drug absorption.

Análisis coste-eficacia de las combinaciones fijas de prostaglandinas/prostamida para el tratamiento del glaucoma / Cost-efficacy analysis of fixed combinations of prostaglandin/prostamide for treating glaucoma

Objetivo: Evaluar la relación coste-eficacia de las tres combinaciones fijas de prostaglandinas/prostamidacon timolol actualmente disponibles en el mercado español [bimatoprost con timolol (BT) -Ganfort®, latanoprost con timolol (LT) - Xalacom®y travoprost con timolol (TT) - DuoTrav®]. Métodos: Dado que no existen estudios que comparende una manera directa la eficacia de estos fármacos,se llevó a cabo una revisión sistemática dela evidencia indirecta en lengua inglesa. Se estimaron el consumo de recursos sanitarios y su coste apartir de un modelo esquemático de la práctica clínica habitual en nuestro medio. Se calcularon para cada fármaco la relación coste-eficacia media y larelación coste-eficacia incremental, en términos de euros por punto porcentual de reducción de presión intraocular (PIO) en un periodo de tres meses. Resultados: BT redujo la PIO en un 35,1%, LT en un 35,0% y TT en un 34,7%. El coste-eficacia medio se estimó para BT en 5,34 € por punto porcentual de reducción de PIO, para LT en 5,40 €, y para TT en 5,45 €. El coste-eficacia incremental (coste adicional por punto porcentual adicional de reducción de PIO) se estimó para LT frente a TT en 94,65 €, y resultó negativo para BT frente a TT y BT frente a LT, debido a que BT en ambos casos eraa la vez más eficaz y más económico. Conclusiones: Bimatoprost/timolol parece ser la alternativa más económica comparada con travoprost/timolol y latanoprost/timolol, a igual o mayor eficacia y tolerabilidad

Objective: To assess the cost-efficacy of three fixed-combination glaucoma treatments currentlyavailable in Spain [bimatoprost with timolol (BT)-Ganfort®, latanoprost with timolol (LT)- Xalacom®,and travoprost with timolol (TT)- DuoTrav®]. Methods: Because no studies are available that give a direct comparison of these drugs, a systematic review was carried out to assess their efficacy. Resource consumption and costs were estimated using a model of usual local practice. For each of the three drugs, average and incremental cost-efficacy ratios were determined in terms of euros perpercentage point of reduction of intraocular pressure (IOP) over a three-month period. Results: BT reduced IOP by 35.1%, LT by 35.0% and TT by 34.7%. Average cost-efficacy was estimated to be € 5.34 per percentage point of IOP reduction with BT, € 5.40 with LT, and € 5.45 withTT. Incremental cost-efficacy (incremental cost perincremental percentage point of IOP reduction) was estimated to be € 94.65 for LT vs. TT, and was negative for BT vs. TT and BT vs. LT, since in bothcases BT was more efficacious and less expensive. Conclusions: Compared to travoprost/timolol andlatanoprost/timolol, bimatoprost/timolol appears to be the most economic alternative, with equal or better efficacy and safety results

Urinary metabolites of timolol from humans and laboratory animals. Syntheses and beta-adrenergic blocking activities.

Syntheses are reported for three metabolites (2-4) of timolol (1) formed by oxidative metabolism of the morpholine ring. GLC-MS comparisons are presented which establish that the two metabolites whose structures were previously in question are identical with their synthetic counterparts 2 and 3. In 2, metabolic oxidation of the 4-morpholinyl group of 1 had occurred at the carbon next to oxygen to give the 2-hydroxy-4-morpholinyl moiety, whereas in 3, the morpholine of 1 has been oxidized one step further and then ring opened to produce the N-(2-hydroxyethyl)glycine substituent. Biological testing of synthetic samples of the three major metabolites from human urine (3, 4, and 6) indicated that only 4, in which the morpholine moiety has been degraded to a 2-hydroxyethylamino group, had significant beta-adrenergic blocking activity (one-seventh that of timolol in anesthetized dogs).