ABSTRACT
The formulation of aqueous ophthalmic solutions containing indomethacin (IND) presents serious problems due to poor solubility and stability of the drug. The purpose of this study was to evaluate a novel 0.1% IND formulation containing a poly(oxyethylene)-poly(oxypropylene) block copolymer (poloxamer 407) as solubilizer. This formulation was evaluated for stability, bioavailability and anti-inflammatory activity in comparison with an ophthalmic IND solution currently on the market. The experimental solution, tested for IND stability at different temperatures, compared favorably with the commercial solution. In rabbits, it produced significantly higher IND levels in the aqueous humor and, in an immunogenic uveitis model, it induced a comparatively faster resolution of the symptoms, as determined by inflammation scores and by IOP measurements. The data indicate poloxamer 407 as a potentially valuable nonirritating, solubilizing and stabilizing agent for indomethacin.
Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/pharmacokinetics , Aqueous Humor/metabolism , Indomethacin/pharmacokinetics , Uveitis/drug therapy , Uveitis/metabolism , Animals , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Biological Availability , Chemistry, Pharmaceutical , Drug Evaluation , Drug Stability , Hot Temperature , Indomethacin/pharmacology , Intraocular Pressure/drug effects , Male , Ophthalmic Solutions/pharmacokinetics , Ophthalmic Solutions/pharmacology , Poloxamer/pharmacology , Rabbits , Serum Albumin, Bovine , Tissue Distribution , Uveitis/chemically inducedABSTRACT
This study was aimed at verifying the performances of a mucoadhesive polysaccharide from tamarind seed (xyloglucan or TSP, tamarind seed polysaccharide) as an adjuvant for ophthalmic vehicles containing timolol. Three formulations (one experimental vehicle based on TSP and two reference commercial eye drops) containing 5 mg/ml timolol base equivalents were administered to the eyes of pigmented rabbits. Drug concentrations in tear fluid, cornea, iris-ciliary body, aqueous humor and plasma were determined, as well as intraocular pressure. The polymer under investigation, in spite of a comparatively low viscosity, produced high timolol concentrations in the ocular tissues and a low systemic absorption. The performances of the TSP vehicle were comparable to those of a reference "in situ" gelling formulation (Timoptic XE). The results point to TSP as a potentially useful adjuvant for ophthalmic delivery systems.
Subject(s)
Adrenergic beta-Antagonists/pharmacokinetics , Anterior Eye Segment/metabolism , Drug Delivery Systems , Glucans , Intraocular Pressure/drug effects , Polysaccharides/pharmacokinetics , Timolol/pharmacokinetics , Xylans , Adrenergic beta-Antagonists/pharmacology , Animals , Aqueous Humor/metabolism , Area Under Curve , Biological Availability , Chromatography, High Pressure Liquid , Ciliary Body/metabolism , Cornea/metabolism , Female , Iris/metabolism , Male , Pharmaceutical Vehicles/pharmacokinetics , Pharmaceutical Vehicles/pharmacology , Polysaccharides/pharmacology , Rabbits , Tears/metabolism , Timolol/pharmacology , Tissue DistributionABSTRACT
The present paper is concerned with the development of a simple dry eye model in the rabbit, induced by daily repeated instillations of 1.0% atropine sulphate. The evolution of the dry eye syndrome in the animals was assessed by the Schirmer I test and by examination of the cornea after fluorescein staining. The model produced rapidly some typical dry eye symptoms and could be satisfactorily used for a preliminary assessment of the protective activity of some polymeric tear substitutes. These were based on hydroxypropylmethylcellulose, sodium hyaluronate, sodium polyacrylate or tamarind gum. The latter polymer showed the best overall results. Ferning tests on the formulations were also performed: their validity as predictors of the efficacy of tear substitutes is discussed.
Subject(s)
Dry Eye Syndromes/drug therapy , Dry Eye Syndromes/metabolism , Ophthalmic Solutions/therapeutic use , Animals , Disease Models, Animal , Evaluation Studies as Topic , Male , Polymers/therapeutic use , Rabbits , Tears/metabolismABSTRACT
The purpose of this study was to gather information on the mechanism by which timolol/pilocarpine (TI/PI) combination eyedrops provide additive ocular hypotensive effects. An hypothesis, according to which the combination eyedrops prolong the intraocular permanence of PI as a consequence of decreased aqueous humor secretion induced by TI, was not supported by clear-cut literature evidence. It was thus sought to verify if repeated instillations in albino rabbits of combination TI/PI eyedrops do effectively prolong the turnover of PI. Commercial eyedrops containing 0.68% w/v TI maleate and 2.0% w/v PI hydrochloride, buffered at pH 6.8, and two reference solutions containing PI hydrochloride alone (2% w/v), buffered at pH 5.5 and 6.8, were instilled b.i.d. in albino rabbits for five days. Aqueous humor samples, analyzed after the last treatment, showed that the aqueous humor PI levels observed after administration of the combination eyedrops were significantly higher than those resulting from administration of the reference formulations. When compared with the pH 6.8 reference solution, the pH 5.5 one produced slightly higher and more sustained drug levels in the aqueous humor. The present results appear to confirm the assumption that an increased retention of PI in the aqueous humor is responsible for the additive effects on intraocular pressure reported by several authors for the combination TI/PI eyedrops.
