【正文】
pward, showing marked changes in flow curve and viscosity curve with rising temperature . It has been reported that the rheological characteristics of ophthalmic solutions greatly influence the precorneal residence time and the feel to the eye [7]. However, there has been almost no research which examined the properties of various polymer solutions from the viewpoint of rheology. The present study aimed at assessing the effect of the position of a thermosetting gel solution vehicle on its rheological properties. Furthermore, rheological properties were pared among different solutions, with the other in situ gelling systems for ophthalmic use as control. Experimental Materials Four different kinds of methylcellulose (MC), that is, Metolose (SM 15, 25, 400, 1500) by ShinEtsu Chemical (Japan) were used. Polyethylene glycol 1000 (mean molecular weight 950–1050), 4000 (mean molecular weight 2600–3800), 6000 (mean molecular weight 7300–9300) (to be abbreviated to PEG 1000, 4000, 6000) and sodium citrate dihydrate (SC) were special grhemical Industries (Japan), and Poloxamer 407 used was Lutrol F127 by BASF (Japan). Timolol maleate was purchased from Industrie Chemiche Italiane (Italy), ketotifen fumarate from Kyowa Yakuhin Kogyo (Japan), Ofloxacin from Sigma (Japan), and betamethasone sodium phosphate from Sicor (France). The other reagents used were all special class grade on the market. Simulated tear fluid was prepared by adding distilled water to g of sodium chloride, g of sodium bicarbonate, and g of calcium chloride dihydrate until the total volume of solution reached 100 mL according to the preparation described by Rozier et al Preparation of thermosetting gel vehicle The thermosetting gel vehicle was prepared according to the method described in a previous paper with slight modification [6]. A hot slurry was prepared by adding g of MC to 50 mL of distilled water heated to 90 _C with stirring and allowing it to disperse sufficiently. The slurry was cooled to 5 _C and mixed with a solution of g SC in 30 mL distilled water, then with a solution of varying amounts (2–10 g) of PEG in 15 mL distilled water. The mixture was stirred until it became transparent. After adjusting its pH with 3 N hydrochloric acid, the mixture was made up to 100 mL with distilled water, and used as the thermosetting gel vehicle. The drug was added after addition of PEG. Preparation of various in situ gelling solutions A hot slurry was prepared by adding MC ( g of SM15 and g of SM 400) to 50 mL of distilled water heated to 90 _C with stirring and allowing it to disperse sufficiently. The slurry was cooled to 5 _C, mixed with a solution of g SC in 30 mL distilled water, then with a solution of g PEG 4000 in 15 mL distilled water. The mixture was stirred until it became transparent. After adjusting its pH to with 3 N hydrochloric acid, the mixture was made up to 100 mL with distilled water and used as the thermosetting gelling solution. Gellan gum solution was prepared by dissolving g gellan gum in 90 mL of M Tris maleate buffer solution (pH ), then mixing it with g mannitol. The resultant solution was made up to 100 mL with M Tris maleate buffer solution (pH ) [8]. 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