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1、可逆熱固性原位膠凝流變特性的解決方案與甲基纖 維素聚乙二醇檸檬酸三元系統(tǒng)Masanobu Takeuchi Shinji Kageyama Hidekazu Suzuki Takahiro著，.譯.摘要可逆性溶膠凝膠溫度的轉(zhuǎn)變受到甲基纖維素 （MC）、聚乙二醇（PEG）、 檸檬酸（SC）三元體系的影響，通過流變學(xué)測(cè)量得出原位凝膠體系的性能。當(dāng)PEG（4000）的濃度在0哌M(jìn)0%圍內(nèi)變化，MC25）和SO度分別保持在1.5%?口3.5% 時(shí)，隨著PE磔度的增加，可逆Tt溶膠轉(zhuǎn)變溫度從38流低至26 C,然而，溫 度降低的程度不受PE6子量的影響，隨著MCR度的增加可逆溶膠凝膠的溫度降 低，同時(shí)隨

2、著ph值的降低可逆溶膠凝膠的溫度升高，在流變特性的比較方面， 目前原位膠凝的設(shè)置解決方案和常規(guī)相比，如結(jié)冷膠溶液或泊洛沙姆407,顯示目前的解決方案從根本上有別于傳統(tǒng)的解決方案，這些研究結(jié)果表明，這項(xiàng)研究中 的三元體系可作為在眼部傳遞灌輸系統(tǒng)的藥物。關(guān)鍵詞熱定形凝膠；溶膠凝膠轉(zhuǎn)變溫度；甲基纖維素聚乙二醇檸檬酸三 元體系1前言本研究提高了眼用溶液在吸收過程中利用度差的問題，例如，在溶液溶解時(shí)利用這個(gè)屬性而由此獲得的聚合物。通過在滴眼液中加入聚合物來延長(zhǎng)持續(xù)時(shí) 問，從而增加藥物在角膜前停留時(shí)間來改善結(jié)膜滲透性。聚合物的使用被認(rèn)為是有效的，因?yàn)樗麄冊(cè)黾恿怂幬锏男в茫酆衔锏氖褂靡灿衅淙秉c(diǎn)，如由于溶液

3、的 粘度高會(huì)出現(xiàn)灌注困難和不適感。我們發(fā)現(xiàn)了一種熱固性凝膠溶液在甲基纖維素聚乙二醇檸檬酸三元系統(tǒng)中 的應(yīng)用，并開發(fā)了一種含馬來酸曝嗎洛爾， 可以用來治療青光眼的眼用溶液，據(jù)報(bào)道，長(zhǎng)效的眼用溶液的流量曲線觸變性在 32 C,呈現(xiàn)出粘度隨溫度升高而明 顯變化的特性。據(jù)報(bào)道，眼科溶液流變特性極大地影響角膜滯留時(shí)間和眼睛的感 覺，我們考察了不同聚合物溶液的性質(zhì)，以前幾乎沒有從流變學(xué)的觀點(diǎn)來研究的 先例。本研究的目的在于評(píng)估熱定形凝膠溶液流變性質(zhì)的影響。止匕外，從流變性方面與其他原位凝膠在眼科中應(yīng)用進(jìn)行比較2實(shí)驗(yàn)材料四種不同的甲基纖維素（MC） ，即，MC（SM15， 25， 400， 1500） ，聚

4、乙二醇1000 （平均分子量950- 1050）, 4000 （平均分子量2600- 3800）, 6000 （平均分 子量7300-9300）簡(jiǎn)稱PEG 100Q 4000, 6000）和二水檸檬酸鈉（S。，泊洛沙 姆407，馬來酸噻嗎洛爾，氧氟沙星，倍他米松磷酸鈉。按羅齊爾等描述的在 0.67克氯化鈉、 0.20克碳酸鈉、 0.008克二水氯化鈣中加入蒸餾水直到總體積達(dá)到100毫升來制備人工淚液。1.1 原位凝膠溶液的制備將50毫升的蒸儲(chǔ)水加熱至90c后力口入MC（0.7克SM150.7: GOF SM400后攪 拌均勻，制備漿料。將其冷卻至5C,在30ml蒸儲(chǔ)水中混合3.5克SG然后在1

5、5ml 蒸儲(chǔ)水溶液中混合2.0克聚乙二醇400。攪拌該混合物直到透明。用3NS酸調(diào)節(jié)其 pHfi至7.8后，在混合物中加蒸儲(chǔ)水至100 mL,作為熱硬化性凝膠溶液。1.2 泊洛沙姆溶液的制備在索倫森緩沖溶液（pH7.0）中溶解25克PM將所得?M合物在5c下放置24 小時(shí)，然后混合2.5克甘露糖醇，將所得70毫升溶液與索倫森緩沖溶液（pH7.0 ）中和至100mL。1.3 膠凝溫度通過試管倒置法測(cè)量通過試管倒置法測(cè)定可逆性溶膠凝膠溫度。將5毫升的樣品放在玻璃測(cè)試管中（ 12貼片機(jī)的直徑，內(nèi)徑10.5 毫米） ，然后將測(cè)試管放在一個(gè)恒溫浴中5分鐘。在該溫度下的樣品沒有流出作為可逆的溶膠凝膠的轉(zhuǎn)變

6、溫度3 結(jié)果與討論3.1 PEG對(duì)可逆溶膠凝膠轉(zhuǎn)變溫度的影響有幾種方法可用來測(cè)量可逆溶膠-凝膠的轉(zhuǎn)變溫度，如測(cè)試管法，落球法， U型管法，流變儀。落球法和異型管法用來測(cè)定凝膠的熔點(diǎn)。由于凝膠的熔點(diǎn)和 凝固點(diǎn)不同，本研究不太適合用落球法和 U形管方法，MOJ置凝膠的凝點(diǎn)很重要 的一點(diǎn)是利用DSC寸溫度不敏感的特性。綜合以上考慮，應(yīng)該使用試管倒置法和彈性力學(xué)與流變儀測(cè)定法。在三元（MCPEGSC1統(tǒng)中特別應(yīng)該注意的是PEG 該添加劑的作用已知。圖1152025303540Temperature ( )圖1溫度對(duì)熱定形凝膠溶液的表觀粘度的影響。聚乙二醇濃度：0 %, 2 %, 4 %, 6 %,8

7、%, 10 %。表觀粘度測(cè)定用流變儀測(cè)定。甲基纖維素( SM 25)和檸檬酸鈉二水合物的濃 度分別恒定保持在 1.5%和3.5%,而聚乙二醇(PEG 4000 )的濃度變化范圍在 0%到10%(3 - -nwEsq售 J 巨部 P8JSSUI 當(dāng)一sddulw UESIIS望202530354045Phase transition temperatureredwith the test tuke inversion mettioci ( )圖2試管反演方法和流變儀測(cè)量法，圖中 x和y分別表示用試管倒置法測(cè)量的相轉(zhuǎn)變溫度和用流變儀測(cè)量的相轉(zhuǎn)變溫度，甲基纖維素(SM 25)和檸檬酸鈉二水物濃度分別

8、保持恒定在2 %和3.5% ,聚乙二醇(PEG 4000 )的濃度變化范圍在 0%到10%之間。圖1和2分別顯示了溫度對(duì)熱定形凝膠溶液的表觀粘度的影響，試管反演方法和流變儀測(cè)量法。如圖所示，當(dāng) MC(SM 25)和SCM度保持恒定在1.5咐口3.5%變時(shí)，同時(shí)PEG 4000濃度的變化范圍在0%到10%之間，可逆的溶膠凝膠轉(zhuǎn)變溫度隨著PE徽度的增加而下降。當(dāng)PE徽度為10%寸，溶液白粘度在24 C時(shí)開始增 加，然而當(dāng)溫度增加到34。CM,溶液的粘度不再增加。膠凝溫度測(cè)試管反演方法 和流變儀方法得到的數(shù)據(jù)之間有明顯的正相關(guān)（相關(guān)系數(shù)R = 0.89 ） 。M東現(xiàn)出溶于水的纖維素，有高的結(jié)晶度和低

9、的水溶性部分。為此，當(dāng)加熱和凝膠分離冷卻時(shí)，MC勺解決方案是可逆的。具膠凝機(jī)理被報(bào)道的三甲基葡萄糖 序列和交聯(lián)結(jié)晶， 可逆的溶膠凝膠轉(zhuǎn)變溫度 （熱固膠凝溫度） 通常是由鹽的加入 而降低， 它是強(qiáng)陰離子的作用效果， 由于檸檬酸強(qiáng)烈的鹽析效應(yīng)， 降低了熱定形 凝膠對(duì)MC勺脫水溫度。當(dāng)PEGI獨(dú)添加到M既時(shí)，溶液的熱定形凝膠溫度只是略 微降低，但大大減少了檸檬酸的加入。PEGI起了葡聚糖水溶液的相分離，此外， 研究發(fā)現(xiàn)，過量添加PE筋導(dǎo)熱定形凝膠（MO PEG SC（統(tǒng)）相分離（微相分離）， 通過上述研究發(fā)現(xiàn)了 PEG!過誘導(dǎo)微相分離加速M(fèi)彰成交聯(lián)的解決方案。PEG勺分子量對(duì)熱定形凝膠溫度的影響，當(dāng)

10、 PEG勺濃度從0%化到10%寸，MC 的濃度（SM 255）和S8別保持恒定在1.5%?口3.5%時(shí)。當(dāng)PEG 100（PEG 6000弋 替PEG 4000寸，熱定形凝膠的溫度依賴于 PEG勺濃度而降低。PEG 1000, 4000, 和 6000他們的影響大致相當(dāng)于減少熱定形凝膠的溫度，隨著SM 25濃度的增加，由于PE映賴熱定形凝膠溫度而使曲線移向較低的溫度，這個(gè)熱定形凝膠溫度隨 MCS液濃度的增加而減少的趨勢(shì)，可由三甲基葡萄糖序列之間的距離而縮短， 這 使結(jié)晶和交聯(lián)的形成變得更容易， 這是凝膠發(fā)生在一個(gè)較低的溫度和短距離的結(jié) 果。同樣的原理似乎將用在低溫下的熱定形凝膠。熱定形凝膠溶液

11、、 結(jié)冷膠溶液、 和泊洛沙姆溶液表現(xiàn)出不同的流動(dòng)性， 這主 要表現(xiàn)為牛頓流體，準(zhǔn)粘性流動(dòng)，和準(zhǔn)塑性流動(dòng)，而所有這些解決方案顯示，通 過溶膠凝膠改善角膜滯留時(shí)間的熱定形凝膠溶液和泊洛沙姆溶液從來沒有凝膠在靠近眼球表面的溫度情況下， 這表明他們狀況是良好的， 此外 , 凝膠溶液和結(jié)冷膠在剪切應(yīng)力中的屈服值為零或非常小 , 表明這些解決方案只是略耐瞬眼并且 會(huì)對(duì)眼睛產(chǎn)生良好的感覺,4 結(jié)論我們通過可逆性溶膠凝膠的過渡溫度來研究三元（MO PEG- SQ系統(tǒng)的影 響。當(dāng)SC&度保持恒定，可逆性溶膠凝膠轉(zhuǎn)變溫度降低取決于PE住口MC勺濃度，但不取決于PE6子量。溶膠凝膠轉(zhuǎn)變溫度隨pH勺增加而減少，止匕外

12、，隨著可逆 性溶膠溶液的轉(zhuǎn)變溫度減低和PE磔度的增加，將會(huì)有更多的眼藥類型供選擇，通過對(duì)熱固性凝膠的流變性能和大家熟知的原位凝膠系統(tǒng)以及結(jié)冷膠和泊洛沙姆的解決方案相比較，很明顯前者的解決方案和后者有明顯的不同， 其作為藥物傳遞系統(tǒng)灌輸?shù)窖鄄康挠锰幒軐?shí)用。參考文獻(xiàn)1 Bourdais CL, Acar L, Zia H, Sado PA , Needham .Leverge R (1998)前衛(wèi)視網(wǎng)膜眼研究17:332 Sasaki H, Nishida K, Nakamura J.Ichikawa M (1996)前衛(wèi)視網(wǎng)膜眼研究 15:5833 Chrai SS. RobinsonJR (1

13、974 ) 醫(yī)藥供應(yīng)鏈 63:12184 Kurimoto K, Eguchi K, Kitajima S,Kishimoto N, Matsumoto N.Otsuki(1991) Atarashii Ganka 8:12595 Kabayama T, Suzuki H, Horiuchi T,Akutagawa Y. Matsuzaki H (1979)日本眼科系統(tǒng)J. 83:3266TakeuchiM,KageyamaS,SuzukiH,WadaT,ToyodaY,OgumaT,EzureY,TsuriyaY,KatoT.Ishii F(1999) 材料技術(shù) 17:4457 Patton

14、 TF.Robinson JR (1975) 藥學(xué)科學(xué) 64:13128 Rozier A, Mazuel C, Grove J, Plazonnet. B (1989)國(guó)際藥學(xué)雜志 57:1639 Kato T, Yokoyama M. Takahashi A(1978)膠體高分子科學(xué) 265:1510 Heymann E (1935)反式法拉 Soc 31:84611 Edmond E. Ogston AG (1968) 生物化學(xué)雜志 109:56912 Miyoshi E .Nishinari K (1998) Kobunshi Ronbunshu 55:56713 Vadnere M,

15、AmidonG, LindenbaumS. JohnL (1984) INTJ 制藥 22:20714 Cho CW,Shin SC.Oh IJ (1997) Drug DevInd Pharm 23:1227Rheological properties of reversible thermo-setting in situ gelling solutions with the methylcellulosepolyethylene glyco lcitric acid ternary systemMasanobu Takeuchi Shinji Kageyama Hidekazu Suzu

16、ki Takahiro Wada Yoshitada Notsu Fumiyoshi IshiiAbstract The composition of vehicle on the reversible so卜 gel transition temperature in a ternary system made up of methylcellulose (MC), polyethylene glycol (PEG), and citric acid (SC) was investigated. The properties of the in situ gelling system wer

17、e estimated by rheological measurement. When PEG (4000) concentration was varied from 0% to 10% while MC (SM25) and SC concentrations were kept constant at 1.5% and 3.5%, respectively, the reversible solgel transition temperature lowered from 38 _C to 26 _C with increasing PEG concentration. However

18、, the extent of lowering in temperature was not influenced by the molecular weight of PEG The reversible sol- gel transition temperature shifted towards the lower temperature with increasing MC concentration, and towards the higher temperature with decreasing pH. Comparison of rheological properties

19、 between the present thermo-setting in situ gelling solution and a conventional one, such as gellan gum solution or Poloxamer 407 solution, revealed that the present solution radically differed from the conventional solutions in the incipient gelling mechanism. These findings suggest that the ternar

20、y system in this study would be useful as a drug delivery system for instillation of drugs into the eye.Keywords Thermo-setting gel Sol gel transition temperature Rheology Methylcellulose - polyethylene glycol - citric acid ternary systemIntroductionStudies have been made to improve the poor bioavai

21、lability of ophthalmic solutions in the eye using various drug delivery systems 1,2. For example, polymers gain in viscosity when dissolved and this property is utilized. Thus, attempts were made to prolong the duration of effect by adding a polymer to the ophthalmic solution, thereby increasing pre

22、corneal residence time of the drug and improving the kerato-conjunctival permeability. The use of biocompatible polymers was found to be effective, because they increased the utility of the preparation 3. However, the use of polymers also has disadvantages, such as difficulty in instillation and dis

23、comfort after instillation due to the high viscosity of the solution.We recently found a thermo-setting gel vehicle that underwent sol gel transition at around the human eye surface temperature (35 _C 4, 5) by application of the methylcellulose - polyethylene glycol - citric acid ternary system, and

24、 developed a long-acting ophthalmic solution (Rysmon TG) containing timolol maleate that is used in the treatment of glaucoma 6.It was reported that theade reagents by Wako Pure Chemical Industries (Japan). The gellan gum used was Gelrite by Wako Pure C long-acting ophthalmic solution exhibited thix

25、otropy at temperatures of 32 _C and upward, 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 h

26、as 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 composition of a thermo-setting gel solution vehicle on its rheological properties. Furthermore, rheological properties were com

27、pared among different solutions, with the other in situ gelling systems for ophthalmic use as control.ExperimentalMaterialsFour different kinds of methylcellulose (MC), that is, Metolose (SM 15, 25, 400, 1500) by Shin-Etsu Chemical (Japan) were used. Polyethylene glycol 1000 (mean molecular weight 9

28、50- 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 f

29、rom 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

30、 water to 0.67 g of sodium chloride, 0.20 g of sodium bicarbonate, and 0.008 g of calcium chloride dihydrate until the total volume of solution reached 100 mL according to the preparation described by Rozier et alPreparation of thermo-setting gel vehicleThe thermo-setting gel vehicle was prepared ac

31、cording to the method described in a previous paper with slight modification 6. A hot slurry was prepared by adding 1.5 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 3.5 g SC in 3

32、0 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 thermo-setting gel v

33、ehicle. The drug was added after addition of PEG.Preparation of various in situ gelling solutionsA hot slurry was prepared by adding MC (0.7 g of SM15 and 0.7 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 _

34、C, mixed with a solution of 3.5 g SC in 30 mL distilled water, then with a solution of 2.0 g PEG 4000 in 15 mL distilled water. The mixture was stirred until it became transparent. After adjusting its pH to 7.8 with3 N hydrochloric acid, the mixture was made up to 100 mL with distilled water and use

35、d as the thermo-setting gelling solution.Gellan gum solution was prepared by dissolving 0.6 g gellan gum in 90 mL of 0.01 M Tris maleate buffer solution (pH 7.0), then mixing it with 5.5 g mannitol. The resultant solution was made up to 100 mL with 0.01 M Tris maleate buffer solution (pH 7.0) 8.Polo

36、xamer solution was prepared by dissolving 25 g poloxamer in 70 mL of So rensen buffer solution (pH 7.0), which was accomplished by allowing the mixture to stand at 5 _C for 24 h, then mixing it with 2.5 g mannitol, and making up the resultant solution to 100 mL with So rensen buffer solution (pH 7.0

37、).Measurement of gelling temperature by the test tube inversion methodThe reversible sol- gel transition temperature for thermo-setting gel solution was measured by the test tube inversion method. A 5 mL portion of sample was placed in a glass test tube (12 mm outer diameter, 10.5 mm inner diameter)

38、, then the test tube was allowed to stand for 5 min in a constant temperature bath and was then inverted. The temperature at which the sample did not flow out on inversion was used as the reversible sol- gel transition temperature.Results and discussionEffect of PEG on reversible sol gel transition

39、temperatureSeveral methods are known for measuring the reversible s olgel transition temperature, such as the test tube inversion method, falling ball method, U-shaped tube method, rheometer method, and differential scanning calorimetry (DSC). The falling ball method and U-shaped tube method are use

40、d to measure the melting point of a gel. Since the gel melting point and gelling point greatly differ from each other because of hysteresis,the falling ball method and U-shaped tube method seemed inappropriate in the present study for the thermo-setting gel, where the gelling point was important. DS

41、C is not very sensitive to the temperature change in solutions. From the above considerations, the test tube inversion method and the determination of viscoelasticity with a rheometer were used. In the ternary MC-PEG-SC system, particular attention was paid to PEG,about which the details of the effe

42、ct of addition were not knownF8015202530354()l emperature ( )y = 0.7647x + 5.098 r = 0,89Fig. 1 Effects of temperature on the apparent viscosity of the thermo-setting gel solution. Polyethylene glycol concentrations: s 0%, e 2%, h 4%, d 6%, r 8%, j 10%. The apparent viscosity was measured with a rhe

43、ometer at shear rate 2001/s. Methylcellulose (SM 25) and sodium citrate dihydrate concentrations were kept constant at 1.5% and 3.5%, respectively, while the concentration of polyethylene glycol (PEG 4000) was varied from 0 to 10% 4035302520202530354045Phase transition temperature measured with the

44、test tube inversion method ( )Fig. 2 Correlation of the phase transition temperature measured by the test tube inversion method and rheometer. In the formula, x and y express phase transition temperature measured with the test tube inversion method and phase transition temperature measured with the

45、rheometer, respectively.Methylcellulose (SM 25) and sodium citrate dihydrate concentrations were kept constant at1.5% and 3.5%, respectively, while the concentration of polyethylene glycol (PEG 4000) was varied from 0 to 10%Figures 1 and 2 show the effect of temperature on the apparent viscosity of

46、the thermo-setting gel solution by rheometer and the relationship between the test tube inversion method and rheometer method, respectively.As shown in Fig. 1, when MC (SM 25) and SC concentrations were kept constant at 1.5% and 3.5%,respectively,and the concentration of PEG 4000 wasvaried from 0 to

47、 10%, the reversible sol gel transition temperature declined with increase in PEG concentration. When the concentration of PEG was 10%, the viscosity of the solution began to increase at 26 _C.However, the viscosity of the solution without PEG increased at 34 _C. On the other hand, from the results

48、of Fig. 2, the gelling temperature changed from 38 _C to 26 _C by the test tube inversion method and from 34 _C to 24 _C by rheometer. There was a positive correlation between the gelling temperatures obtained by the test tube inversion methods and those of the rheometer (least square method, correl

49、ation coefficient r=0.89).MC was rendered soluble in water by partial methylation of cellulose that had a high crystallinity and low water solubility. For this reason, MC solution is thermoreversible, gelated when heated and solated when cooled. The mechanism of its gelation was reported to involve

50、crystallization of a trimethyl-glucose sequence and formation of cross linkage 9. The reversible sob gel transition temperature (thermo-setting gelling temperature) is generally reduced by addition of a salt, the effect of which is strong with anions and varies according to lyotropic series 10. Citr

51、ic acid, with its strong salting out effect, reduces the thermo-setting gelling temperature by dehydration of MC.When PEG alone was added to MC solution, the thermo-setting gelling temperature decreased only slightly 6, but the decrease was greatly amplified by the simultaneous addition of citric ac

52、id. PEG was reported to cause phase separation of aqueous dextran solution 11. Furthermore, it was found that excessive addition of PEG induced phase separation (macrophase separation) of the present thermo-setting gel (MC PEG - SC system). It was inferred from the above findings that PEG accelerate

53、d the formation of cross linkage of MC by inducing microphase separation of the solution.The effect of the molecular weight of PEG on the thermo-setting gelling temperature when the PEG concentration was varied from 0 to 10% while the concentrations of MC(SM 25) and SC were kept constant at 1.5% and

54、 3.5%, respectively, is shown in Fig. 3. On the other hand, the effect of the MC (SM 25) concentration on the thermo-setting gelling temperature when the PEG 4000 concentration was varied from 0 to 10%, is shown in Fig. 4. When PEG 1000 or PEG 6000 was used instead of PEG 4000, the thermosetting gel

55、ling temperature dependent on PEG concentration was also reduced. PEG 1000, 4000, and 6000 were roughly equivalent in their effect at reducing thermo-setting gelling temperature. When the SM 25 concentration was increased, the PEG-dependent thermo- setting gelling temperature curve shifted toward th

56、e lower temperature. There was a tendency for the thermo-setting gelling temperature to decrease with increase in MC solutionconcentration, which can be explained by a shortening of distances between trimethylglucose sequences 9. That is, crystallization and formation of cross linkage became easier

57、with a shortening of distances, with a result that gelling occurred at a lower temperature. The same mechanism seemed to be operating in the shift towards the lower temperature in the present thermo-setting gel.Thermo-setting gel solution, gellan gum solution, and poloxamer solution showed different

58、 types of fluidity, which were manifested respectively as Newtonian flow, quasi-viscous flow, and quasi-plastic flow. While all these solutions showed improvement in precorneal residence time by so卜 gel transition, the thermo-setting gel solution and poloxamer solution never failed to undergo gelation at a temperature near the ocular surface temperature, which suggested that their residence behavior was excellent. In addition, yield value in shear stress waszero or extremely small for the thermo-setting gel