外文翻譯--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)

1、<p><b>　　中文2726字</b></p><p>　　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)</p><p>　　Masanobu Takeuchi Shinji Kageyama Hidekazu Suzuki Takahiro著，…..譯.</p><p>　　[摘要] 可逆性溶膠凝膠溫度

2、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%到10%范圍內(nèi)變化，MC（25）和SC濃度分別保持在1.5%和3.5%時(shí)，隨著PEG濃度的增加，可逆性溶膠轉(zhuǎn)變溫度從38°C降低至26°C，然而，溫度降低的程度不受PEG分子量的影響，隨著MC濃度的增加可逆溶膠~凝膠的溫度降低，同時(shí)隨著ph值的降低可逆溶膠~凝膠的溫度

3、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。</p><p>　　[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</p><p><b>　　1 前言</b></p

4、><p>　　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)間，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?，聚合物的使用也有其缺點(diǎn)，如由于溶液的粘度高會(huì)出現(xiàn)灌注困難和不適感。</p><p>　　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

5、元系統(tǒng)中的應(yīng)用，并開發(fā)了一種含馬來酸噻嗎洛爾，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。</p><p>　　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。此外，從流變性方面與其他原位凝膠在眼科

6、中應(yīng)用進(jìn)行比較。</p><p><b>　　2 實(shí)驗(yàn)材料</b></p><p>　　四種不同的甲基纖維素（MC），即，MC（SM 15，25，400，1500），聚乙二醇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 1000，4000，6000）和二水檸檬酸鈉（SC），泊洛沙姆

7、407，馬來酸噻嗎洛爾，氧氟沙星，倍他米松磷酸鈉。</p><p>　　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。</p><p>　　2.1 原位凝膠溶液的制備</p><p>　　將50毫升的蒸餾水加熱至90℃后加入MC（0.7克SM150.7：GOF SM400）后攪拌均勻，

8、制備漿料。將其冷卻至5℃，在30ml蒸餾水中混合3.5克SC，然后在15ml蒸餾水溶液中混合2.0克聚乙二醇400。攪拌該混合物直到透明。用3N鹽酸調(diào)節(jié)其pH值至7.8后，在混合物中加蒸餾水至100 mL，作為熱硬化性凝膠溶液。</p><p>　　2.2 泊洛沙姆溶液的制備</p><p>　　在索倫森緩沖溶液（pH7.0）中溶解25克PM，將所得混合物在5℃下放置24小時(shí)，然后混合2.

9、5克甘露糖醇，將所得70毫升溶液與索倫森緩沖溶液（pH 7.0）中和至100mL。</p><p>　　2.3 膠凝溫度通過試管倒置法測(cè)量</p><p>　　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)變溫度</p><p&

10、gt;<b>　　3 結(jié)果與討論</b></p><p>　　3.1 PEG對(duì)可逆溶膠凝膠轉(zhuǎn)變溫度的影響</p><p>　　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，MO設(shè)置凝膠的凝點(diǎn)很重要的一點(diǎn)是利用DSC對(duì)溫度不敏感的特性

11、。 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（MC~PEG~SC）系統(tǒng)中特別應(yīng)該注意的是PEG，該添加劑的作用已知。</p><p><b>　　圖1</b></p><p>　　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 %，10 %。表觀粘度測(cè)定用流變儀測(cè)定。甲基纖維素（SM 25

12、）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%</p><p>　　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。</p><

13、p>　　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SC濃度保持恒定在1.5%和3.5%不變時(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PEG濃度的增加而下降。當(dāng)PEG濃度為10%時(shí)，溶液的粘度在24°C 時(shí)開始增加,然而當(dāng)溫度增加到34°C時(shí)，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

14、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）。</p><p>　　MC呈現(xiàn)出溶于水的纖維素，有高的結(jié)晶度和低的水溶性部分。為此，當(dāng)加熱和凝膠分離冷卻時(shí)，MC的解決方案是可逆的。其膠凝機(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的脫水溫度。當(dāng)PEG單獨(dú)添加到MC中時(shí)，溶液的熱

15、定形凝膠溫度只是略微降低，但大大減少了檸檬酸的加入。PEG引起了葡聚糖水溶液的相分離，此外，研究發(fā)現(xiàn)，過量添加PEG誘導(dǎo)熱定形凝膠（MC–PEG–SC系統(tǒng)）相分離（微相分離），通過上述研究發(fā)現(xiàn)了PEG通過誘導(dǎo)微相分離加速M(fèi)C形成交聯(lián)的解決方案。</p><p>　　PEG的分子量對(duì)熱定形凝膠溫度的影響，當(dāng)PEG的濃度從0%變化到10%時(shí)，MC的濃度（SM 25）和SC分別保持恒定在1.5%和3.5%時(shí)。當(dāng)PEG

16、1000和PEG 6000代替PEG 4000時(shí)，熱定形凝膠的溫度依賴于PEG的濃度而降低。 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PEG依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MC溶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

17、溫下的熱定形凝膠。</p><p>　　熱定形凝膠溶液、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,<

18、;/p><p><b>　　4 結(jié)論</b></p><p>　　我們通過可逆性溶膠~凝膠的過渡溫度來研究三元（MC–PEG–SC）系統(tǒng)的影響。當(dāng)SC濃度保持恒定，可逆性溶膠凝膠轉(zhuǎn)變溫度降低取決于PEG和MC的濃度，但不取決于PEG分子量。溶膠凝膠轉(zhuǎn)變溫度隨pH的增加而減少，此外，隨著可逆性溶膠溶液的轉(zhuǎn)變溫度減低和PEG濃度的增加，將會(huì)有更多的眼藥類型供選擇，通過對(duì)熱固性

19、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。</p><p><b>　　參考文獻(xiàn)</b></p><p>　　[1] Bourdais CL, Acar L, Zia H, Sado PA , Needham .Leverge R (1998)

20、前衛(wèi)視網(wǎng)膜眼研究 17:33</p><p>　　[2] Sasaki H, Nishida K, Nakamura J.Ichikawa M (1996) 前衛(wèi)視網(wǎng)膜眼研究 15:583</p><p>　　[3] Chrai SS. RobinsonJR (1974 ) 醫(yī)藥供應(yīng)鏈 63:1218</p><p>　　[4] Kurimoto K, Eguchi

21、 K, Kitajima S,Kishimoto N, Matsumoto N.Otsuki(1991) Atarashii Ganka 8:1259</p><p>　　[5] Kabayama T, Suzuki H, Horiuchi T,Akutagawa Y. Matsuzaki H (1979) 日本眼科系統(tǒng)[J]. 83:326</p><p>　　[6]TakeuchiM,

22、KageyamaS,SuzukiH,WadaT,ToyodaY,OgumaT,EzureY,TsuriyaY,KatoT.IshiiF(1999) 材料技術(shù) 17:445</p><p>　　[7] Patton TF.Robinson JR (1975) 藥學(xué)科學(xué) 64:1312</p><p>　　[8] Rozier A, Mazuel C, Grove J, Plazon~net.

23、 B (1989) 國(guó)際藥學(xué)雜志 57:163</p><p>　　[9] Kato T, Yokoyama M. Takahashi A(1978) 膠體高分子科學(xué) 265:15</p><p>　　[10] Heymann E (1935) 反式法拉Soc 31:846[11] Edmond E. Ogston AG (1968) 生物化學(xué)雜志 109:569[12] Miyos

24、hi E .Nishinari K (1998) Kobun~shi Ronbunshu 55:567[13] Vadnere M,AmidonG, LindenbaumS. JohnL (1984) INTJ制藥 22:207[14] Cho CW,Shin SC.Oh IJ (1997) Drug DevInd Pharm 23:1227</p><p>　　Rheological properties

25、of reversible thermo-setting in situ gelling solutions with the methylcellulose–polyethylene glycol–citric acid ternary system</p><p>　　Masanobu Takeuchi Shinji Kageyama Hidekazu Suzuki Takahiro Wada Yoshita

26、da Notsu Fumiyoshi Ishii</p><p>　　Abstract The composition of vehicle on the reversible sol–gel transition temperature in a ternary system made up of methylcellulose (MC), polyethylene glycol (PEG), and citr

27、ic acid (SC) was investigated. The properties of the in situ gelling system were estimated by rheological measurement. When PEG (4000) concentration was varied from 0% to 10% while MC (SM25) and SC concentrations were ke

28、pt constant at 1.5% and 3.5%, respectively, the reversible sol–gel transition temperature lowered from 38 _</p><p>　　Keywords Thermo-setting gel Sol–gel transition temperature Rheology Methylcellulose–polye

29、thylene glycol–citric acid ternary system</p><p>　　Introduction</p><p>　　Studies have been made to improve the poor bioavailability of ophthalmic solutions in the eye using various drug delivery

30、 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 in

31、creasing precorneal residence time of the drug and improving the kerato-conjunctival permeability. The use of biocompatible polymers was found to be effective,</p><p>　　We recently found a thermo-setting gel

32、 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 developed a long-acting opht

33、halmic solution (Rysmon TG) containing timolol maleate that is used in the treatment of glaucoma [6]. </p><p>　　It was reported that the ade reagents by Wako Pure Chemical Industries (Japan). The gellan gum

34、used was Gelrite by Wako Pure Clong-acting ophthalmic solution exhibited thixotropy at temperatures of 32 _C and upward, showing marked changes in flow curve and viscosity curve with rising temperature . It has been repo

35、rted 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</p><p>　　The present

36、study aimed at assessing the effect of the composition of a thermo-setting gel solution vehicle on its rheological properties. Furthermore, rheological properties were compared among different solutions, with the other i

37、n situ gelling systems for ophthalmic use as control.</p><p>　　Experimental</p><p><b>　　Materials</b></p><p>　　Four different kinds of methylcellulose (MC), that is, Met

38、olose (SM 15, 25, 400, 1500) by Shin-Etsu 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 abbre

39、viated 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 I

40、ta</p><p>　　Simulated tear fluid was prepared by adding distilled 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 solutio

41、n reached 100 mL according to the preparation described by Rozier et al</p><p>　　Preparation of thermo-setting gel vehicle</p><p>　　The thermo-setting gel vehicle was prepared according to the m

42、ethod 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 sl

43、urry was cooled to 5 _C and mixed with a solution of 3.5 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 transpar&l

44、t;/p><p>　　Preparation of various in situ gelling solutions</p><p>　　A 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 stir

45、ring and allowing it to disperse sufficiently. The slurry was cooled to 5 _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 s

46、tirred until it became transparent. After adjusting its pH to 7.8 with 3 N hydrochloric acid, the mixture was made up to 100 mL with distilled water and</p><p>　　Gellan gum solution was prepared by dissolvin

47、g 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]. </p&

48、gt;<p>　　Poloxamer 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

49、with 2.5 g mannitol, and making up the resultant solution to 100 mL with So¨ rensen buffer solution (pH 7.0).</p><p>　　Measurement of gelling temperature by the test tube inversion method</p><

50、;p>　　The 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 m

51、m inner diameter), 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–

52、gel transition temperature.</p><p>　　Results and discussion</p><p>　　Effect of PEG on reversible sol–gel transition temperature</p><p>　　Several methods are known for measuring the

53、reversible sol–gel 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-s

54、haped tube method are used 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

55、 inappropriate i</p><p>　　were not known</p><p>　　Fig. 1 Effects of temperature on the apparent viscosity of the thermo-setting gel solution. Polyethylene glycol concentrations: s 0%, e 2%, h 4%

56、, d 6%, r 8%, j 10%. The apparent viscosity was measured with a rheometer at shear rate 200[1/s]. Methylcellulose (SM 25) and sodium citrate dihydrate concentrations were kept constant at 1.5% and 3.5%, respectively, whi

57、le the concentration of polyethylene glycol (PEG 4000) was varied from 0 to 10%</p><p>　　Fig. 2 Correlation of the phase transition temperature measured by the test tube inversion method and rheometer. In th

58、e formula, x and y express phase transition temperature measured with the test tube inversion method and phase transition temperature measured with the rheometer, respectively. Methylcellulose (SM 25) and sodium citrate

59、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%</p><p>　　Figures 1 and 2 show the effect of tempe

60、rature on the apparent viscosity of 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 c

61、oncentrations were kept constant at 1.5% and 3.5%,respectively,and the concentration of PEG 4000 wasvaried from 0 to 10%, the reversible sol–gel transition temperature declined with increase in PEG concentration. When th

62、e concentration of P</p><p>　　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, ge

63、lated when heated and solated when cooled. The mechanism of its gelation was reported to involve crystallization of a trimethyl-glucose sequence and formation of cross linkage [9]. The reversible sol–gel transition tempe

64、rature (thermo-setting gelling temperature) is generally reduced by addition of a salt, the effect of w</p><p>　　The effect of the molecular weight of PEG on the thermo-setting gelling temperature when the P

65、EG concentration was varied from 0 to 10% while the concentrations of MC(SM 25) and SC were kept constant at 1.5% and 3.5%, respectively, is shown in Fig. 3. On the other hand, the effect of the MC (SM 25) concentration

66、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 thermo</p><p>　　trimethylgl

67、ucose sequences [9]. That is, crystallization and formation of cross linkage became easier with a shortening of distances, with a result that gelling occurred at a lower temperature. The same mechanism seemed to be opera

68、ting in the shift towards the lower temperature in the present thermo-setting gel.</p><p>　　Thermo-setting gel solution, gellan gum solution, and poloxamer solution showed different types of fluidity, which

69、were manifested respectively as Newtonian flow, quasi-viscous flow, and quasi-plastic flow. While all these solutions showed improvement in precorneal residence time by sol–gel transition, the thermo-setting gel solution

70、 and poloxamer solution never failed to undergo gelation at a temperature near the ocular surface temperature, which suggested that their residence behavior was exce</p><p>　　Conclusion</p><p>　

71、　We investigated the effect of the ternary MC–PEG–SC system vehicle composition on reversible sol–gel transition temperature. A decrease in the reversible sol–gel transition temperature depended on PEG and MC concentrati

72、ons when the SC concentration was kept constant, but did not depend on PEG molecular weight. The sol–gel transition temperature increased with decrease in pH. Furthermore, decrease in reversible sol–gel transition temper

73、ature with increasing PEG concentration was observed in the p</p><p>　　References</p><p>　　1. Bourlais CL, Acar L, Zia H, Sado PA, Needham T, Leverge R (1998) Prog Retin Eye Res 17:33</p>

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