1296275 九、發明說明： 【發明所屬之技術領域】 本發明係有關一種聚合物凝膠的製備，尤指一種低毒 性聚丙烯酸酯類聚合物凝膠(DEMBIG)的組成配方與製備方 法，該聚丙烯酸酯類聚合物凝膠可應用在各種放射治療之 劑量評估上，如近接治療、強度調控治療（IMRT)、立體定 位放射治療手術(SRS)，以便於做為呈現病人體内3D劑量 的輕射度量工具。 【先前技術】 在放射治療技術中，最重要的是一套治療計晝的劑量 驗證工作。在治療病人前，若我們能事先模擬實際輻射吸 收4彳里刀佈’就能有效评估治療過程中及治療後的狀況。 目前在臨床劑量驗證工作上常使用的輻射度量工具， 例如游離腔、半導體偵測器、熱發光劑量計^!^)，及作為 二度空間劑量分布量測的底片…等，前三者量測的誤差雖 可在3〜5%之内，但僅能做點的量測，且對於腫瘤與正常組 織交接處的劇烈劑量梯度變化空間解析度不佳，對於目前 走向三度空間且愈來愈複雜的放射治療而言，愈需要高空 間解析度且模擬人體的劑量量測系統。 為了克服這些缺點，我們將應用新的輻射度量工具一 聚合物凝膠，它能夠提供高準確度、高空間解析度及三度 門的幸田射度1，足以因應現代愈複雜與愈需要精準劑量 5 1296275 確§忍的放射線治療，如強度調控治療和放射治療手術。因 此，聚合物凝膠之發展在放射治療測量3D吸收劑量分佈是 非常有用的工具，並具有劃時代的重要意義。 但是聚合物凝膠仍有些問題存在，以至於未能實際用 於臨床上，例如須在實驗室製備、凝膠成分毒性過高及凝 膠易受外在環境變化而影響，如光、溫度、和氧氣…等。 1993年’ Maryanski首先發現使用聚合物凝膠可用於 幅射劑里里測’唯以南毒性之丙醯胺（acrylamide，124 mg .kg_1 ;餵食大鼠）為單體，之後雖有丙烯酸（acryHc acid ’ 300 mg · kg'·餵食大鼠）與甲基丙烯酸（methacryl ic acid ’ BANG-3 ; 1060 mg .kg1 ;餵食大鼠）為單體，其缺 點除毒性仍偏高外，劑量之敏感度亦偏低。 雖然最近由Fong在2001年發表的MAGIC凝膠有了重 要的犬破’其成份結合金屬有機化合物(COpper—ascorbate complex)，使其在有氧狀況下反應良好，但該MAGIC凝膠 的缺點為剛製備完後容易霧化，若使用光密度掃描儀測量 會造成顯著誤差，因此對臨床應用上，沒有助益。 另外，關於聚合物凝膠的製備，先前文獻之製作方法 皆不相同，也各有其優缺點，對於想要製作聚合物凝膠的· 人目前沒有一套完整的製備程序可以遵從。 因此，如何製作新的聚合物凝膠，使其在作為輻射度 6 1296275 $卫具之同時’具有低毒性，且對劑量的敏感度更高，以 便於呈現病人體㈣㈣的怖_ ;以及如何從過去製 , 備方法中’去其缺失，並進喊立出—套完整的製備程序， 使凝膠可以準確的測量出劑量，則是本發明的主要目標。 【發明内容】 本發明主要包括二個部份··第一部份為聚合物凝膠組 成配方及其製備方法；第二部份是提供快速凝膠液去氧方 瞻 法以及提供快速去氧的設備，緣此： 本發明主要的目的在提供一種新成份的聚合物凝膠， 其具有低毒性，對劑量的敏感度更高，又可降低受環境變 異的影響的特性，可直接用於呈現病人體内3D劑量分布情 形，以期改善治療計晝，增進病人安全。 本發明之另一目的在提供一種快速凝膠液去氧方法的 設備，使可大幅縮短凝膠的製備時間。 • 為達上述之目的，本發明所設之低毒性聚丙烯酸酯類聚 合物凝膠係由下列物質所組成，及其重量百分比亦如下所 示·（a) 1 -l〇wt%的蛋白膠(Gelatin) ; (b) 1 - 10wt%的單體 甲基丙烯酸-（τΓ , f —二烷基胺基）烷基酯 (#，# -dialkylamino)alkyl methacrylate)，且烧基 (alkyl)所代表的碳數目為卜4 ; (c) 1—1〇的％的π — 曱基雙醯胺（f —methylene-bisacrylamide) (BIS) ; (d)至少lwt%的鹼性溶液；以及(e) 69-96wt°/〇的 7 (8^ 1296275 水0 較佳的實施例是，其中該單體為曱基丙烯酸一2一(二曱 基胺基）乙基酯（2-(Dimethylamino)ethyl methacrylate) (DEMA) 〇 較佳的實施例是，所述蛋白膠(Gelatin)的重量百分比 比單體和交聯劑（BIS)高1〜2%，使凝膠凝固性最佳。 較佳的實施例是，該聚丙烯酸酯類聚合物凝膠③EMBIG) 最佳比例為蛋白膠(gelatin):單體··交聯劑是5 ·· 3 : 3， 使凝膠的敏感度與凝固性良好。 較佳的實施例是，該DEMA為單體分子，該BIS為交聯 劑’可使輻射照射而進行聚合反應。 此外’本發明所述之低毒性聚丙烯酸酯類聚合物凝膠 之製備步驟為： (a) 提供一内含有去離子水的密封容器； (b) 通過高純度氬氣，以排除去離子水中的氧氣； (c) 加入1-i〇wt%的蛋白膠(Gelatin)，並使該蛋白膠 (Gelatin)溶解澄清； (d) 加入1-l〇wt%的單體曱基丙烯酸—二烷 基胺基)烧基酯（F-dialkylamino)alkyl methacrylate)，且烷基(alkyl)所代表的碳數目為 1 -4 ’並使其溶解； (e) 加入至少iwt%的鹼性溶液；以及 (0加入1-l〇wt%的#曱基雙醯胺 1296275 (#，# -methylene-bisacrylamide) (BIS)，並 使其溶解。 較佳的實施例是，所述的鹼性溶液為氳氧化鈉 (NaOH)，以能將酸性的離子水中和。 車父佳的實施例是，為了使所完成的聚合物凝膠可進一 步驅離其凝膠溶液内的含氧量，所述步驟（f)還包括： (g)再一次通過氬氣氣體。 為能進一步暸解本發明，以下舉之實施例，配合圖示、 圖號，將本發明之具體構成内容及其所達成的功效詳細說 明如后： 【實施方式】 本發明主要包括二個部份：第一部份為聚合物凝膠的 組成配方及其製備方法；第二部份是提供—種可快速去除 凝膠液中的氧氣之方法及裝置。但為使同—技術領域之人 士可將製成的凝膠做完整的應用，製成後的凝膠尚需包括 輻射度量校正、輻射照射、磁振照影、以及賴分析等流 程。為此，茲將本凝膠的製備方法及其驗證過程包括：（一） 聚合物凝膠的成份、（二）聚合物凝膠的製備方法、（三）輻 射度篁杈正、（四）輻射照射、（五)磁振照影、（六）電腦分 析0 第一部份聚合物凝膠的組成配方及其製備方法 (一）聚合物凝膠的成分 1296275 / 首先，對本發明所述之低毒性聚丙烯酸酯類聚合物凝 ' 膠（簡稱DEMBIG)之組成成份及其重量百分比詳細說明如 下，該聚合物凝膠包括： _ (a) 1 - 10wt%的蛋白膠(Gelatin) ; (b)l- 10wt%的單體甲基 丙烯酸-（yf -二烷基胺基）烷基酯 (ΤΓ,ΤΓ -dialkylamino)alkyl methacrylate)，且烧基 (alkyl)所代表的碳數目為1-4; (c) 1-10wt°/〇的#W - ⑩ 甲基雙醯胺（ΥΊ -methylene-bisacrylamide) (BIS); (d)至少lwt%的鹼性溶液；以及(e) 69-96wt%的水(H2O)。 該蛋白膠(Gelatin)的重量百分比在整個聚合物凝膠 中較佳為3-5wt%。蛋白膠主要是由膠原蛋白（Collagen)所 提煉出來，其主要的胺基酸(amino acid)組成比例如表一 所示。由豬皮（porcine skin)所提煉的蛋白膠（Bloom number 300，Sigma Chemical Co·, USA)，平均分子量為 ® 50, 000〜100, 〇〇〇道耳吞(dait〇n)，主要化學結構式如下圖 所示。由於蛋白膠的製備步驟中需破壞膠原蛋白的二級結 構’以致於在機械特性及溶解度方向有了基本的改變，當 置於冰水中會因吸水而使體積膨脹，但不會溶於冰水；若 是加熱增溫，則蛋白膠將慢慢地溶解於熱水中形成高黏度 的溶液，當完全溶解後再給予冷卻，則發現蛋白膠溶液會 逐渐硬化轉變成果凍狀（jelly type)。實施例使用之蛋白 1296275 . 膠(Bloom number 300)即是應用冷熱水使束狀成符合劑量 量測使用MRI造影所需的狀態。 蛋白膠中胺基酸組成比例（Amino Acid Content (%)) Alanine 8·700 - 9· 600 Hydroxylysine 0.760 - 1.500 Arginine 8.600 - 9.300 Hydroxy pro line 12. 600 - 14. 400 Aspartic Acid 5.500 - 6· 800 Isoleucine 1.400 - 1.700 Cystine 0.100 - 0.200 Leucine 3.200 - 3· 600 Glutamic Acid 10.200 - 11.700 Lysine 4· 100 — 5· 900 Glycine 26.000 - 27·000 Methionine 0.600 - 1.000 Histidine 0.600 - 1.000 Phenylalanine 2.200 - 2. 600 Proline 14.800 - 17.600 Serine 3. 200 - 3. 800 Threonine 1.900 - 2.200 Tryptophan 0·000 - 〇· 003 Tyrosine 0.490 - 1.100 Valine 2.500 - 2. 700 表一蛋白膠中胺基酸組成比例（Approximate)1296275 IX. Description of the invention: [Technical field of the invention] The present invention relates to the preparation of a polymer gel, in particular to a composition and preparation method of a low toxicity polyacrylate polymer gel (DEMBIG). Acrylate polymer gels can be used in a variety of radiation therapy dose assessments, such as proximity therapy, intensity-modulated therapy (IMRT), and stereotactic radiotherapy (SRS), to facilitate the presentation of 3D doses in patients. Shot measurement tool. [Prior Art] Of the radiotherapy techniques, the most important is the dose verification work of a treatment plan. Before the treatment of patients, if we can simulate the actual radiation absorption of 4 knives in advance, we can effectively assess the status of the treatment and after treatment. Radiation measurement tools currently used in clinical dose verification work, such as free cavity, semiconductor detector, thermal luminescence dosimeter ^!^), and negative film as a second-degree dose distribution measurement, etc., the first three Although the measured error can be within 3~5%, it can only do the measurement of the point, and the spatial resolution of the severe dose gradient change at the junction of the tumor and the normal tissue is not good, for the current three-dimensional space and more and more The more complex radiotherapy, the more need for high spatial resolution and simulation of the human body's dose measurement system. In order to overcome these shortcomings, we will apply a new radiation metric tool, a polymer gel, which can provide high accuracy, high spatial resolution and Kodak radiance of the third degree door, which is sufficient for the modern complex and more precise doses. 5 1296275 Radiation therapy, such as intensity-modulated therapy and radiation therapy. Therefore, the development of polymer gels is a very useful tool for measuring 3D absorbed dose distribution in radiation therapy and is of epoch-making significance. However, polymer gels still have some problems, so that they are not practically used in clinical practice, such as preparation in the laboratory, excessive toxicity of the gel components, and the gel is susceptible to external environmental changes such as light, temperature, And oxygen...etc. In 1993, 'Maryanski first discovered that the use of polymer gels can be used in the radiant to measure 'only toxic acrylamide (124 mg.kg_1; fed rats) as a monomer, followed by acrylic acid (acryHc) Acid '300 mg · kg'·feeding rats) and methacrylic acid (methacrylic acid 'BANG-3; 1060 mg.kg1; feeding rats) are monomers, and their disadvantages are high in addition to toxicity, dose sensitivity The degree is also low. Although the MAGIC gel recently published by Fong in 2001 has an important dog-breaking composition that combines with the COpper-ascorbate complex to make it react well under aerobic conditions, the disadvantage of the MAGIC gel is It is easy to atomize just after preparation. If it is measured by optical density scanner, it will cause significant error, so it is not helpful for clinical application. In addition, regarding the preparation of polymer gels, the preparation methods of the prior literature are different, and each has its own advantages and disadvantages. For those who want to make polymer gels, there is currently no complete preparation procedure to follow. Therefore, how to make a new polymer gel, which has low toxicity and sensitivity to doses as a radiant 6 1296275 $, in order to present the patient's body (4) (4); and how It is the main object of the present invention from the past system, the preparation method to 'go its missing, and to scream out the complete preparation procedure, so that the gel can accurately measure the dose. SUMMARY OF THE INVENTION The present invention mainly comprises two parts. The first part is a polymer gel composition formula and a preparation method thereof. The second part is to provide a rapid gel liquid deoxygenation method and provide rapid deoxidation. The main purpose of the present invention is to provide a polymer gel of a new composition which has low toxicity, is more sensitive to dose, and can reduce the influence of environmental variability, and can be directly used for Presenting the 3D dose distribution in the patient's body, in order to improve the treatment plan and improve patient safety. Another object of the present invention is to provide an apparatus for a rapid gel liquid deoxidation method which greatly shortens the preparation time of the gel. • For the above purposes, the low toxicity polyacrylate polymer gel of the present invention is composed of the following materials, and the weight percentage thereof is also as follows: (a) 1 - l〇wt% of protein glue (Gelatin); (b) 1 - 10% by weight of a monomeric methacrylic acid-(τ,#-dialkylamino)alkyl methacrylate, and an alkyl group The number of carbons represented is b; (c) 1-1% of π-methylene-bisacrylamide (BIS); (d) at least 1 wt% of an alkaline solution; and (e) 7-(8^1296275 water 0) A preferred embodiment is one in which the monomer is 2-(dimethylamino)ethyl 2-(dimethylamino)ethyl A preferred embodiment of the methacrylate (DEMA) 是 is that the gelatin (Gelatin) is 1% to 2% more by weight than the monomer and crosslinker (BIS) to optimize gel coagulability. In the embodiment, the optimum ratio of the polyacrylate polymer gel 3EMBIG) is gelatin: the monomer··crosslinking agent is 5··3:3, which makes the gel sensitive and coagulable. . In a preferred embodiment, the DEMA is a monomer molecule, and the BIS is a crosslinking agent, and the polymerization can be carried out by irradiation with radiation. Further, the preparation steps of the low toxicity polyacrylate polymer gel described in the present invention are as follows: (a) providing a sealed container containing deionized water; (b) passing high purity argon gas to remove deionized water (c) Add 1-i〇wt% of gelatin (Gelatin) and dissolve the gelatin (Gelatin) to clarify; (d) Add 1-l〇wt% of monomeric methacrylic acid-dialkyl F-dialkylaminoalkyl methacrylate), and the number of carbons represented by the alkyl group is 1-4' and dissolved; (e) adding at least iwt% of an alkaline solution; (0) 1- l〇wt% of #曱基双醯amine 1296275 (#,# -methylene-bisacrylamide) (BIS) is added and dissolved. In a preferred embodiment, the alkaline solution is 氲Sodium oxide (NaOH) to neutralize acidic ions. In the embodiment of the car, in order to allow the completed polymer gel to further drive away the oxygen content in its gel solution, the step ( f) further includes: (g) passing argon gas again. In order to further understand the present invention, the following embodiments, together with the drawings and drawings, will The specific constitution of the invention and the effect achieved by the invention are as follows: [Embodiment] The invention mainly comprises two parts: the first part is a composition formula of a polymer gel and a preparation method thereof; the second part It is a method and a device for rapidly removing oxygen in a gel solution, but in order to enable a person to perform a complete application of the gel produced by the same technical field, the gel after the preparation needs to include a radiation metric. Correction, radiation exposure, magnetic resonance, and analysis. For this reason, the preparation method and verification process of the gel include: (1) the composition of the polymer gel, and (2) the polymer gel. Preparation method, (3) radiance correction, (4) radiation irradiation, (5) magnetic resonance, (6) computer analysis 0 composition formula of the first part of the polymer gel and preparation method thereof Component of Polymer Gel 1296275 / First, the composition and weight percentage of the low toxicity polyacrylate polymer gel (DEMBIG) described in the present invention are as follows, and the polymer gel includes:(a) 1 - 10% by weight of gelatin (Gelatin); (b) 1 - 10% by weight of y-dialkylaminoalkyl methacrylate And the number of carbons represented by the alkyl group is 1-4; (c) 1-10wt ° / 〇 of #W - 10 - dimethyl-bisacrylamide (BIS); (d) At least 1 wt% of an alkaline solution; and (e) 69-96 wt% of water (H2O). The weight percentage of the gelatin (Gelatin) is preferably 3-5 wt% throughout the polymer gel. The protein gel is mainly extracted from collagen (Collagen), and its main amino acid composition ratio is shown in Table 1. Protein gel extracted from porcine skin (Bloom number 300, Sigma Chemical Co., USA), with an average molecular weight of 510 000~100, dait〇n, main chemical structure The formula is shown below. Since the secondary structure of collagen is destroyed in the preparation step of the protein gel, so that there is a fundamental change in the mechanical properties and solubility direction, when placed in ice water, the volume expands due to water absorption, but it does not dissolve in ice water. If heated and warmed, the protein gel will slowly dissolve in hot water to form a high-viscosity solution. When it is completely dissolved and then cooled, it is found that the protein gel solution will gradually harden and transform into a jelly type. The protein used in the examples 1296275. The Bloom number 300 is the state required to apply the hot and cold water to make the bundle conform to the dose measurement using MRI. Amino Acid Content (%) in protein gel (Amino Acid Content (%)) Alanine 8·700 - 9· 600 Hydroxylysine 0.760 - 1.500 Arginine 8.600 - 9.300 Hydroxy pro line 12. 600 - 14. 400 Aspartic Acid 5.500 - 6·800 Isoleucine 1.400 - 1.700 Cystine 0.100 - 0.200 Leucine 3.200 - 3· 600 Glutamic Acid 10.200 - 11.700 Lysine 4· 100 — 5· 900 Glycine 26.000 - 27·000 Methionine 0.600 - 1.000 Histidine 0.600 - 1.000 Phenylalanine 2.200 - 2. 600 Proline 14.800 - 17.600 Serine 3. 200 - 3. 800 Threonine 1.900 - 2.200 Tryptophan 0·000 - 〇· 003 Tyrosine 0.490 - 1.100 Valine 2.500 - 2. 700 Amino acid composition ratio in the protein gel (Approximate)
圖 蛋白膠的主要化學結構式 !296275 所述單體較佳為甲基丙烯酸-2-(二曱基胺基)乙基醋 (2-(Dimethylamino)ethyl methacrylate) (DEMA)。其重 量百分比在整個聚合物凝膠中較佳為3-5wt%。且所述的二 甲基（Dimethy 1)與乙基（ethy 1)可分別置換為乙基（―CH2 CH3)、丙基(-CH2 CH2 CH3)、或是丁基(-CH2 CH2 CH2 CHs)， 其為熟於本項技術領域者所易於思及。 _ 該 Ν’，Ν’ - 甲 基雙 醯胺 (f ,水-methylene-bisacrylamide) (BIS)是交聯劑的一 種，其重量百分比在整個聚合物凝膠中較佳為3-5wt%。BIS 之分子式為C晶5〇2。 該驗性溶液較佳為氫氧化鈉（NaOH)。而所述蛋白膠 (Gelatin)的重量百分比比單體和交聯劑卬岱）高， 使凝膠凝固性最佳。 關於本發明的聚合物凝膠(DEMBIG)之組成成分化學資 •料如下表二所示，單體分子中除擁有碳—碳雙鍵可供輻射產 生自由基，再進而發生連續反應(proparagati〇n reacti〇n) 產生聚合物外，且為標示最低毒性之單體，對操作者相當 有利。 fs 12 1296275The main chemical structural formula of the protein gel is 296275. The monomer is preferably 2-(Dimethylamino)ethyl methacrylate (DEMA). The weight percentage thereof is preferably from 3 to 5% by weight in the entire polymer gel. And the dimethyl (Dimethy 1) and ethyl (ethy 1) can be replaced by ethyl (-CH2 CH3), propyl (-CH2 CH2 CH3), or butyl (-CH2 CH2 CH2 CHs), respectively. It is easy to think for those skilled in the art. The Ν', Ν'-methylene-bisacrylamide (BIS) is a crosslinking agent, and the weight percentage thereof is preferably 3-5 wt% in the entire polymer gel. The molecular formula of BIS is C crystal 5〇2. The test solution is preferably sodium hydroxide (NaOH). The gelatin (Gelatin) is higher in weight percentage than the monomer and crosslinker, and the gel is most coagulable. Regarding the chemical composition of the polymer gel (DEMBIG) of the present invention, as shown in Table 2 below, in addition to the carbon-carbon double bond in the monomer molecule, radiation can generate free radicals, and then a continuous reaction occurs (proparagati〇). n reacti〇n) It is quite advantageous for the operator to produce a monomer other than the one that indicates the lowest toxicity. Fs 12 1296275
Monomer 甲基丙烯酸-2-(二甲基胺基）乙 基酯（2-(Dimethylamino)ethyl methacrylate) (DEMA) Chemical structure fj ch3 H2C二?-C-OCH2 CH2 -N: ch3 ch3 LD50 (oral/rat; mg/ kg) 1751 表二聚合物凝膠(DEMBIG)之組成成分化學資料 (二)製備該聚合物凝勝的方法 請先參閱第1圖，本發明之聚合物凝膠係在一密封型 容器（10)内被製造。該容器（10)上具有四個進出口（12)、 (14)、（15)、（16)，其中，該第一個進出口（12)可供插入 一軟管（13)，該軟管（13)係供通過高純度氬氣以排除容器 (10)内離子水(11)中的氧氣。所述軟管（13)的材質較佳為 Tygon，或任何使軟管（13)本身不亦與容器（丨〇)内的其它化 學物質產生化學反應的材質。該軟管（13)的形狀較佳為由 上而下地呈捲撓狀，使得軟管（13)可以與容器（1〇)中的離 子水开>成大範圍地接觸。軟管（13)上還設有直徑約小於/等 於1mm的複數小孔（131)，藉此該複數的小孔（el)可使所 通過尚純度氬氣廣範圍地、且徹底地進行離子水中的去氧 動作。该第二個進出口（14)係供通過水中的氬氣排出之Monomer 2-(Dimethylamino)ethyl methacrylate (DEMA) Chemical structure fj ch3 H2C bis-C-OCH2 CH2 -N: ch3 ch3 LD50 (oral/ Rat; mg/kg) 1751 Table II Polymer gel (DEMBIG) composition chemical data (2) Preparation of the polymer gel method Please refer to Figure 1, the polymer gel of the present invention is sealed in a seal The inside of the type container (10) is manufactured. The container (10) has four inlets and outlets (12), (14), (15), (16), wherein the first inlet and outlet (12) are for inserting a hose (13), the soft The tube (13) is passed through high purity argon to remove oxygen from the ionic water (11) in the vessel (10). The material of the hose (13) is preferably Tygon, or any material that causes the hose (13) itself to chemically react with other chemicals in the container. The shape of the hose (13) is preferably wound from top to bottom such that the hose (13) can be in wide contact with the ion water in the container (1). The hose (13) is further provided with a plurality of small holes (131) having a diameter of less than or equal to 1 mm, whereby the plurality of small holes (el) allow the ion to pass through the argon gas of a wide range and thoroughly and thoroughly. Deoxygenation action in the water. The second inlet and outlet (14) is for discharging argon through the water.
Cs 13 1296275 用。該第三個進出口（15)可供放置溫度計，以準確的測量 容器（10)内的溫度，以便於確知何時可再加入下一個化學 物質做為反應。該第四個進出口（16)則供所需加入的各化 學物質加入容器（10)内，以便進行反應。 請參第2圖，圖示内容為以低毒性的£)51人單體成分的 聚合物凝膠(DEMBIG)為例來製作聚合物凝膠的流程圖。 首先’於谷裔（10)的軟管（13)内通過高純度氬氣 (>99· 999%)，以排除離子水中（11)的氧氣(2〇)。然後，在 室溫（21)下加人 3-5wt %的蛋白膠(geiatin)(Bloom number 300) (30)，加熱攪拌至5〇°c (31)，等蛋白膠溶解（4〇)， 並等待約30分鐘使其降溫至4〇°c (41)後，再加入3-5wt %的單體甲基丙烯酸一2 -（二甲基胺基）乙基酯 (2_(Dimethylamino)ethyl methacrylate) (DEMA) (50)， 並覆蓋銘珀片後’再等待1〇分鐘（51)，加入至少丨的％的 鹼性溶液，如氫氧化鈉（NaOH)(60)，攪拌等待10分鐘（w ) 加入3-5 wt%的交聯劑#—曱基雙醯胺 (介-methylene-bisacrylamide) (BIS) (70)，等其 溶解冷卻（80)(時間約為30分鐘才會溶解冷卻（71))， 即完成本凝膠之製備。但為使所完成的凝膠完全去除其氧 氣，可再一次通過高純度氬氣（9〇)(其係在充滿氬氣的特 製手套袋（glove bag)中進行（91))。凝膠再一次去氧 14 1296275 完成後’即可送入假體⑽）中，準備輕射照射的進行。 製成之凝膠需冰箱冷藏24h使其凝固，再進行凝膠照 射（110) ’照射後放置室溫下儲存四天，最後才能進行磁 振照影MRI或光密度掃猫儀0CT (12〇)的應用。其中上述 之DEMA為單體分子，而BIS為交聯劑，使單體分子連結成 回刀子複合物；而氫氣化鈉(Na〇H)的功用則為調整凝膠邱 值。 以上所述乃本發明之凝膠主要製成配方及其製備方 法’但為讓同-技術領域之人士可將製成的娜做完整的 應用，製成後的凝膠尚需包括輻射度量校正、輻射照射、 磁振照影、以及電腦分析等流程，為此茲將本凝膠的應用 流程及其驗證方法簡述如下： (三)輻射度量校正 在將凝膠裝入假體進行正式照相前，使其充填於樣本 瓶之容器内’給予照射不同劑量，然後使用磁振照影照相， 進行校正。如第3圖所示，校正採用多試樣本瓶方法，使 用數個裝滿凝膠小樣本瓶給予已知的劑量照射，樣本瓶壁 要薄’將這些燒杯放置在與人體組織相近的水假體中，給 予不同的劑量照射’照射後4天使用磁振照影測量，建立 遲豫率R2-劑量校正曲線。Cs 13 1296275 used. The third inlet and outlet (15) can be used to place a thermometer to accurately measure the temperature in the vessel (10) in order to know when the next chemical can be added as a reaction. The fourth inlet and outlet (16) is supplied to the vessel (10) for each chemical substance to be added to carry out the reaction. Please refer to Fig. 2, which shows a flow chart for making a polymer gel using a low-toxicity polymer polymer gel (DEMBIG) of 51 human monomers. First, high purity argon (>99·999%) was passed through the hose (13) of the Gu (10) to remove oxygen (2 〇) from the ionic water (11). Then, add 3-5 wt% of gelatin (Bloom number 300) (30) at room temperature (21), stir to 5 °C (31) with heating, and dissolve the protein gel (4 〇). And wait for about 30 minutes to cool it to 4 ° ° C (41), then add 3-5 wt % of monomeric 2-(dimethylamino)ethyl methacrylate (2_(Dimethylamino)ethyl methacrylate) (DEMA) (50), and after covering the Mingpo tablets, 'wait another 1 minute (51), add at least 丨% of the alkaline solution, such as sodium hydroxide (NaOH) (60), stir for 10 minutes ( w) Add 3-5 wt% of crosslinker #- dimethyl-bisacrylamide (BIS) (70), wait for its dissolution to cool (80) (time is about 30 minutes to dissolve cooling (71)), that is, the preparation of the gel is completed. However, in order to completely remove the oxygen from the finished gel, it can be again passed through high purity argon (9 Torr) (which is carried out in a special lg-filled glove bag (91)). Once the gel is deoxygenated again, 14 1296275 can be sent to the prosthesis (10) and ready for light exposure. The prepared gel needs to be refrigerated in a refrigerator for 24 hours to be solidified, and then subjected to gel irradiation (110). After being irradiated, it is stored at room temperature for four days, and finally can be subjected to magnetic resonance MRI or optical density scanning cat instrument 0CT (12〇 )Applications. The above-mentioned DEMA is a monomer molecule, and BIS is a crosslinking agent, so that the monomer molecules are linked into a knife-knife complex; and the function of sodium hydrogen sulfide (Na〇H) is to adjust the gel value. The above is the main formulation of the gel of the present invention and the preparation method thereof. However, in order to allow the person skilled in the art to complete the application, the prepared gel needs to include the radiation metric correction. The process of radiation irradiation, magnetic resonance imaging, and computer analysis, for which the application flow and verification method of the gel are briefly described as follows: (3) Radiation metric correction: The gel is loaded into the prosthesis for formal photography. Before, it is filled in a container of a sample bottle', and different doses are irradiated, and then a magnetic photogram is taken for correction. As shown in Figure 3, the calibration uses a multi-sample bottle method, using a number of filled small vials to give a known dose of light, the sample wall is thin 'place these beakers in water close to human tissue In the prosthesis, different doses of radiation were administered. 4 days after the irradiation, the magnetic resonance photogrammetry was used to establish a delay rate R2-dose calibration curve.
1296275 (四）輻射照射 輕射照射可以使用直線加速器、加瑪刀 機器給予輻射照射，射束的能量和_可以^療 X哪、電子射束紅謂，且廣泛_在強度調控治療如 立體定位放射治射術、碳離子射絲療、治療_ 中子捕獲治療…等。 ' 本實驗將凝縣人多個試樣本瓶後，再置人冰箱至少 冷藏24小時，我們採❹試樣本瓶方法校正，使用醫院中 所提供的直線加速器（6MV光子)進行照射（第4圖），將這 些試官放置在lGxlGxlGcm的水箱中’平行照射5個裝有凝 膠的試樣本觀，給予已知劑量1. 8、3. 7、5 5、7 3 和9.1Gy，拿取其中-樣本瓶#作#景财給予照射（〇 Gy)，小瓶放置水箱深度為7· icm，射源到中心軸距離為 100cm，照野15x10cm，劑量率：400MU/min，參考輸出量： lGy / 100MU。 (五)磁振照影 目前最常使用照相的工具是磁振照影，其他有光掃描 儀、X-ray電腦斷層攝影及超音波。磁振照影（Magnetic Resonance Imaging ; MRI)藉由給予凝膠射頻電磁波激發 水質子，等其回復平衡狀態，測量遲豫率R2 (=1 / T2)， 經過過濾後收集而得的資料至少需要兩點，才可以形成T2 1296275 遲豫曲線。將經過照射後的凝膠進行照相，測量遲豫率（R2) 以評估凝膠的結構與密度，結果經由軟體Excel繪出R2_ 劑量曲線。 另外，當給予凝膠增加輻射劑量時，其凝膠阻光度也 會增加，藉由此原理發展出光掃描儀（0ptical scanning)， 描述出3D劑量分布。當增加〇到5Gy的劑量時，對於5〇〇nm 波長的雷射光而言，凝膠的衰減係數約0 7mnfl。通常光掃 描儀能替代或支持磁振照影數據。 本實驗凝膠經過直線加速器照射後4天，進行磁振照 影(MRI)，在磁振照影(MRI)測量前凝膠先儲存在磁振照影 (MRI)房間至少一晚（或1〇個小時），使其熱平衡。我們使 用醫院所提供的Siemens 1.5T version MRI系統進行T2 量測，將裝有凝膠的樣本瓶和假體放置RF頭部線圈内 (head coil)(第5圖），使用16個回波的多重自旋回波 脈衝序列（multiple spin-echo sequence)，其餘參數包括 重複時間TR:3000 ms、回波時間TE:50ms、切片厚度5mm 及照野26x26cm等。 整個照影時間大約20分鐘，然後將所得到的T2影像 圖之橫向切面圖（如第6圖所示），利用工作站電腦進行 T2衫像分析，使用Excel軟體建立R2-劑量曲線。 17 1296275 (六）電膜分析的結果 (1) R2-劑量曲線 藉由MRI T2影像，選取有興趣的地方（104 pixels)， 測出其遲解R2(M/T2)與相對應劑量晝出R2—劑量曲線， 第7圖顯不了 DEMBIG凝膠的R2-劑量曲線，顯示在劑量範 圍0〜9· lGy是線性關係，具有最佳劑量的敏感度，dembig 所异出來的斜率為 〇· 464±〇· 〇1 s Ay1 (r2=〇· 99)，而 BANG-3 ’ 的斜率0· 282 ±〇· 〇ΐ 3Κγ2=0· 99)，顯示腦則對劑 量的敏感度佳，相關性r2也較高。 (2) 凝膠組成成分比重變化 我們將研究比較DEMBIG和BANG-3改變其成分比重變 化對凝膠敏感度的影響，代表在BIS與DEMA中，其BIS 比例所佔比例。另外為了探討DEMBIG的最大劑量與低劑量 區其敏感度反應與相關性，我們將兩組DEMBIG分別照射不 _ 同劑量，第一組照射 2. 9、4. 6、9. 5、13. 7、18. 2，22. 8、 27· 3 Gy····等劑量，第二組照射 〇· 5、〇. 9、1. 4，1. 9、 2.4、2.9、3· 8Gy···等劑量，兩組皆拿一様本瓶當作背景 值不給予照射，使用MRI測量結果，建立R2-劑量曲線，評 估其劑量敏感度。 下表三和第9A、9B圖為DEMBIG和BANG-3改變凝膠成 分比重得其敏感度結果，分兩種項目探討（a)蛋白膠 1296275 (Gelatin) (b) %C (c)氫氧化鈉（NaOH) Sensitivity Batch %c (GyV1) r2 DEMBIG- I 5°/〇gelatin, 3°/〇DEMA, 3°/〇BIS 50 0. 405+0. 01 0.99 DEMBIG-Π 3°/〇gelatin, 3°/〇DEMA, 3°/〇BIS 50 〇. 49±0. 01 0.94 DEMBIG- I I I 5%gelatin, 3. 6%DEMA, 2. 4°/〇BIS 60 〇. 36±0. 02 0. 92 DEMBIG- IV 5%gelatin, 3%DEMA, 3%BIS, 〇. 30±0. 〇2 0. 97 none NaOH 50 BANG-3 5%gelatin, 3%MAA, 3%BIS 0/Γ.卉 DTC丄Γ07ΜΛ r»Tr> ....... 50 〇. 28+0. 〇l 0. 93 表， 在第8 A圖為麵心⑽灿⑽與_ geiatin)比較3%蛋白膠（gelatin)敏感度大於5%蛋白膠 (gelatin)，齡3最小，因為單體不同的關係。蛋白膠 (Gelatin)為提供凝膠凝固仙，對兩種凝膠而言，當 蛋白膠（Gelatin)比例增加時，皆會抑制凝膠敏感度，而 比例小於辦，凝膠不易凝固，所以蛋白膠⑽atin) 1296275 比例要維持一疋里’基本上比例要比單體與交聯劑高1〜挪。 在第 8 B 圖 D腦1G~ 1 (50%C)與 I I I (6〇%c)比較 BIS所佔比例，敏感度分別為〇· 41和〇. 36 (Gy-vl)，5〇%c . 敏感度大於60%C ’ BANG-3最小。表示DEMBIG中BIS所佔 比例增加時敏感度會減少。隨著交聯劑的重量百分比增 加，對劑量飽和度也跟著增加。㈣ANG_3的劑量反應曲線 帽知’在低齡G〜4Gy間其咖量敏缝較偏低(斜率 • 低）’ *臓BIG對劑量敏感度高(斜率較大)是因為受微量 氧氣的影響較小的緣固，顯示在環境影響中我們自製的凝 膠其穩定度較高。 在DEMBIG- I與IV比較有無添 化鈉NaOH)，敏感度分別為〇· 41和〇· 23 (Gy V1)，表示敏 感度在添加時較大，BANG-3最小。因為Gelatin為酸性物 質，而氳氧化鈉為驗性物質，所以氫氧化鈉可調節凝膠酸 • 鹼值，實驗結果指出當凝膠酸鹼值維持在中性時，其敏感 度最大。 由上述實驗結果可得知DEMBIG最佳比例為 gelatin :單體：交聯劑=5 : 3 : 3，其敏感度與凝固性良 好，若比例太低其凝固性差，無法描述劑量分布。 义 第9A、9B圖為測試腦BIG的高劑量區與低劑量區反 應’結果顯示DEMBIG於高、低劑量其敏感度良好，第从圖1296275 (4) Radiation exposure Radiation can be irradiated with a linear accelerator and a Gamma knife. The energy of the beam can be treated with X, electron beam red, and extensively. Radiotherapy, carbon ion wire therapy, treatment _ neutron capture therapy...etc. ' This experiment will be used to set up a number of samples in the county, and then refrigerated for at least 24 hours in the refrigerator. We calibrated the sample bottle method and used the linear accelerator (6MV photon) provided in the hospital for illumination. 4)), placed these testers in a lGxlGxlGcm water tank's parallel irradiation of 5 gel-containing samples, given the known doses of 1.8, 3.7, 5 5, 7 3 and 9.1 Gy, Take the sample - sample bottle #作# Jingcai to give irradiation (〇Gy), the depth of the vial to the tank is 7·icm, the distance from the source to the central axis is 100cm, the field is 15x10cm, the dose rate is 400MU/min, the reference output : lGy / 100MU. (5) Magnetic resonance photo The most commonly used tools for photography are magnetic resonance, other optical scanners, X-ray computed tomography and ultrasound. Magnetic Resonance Imaging (MRI) measures the retardation rate R2 (=1 / T2) by giving the gel radio frequency electromagnetic waves to the water, and measuring the delay rate R2 (=1 / T2). Two points can form the T2 1296275 delay curve. The irradiated gel was photographed, and the retardation rate (R2) was measured to evaluate the structure and density of the gel, and the R2_dose curve was plotted via software Excel. In addition, when the gel is administered to increase the radiation dose, the gel opacity is also increased, and by this principle, an optical scanner is developed to describe the 3D dose distribution. When the dose of 〇 to 5 Gy is increased, the attenuation coefficient of the gel is about 0 7 mnfl for laser light of 5 〇〇 nm wavelength. Usually the light scanner can replace or support the magnetic image data. The experimental gel was subjected to magnetic resonance imaging (MRI) 4 days after being irradiated by a linear accelerator, and the gel was stored in a magnetic resonance photo (MRI) room for at least one night (or 1) before the magnetic resonance imaging (MRI) measurement. 〇hours) to make it heat balanced. We used the Siemens 1.5T version MRI system provided by the hospital for T2 measurements, placing the gel-containing vials and prosthesis in the RF head coil (Figure 5), using 16 echoes. Multiple spin-echo sequence, the remaining parameters include repetition time TR: 3000 ms, echo time TE: 50 ms, slice thickness 5 mm, and field 26 x 26 cm. The entire photo taking time is about 20 minutes, and then the transverse view of the obtained T2 image (as shown in Fig. 6) is used to analyze the T2 shirt image using a workstation computer, and the R2-dose curve is established using Excel software. 17 1296275 (6) Results of electro-membrane analysis (1) R2-dose curve by MRI T2 image, select the place of interest (104 pixels), and measure its late solution R2 (M/T2) and corresponding dose R2—dose curve, Figure 7 shows the R2-dose curve of DEMBIG gel, showing a linear relationship in the dose range 0~9·lGy, with the sensitivity of the optimal dose, and the slope of dembig is 〇·464 ±〇· 〇1 s Ay1 (r2=〇· 99), and the slope of BANG-3 '0· 282 ±〇· 〇ΐ 3Κγ2=0· 99), indicating that the brain is sensitive to the dose, correlation r2 Also higher. (2) Change in specific gravity of gel composition We will compare the effects of DEMBIG and BANG-3 on the sensitivity of the composition to the gel sensitivity, representing the proportion of BIS in BIS and DEMA. In addition, in order to investigate the sensitivity and correlation of the maximum dose of the DEMBIG and the low-dose area, we will irradiate the two groups of DEMBIG separately without the same dose, the first group of irradiation 2. 9 , 4.6, 9. 5, 13. 7 , 18. 2, 22. 8, 27· 3 Gy····, etc., the second group of irradiation 〇·5, 〇. 9, 1. 4, 1. 9, 2.4, 2.9, 3·8Gy··· At the same dose, the two groups were given a bottle as the background value and no radiation was applied. Using the MRI measurement results, an R2-dose curve was established to evaluate the dose sensitivity. Tables 3 and 9A and 9B below show the sensitivity of DEMBIG and BANG-3 to change the specific gravity of the gel component. The two items are discussed. (a) Protein gel 1296275 (Gelatin) (b) %C (c) Hydroxide Sodium (NaOH) Sensitivity Batch %c (GyV1) r2 DEMBIG- I 5°/〇gelatin, 3°/〇DEMA, 3°/〇BIS 50 0. 405+0. 01 0.99 DEMBIG-Π 3°/〇gelatin, 3°/〇DEMA, 3°/〇BIS 50 〇. 49±0. 01 0.94 DEMBIG- III 5% gelatin, 3. 6%DEMA, 2. 4°/〇BIS 60 〇. 36±0. 02 0. 92 DEMBIG- IV 5% gelatin, 3% DEMA, 3% BIS, 〇. 30±0. 〇2 0. 97 none NaOH 50 BANG-3 5% gelatin, 3% MAA, 3% BIS 0/Γ.丄Γ07ΜΛ r»Tr> ....... 50 〇. 28+0. 〇l 0. 93 Table, in Figure 8 A is the face center (10) Can (10) compared with _ geiatin) 3% protein gel (gelatin) The sensitivity is greater than 5% gelatin, and age 3 is the smallest because of the different relationship of monomers. Gelatin (Gelatin) provides gel coagulation. For both gels, when the proportion of gelatin increases, the gel sensitivity is inhibited, and the ratio is less than that. The gel is not easy to coagulate, so the protein Glue (10)atin) 1296275 The ratio should be maintained within one mile 'the basic ratio is 1~ move higher than the monomer and crosslinker. In the 8th B-ray D brain 1G~ 1 (50%C) and III (6〇%c), the proportion of BIS is compared, the sensitivity is 〇·41 and 〇. 36 (Gy-vl), 5〇%c Sensitivity greater than 60% C 'BANG-3 minimum. Indicates that sensitivity will decrease when the proportion of BIS in DEMBIG increases. As the weight percent of crosslinker increases, so does the dose saturation. (4) The dose response curve of ANG_3 is known as 'the low sensitivity (slope • low) between the low G~4Gy's * 臓BIG is highly sensitive to the dose (large slope) because it is less affected by trace oxygen The edge of the solid shows that our self-made gel has a higher stability in environmental impact. Compared with DEMBIG-I and IV, there is no added sodium NaOH. The sensitivity is 〇·41 and 〇· 23 (Gy V1), respectively, indicating that the sensitivity is larger when added and BANG-3 is the smallest. Since Gelatin is an acidic substance and sodium bismuth oxide is an experimental substance, sodium hydroxide can adjust the gel acid/base value. The experimental results indicate that the sensitivity of the gel is the highest when the pH value of the gel is maintained at neutral. From the above experimental results, it can be known that the optimum ratio of DEMBIG is gelatin: monomer: crosslinker = 5:3:3, and its sensitivity and coagulability are good. If the ratio is too low, the coagulability is poor, and the dose distribution cannot be described. Figures 9A and 9B show the high-dose and low-dose reactions of brain BIG. The results show that DEMBIG has good sensitivity at high and low doses.
(S 20 1296275 顯示在劑量範圍〇〜27· 3Gy内其數據分布情形’在接近 約14. 3Gy後的數據分布趨於平缓且對劑量的敏感度降 低，在劑量範圍0〜14.3Gy内呈現線性劑量關係’其 敏感度為0.400 3^/(1^=0.99) ’表示DEMBIG的最大劑 量到達14· 3Gy，與BANG-3的最大劑量只到達l〇Gy比較，對 於BANG-3使用到較高劑量（1〇〜25 Gy)的放射治療如立體定 位放射治療手術（stereotactic radiosurgery ; SRS)劑 量測較不準確。第9B圖顯示DEMBIG凝膠在低劑量區的反 應，其敏感度〇· 996 s^Gy1 (r2=0· 99)，在劑量範圍 0〜14· 3Gy内，劑量與R2呈線性關係，且可以量測低 於0.5Gy的劑量，與BANG-3在低劑量區的反應不靈敏比 較，對於BANG-3使用到低劑量（〇〜1 Gy)的放射治療如近接 放射治療（brachytherapy)劑量測難以準確。以上顯示出 我們新發明的DEMBIG的種種優勢。 為了評估DEMBIG凝膠照射後隨時間的增加其穩定度變 化’分別在照射卜2、4、6、8、12、16、20和24天，使 用MRI測量結果，我們將穩定度變化分兩部份評估，一部 份是其凝固性維持與否，一部份是由MRI測量其敏咸度。 就其凝固性維持與否，DEMBIG遠優於bang—3。第二部份敏 感度評估，第10圖為DEMBIG與BANG_3的照射後其凝膠穩 定度變化。兩觀膠都在前2_(8. 3天）其敏感度和遲豫 21 1296275 率(R2)持績增加’也代表聚合反應持續增加，8天後變化較 小呈現對劑量飽和狀態，兩種凝膠照射後4天到一個月基 本上穩定度維持一定變化，但隨時間的增加，氧氣進入凝 膠的可能性增加而標準差也隨著增加，凝固性及敏感度都 會下降，尤其BANG-3在第28天敏感度更明顯下降，顯示 DEMBIG穩定性優於BANG-3。第11圖為本發明之立體定位 放射治療手術所使用的假體，内層為凝膠，外層充填與人 體組織密度相近的水示意圖。 第二部份提供快速凝膠液去氧方法以及提供快速去氧的 設備 我們设计在凝膠製備程序中，添加新的物理方法 以快速去除凝膠液中的氧氣。在凝膠製備前使用煮沸法 加熱去離子水，使水中的含氧量快速去除，表四與第12 •圖顯示使用煮沸法與通過高純度氬氣法時水中的含氧量 變化，發現水煮沸15分鐘後，此時的氧濃度已達最低。 我們將去離子水通過高純度氬氣，測試水中的含氧量變 化，結果發現在第30分鐘後，此時的氧濃度最低。基 於上述結果’我們結合此兩項去氧物理方法加入成為 新的製備凝膠程序，如前所述的製備步驟（a)中，在 一密封容器内，先將去離子水煮沸15分鐘後，立即使用(S 20 1296275 shows its data distribution in the dose range 〇~27·3Gy'. The data distribution after approximating about 14.3Gy tends to be gentle and the sensitivity to the dose is reduced, showing linearity in the dose range 0~14.3Gy. The dose relationship 'the sensitivity is 0.400 3^ / (1 ^ = 0.99) ' indicates that the maximum dose of DEMBIG reaches 14. 3Gy, compared with the maximum dose of BANG-3 only reaches l〇Gy, the higher the use of BANG-3 Dosimetry (1〇~25 Gy) for radiation therapy such as stereotactic radiosurgery (SRS) is less accurate. Figure 9B shows the response of DEMBIG gel in the low-dose region with sensitivity 〇· 996 s^Gy1 (r2=0·99), in the dose range 0~14·3Gy, the dose is linear with R2, and can measure the dose below 0.5Gy, and the reaction with BANG-3 in the low dose area is not Sensitive comparisons, the use of low-dose (〇~1 Gy) radiation therapy, such as brachytherapy, for BANG-3 is difficult to quantify. The above shows the advantages of our newly invented DEMBIG. To evaluate DEMBIG gel Stability after irradiation increases with time Using the MRI measurements on the 2, 4, 6, 8, 12, 16, 20 and 24 days respectively, we measured the stability change in two parts, part of which was whether the coagulability was maintained or not. Part of it is measured by MRI to measure its saltiness. DEMBIG is far superior to bang-3 in terms of its coagulation maintenance. The second part of the sensitivity evaluation, the 10th picture shows the gel stability of DEMBIG and BANG_3 after irradiation. Degree change. Both of the two gels in the first 2_ (8.3 days) its sensitivity and delay 21 1296275 rate (R2) increased performance 'also represents a continuous increase in polymerization, 8 days after the change is small to the dose saturation state The stability of the two gels maintains a certain change from 4 days to one month after irradiation, but as time increases, the possibility of oxygen entering the gel increases and the standard deviation increases, and the coagulability and sensitivity decrease. In particular, the sensitivity of BANG-3 decreased significantly on the 28th day, indicating that DEMBIG stability is better than BANG-3. Figure 11 is the prosthesis used in the stereotactic radiotherapy operation of the present invention, the inner layer is gel, the outer layer is filled with the human body. Schematic diagram of water with similar tissue density. The second part mentions For rapid gel deoxygenation and rapid deoxygenation, we designed a new physical method to quickly remove oxygen from the gel during the gel preparation process. Use the boiling method to heat the deionization before the gel is prepared. Water, the oxygen content in the water is quickly removed, Table 4 and Figure 12 show the change in oxygen content in the water using the boiling method and the high purity argon method. It is found that the water concentration has been boiled for 15 minutes. The lowest. We passed the deionized water through high-purity argon gas to test the change in oxygen content in the water. It was found that the oxygen concentration was the lowest at the 30th minute. Based on the above results, we combined these two deoxygenation methods into a new preparation gel procedure. In the preparation step (a) as described above, in a sealed container, the deionized water was boiled for 15 minutes. use immediately
(S 22 1296275 : 冰水浴降溫，並通過高純度氬氣30分鐘以排除去離子水 _ 中的氧氣，結果顯示凝膠對劑量的敏感度更高，而且 整個製備時間從原來的8小時縮短為2小時。其中， 整個製備時間的大幅縮短除了上述兩項去氧物理方 法的加入外，本發明所使用的密封容器更是一重要的 關鍵。為使密封容器中的凝膠液快速去氧，本發明在 該密封容器中裝設有一軟管，該軟管的形狀較佳為由上 而下地呈捲撓狀，使得軟管可以與容器中的離子水形成大 範圍地接觸，且軟管上敍有直麵小於/等於lmm的複數 小孔，藉此該複數的小孔可使所通過高純度氬氣廣範圍 地、且徹底地進行離子水中的去氧動作。具有複數小孔的 軟官亦為在同一技術領域中，製造凝膠時前所未有的創舉。 又，在本發明中選擇高純度氬氣的原因在於氬氣是一種 情性氣體，不易與其它物質反應，是一種無色無味氣體， 比重大於空氣且比氮氣不易氧化。 — °2 (%，百分比濃 度） 煮沸 通Ar氣 時間（min) 法 體法 0 42 43.4 23.1 11.5 10 10.4 23 1296275 15 12.4 7.4 20 13.2 5.7 25 13 5.1 30 13.1 3.4 35 13 3.3 45 13 3.4 55 13 3.5 *含氧量〇2 (%，百分比濃度）定義為在水中含氧量達100%濃度時， 其相對應含氧量約8. 3mg/L。 表四使用煮沸法與通過高純度氬氣時水中的氧氣變化 【本發明的優勢和成果】 本發明的優勢和成果彙整如下表五所示： rs 項目 DEMBIG BANG3 製作凝膠時間 短（2小時） 長（8小時） 製作流程 簡化 複雜 成分毒性 低 (LD50: 1751mg. kg'1) (LD50:1060mg. kg"1) 通過氬氣 去氧時間 短（30分鐘） 長(2小時） 劑量敏感度 高（大約 0.45S_1Gy-1) 低（大約0.25 S^Gy"1) 最大與最低劑量區 反應良好 反應差 穩定性 高 低 表五 24 1296275 射^膠葡3D驗布_，騎縣各種複雜的放 ^口療測讀量而言，是非常有用的I具。藉由上述之揭 路本《明提供了一種低毒性聚丙稀酸類聚合物凝膠，宜 降2膠成分毒性、降低對氧氣的影響、增加敎度而降 低__化的影響或增加最賴量範圍、使凝膠製備更 容易、ϋ射度量更為準確、敏感。此外，本發明亦率先提 出製備該聚合物_之快速絲的方法，其可大幅減少凝(S 22 1296275: The ice bath is cooled and passed through high purity argon for 30 minutes to remove oxygen from the deionized water. The results show that the gel is more sensitive to the dose and the overall preparation time is shortened from the original 8 hours to 2 hours. Among them, the entire preparation time is greatly shortened. In addition to the above two deoxygenation physical methods, the sealed container used in the present invention is an important key. In order to rapidly deoxidize the gel liquid in the sealed container, The invention is provided with a hose in the sealed container, and the shape of the hose is preferably wound from top to bottom so that the hose can form a wide range of contact with the ionic water in the container, and the hose is on the hose. A plurality of small holes having a straight surface smaller than/equal to 1 mm are described, whereby the plurality of small holes allow the high-purity argon gas to pass through the deoxidizing action in the ionic water in a wide range and thoroughly. The soft official with a plurality of small holes It is also an unprecedented innovation in the manufacture of gels in the same technical field. Moreover, the reason for selecting high-purity argon in the present invention is that argon gas is an inert gas and is not easily reacted with other substances. A colorless and odorless gas with a specific gravity greater than air and less oxidized than nitrogen. — °2 (%, percentage concentration) Boiling time for Ar gas (min) Method of body method 0 42 43.4 23.1 11.5 10 10.4 23 1296275 15 12.4 7.4 20 13.2 5.7 25 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 L. Table 4 Use of boiling method and oxygen change in water when passing high purity argon [Advantages and results of the present invention] The advantages and results of the present invention are summarized in Table 5 below: rs Project DEMBIG BANG3 Short gel time (2 Hour) Long (8 hours) Simplified production process. Complex components are low in toxicity (LD50: 1751mg. kg'1) (LD50: 1060mg. kg"1) Deoxygenation time by argon is short (30 minutes) Long (2 hours) Dose sensitive High degree (about 0.45S_1Gy-1) low (about 0.25 S^Gy"1) Maximum response with the lowest dose area Good reaction difference Stability level Table 5 24 1296275 Shooting glue 3D inspection cloth _, riding county various complex put ^Oral therapy In terms of reading volume, it is a very useful tool. According to the above-mentioned method, the invention provides a low-toxicity polyacrylic acid polymer gel, which is suitable for reducing the toxicity of 2 rubber components, reducing the influence on oxygen, and increasing the twist. It reduces the influence of __ or increases the range of the most suitable, makes gel preparation easier, and the radiance measurement is more accurate and sensitive. In addition, the present invention also provides a method for preparing a fast filament of the polymer, which can greatly reduce condensation.
膠之製備時間。 综上所述，本發明確可達到預期之目的，提供一種低 毋性聚丙湘峨聚合物凝膠之城配枝其製備方法，其 極具產#上彻之價值，纽法提出發明專利申請。 【圖式簡單說明】 ，1圖係為本發明之凝膠在密封容器内製作之示意圖； ，2圖係為本發明以DEMBIG凝膠為例製作凝膠的流程圖；The preparation time of the glue. In summary, the present invention can indeed achieve the intended purpose, and provides a preparation method of a low-density polyacrylonitrile polymer gel, which is extremely valuable in the production of invention patents. . BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 is a schematic view showing the gel of the present invention produced in a sealed container; and FIG. 2 is a flow chart of the present invention using a DEMBIG gel as an example;
第3圖係為採用多樣品瓶方法校正，使用數個裝滿凝膠之 樣本瓶給予照射〇到9· lGy的不同劑量； 第4圖係為使用醫院中所提供的直線加速器（6MV光子）進行 照射； 第5圖使用醫院所提供的siemens 1·5 T version MRI系 統進行T2量測，將裝有凝膠的校正瓶和假體放置rf 頭部線圈内（head coil); 第6圖係本發明使用ΐ· 5 T version MRI系統進行校正的 MRI-T2影像橫向切面圖； 第7圖係為本發明使用DEMBIG與BANG-3凝膠校正後的劑 量反應曲線，顯示DEMBIG對劑量的敏感度比 25 1296275 ' BANG-3大，相關性也較高； - 第8 A圖和第8 B圖為DEMBIG和BANG-3改變凝膠成分比 - 重得其敏感度結果，分兩種項目探討（a) Gelatin (b) °/〇C ;其中第8A圖為DEMBIG- I與π比較 3%gelatine敏感度大於5%gelatine，惟其凝固性不 佳，而BANG-3最小；而第8 B圖為DEMBIG- I與 I I I比較BIS所佔比例，50%C之凝膠敏感度/大 於 60%C，BANG-3 最小； 第9A圖為測試DEMBIG的南劑量區反應’在劑量範圍 • 0〜27· 3Gy内其數據分布，在14· 3Gy後數據分 _ 布趨於平緩，0〜14· 3Gy其對劑量敏感度表現良好; 弟9B圖為測試DEMBIG的低劑量區反應，在劑量範圍 0〜3. 8Gy内其對劑量敏感度表現良好； 弟10圖為DEMBIG與BANG-3的照射後其凝膠穩定度變化； 第11圖係為本發明之立體定位放射治療手術所使用的假 體，内層為凝膠，外層充填與人體組織密度相近的 水示意圖； 第12圖係為使用煮沸法與通過高純度氬氣時水中的氧氣 變化，發現水煮沸15分鐘後，此時的氧氣濃度 • 達到最低；將去離子水通過高純度氬氣，測試水 中的含氧量變化，發現在第30分鐘後，此時的氧 濃度最低。 【主要元件符號說明】 密封型容器（10) 進出口（12)(14)(15)(16) 去離子水(11) 試管（13) 小孔（131) 去離子水通過高純度氬氣體(20) 室溫(21) 加入蛋白膠（30) 26 1296275 加熱至50°C(31) 等待蛋白膠溶解(40) 降溫至30°C(41) 加入 2-(Dimethylamino)ethyl methacrylate(DEMA) (50) 覆蓋鋁箔片再等10分鐘（51)加入鹼性溶液(如NaOH)(60) 等待10分鐘（61) 加入 F ,ΤΓ -methylene-bisacrylamide (BIS) (70) 等待(BIS)溶解冷卻（80) (BIS)約為30分鐘才會冷卻（71) 再一次通過高純度氬氣（90) 在充滿氬氣之glove bag中進行（91) 將凝膠送入假體（100) 進行凝膠輻射照射（110) 磁振照影照相MRI或光密度掃瞄儀oct (120)Figure 3 is a multi-vial method calibration using several sample bottles filled with gel to give different doses of 9·lGy; Figure 4 is the use of a linear accelerator (6MV photon) provided in the hospital. Irradiation; Figure 5 uses the siemens 1·5 T version MRI system provided by the hospital for T2 measurement, and the gel-equipped calibration bottle and prosthesis are placed in the rf head coil; The present invention uses a ΐ·5 T version MRI system to correct the cross-sectional view of the MRI-T2 image; Figure 7 is a dose response curve of the DEMBIG and BANG-3 gel corrected for the present invention, showing the sensitivity of DEMBIG to the dose. More than 25 1296275 'BANG-3, the correlation is also higher; - 8A and 8B are DEMBIG and BANG-3 change the gel composition ratio - regain its sensitivity results, divided into two projects ( a) Gelatin (b) ° / 〇C; wherein Figure 8A shows DEMBIG-I compared with π 3% gelatine sensitivity is greater than 5% gelatine, but its coagulability is poor, while BANG-3 is the smallest; and Figure 8 B is DEMBIG-I compares with BIS in proportion of BIS, 50% C gel sensitivity / greater than 60% C, BANG-3 most Figure 9A is a test of DEMBIG's southern dose response [in the dose range • 0~27·3Gy its data distribution, after 14·3Gy data points _ cloth tends to be gentle, 0~14·3Gy its dose sensitivity The performance is good; the younger 9B picture is the low-dose area reaction of DEMBIG, and its dose sensitivity is good in the dose range of 0~3. 8Gy; the 10th picture shows the gel stability change after DEMBIG and BANG-3 irradiation. Figure 11 is a prosthesis used in the stereotactic radiotherapy operation of the present invention, wherein the inner layer is a gel, the outer layer is filled with water having a density similar to that of human tissue; and the 12th is a method of using boiling and high-purity argon gas; When the oxygen in the water changes, it is found that after the water is boiled for 15 minutes, the oxygen concentration at this time reaches the minimum; the deionized water is passed through the high-purity argon gas to test the oxygen content change in the water, and it is found after the 30th minute. The oxygen concentration is the lowest. [Main component symbol description] Sealed container (10) Import and export (12) (14) (15) (16) Deionized water (11) Test tube (13) Small hole (131) Deionized water passes through high purity argon gas ( 20) Add protein gel (30) at room temperature (21) 26 1296275 Heat to 50 ° C (31) Wait for protein gel to dissolve (40) Cool down to 30 ° C (41) Add 2-(Dimethylamino)ethyl methacrylate (DEMA) ( 50) Cover the aluminum foil and wait for another 10 minutes (51) add alkaline solution (such as NaOH) (60) Wait 10 minutes (61) Add F, ΤΓ -methylene-bisacrylamide (BIS) (70) Wait (BIS) to dissolve and cool ( 80) (BIS) is about 30 minutes to cool (71) again by high purity argon (90) in arg-filled glove bag (91) to send the gel to the prosthesis (100) for gelation Radiation Irradiation (110) Magnetic Photographic MRI or Optical Density Scanner oct (120)
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