4 6 61 15 經濟部中央標準局員工消費合作社印裂 A7 B7___五、發明説明（1 ) 發明背景 生物産生的自由基围牽涉多種疾病狀態。蒲氣有機臞 於氣氣環墳下存活牽涉到生物産生自由基圃這種極高反 應性化學物種與有機體控制自由基圃産生的能力間複雜 的交互作用（D e 1 M a e s t r 〇 R F , A c t a P h y S c a n S U p p 1 . 492··153-68〇980))β寄主有機體舆生物産生的自由基 圃交互作用結果導致嚴重生物化學改變，最終造成細胞 傷害與有機體死亡。自由基®反應産物的堆積造成大量 疾病狀態，此等疾病部份來自於胞内自由基團通量增高 誘發的細胞傷害。此等疾病包含但非限於癌症，心血管 病，中植神經条統病症，骨病，老化，阿兹海黙氏癡呆 ，發炎病症，類風濕性關節炎，自體免疫病，呼趿窘迫 及肺氣腫》 自由基團傷害輿多種疾病狀態的闋聯於文獻上有詳細 記載，多種細胞組成份包含酶、離子通道、結構蛋白質 及膜脂質皆為反應性自由基團物種可能的攻擊目檫（Rice-Evans C, Hoi Aspects of Med 13(1): 1-111(1992)) e於適當部位之抗氧化狀態可限制細胞傷害e自由基圃 舆此等可能目標的反應可能損壊某種範圍的細胞功能， 結果導致病理變化及最終導致細胞死亡。於可能反醮部 位之抗氧化狀態可限制損害。抗氣化劑於保護DNA、蛋 白質《包含脂蛋白）及膜腊質對抗氣化傷害扮演要角。 有強力證據提示自由基團傷害促成多種慢性健康問題 的病因。對大部份人類疾病而言，由内生來源形成的氣 --------—0^.— (請先閱讀背面之注意事項再填寫本页) Ϊ 訂 本紙張尺度適用中國國家標準（CNS ) Λ4規格（210 X 297公釐） 4661 5 Α7 Β7 i、發明説明（> ) 化m繼發於初步病症之後，但氣化傷害使原發病變加重 。例如，再灌流傷寄定義為於缺血發作後，器官重新建 立血流造成的傷害。氧的恢復雖然需要，但會造成受傷 組纗的氣化劑生成而暫時惡化傷害（Draizee Α, Circulation 75(6): 1237-1248(1987))。缺氧心肌於 再氣化時因脂質過氣化反應增高對抗氧化劑防衛下降由 6uanieri報告（Biochim-Biophys-ACTA 718(2): 157-164 <1982))。再灌流傷害中，缺血發作後内皮受傷部位的 發炎反應由嚙中性細胞黏著及活化而産生超氣化物。多 種不同臨床病情中，肝臓産生的氣自由基圃也增加。病 毒性肝炎及慢性活動性肝炎中，大量受剌激的巨噬細胞 積聚於肝臓而産生自由基圑。因肝臟産生的自由基画增 加，大量有毒化學品引起毒性肝傷寄，經常傺由細胞色 素P-450媒介。可歸結由鐵立丁（Ferritin)釋放鐵催化 羥基基團生成乃造成多種肝臟疾病的機構（Lee WR, N Eng J of Med; Review P . 1118(1995))® 經濟部中央標準局員工消費合作社印製 (請先閲讀背面之注意事項再填"·本頁) 氣化及使用抗氣化劑對多種發炎病情的治療相當重要 。類風濕性關節炎（RA)傜最常見的悝性發炎病。流行病 學研究顯示典型及特定RA的盛行率為0.3至1.5%。慢性 持缠性發炎的關節病伴睹箸發炎的類風濕關節炎生成H2〇2。 發炎過程中，氣自由基圃也産生，特別由多形核白血球 (PMN)及巨噬細胞産生。任何慢性或急性發炎病中，PMN 及巨噬細胞可産生〇2及Η202β肺結核.乾癣，条統性 紅斑性狼瘡，其它自體免疫病及成人呼吸窘迫症候群也 本紙張尺度適用中國國家標準（CNS ) Α4規格（210Χ297公釐> 經濟部中央標準局貝工消費合作社印製 46 6115 A7 B7 ____ 五、發明説明（—） 值得一提為靥於氣化促成的發炎病，9外尚有多種其它 疾病。 氣基國産生及脂質過頜化反應過變成中植神經条 统（CNS)創傷及中風（例如缺血 >領域研究學者注意的焦 點》許多研究顯箸證實於受傷或缺血的CNS發生自由基 圃及腊質遇氣化反應（Hall ED，J-NeUI><)tl>aUIia MSUPP1 1> : S165-S 1 7 2 ( 1 9 9 2 ) > 〇 曾經提謙抗氣化劑可保護不發生乳癌及其它癌症’包 含腦癌及肝癌，以及保護腦血管病及鬆骨病（WiSe*an Η ，Free Radical Res 21(3): 187-94 (1334))。驗證可 保護模式性細胞膜包含核膜不受致癌自由基圃中間物及 脂質過氣化産物可能的傷害。動脈粥瘤硬化造成联重併 發症且發生率高使研究學者注意力集中於預防及治療此 種血管病態，可能經由保護低密度脂蛋白（ΙΙ)Ιι)不受氧 化傷害（Steinberg D, H Engl J of Med 14 : 915-924 (1 98 9 ))。 發明說明 根據本發明，提供一種治療或抑制自由基豳誘發疾病 狀態之方法，係經由對有需要的晡乳類投予抗氧化數量 之雌馬性素酮或其3 -硫酸醋之醫藥可接受性鹽由該過 程推論本發明提供一種於晡乳類治療自由基囿與酶、離 子通道、結構蛋白質及膜脂質反應之方法，包括投予雌 馬性素ffi或其轚_可接受性硫酸酯鹽做為镰牲酶基質而 其投予數量偽足夠選擇性與自由基圍反應並抑制自由基 本纸依尺度適用中國國家標準（CNS ) A4規格（210X297公釐} (請先聞讀背面之注意事項再填寫本頁)4 6 61 15 Employees' cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs of the People's Republic of China A7 B7___ V. Description of the invention (1) Background of the invention Free radicals generated by organisms are involved in various disease states. The survival of Puqi organic crickets under the Qiqi ring grave involves a complex interaction between a highly reactive chemical species that produces biological free radicals and the organism's ability to control the production of free radicals (D e 1 M aestr 〇RF, A cta P hy S can SU pp 1. 492 ·· 153-68〇980)) The result of the interaction of the free radical garden produced by β-host organisms with biological organisms results in severe biochemical changes, eventually causing cell damage and organism death. The accumulation of free radical® reaction products causes a number of disease states, which are partly due to cellular injury induced by increased intracellular free radical flux. These diseases include, but are not limited to, cancer, cardiovascular disease, mesangial nervous system disorders, bone disease, aging, Alzheimer's dementia, inflammatory conditions, rheumatoid arthritis, autoimmune disease, snoring distress and Emphysema "Free radical group harms a variety of disease states, which are well documented in the literature. A variety of cellular components including enzymes, ion channels, structural proteins and membrane lipids are all possible targets for reactive free radical groups. (Rice-Evans C, Hoi Aspects of Med 13 (1): 1-111 (1992)) The antioxidant status at the appropriate site can limit cell damage e Free radicals The response of these possible targets may damage a certain range Cell function, resulting in pathological changes and ultimately cell death. The state of oxidation at the potential anti-cancer site limits damage. Anti-gasification agents play an important role in protecting DNA, proteins (including lipoproteins) and membrane waxes from gasification damage. There is strong evidence that free radical damage can contribute to a number of chronic health problems. For most human diseases, the gas formed by endogenous sources --------- 0 ^ .— (Please read the precautions on the back before filling this page) Ϊ The size of the paper is applicable to China Standard (CNS) Λ4 specification (210 X 297 mm) 4661 5 Α7 B7 i. Description of invention (>) The m is secondary to the initial disease, but the gasification damage exacerbates the primary lesion. For example, reperfusion injury is defined as the damage caused by an organ to reestablish blood flow after an ischemic attack. Although oxygen recovery is required, it can temporarily cause injury due to the generation of gasifiers in the injured group (Draizee Α, Circulation 75 (6): 1237-1248 (1987)). Hypoxic myocardium due to an increase in lipid over-gasification during anti-regasification due to an increase in antioxidant defense is reported by 6uanieri (Biochim-Biophys-ACTA 718 (2): 157-164 < 1982). In reperfusion injury, the inflammatory response of the injured endothelium after an ischemic attack is caused by the adhesion and activation of neutrophils to produce super-gas. In a variety of different clinical conditions, the amount of gas free radicals produced by the liver is also increased. In viral hepatitis and chronic active hepatitis, a large number of stimulated macrophages accumulate in the liver and generate free radicals. Due to the increase of free radicals generated by the liver, a large number of toxic chemicals cause toxic liver injury, often mediated by cytochrome P-450. Can be attributed to the release of ferritin from iron to catalyze the formation of hydroxyl groups to cause a variety of liver diseases (Lee WR, N Eng J of Med; Review P. 1118 (1995)) Printed (please read the precautions on the back before filling in "This page") Vaporization and the use of anti-gasification agents are very important for the treatment of various inflammatory conditions. Rheumatoid arthritis (RA) is the most common inflammatory disease. Epidemiological studies have shown that the prevalence of typical and specific RAs is 0.3 to 1.5%. Chronic persistent inflammatory joint disease is accompanied by inflammation of rheumatoid arthritis producing H202. During the inflammation, air free radicals are also produced, especially by polymorphonuclear leukocytes (PMN) and macrophages. In any chronic or acute inflammatory disease, PMN and macrophages can produce 02 and Η202β tuberculosis. Psoriasis, systemic lupus erythematosus, other autoimmune diseases and adult respiratory distress syndrome are also applicable to this paper. Chinese national standards ( CNS) Α4 specifications (210 × 297 mm)> Printed by the Shellfish Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 46 6115 A7 B7 ____ 5. Description of the invention (—) It is worth mentioning that it is caused by the inflammation caused by gasification. A variety of other diseases. Air-based production and lipid overmaxillization have become traumas and strokes in the CNS (for example, ischemia). Many studies have focused on injury or ischemia. Free radicals and waxy gasification reaction of CNS (Hall ED, J-NeUI > <) tl > aUIia MSUPP1 1 >: S165-S 1 7 2 (1 9 9 2) > Vaporizing agents can protect breast and other cancers, including brain and liver cancer, as well as cerebrovascular disease and osteoporosis (WiSe * an Η, Free Radical Res 21 (3): 187-94 (1334)). Verification Protective model cell membrane including nuclear membrane Possible damage of carcinogenic free radical intermediates and lipid over-gasification products. Atherosclerosis causes joint complications with a high incidence, leading researchers to focus on the prevention and treatment of this vascular disease, possibly by protecting low-density lipids Protein (ΙΙ) Ιι) is not damaged by oxidation (Steinberg D, H Engl J of Med 14: 915-924 (1 98 9)). DESCRIPTION OF THE INVENTION According to the present invention, a method for treating or inhibiting free radical-induced disease states is provided. It is inferred from this process that by administering an antioxidant amount of equolone or its 3-sulfate pharmaceutically acceptable salt to the milky milks in need, the present invention provides a method for treating free radicals and enzymes in milky milks, Method for reacting ion channels, structural proteins, and membrane lipids, including administering equin ffi or 轚 -acceptable sulfate salt as a sickle enzyme substrate, and its administration amount is sufficiently selective to react with and inhibit free radicals Free basic paper applies Chinese National Standard (CNS) A4 specifications (210X297 mm) according to the standard (Please read the precautions on the back before filling this page)
經濟部中央標準局負工消費合作社印掣 4 6 61 15 A7 B7 五、發明説明（* ) 團舆病人的酶、離子通道、結構蛋白質或膜脂質反應的 數量。抗氣化劑治療持別有效的病情為癌症，中植神經 糸統病症，骨病，老化，周邊血管病，類風濕性闋節炎 ，自體免疫病，呼吸窘迫，肺氣腫，預防再灌流傷害， 病春性肝炎，慢性活動性肝炎，肺結核，乾癖，条統性 紅斑性狼瘡，成人呼趿窘迫症候群，中榧神經糸統創傷 及中風。 用於本發明，治療一詞涵蓋治療既有病情，改善病情 或提供緩解病情；而抑制一讁包含抑制或預防病情的進 行或發展。 雌馬性素酮-3-硫酸酯之酱藥可接受性鹽包含但非僅 限於鐮金羼鹽，鹾土金屬鹽，銨鹽，含1-6儕硪原子之 烷基胺鹽或各痼烷基含1-6锢碩原子之二烷基胺鹽。 雌馬性素酮之抗氧化性質係於標準藥理試驗程序建立 ,該藥理試驗程序係藉TBARS(硫巴比妥酸反暱性物質方 法）分析自由醛（Yagi £.,Biochen iied 15:212- 2 1 6 ( 1 9 7 6 ) 測量雌馬性素酮抑制暴露於Cu ++離子或培餐内皮細胞 誘發生成氧化改質低密度脂蛋白（LDU的能力 (Parthasarathy S, Proc Natl Acad Sci USA 8 6 : 1 046 - 1 0 5 0 ( 1 9 8 9 ) ) 0 此種擦準藥理試驗程序所桿結果驗證雌馬性素酮乃LDL 氣化之強力抑制劑，可抑制氣化過程高建99%。於Cu+ + 媒介氣化及豬主動脈内皮細胞媒介氣化分別獲得ICbo為 及0.19//JU供比較用，於豬主動脈内皮細胞 本紙張尺度適用中國國家標準{ CNS ) A4規格（2丨0X297公釐） --------ο农-- (請先閱讀背面之注意事項再填寫本頁) 訂 4 6 61 15 A7 B7 五、發明説明（f ) 媒介氧化試驗程序對雌酮獲得1Cso為0·56/<Μ。此種試 驗程序也驗證雌馬性素麵為HDL及血漿氣化的之強力抑 (請先閲讀背面之注意事項再填寫本頁) 制劑。獲得 ICert 為〇.〇47/<>1 及 〇·〇62/ίΗ。 50 雌馬性素酮之抗氧化性質也對其於Cu+ +存在下涉及 LDL, HDL及血黎氣化動力學的影瘡評估，該技術為用來 誘發LDL修改的標準技術（Esterbauer H，Ann NY acad Sci 1989; 570: 254-267, Huber LA, Free Rad ResPrinted by the Central Standards Bureau of the Ministry of Economic Affairs, Consumer Cooperatives 4 6 61 15 A7 B7 V. Description of the invention (*) The number of enzyme, ion channel, structural protein or membrane lipid reactions of the patients. Anti-gasifying agents are effective in treating cancer, mesangial neuropathy, bone disease, aging, peripheral vascular disease, rheumatoid arthritis, autoimmune disease, respiratory distress, emphysema, prevention of recurrence Perfusion injury, ill spring hepatitis, chronic active hepatitis, tuberculosis, dry addiction, systemic lupus erythematosus, adult snoring distress syndrome, middle sacral nervous system trauma and stroke. As used in the present invention, the term treatment encompasses treating an existing condition, improving the condition, or providing remission; and inhibiting a condition includes inhibiting or preventing the progress or development of the condition. Sauce-acceptable salts of equolone-3-sulfate include, but are not limited to, fusarium salt, samarium earth metal salt, ammonium salt, alkylamine salt containing 1-6 fluorene atoms or each fluorene alkyl group A dialkylamine salt containing 1-6 ammonium atoms. The antioxidant properties of estradiolone were established in a standard pharmacological test procedure, which is based on the analysis of free aldehydes (Yagi £., Biochen iied 15: 212- 2 1 by TBARS (thiobarbituric acid inverse substance method). 6 (1 9 7 6) Measure the ability of equol to inhibit the exposure to Cu ++ ions or cultivate endothelial cells to induce the production of oxidatively modified low density lipoprotein (LDU) (Parthasarathy S, Proc Natl Acad Sci USA 8 6: 1 046 -1 0 5 0 (1 9 8 9)) 0 The results of this quasi-pharmacological test procedure verify that equol is a powerful inhibitor of LDL gasification and can inhibit the gasification process by up to 99%. In Cu + + media Vaporization and porcine aortic endothelial cell mediator ICbo and 0.19 // JU were obtained for comparison. For pig aortic endothelial cells, the Chinese paper standard {CNS) A4 specification (2 丨 0X297 mm)- ------- ο 农-(Please read the notes on the back before filling out this page) Order 4 6 61 15 A7 B7 V. Description of the invention (f) The procedure of the medium oxidation test to obtain 1Cso for estrone is 0 · 56 / < M. This test procedure also verifies that the equestrian sex surface is a component of HDL and plasma gasification. Strong inhibitor (please read the precautions on the back before filling out this page) Preparations. ICerts obtained were 0.047 / < &1; and 〇 · 〇62 / ίΗ. 50 The antioxidant properties of equin Assessment of shadow sores involving LDL, HDL, and blood gasification kinetics in the presence of Cu + +, this technique is a standard technique used to induce modification of LDL (Esterbauer H, Ann NY acad Sci 1989; 570: 254-267, Huber LA, Free Rad Res
Conns 1990； 8: 167-173, Vossen Rcr·, Lipid 1993 ;8: 857-861, Jialal Lipid Res 1992; 33: 899 - 9 0 6 )0共轭二烯乃初步脂質過氣化反應之主産物，以 光譜學追蹤。評估下列參照：延遲期或Tmin :開始氣化 所需時間；Tso : 50%共軛二烯形成所需時間；及Tmax :達到最大氧化所餺時間。 馬性素酮於2δηΗ獏度試驗時可延長人類LDL之共軛 二烯形成之延遲期達30%。Τ 5〇及1^&也延長21%»相 同檢定分析中，25ηΜ雄酮增加金部參照僅25ηΜ 雌馬性素酮對人類HD L共軛二烯之生成具有顯箸抑制作 用》可延長延娌期逹282%。Tso及^^分別延長120% 經濟部中央標準局負工消費合作社印製 及10596。柑冏濃度雌酮影韉HDL之共軛二烯生成分別為 延長延遲期20%,延長Tb〇38%,及延長Tmax46%e 25nM 雌馬性素酮可延長人類血漿共軛二烯之延運期連3% , 及延長T bo及Τ_達21%及31%,指示雖然對引發氧化 作用的效果小，但可滅慢氣化速率β此種體条中，雌酮 對延遲期無作用，而對1：50及Twax之作用分別僅5%及 本紙張尺度適用中芩樣準（CMS > A4規格（210X297公釐） 4 6 61 1 5 A7 B7 五、發明説明（& ) 10% β 欲進一步驗證雌馬性素釅之抗氧化性質•使用培養細 胞又進行兩種樺準藥理試驗程序。第一試驗程序中，放 射性樺記 LDL^si-LDLMMcFarlane AS, In: Munro HN， a 11 ison JB, eds. Hanaalian Protein metabolism,Conns 1990; 8: 167-173, Vossen Rcr ·, Lipid 1993; 8: 857-861, Jialal Lipid Res 1992; 33: 899-9 0 6) 0 Conjugated diene is the main product of the preliminary lipid overgasification reaction Tracked by spectroscopy. The following references were evaluated: delay period or Tmin: time required to start gasification; Tso: time required for 50% conjugated diene formation; and Tmax: time required to reach maximum oxidation. Equine ketones can extend the delay in the formation of conjugated diene in human LDL by up to 30% during the 2δηΗ 貘 test. T50 and 1 ^ & also extended by 21% »In the same assay analysis, 25ηΜ androsterone increases the gold fraction with reference to only 25ηΜ estrogenone has a significant inhibitory effect on the production of human HD L conjugated diene. The period is 282%. Tso and ^^ were extended by 120% and 10596 respectively by the Central Standards Bureau of the Ministry of Economic Affairs and the Consumer Cooperatives. The conjugated diene production of citrate concentration estrone-influenced HDL is prolonged by 20%, Tb38%, and Tmax46% e 25nM estrogenone can prolong the delay of human plasma conjugated diene. 3%, and prolong Tbo and T_ by 21% and 31%, indicating that although it has a small effect on initiating oxidation, it can slow the slow gasification rate β. In this type of sliver, estrone has no effect on the delay period, and The effect on 1:50 and Twax is only 5% respectively, and the standard of this paper is applicable to the standard (CMS > A4 size (210X297mm) 4 6 61 1 5 A7 B7 5. & Description of the invention (&) 10% β To further verify the antioxidative properties of equine sextin • Use cultured cells to perform two more birch quasi-pharmacological test procedures. In the first test procedure, radioactive birch LDL ^ si-LDLMMcFarlane AS, In: Munro HN, a 11 ison JB, eds. Hanaalian Protein metabolism,
Vo 1 . 1. New York: Academic Press 297-341(1964)) 於有及無雌馬性素酮存在下暴露號於於Cu+ +修改。其 次，J774巨噬細胞暴露於經處理的ttSI-LDL, J774巨噬 細胞表現清除劑脂蛋白受體，該受體結合被氣化修改的 LDL。實驗結果驗證於雌馬性素酮存在下被氧化的經 Cu+ +處理LDL之結合百分率（於2.5及0.25>«^雌馬性素 爾）時分別降低60%及37%^供比較用，相等濃度雌酮 影辑可降低被氣化LDL的結合百分率分別為39%及0¾ β 因氧化LDL被巨噬細胞結合及代謝強力促成泡沫細胞形 成因而促成動脈粥瘤斑塊形成，故相信此種減少LDL氧 化随後減少結合至清除剤受雔的作用具有顯箸效果。 經濟部中央標準扃員工消費合作社印衆 (請先聞讀背面之注意事項存填¾本頁)Vo 1. 1. New York: Academic Press 297-341 (1964)) Exposure to Cu + + in the presence and absence of equol. Second, J774 macrophages were exposed to treated ttSI-LDL, and J774 macrophages exhibited scavenger lipoprotein receptors that bind to LDL that is modified by vaporization. The experimental results verified that the combined percentage of Cu ++-treated LDL that was oxidized in the presence of estrogen ketones (at 2.5 and 0.25 > ^^ estrogen) decreased by 60% and 37%, respectively, for comparison, equal concentrations of estrone The film can reduce the binding percentage of vaporized LDL to 39% and 0¾ β. Because oxidized LDL is bound by macrophages and is strongly metabolized to promote the formation of foam cells and thus atheromatous plaque formation. The effect of reducing the binding to clearing the receptors has a significant effect. Central Standards of the Ministry of Economic Affairs 扃 Employee Consumer Cooperatives (Please read the notes on the back and fill in this page)
第二試驗程序中，豬主動脲内皮細胞（PAEC)暴露於已 經如前述，於有及無雌馬性素酮存在下_暴露於Cu+ + 修改的LBL。氣化LDL驗證對内皮細胞具有細胞毒性，此 種過程也強力促成動脈粥瘤生成遇程。細胞與經處理的 LDL培養24小時後，進行ΜΤΤ檢定分析來^估細胞毒性 (Hansen MB, J I祖丨u Methods 199: 203-210(1989))。 此種試驗程序評估特定檢定分析中存活細胞百分率。檢 定分析中，於無化合物存在下暴露於25撖克/毫升LDL 8 ~ 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） 經濟部中央標準扃員工消費合作社印製 4 6 61 1 5 A7 B7 五、發明説明（7 ) 後僅2%細胞存活》相反地，於雌馬性素ϋ (0.25// «)存 在下暴露於經處理的LDL Cu + + 後存活細咆百分率為 100%或以上。本檢定分析試驗之其它化合物對PAEC的 保護效果極低U7点-雌二酵=11%存活；馬烯雌酮 (Equilin)=4%存活；雌銅= 3796存活）。試驗程序結 果驗證於雌馬性素醑存在下修改的LDL不具細胞毒性， 因此，該資料符合藉前述TBARS方法驗證《馬性素釀可 抑制氣化修改作用β 基於此等試驗程序所得結果，雌馬性素掘及其硫酸_ 之醫藥可接受性鹽，例如鑣金觴鹽，驗土金癟鹽，铵鹽 ，含1-6偁硝原子之烷基胺_或各傾烷基含1-6個硪原子 之二烷基胺鹽可用做抗氣化雨，用於治療或抑制自由基 團誘發疾病狀態。 本發明之抗氧化劑可淨或舆翳藥載劑配方供投藥，配 方比例係由化合物溶解度及化學性質，選用的抗藥途徑 及標準藥理實務決定。轚藥載劑可為固腊或液體〇 固體載劑包含一種或多種物質也可做為矯味爾.潤滑 劑，增溶劑，懸浮劑，填充劑*滑動劑*鼷縮助劑，黏 結劑，或錠劑-崩散剤；也可做為包膠材料。散劑中， 載劑為細分固體其與細分活性成份混合<·錠劑中，活性 成份與具有所需歷縮性質的載劑以適當比例混合並壓縮 成所需形狀及大小。散劑及錠劑較佳含高逹99%活性成 份。適當固體載剤包含例如碟酸鈣，硬脂酸鎂，滑石， 糖類，乳糖，糊精，澱粉》明_，纖維素，甲基纖維素 本紙張尺度適用中國國家標準（CNS ) Α4规格（2Ι〇 ν 297公廣} (請先聞讀背面之注意事項再填寫本頁) 訂 〆， (4 6 61 1 5 A7 B7 五、發明説明（，） ，羧甲基纖維素納，聚乙烯基吡咯啶，低熔點蟥及離子 交換樹脂。 液體載劑用於製備溶液劑，懸浮掖削，乳液劑，糖漿 劑，酏劑及加壓组成物。活性成份可溶解或懸浮於醫藥 可接受性液體載劑如水，有機溶劑，二者之混合物或轚 榮可接受性油類或脂肪類。液體載劑含有其它適當酱藥 添加劑例如增溶劑，乳化剤，缓衝劑，保赖劑，甜味剤 ，矯味劑，懸浮劑，增稠劑，色料，鈷度諝節劑，安定 劑或滲透壓調節劑。經口及腸外投藥用之液體載劑之逸 例包含水（部份含前述添加剤例如纗維素衍生物，較佳 羧甲基纖維素納鹽溶液），醇類（包含一元酵及多元醇如 二醇類）及其衍生物，卵磷脂類及油類（例如分皤椰子油 及花生油）。供賭外投藥，載劑亦可為油性酯如油酸乙 酯及油酸異丙酯β無菌液體載劑可用於無菌液體型組成 物供腸外投藥。加壓組成物之液體載劑可為鹵素化烴或 其它醫藥坷接受性推進劑。 經濟部中央標準局員工消費合作社印製 {請先閲讀背面之注意事項再填邕本頁) 無菌溶液劑或懸浮液劑等液體醫藥組成物可供例如肌 肉、腹内或皮下注射用。無菌溶液劑也可經靜脈投藥β 本發明化合物也可呈液體或固體組成物劑型經口投藥。 本發明之抗氣化劑可以習知栓劑形式經直腸投藥 藉 i #内或支氣管内吸入或吹入投蕖用，本發明之抗氣化劑 可配方成水溶液或部份水溶液，然後成氣霧劑型式使用 ••本發明化合物可經皮投藥，偽使用經皮貼布内含活性 化合物及載翔I,該載劑對活性化合物呈惰性，對皮膚無 -1 〇 -本紙钱尺度適用中國國家標準（CNS ) A4規格（210X 297公釐） 4 6 61 1 5 A7 B7 經濟部中央標準局員工消費合作社印製 五、發明説明（ 9 ) i ! 毒 且 可 使 活 性 劑 經 由 皮 慮 輸 送 供 糸 統 性 吸 收 入 血 流 〇 載 1 1 劑 可 呈 任 —·. 種 形 式 例 如 乳 m 劑 及 軟 脅 劑 ， 糊 精 » 膠 漿 劑 1 1 及 封 阻 裝 置 〇 乳 苷 劑 及 軟 劑 可 為 油 / 水 或 水 / 油 型 黏 請 I I 稠 液 體 或 半 固 體 乳 液 〇 糊 劑 包 括 可 吸 收 粉 末 分 散 於 石 蠟 先 閱 1 I 讀 1 1 或 含 活 性 成 份 之 親 水 石 锻 也 適 用 〇 多 種 封 阻 裝 置 可 用 於 背 面 1 I 之 1 將 活 性 成 份 釋 放 入 血 流 例 如 内 含 活 性 成 份 含 或 未 含 載 劑 注 意 1 1 之 貯 器 上 方 覆 蓋 半 透 膜 » 或 内 含 活 性 成 份 之 基 體 〇 其 它 事 項 1 I 再 1 /- 封 阻 裝 置 由 參 考 文 獻 已 知 〇 填 寫 本 r k 此 外 本 發 明 之 抗 氣 化 劑 可 經 由 與 醫 藥 可 接 受 性 媒 劑 頁 1 配 方 成 含 有 0 , 1 ^ -5 % 9 較 佳 2%活性化合物之溶液劑， 乳 t 1 帝 劑 或 洗 劑 可 投 予 真 菌 患 部 〇 1 I 劑 量 需 求 隨 使 用 特 定 組 成 物 4 投 藥 途 徑 存 在 的 病 情 1 1 訂 1 駸 重 程 度 及 接 受 治 療 的 特 定 固 體 改 變 〇 基 於 標 準 藥 理 試 驗 程 序 所 得 結 果 > 預 期 活 性 化 合 物 每 曰 劑 量 為 0 - 0 2微 1 I 克 / 千 克 -5 00徹 克 / 千 克 〇 治 療 通 常 以 低 於 化 合 物 最 佳 1 1 劑 量 之 小 劑 量 開 始 〇 隨 後 增 高 劑 量 至 達 到 該 種 情 況 下 最 1 I 佳 效 果 為 止 經 η 腸 外 經 銲 或 支 氣 管 内 投 藥 的 正 確 厂 劑 量 將 由 處 方 醫 生 基 於 對 各 別 接 受 治 療 病 人 的 經 驗 決 定 1 1 0 較 佳 醫 藥 組 成 物 係 呈 早 位 劑 型 例 如 錠 劑 或 膠 囊 劑 0 於 1 I 此 等 劑 型 9 組 成 物 可 再 分 成 含 適 量 活 性 成 份 的 αο 早 位 劑 量 1 I t3〇 位 劑 型 可 為 封 裝 組 成 物 例 如 封 裝 散 劑 9 小 瓶 劑 安 I i 瓶 劑 預 先 填 充 注 射 器 9 含 液 體 m 袋 〇 劑( 型 例 如 可 為 膠 1 I 囊 劑或錠劑本身， 或為適當數量之此等組成物之封包 1 形 式 〇 -1 1 - 1 1 1 1 1 1 本紙張尺度適用中國國家標準（CNS ) Ad規格（210X 公釐）In a second test procedure, porcine active urea endothelial cells (PAEC) were exposed to Cu + modified LBL, as previously described, in the presence and absence of androgens. Vaporized LDL has been verified to be cytotoxic to endothelial cells, and this process also strongly promotes the process of atheroma formation. After the cells were cultured with the treated LDL for 24 hours, the MTT assay was performed to evaluate the cytotoxicity (Hansen MB, J. Izu Methods 199: 203-210 (1989)). This test procedure evaluates the percentage of viable cells in a particular assay. In the analysis, it was exposed to 25 g / ml LDL in the absence of compounds 8 ~ This paper size is applicable to the Chinese National Standard (CNS) A4 (210X297 mm) Central Standard of the Ministry of Economics 扃 Printed by Employee Consumer Cooperatives 4 6 61 1 5 A7 B7 5. Invention description (7) Only 2% of cells survive "Conversely, the percentage of survival fines after exposure to treated LDL Cu + + in the presence of equine sex hormone ϋ (0.25 //«) was 100% or the above. The protective effect of other compounds in this assay on PAEC is extremely low. U7 points-estrogen = 11% survival; equinestrone (Equilin) = 4% survival; estrogen = 3796 survival). The results of the test procedure verify that LDL modified in the presence of equine sex hormones is not cytotoxic. Therefore, this data is consistent with the verification of the aforementioned TBARS method, "Horse hormones can inhibit the modification of gasification β. Based on the results of these test procedures, Pharmaceutically acceptable salts of sulfuric acid, such as osmium osmium salt, soil test osmium salt, ammonium salt, alkylamines containing 1-6 hydrazone nitrate _ or each peptidyl group containing 1-6 fluorene atoms Alkylamine salts can be used as anti-gasification rain, for treating or inhibiting free radical groups to induce disease states. The antioxidant of the present invention can be administered in a net or a drug carrier formulation, and the formulation ratio is determined by the solubility and chemical properties of the compound, the selected drug resistance route and standard pharmacological practice. The peony carrier can be solid wax or liquid. The solid carrier contains one or more substances and can also be used as a flavoring agent. Lubricants, solubilizers, suspending agents, fillers * sliding agents * shrinkage aids, binders, or Lozenges-disintegrate; can also be used as encapsulating material. In powders, the carrier is a finely divided solid which is mixed with the finely divided active ingredients. In a lozenge, the active ingredients are mixed with a carrier having the required shrinkage properties at an appropriate ratio and compressed into a desired shape and size. The powders and lozenges preferably contain 99% high active ingredient. Suitable solid carriers include, for example, calcium dishate, magnesium stearate, talc, sugars, lactose, dextrin, starch, cellulose, methylcellulose. This paper is sized to the Chinese National Standard (CNS) A4 specification (2I 〇ν 297 公 广} (Please read the notes on the back before filling in this page) Order, (4 6 61 1 5 A7 B7 V. Description of the invention (,), carboxymethyl cellulose sodium, polyvinylpyrrole Pyridine, low melting point rhenium, and ion exchange resin. Liquid carriers are used to prepare solutions, suspensions, emulsions, syrups, elixirs, and pressurized compositions. The active ingredients can be dissolved or suspended in a pharmaceutically acceptable liquid carrier Agents such as water, organic solvents, mixtures of the two or acceptable oils or fats. Liquid carriers contain other appropriate soy additives such as solubilizers, emulsifiers, buffers, lyophiles, sweeteners, flavors Agents, suspending agents, thickeners, pigments, cobalt degrees tinctures, stabilizers or osmotic pressure regulators. Examples of liquid carriers for oral and parenteral use include water (some of which contain the aforementioned additives, such as Avidin derivatives, preferably carboxyl Methylcellulose sodium salt solution), alcohols (including monoenzymes and polyhydric alcohols such as glycols) and their derivatives, lecithins and oils (such as tillered coconut oil and peanut oil). The agent can also be an oily ester such as ethyl oleate and isopropyl oleate β. Sterile liquid carriers can be used in sterile liquid compositions for parenteral administration. Liquid carriers for pressurized compositions can be halogenated hydrocarbons or other medicines坷 Acceptable propellants. Printed by the Consumer Cooperatives of the Central Bureau of Standards, Ministry of Economic Affairs {Please read the notes on the back before filling this page) Liquid pharmaceutical compositions such as sterile solutions or suspensions can be used for muscle, abdominal or For subcutaneous injection. Sterile solutions can also be administered intravenously β The compound of the present invention can also be administered orally in the form of a liquid or solid composition. The anti-gasification agent of the present invention can be administered rectally in the form of a suppository or intrabronchally For internal inhalation or insufflation, the anti-gasification agent of the present invention can be formulated as an aqueous solution or a part of an aqueous solution, and then used as an aerosol. • The compound of the present invention can be administered transdermally, and a percutaneous patch is pseudo-used. Contains active compound and carrier I, the carrier is inert to the active compound, and has no effect on the skin -1 〇- This paper money scale applies Chinese National Standard (CNS) A4 specification (210X 297 mm) 4 6 61 1 5 A7 B7 Economy Printed by the Consumer Standards Cooperative of the Ministry of Standards of the People's Republic of China V. Invention Description (9) i! Poisonous and can make the active agent be absorbed into the bloodstream through dermatological delivery system. 1 1 agent can take any role ... Emulsions and softeners, dextrin »Glue agent 1 1 and blocking device 0 lactosides and softeners can be oil / water or water / oil-type viscosity II thick liquid or semi-solid emulsions 0 pastes include Absorbable powder is dispersed in paraffin. Read 1 I Read 1 1 or hydrophilic stone forging containing active ingredients is also applicable. A variety of blocking devices can be used on the back 1 I 1 to release the active ingredients into the blood stream such as containing active ingredients containing or Without carrier Note 1 1 Above the reservoir Cover the semi-permeable membrane »or the matrix containing the active ingredient. ○ Other matters 1 I again 1 /-The blocking device is known from the reference. Fill out this rk. In addition, the anti-gasification agent of the present invention can be passed with a pharmaceutically acceptable vehicle. Page 1 Formulated as a solution containing 0, 1 ^ -5% 9 and preferably 2% of active compound, milk t 1 emperor or lotion can be administered to the affected part of the fungus. 0 1 I Dosage requirements exist with the use of specific compositions 4 Administration routes Condition 1 1 Order 1 Weight change and specific solid changes under treatment 0 Based on results obtained from standard pharmacological test procedures > Expected dose of active compound per day is 0-0 2 micro 1 I g / kg-5 00 chek / kg 〇Treatment usually starts with a small dose below the optimal 11 dose of the compound. 〇Then increase the dose until the best effect in this case is achieved by η parenteral welding or branching. The correct plant dosage for in-tube administration will be determined by the prescribing physician based on the experience of each individual patient receiving treatment. 1 1 0 Preferred pharmaceutical compositions are in early dosage forms such as lozenges or capsules. 0 to 1 I. These dosage forms can be reconstituted. Divided into αο containing the appropriate amount of active ingredients. Early dose 1 I t30. The dosage form can be a packaged composition such as encapsulated powder 9 vials amp. I i bottle pre-filled syringe 9 containing liquid m bag 0 type (type can be glue 1 I Capsules or lozenges themselves, or packets 1 of these compositions in the appropriate quantity 1 form 0-1 1-1 1 1 1 1 1 This paper size applies the Chinese National Standard (CNS) Ad specifications (210X mm)