200404577 (1) 玖、發明說明 【發明所屬之技術領域】 本發明係關於控制對於血漿蛋白質具有結合親和性之 有效成份之血液中游離濃度用製劑及其投予方法。更詳細 而言’本發明係關於投予含有對於血漿蛋白質具有結合親 和性之有效成份之製劑時，投予對於與該有效成份共同的 血漿蛋白質具有結合親和性之單一或多數個胺基酸之製 劑’控制該有效成份結合於血漿蛋白質之製劑及其投予方 法。 【先前技術】 一般以治療、診斷等爲目的所投予的藥劑係經由一次 全身血液循環，歷經吸收、分佈、代謝及排泄等過程。於 吸收及分佈之過程中，藥劑係隨著血液流動而移動，而血 管內、組織間隙及細胞內之各空間之移動係以未與蛋白質 等結合之狀態之游離型藥劑之擴散及運送而發生，而到達 目的作用部位。移動到達恆定狀態時，游離型藥劑之濃度 於各空間均勻，整體的濃度模式係依據與蛋白質等之結合 的大小而決定。 因此，在生物體中之藥劑係因應其特性，與一部份之 血漿蛋白質等之生物體高子成可逆性結合的存在。因爲一 般可透過微血管壁或細胞膜等者爲非結合型藥劑，作爲有 效成份可作用者係不與蛋白質等結合之游離型藥劑，移動 至其作用部位係受到與血漿蛋白質等之結合之影響大。 -4- (2) (2)200404577 由相關觀點，於國際公開00/7 83 5 2號公報記載，投 予與血漿蛋白質具有結合親和性之第一個藥劑時，投予對 於與該第一個藥劑共同的血漿蛋白質具有結合親和性之第 二個藥劑’可控制第一個藥劑結合於血漿蛋白質之藥劑之 投予方法及製劑。亦即，該公報記載，與投予第一個藥劑 之同時或其前後，投予相關之第二個藥劑，控制第一個藥 劑結合於血漿蛋白質，可提高或降低血液中之第一個藥劑 之游離濃度（參考國際公開00/78 3 52號目錄）。 例如9 9 m -鍩標識疏基乙醯基甘胺醯替甘胺醯替甘胺 酸（99mTc-MAG3)係以腎臟中之腎小管分泌而有效率地 排泄於尿中，所以以診斷腎及泌尿道疾病爲目的之廣受使 用之體內放射性醫藥品。診斷劑之用量，已知99mTc-MAG3係結合其之約 90 %於血漿蛋白質。國際公開 00/783 52號公報中記載，以99mTc-MAG3爲第一個藥劑 時，因投予第二個藥劑之 bucolome、cefazolin 及 valproic acid等，抑制99mTc-MAG3與血漿蛋白質結合， 而可提高99mTc-MAG3之游離濃度，結果係99mTc-MAG3 更有效率地排泄於尿中。 然而，國際公開00/783 5 2號公報中所舉例之對於與 第一個藥劑共同之血漿蛋白質具有結合親和性之第二個藥 劑之 bucolome、cefazolin、Etoposide、苯丁 Π坐酮 (Phenylbutazone )及阿司匹靈（Aspirin)等，原本係作爲 治療藥使用之顯示一定藥效之藥劑。因此，投予相關之第 二個藥劑時，必須慎重地考量第二個藥劑其本身對於生物 (3) (3)200404577 體之影響。亦即是該藥劑原本的藥理作用必須爲臨床上所 容許的範圍。 【發明內容】 發明之揭示 本發明係有鑑於上述現狀而成者’係以提供可控制有 效成份結合於血漿蛋白質之製劑，以及提供控制有效成份 結合於血漿蛋白質之適當地投予製劑的方法爲目的。 亦即，本發明係關於可控制有效成份結合於血漿蛋白 質之製劑及其投予方法，作爲控制該結合用所投予的製 劑，係以提供對於生物體的影響較少，而且更適合於現實 上投予之製劑爲目的。 以本發明之控制藥物結合於血漿蛋白質用製劑，控制 有效成份結合於血漿蛋白質，因此，可提供可調節有效成 份之血液中游離濃度之適當之製劑及其投予方法。亦即， 本發明中爲控制有效成份結合於蛋白質，爲投予含有單一 或多數個胺基酸之製劑，可提供控制該結合用製劑本身對 於生物體之影響較少，而且更適合於現實上投予之製劑。 本發明係投予含有與血漿蛋白質具有結合親和性之有 效成份（通常爲期待診斷或治療效果之藥物）之製劑時， 將含有對於與有效成份共同之血漿蛋白質具有結合親和个生 之單一或多數個胺基酸之製劑，於投予含有有效成份製劑 之同時或其前後投予，控制該有效成份結合於血漿蛋白質 爲特徵之提供控制藥物結合於血漿蛋白質用製劑及其投予 -6 - (4) 200404577 方法。 尤其抑制有效成份與血漿蛋白質結合時，有 胺基酸二者，以對於共同的血漿蛋白質之結合部 合親和性爲宜。另外，投予含有胺基酸製劑時期 含有有效成份製劑之前後或同時均可，因應可得 份之適當效果之血液中游離濃度之所得時期而 擇。另外，胺基酸可爲單一，亦可倂用多數個胺 其期待相乘效果時，可倂用多數個胺基酸。 可同時投予含有有效成份製劑及含有胺基酸 亦可作爲含有有效成份及胺基酸之一個製劑供給 亦可分別充塡有效成份及胺基酸於不同容器，作 之試劑組供給。作爲如此之試劑組時，當然亦可 合而同時投予，亦可將有效成份及胺基酸以不同 同投予途徑投予。作爲其他之試劑組型態，亦可 效成份製劑及含有胺基酸製劑，充塡於單一容器 間’成爲使用時混合型式之試劑組。另外，含有 製劑及含有胺基酸製劑係二者或其中一方爲已存 亦可。 含有有效成份製劑選自體內用放射性診斷藥 放射性治療藥時，該放射性核種係選自1 1 -碳 15— 氧（15〇) 、18 一氟（】8f) 、32-磷（32P) (Fe) 、67 —銅（67Cu) 、67 —錄（67Ga)、 (81mK〇 、81 —铷（81Rb ) 、89 —緦（89Sr ) (9〇Y ) 、9 9m —錯（99mTc ) 、：l 1 1 一銦（11 4η ) 效成份及 位具有結 係於投予 到有效成 適當地選 基酸。尤 製劑時， 。另外， 爲製劑化 使用時混 時期或不 將含有有 之不同區 有效成份 之醫藥品 或體內用 (MC)、 、59—鐵 8 1 m —氪 、90 -釔 ' 123- -7- 200404577200404577 (1) (ii) Description of the invention [Technical field to which the invention belongs] The present invention relates to a preparation for controlling free concentration in blood of an active ingredient having binding affinity for plasma proteins and a method for administering the same. In more detail, the present invention relates to the administration of a single or a plurality of amino acids having a binding affinity for a plasma protein in common with the active ingredient when a preparation containing the active ingredient having a binding affinity for a plasma protein is administered. Formulation 'A formulation that controls the binding of the active ingredient to plasma proteins and the method of administration. [Prior art] Pharmaceuticals generally administered for the purpose of treatment, diagnosis, etc. are administered through a systemic blood circulation through absorption, distribution, metabolism, and excretion. During the process of absorption and distribution, the medicine moves with the flow of blood, and the movement of the various spaces within the blood vessels, tissue spaces and cells occurs with the diffusion and transportation of free medicines in a state that is not bound to proteins and the like. , And reach the target action site. When the movement reaches a constant state, the concentration of the free drug is uniform in each space, and the overall concentration pattern is determined according to the size of the combination with the protein and the like. Therefore, depending on its characteristics, a pharmaceutical agent in a living body is reversibly combined with a part of biological proteins such as plasma proteins. Generally, those that can pass through the microvascular wall or cell membrane are non-binding drugs. As the effective ingredients, those that can act are free drugs that do not bind to proteins. Moving to the action site is greatly affected by the binding with plasma proteins. -4- (2) (2) 200404577 From a related point of view, it is described in International Publication No. 00/7 83 5 2 that when a first agent having a binding affinity to plasma proteins is administered, the drug is administered to the first agent. The second agent having a binding affinity for the plasma protein common to each agent can control the administration method and preparation of the agent for binding the first agent to the plasma protein. That is, the bulletin states that the administration of the second drug related to the first drug at the same time as or before the first drug, and controlling the binding of the first drug to the plasma protein can increase or decrease the first drug in the blood. Free concentration (refer to International Publication No. 00/78 3 52). For example, the 9 9 m- 鍩 -labeled succinylethylglycine, tidyglycine, and tidyglycine (99mTc-MAG3) are efficiently excreted in the urine by renal tubular secretion in the kidney. In vivo radiopharmaceuticals widely used for urinary tract diseases. It is known that the amount of diagnostic agent 99mTc-MAG3 binds to about 90% of plasma protein. According to International Publication No. 00/783 52, when 99mTc-MAG3 is used as the first agent, bucolome, cefazolin, and valproic acid, etc. of the second agent are administered to inhibit the binding of 99mTc-MAG3 to plasma proteins, which can increase the The free concentration of 99mTc-MAG3, the result is that 99mTc-MAG3 is more efficiently excreted in the urine. However, Bucolome, cefazolin, Etoposide, Phenylbutazone, and Phenylbutazone, which are second drugs having binding affinity for plasma proteins common to the first drug, are exemplified in International Publication No. 00/783 5 2. Aspirin, etc., was originally used as a therapeutic drug and showed a certain effect. Therefore, when the relevant second agent is administered, the effect of the second agent on the biological (3) (3) 200404577 body must be carefully considered. That is, the original pharmacological effect of the agent must be in a clinically acceptable range. [Disclosure of the invention] The present invention was developed in view of the above-mentioned current situation, and is a method for providing an agent capable of controlling the binding of active ingredients to plasma proteins, and a method for appropriately administering the agents to control the binding of active ingredients to plasma proteins. purpose. That is, the present invention relates to a preparation capable of controlling the binding of an active ingredient to plasma proteins and a method for administering the same. As a preparation for administering the combination, it is intended to provide less influence on the organism and is more suitable for reality. For the purpose of the preparation administered above. With the preparation for controlling the binding of the drug to the plasma protein of the present invention and the binding of the active ingredient to the plasma protein, it is possible to provide an appropriate preparation capable of adjusting the free concentration in the blood of the effective component and a method for administering the same. That is, in the present invention, in order to control the binding of an active ingredient to a protein, and to administer a preparation containing a single or a plurality of amino acids, it can be provided that the combined preparation itself has less influence on the organism, and is more suitable for reality Administration of the preparation. When the present invention is administered to a preparation containing an active ingredient with binding affinity for plasma proteins (usually a drug that is expected to have a diagnostic or therapeutic effect), it will contain a single or multiple individuals with binding affinity for the plasma protein in common with the active ingredient. An amino acid preparation is administered at the same time or before or after administration of a preparation containing an active ingredient, and a preparation for controlling the binding of a drug to a plasma protein, which is characterized by controlling the binding of the active ingredient to a plasma protein, and its administration -6-( 4) 200404577 method. In particular, when inhibiting the binding of the active ingredient to the plasma protein, both amino acids are preferred, and the affinity for the binding portion of the common plasma protein is preferred. In addition, the period of administration of the amino acid-containing preparation may be before, after, or at the same time as the preparation containing the active ingredient. In addition, a single amino acid may be used singly or a plurality of amines may be used. When a synergistic effect is expected, a plurality of amino acids may be used. It can be administered at the same time as the preparation containing the active ingredient and the amino acid. It can also be supplied as a preparation containing the active ingredient and the amino acid. It can also be filled with the active ingredient and the amino acid in different containers and supplied as reagent groups. When such a reagent group is used, it is of course possible to administer them simultaneously and simultaneously, or to administer the active ingredient and amino acid in different co-administration routes. As other types of reagent groups, it is also possible to use active ingredient preparations and amino acid-containing preparations filled in a single container 'to become a mixed-type reagent group in use. In addition, either or both of the preparation containing the amino acid preparation and the preparation containing the amino acid may exist. When the preparation containing the active ingredient is selected from the radioactive diagnostic drug for in vivo use, the radionuclide species is selected from the group consisting of 1 1-carbon 15-oxygen (15), 18-fluoro (] 8f), 32-phosphorus (32P) (Fe ), 67—copper (67Cu), 67—record (67Ga), (81mK〇, 81— 铷 (81Rb), 89— 缌 (89Sr) (90〇Y), 9 9m—wrong (99mTc), l 1 1 Indium (11 4η) The active ingredient and site are bound to the proper selection of the base acid when administered to the effective. Especially in the preparation, In addition, for the preparation of the mixed use period or do not contain the active ingredients in different areas Medicines or in vivo (MC), 59-iron 8 1 m-gadolinium, 90-yttrium '123- -7- 200404577
碘（ 123" 、125 -碘 ( 】251 ) > 131 —砩（ 1311 ) 、1 33 — 氙（ 133Xe ) 、1 1 7m — 錫 ^ 】1 7 r nSn )、 153 — 釤（1 5 3 S m )、 186 一銶（ 186Re ) \ 18 8 — 鍊（ 】88Re )' 2 0 1 —銳 (201 'T1 )、 2 1 2 —鉍（ 2 1 2Bi ) 、2 1 3 — 鉍（2 】3Bi ) 及 211- 攻（21 1 At )等。 此時’該體內用放射性診斷藥或體內用放射性治療藥 所具有之依上述放射性核種所標識之螯合基或受體配位基 等之化合物係選自例如雙胺基硫醇或其衍生物、單胺基單 醯胺基雙硫醇或其衍生物、雙醯胺基雙硫醇或其衍生物、 锍基乙醯基甘胺醯替甘胺醯替甘胺酸或其衍生物、六甲基 丙烯基胺基肟或其衍生物、亞甲基雙[雙（2 -乙氧基乙 基）膦](tetrophosmin )或其衍生物、2,3 -二锍基琥珀 酸或其衍生物、亞甲基半胱胺酸二聚體或其衍生物、甲氧 基異丁基異腈或其衍生物、聚胺衍生物、pyridoxilidene-aminate 衍生物、亞甲基二磷酸鹽 （methylene diphosphonate )、羥基亞甲基二磷酸鹽衍生物、甲基-ω-苯基十五院酸（0 -methyl-co-phenylp entadecanoic acid )或其衍生物、N-異丙基安非他命、馬尿酸 (hippurate )、卞基胍及莨菪烷衍生物等。 另一方面，本發明之製劑所含之胺基酸係選自例如色 胺酸、天冬醯胺酸、甘胺酸、絲胺酸、白胺酸、甲硫胺 酸、苯丙胺酸、蘇胺酸、纈胺酸、脯胺酸、半胱胺酸及丙 胺酸或此等之鹽類以及此等之衍生物或此等衍生物之鹽 等。亦即，本發明中之胺基酸，亦包含N -乙醯基色胺酸 -8- (6) (6)200404577 及羥基苯甘胺酸等之胺基酸分子中導入取代基之胺基酸衍 生物及此等之鹽。此時，例如期待控制有效成份對於多數 個血漿蛋白質或人血淸白蛋白之多數個結合部位之結合 時，期待相乘效果時等，亦可選擇多數個胺基酸。另外， 使用多數個胺基酸時，亦可選擇包含Proteamin 12X (註 冊商標）及kidomin (註冊商標）等之胺基酸輸液，亦可 作爲含有與此等輸液相同組成或成份量之製劑。爲控制有 效成份結合於血漿蛋白質，使用單一或多數個胺基酸，可 提供控制血漿蛋白質結合用製劑本身，對於生物體的影響 較少，而且更適合於現實上投予之製劑。 用以實施發明之最佳型態 投予含有與血漿蛋白質具有結合親和性之有效成份之 製劑之同時或其前後，若投予含有對於共同的血漿蛋白質 具有高的結合親和性之胺基酸製劑時，認爲於結合部位發 生競爭性取代’增加有效成份之游離濃度（取代效果）， 因此’可期待得到比單獨投予含有有效成份製劑時高的藥 劑活性。相反地’因含有胺基酸製劑之作用，提高有效成 份結合於血漿蛋白質時，減低有效成份之游離濃度（減低 游離濃度效果）’血液中有效成份之游離濃度經長時間維 ί寸較低彳辰度而降低淸除率（clearance)，亦可期待達成持 續性藥效發生。 本發明中’含有與相關之血漿蛋白質具有結合親和性 之有效成份製劑係只要符合投予的目的之製劑，治療藥或 -9- (7) (7)200404577 診斷藥均可。 另一方面，本發明之含有胺基酸製劑所包含之胺基酸 係爲得到上述之取代效果，以選自具有對於與有效成份相 同的血漿蛋白質之競爭性結合親和性，阻礙有效成份結合 於血漿蛋白質，增加有效成份之血液中游離濃度者，或與 有效成份對於血漿蛋白質之結合部位相同，而且結合親和 性更高者爲宜。相反地，爲得到減低游離濃度效果，依據 胺基酸結合於血漿蛋白質，由提升有效成份之血漿蛋白質 結合率之胺基酸，選擇其效果高者而可達成目的。 關於劑型，有效成份與胺基酸不因配合而有分解等之 變化時，而且可同時投予兩者時，亦可混合有效成份與胺 基酸，作爲充塡於同一容器之製劑供給。混合製劑亦可添 加酸鹼値調節劑、滲透壓調節用之無機鹽類，安定化各成 份用安定劑等之醫療用上所允許使用之成份。 另外，考慮混合製劑之組成成份及保存性等，亦可加 工成液劑、冷凍乾燥製劑等之適當的劑型。 另外，亦可將含有有效成份製劑及含有胺基酸製劑， 作爲分別充塡於不同容器之試劑組供給。混合製劑同樣 地，亦可於各製劑中添加安定化劑等之醫療用上所允許使 用之成份，考慮各製劑之投予法及安定性等，亦可加工成 液劑或冷凍乾燥劑等之最適合之製劑。將成份作爲如此之 分別容器之試劑組時，亦可分別投予含有有效成份製劑及 含有胺基酸製劑，亦可用時混合而同時投予。尤其若混合 含有有效成份及胺基酸製劑時，預測長期保存時發生分解 -10- (8) (8)200404577 等之變化時，必須選擇其他投予途徑時，或必須隔離投予 時期時，充塡於不同容器製劑化之試劑組係有效的。 作爲試劑組，亦可採用將含有有效成份製劑及含有胺 基酸製劑，充塡於單一容器之不同區間，使用時混合之型 態。例如作爲試劑組之容器，具有以連接器相連接之多數 區間之塑膠容器，各區間充塡溶解劑、稀釋劑或含有有效 成份之醫藥，使用時，由充塡溶解劑或稀釋劑之區間，介 由連接器，將充塡溶解劑或稀釋劑流入含有有效成份醫藥 之區間，調製成最終的投予型態之製劑者。利用此型態之 谷窃時’例如於3區間型物之各區間’充塡含有有效成份 之粉末製劑、含有胺基酸之粉末製劑及溶解劑，使溶解劑 流入含有胺基酸之粉末製劑後，再流入含有有效成份之粉 末製劑’調製成最終之投予液劑，或於2區間型物之各區 間’充塡含有有效成份之粉末或液狀製劑及含有胺基酸之 '液狀製劑’使含有胺基酸之液狀製劑流入含有有效成份之 粉末或液狀製劑，調製成最終之投予液劑等，可作成多樣 化的試劑組。 另外’其他型態，亦有具有收容成份用之多數個區間 之注射器型容器，利用如此之容器，可提供便利性優異之 試劑組。 -般作爲有效成份結合之血漿蛋白質係人血淸白血球 (HSA) 、α] —氧化糖蛋白質（AGP) 、r —球蛋白及脂 蛋白質等，以結合於HSA或AGP爲多。選擇胺基酸，例 如有效成份主要係對於HAS具有結合親和性時，以選自 -11 - (9) (9)200404577 對於HAS具有結合親和性者爲宜，有效成份對於AGP具 有結合親和性時，以選自結合於A G P者爲宜。 另外，有效成份對於多數個血漿蛋白質具有結合親和 性時或對於單一蛋白質中之相異的結合部位具有結合親和 性等時，有時倂用多數的胺基酸係有效的。含有胺基酸製 劑之投予時期係與投予有效成份之同時或其前後均可，適 當地選擇以達成符合投予有效成份目的之效果。投予製劑 的途徑係可適當地選自靜脈內、動脈內、皮下、淋巴管及 經口等。 爲含有有效成份製劑，爲具有與血漿蛋白質之結合親 和性之體內用放射性診斷藥或體內用放射性治療藥，作爲 放射性核種所標識之螯合基或受體配位基等之化合物，可 舉例如锍基乙醯基甘胺醯替甘胺醯替甘胺酸 (Mercapto acetyl glycylglycylglycine ?M AG3 )或其衍生 物、六甲基丙烯基胺基肟 (hexamethylpropyleneamineoxime，HMPAO ) 或其衍生 物、亞甲基雙[雙（2 -乙氧基乙基）膦](tetrofosmin ) 或其衍生物、2,3 —二疏基號拍酸（dimercaptosuccinic acid，DMSA)或其衍生物、N，N’ -亞甲基—L —半胱胺酸 二乙基醚等之亞甲基半胱胺酸二聚體（ethylcysteinate dimer，ECD )衍生物、甲氧基異丁基異腈（methoxy isobutyl isonitrile，MIBI)衍生物、二亞甲基三胺五醋酸 (diethylenetriamine pentaacetic acid，DTPA)等之聚胺衍生 物、pyridoxilene isoleucine 等之 pyridoxilidenaminate 衍 -12- (10) (10)200404577 生物、其他的亞甲基二磷酸鹽 （methylene diphosphonate?MDP )及羥基亞甲基二磷酸鹽（HMDP )衍 生物等之與放射性金屬形成配位化合物之螯合基等，或以 碘標識之）β -甲基-對·苯基十五院酸（々-11^11丫1-卩-iodophenylpentadecanoicacid，BMIPP ) 、Ν-異丙基對砩安 非他命（N-isopropyl-p-i〇doamphetamine，IMP)、鄰姚馬 尿酸（orthoiodohippurate，OIH)、3 -卞基胍（3 -1 o d o b e n z y 1 Guanidine，MIBG)、N— (3 —氟丙基）碳酸甲氧基· 3/3 - ( 4-碘：苯基）黃菪院(N- ( 3-fluoropropyl ) -2 β - carbomethoxy-3 冷-(4_i〇dophenyl)tropane， FP.CIT)或 N-甲 基- 碳酸甲氧基- 3yS-(4 -碘苯基）莨菪烷（CIT)等之 莨菪烷衍生物等。 另外， 作爲放射性核種， 可舉例如1 1 —碳 (Mc ) 、 1 5 — 氧（15 〇 ) 、18 一 氟 (18f )' 32 一磷（ 32P ) 、59 - 鐵 (59 Fe )、 67 - 銅 (6 7C U )、 67 - -鎵（67Ga )、 81m - 氪 (81 mKr ) 、81 ( 8 1 Rb ) 、89 丨 _ 緦（8 9Sr ) 、90 - 釔 ^90 Y ) 、99m - -！荅 ( 99]τ lTc ) > 11 1 - -銦（ ηιΙη) 、123 — 碘（ 123I ) 、1 25 -: ( 125I ) > 1 3 1 一碘（ 131I ) > 133 — 氣（ 133Xe ) > 1 17m — 錫 (117mSn) 153- 釤（1 53Sm) 、 1 86 _銶（ 18 6 Re ) 、 18 8 — 銶 ( 188Re )' 201 - 鉈 (20 】丁1 )、 2 12 一鉍 ( 21： lBi ) 、21 3 一 鉍（2 13Bi ) 及211 — 政（ 211At ) 等 ，作 爲 診 斷用 ，多 使 用18 一氟 (18f ) 、 9 9m -鐯 ^ 9 9 mTc ) N 6 7 - -鎵 ( 67Ga )' 111- 銦 (11 】In )、 123 一硕 ( 123 ，I)及 13 1 一 碘（13 ]I)等 0 -13- (11) (11)200404577 含有單一或多數個胺基酸之製劑，可使用單一或多數 個選自如色胺酸、天冬醯胺酸、甘胺酸、絲胺酸、白胺 酸、甲硫胺酸、苯丙胺酸、蘇胺酸、纈胺酸、脯胺酸、半 胱胺酸及丙胺酸或此等之鹽類以及此等之衍生物或此等衍 生物之鹽等之胺基酸。另外，使用多數個胺基酸時，亦可 選擇包含proteamin 12X(註冊商標）及kidomin(註冊商 標）等之胺基酸輸液，亦可作爲含有與此等輸液相同組成 或成份量之製劑。因本發明之製劑爲包含一個或多數個胺 基酸、或含有胺基酸之輸液者，其本身對於生物體的影響 少，而且可提供更適合於現實上投予之製劑。 包含增加有效成份之血液中游離濃度之胺基酸之製 劑，亦即，作爲產生取代效果之製劑，可舉例如包含選自 色胺酸及其衍生物、天冬醯胺酸、甘胺酸、絲胺酸、白胺 酸、甲硫胺酸、苯丙胺酸、蘇胺酸、纈胺酸、脯胺酸及半 胱胺酸或其鹽類等之胺基酸之製劑。同樣地，作爲產生取 代效果之製劑，可舉例如包含選自proteamin 12X(註冊 商標）及kidomin (註冊商標）等之胺基酸輸液、或包含 具有與其相同組成或成份量之多數個胺基酸之製劑。尤其 以包含一個或多數個選自色胺酸、天冬醯胺酸、甘胺酸、 絲胺酸、苯丙胺酸及N -乙醯基色胺酸或其鹽類之胺基酸 之製劑’以及包含選自proteamin 12X (註冊商標）及 k i d 〇 m i η (註冊商標）之胺基酸輸液、或與其相同組成或 成份量之胺基酸之製劑爲宜。相對地，提高有效成份與血 漿蛋白質之結合，減低游離濃度之製劑，亦即作爲含有產 -14- (12) (12)200404577 生減低游離濃度效果之胺基酸製劑，以含有一個或多數個 選自丙胺酸及羥基苯甘胺酸或其鹽之胺基酸之製劑爲宜。 【實施方式】 實施例 以下係依據實施例更詳細地說明本發明，本發明並不 局限於此等之實施例。 實施例1 檢討對於結合於血漿蛋白質之標識放射性 碘IMP之取代效果 使用人類血淸，檢討對於結合於血淸蛋白之123I-IMP (以1231標識之N_異丙基對碘安非他命）或之 胺基酸或胺基酸輸液（取代藥）之取代效果 預先測定市售之人類血淸池（human pool serum) (Cosmobio 製 Lot· No.13768)之球蛋白濃度等，以 1/15M之磷酸緩衝溶液（ΡΗ = 7·4)稀釋球蛋白濃度成爲 500//Μ。於此500//L之血淸溶液中，添加20//L之表1 及表2所表示之取代藥（胺基酸或胺基酸輸液）。此時， 胺基酸以生理食鹽水溶解，添加於血淸溶液，使成爲表i 及表2所示之試驗濃度。之後，添加2 0 // L之（約爲 220kBq) 123I-IMP或125I-IMP作爲試驗溶液。作爲對照溶 液係使用於上述血淸溶液中，添加2 0 // L之生理食鹽水以 代替取代藥。 由對照溶液及各試驗溶液，各採取2 0 // L爲超濾前之 -15- (13) (13)200404577 試樣。其次’由對照溶液及各試驗溶液，採取4 5 0 // L於 超濾器（TOSO製UltracentIO )，以離心分離機（TOMY 製 RLX — 135 )，以3 00 0rpm，10分鐘離心，進行超濾。 離心操作後’採取2 0 // L之各濾液爲超濾後之試樣。超濾 前後之各試樣之放射能（cpm)，以 auto well gamma counter ( ALOKA製 ARC - 380)測定，依據下述式求出 各試驗溶液之游離率（％ )以及添加胺基酸或胺基酸輸液 之游離率之變化率。 游離率（％ ) = {超濾後之放射能（cpm ) /超濾前之 放射能（C p m ) } X 1 〇 〇 變化率（倍）=試驗溶液之游離率（％ )/對照溶液 之游離率（％ ) 結果如表1及表2所示。另外，對照溶液及各試驗濃 度之游離率係n=3之平均値。 添加色胺酸、天冬醯胺酸、甘胺酸及絲胺酸時，對照 溶液之123I-IMP游離率（ 2 8.00 %)隨著所添加之胺基酸 濃度而增加。發現尤其以色胺酸及天冬醯胺酸明顯地增 加。另外，添加白胺酸、甲硫胺酸、苯丙胺酸、蘇胺酸、 纈胺酸、脯胺酸、半胱胺酸、p 1· 〇 t e a m i η 1 2 X及k i d 〇 m i η 時，觀測出超過3 0.00 %之I23i-iMP游離率。另一方面， 添加丙胺酸時，123I-IMP游離率降至24.80 %，發現降低 游離濃度的效果。 - 16- (14) 200404577 另外，添加胺基酸衍生物之N -乙醯基色胺酸時，增 加125I-IMP之游離率。添加羥基苯甘胺酸時，125I-IMP之 游離率僅些許增加，不如N -乙醯基色胺酸之效果。 -17- (15) (15)200404577 表1對於血淸蛋白結合123I-IMP之胺基酸或胺基酸輸液 之取代效果 取代藥 試驗濃度 游離率（％ ) 變化率（倍） 對照溶液 — 28.00 一 異白胺酸 2 0 0 μ m 28.19 1.01 400pm 27.96 1 .00 白胺酸 4 0 0pm 3 1.20 1.11 賴胺酸 4 0 0 μ m 28.92 1 .03 甲硫胺酸 2 0 0 μ m 30.60 1 .09 4 0 0 μ m 30.26 1.08 苯丙胺酸 2 0 0 μ m 30.05 1.07 400pm 3 1.07 1.11 蘇胺酸 4 0 0 μ m 30.17 1.08 色胺酸 1 ΟΟμιη 3 1.33 1.12 400μπι 35.47 1.27 纈胺酸 400pm 29.40 1.05 8 0 0 μ m 30.79 1.10 精胺酸 2 0 0 μ m 27.27 0.97 400ym 29.40 1.05 8 0 0 μ m 29.82 1 .07 組胺酸 2 0 0 μ m 26.90 0.96 4 0 0 μ m 27.92 1 .00 丙胺酸 400pm 24.80 0.89 800pm 22.8 1 0.8 1 天冬醯胺酸 1 00pm 25.81 0.92 4 0 0pm 32.14 1.15 麩醯胺酸 1 00pm 29.35 1 .05 4 0 0 μ m 29.03 1 .04 甘胺酸 400pm 28.80 1.03 1 2 0 0 μ m 3 1.33 1.12 脯胺酸 4 0 0 μ m 30.20 1.08 8 00ym 30.06 1 .07 絲胺酸 2 0 0 μ m 28.77 1 .03 4 0 0 μ m 30.99 1.11 半胱胺酸 1 0 0 μ m 30.34 1.08 4 0 0 μ m 30.07 1.07 proteamin 1 2 X 1/100 3 1.55 1.13 k i d 〇 m i η 1/100 30.90 1.10 (16) (16)200404577 表2 對於血淸蛋白結合1 25I-IMP 之月 安基酸之取代效果 取代藥 試驗濃度 游離率（％ ) 變化率（倍） 對照溶液 — 23.96 N —乙醯基色胺酸 4 0 0pm 26.35 1.10 羥基苯甘胺酸 400ym 24.64 1.03 實施例2檢討結合於血淸蛋白質之各種藥物之取代 效果 使用一般治療樂之有效成份之d i a z e p a m (實驗上使 用14C標識體：14C-DZP)及propran〇l〇i (實驗上使用3H 標識體：3H-PPL)，以與實施例1相同的方法，檢討對於 結合於血淸蛋白質之各種藥物之色胺酸、天冬醯胺酸、N 一乙醯基色胺酸、羥基苯甘胺酸（試驗濃度：400 // M) 、pr〇teamin 12X 及 kidomin (試驗濃度：ι/loo)之 取代效果。 本實驗中，由正常成人男性之血液所分離之血淸球蛋 白濃度，以1/15M之磷酸緩衝溶液（ΡΗ = 7·4 )稀釋成爲 500#Μ。於此500//L之血淸溶液中，添加14C-DZP(3.7 X 1 〇']kBq/5 β L )或 3H-PPL ( 9.25父1〇-]]^9/5// L)，超 濾前後之試樣液量爲5 // L。將結果與實施例1之放射性 碘標識IMP的結果一起表示於表3及表4。 色胺酸顯示對於14C-DZP及放射性碘標識IMP爲有 效的取代藥。尤其對於14C-DZP之取代效果顯著。另外， -19- (17) (17)200404577 色胺酸衍生物之N -乙醯基色胺酸係對於MC-Dzp及放射 性碘標識IMP爲有效的取代藥，另一方面，對於3H-ppL 則顯示減低些許游離濃度之效果。天冬醯胺酸係對於！4 c _ DZP、3H-PPL及放射性碘標識imp爲有效的取代藥。另 外，甘胺酸衍生物之羥基苯甘胺酸對於“C_dzp及3H_ PPL顯示減低游離濃度之效果。相對於此，如於 proteamin 12X及kidomin之例（表3 )所表示，胺基酸混 合物之胺基酸輸液雖因其組成而取代效果的程度有所不 同，但任何化合物均顯示取代效果，顯示可利用作爲泛用 取代藥之可能性。 表3對於血淸蛋白結合藥物之胺基酸或胺基酸輸液之取代 效果 取代藥 14c-dzp 3h-ppl 123I-IMP 對照溶液游離率（％) 1.38 16.82 28.00 色胺酸 游離率（％ ) 4.05 17.64 35.47 變化率（倍） 2.93 1 .05 1.27 天冬醯胺酸 游離率（％ ) 1.67 19.53 32.14 變化率（倍） 1.2 1 1.16 1.15 protea min 12 X 游離率（％ ) 1.87 18.61 3 1.55 變化率（倍） 1.3 8 1.11 1.13 k i d o m i η 游離率（％ ) 3.3 8 18.83 3.0.90 變化率（倍） 2.44 1.12 1.10 -20- (18) 200404577 _對於血淸蛋白|^合藥物之胺基酸衍生物之取代效果 取代藥 14c-dzp 3h-ppl :Ί、从木 125ι-ιμρ 對照溶液游離率（％ ) 2.54 12.34 23.96 N-乙醯基色胺酸 游離率（％ ) 3.08 11.54 26.35 變化率（倍） 1.2 1 0.94 1.10 羥基苯甘胺酸 游離率（％ ) 2.39 10.68 24.64 變化率（倍） 0.94 0.87 1.03 實施例3檢討胺基酸輸液之體內（in vivo)取代效果 將日本猴（雌性：體重爲 4.5至 4.6kg )，以 pentobarbital進行腹腔內麻醉，由前腕靜脈投予mMMP (37MBq/lmL生理食鹽水）。2檢出器型之閃爍攝影機 (Scintillation Camera) (Picker 社製 Prism2000)，由剛 投予後至60分鐘，每隔1分鐘經時地撮影全身影像 (planer )。之後，接著以 3檢出器型之閃爍攝影機 (Scintillation Camera) (Picker 社製 Prism 3000)，攝影 腦部斷層影像。投予1 〇分鐘後，由另一側前腕抽血，以 超濾法測定1231-IMP之血中游離率。依據上述之步驟，得 到胺基酸輸液無負荷時之數據後，等待放射能的減退，而 得同一個體之胺基酸輸液負荷時之數據。作爲胺基酸輸 液，可使用pro te ami η 12X，於投予1231· IMP稍前，靜脈 注射5mL後，30分鐘之0.5/min之速度進行點滴而負 荷。其他則與無負荷時相同的步驟進行實驗。以上的實驗 -21 - (19) 2〇〇4〇4577 係實施於2隻猴子。 認爲如圖1所示之p r 〇 t e a m i η 1 2 X之負荷比相對 荷時，顯著地增加1 .4至1 ·6倍之腦部堆積。另外’ 彳$ 1〇分鐘之123Ι-ΙΜΡ之血中游離率亦明顯地增加相 負荷時之1.27至1.47倍。另一方面，比較protea min 之負荷時與無負荷時之腦部斷層影像時，認爲二者之 所在模式並無差異。由以上顯示，proteam in 12X 123I-IMP之血中游離率，雖因此提高123I-IMP之腦部 率，但不影響腦內所在模式。 【圖式簡單說明】 圖1係表不1 2 31 — IΜ P經時堆積於猴腦之曲線圖 中，實線係表示對照溶液，虛線係表示給予Prote 12X負荷者。 te倉 投予 對無 1 2X 腦內 提局 堆積 。圖 am i η -22-Iodine (123 ", 125 -iodine () 251) > 131-krypton (1311), 1 33-xenon (133Xe), 1 1 7m-tin ^) 1 7 r nSn), 153-krypton (1 5 3 S m), 186 銶 (186Re) \ 18 8 — chain (】 88Re) '2 0 1 — sharp (201' T1), 2 1 2 — bismuth (2 1 2Bi), 2 1 3 — bismuth (2) 3Bi ) And 211- attack (21 1 At). In this case, the compound contained in the radioactive diagnostic agent for in vivo use or the radioactive therapeutic agent for in vivo use, which is identified by the above-mentioned radionuclide chelating group or receptor ligand, is selected from, for example, diaminothiol or a derivative thereof. , Monoaminomonofluorenyldithiol or a derivative thereof, bisfluorenyldithiol or a derivative thereof, fluorenylethylfluorenylglycine, thioglycine, thioglycine or a derivative thereof, six Methacrylamino oxime or derivative thereof, methylene bis [bis (2-ethoxyethyl) phosphine] (tetrophosmin) or derivative thereof, 2,3-difluorenylsuccinic acid or derivative thereof , Methylene cysteine dimer or its derivative, methoxyisobutyl isonitrile or its derivative, polyamine derivative, pyridoxilidene-aminate derivative, methylene diphosphonate , Hydroxymethylene diphosphate derivatives, 0-methyl-co-phenylp entadecanoic acid or its derivatives, N-isopropylamphetamine, hippurate , Fluorenylguanidine, and pinane derivatives. In another aspect, the amino acid contained in the preparation of the present invention is selected from, for example, tryptophan, aspartic acid, glycine, serine, leucine, methionine, phenylalanine, and threonine. Acids, valine, proline, cysteine, and alanine or these salts and their derivatives or their salts. That is, the amino acids in the present invention also include amino acids in which substituents are introduced into amino acid molecules such as N-acetamidine tryptophan-8- (6) (6) 200404577 and hydroxyphenylglycine. Derivatives and these salts. In this case, for example, when it is desired to control the binding of an active ingredient to a plurality of binding sites of plasma proteins or human albumin, and when a synergistic effect is expected, a plurality of amino acids may be selected. In addition, when using a large number of amino acids, an amino acid infusion containing Proteamin 12X (registered trademark), kidin (registered trademark), or the like can be selected, and it can also be used as a preparation containing the same composition or component amount as these infusions. In order to control the binding of effective ingredients to plasma proteins, the use of a single or a plurality of amino acids can provide a preparation for controlling plasma protein binding itself, which has less influence on the organism, and is more suitable for practically administered preparations. The best form for carrying out the invention is to administer a preparation containing an active ingredient having a binding affinity for plasma proteins at the same time or before and after the administration of an amino acid preparation containing a high binding affinity for a common plasma protein. At that time, it was considered that a competitive substitution at the binding site 'increased the free concentration (substitution effect) of the active ingredient, and therefore,' higher pharmaceutical activity than when the preparation containing the active ingredient was administered alone was expected. Conversely, 'the free concentration of the active ingredient is reduced (the effect of reducing the free concentration) when the active ingredient is combined with the plasma protein due to the action of the amino acid-containing preparation,' the free concentration of the active ingredient in the blood is low over a long period of time. It can reduce the elimination rate (clearance), and can also expect to achieve a sustained effect. In the present invention, an active ingredient preparation containing a binding affinity with a related plasma protein is a preparation, a therapeutic agent, or a -9- (7) (7) 200404577 diagnostic agent as long as it meets the purpose of administration. On the other hand, in order to obtain the above-mentioned substitution effect, the amino acid contained in the amino acid-containing preparation of the present invention is selected from compounds having a competitive binding affinity for the same plasma protein as the active ingredient, preventing the active ingredient from binding to Plasma protein, which increases the free concentration of the active ingredient in the blood, or is the same as the binding site of the active ingredient to the plasma protein, and has a higher binding affinity. On the contrary, in order to obtain the effect of reducing the free concentration, the amino acid is bound to the plasma protein, and the amino acid that increases the plasma protein binding rate of the active ingredient is selected to achieve the effect. Regarding the dosage form, when the active ingredient and the amino acid are not decomposed due to the combination, and the two can be administered at the same time, the active ingredient and the amino acid may be mixed and supplied as a preparation filled in the same container. Mixed preparations can also be added with acid-base 値 regulators, inorganic salts for osmotic pressure adjustment, stabilizers, and other medically acceptable ingredients such as stabilizers. In addition, considering the composition and storage stability of the mixed preparation, suitable formulations such as liquid preparations and freeze-dried preparations can also be processed. In addition, the preparation containing the active ingredient and the preparation containing the amino acid may be supplied as a reagent group filled in different containers. Similarly, mixed preparations can also be added to each preparation with medically acceptable ingredients such as stabilizers. Considering the method of administration and stability of each preparation, it can also be processed into liquid or freeze-dried agents. The most suitable formulation. When the ingredients are used as the reagent sets of such separate containers, the preparation containing the active ingredient and the preparation containing the amino acid may be separately administered, or they may be mixed and administered at the same time. In particular, if a mixture containing an active ingredient and an amino acid preparation is expected to decompose when stored for a long time -10- (8) (8) 200404577, etc., when another route of administration must be selected, or when the period of administration must be segregated, The set of reagents filled in different containers is effective. As the reagent group, a form containing the active ingredient preparation and the amino acid-containing preparation can be filled in different sections of a single container and mixed in use. For example, as a container of a reagent group, a plastic container having a plurality of sections connected by a connector, each section is filled with a dissolving agent, a diluent, or a medicine containing an active ingredient. When in use, a section filled with a dissolving agent or a diluent is used. Those who fill the dissolving agent or diluent through the connector into the section containing the active ingredient medicine to prepare the final dosage form. When using this type of valley, 'for example, in each section of a 3-zone type', it is filled with a powder preparation containing an active ingredient, a powder preparation containing an amino acid, and a dissolving agent, so that the dissolving agent flows into the powder preparation containing the amino acid. Then, the powder preparation containing the active ingredient is poured into the final liquid preparation, or the powder or liquid preparation containing the active ingredient and the liquid containing the amino acid are filled in each section of the 2 section type. Formulation 'The liquid formulation containing an amino acid flows into a powder or a liquid formulation containing an active ingredient, and is prepared into a final administration liquid formulation, etc., and can be made into various reagent groups. In addition, in other types, there are syringe-type containers having a plurality of sections for accommodating components. With such containers, a reagent set having excellent convenience can be provided. -Plasma proteins that are generally bound as active ingredients are human blood cell white blood cells (HSA), α] -oxidized glycoprotein (AGP), r-globulin, and lipoproteins, and most are bound to HSA or AGP. Select amino acid, for example, when the active ingredient mainly has binding affinity for HAS, it is appropriate to select from -11-(9) (9) 200404577 for HAS having binding affinity. When the active ingredient has binding affinity for AGP It is preferably selected from those bound to AGP. In addition, when the active ingredient has binding affinity for a plurality of plasma proteins, or binding affinity for different binding sites in a single protein, etc., it may be effective to use a large number of amino acids. The administration period of the amino acid-containing agent is at the same time as or after the effective ingredient is administered, and can be appropriately selected to achieve the effect consistent with the purpose of the effective ingredient administration. The route of administration of the preparation can be appropriately selected from the group consisting of intravenous, intraarterial, subcutaneous, lymphatic, and oral. It is a preparation containing an active ingredient, an in vivo radioactive diagnostic drug or an in vivo radioactive therapeutic drug with binding affinity to plasma proteins, and a compound such as a chelating group or a receptor ligand identified by a radionuclide, for example, Mercapto acetyl glycylglycylglycine (M AG3) or its derivative, hexamethylpropyleneamine oxime (HMPAO) or its derivative, methylene Bis [bis (2-ethoxyethyl) phosphine] (tetrofosmin) or its derivative, 2,3-dimercaptosuccinic acid (DMSA) or its derivative, N, N'-methylene -L-cysteine diethyl ether and other methylene cysteine dimer (ECD) derivatives, methoxy isobutyl isonitrile (MIBI) derivatives , Polyamine derivatives such as diethylenetriamine pentaacetic acid (DTPA), pyridoxilidee isoleucine and other pyridoxilidenaminate derivatives-12- (10) (10) 200404577 biology, other methylene diamines (Methylene diphosphonate? MDP) and hydroxymethylene diphosphate (HMDP) derivatives, etc. chelating groups that form coordination compounds with radioactive metals, etc., or labeled with iodine β-methyl-p-benzene Pentadecanoic acid (々-11 ^ 11 丫 1- 卩 -iodophenylpentadecanoicacid (BMIPP)), N-isopropyl p-amphetamine (IMP), orthoiodohippurate (OIH) , 3-guanidinoguanidine (3 -1 odobenzy 1 Guanidine, MIBG), N- (3-fluoropropyl) methoxycarbonate · 3/3-(4-iodo: phenyl) Huanghuayuan (N- (3- fluoropropyl) -2 β-carbomethoxy-3 cold- (4_iodophenyl) tropane (FP.CIT) or N-methyl-methoxycarbonate-3yS- (4-iodophenyl) pinene (CIT) Alkane derivatives and the like. Examples of the radionuclide include 1 1-carbon (Mc), 15-oxygen (150), 18-fluoro (18f) '32-phosphorus (32P), 59-iron (59 Fe), 67- Copper (6 7C U), 67--Gallium (67Ga), 81m-氪 (81 mKr), 81 (8 1 Rb), 89 丨 _ 缌 (8 9Sr), 90-Yttrium ^ 90 Y), 99m-- !!荅 (99) τ lTc) > 11 1--Indium (ηιΙη), 123 — Iodine (123I), 1 25-: (125I) > 1 3 1 Iodine (131I) > 133 — Gas (133Xe) > 1 17m — tin (117mSn) 153- 钐 (1 53Sm), 1 86 _ 銶 (18 6 Re), 18 8 — 銶 (188Re) '201-铊 (20) Ding 1), 2 12 bismuth ( 21: lBi), 21 3 bismuth (2 13Bi), 211 — government (211At), etc. For diagnosis, 18 fluoro (18f), 9 9m-鐯 ^ 9 9 mTc) N 6 7--gallium (67Ga) '111- Indium (11) In), 123 Iso (123, I) and 13 1 Iodine (13) I), etc. 0 -13- (11) (11) 200404577 contains single or multiple amine groups For acid preparations, a single or a plurality of members selected from, for example, tryptophan, aspartic acid, glycine, serine, leucine, methionine, phenylalanine, threonine, valine, Proline, cysteine, and alanine or their salts and their derivatives or their amino acids. In addition, when using a large number of amino acids, an amino acid infusion including proteamin 12X (registered trademark) and kidomin (registered trademark) can also be selected, and it can also be used as a preparation containing the same composition or component amount as these infusions. Since the preparation of the present invention is an infusion solution containing one or more amino acids, or an amino acid-containing infusion solution, it has little effect on the organism itself, and can provide a more suitable preparation for practical administration. A preparation containing an amino acid that increases the free concentration of blood in the active ingredient, that is, a preparation that produces a substitution effect, for example, a preparation containing a substance selected from tryptophan and its derivatives, aspartic acid, glycine, Preparations of amino acids such as serine, leucine, methionine, phenylalanine, threonine, valine, proline, and cysteine or their salts. Similarly, as a preparation that produces a substitution effect, for example, an amino acid infusion solution selected from the group consisting of proteamin 12X (registered trademark) and kidomin (registered trademark) may be used, or a plurality of amino acids having the same composition or component amount as the same Of the preparation. In particular, a formulation comprising one or more amino acids selected from the group consisting of tryptophan, aspartic acid, glycine, serine, phenylalanine, and N-acetamidotryptophan or a salt thereof, and comprising An amino acid infusion solution selected from proteamin 12X (registered trademark) and kid omi (registered trademark), or an amino acid preparation having the same composition or component amount as the amino acid infusion solution is suitable. In contrast, preparations that increase the combination of active ingredients with plasma proteins and reduce free concentration, that is, amino acid preparations containing the effect of reducing free concentration by producing -14- (12) (12) 200404577, containing one or more Formulations of amino acids selected from alanine and hydroxyphenylglycine or a salt thereof are suitable. [Embodiments] Examples The present invention will be described in more detail with reference to examples, but the present invention is not limited to these examples. Example 1 Review of substitution effect of labeled radioactive iodine IMP bound to plasma proteins Using human blood cymbals, review of 123I-IMP (N_isopropyl-iodoamphetamine labeled with 1231) or amines bound to blood plasma proteins Substituting effect of amino acid or amino acid infusion (substitute medicine) The globulin concentration of commercially available human pool serum (Lot · No. 13768 by Cosmobio) was measured in advance, and buffered with 1 / 15M phosphate The solution (PG = 7.4) diluted globulin to a concentration of 500 // M. To this 500 // L blood limulus solution, 20 // L of the substitution medicine (amino acid or amino acid infusion) shown in Table 1 and Table 2 was added. At this time, the amino acid was dissolved in physiological saline and added to the blood sacral solution so as to have the test concentrations shown in Table i and Table 2. After that, 20 / L (approximately 220kBq) of 123I-IMP or 125I-IMP was added as a test solution. As a control solution, the above-mentioned blood limulus solution was used, and 20 / L of physiological saline was added instead of the substitute medicine. From the control solution and each test solution, take 20 // L as the -15- (13) (13) 200404577 sample before ultrafiltration. Secondly, from the control solution and each test solution, take 4 5 0 // L in an ultrafilter (UltracentIO manufactured by TOSO), centrifuge in a centrifugal separator (RLX — 135 manufactured by TOMY) at 3000 rpm for 10 minutes, and perform ultrafiltration. . After the centrifugation operation, 20 / L of each filtrate was taken as the sample after ultrafiltration. The radiant energy (cpm) of each sample before and after ultrafiltration was measured with an auto well gamma counter (ARC-380 manufactured by ALOKA), and the free ratio (%) of each test solution and the addition of amino acid or amine were calculated according to the following formula. Change rate of free rate of base acid infusion. Free rate (%) = {radiation energy after ultrafiltration (cpm) / radiation energy before ultrafiltration (C pm)} X 1 〇00 Change rate (times) = free rate of test solution (%) / control solution The free ratio (%) is shown in Tables 1 and 2. In addition, the free ratio of the control solution and each test concentration is an average of n = 3. When tryptophan, aspartic acid, glycine and serine were added, the 123I-IMP free rate (2 8.00%) of the control solution increased with the concentration of the amino acid added. It was found that especially tryptophan and aspartic acid increased significantly. In addition, when leucine, methionine, phenylalanine, threonine, valine, proline, cysteine, p 1 · 〇teami η 1 2 X, and kid 0 mi η were added, it was observed I23i-iMP free rate exceeding 3 0.00%. On the other hand, when alanine was added, the 123I-IMP free rate was reduced to 24.80%, and the effect of reducing the free concentration was found. -16- (14) 200404577 In addition, when N-acetamidotryptophan, an amino acid derivative, is added, the free rate of 125I-IMP is increased. When hydroxyphenylglycine is added, the free rate of 125I-IMP increases only slightly, which is not as good as that of N-acetamidotryptophan. -17- (15) (15) 200404577 Table 1 Substitute effect of amino acid or amino acid infusion for hemoglobin binding to 123I-IMP Replacement drug test Concentration free rate (%) Change rate (times) Control solution — 28.00 Monoisoleucine 2.0 0 μm 28.19 1.01 400pm 27.96 1 .00 Leucine 4 00pm 3 1.20 1.11 Lysine 4 00 μm 28.92 1. .03 Methionine 20 0 μm 30.60 1. 09 4 0 0 μm 30.26 1.08 phenylalanine 2 0 0 μm 30.05 1.07 400pm 3 1.07 1.11 threonine 4 0 0 μm 30.17 1.08 tryptophan 1 100 μm 3 1.33 1.12 400 μm 35.47 1.27 valine 400pm 29.40 1.05 8 0 0 μm 30.79 1.10 Arginine 20 0 μm 27.27 0.97 400ym 29.40 1.05 8 0 0 μm 29.82 1.07 Histamine 2 0 0 μm 26.90 0.96 4 0 0 μm 27.92 1. 00 Alanine 400pm 24.80 0.89 800pm 22.8 1 0.8 1 Aspartic acid 1 00pm 25.81 0.92 4 0 0pm 32.14 1.15 Glutamic acid 1 00pm 29.35 1 .05 4 0 0 μ m 29.03 1 .04 Glycine 400pm 28.80 1.03 1 2 0 0 μ m 3 1.33 1.12 Proline 4 0 0 μ m 30.20 1.08 8 00ym 30.06 1 .07 Serine 2 0 0 μ m 28.77 1 .03 4 0 0 μm 30.99 1.11 Cysteine 1 0 0 μm 30.34 1.08 4 0 0 μm 30.07 1.07 proteamin 1 2 X 1/100 3 1.55 1.13 kid 〇mi η 1/100 30.90 1.10 (16) ( 16) 200404577 Table 2 Substitute effect of hemoglobin binding to 1 25I-IMP for the replacement effect of luenic acid in the substitution drug Test concentration free rate (%) Change rate (times) Control solution — 23.96 N —acetamidine tryptophan 4 0 0pm 26.35 1.10 Hydroxyphenylglycylic acid 400ym 24.64 1.03 Example 2 reviews the substitution effect of various drugs combined with blood sacral protein using diazepam (the 14C marker: 14C-DZP) and propran〇l 〇i (3H marker was used experimentally: 3H-PPL). Tryptophan, aspartic acid, and N-acetamidine were examined for various drugs bound to blood glutenin protein in the same manner as in Example 1. Substitute effect of amine acid, hydroxyphenylglycine (test concentration: 400 // M), prOteamin 12X and kidomin (test concentration: ι / loo). In this experiment, the concentration of hemoglobin protein isolated from the blood of a normal adult male was diluted to 500 # M with a 1 / 15M phosphate buffer solution (P = 7.4). To this blood solution of 500 // L, add 14C-DZP (3.7 X 1 〇 '] kBq / 5 β L) or 3H-PPL (9.25 parent 1〇-]] ^ 9/5 // L), The sample volume before and after ultrafiltration is 5 // L. The results are shown in Tables 3 and 4 together with the results of the radioactive iodine-labeled IMP of Example 1. Tryptophan has been shown to be an effective substitute for 14C-DZP and radioactive iodine-labeled IMP. Especially for 14C-DZP substitution effect is significant. In addition, -19- (17) (17) 200404577 N-acetamidotryptophan is an effective substitute for MC-Dzp and radioactive iodine-labeled IMP, and for 3H-ppL It shows the effect of reducing the free concentration slightly. Aspartic acid is for! 4 c _ DZP, 3H-PPL and radioactive iodine label imp are effective substitutes. In addition, hydroxyphenylglycine of a glycine derivative shows an effect of reducing the free concentration of "C_dzp and 3H_PPL. In contrast, as shown in the examples of proteamin 12X and kidomin (Table 3), Although the degree of substitution effect of amino acid infusion varies depending on its composition, any compound shows a substitution effect and shows the possibility of being used as a general-purpose substitution drug. Table 3 For amino acid or Replacement effect of amino acid infusion 14c-dzp 3h-ppl 123I-IMP Control solution free rate (%) 1.38 16.82 28.00 Tryptophan free rate (%) 4.05 17.64 35.47 Change rate (fold) 2.93 1.05 1.27 days Aspartic acid free rate (%) 1.67 19.53 32.14 Change rate (fold) 1.2 1 1.16 1.15 protea min 12 X Free rate (%) 1.87 18.61 3 1.55 Change rate (fold) 1.3 8 1.11 1.13 kidomi η free rate (%) 3.3 8 18.83 3.0.90 Change rate (times) 2.44 1.12 1.10 -20- (18) 200404577 _ For substitution effect of amino acid derivatives of hemagglutinin | ^ drugs Substitute drugs 14c-dzp 3h-ppl: Ί, Free rate of wood 125ι-ιμρ control solution (%) 2.54 12.34 23.96 Free rate of N-acetamidotryptophan (%) 3.08 11.54 26.35 Change rate (fold) 1.2 1 0.94 1.10 Free rate of hydroxyphenylglycinate (%) 2.39 10.68 24.64 Change rate (times) 0.94 0.87 1.03 Example 3 Review of in vivo substitution effect of amino acid infusion Japanese monkeys (females: body weight: 4.5 to 4.6 kg) were intraperitoneally anesthetized with pentobarbital and administered from the anterior wrist vein MMMP (37MBq / lmL physiological saline). 2 detector type Scintillation Camera (Prism2000 manufactured by Picker) was taken from the moment of administration to 60 minutes, and the whole body image was taken every 1 minute (planer). Then, a 3 detector type Scintillation Camera (Prism 3000 manufactured by Picker) was used to take a tomographic image of the brain. After 10 minutes of administration, blood was drawn from the other side of the forearm for ultrafiltration The free rate in blood of 1231-IMP was determined by the method. According to the above steps, after obtaining the data of amino acid infusion without load, wait for the decrease of radioactive energy, and obtain the data of amino acid infusion load of the same individual. As the amino acid infusion, pro te ami η 12X can be used, and the load can be dripped at a rate of 0.5 / min for 30 minutes after intravenous injection of 5 mL just before administration of 1231 · IMP. Other experiments were performed in the same procedure as when there was no load. The above experiments -21-(19) 20044577 were performed on 2 monkeys. It is considered that when the load ratio of p r 〇 t e a m i η 1 2 X shown in FIG. 1 is relatively increased, brain accumulation significantly increased by 1.4 to 1.6 times. In addition, the free rate of 123Ι-ΙΜΡ in the blood of 10 minutes was also significantly increased by 1.27 to 1.47 times under the phase load. On the other hand, when comparing the brain tomography images of protea min with no load, there is no difference between the two modes. From the above, the free rate of blood in proteam in 12X 123I-IMP, although it increases the brain rate of 123I-IMP, does not affect the pattern in the brain. [Brief description of the figure] Figure 1 shows the graph of 1 2 31—IMP stacked on the monkey brain over time. The solid line indicates the control solution, and the dashed line indicates those who are given Prote 12X load. te warehouse investment for no 1 2x brain brain accumulation. Figure am i η -22-