JPH03128321A - Artificial oxygen-carrier - Google Patents
Artificial oxygen-carrierInfo
- Publication number
- JPH03128321A JPH03128321A JP14888789A JP14888789A JPH03128321A JP H03128321 A JPH03128321 A JP H03128321A JP 14888789 A JP14888789 A JP 14888789A JP 14888789 A JP14888789 A JP 14888789A JP H03128321 A JPH03128321 A JP H03128321A
- Authority
- JP
- Japan
- Prior art keywords
- oxygen
- artificial
- iron
- fatty acid
- carrier
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 239000001301 oxygen Substances 0.000 claims abstract description 68
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 68
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims abstract description 65
- JQRLYSGCPHSLJI-UHFFFAOYSA-N [Fe].N1C(C=C2N=C(C=C3NC(=C4)C=C3)C=C2)=CC=C1C=C1C=CC4=N1 Chemical compound [Fe].N1C(C=C2N=C(C=C3NC(=C4)C=C3)C=C2)=CC=C1C=C1C=CC4=N1 JQRLYSGCPHSLJI-UHFFFAOYSA-N 0.000 claims abstract description 34
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 claims abstract description 20
- 235000014113 dietary fatty acids Nutrition 0.000 claims abstract description 19
- 239000000194 fatty acid Substances 0.000 claims abstract description 19
- 229930195729 fatty acid Natural products 0.000 claims abstract description 19
- 150000004665 fatty acids Chemical class 0.000 claims abstract description 18
- 150000002460 imidazoles Chemical class 0.000 claims abstract description 9
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 4
- 125000004432 carbon atom Chemical group C* 0.000 claims description 3
- 239000002473 artificial blood Substances 0.000 abstract description 8
- 230000002209 hydrophobic effect Effects 0.000 abstract description 4
- 239000007788 liquid Substances 0.000 abstract description 3
- 210000004072 lung Anatomy 0.000 abstract description 3
- 239000000082 organ preservation Substances 0.000 abstract description 2
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 13
- 150000003278 haem Chemical class 0.000 description 9
- 239000002245 particle Substances 0.000 description 9
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 8
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 7
- 210000004369 blood Anatomy 0.000 description 7
- 239000008280 blood Substances 0.000 description 7
- 229910052742 iron Inorganic materials 0.000 description 7
- 238000000034 method Methods 0.000 description 7
- 108010054147 Hemoglobins Proteins 0.000 description 6
- 102000001554 Hemoglobins Human genes 0.000 description 6
- -1 porphyrin compound Chemical class 0.000 description 6
- 239000004094 surface-active agent Substances 0.000 description 6
- 239000000839 emulsion Substances 0.000 description 5
- 238000005259 measurement Methods 0.000 description 5
- 239000002202 Polyethylene glycol Substances 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- 229960005070 ascorbic acid Drugs 0.000 description 4
- 235000010323 ascorbic acid Nutrition 0.000 description 4
- 239000011668 ascorbic acid Substances 0.000 description 4
- 238000003795 desorption Methods 0.000 description 4
- 239000006185 dispersion Substances 0.000 description 4
- 210000003743 erythrocyte Anatomy 0.000 description 4
- 150000002632 lipids Chemical class 0.000 description 4
- 150000003904 phospholipids Chemical class 0.000 description 4
- 239000002504 physiological saline solution Substances 0.000 description 4
- 229920001223 polyethylene glycol Polymers 0.000 description 4
- 229920001451 polypropylene glycol Polymers 0.000 description 4
- 230000002441 reversible effect Effects 0.000 description 4
- 238000001179 sorption measurement Methods 0.000 description 4
- MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 239000012736 aqueous medium Substances 0.000 description 3
- 229920001400 block copolymer Polymers 0.000 description 3
- 230000008859 change Effects 0.000 description 3
- 230000006866 deterioration Effects 0.000 description 3
- 229910001882 dioxygen Inorganic materials 0.000 description 3
- GRWZHXKQBITJKP-UHFFFAOYSA-L dithionite(2-) Chemical compound [O-]S(=O)S([O-])=O GRWZHXKQBITJKP-UHFFFAOYSA-L 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- JQWAHKMIYCERGA-UHFFFAOYSA-N (2-nonanoyloxy-3-octadeca-9,12-dienoyloxypropoxy)-[2-(trimethylazaniumyl)ethyl]phosphinate Chemical compound CCCCCCCCC(=O)OC(COP([O-])(=O)CC[N+](C)(C)C)COC(=O)CCCCCCCC=CCC=CCCCCC JQWAHKMIYCERGA-UHFFFAOYSA-N 0.000 description 2
- 241000283973 Oryctolagus cuniculus Species 0.000 description 2
- 238000000862 absorption spectrum Methods 0.000 description 2
- 210000001124 body fluid Anatomy 0.000 description 2
- 239000010839 body fluid Substances 0.000 description 2
- 239000000969 carrier Substances 0.000 description 2
- 239000003638 chemical reducing agent Substances 0.000 description 2
- 238000002296 dynamic light scattering Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000004945 emulsification Methods 0.000 description 2
- 239000012530 fluid Substances 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 230000002427 irreversible effect Effects 0.000 description 2
- 150000004667 medium chain fatty acids Chemical class 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 238000002336 sorption--desorption measurement Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- JMTFLSQHQSFNTE-UHFFFAOYSA-N 1-dodecylimidazole Chemical compound CCCCCCCCCCCCN1C=CN=C1 JMTFLSQHQSFNTE-UHFFFAOYSA-N 0.000 description 1
- NPZDCTUDQYGYQD-UHFFFAOYSA-N 1-tritylimidazole Chemical compound C1=NC=CN1C(C=1C=CC=CC=1)(C=1C=CC=CC=1)C1=CC=CC=C1 NPZDCTUDQYGYQD-UHFFFAOYSA-N 0.000 description 1
- LXBGSDVWAMZHDD-UHFFFAOYSA-N 2-methyl-1h-imidazole Chemical compound CC1=NC=CN1 LXBGSDVWAMZHDD-UHFFFAOYSA-N 0.000 description 1
- VTLYFUHAOXGGBS-UHFFFAOYSA-N Fe3+ Chemical compound [Fe+3] VTLYFUHAOXGGBS-UHFFFAOYSA-N 0.000 description 1
- 108010064719 Oxyhemoglobins Proteins 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- 239000004743 Polypropylene Substances 0.000 description 1
- OUUQCZGPVNCOIJ-UHFFFAOYSA-M Superoxide Chemical compound [O-][O] OUUQCZGPVNCOIJ-UHFFFAOYSA-M 0.000 description 1
- 241000700605 Viruses Species 0.000 description 1
- 230000005856 abnormality Effects 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 150000004982 aromatic amines Chemical group 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 229910001873 dinitrogen Inorganic materials 0.000 description 1
- 238000010494 dissociation reaction Methods 0.000 description 1
- 230000005593 dissociations Effects 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- NBVXSUQYWXRMNV-UHFFFAOYSA-N fluoromethane Chemical compound FC NBVXSUQYWXRMNV-UHFFFAOYSA-N 0.000 description 1
- 238000005227 gel permeation chromatography Methods 0.000 description 1
- 125000003827 glycol group Chemical group 0.000 description 1
- 208000006750 hematuria Diseases 0.000 description 1
- 229940079865 intestinal antiinfectives imidazole derivative Drugs 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 230000001678 irradiating effect Effects 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 239000002960 lipid emulsion Substances 0.000 description 1
- 239000002502 liposome Substances 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- XLSZMDLNRCVEIJ-UHFFFAOYSA-N methylimidazole Natural products CC1=CNC=N1 XLSZMDLNRCVEIJ-UHFFFAOYSA-N 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 230000004962 physiological condition Effects 0.000 description 1
- 150000004032 porphyrins Chemical class 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000004626 scanning electron microscopy Methods 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- TXEYQDLBPFQVAA-UHFFFAOYSA-N tetrafluoromethane Chemical compound FC(F)(F)F TXEYQDLBPFQVAA-UHFFFAOYSA-N 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- LADGBHLMCUINGV-UHFFFAOYSA-N tricaprin Chemical compound CCCCCCCCCC(=O)OCC(OC(=O)CCCCCCCCC)COC(=O)CCCCCCCCC LADGBHLMCUINGV-UHFFFAOYSA-N 0.000 description 1
- 229940093633 tricaprin Drugs 0.000 description 1
- 229940093609 tricaprylin Drugs 0.000 description 1
- VLPFTAMPNXLGLX-UHFFFAOYSA-N trioctanoin Chemical compound CCCCCCCC(=O)OCC(OC(=O)CCCCCCC)COC(=O)CCCCCCC VLPFTAMPNXLGLX-UHFFFAOYSA-N 0.000 description 1
- 238000001429 visible spectrum Methods 0.000 description 1
Abstract
Description
【発明の詳細な説明】
（産業上の利用分野〕
本発明は、人工血液や臓器保存液、人工肺などの酸素供
給液として使用される酸素運搬体に関し、さらに詳しく
は、酸素を迅速かつ可逆的に吸脱着できる特性を有する
新規な人工酸素運搬体に関する。Detailed Description of the Invention (Industrial Application Field) The present invention relates to an oxygen carrier used as an oxygen supplying fluid for artificial blood, organ preservation fluid, oxygenator lungs, etc. This invention relates to a novel artificial oxygen carrier that has the property of being able to adsorb and desorb.
人工血液等として使用される酸素運搬体としては、（１
）フルオロカーボン乳剤、（２）ヘモグロビン修飾物、
（３）鉄ポルフィリン錯体を利用したもの、が開発研究
されている。Oxygen carriers used as artificial blood, etc. include (1
) fluorocarbon emulsion, (2) hemoglobin modified product,
(3) Products using iron porphyrin complexes are being developed and researched.
（１）は酸素を物理的に溶解するパーフルオロカーボン
を界面活性剤を用いて生理食塩水に分散した液であるが
酸素運搬量は高くない。また、パーフルオロカーボンの
生体毒性が完全には解消されてはいないため、現在人工
血液としては利用されていない。（２）はヒトヘモグロ
ビンを化学修飾し、またはマイクロカプセル化すること
によって、半人工の酸素運搬体を得ようとするものであ
るが、ヘモグロビンの変質などにともない、酸素運搬量
は低くとどまり、また原料とするヒトヘモグロビンの精
製技術も確立していない。（３）は本発明者らが提案し
たものであり、全合成の鉄ポルフィリン錯体が一定条件
で酸素を迅速かつ可逆的に吸脱着できる性質を利用して
リン脂質リポソームに鉄ポルフィリン錯体を包埋させ、
人工酸素運搬体としたものである（特公昭５９−２５７
６７号公報参照）。(1) is a liquid in which perfluorocarbon, which physically dissolves oxygen, is dispersed in physiological saline using a surfactant, but the amount of oxygen carried is not high. Furthermore, since the biotoxicity of perfluorocarbons has not been completely eliminated, they are not currently used in artificial blood. (2) attempts to obtain a semi-artificial oxygen carrier by chemically modifying or microencapsulating human hemoglobin, but due to deterioration of hemoglobin, the amount of oxygen carried remains low, and The technology for purifying human hemoglobin, the raw material, has not yet been established. (3) was proposed by the present inventors, and utilizes the property of a fully synthesized iron porphyrin complex to adsorb and desorb oxygen rapidly and reversibly under certain conditions to embed the iron porphyrin complex in phospholipid liposomes. let me,
It was made into an artificial oxygen carrier (Special Publication Publication No. 59-257
(See Publication No. 67).
（３）の人工酸素運搬体は全合成系であり、しかも天然
ヘモグロビンの活性中心である鉄ポルフィリン錯体によ
る酸素吸脱着であるため、■酸素吸脱着が迅速、■酸素
親和性が人血に匹敵、■色調が血液と同しく赤色、■長
期保存可能、■大量合成可能等の特徴を有している。(3) The artificial oxygen carrier is a fully synthetic system, and oxygen adsorption and desorption is performed by iron porphyrin complexes, which are the active centers of natural hemoglobin. Therefore, ■Oxygen adsorption and desorption is rapid, and ■Oxygen affinity is comparable to that of human blood. It has the following characteristics: 1) It has a red color similar to blood, 2) It can be stored for a long time, and 2) It can be synthesized in large quantities.
〔発明が解決しようとする課題］
前記（３）の人工酸素運搬体は次世代の人工血液と目さ
れているが、次の様な点で未だ問題がある。[Problems to be Solved by the Invention] The artificial oxygen carrier described in (3) above is considered to be the next generation of artificial blood, but there are still problems in the following points.
（１）鉄ポルフィリン錯体の溶解濃度が１０ｍｍｏ ｌ
／ Ｉ程度であり、酸素運搬量が２０ｎ＋ ｌ酸素／
１００ｍ１媒体にとどまる。（２）大量のリン脂質を利
用するため、その毒性が一部未解決である。（３）両親
媒性の鉄ポルフィリン錯体が必要であるが、この様な鉄
ポルフィリン錯体の合成は煩雑である。(1) Dissolved concentration of iron porphyrin complex is 10 mmol
/I, and the amount of oxygen carried is 20n+l oxygen/
Stay in 100ml medium. (2) Since a large amount of phospholipid is used, its toxicity is partially unresolved. (3) An amphipathic iron porphyrin complex is required, but the synthesis of such an iron porphyrin complex is complicated.
このため、上記■〜■の利点を保持したまま、より簡略
な鉄ポルフイリン錯体系で人工酸素運搬体を組み立てる
ことができれば、その意義は大きい。Therefore, it would be of great significance if an artificial oxygen carrier could be assembled using a simpler iron porphyrin complex system while retaining the above-mentioned advantages.
しかし、鉄ポルフィリン錯体に酸素の可逆的な吸脱着能
を発現させるためには、（１）ポルフィリン化合物の面
上に適当な置換基を設け、ポルフィリン鉄の不可逆劣化
を抑える、（２）鉄ポルフィリン錯体を疎水的環境に置
く、（３）ポルフィリン鉄をイミダゾールなどの含窒素
芳香族と配位結合させ、酸素結合の親和力を発揮しうる
様にすることが必要である。他方、鉄ポルフィリン錯体
を生体内に投与するためには、（１）鉄ポルフィリン錯
体の毒性を徐放効果などによって抑える、（２）鉄ポル
フィリン錯体を生理食塩水など生理条件を満足した水媒
体中に安定に分散させる、（３）分散体の粒径を十分小
さくして毛細血管を通過できる様にすると共に、生体内
で速やかには貧食、消去されない様にする、等が必要で
ある。このように鉄ポルフィリン錯体を人工酸素運搬体
に適用するためには多くの問題が解決できないままであ
る。However, in order to make the iron porphyrin complex exhibit the ability to reversibly adsorb and desorb oxygen, it is necessary to (1) provide an appropriate substituent on the surface of the porphyrin compound to suppress irreversible deterioration of the iron porphyrin, and (2) to suppress the irreversible deterioration of the iron porphyrin. It is necessary to place the complex in a hydrophobic environment and (3) coordinate the porphyrin iron with a nitrogen-containing aromatic group such as imidazole so that the affinity of the oxygen bond can be exerted. On the other hand, in order to administer the iron porphyrin complex into a living body, (1) the toxicity of the iron porphyrin complex is suppressed by a sustained release effect, and (2) the iron porphyrin complex is placed in an aqueous medium that satisfies physiological conditions, such as physiological saline. (3) It is necessary to make the particle size of the dispersion sufficiently small so that it can pass through capillaries, and to prevent it from being rapidly phagocytized and eliminated in vivo. Thus, many problems remain unsolved in applying iron porphyrin complexes to artificial oxygen carriers.
本発明者は従来より酸素を可逆的に吸脱着できる鉄ポル
フィリン錯体の調製と、これらの物質の生体内挙動の解
明を継続的におこなってきた。The present inventors have continued to prepare iron porphyrin complexes that can reversibly adsorb and desorb oxygen, and to elucidate the in vivo behavior of these substances.
本発明はその結果到達したものであり、鉄ポルフィリン
錯体と脂肪酸トリグリセリドとからなる人工酸素運搬体
に係るものである。The present invention was achieved as a result of these efforts, and relates to an artificial oxygen carrier comprising an iron porphyrin complex and fatty acid triglyceride.
ここで鉄ポルフィリン錯体としては、ポルフィリン鉄の
不可逆劣化を抑える上で、メソ−テトラ（α、α、α、
α−０−ピバラミドフェニル）ポルフィナト鉄（Ｉｆ）
が望ましい。Here, the iron porphyrin complex is meso-tetra (α, α, α,
α-0-pivalamidophenyl)porfinatoiron(If)
is desirable.
更にこの鉄ポルフィリン錯体には、酸素親和力向上の為
にイミダゾール誘導体を配位させることができる。鉄ポ
ルフィリン錯体に配位させるイミダゾール誘導体として
は、鉄ポルフィリン錯体およびイミダゾール誘導体自身
の水相への漏れ出しを防ぐため、疎水性のイミダゾール
誘導体が望ましい。この疎水性のイミダゾール誘導体と
しては、１−ラウリルイミダゾール、ｌ−ラウリル−２
メチルイミダゾールなどの長鎖アルキルイミダゾール、
及び１−トリチルイミダゾール、１−トリチル−２−メ
チルイ【ダゾール等が例示できる。Furthermore, an imidazole derivative can be coordinated to this iron porphyrin complex in order to improve the oxygen affinity. The imidazole derivative to be coordinated with the iron porphyrin complex is preferably a hydrophobic imidazole derivative in order to prevent the iron porphyrin complex and the imidazole derivative itself from leaking into the aqueous phase. Examples of the hydrophobic imidazole derivatives include 1-lauryl imidazole, l-lauryl-2
long-chain alkylimidazoles, such as methylimidazole;
Examples include 1-tritylimidazole and 1-trityl-2-methyl-[dazole].
脂肪酸トリグリセリドは、鉄ポルフィリン錯体を水媒体
中で破水雰囲気に保つための担体である。Fatty acid triglyceride is a carrier for maintaining the iron porphyrin complex in a water-broken atmosphere in an aqueous medium.
この脂肪酸トリグリセリドとしては、水中での分散安定
性の良さや鉄ポルフィリン錯体の溶解能力の良さの点で
、アルキル基炭素数６〜１０の脂肪酸トリグリセリドが
望ましい。As the fatty acid triglyceride, a fatty acid triglyceride having an alkyl group having 6 to 10 carbon atoms is preferable in terms of good dispersion stability in water and good ability to dissolve iron porphyrin complexes.
本発明の人工酸素運搬体の具体的調製に当たっては、脂
肪酸トリグリセリドに鉄ポルフィリン錯体を溶解した後
、この鉄ポルフィリン錯体を溶存させた脂肪酸トリグリ
セリドを、リン脂質、ポリオキシエチレン、ポリプロピ
レンとポリエチレングリコールとのブロック共重合体等
の界面活性剤の存在下に超音波乳化法やＤ相乳化法で水
中に分散させれば良い。In the specific preparation of the artificial oxygen carrier of the present invention, an iron porphyrin complex is dissolved in fatty acid triglyceride, and then the fatty acid triglyceride in which the iron porphyrin complex is dissolved is mixed with phospholipids, polyoxyethylene, polypropylene, and polyethylene glycol. It may be dispersed in water by ultrasonic emulsification or D-phase emulsification in the presence of a surfactant such as a block copolymer.
最終の分散液中の脂肪酸トリグリセリドの含量は５〜３
０ｗｔ％が適当である。鉄ポルフィリン錯体を構築する
鉄イオンとイミダゾール誘導体中に含まれる芳香族アミ
ン残基（配位子）のモル比は１〜１０倍の範囲内が適当
である。また、界面活性剤の配合量は、例えばリン脂質
又はポリプロピレングリコールとポリエチレングリコー
ルのブロック共重合体である高分子界面活性剤を使用す
る場合で、脂肪酸トリグリセリドの１７１０〜１／１０
０倍（重量比）とすれば良い。The content of fatty acid triglycerides in the final dispersion is between 5 and 3.
0 wt% is appropriate. The molar ratio of the iron ions constituting the iron porphyrin complex to the aromatic amine residue (ligand) contained in the imidazole derivative is suitably within the range of 1 to 10 times. In addition, the amount of the surfactant to be blended is, for example, when using a polymeric surfactant that is a phospholipid or a block copolymer of polypropylene glycol and polyethylene glycol, and the amount is 1710 to 1/10 of the fatty acid triglyceride.
It may be set to 0 times (weight ratio).
メソ−テトラ（α、α、α、α−Ｏ−ビバラミドフェニ
ル）ポルフィナト鉄（Ｉｆ）は、人工酸素運搬体を調製
する際に当初添加しておいたメソ−テトラ（α、α、α
、α−０−ピバラミドフェニル）ポルフィナト鉄（ＩＩ
Ｉ）に、後に亜ニチオン酸又はアスコルビン酸などの還
元剤を添加することによって還元生成することができる
。この亜ニチオン酸又はアスコルビン酸などの還元剤は
、鉄ポルフィリン錯体を構築する鉄イオンの１〜１０倍
（モル比）の範囲内で例えば窒素雰囲気下で添加すれば
良い。Meso-tetra(α,α,α,α-O-bivaramidophenyl)porphinatoiron (If) was added initially when preparing the artificial oxygen carrier.
, α-0-pivalamidophenyl)porfinatoiron(II)
I) can be produced by reduction by subsequently adding a reducing agent such as dithionite or ascorbic acid. The reducing agent such as dithionite or ascorbic acid may be added in an amount of 1 to 10 times (molar ratio) the amount of iron ions constituting the iron porphyrin complex, for example, under a nitrogen atmosphere.
実施例１
アルキル鎖長の炭素数が８である中鎖脂肪酸トリグリセ
リド（トリカブリリン）２０ｇにメソ−テトラ（α、α
、α、α−０−ビバラ旦ドフェニル）ポルフィナト鉄（
Ｉ［［） （１１１１０１０１）および１−ラウリル
−２−メチルイもダゾール（５ｍｍｏｌ ）を溶解させ
、卵黄レシチン（１ｇ）を加えた後、生理食塩水（２０
０ｎ＋１）を加えながら、窒素下において超音波を照射
して乳化する。炭酸水素ナトリウムにてｐＨ７，４に調
製し、アスコルビン酸（１０ｍｍｏｌ）を加え、ポルフ
ィナト鉄を還元することにより調製した。Example 1 Meso-tetra (α, α
, α, α-0-Vivalandophenyl) porphinate iron (
Dissolve I[[) (11110101) and 1-lauryl-2-methylidazole (5 mmol), add egg yolk lecithin (1 g), and then dissolve in physiological saline (20 mmol).
While adding 0n+1), emulsify by irradiating ultrasonic waves under nitrogen. It was prepared by adjusting the pH to 7.4 with sodium hydrogen carbonate, adding ascorbic acid (10 mmol), and reducing iron porphynate.
得られた赤色乳濁液は、動的光散乱法での粒径分布測定
によれば２００±５０ｎｍの小粒子分散液であり、走査
型電顕観察から球状の形態を確認した。The obtained red emulsion was a small particle dispersion of 200±50 nm according to particle size distribution measurement using a dynamic light scattering method, and a spherical morphology was confirmed from scanning electron microscopy.
これらの粒径は室温で数カ月間保存後も変化はなり、安
定であった。ゲルパーミェーションクロマトグラフィ測
定においてメソ−テトラ（α、α。These particle sizes did not change and remained stable even after several months of storage at room temperature. Meso-tetra (α, α) in gel permeation chromatography measurements.
α、α−Ｏ−ピバラミドフェニル）ポルフィナト鉄（ｍ
） （４２０ｎ＋ｉ）および卵黄レシチン（２６０
ｎｍ）に基づく溶出曲線の一致により、ヘム誘導体が脂
肪酸トリグリセリド小粒子中へ包含されていることを確
認した。さらに、ヘム誘導体の脂肪酸トリグリセリド乳
剤中への包含率は、脂質法／ヘム＝１０〜４０／１（重
量比）でほぼ１００％と高い効率であることをｉ認した
。α, α-O-pivalamidophenyl) porphinate iron (m
) (420n+i) and egg yolk lecithin (260n+i)
The inclusion of the heme derivative into the fatty acid triglyceride small particles was confirmed by the matching of the elution curves based on (nm). Furthermore, it was confirmed that the inclusion rate of the heme derivative in the fatty acid triglyceride emulsion is as high as approximately 100% when the lipid method/heme ratio is 10 to 40/1 (weight ratio).
以上より、トリグリセリド脂質法は高い濃度のヘム誘導
体を水中に安定分散できることが明らかになった。From the above, it has become clear that the triglyceride lipid method can stably disperse high concentrations of heme derivatives in water.
この、人工酸素運搬体への酸素の可逆的な吸脱着は、例
えば可視スペクトルから確認できる。脱酸素化ヘム（λ
□ＩＩ ； ４３８．５３３，５６０ｎｍ）の人工酸素
運搬体に酸素ガスを吹き込むと、ヘム−酸素錯体（λ、
□； ４２２，５４５ｎｔａ）を形成した。これに窒素
ガスを吹き込むとデオキシ型に戻った。このデオキシ−
オキシサイクルは３７°Ｃでｔｏｏｏ回以上観測できた
。This reversible adsorption and desorption of oxygen to the artificial oxygen carrier can be confirmed, for example, from the visible spectrum. Deoxygenated heme (λ
□II; When oxygen gas is blown into an artificial oxygen carrier (438, 533, 560 nm), a heme-oxygen complex (λ,
□; 422,545 nta) was formed. When nitrogen gas was blown into this, it returned to the deoxy form. This deoxy-
Oxycycle could be observed more than too many times at 37°C.
この人工酸素運搬体は、その酸素錯体の赤外吸収スペク
トルによれば、酸素伸縮振動（ν。２）が１１６０Ｃ１
ｌ−’ （半値幅１４Ｃ１１−’）であり、ガス状０□
とは異なってスーパーオキシドのνａｚ （１１４５Ｃ
Ｉ１１−’ ）に近いことから、ｂｅｎｔ／ｅｎｄ−ｏ
ｎ型の酸素配位様式で、Ｆｅ（ＩＩＩ）−０□に電荷分
離した電子状態にあることがわかった。この結果は赤血
球内のオキシヘモグロビンと同じであり１．赤血球と同
じ原理に基づいて酸素運搬ができることを示している。According to the infrared absorption spectrum of the oxygen complex, this artificial oxygen carrier has an oxygen stretching vibration (ν.2) of 1160C1
l-' (half width 14C11-'), gaseous 0□
Unlike νaz of superoxide (1145C
I11-'), bent/end-o
It was found that it has an n-type oxygen coordination mode and is in a charge-separated electronic state to Fe(III)-0□. This result is the same as that of oxyhemoglobin in red blood cells, and 1. This shows that they can transport oxygen based on the same principle as red blood cells.
また酸素結合解離平衡曲線測定によれば、肺（１１０＋
ａｍＨｇ）−末梢組織（４０ｎｍＨｇ）の酸素分圧差間
の酸素運搬効率は約２５％（３７℃）で、人工血液とし
て有効に働くことを示している。Furthermore, according to oxygen bond dissociation equilibrium curve measurements, lungs (110+
The oxygen transport efficiency between the oxygen partial pressure difference between amHg) and peripheral tissue (40 nmHg) was approximately 25% (37°C), indicating that it works effectively as an artificial blood.
酸素親和性（ＰＩ／２） ２６ｍｍ＋Ｈｇ、酸素結合の
エンタルピー変化−１４ｋｃａｌ／ｍｏｌ、エントロピ
ー変化−４２ｋｃａｌ／ｄｅｇ−ｍｏｌより、人工酸素
運搬体の酸素結合の挙動は赤血球中のヘモグロビンのそ
れらの値（各々２７ｍｍ１ｇ、 −１４ｋｃａｉ１０＋
ｏｌ、 −４２ｋｃａｌ／ｄｅｇ−ｍ。Oxygen affinity (PI/2) 26 mm + Hg, enthalpy change of oxygen binding -14 kcal/mol, entropy change -42 kcal/deg-mol, the oxygen binding behavior of the artificial oxygen carrier is determined by the values of hemoglobin in red blood cells (each 27mm1g, -14kcai10+
ol, -42 kcal/deg-m.
ｌ）とほぼ一致することを確認した。フラッシュホトリ
ンス法、ストップドラロー法により求めた酸素結合速度
定数（ｋ、、）は約１０’ （Ｍ−’ Ｓ−’）で、迅
速な酸素結合能力も明らかになった。以上の結果は体内
を高速流動し−たときもそれに追随して酸素運搬できる
ことを示している。It was confirmed that the result was almost the same as 1). The oxygen binding rate constant (k, ) determined by the flash photorinse method and the stop draw low method was approximately 10'(M-'S-'), and the rapid oxygen binding ability was also revealed. The above results indicate that oxygen can be transported even when it flows at high speed in the body.
このようにして調製した人工酸素運搬体液に充分空気を
吹き込み、兎（約３Ｋｇ体重）の血中に５０ｍ１を脱血
してから同量投与し、その酸素運搬能を検討した（５羽
実施）。脱直後、混合静脈血の赤血球の酸素飽和度は３
４％に低下したが、本漬の投与により５３％に回復した
（脱血前は６２％）、投与後一定時間毎の採血液の血漿
層にあるヘムの可視吸収スペクトルから、ヘム残留量を
測定したところ、血管内半減期は約６時間であることが
わかった。血尿は全く認められなかった。臓器所見では
特に異常を認めなかった。Sufficient air was blown into the artificial oxygen-carrying body fluid prepared in this way, and the same amount was administered to rabbits (approximately 3 kg in weight) after removing 50 ml of blood to examine its oxygen-carrying ability (conducted on 5 rabbits). . Immediately after withdrawal, the oxygen saturation of red blood cells in mixed venous blood is 3.
The amount of heme remaining was determined from the visible absorption spectrum of heme in the plasma layer of blood collected at regular intervals after administration. Measurements showed that the intravascular half-life was approximately 6 hours. No hematuria was observed. No particular abnormality was observed in the organ findings.
実施例２
アルキル鎖長の炭素数が１０である中鎖脂肪酸トリグリ
セリド（トリカプリン）２０ｇに、メソ−テトラ（α、
α、α、α−Ｏ−ピバラξドフェニル）ポルフィナト鉄
（ＩＩＩ） （Ｉｍｍｏｌ）、■−ラウリルイミダゾ
ール（２ｍｎ＋ｏｌ）、ポリプロピレングリコールとポ
リエチレングリコールとのブロック共重合体である高分
子界面活性剤（平均分子量３３３０、ポリプロピレング
リコール部の平均分子量２０００、製品中に４０％のポ
リエチレングリコール部を含む） （１，２ｇ）を加
え、さらにプロピレノグリコール（１２ｍｌ）を混ぜた
後、これを窒素下７０°Ｃで攪拌（１００００ｒｐｍ
Ｘ３０分）し、生理食塩水（２００ｍｌ）を加えた後、
窒素下３０°Ｃで再び攪拌（１００００ｒｐｍＸ１５分
）した。この液を炭酸水素ナトリウムにてｐＨ７，４に
調製した後、亜ニチオン酸（３ｍｍｏｌ ）を加え、鉄
を還元することにより赤色乳濁液を調製した。Example 2 Meso-tetra (α,
α, α, α-O-pivala ξdophenyl)porfinatoiron(III) (Immol), ■-laurylimidazole (2 mn+ol), a polymeric surfactant that is a block copolymer of polypropylene glycol and polyethylene glycol (average molecular weight 3330, average molecular weight of polypropylene glycol part 2000, product contains 40% polyethylene glycol part) (1.2 g), and then mixed with propylene glycol (12 ml), and then heated at 70°C under nitrogen. Stirring (10000 rpm
x 30 minutes) and added physiological saline (200 ml),
The mixture was stirred again at 30°C under nitrogen (10,000 rpm for 15 minutes). This solution was adjusted to pH 7.4 with sodium hydrogen carbonate, and then dithionite (3 mmol) was added to reduce iron to prepare a red emulsion.
動的光散乱法での粒径分布測定によれば脂質粒子の直径
は６００±２００ｎｏ＋であり、この粒径は室温で数カ
月間変化がなかった。According to particle size distribution measurement using dynamic light scattering, the diameter of the lipid particles was 600±200 no+, and this particle size remained unchanged for several months at room temperature.
実施例１と同様にしてヘム誘導体の脂質小粒子への包含
を確認し、更に、ヘム誘導体の脂質球への包含率は、は
ぼ１００％と高い効率であることを確認した。 酸素の
迅速、且つ可逆的な吸脱着能は、実施例１の場合と同様
であり、Ｐ ｒ ｙ ｚ ＝ ３６ｍ＋ｍＨｇ。In the same manner as in Example 1, inclusion of heme derivatives in small lipid particles was confirmed, and furthermore, it was confirmed that the inclusion rate of heme derivatives in lipid spheres was as high as 100%. The ability to rapidly and reversibly adsorb and desorb oxygen is the same as in Example 1, P ry z = 36 m+mHg.
ｋ、、＝ＩＯ’Ｍ−’ Ｓ−’の結果を得た。We obtained the result k, ,=IO'M-'S-'.
以上により本実施例で得た人工酸素運搬体が人工血液と
して有効に働くことがわかった。From the above, it was found that the artificial oxygen carrier obtained in this example works effectively as an artificial blood.
実施例３
実施例１のメソ−テトラ（α、α、α２ α−〇ビバラ
果ドラドフェニルルフィナト鉄（ＩＩＩ）の仕込量を４
＋＋ｖ＋ｏｆ 、 １−ラウリル−２−メチルイ多ダ
ゾールの量を１２ｍｍｏｌ、アスコルビン酸の添加量を
５Ｑｍｍｏ Ｉとする他は同実施例と同様にして人工酸
素運搬体を調製した。Example 3 The amount of meso-tetra (α, α, α2 α-〇 Vivara doradophenylrufinate iron (III) of Example 1 was changed to 4
++v+of An artificial oxygen carrier was prepared in the same manner as in the same Example, except that the amount of 1-lauryl-2-methylidazole was 12 mmol and the amount of ascorbic acid added was 5Qmmo I.
血液への酸素溶解量を定量する方法として常用されるＶ
ａｎ ５ｌｙｋｅ法（Ｊ、Ｂｉｏｌ、Ｃｈｅｍ、６１巻
、 ５２３−５２７真、 １９２４年）にて、本人工酸
素運搬体液１００ｍ１当たりの酸素ガス溶解量を３７℃
で測定したところ４４ｍ１と極めて高い酸素保持量を示
した。V is commonly used as a method to quantify the amount of oxygen dissolved in blood.
Using the an5lyke method (J, Biol, Chem, vol. 61, 523-527, 1924), the amount of dissolved oxygen gas per 100 ml of this artificial oxygen-carrying body fluid was measured at 37°C.
When measured, it showed an extremely high oxygen retention amount of 44 ml.
実施例４
実施例１のアルキル鎖長の炭素数が８である中鎖脂肪酸
トリグリセリド（トリカブリリン）のかわりにトリカプ
リリン中にトリカプリンを１０．５０又は７５−Ｌ％混
合させた脂肪酸トリグリセリドを用い、その他は実施例
１と同様にして人工酸素運搬体を調製し、その酸素吸脱
着能測定を行った。Example 4 A fatty acid triglyceride prepared by mixing 10.50 or 75-L% of tricaprin in tricaprylin was used instead of the medium chain fatty acid triglyceride (tricabrylin) whose alkyl chain length had 8 carbon atoms as in Example 1, and other prepared an artificial oxygen carrier in the same manner as in Example 1, and measured its oxygen adsorption/desorption ability.
酸素の迅速、且つ可逆的な吸脱着能は、実施例１の場合
と同様であり、本実施例で得た人工酸素運搬体が人工血
液として有効に働くことがわかった。The rapid and reversible ability to adsorb and desorb oxygen was the same as in Example 1, and it was found that the artificial oxygen carrier obtained in this example worked effectively as an artificial blood.
実施例５
実施例１のポルフィナト鉄としてメソ−テトラ（α、α
、α、α−ｏ−２０’−ベンジロキシ−２゜２′−ジメ
チルエイコサンアミドフェニル）ポルフィナト鉄（ＩＩ
Ｉ）を用い、その他は実施例１と同様にして人工酸素運
搬体を調製し、その酸素吸脱着能を測定した。その結果
はＰ＋ｚｚ＝３０＋１ｍ）Ｉｇ、に、ｎ＝１０’Ｍ−’
Ｓ−’で酸素の迅速且つ可逆的な吸脱着能が認められ
た。Example 5 Meso-tetra (α, α
, α, α-o-20'-benzyloxy-2゜2'-dimethyleicosanamidophenyl)porphinatoferric(II
An artificial oxygen carrier was prepared using I) in the same manner as in Example 1, and its oxygen adsorption/desorption ability was measured. The result is P+zz=30+1m)Ig, n=10'M-'
A rapid and reversible ability to adsorb and desorb oxygen was observed in S-'.
本発明の人工酸素運搬体によれば、脂肪酸トリグリセリ
ドをキャリアーとして鉄ポルフィリン錯体を水媒体中に
極めて高い濃度（人血を上回る２０ｍＭ）まで溶解する
ことが可能である。即ち、媒体１００＋ａｌ 当り５０
０１１近い酸素ガス（物理的に溶解できる量の約１５０
倍）を保持できる。According to the artificial oxygen carrier of the present invention, it is possible to dissolve an iron porphyrin complex in an aqueous medium to an extremely high concentration (20 mM, which is higher than human blood) using fatty acid triglyceride as a carrier. That is, 50 per 100+ al of media
Oxygen gas close to 0.011% (approximately 150% of the amount that can be physically dissolved)
(times) can be held.
また本発明の一成分である脂肪酸トリグリセリドは、従
来、中鎖脂肪酸トリグリセリドと界面活柱側とからなる
乳剤が静注用脂肪乳剤として汎用され、脂溶性薬物の運
搬体として広く応用されているところから明らかな様に
大量投与し７ても毒性のない数少ない物質であり、安心
して使用可能である。In addition, fatty acid triglyceride, which is a component of the present invention, has conventionally been used as an emulsion consisting of medium-chain fatty acid triglyceride and a surfactant column as a fat emulsion for intravenous injection, and has been widely applied as a carrier for fat-soluble drugs. As is clear from the above, it is one of the few substances that is not toxic even when administered in large quantities, and can be used with confidence.
以上のほか本発明の人工酸素運搬体は、（１）酸素吸脱
着が迅速かつ可逆的であり、酸素親和力も適切である
（２）室温にて数カ月を越えて保存できる （３）全合
成物であるためウィルスなどに汚染されていない（３）
比較的構造の簡単な鉄ポルフィリン錯体と安価な脂肪酸
トリグリセリドからなり経済性が良い、等の数々の利点
を有するものである。In addition to the above, the artificial oxygen carrier of the present invention has (1) rapid and reversible oxygen adsorption and desorption, and appropriate oxygen affinity;
(2) Can be stored at room temperature for more than several months (3) Since it is a fully synthetic product, it is not contaminated with viruses etc. (3)
It is composed of an iron porphyrin complex with a relatively simple structure and an inexpensive fatty acid triglyceride, and has many advantages such as being economical.
Claims (4)
なることを特徴とする人工酸素運搬体。(1) An artificial oxygen carrier comprising an iron porphyrin complex and fatty acid triglyceride.
、α−ｏ−ピバラミドフェニル）ポルフィナト鉄（II）
である請求項１記載の人工酸素運搬体。(2) The iron porphyrin complex is meso-tetra (α, α, α
, α-o-pivalamidophenyl)porphinatoiron(II)
The artificial oxygen carrier according to claim 1.
したものである請求項１又は２記載の人工酸素運搬体(3) The artificial oxygen carrier according to claim 1 or 2, wherein the iron porphyrin complex is coordinated with an imidazole derivative.
０の脂肪酸トリグリセリドである請求項１乃至３のいず
れかに記載の人工酸素運搬体。(4) Fatty acid triglyceride has an alkyl group with 6 to 1 carbon atoms
The artificial oxygen carrier according to any one of claims 1 to 3, which is a fatty acid triglyceride of 0%.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP14888789A JPH03128321A (en) | 1989-06-12 | 1989-06-12 | Artificial oxygen-carrier |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP14888789A JPH03128321A (en) | 1989-06-12 | 1989-06-12 | Artificial oxygen-carrier |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH03128321A true JPH03128321A (en) | 1991-05-31 |
Family
ID=15462927
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP14888789A Pending JPH03128321A (en) | 1989-06-12 | 1989-06-12 | Artificial oxygen-carrier |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH03128321A (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5773417A (en) * | 1994-07-22 | 1998-06-30 | Duke University | Human serum albumin-porphyrin complexes with the ability to bind oxygen and therapeutic uses thereof |
| JP2005193134A (en) * | 2004-01-06 | 2005-07-21 | Shiseido Co Ltd | One-phase microemulsion composition and its manufacturing method |
| US8461214B2 (en) | 2004-01-06 | 2013-06-11 | Shiseido Co., Ltd. | One-phase microemulsion compositions, O/W ultrafine emulsion external formulations and method for producing the same |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5925767A (en) * | 1982-08-04 | 1984-02-09 | 株式会社精工舎 | Net ball judging apparatus |
| JPS6348214A (en) * | 1986-08-18 | 1988-02-29 | Morishita Seiyaku Kk | O/w-type fat emulsion containing 1-(2-(2,4-dichlorophenyl)-3-methyl-1-pentenyl)-1h-imidazole |
| JPS63246320A (en) * | 1987-01-27 | 1988-10-13 | ネクスター・フアーマシユーテイカルズ・インコーポレイテツド | Phospholipid transportation vehicle for water-insoluble effective component |
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1989
- 1989-06-12 JP JP14888789A patent/JPH03128321A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5925767A (en) * | 1982-08-04 | 1984-02-09 | 株式会社精工舎 | Net ball judging apparatus |
| JPS6348214A (en) * | 1986-08-18 | 1988-02-29 | Morishita Seiyaku Kk | O/w-type fat emulsion containing 1-(2-(2,4-dichlorophenyl)-3-methyl-1-pentenyl)-1h-imidazole |
| JPS63246320A (en) * | 1987-01-27 | 1988-10-13 | ネクスター・フアーマシユーテイカルズ・インコーポレイテツド | Phospholipid transportation vehicle for water-insoluble effective component |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5773417A (en) * | 1994-07-22 | 1998-06-30 | Duke University | Human serum albumin-porphyrin complexes with the ability to bind oxygen and therapeutic uses thereof |
| JP2005193134A (en) * | 2004-01-06 | 2005-07-21 | Shiseido Co Ltd | One-phase microemulsion composition and its manufacturing method |
| US8461214B2 (en) | 2004-01-06 | 2013-06-11 | Shiseido Co., Ltd. | One-phase microemulsion compositions, O/W ultrafine emulsion external formulations and method for producing the same |
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