JPS6320436B2 - - Google Patents

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Publication number
JPS6320436B2
JPS6320436B2 JP57121389A JP12138982A JPS6320436B2 JP S6320436 B2 JPS6320436 B2 JP S6320436B2 JP 57121389 A JP57121389 A JP 57121389A JP 12138982 A JP12138982 A JP 12138982A JP S6320436 B2 JPS6320436 B2 JP S6320436B2
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JP
Japan
Prior art keywords
compound
group
hydrogen
phosphatidylethanolamine
carboxyl
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.)
Expired
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JPS5849393A (ja
Inventor
Deii Shiaazu Barii
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RIBITSUDO SUPESHARUTEIZU Inc
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RIBITSUDO SUPESHARUTEIZU Inc
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Publication of JPS5849393A publication Critical patent/JPS5849393A/ja
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/127—Synthetic bilayered vehicles, e.g. liposomes or liposomes with cholesterol as the only non-phosphatidyl surfactant
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/127—Synthetic bilayered vehicles, e.g. liposomes or liposomes with cholesterol as the only non-phosphatidyl surfactant
    • A61K9/1271—Non-conventional liposomes, e.g. PEGylated liposomes or liposomes coated or grafted with polymers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/06—Phosphorus compounds without P—C bonds
    • C07F9/08—Esters of oxyacids of phosphorus
    • C07F9/09—Esters of phosphoric acids
    • C07F9/10—Phosphatides, e.g. lecithin
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G65/00—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule
    • C08G65/02—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from cyclic ethers by opening of the heterocyclic ring
    • C08G65/32—Polymers modified by chemical after-treatment
    • C08G65/329—Polymers modified by chemical after-treatment with organic compounds
    • C08G65/335—Polymers modified by chemical after-treatment with organic compounds containing phosphorus
    • C08G65/3356—Polymers modified by chemical after-treatment with organic compounds containing phosphorus having nitrogen in addition to phosphorus

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  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Dispersion Chemistry (AREA)
  • Epidemiology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Molecular Biology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Polymers & Plastics (AREA)
  • Biochemistry (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Cardiology (AREA)
  • Vascular Medicine (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Urology & Nephrology (AREA)
  • Medicinal Preparation (AREA)
  • Cosmetics (AREA)
  • Manufacturing Of Micro-Capsules (AREA)
  • Formation And Processing Of Food Products (AREA)

Description

【発明の詳細な説明】 本発明は新規な合成りん脂質化合物とその製造
方法にかかわる。
レシチンの如きりん脂質は、それが疎水性基と
親水性基或は疎水性部と親水性部を同一分子内に
もつことで両親媒性化合物である。而して、これ
ら疎水性部と親水性部とのバランスは、水性環境
における該化合物の物理的性質を決定する。天然
りん脂質は添加剤として、食品工業（例えば乳化
剤として）、化粧品、産業用そして製薬工業特に
投薬手段（drug−delivery system）の調製で多
く用いられている。米国特許第4086257号、同第
4097502号、同第4097503号、同第4145410号およ
び同第4159988号には、天然りん脂質の極性頭基
部（polar−head−group region）の各種変性と
それによりもたらされるユニークにして予想外な
物理的性質が開示されている。
なお、レシチンのいろいろな誘導体が知られて
おり、その中に、例えばオキシアルキル化レシチ
ン化合物（米国特許第2310679号および同第
3085100号参照のこと）やホスフアチジルアルカ
ノールアミン誘導体（例 米国特許第2801255号、
同第3542820号、同第3577446号および同第
4254115号）がある。特に、高められたしかも制
御される溶解性を水性環境において示す新規な合
成りん脂質を提供することが望ましい。
概記するに、本発明は、りん脂質化合物、その
製造方法および該りん脂質化合物の、特に水性環
境での使用にかかわる。更に特定するに、本発明
は新規な合成ホスフアチジルポリエチレンオキシ
ド化合物、その製造および、投薬手段としての薬
物カプセル化における該化合物の使用にかかわ
る。
本発明は、極性頭基部が各種分子量のポリアル
キレンオキシド重合体の共有結合により変性され
ている、新規系列のりん脂質化合物を提供する。
このりん脂質化合物は下記構造式を有する。
ここで、R1およびR2は水素又は、飽和ないし
不飽和の直鎖若しくは枝分れ鎖アシル基を表わ
し、R3はアルキレン基特に、限定されるもので
はないがエチレン、プロピレンおよびこれらの混
合物を表わし、R4はC2〜C10アルキレン基特に、
天然レシチンにみられる如きジメチレン基−
CH2CH2−を表わす。上記式中ｎで示される、重
合体中のアルキレンオキシド基の数は０〜数200
若しくはそれ以上の範囲でありうるが、例えば10
〜100、更には３〜20とすることができる。また、
式中Ｘは水素又はアルキル基例えば、メチル基を
含むC1〜C4アルキル基である。水性環境におい
てりん脂質化合物がユニークな溶解性を示すよう
に、比較的親水性のポリアルキレンオキシド重合
体特にポリエチレンオキシドを結合させてりん脂
質内の親水性部と疎水性部とのバランスを変え
る。
この新規な化合物は、例えば米国特許第
2310679号および同第3085100号に記載の、粗製大
豆「レシチン」にエチレンオキシド又は類似化合
物を結合させてなる生成物とは明らかに別異の化
学組成を有する。用語「レシチン」の使用は、エ
チレンオキシドとは反応し得ないレシチン化合物
すなわちホスフアチジルコリンを含むいくつかの
化合物を意味する。他方、大豆「レシチン」はホ
スフアチジルエタノールアミン、ホスフアチジル
イノシツトおよび種々のグリコリピド（糖脂質）
を含む。粗製「レシチン」中のこれら化合物は全
て、エチレンオキシド又は、反応性シクロオキシ
ド基を含有する類似化合物と反応して種々の付加
物を形成することができる。例えば、ホスフアチ
ジルイノシツトにおいて、またグリコリピドに関
し、これら分子中の反応性基はヒドロキシル基で
あり、而してこの基は、エチレンオキシドとの反
応時エーテル結合を形成する。第一アミノ基を含
むホスフアチジルエタノールアミンはエチレンオ
キシドと反応してアルキルアミン結合を構成す
る。〔N.Schonfeldt、「表面活性エチレンオキシ
ド付加物（Surface Active Ethylene Oxide
Adducts）」（Pergamon Press発行、1969）参照
のこと〕。いずれにせよ、これら付加物は生物学
上減成すべきでなく、それ故かかる化合物は、化
粧品ないし製薬工業での使用に望ましくない。
本発明のりん脂質は、合成エチレンオキシド若
しくはプロピレンオキシド重合体と天然産出りん
脂質との結合が、生物学上減成しうる、アミド結
合の如き結合である合成りん脂質よりなる。かか
る結合は、これら新規なりん脂質化合物をして、
化粧品ないし製薬用途に適したものとする。
本化合物の製造は、ホスフアチジルエタノール
アミン分子の如きホスフアチジルアルカノールア
ミン分子にポリアルキレンオキシド重合体の適当
なカルボキシル類似体をカツプリングさせること
によつて最もよく遂行される。例えば、この類似
体として、次式構造 （ここでＸは水素又はアルキル基であり、ｎは
０〜約200範囲で変動しうる）を有するポリエチ
レンオキシド重合体のカルボキシル類似体が挙げ
られる。このポリエチレンオキシド重合体のカル
ボキシル類似体は、KMnO4、ピリジニウムジク
ロメート又は他の酸化剤を用いて、式 OH−CH2−CH2−（Ｏ−CH2−CH2）o−OX （ここでＸは水素又はアルキル基であり、ｎは０
〜約200範囲で変動しうる）により示される如き
適当な出発物質ポリアルキレンオキシド重合体を
酸化させることにより調製されうる。この酸化さ
れた化合物は次いで、蒸留若しくはイオン交換ク
ロマトグラフイーによつて精製処理される。ポリ
エチレンオキシド重合体のカルボキシル類似体
は、塩化オキサリル又は１，１−カルボニルジイ
ミダゾールの如き簡便な活性剤によつて賦活され
る。かくして得られたポリエチレンオキシド重合
体の活性化カルボキシル誘導体は、ホスフアチジ
ルエタノールアミンにアミド結合を介してカツプ
リングさせることにより、本発明のりん脂質類似
体化合物を形成する。
ホスフアチジルエタノールアミンは天然源から
単離され、またホスフアチジルエタノールアミン
の合成類似体は、確立された化学手順により、或
はエタノールおよびホスホリパーゼＤの存在で対
応ホスフアチジルコリン化合物を用いた酵素によ
り合成されうる。R1およびR2は、炭素原子２〜
24個好ましくはC2〜C20範囲の直鎖若しくは枝分
れ鎖アシル基を意味する。かかる基として例え
ば、オレイン酸、ステアリン酸、リノール酸、リ
ノレン酸、パルミチン酸、ミリスチン酸又はアラ
キドン酸の如き不飽和脂肪酸のアシル基が挙げら
れるが、これに制約されるものではない。
ホスフアチジルエタノールアミンとポリエチレ
ンオキシド重合体のカルボキシル誘導体との反応
は乾燥ベンゼンの如き不活性溶剤中で遂行され
る。反応の進展は薄層クロマトグラフイーによつ
てモニターされうる。必要なら、カラムクロマト
グラフイーを用いて、最終生成物の精製を行なう
ことができる。
本発明のりん脂質化合物の場合、その中にポリ
アルキレンオキシド重合体が含まれているため、
ホスフアチジルエタノールアミンの極性頭基は既
に変性されており、而して物理的性質も改変され
ている。本発明の新規な合成りん脂質化合物は、
投薬手段、化粧品、食品ないし産業用途、アテロ
ーム性動脈硬化症治療、静脈内栄養等天然りん脂
質が用いられている全ゆる分野で単独使用し得、
或は他の天然りん脂質特にホスフアチジルコリン
と混合使用することができる。合成りん脂質は、
生物学上、生理学的に不活性である。例えば、た
ん白質に結合したポリアルキレンオキシド重合体
は非免疫原性であつて、人体に十分許容される。
〔Abuchowski等、J.Biol.Chem.，252，p.3578〜
3581（1977）〕。ポリエチレンオキシド重合体とホ
スフアチジルエタノールアミンとの共有結合は生
物学的に減成し得、ホスフアチジルエタノールア
ミンそのものは天然化合物である。
その結果、これら新規な化合物は、経口又は注
射のいずれかで投与することのできる投薬手段と
して薬物をカプセル化する際にきわめて有用であ
る。該新規な化合物が小球体又はミセル形成性物
質とに薬物のカプセル化に用いられる態様につい
ては、米国特許第4320121号および米国特許第
4016100号に開示されているので、必要に応じこ
れを参照されたい。
また、本発明の新規なりん脂質中に親水性アル
キレンオキシド重合体特にポリエチレンオキシド
重合体部分が存在することによつて、水性環境で
の新規且つ予想外な物理的性質が発現される。不
飽和ホスフアチジルエタノールアミン特に大豆か
ら単離されたものは、水中でいかなる安定型構造
をも形成しない。他方、ガングリオシドはホスフ
アチジルエタノールアミンに似た疎水性部を有す
るが、ガングリオシド分子の極性部は親水性少糖
類よりなる。これら少糖類の存在は、水による水
和時、ガングリオシドをして、安定なミセルに編
成させる。ポリエチレンオキシド重合体の如き親
水性重合体をホスフアチジルエタノールアミンに
共有結合させることによつて、本質上ガングリオ
シド類似体りん脂質が合成される。更に、注目す
べきは、ホスフアチジルエタノールアミンの分子
種がいずれも水性環境において安定構造を形成し
ないのに対し、本発明に開示せるりん脂質類似体
化合物は水和しても安定な構造を形成するという
ことである。
しかしながら、これら構造の実際的な編成は、
ホスフアチジルエタノールアミンの被選定アシル
鎖構造やアルキレンオキシド重合体の長さに少く
とも部分的に依存する。また、これら新規なりん
脂質類似体と天然のりん脂質とを特に超音波処理
せるりん脂質小胞内で組合せることにより、その
まゝでは不安定な小胞が安定化される。この安定
化はポリアルキレンオキシド重合体の存在によつ
て生じうる。なぜなら、該重合体は、小胞同士が
接触して超音波処理せるりん脂質小胞が合着する
ことのないよう物理的障害として作用するからで
ある。
以下、本発明を、或る特定の好ましい組成物の
製造にのみ関連させて説示するけれども、本発明
の範囲ないし精神を逸脱することなく、他の化合
物を処方し得、また他の製造態様を用い得ること
は理解されよう。
例 １ 大豆ホスフアチジルエタノールアミン1120μM
を高い減圧下で乾燥させた。モノメチルポリエチ
レンオキシドカルボキシル誘導体（平均分子量
134）4480μMと１，１−カルボニルジイミダゾ
ール2240μMを乾燥ベンゼン５ml中で混合せしめ
た。該混合物を、バブルが発生しなくなるまで40
℃に加熱した。次いで、この溶液を、乾燥りん脂
質に加え、最終容量を３mlに減じ、65℃で３時間
加熱した。薄層クロマトグラフイーから、これが
完全反応であるとわかつた。生成物をけい酸クロ
マトグラフイーによつて精製した。精製物の最終
的収率は74％であつた。この生成物は、混合比
75／25／１のCHCl3／メタノール／NH4OHより
なる溶媒系で0.46のRf値を示した。同じ溶媒系
で、ホスフアチジルエタノールアミンのRfは0.14
であつた。
例 ２ 精製した大豆ホスフアチジルエタノールアミン
1120μMを高い減圧下で乾燥させた。モノメチル
ポリエチレンオキシドカルボキシル誘導体（平均
分子量1900）1680μMと１，１−カルボニルジイ
ミダゾール1400μMを乾燥ベンゼン10mlに溶かし
た。この溶液を、バブルが発生しなくなるまで40
℃で加熱した。次いで、これを乾燥りん脂質に加
え、全容量を５mlに減じ、３時間65℃で加熱し
た。生成物をけい酸クロマトグラフイーで精製し
て、総収率７％を得た。生成物のRfは、例１と
同じ溶媒系中0.78であつた。
例 ３ 精製した大豆ホスフアチジルエタノールアミン
800μMを高い減圧下で乾燥させた。モノメチル
ポリエチレンオキシドカルボキシル誘導体（平均
分子量266）2400μMを乾燥ベンゼン11mlに溶か
し、１，１−カルボニルジイミダゾール2160μM
を、バブルが発生しなくなるまで40℃で加熱し
た。次いで、この溶液を乾燥りん脂質に加え、全
容量を３mlに減じ、３時間65℃で加熱した。生成
物をけい酸クロマトグラフイーで精製して、収率
34％を得た。生成物のRfは、例１と同じ溶媒系
中0.62であつた。
例 ４ 大豆ホスフアチジルエタノールアミン491μM
を高い減圧下で乾燥させた。メトキシ酢酸
1560μMと１，１−カルボニルジイミダゾール
1560μMを乾燥ベンゼン10mlに溶かし、これを、
バブルが発生しなくなるまで40℃で加熱した。次
いで、この溶液を乾燥ホスフアチジルエタノール
アミンに加え、全容量を３mlに減じ、３時間60℃
で加熱した。薄層クロマトグラフイーから、これ
が完全反応であるとわかつた。生成物をFolch抽
出装置で抽出し、下部相を乾燥させた。収率は92
％であつた。生成物のRfは、例１と同じ溶媒系
中0.44であつた。
例 ５ 大豆ホスフアチジルエタノールアミン1120μM
を高い減圧下で乾燥させた。モノメチルポリエチ
レンオキシドカルボキシル誘導体（平均分子量
224）3360μMと１，１−カルボニルジイミダゾ
ール2240μMを乾燥ベンゼン10mlに溶かし、これ
を、バブルが発生しなくなるまで40℃で加熱し
た。次いで、この溶液を乾燥りん脂質に加え、容
量を３mlに減じ、３時間70℃で加熱した。生成物
をけい酸クロマトグラフイーで精製して、53％の
収率を得た。生成物のRfは、例１と同じ溶媒系
中0.61であつた。

Claims (1)

  1. 【特許請求の範囲】 １ 構造式 （ここでR1およびR2は水素又は有機C2〜C25ア
    シル基であり、R3はC2〜C3メチレン基であり、
    R4はC2〜C10メチレン基であり、Ｘは水素又は低
    級アルキル基であり、ｎは０〜約200範囲の数で
    ある）を有するホスフアチジルアルキレンオキシ
    ド化合物。 ２ R1およびR2がC8〜C20脂肪酸基である特許請
    求の範囲第１項記載の化合物。 ３ ｎが約３〜20範囲の数である特許請求の範囲
    第１項記載の化合物。 ４ R4がジメチレン基である特許請求の範囲第
    １項記載の化合物。 ５ R1およびR2が、大豆りん脂質中に見出され
    るアシル基である特許請求の範囲第１項記載の化
    合物。 ６ R1およびR2が卵りん脂質中に見出されるア
    シル基である特許請求の範囲第１項記載の化合
    物。 ７ 化合物が構造式 （ここでR1およびR2は水素又はC8〜C20脂肪酸
    基であり、ｎは〜約200範囲の数であり、Ｘは水
    素又は低級アルキル基である）を有する、特許請
    求の範囲第１項記載の化合物。 ８ 構造式 （ここでR1およびR2は水素又は有機C1〜C25ア
    シル基であり、R3はC2〜C3メチレン基であり、
    R4はC2〜C10メチレン基であり、Ｘは水素又は低
    級アルキル基であり、ｎは０〜約200範囲の数で
    ある）のホスフアチジルアルキレンオキシド化合
    物を製造するに当り、対応するホスフアチジル
    C2〜C10アルカノールアミノ化合物を、構造式 （ここでR3はC2〜C3メチレン基であり、Ｘは
    水素又は低級アルキル基であり、ｎは０〜約200
    の数である）のカルボキシルポリアルキレンオキ
    シド化合物と共有結合反応させることよりなる方
    法。 ９ ホスフアチジルアルカノールアミノ化合物が
    ホスフアチジルエタノールアミンである特許請求
    の範囲第８項記載の方法。 １０ ホスフアチジルエタノールアミンが大豆レ
    シチンに含まれたものである特許請求の範囲第９
    項記載の方法。 １１ 反応を、カルボキシルポリアルキレンオキ
    シド化合物用活性剤の存在で実施する特許請求の
    範囲第８項記載の方法。 １２ 活性剤が塩化オキサリル又は１，１−カル
    ボニルジイミダゾールである特許請求の範囲第１
    １項記載の方法。 １３ ｎが約10〜100の数である特許請求の範囲
    第８項記載の方法。 １４ Ｘがメチル基である特許請求の範囲第８項
    記載の方法。 １５ カルボキシルポリアルキレンオキシド化合
    物がカルボキシルモノメチルポリエチレンオキシ
    ド化合物である特許請求の範囲第８項記載の方
    法。 １６ ポリアルキレンオキシド化合物がメトキシ
    酢酸である特許請求の範囲第８項記載の方法。
JP57121389A 1981-07-20 1982-07-14 合成りん脂質化合物とその製造方法 Granted JPS5849393A (ja)

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Application Number Priority Date Filing Date Title
US06/284,675 US4426330A (en) 1981-07-20 1981-07-20 Synthetic phospholipid compounds
US284675 1981-07-20

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JPS5849393A JPS5849393A (ja) 1983-03-23
JPS6320436B2 true JPS6320436B2 (ja) 1988-04-27

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EP (1) EP0072111B1 (ja)
JP (1) JPS5849393A (ja)
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