JPH03275625A - Carcinostatic agent and production thereof - Google Patents
Carcinostatic agent and production thereofInfo
- Publication number
- JPH03275625A JPH03275625A JP7216390A JP7216390A JPH03275625A JP H03275625 A JPH03275625 A JP H03275625A JP 7216390 A JP7216390 A JP 7216390A JP 7216390 A JP7216390 A JP 7216390A JP H03275625 A JPH03275625 A JP H03275625A
- Authority
- JP
- Japan
- Prior art keywords
- phosphatidylcholine
- unsaturated fatty
- highly unsaturated
- aqueous suspension
- mixture
- 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
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- 239000007787 solid Substances 0.000 description 1
- 230000003381 solubilizing effect Effects 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 150000008163 sugars Chemical group 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 230000008719 thickening Effects 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 239000003053 toxin Substances 0.000 description 1
- 231100000765 toxin Toxicity 0.000 description 1
- 108700012359 toxins Proteins 0.000 description 1
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 description 1
- 241001446247 uncultured actinomycete Species 0.000 description 1
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Abstract
Description
【発明の詳細な説明】
（産業上の利用分野）
本発明は、新規な制癌剤に関するものであり、更に詳し
くは、フラボノイドとω−３系高度不飽和脂肪酸含有ホ
スファチジルコリンを含有する制癌剤およびその製造方
法に関する。Detailed Description of the Invention (Field of Industrial Application) The present invention relates to a novel anticancer agent, and more specifically, an anticancer agent containing flavonoids and phosphatidylcholine containing omega-3 highly unsaturated fatty acids, and a method for producing the same. Regarding.
（従来の技術）
従来、癌化学療法剤として、アルキル化剤、代謝拮抗剤
、抗癌性抗生物質、植物性核***毒、免疫療法剤、ホル
モン剤、酵素製剤等が用いられてきた。しかしながら、
その殆どは、細胞毒型の物質であり、重大な副作用を呈
するため、低毒性で優れた制癌活性を有する制癌剤の開
発が強く望まれている。(Prior Art) Conventionally, alkylating agents, antimetabolites, anticancer antibiotics, plant fission toxins, immunotherapeutics, hormones, enzyme preparations, and the like have been used as cancer chemotherapy agents. however,
Most of them are cytotoxic substances and exhibit serious side effects, so there is a strong desire to develop anticancer agents with low toxicity and excellent anticancer activity.
本発明者らは、そのような趣旨に鑑み、低毒性で制癌性
を有する物質を探索して、既に数種の物質を見出した。With this in mind, the present inventors have searched for substances with low toxicity and anticancer properties, and have already found several types of substances.
例えば、ニジマス胚より単離したドコサヘキサエン酸を
有するホスファチジルコリンおよびジグリセリド（特開
昭５９−４６２２６号）、ザリガニ生体中より単離した
高度不飽和脂肪酸を有するリゾホスファチジルコリン（
特開昭６０−１９９８２１号）及び放線菌の培養液より
単離したフラボノイド（特開昭６０−１９９８１７号）
等が奇形腫細胞、赤芽球性白血病細胞及び骨髄性白血病
細胞等の動物の腫瘍細胞に対して分化誘導活性を有して
いた。For example, phosphatidylcholine and diglyceride containing docosahexaenoic acid isolated from rainbow trout embryos (JP-A-59-46226), lysophosphatidylcholine containing highly unsaturated fatty acids isolated from living crayfish
JP-A-60-199821) and flavonoids isolated from actinomycete culture fluid (JP-A-60-199817)
etc. had differentiation-inducing activity against animal tumor cells such as teratoma cells, erythroblastic leukemia cells, and myeloid leukemia cells.
これらの物質は、人、家畜、犬、猫などの温血動物に対
する優れた癌化学療法剤となり得るものである。These substances can be excellent cancer chemotherapeutic agents for humans, domestic animals, and warm-blooded animals such as dogs and cats.
その後、更に研究を進めた結果、未分化な腫瘍細胞の分
化誘導に関し、より直接的に分化を誘導したり、分化の
方向づけを行っているのは、蛋白質性や糖蛋白質性の因
子であるが、これらの諸因子は種々の低分子により誘導
可能と思われてきた。Subsequently, as a result of further research, it was found that proteinaceous and glycoprotein factors more directly induce differentiation or direct differentiation in undifferentiated tumor cells. It has been thought that these factors can be induced by various small molecules.
そこで、広い範囲の糖蛋白質性の分化誘導因子の誘導が
可能であり、且つ毒性のない低分子の内因性や外因性の
物質を組み合わせた制癌剤およびその製造法の開発を行
ってきた。Therefore, we have been developing anticancer agents that can induce a wide range of glycoprotein differentiation-inducing factors and that combine non-toxic low-molecular endogenous and exogenous substances, as well as methods for producing the same.
（発明が解決しようとする課題）
前述した如く、直接的な糖蛋白質性の分化誘導因子の誘
導は、低分子の天然物質で可能であるが、その誘導され
る範囲は、内因性や外因性の物質を組み合わせたもので
一層広くなる。(Problems to be Solved by the Invention) As mentioned above, direct induction of glycoprotein differentiation-inducing factors is possible with low-molecular natural substances, but the range of induction is limited to endogenous and exogenous agents. It becomes even wider when a combination of substances is used.
低分子の天然の内因性物質としては、細胞膜の修飾に影
響を与える界面活性作用を示す一連の物質で、高度不飽
和脂肪酸を有するリン脂質やグリセライドなどが見出さ
れている。また低分子の天然の外因性物質としては、酸
化−還元機構に影響を与える抗酸化作用を示す一連の物
質でビエリシディンＡ、ＢＨＴ、フラボノイド化合物な
どが見出されている。As low-molecular-weight natural endogenous substances, phospholipids and glycerides containing highly unsaturated fatty acids have been found to be a series of substances that exhibit surfactant effects that affect the modification of cell membranes. Furthermore, as low-molecular natural exogenous substances, biericidin A, BHT, and flavonoid compounds have been found to be a series of substances that exhibit antioxidant effects that affect the oxidation-reduction mechanism.
現在までに見出されている低分子の因子のうち、分化誘
導される未分化細胞の範囲と分化誘導活性の強さから、
内因性物質としては高度不飽和脂肪酸を有するホスファ
チジルコリンと、外因性物質としてはフラボノイド化合
物が適している。さらにホスファチジルコリンに関して
は、リポソーム化等で知られるように、薬剤のデリバリ
−の改善効果も期待されている。Among the low-molecular-weight factors that have been discovered to date, there are
Phosphatidylcholine having highly unsaturated fatty acids is suitable as the endogenous substance, and flavonoid compounds are suitable as the exogenous substance. Furthermore, phosphatidylcholine is also expected to have an effect on improving drug delivery, as is known from liposome formation.
フラボノイド化合物の多くは糖と結合した配糖体として
天然に存在するが、その分化誘導活性は、加水分解を受
けた遊離型のものに一層強くその効果がある。しかし、
配糖体は水への親和性を少し有しているが、遊離型は水
への溶解度が著しく低いため、水溶液として用いること
が難しい。また、遊離型は熱水、熱メタノール、熱エタ
ノール、熱含水アルコール、熱アセトンなどで溶解度が
向上することが判明しているが、冷却されると直ちに結
晶が析出してくるので、医薬品の溶媒としては不適であ
る。有機溶媒ではアプロチック溶剤、高極性非プロトン
系溶剤、塩素系溶媒を配合した溶剤などの一部に溶解す
るが、これらの溶剤を医薬品の溶媒として生体内に投与
することは、毒性があることから好ましくない。Many flavonoid compounds exist naturally as glycosides bound to sugars, but their differentiation-inducing activity is even stronger in the free form that has undergone hydrolysis. but,
Glycosides have a small affinity for water, but the free form has extremely low solubility in water, making it difficult to use as an aqueous solution. In addition, it has been found that the solubility of the free form is improved in hot water, hot methanol, hot ethanol, hot hydrous alcohol, hot acetone, etc., but crystals precipitate immediately when cooled, so it is difficult to use as a solvent for pharmaceuticals. It is inappropriate as such. It dissolves in some organic solvents such as aprotic solvents, highly polar aprotic solvents, and solvents containing chlorinated solvents, but these solvents should not be administered to living organisms as pharmaceutical solvents because they are toxic. Undesirable.
特に、遊離型のフラボノイドは数個の芳香族系の水酸基
を有しているので、これをアセチル化、グルコシド化、
メチルエーテル化などの修飾が出来るが、これらの修飾
によって分化誘導活性が低下し、水に対する溶解度もあ
まり改善されない。In particular, free flavonoids have several aromatic hydroxyl groups, so they can be acetylated, glucosidated,
Modifications such as methyl etherification can be made, but these modifications reduce differentiation-inducing activity and do not significantly improve water solubility.
こうした理由により、フラボノイドの制癌活性は、例え
ばピリジン溶液で検定されたり、非常に微量しか可溶化
出来ない蛋白質可溶化剤に可溶化して検出されたり、不
均一に微量しか分散出来ない増粘剤で懸濁させて検出さ
れてきた。これらの方法は生体に及ぼす毒性、必要量の
確保、医薬品製剤の均質性、および医薬品としての取り
扱いなどから直ちに適用出来ない。また常温で、フラボ
ノイドは固体で高度不飽和脂肪酸を有するホスファチジ
ルコリンはペースト状である点から、タフレット、カプ
セル、顆粒および座薬などへの加工は容易であるが、液
剤、シロップなどの水性の分散物としては、前述した処
理を行っても加工し難い。For these reasons, the anticancer activity of flavonoids is often detected by, for example, assaying in pyridine solutions, solubilizing in protein solubilizers that can only solubilize very small amounts, or detecting flavonoids by thickening, which can only be dispersed unevenly in small amounts. It has been detected by suspending it in an agent. These methods cannot be immediately applied due to the toxicity to living organisms, securing the necessary amount, homogeneity of pharmaceutical preparations, and handling as pharmaceuticals. Furthermore, at room temperature, flavonoids are solid and phosphatidylcholine, which has highly unsaturated fatty acids, is in the form of a paste, so it is easy to process it into tufflets, capsules, granules, suppositories, etc., but it can be easily processed into aqueous dispersions such as liquids and syrups. is difficult to process even if the above-mentioned processing is performed.
一方、ホスファチジルコリンは疎水性領域と親水性領域
を合わせもつ両親媒性の分子である。そのため、水の中
では二分子が互いに炭化水素鎖を接し、極性基を水の方
に向けて層状に会合するベシクルが作られる。しかし、
水にも有機溶媒にも難溶性であるフラボノイドを、この
ベシクル中に包埋することは難しい、従って、これらの
問題点を解決した使いやすい形態の制癌剤およびその剤
型加工法の出現が望まれている。On the other hand, phosphatidylcholine is an amphipathic molecule that has both hydrophobic and hydrophilic regions. Therefore, in water, vesicles are formed in which two molecules assemble in a layered manner, with their hydrocarbon chains in contact with each other and their polar groups facing the water. but,
It is difficult to embed flavonoids, which are sparingly soluble in both water and organic solvents, in these vesicles.Therefore, it is desired to develop an easy-to-use anticancer drug that solves these problems and a method for processing its dosage form. ing.
（課題を解決するための手段）
本発明は、フラボノイドと炭素数１８〜２２のω３系高
度不飽和脂肪酸を有するホスファチジルコリンとを含有
することを特徴とする制癌剤である。(Means for Solving the Problems) The present invention is an anticancer agent characterized by containing a flavonoid and phosphatidylcholine having an ω3 highly unsaturated fatty acid having 18 to 22 carbon atoms.
本発明の第二の発明は、この制癌剤を製造する際に、ポ
リオキシエチレン硬化しマシ油を界面活性剤として０．
０１〜５重量％含有させ、乳化処理により水系懸濁液製
剤とすることを特徴とする制癌剤の製造法である。The second invention of the present invention is that when producing this anticancer agent, polyoxyethylene is hardened and mustard oil is used as a surfactant.
This is a method for producing an anticancer drug, which is characterized by containing 01 to 5% by weight and preparing an aqueous suspension preparation by emulsification treatment.
本発明の第三の発明は、フラボノイドと炭素数１８〜２
２のω−３系高度不飽和脂肪酸を有するホスファチジル
コリンの両者を溶解する単一系又は複合系溶媒にこの両
者を溶解し、次いで脱溶媒して得られる混合物を乳化処
理により水系懸濁剤製剤とすることを特徴とする制癌剤
の製造法である。The third invention of the present invention is a flavonoid and a carbon number of 18 to 2.
Both of the phosphatidylcholine and ω-3 highly unsaturated fatty acids are dissolved in a single or combined solvent that dissolves them, and then the mixture obtained by removing the solvent is emulsified to form an aqueous suspension formulation. This is a method for producing an anticancer drug.
本発明に用いられるフラボノイドには下記の基本骨格を
有する化合物を挙げることが出来る。Flavonoids used in the present invention include compounds having the following basic skeletons.
ＣＩ） （ＩＩ） ＣＩ
［Ｉ）（式中のρｈはフェニル基を示す。）
その具体例としては、次の化合物を挙げることができる
。CI) (II) CI
[I) (ρh in the formula represents a phenyl group.) Specific examples thereof include the following compounds.
〔Ｉ〕はフラボン類であり、クリシン、トリンキン、ア
ビゲニン、コスモシインなどがある。[I] is a flavonoid, and includes chrysin, torinkin, abigenin, and cosmosyin.
（ｎ）はフラバノン類であり、ピノセンプリン、ナリン
ゲニン、セリプルビンなどがあり、３位に水酸基を有す
るフラボノール類にはケンフェロール、アストラガリン
、クエルセチンなどがあり、さらに水酸基が増したジハ
イドロフラバノール類にはピノバンクシン、アスチルビ
ル、フスチンなどがある。(n) are flavanones, such as pinosemprin, naringenin, and selipulvin; flavonols with a hydroxyl group at the 3-position include kaempferol, astragalin, and quercetin; and dihydroflavanols with an increased hydroxyl group These include pinobankin, astilvir, and fuscin.
（Ｉ［［）はイソフラボン類でありダイゼイン、ゲニス
タイン、ゲニスチンなどがある。(I[[) is an isoflavone such as daidzein, genistein, and genistin.
天然フラボンは前述の如きフラボノイド骨格の主として
７位に、まれに５位、３位に単糖および多糖が結合した
配糖体として存在することが知られている。しかし、本
発明においては、これらの配糖体をエマルジョンで酵素
的に加水分解したり、硫酸との煮沸やメタノール性塩酸
との煮沸で化学的に加水分解した遊離型のフラボノイド
が好ましい。Natural flavones are known to exist as glycosides in which monosaccharides and polysaccharides are bound mainly at the 7-position, and rarely at the 5- and 3-positions, of the flavonoid skeleton as described above. However, in the present invention, free flavonoids obtained by enzymatically hydrolyzing these glycosides in an emulsion or chemically hydrolyzing them by boiling with sulfuric acid or methanolic hydrochloric acid are preferred.
従来報告されているフラボノイドの分化誘導活性に関し
、構造既知なフラボノイド配糖体の活性は、糖を含まな
いフラボノイド化合物のそれより低いことが証明されて
いる（キノシタ・ティ、サンカワ・ニー、タクマ・ティ
ー、アサヒ・ケイ、Ｊ 、 Ｐｈａｒｍａｃｏｂｉｏ−
Ｄｙｎ ８： ５−６４＋ １９８５） ６また、遊離
型のフラボン類の代表例であるアビゲニンはダリアやフ
ジモドキの花、高梁の包葉、種子、茎に含まれており、
これらの天然産の遊離型のフラボノイドを分離精製して
利用できる。遊離型のイソフラボン類の代表例であるゲ
ニスタインは、センプレンらによって合成法が確立され
ており（Ａｃｔａ Ｃｈｉｎ、 Ａｃａｄ、 Ｓｃｉ、
［１ｕｎｇ、ユ９．２７７、１９５９）、その他多く
の遊離型のフラボノイドについて多数の化学合成研究者
から合成法が報告されており、これらの化学合成品の遊
離型のフラボノイドも利用できる。さらに市販の遊離型
フラボノイドも利用できる。Regarding the previously reported differentiation-inducing activity of flavonoids, it has been proven that the activity of flavonoid glycosides with known structures is lower than that of sugar-free flavonoid compounds (Kinoshita T., Sankawa N., Takuma et al. T., Asahi K., J., Pharmacobio-
Dyn 8: 5-64+ 1985) 6 In addition, abigenin, which is a representative example of free flavones, is contained in dahlia and Fujimodoki flowers, bracts, seeds, and stems of Takahashi.
These naturally occurring free flavonoids can be separated and purified for use. The synthesis method for genistein, which is a representative example of free isoflavones, has been established by Semplen et al. (Acta Chin, Acad, Sci,
[1ung, Yu 9.277, 1959), and many other chemical synthesis researchers have reported synthetic methods for many other free flavonoids, and these chemically synthesized free flavonoids can also be used. Additionally, commercially available free flavonoids can also be used.
フラボノイドの使用量は水系懸濁液中０．０５〜３重量
％、好ましくは０．１〜２重量％であり、０．０５重量
％未満では薬効が不足し、３重量％を超えると良好な懸
濁液が得られない。The amount of flavonoid used in the aqueous suspension is 0.05 to 3% by weight, preferably 0.1 to 2% by weight. If it is less than 0.05% by weight, the medicinal efficacy is insufficient, and if it exceeds 3% by weight, it is not good. A suspension cannot be obtained.
本発明に用いられる炭素数１８〜２２のω−３系高度不
飽和脂肪酸を有するホスファチジルコリンには、下記の
基本骨格を有する化合物を挙げることが出来る。Examples of the phosphatidylcholine having an ω-3 highly unsaturated fatty acid having 18 to 22 carbon atoms used in the present invention include compounds having the following basic skeletons.
Ｈ，Ｃ−０−Ｒ。H, C-0-R.
Ｈ−Ｃ−０−Ｒ２（ＩＶ）
ＨｔＣ−ＰＯａ−−ＣＨｚ−ＣＨｚ−Ｎ”（ＣＨｚ）ｚ
（式中、Ｒ１とＲ２の少なくとも１つは炭素数１８〜２
２のω−３系高度不飽和脂肪酸基である。）炭素数１８
〜２２のω−３系高度不飽和脂肪酸基を有するホスファ
チジルコリンには強い分化誘導活性が認められている（
特開昭５９−４６２２６号、特開昭６３−１６１５４８
号、特開平１−２０３３３１号）。H-C-0-R2(IV) HtC-POa--CHz-CHz-N"(CHz)z
(In the formula, at least one of R1 and R2 has 18 to 2 carbon atoms.
It is the ω-3 highly unsaturated fatty acid group of No. 2. ) carbon number 18
Phosphatidylcholine, which has ~22 ω-3 highly unsaturated fatty acid groups, has been shown to have strong differentiation-inducing activity (
JP-A-59-46226, JP-A-63-161548
No., JP-A No. 1-203331).
炭素数１８〜２２のω−３系高度不飽和脂肪酸にはオク
タデカテトラエン酸（ＣＩＩＨ４ω−３）、エイコサテ
トラエン酸（ＣＺ。、４ω−３）、エイコサペンタエン
ｆｉｔ （ｃ、。８．ω−３）、ヘンエイコサペンタエ
ンｅｌｌ （Ｃｚ Ｉ： ｓω−３）、ドコサペンクエ
ン酸（Ｃ２２：Ｓω−３〉、ドコサヘキサエン酸（ＣＺ
□、ｈω−３）等がある。The ω-3 highly unsaturated fatty acids having 18 to 22 carbon atoms include octadecatetraenoic acid (CIIH4ω-3), eicosatetraenoic acid (CZ., 4ω-3), and eicosapentaene fit (c, .8. ω-3), heneicosapentaenoic acid (Cz I: sω-3), docosapene citric acid (C22: Sω-3), docosahexaenoic acid (CZ
□, hω-3), etc.
炭素数１８〜２２のω−３系高度不飽和脂肪酸を有する
ホスファチジルコリンの具体例として次の化合物を挙げ
ることが出来る。Specific examples of phosphatidylcholine having ω-3 highly unsaturated fatty acids having 18 to 22 carbon atoms include the following compounds.
例えば、ジエイコサペンタエノイルーホスファチジルコ
リン、シトコサヘキサエノイル−ホスファチジルコリン
、５ｎ−１バルミトイル−２−エイコサペンタエノイル
−ホスファチジルコリン、５ｎ−１オレオイル−２−エ
イコサペンタエノイル−ホスファチジルコリン、５ｎ−
１バルミトイル−２−ドコサヘキサエノイル−ホスファ
チジルコリン、および５ｎ−１オレオイル−２−ドコサ
ヘキサエノイル−ホスファチジルコリン等がある。For example, dieicosapentaenoyl-phosphatidylcholine, cytocosahexaenoyl-phosphatidylcholine, 5n-1 valmitoyl-2-eicosapentaenoyl-phosphatidylcholine, 5n-1 oleoyl-2-eicosapentaenoyl-phosphatidylcholine, 5n-
Examples include 1 valmitoyl-2-docosahexaenoyl-phosphatidylcholine and 5n-1 oleoyl-2-docosahexaenoyl-phosphatidylcholine.
これらの各化合物は、ホスファチジルコリンとして単独
又は混合状態で使用することが出来る。Each of these compounds can be used alone or in a mixed state as phosphatidylcholine.
又、これらの化合物は天然物からの抽出や合成法により
調製出来る。Moreover, these compounds can be prepared by extraction from natural products or by synthetic methods.
天然脂質原料からの抽出では、例えば、ニジマス胚を含
む魚卵の脂質から溶剤分別とカラム精製を用いた大量調
製法（特開平１−１６０９８９号）がある。合成法では
、例えば、高度不飽和脂肪酸と脱アシルリン脂体である
５ｎ−３グリセロホスホコリンとの縮合を経由した方法
（特開昭６２−１６４３９号、特開昭６４−２５８９号
）がある。For extraction from natural lipid raw materials, for example, there is a large-scale preparation method using solvent fractionation and column purification from lipids of fish eggs including rainbow trout embryos (Japanese Patent Application Laid-open No. 1-160989). As a synthetic method, for example, there is a method via condensation of a highly unsaturated fatty acid with 5n-3 glycerophosphocholine, which is a deacyl phospholipid (Japanese Patent Application Laid-open No. 62-16439, JP-A No. 64-2589).
ホスファチジルコリンの使用量は水系懸濁液中０．５〜
ｌＯ重量％、好ましくは１〜５重量％であり、０．５重
置％未満では薬効が不足し、１０重量％を超えると良好
な懸濁液が得られない。The amount of phosphatidylcholine used in the aqueous suspension is 0.5~
It is 10% by weight, preferably 1 to 5% by weight; if it is less than 0.5% by weight, the medicinal effect is insufficient, and if it exceeds 10% by weight, a good suspension cannot be obtained.
本発明の第二の発明に使用される界面活性剤としては、
非イオン性界面活性剤のポリオキシエチレン硬化ヒマシ
油が好適である。この活性剤に関し、本発明者らは、分
化誘導作用に何ら影響を与えないことを立証した（特開
昭６０−１７８８１６号）。As the surfactant used in the second invention of the present invention,
The nonionic surfactant polyoxyethylene hydrogenated castor oil is preferred. Regarding this active agent, the present inventors have demonstrated that it does not have any effect on the differentiation-inducing effect (Japanese Patent Application Laid-open No. 178816/1983).
この活性剤は疎水基原料に硬化しマシ油トリグリセリド
を使用し、親水基原料にポリエチレングリコール型のエ
チレンオキシドを使用して台底され、−船釣にはＲＣｏ
ｏ（Ｃ２）１４０）、ＩＨと表記される化学式で示され
る。エチレンオキシドの付加量はｎ＝１０〜８０程度で
あるが、使い易さ、懸濁力の強さから、本発明ではｎ＝
５０〜７５程度が特に好ましい。その添加量は０．０１
〜５重量％、好ましくは０．１〜２．５重量％である。This activator is hardened into a hydrophobic base raw material and uses mustard oil triglyceride, and the bottom is made using polyethylene glycol type ethylene oxide as a hydrophilic base raw material.
o(C2)140), represented by the chemical formula IH. The amount of ethylene oxide added is about n = 10 to 80, but in the present invention n =
About 50 to 75 is particularly preferable. The amount added is 0.01
-5% by weight, preferably 0.1-2.5% by weight.
この添加量が０．１重量％未満では乳化力が不足し、懸
濁液の調製後に沈降したフラボノイド化合物を、使用時
に振盪しても長時間良好な懸濁状態を保持出来ず、５重
量％を超えると、調製された懸濁液の粘性が著しく高く
なり、非常に取り扱い難い性状を示す。If the amount added is less than 0.1% by weight, the emulsifying power will be insufficient, and the flavonoid compounds that have precipitated after preparing the suspension will not be able to maintain a good suspension state for a long time even if shaken during use. If it exceeds this, the viscosity of the prepared suspension becomes extremely high and exhibits properties that are extremely difficult to handle.
また、本発明において、ポリオキシエチレン硬化ヒマシ
油の他に、さらにこれと同等の界面活性を示すポリオキ
シエチレンーポリオキシブロビレン共重合体、ポリアル
キレンゲリコール、ポリオキシアルキレン共重合体およ
びヒマシ油ポリオキシアルキレン誘導体など医療用に精
製されているものを併用することも可能である。In the present invention, in addition to polyoxyethylene hydrogenated castor oil, polyoxyethylene-polyoxybrobylene copolymers, polyalkylene gellicols, polyoxyalkylene copolymers, and castor It is also possible to use together with those purified for medical use such as oil polyoxyalkylene derivatives.
本発明に用いられる水は、注射用蒸留水又は注射用精製
水である。静注用に使用するために、グリセリンやブド
ー糖等の等張化剤を任意に添加することができる。The water used in the present invention is distilled water for injection or purified water for injection. For intravenous use, tonicity agents such as glycerin or glucose can optionally be added.
本発明の制癌剤の調製は、ポルテックスミキサ、超音波
ホモジナイザーおよび超音波細胞破砕機を用いることに
よって行われる。具体的には、炭素数１８〜２２のω−
３系高度不飽和脂肪酸を有するホスファチジルコリンを
有機溶媒に溶解し、不活性ガス気流下で脱溶媒しながら
容器中で薄膜状にする。この容器内に、ホスファチジル
コリン量に対し所要量のフラボノイドと界面活性剤を量
りとり、さらに接触面積を増すためにガラスピーズを入
れる０次いで、前述の乳化機で容器全体を撹拌振動させ
ながら、所要量の精製水、又は所望により等張化剤を加
えた精製水を微量ずつ添加し、約１時間均質化を行い、
水系懸濁液製剤とする。The anticancer agent of the present invention is prepared using a portex mixer, an ultrasonic homogenizer, and an ultrasonic cell disrupter. Specifically, ω- having 18 to 22 carbon atoms
Phosphatidylcholine having a tertiary highly unsaturated fatty acid is dissolved in an organic solvent and formed into a thin film in a container while removing the solvent under a stream of inert gas. Into this container, measure out the required amount of flavonoid and surfactant for the amount of phosphatidylcholine, and add glass beads to increase the contact area.Next, while stirring and vibrating the entire container with the emulsifier mentioned above, of purified water, or purified water added with an isotonic agent if desired, is added in small amounts, homogenized for about 1 hour,
Prepare as an aqueous suspension.
本発明の第三の発明に使用されるフラボノイドと炭素数
１８〜２２のω−３系高度不飽和脂肪酸を有するホスフ
ァチジルコリンの両者を溶解する溶媒には、単一系と複
合系がある。The solvent used in the third aspect of the present invention that dissolves both the flavonoid and the phosphatidylcholine having an ω-3 highly unsaturated fatty acid having 18 to 22 carbon atoms includes a single type and a composite type.
単一系溶媒にはピリジン、ジクロルメタンが挙げられ、
複合系溶媒にはジクロルメタン又はジオキサンにメタノ
ールを５〜４０重量％配合した混合液が挙げられる。上
記の溶媒系に対してｌ−当たりフラボノイドを１０〜１
００ｍｇと炭素数１８〜２２のω３系高度不飽和脂肪酸
を有するホスファチジルコリン５０〜Ｉ 、 ０００ｍ
ｇの両者を添加し、加熱還流して両者の溶解を確認後、
室温で５〜６時間、本溶液を減圧乾燥や凍結乾燥で脱溶
媒すると、粘着性混合物が調製される。この混合物は機
械的に水中に懸濁出来る。Single solvents include pyridine and dichloromethane,
Examples of the composite solvent include a mixture of dichloromethane or dioxane and methanol in an amount of 5 to 40% by weight. 10 to 1 flavonoid per liter for the above solvent system.
00mg and phosphatidylcholine 50-I, 000m containing ω3 highly unsaturated fatty acids having 18 to 22 carbon atoms.
After adding both g and heating to reflux to confirm dissolution of both,
A sticky mixture is prepared by removing the solvent by vacuum drying or freeze-drying the solution for 5-6 hours at room temperature. This mixture can be mechanically suspended in water.
上記粘着性混合物の懸濁液製剤への調製は、ポルテック
スミキサー、超音波ホモジナイザーおよび超音波細胞破
砕機等を用いることによって行われる。具体的には、炭
素数１８〜２２のω−３系高度不飽和脂肪酸を有するホ
スファチジルコリンとこのホスファチジルコリン量に対
して所要量のフラボノイドを量りとり、これらを前述の
溶媒系で加熱還流して完全に溶解する。次いで、不活性
ガス気流下で脱溶媒すると、残渣として黄褐色の粘着性
混合物が得られる。Preparation of the above-mentioned sticky mixture into a suspension preparation is performed by using a portex mixer, an ultrasonic homogenizer, an ultrasonic cell disrupter, and the like. Specifically, phosphatidylcholine having an ω-3 highly unsaturated fatty acid having 18 to 22 carbon atoms and the required amount of flavonoids for the amount of phosphatidylcholine are weighed out, and these are heated and refluxed in the above-mentioned solvent system to completely dissolve the phosphatidylcholine. dissolve. The solvent is then removed under a stream of inert gas, leaving a yellow-brown sticky mixture as a residue.
次いで乳化時の水との接触面積を増すため、容器中にガ
ラスピーズを入れたり、前述の乳化機で容器全体から撹
拌振動させたりしながら、所要量の精製水を添加し、約
１時間均質化を行い、水系懸濁液製剤とする。Next, in order to increase the contact area with water during emulsification, glass peas were placed in the container, and while stirring and vibrating the entire container using the emulsifying machine mentioned above, the required amount of purified water was added, and the mixture was left homogeneous for about 1 hour. and prepare an aqueous suspension.
以上のようにして得た本発明の水系懸濁液製剤は微黄褐
色を帯びた牛乳様溶液であり、粘性は牛乳と同じである
。本則は製造直後均質の溶液であるが、−昼夜保存後、
容器上部に浮遊物あるいは容器底部に沈澱物が生じる。The aqueous suspension preparation of the present invention obtained as described above is a milk-like solution with a slight yellowish brown color, and the viscosity is the same as that of milk. The basic rule is that the solution should be homogeneous immediately after production, but - after storage day and night,
Floating matter may appear at the top of the container or sediment may form at the bottom of the container.
しかし、容器全体を振動することにより製造直後の均質
な状態にもどり、その状態は数時間保持され、この変化
は半年以上保存後も再現出来る。そのため、本則は使用
直前に振動することにより随時均質な水系懸濁液製剤と
して使用出来る。However, by vibrating the entire container, it returns to its homogeneous state immediately after manufacture, and this state is maintained for several hours, and this change can be reproduced even after storage for more than half a year. Therefore, the main rule is that it can be used as a homogeneous aqueous suspension preparation at any time by shaking immediately before use.
本制癌剤は経口的利用や非経口的利用にかかわらず高圧
蒸気殺菌が必要であり、ホスファチジルコリン調製力・
らフラボノイドとの製剤化および殺菌操作に至る一連の
工程は、高度不飽和脂肪酸の保護のため不活性ガス気流
下で実施し、常に過酸化脂質量の管理が必要である。本
制癌剤の投与方法は目的とする臓器により、ルートを選
択出来る。This anticancer drug requires high-pressure steam sterilization regardless of whether it is used orally or parenterally.
The series of steps from formulation with flavonoids to sterilization are carried out under an inert gas stream to protect the highly unsaturated fatty acids, and the amount of lipid peroxide must be constantly controlled. The administration route for this anticancer drug can be selected depending on the target organ.
ただし、経静脈、経管筋肉内、腹腔内、皮肉、皮下環の
非経口の場合は、本組成物の安定性、生菌数等は通常の
脂肪乳剤と同し品質管理が必要である。また、投与量は
、対象腫瘍を有効に治療するに十分な量であり、腫瘍の
症状、投与ルートなどによって影響されるが、一般に、
経口投与の場合、大人では１日当たり約５０〜５００
ｍｇ／ｋｇ体重く子供では３０〜３００ ｍｇ／ｋｇ体
重）の範囲で、その上限は、好ましくは約３００ ｍｇ
／ｋｇ体重、更に好ましくは約２００ ｍｇ／ｋｇ体重
である。非経口投与の場合、その上限は、好ましくは約
４００ ｍｇ／ｋｇ体重程度であり、好ましくは約１８
０ ｍｇ／ｋｇ体重が適当である。なお、本制癌剤は、
腫瘍を有効に治療するに十分な量以上を実験動物の腹腔
内へ投与しても、何らの毒性の発現が認められなかった
。However, in the case of parenteral administration (intravenous, intramuscular, intraperitoneal, intravenous, subcutaneous), the stability, viable bacterial count, etc. of this composition require the same quality control as ordinary fat emulsions. In addition, the dosage is sufficient to effectively treat the target tumor, and is influenced by tumor symptoms, administration route, etc., but in general,
For adults, approximately 50 to 500 doses per day when administered orally.
mg/kg body weight (30 to 300 mg/kg body weight in children), with an upper limit of preferably about 300 mg/kg body weight.
/kg body weight, more preferably about 200 mg/kg body weight. In the case of parenteral administration, the upper limit is preferably about 400 mg/kg body weight, preferably about 18
0 mg/kg body weight is appropriate. In addition, this anticancer drug is
No toxicity was observed even when administered intraperitoneally to experimental animals in an amount sufficient to effectively treat tumors.
（発明の効果）
本発明によれば、内因性と外因性の分化誘導因子を有す
る薬剤を組み合わせることが出来るので、広範囲の未分
化な腫瘍細胞を正常な細胞に分化誘導する毒性の低い制
癌剤が提供される。また、水に不溶性でアプロチック溶
剤にしか溶解しなかったフラボノイドを懸濁液製剤に加
工することが出来るので、使用の容易な水性液剤が得ら
れる。そのため本発明によって提供される制癌剤は経口
投与、経静脈及び筋肉内、腹腔内、皮肉、皮下環の非経
口投与によって補給出来る。(Effects of the Invention) According to the present invention, since drugs having endogenous and exogenous differentiation-inducing factors can be combined, a low-toxicity anticancer drug that induces the differentiation of a wide range of undifferentiated tumor cells into normal cells can be obtained. provided. Furthermore, since flavonoids that are insoluble in water and soluble only in aprotic solvents can be processed into suspension preparations, easy-to-use aqueous solutions can be obtained. Therefore, the anticancer agent provided by the present invention can be supplemented by oral administration, intravenous, intramuscular, intraperitoneal, intravenous, or parenteral administration.
（実施例）
以下、実施例に基づき本発明をさらに具体的に説明する
。(Examples) Hereinafter, the present invention will be explained in more detail based on Examples.
実施例１
窒素気流下、２００−のナスフラスコに５ｎ−１オレオ
イル−３ｎ−２ドコサヘキサエノイル−ホスファチジル
コリ７ （ＦＡＢ−ＭＳ： （Ｍ＋Ｈ）” ８３２、
過酸化物量：電位差滴定法２２ｍｅｑ ／ ｋｇ ）を
６００ ｖｓｇ量りとり、エチルアルコール５０＋ｄを
添加して、加熱撹拌しながら溶解した。エバポレーター
で窒素気流下、ナスフラスコ中の溶媒を４０℃以下で留
去しホスファチジルコリンを薄膜状にした。このすスフ
ラスコ中にアビゲニン（ＧＥＮＡＹ社製） １５０ ｍ
ｇとポリオキシエチレン硬化ヒマシ油（ユニオフクスＨ
Ｃ−６０、日本油脂株式会社製、エチレンオキシド付加
量６２モル、水酸基価４２．４） １６５ ｍｇを量り
とり、直径２１１１１のガラスピーズ８０ｄ分と注射用
精製水０．５ ｄを加え、窒素シール後、ガラス栓でふ
たをした。このフラスコを、ポルテックスミキサー（Ｓ
ＣＩＥＮＴＩＦＩＣＩＮＤＵＳＴＲＩＥＳ ＩＮＣ，製
、ＶＯＲＴＥＸ ＧＥＮＩＢ−２型）で２５℃、１０分
間、振動撹拌を行った。Example 1 5n-1 oleoyl-3n-2 docosahexaenoyl-phosphatidyl coli 7 (FAB-MS: (M+H)" 832,
Amount of peroxide: potentiometric titration method 22 meq/kg) was weighed out to 600 vsg, 50+d of ethyl alcohol was added, and the mixture was dissolved with heating and stirring. The solvent in the eggplant flask was distilled off at 40° C. or lower using an evaporator under a nitrogen stream to form phosphatidylcholine into a thin film. Abigenin (manufactured by GENAY) 150 m in this flask
g and polyoxyethylene hydrogenated castor oil (Uniofx H
Weigh out 165 mg of C-60 (manufactured by NOF Corporation, ethylene oxide addition amount: 62 mol, hydroxyl value: 42.4), add 80 d of glass beads with a diameter of 21111 and 0.5 d of purified water for injection, and seal with nitrogen. , capped with a glass stopper. Add this flask to the Portex Mixer (S).
Vibration stirring was performed at 25° C. for 10 minutes using a VORTEX GENIB-2 model manufactured by CIENTIFICINDUSTRIES INC.
次いで、ふたをはずして窒素気流下、注射用精製水１−
を加え、ふたをしてポルテックスごキサ−で２５℃、１
０分間、振動撹拌を行った。Next, remove the lid and add purified water for injection 1- under a nitrogen stream.
Add to
Vibration stirring was performed for 0 minutes.
以上の操作を繰り返しながら、最終的に注射用精製水１
５−になるように加えてから、１時間振動撹拌した。得
られた懸濁液を窒素気流下、褐色ビンにＩＭｌずつ分注
した。While repeating the above operations, you will finally get 1 part of purified water for injection.
After adding the mixture at a concentration of 5-5, the mixture was stirred with vibration for 1 hour. The resulting suspension was dispensed into brown bottles in IM portions under a nitrogen stream.
得られた懸濁液製剤は、ｐＨ４，０７であり、淡黄色を
帯びた懸濁液で、牛乳と同様の粘性を示し、−昼夜の室
温保存で底部に白色微粉末の沈澱が生じた。保存状態で
の不均一な分散液は容器全体を振動することにより製造
直後の均質な状態にもどり、この状態はまた一昼夜保持
された。この保存状態での不均一な分散状態から均質な
懸濁液への可逆性は６ケ月以上の冷蔵保存後においても
再現出来た。The obtained suspension preparation had a pH of 4.07, was a pale yellowish suspension, and had a viscosity similar to that of milk, and a fine white powder was precipitated at the bottom when stored at room temperature day and night. The non-uniform dispersion in the stored state was returned to the homogeneous state immediately after production by vibrating the entire container, and this state was maintained again throughout the day. This reversibility from a non-uniform dispersion state to a homogeneous suspension under storage conditions was reproducible even after 6 months or more of refrigerated storage.
実施例２
窒素気流下、２００−のナスフラスコに５ｎ−１バルミ
トイル−３ｎ−２エイコサペンタエノイル−ホスファチ
ジルコリン（ＦＡＢ−ＭＳ： （Ｍ＋Ｈ）”７７９、
過酸化物量：電位差滴定法１８ｍｅｑ／ｋｇ）を１．５
ｇ量りとり、エチルアルコール３０−を添加して加熱撹
拌しながら溶解した。エバポレーターで窒素気流下、ナ
スフラスコ中の溶媒を４０℃以下で留去し、ホスファチ
ジルコリンを薄膜状にした。このナスフラスコにゲニス
タイン（ＧＥＮＡＹ社製） ０．３ｇとポリオキシエチ
レン硬化ヒマシ油（エチレンオキシド付加量６０モル）
０．７５ｇを量りとった。一方、注射用精製水１５０−
にグリセリン（局方、日本油脂株式会社製） ３．７５
ｇを添加し、撹拌下に均一溶液とする。この溶液を前述
のナスフラスコ中に添加し、窒素気流下超音波ホモジナ
イザー（井内盛栄堂株式会社製、型番ＵＳ−３００、出
力３００ Ｗ）で１時間超音波処理を室温で行った。得
られた懸濁液を窒素気流下褐色ビンに５Ｍｌずつ分注し
た。Example 2 5n-1 valmitoyl-3n-2 eicosapentaenoyl-phosphatidylcholine (FAB-MS: (M+H)"779,
Peroxide amount: Potentiometric titration method (18 meq/kg) 1.5
30 g of ethyl alcohol was added and dissolved while heating and stirring. The solvent in the eggplant flask was distilled off at 40°C or lower using an evaporator under a nitrogen stream to form phosphatidylcholine into a thin film. In this eggplant flask, 0.3 g of Genistein (manufactured by GENAY) and polyoxyethylene hydrogenated castor oil (60 mol of ethylene oxide added)
0.75g was weighed out. On the other hand, purified water for injection 150-
Glycerin (pharmacopoeia, manufactured by NOF Corporation) 3.75
g and stirred to form a homogeneous solution. This solution was added to the above-mentioned eggplant flask, and ultrasonication was performed at room temperature for 1 hour using an ultrasonic homogenizer (manufactured by Iuchi Seieido Co., Ltd., model number US-300, output 300 W) under a nitrogen stream. The resulting suspension was dispensed in 5 ml portions into brown bottles under a nitrogen stream.
得られた懸濁液製剤はｐＨ４，１３であり、淡黄色を帯
びた懸濁液で、牛乳と同様の粘性を示し、−昼夜の室温
保存でビンの底部に少量の白色微粉末の沈澱が生じた。The resulting suspension preparation had a pH of 4.13, was a pale yellowish suspension, and had a viscosity similar to that of milk; - A small amount of fine white powder was deposited at the bottom of the bottle when stored at room temperature day and night. occured.
保存状態での不均一な分散液は容器全体を振動すること
により製造直後の均質な状態にもどり、この状態はまた
一昼夜保持された。The non-uniform dispersion in the stored state was returned to the homogeneous state immediately after production by vibrating the entire container, and this state was maintained again throughout the day.
この保存状態での不均一な分散状態から均質な懸濁液へ
の可逆性は６ケ月以上の冷蔵保存後においても再現出来
た。This reversibility from a non-uniform dispersion state to a homogeneous suspension under storage conditions was reproducible even after 6 months or more of refrigerated storage.
実施例３
窒素気流下、２００−のナスフラスコにシトコサヘキサ
エノイル−ホスファチジルコリン（ＦＡＲ−ＭＳ：ＣＭ
＋Ｈ）”８７７ 、過酸化物量：電位差滴定法３３ｓ
ｅｑ ／ｋｇ）を３，１２５ Ｂ量りとり、エチＪＬｙ
アルコール８０−を添加して、加熱撹拌しながら溶解し
た。Example 3 Cytocosahexaenoyl-phosphatidylcholine (FAR-MS:CM
+H)”877, amount of peroxide: potentiometric titration method 33s
Weigh out 3,125 B (eq/kg),
Alcohol 80- was added and dissolved with heating and stirring.
エバポレーターで窒素気流下、ナスフラスコ中のｉ媒を
４０℃以下で留去し、ホスファチジルコリンを薄膜状に
した。このナスフラスコ中にケンフェロール（Ｍｅｒｃ
ｋ ＆ Ｃｏ、、 Ｉｎｃ、製） ８７５ ｔａｇとポ
リオキシエチレン硬化ヒマシ油（ユニオンクスＨＣ６０
、日本油脂株式会社製、エチレンオキシド付加量６２モ
ル、水酸基価４２．４） １，０００ ｔａｇを量りと
り、直径２ｍｍのガラスピーズ８０＋Ｒ１分と注射用精
製水ｌ−を加え窒素シール後、ガラス栓でふたをした。The i medium in the eggplant flask was distilled off at 40° C. or lower under a nitrogen stream using an evaporator to form phosphatidylcholine into a thin film. In this eggplant flask, kaempferol (Merc
K & Co, Inc.) 875 tag and polyoxyethylene hydrogenated castor oil (Unionx HC60
, manufactured by NOF Corporation, ethylene oxide addition amount 62 mol, hydroxyl value 42.4) Weigh out 1,000 tags, add 2 mm diameter glass beads 80 + R 1 minute and purified water for injection 1 -, seal with nitrogen, and then pour with a glass stopper. I put the lid on.
このフラスコを、ポルテックスミキサー（ＳＣＩＥＮＴ
ＩＦＩＣＩＮＤＵＳＴＲＩＥＳ、 ＩＮＣ，製、ＶＯＲ
ＴＥＸ ＧＥＮＩＥ−２型）で２５℃、１０分間、振動
撹拌を行った。次いでふたをはずし窒素気流下、注射用
精製水５１ｍ１を加え、ふたをしてポルテックスミキサ
ーで２５℃、１０分間振動撹拌を行った。This flask was mixed with a portex mixer (SCIENT).
Manufactured by IFICINDUSTRIES, INC., VOR
Vibration stirring was performed at 25° C. for 10 minutes using a TEX GENIE-2 model). Next, the lid was removed, and 51 ml of purified water for injection was added under a nitrogen stream, the lid was closed, and vibration stirring was performed at 25° C. for 10 minutes using a portex mixer.
以上の操作を繰り返しながら、最終的に注射用精製水１
００ ｉｄになるように加えてから１時間保持した。得
られた懸濁液を窒素気流下、褐色ビンに５ｄずつ分注し
た。While repeating the above operations, you will finally get 1 part of purified water for injection.
00 id and held for 1 hour. The resulting suspension was dispensed into brown bottles in 5 d portions under a nitrogen stream.
得られた懸濁液製剤はｐ Ｈ３，９２であり、淡黄色を
帯びた懸濁液で、牛乳と同様の粘性を示し、昼夜の室温
保存で底部に白色微粉末の沈澱が生じた。保存状態での
不均一な分散液は容器全体を振動することにより製造直
後の均質な状態に戻り、この状態はまた一昼夜保持され
た。この保存状態での不均一な分散状態から均質な懸濁
液への可逆性は６ケ月以上の冷蔵保存後において再現出
来た。The obtained suspension preparation had a pH of 3.92, was a pale yellowish suspension, and had a viscosity similar to that of milk, and a fine white powder was precipitated at the bottom when stored at room temperature day and night. The non-uniform dispersion in the stored state was returned to the homogeneous state immediately after production by vibrating the entire container, and this state was maintained again throughout the day. This reversibility from a non-uniform dispersion state to a homogeneous suspension under storage conditions was reproducible after 6 months or more of refrigerated storage.
実施例４
窒素気流下、３００ ｗｌｌのナスフラスコに５ｎ−１
オレオイル−５ｎ−２ドコサヘキサエノイル−ホスファ
チジルコリン（ＦＡＢ−ＭＳ： （Ｍ十Ｈ）ゝ８３２
、過酸化物量：電位差滴定法２２ｍｅｑ／ｋｇ）を１，
５００ｍｇとアビゲニンＣＧＥＮＡＹ社製） ２２５
ｍｇを量りとり、さらにピリジン１０−を添加し、加熱
還流して完全に溶解した。このピリジン溶液を一８５℃
で一晩凍結状態を保持し、室温で６時間凍結乾燥し、残
渣として黄褐色の粘着性混合物を得た。このフラスコ中
に直径２ｍｍのガラスピーズ２Ｏｄ分と注射用精製水０
．５ ｄを加え、窒素シール後、ガラス栓でふたをした
。このフラスコをポルテックスミキサー（ＳＣＩＥＮＴ
ＩＦＩＣＩＮＤＩＪＳＴＲＩＥＳ、 ＩＮＣ，製、
ＶＯＲＴＥＸ ＧＥＮＩＥ２型）で２５℃、１０分間
振動撹拌を行った。次いで、ふたをはずし窒素気流下、
注射用精製水ｌ−を加え、ふたをしてポルテックスミキ
サーで２５℃、１０分間振動撹拌を行った。Example 4 5n-1 in a 300 wll eggplant flask under nitrogen flow
Oleoyl-5n-2 docosahexaenoyl-phosphatidylcholine (FAB-MS: (M×H)ゝ832
, peroxide amount: potentiometric titration method 22 meq/kg) 1,
500mg and Abigenin (manufactured by CGENAY) 225
mg was weighed out, pyridine 10- was further added thereto, and the mixture was heated to reflux to completely dissolve. This pyridine solution was heated to -85°C.
The mixture was kept frozen overnight at room temperature, and lyophilized for 6 hours at room temperature, yielding a tan sticky mixture as a residue. In this flask, there are 2 Od of glass beads with a diameter of 2 mm and 0 of purified water for injection.
．． After adding 5 d of water and sealing with nitrogen, the container was covered with a glass stopper. This flask was mixed with a portex mixer (SCIENT).
Manufactured by IFICIINDIJSTRIES, INC.
Vibration stirring was performed at 25° C. for 10 minutes using a VORTEX GENIE Model 2). Next, remove the lid and under a nitrogen stream,
One liter of purified water for injection was added, the mixture was covered with a lid, and the mixture was subjected to vibration stirring at 25° C. for 10 minutes using a portex mixer.
上記の操作を繰り返しながら、最終的に注射用精製水１
５０ ｍになるように加えてから１時間振動撹拌を行っ
た。得られた懸濁液を窒素気流下、褐色ビンにＩＭｌず
つ分注した。得られた懸濁液製剤はｐ Ｈ４，１７であ
り、淡黄色を帯びた懸濁液で、牛乳と同様の粘性を示し
、−昼夜保存後、容器上部に浮遊物が生じた。この保存
期間中に生じた不均一な分散状態は容器全体を振動する
ことにより製造直後の均質な状態に戻り、この状態は数
時間保持された。この保存期間中の不均一な分散状態か
ら均質な懸濁液への可逆性は６ケ月以上の冷蔵保存後に
おいても再現出来た。While repeating the above operations, finally 1 liter of purified water for injection
After adding the solution to a total thickness of 50 m, vibration stirring was performed for 1 hour. The resulting suspension was dispensed into brown bottles in IM portions under a nitrogen stream. The resulting suspension formulation had a pH of 4.17, was a pale yellowish suspension, and had a viscosity similar to that of milk, with floating matter forming at the top of the container after being stored day and night. The non-uniform dispersion state that occurred during this storage period was returned to the homogeneous state immediately after production by vibrating the entire container, and this state was maintained for several hours. This reversibility from a non-uniform dispersion state to a homogeneous suspension during the storage period was reproducible even after refrigerated storage for more than 6 months.
実施例５
窒素気流下、３００Ｍ１のナスフラスコに５ｎ−１バル
ミトイル−５ｎ−２エイコサペンタエノイル−ホスファ
チシルコリ７ （ＦＡＢ−ＭＳ： （Ｍ＋Ｈ）”７７
９、過酸化物量：電位差滴定法１８ｍｅｑ／ｋｇ）２、
０００＋ｗｇとゲニスタイン（ＧＥＮＡＹ社製） ４０
０ｍｇを量りとり、さらにジクロルメタン１０−を添加
し加熱還流して完全に溶解した。このジクロルメタン溶
液を４０℃以下で少量になるまで濃縮し、さらに室温で
５時間減圧乾燥し、残渣として黄褐色の粘着性混合物を
得た。このフラスコ中に注射用精製水２００−を添加し
、窒素気流下、超音波ホモジナイザー（井内盛栄堂株式
会社、型番ＵＳ−３００、出力３００ Ｗ）で１時間超
音波処理を室温で行った。Example 5 5n-1 valmitoyl-5n-2 eicosapentaenoyl-phosphatisilcoli 7 (FAB-MS: (M+H)"77 in a 300 M1 eggplant flask under nitrogen flow
9. Peroxide amount: potentiometric titration method 18 meq/kg) 2.
000+wg and Genistein (manufactured by GENAY) 40
0 mg was weighed out, 10-dichloromethane was further added, and the mixture was heated and refluxed to completely dissolve. This dichloromethane solution was concentrated to a small amount below 40° C., and further dried under reduced pressure at room temperature for 5 hours to obtain a yellowish brown sticky mixture as a residue. 200 ml of purified water for injection was added to this flask, and ultrasonication was performed at room temperature for 1 hour using an ultrasonic homogenizer (Iuchi Seieido Co., Ltd., model number US-300, output 300 W) under a nitrogen stream.
得られた懸濁液を窒素気流下、褐色ビンに５−ずつ分注
した。The resulting suspension was dispensed into brown bottles in 5 portions under a nitrogen stream.
得られた懸濁液製剤はｐ Ｈ４，１８であり、淡黄色を
帯びた懸濁液で、牛乳と同様の粘性を示し、昼夜の室温
保存後、容器上部に浮遊物が生した。The obtained suspension preparation had a pH of 4.18, was a pale yellowish suspension, and had a viscosity similar to that of milk, and floating matter formed at the top of the container after being stored at room temperature day and night.
この保存期間中に生した不均一な分散状態は、容器全体
を振動することにより製造直後の均質な状態に戻り、こ
の状態は数時間保持された。この保存期間中の不均一な
分散状態から均質な懸濁液への可逆性は６ケ月以上の冷
蔵保存後においても再現出来た。The non-uniform dispersion state that occurred during this storage period was returned to the homogeneous state immediately after production by vibrating the entire container, and this state was maintained for several hours. This reversibility from a non-uniform dispersion state to a homogeneous suspension during the storage period was reproducible even after refrigerated storage for more than 6 months.
実施例６
窒素気流下、２００ ｄのナスフラスコにシトコサヘキ
サエノイル−ホスファチジルコリン（ＦＡＢ−ＭＳ：（
Ｍ＋Ｈ）”８７７、過酸化物量：電位差滴定法３３ｍｅ
ｑ／ ｋｇ） １，０００ｍｇとケンフェロール（Ｍｅ
ｒｃｋ ＆ Ｃｏ、。Example 6 Cytocosahexaenoyl-phosphatidylcholine (FAB-MS: (
M+H)"877, amount of peroxide: potentiometric titration method 33me
q/kg) 1,000mg and kaempferol (Me
rck & co.
Ｉｎｃ、製） １００ ｍｇを量りとり、さらにジオキ
サン／メタノール混液（７／３、ｖ／ｖ）ｌＯｄを添加
し加熱還流して完全に溶解した。この溶液を一８５℃で
一晩凍結状態を保持し、室温で６時間凍結乾燥し、残渣
として黄褐色の粘着性混合物を得た。このフラスコ中に
注射用精製水１００−を添加し、窒素気流下、超音波ホ
モジナイザー（井内盛栄堂株式会社、型番ＵＳ−３００
、出力３００ Ｗ）で１時間超音波処理を室温で行った
。得られた懸濁液を窒素気流下、褐色ビンに５−ずつ分
注した。Inc.) 100 mg was weighed out, and 1Od of dioxane/methanol mixture (7/3, v/v) was added and heated to reflux to completely dissolve. The solution was kept frozen at -85° C. overnight and freeze-dried at room temperature for 6 hours, yielding a tan sticky mixture as a residue. Add 100% of purified water for injection into this flask, and use an ultrasonic homogenizer (Iuchi Seieido Co., Ltd., model number US-300) under a nitrogen stream.
, output power 300 W) for 1 hour at room temperature. The resulting suspension was dispensed into brown bottles in 5 portions under a nitrogen stream.
得られた懸濁液製剤はｐ Ｈ３，９７であり、淡黄色を
帯びた懸濁液で、牛乳と同様の粘性を示し、−昼夜の室
温保存後、容器上部に浮遊物が生じた。The resulting suspension formulation had a pH of 3.97, was a pale yellowish suspension, and had a viscosity similar to that of milk, with floating matter forming at the top of the container after storage at room temperature day and night.
この保存期間中に生じた不均一な分散状態は容器全体を
振動することにより製造直後の均質な状態に戻り、この
状態は数時間保持された。この保存期間中の不均一な分
散状態から均質な懸濁液への可逆性は６ケ月以上の冷蔵
保存後においても再現出来た。The non-uniform dispersion state that occurred during this storage period was returned to the homogeneous state immediately after production by vibrating the entire container, and this state was maintained for several hours. This reversibility from a non-uniform dispersion state to a homogeneous suspension during the storage period was reproducible even after refrigerated storage for more than 6 months.
実施例７
窒素気流下、３００ Ｍｌのナスフラスコに５ｎ−１オ
レオイル−３ｎ−２ドコサヘキサエノイル−ホスファチ
ジルコリン（ＦＡＢ−ＭＳ： （Ｍ十Ｈ）” ８３２
、過酸化物量：電位差滴定法２２ｍｅｑ／ｋｇ）を６２
５■とアビゲニン（ＧｌｌｉＮＡＹ社製）１７５■を量
りとり、さらにピリジン１０−を添加し、加熱還流して
完全に溶解した。このピリジン溶液を一８５℃で一晩凍
結状態を保持し、室温で６時間凍結乾燥し、残渣として
黄褐色の粘着性混合物を得た。このフラスコ中に直径２
箇のガラスピーズ２０＋ｄ分と注射用精製水０．５＋ｄ
を加え、窒素シール後、ガラス栓でふたをした。このフ
ラスコをポルテックスミキサー（ＳＣｒＥＮＴＩＦＩＣ
１Ｎ０ＵＳＴＲＩＥＳ、 ＩＮＣ，製、ＶＯＲＴＥχＧ
ＥＮＩＥ−２型）で２５℃、１０分間振動撹拌を行った
。次いで、ふたをはずし窒素気流下、注射用精製水１−
を加え、ふたをしてポルテックスミキサーで２５℃、１
０分間振動撹拌を行った。Example 7 Under a nitrogen stream, 5n-1 oleoyl-3n-2 docosahexaenoyl-phosphatidylcholine (FAB-MS: (M+H)" 832
, peroxide amount: potentiometric titration method 22 meq/kg) to 62
5 .mu. and Abigenin (manufactured by GlliNAY) 175 .mu. were weighed out, pyridine 10- was added thereto, and the mixture was heated and refluxed to completely dissolve. The pyridine solution was kept frozen at -85° C. overnight and freeze-dried at room temperature for 6 hours to obtain a tan sticky mixture as a residue. In this flask, there is a diameter of 2
Glass beads 20+d and purified water for injection 0.5+d
was added, sealed with nitrogen, and then covered with a glass stopper. This flask was mixed with a portex mixer (SCrENTIFIC).
1N0USTRIES, Inc., VORTEχG
Vibration stirring was performed at 25° C. for 10 minutes using an ENIE-2 model). Next, remove the lid and add purified water for injection 1- under a nitrogen stream.
Add to
Vibration stirring was performed for 0 minutes.
上記の操作を繰り返しながら、最終的に注射用精製水１
００ ｍになるように加えてから１時間振動撹拌を行っ
た。得られた懸濁液を窒素気流下、褐色ビンに１１ｄず
つ分注した。得られた懸濁液製剤はｐＨ４，２０であり
、淡黄色を帯びた懸濁液で、牛乳と同様の粘性を示し、
−昼夜保存後、容器上部に浮遊物が生じた。この保存期
間中に生じた不均一な分散状態は容器全体を振動するこ
とにより製造直後の均質な状態に戻り、この状態は数時
間保持された。この保存期間中の不均一な分散状態から
均質な懸濁液への可逆性は６ケ月以上の冷蔵保存後にお
いても再現出来た。While repeating the above operations, finally 1 liter of purified water for injection
After addition, vibration stirring was performed for 1 hour. The obtained suspension was dispensed into brown bottles in 11 d portions under a nitrogen stream. The resulting suspension formulation had a pH of 4.20, was a pale yellowish suspension, and had a viscosity similar to that of milk.
- After storage for days and nights, floating matter appeared on the top of the container. The non-uniform dispersion state that occurred during this storage period was returned to the homogeneous state immediately after production by vibrating the entire container, and this state was maintained for several hours. This reversibility from a non-uniform dispersion state to a homogeneous suspension during the storage period was reproducible even after refrigerated storage for more than 6 months.
〔急性毒性１ （マウス）〕
実施例で調製した懸濁液製剤を投与直前に振動し、体重
２５〜３０ｇの４週令の雌雄の１２９系マウス（ジャク
ソンラボ製）６匹に、ゾンデを通して経口で胃腔内に強
制的に２ｉ！１間の期間に１回０．１ｍｆずつ断続的に
７回投与し、さらに最終投与後７日間観察した。[Acute Toxicity 1 (Mouse)] Immediately before administration, the suspension preparation prepared in Example was vibrated and administered orally through a sonde to six 4-week-old male and female 129 strain mice (manufactured by Jackson Labs) weighing 25 to 30 g. 2i forcibly into the gastric cavity! The drug was administered intermittently at a dose of 0.1 mf 7 times over a period of 1 hour, and further observed for 7 days after the final administration.
その結果、いずれの実施例についても、本則に基因する
と思われる著明な急性毒性症状を発現したものはなかっ
た。As a result, none of the Examples developed significant acute toxicity symptoms that were considered to be caused by the main rule.
〔急性毒性２ （マウス）〕
実施例で調製した懸濁液製剤を投与直前に振動し、注射
器で採取し、体重２５〜３０ｇの４週令の雌雄の１２９
系マウス（ジャクソンラボ製）４匹に、腹腔内に２週間
の期間に１回０．４−ずつ断続的に７回投与し、さらに
最終投与後７日間観察した。[Acute Toxicity 2 (Mice)] Immediately before administration, the suspension preparation prepared in Example was shaken and collected with a syringe.
Four mouse mice (manufactured by Jackson Labs) were intraperitoneally administered with 0.4-dose intermittently 7 times over a 2-week period, and further observed for 7 days after the final administration.
その結果、いずれの実施例についても本則に基因すると
思われる著明な急性毒性症状を発現したものはなかった
。As a result, none of the Examples developed significant acute toxicity symptoms that were considered to be caused by the main rule.
〔制癌テスト１〕
制癌テストに用いた奇形腫細胞は、毎月−度、１２９系
マウス（ジャクソンラボ製）の腹腔から腹腔へと移植す
ることにより継代を行った。アッセイを行う際にも、移
植後約１ケ月のマウスより腹水を採取し、その約０．１
５−を２５〜２６ｇの検定用マウス（ジャクフンラボ製
１２９系マウス、−群６匹）の腹腔に移植した。その際
、細胞数から必要に応じ、腹水を生理的食塩水で２〜３
倍に希釈後、腹腔に移植した。移植の翌日より実施例４
で調製した懸濁液製剤を投与直前に振動し、注射器で採
取し、腹腔内に１４日間の期間に１回０．４−ずつ断続
的に７回投与した。その結果、平均生存日数はコントロ
ール群で４０．７日であったが、投与群で４４．７日と
有意に制癌効果が認められた。[Cancer control test 1] The teratoma cells used in the cancer control test were subcultured by transplanting them into the peritoneal cavity of 129 strain mice (manufactured by Jackson Lab) once every month. When conducting the assay, ascites fluid was collected from mice approximately 1 month after transplantation, and about 0.1
5- was transplanted into the abdominal cavity of 25 to 26 g test mice (129 series mice manufactured by Jakuhun Lab, 6 mice in the - group). At that time, depending on the number of cells, ascites should be diluted with physiological saline for 2 to 3 minutes.
After diluting it twice, it was transplanted into the peritoneal cavity. Example 4 from the day after transplantation
The suspension preparation prepared above was shaken immediately before administration, collected with a syringe, and administered intraperitoneally intermittently at a dose of 0.4 - 7 times over a 14-day period. As a result, the average survival time was 40.7 days in the control group, but 44.7 days in the treated group, indicating a significant anticancer effect.
〔制癌テスト２〕
制癌テストに用いた奇形腫細胞は、毎月−度、１２９系
マウス（ジャクソンラボ製）の腹腔から腹腔へと移植す
ることにより継代を行った。アッセイを行う際にも、移
植後約１ケ月のマウスより腹水を採取し、その約０．１
５−を２５〜２６ｇの検定用マウス（ジャクフンラボ製
１２９系マウス、−群６匹）の腹腔に移植した。移植の
翌日より実施例７で調製した懸濁液製剤を投与直前に振
動し、注射器で採取し、腹腔内に１４日間の期間に１回
０．４＋ｄずっ断続的に７回投与した。その結果、平均
生存日数はコントロール群で２５．７日であったが、投
与群で２８．７日と有意に制癌効果が認められた。[Cancer control test 2] The teratoma cells used in the cancer control test were subcultured by transplanting them into the peritoneal cavity of 129 strain mice (manufactured by Jackson Lab) once every month. When conducting the assay, ascites fluid was collected from mice approximately 1 month after transplantation, and about 0.1
5- was transplanted into the abdominal cavity of 25 to 26 g test mice (129 series mice manufactured by Jakuhun Lab, 6 mice in the - group). Starting the day after transplantation, the suspension preparation prepared in Example 7 was shaken immediately before administration, collected with a syringe, and administered intraperitoneally intermittently for 0.4+d each time for 7 times over a 14-day period. As a result, the average survival time was 25.7 days in the control group, but 28.7 days in the treated group, indicating a significant anticancer effect.
Claims (3)
不飽和脂肪酸を有するホスファチジルコリンとを含有す
ることを特徴とする制癌剤。(1) An anticancer agent characterized by containing a flavonoid and phosphatidylcholine having an ω-3 highly unsaturated fatty acid having 18 to 22 carbon atoms.
シエチレン硬化ヒマシ油を界面活性剤として０．０１〜
５重量％含有させ、乳化処理により水系懸濁液製剤とす
ることを特徴とする制癌剤の製造法。(2) When producing the anticancer agent according to claim 1, polyoxyethylene hydrogenated castor oil is used as a surfactant from 0.01 to
1. A method for producing an anticancer drug, which comprises containing 5% by weight and preparing an aqueous suspension preparation by emulsification treatment.
不飽和脂肪酸を有するホスファチジルコリンの両者を溶
解する単一系又は複合系溶媒にこの両者を溶解し、次い
で脱溶媒して得られる混合物を乳化処理により水系懸濁
剤製剤とすることを特徴とする制癌剤の製造法。(3) Dissolve both flavonoids and phosphatidylcholine containing omega-3 highly unsaturated fatty acids having 18 to 22 carbon atoms in a single or combined solvent, and then remove the solvent to obtain a mixture. A method for producing an anticancer agent, which comprises preparing an aqueous suspension formulation through emulsification treatment.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP7216390A JPH03275625A (en) | 1990-03-23 | 1990-03-23 | Carcinostatic agent and production thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP7216390A JPH03275625A (en) | 1990-03-23 | 1990-03-23 | Carcinostatic agent and production thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH03275625A true JPH03275625A (en) | 1991-12-06 |
Family
ID=13481308
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP7216390A Pending JPH03275625A (en) | 1990-03-23 | 1990-03-23 | Carcinostatic agent and production thereof |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH03275625A (en) |
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0633022A2 (en) | 1993-07-09 | 1995-01-11 | Kureha Chemical Industry Co., Ltd. | Chondroprotective flavones |
| EP0691852A1 (en) * | 1993-03-31 | 1996-01-17 | D-Pharm, Ltd. | Prodrugs with enhanced penetration into cells |
| US5587459A (en) * | 1994-08-19 | 1996-12-24 | Regents Of The University Of Minnesota | Immunoconjugates comprising tyrosine kinase inhibitors |
| WO1998016221A1 (en) * | 1996-10-14 | 1998-04-23 | Korea Institute Of Science And Technology | NARINGIN AND NARINGENIN AS 3-HYDROXY-3-METHYLGLUTARYL CoA(HMG-CoA) REDUCTASE INHIBITOR |
| WO1999021548A1 (en) * | 1997-10-28 | 1999-05-06 | Korea Institute Of Science And Technology | Naringin and naringenin as inhibitor of acyl coa-cholesterol-o-acyltransferase, inhibitor of macrophage-lipid complex accumulation on the arterial wall and preventive or treating agent for hepatic diseases |
| US5911995A (en) * | 1994-08-19 | 1999-06-15 | Regents Of The University Of Minnesota | EGF-genistein conjugates for the treatment of cancer |
| EP1329219A4 (en) * | 2000-09-29 | 2004-10-20 | Kimigafuchi Gakuen | Apoptosis inducers, caspase cascade activators and anticancer agents |
| ES2275435A1 (en) * | 2005-11-18 | 2007-06-01 | Farmaleis, S.L. | A combination comprising squalene, a phospholipid and an omega 3 fatty acid for the treatment of cancer |
| JP2012522730A (en) * | 2009-04-03 | 2012-09-27 | ウーハン ダーアン ジーイャオ ヨウシェンゴンス | Polysaccharide liposomes, their preparation and use |
-
1990
- 1990-03-23 JP JP7216390A patent/JPH03275625A/en active Pending
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0691852A1 (en) * | 1993-03-31 | 1996-01-17 | D-Pharm, Ltd. | Prodrugs with enhanced penetration into cells |
| EP0633022A2 (en) | 1993-07-09 | 1995-01-11 | Kureha Chemical Industry Co., Ltd. | Chondroprotective flavones |
| US5587459A (en) * | 1994-08-19 | 1996-12-24 | Regents Of The University Of Minnesota | Immunoconjugates comprising tyrosine kinase inhibitors |
| US5911995A (en) * | 1994-08-19 | 1999-06-15 | Regents Of The University Of Minnesota | EGF-genistein conjugates for the treatment of cancer |
| WO1998016221A1 (en) * | 1996-10-14 | 1998-04-23 | Korea Institute Of Science And Technology | NARINGIN AND NARINGENIN AS 3-HYDROXY-3-METHYLGLUTARYL CoA(HMG-CoA) REDUCTASE INHIBITOR |
| WO1999021548A1 (en) * | 1997-10-28 | 1999-05-06 | Korea Institute Of Science And Technology | Naringin and naringenin as inhibitor of acyl coa-cholesterol-o-acyltransferase, inhibitor of macrophage-lipid complex accumulation on the arterial wall and preventive or treating agent for hepatic diseases |
| EP1329219A4 (en) * | 2000-09-29 | 2004-10-20 | Kimigafuchi Gakuen | Apoptosis inducers, caspase cascade activators and anticancer agents |
| ES2275435A1 (en) * | 2005-11-18 | 2007-06-01 | Farmaleis, S.L. | A combination comprising squalene, a phospholipid and an omega 3 fatty acid for the treatment of cancer |
| JP2012522730A (en) * | 2009-04-03 | 2012-09-27 | ウーハン ダーアン ジーイャオ ヨウシェンゴンス | Polysaccharide liposomes, their preparation and use |
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