JPH01203330A - Carcinostatic agent - Google Patents
Carcinostatic agentInfo
- Publication number
- JPH01203330A JPH01203330A JP2534288A JP2534288A JPH01203330A JP H01203330 A JPH01203330 A JP H01203330A JP 2534288 A JP2534288 A JP 2534288A JP 2534288 A JP2534288 A JP 2534288A JP H01203330 A JPH01203330 A JP H01203330A
- Authority
- JP
- Japan
- Prior art keywords
- lpc
- docosahexaenoyl
- oil
- acid
- reacting
- 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
- 230000003327 cancerostatic effect Effects 0.000 title abstract 3
- 239000002246 antineoplastic agent Substances 0.000 claims abstract description 7
- 239000004480 active ingredient Substances 0.000 claims description 6
- 229940041181 antineoplastic drug Drugs 0.000 claims 1
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 abstract description 6
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 abstract description 6
- 239000002904 solvent Substances 0.000 abstract description 6
- MBMBGCFOFBJSGT-KUBAVDMBSA-N all-cis-docosa-4,7,10,13,16,19-hexaenoic acid Chemical compound CC\C=C/C\C=C/C\C=C/C\C=C/C\C=C/C\C=C/CCC(O)=O MBMBGCFOFBJSGT-KUBAVDMBSA-N 0.000 abstract description 5
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical class ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 abstract description 3
- 231100000053 low toxicity Toxicity 0.000 abstract description 3
- 239000008777 Glycerylphosphorylcholine Substances 0.000 abstract description 2
- 239000002253 acid Substances 0.000 abstract description 2
- 239000003054 catalyst Substances 0.000 abstract description 2
- 239000003795 chemical substances by application Substances 0.000 abstract description 2
- SUHOQUVVVLNYQR-MRVPVSSYSA-N choline alfoscerate Chemical compound C[N+](C)(C)CCOP([O-])(=O)OC[C@H](O)CO SUHOQUVVVLNYQR-MRVPVSSYSA-N 0.000 abstract description 2
- 229940090949 docosahexaenoic acid Drugs 0.000 abstract description 2
- 235000020669 docosahexaenoic acid Nutrition 0.000 abstract description 2
- 229960004956 glycerylphosphorylcholine Drugs 0.000 abstract description 2
- 238000000034 method Methods 0.000 abstract description 2
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- WTJKGGKOPKCXLL-RRHRGVEJSA-N phosphatidylcholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCC=CCCCCCCCC WTJKGGKOPKCXLL-RRHRGVEJSA-N 0.000 description 8
- 150000001875 compounds Chemical class 0.000 description 7
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- WORJEOGGNQDSOE-UHFFFAOYSA-N chloroform;methanol Chemical compound OC.ClC(Cl)Cl WORJEOGGNQDSOE-UHFFFAOYSA-N 0.000 description 5
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- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical class OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 4
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- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 3
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- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 2
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- BAPJBEWLBFYGME-UHFFFAOYSA-N Methyl acrylate Chemical compound COC(=O)C=C BAPJBEWLBFYGME-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
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- 208000021841 acute erythroid leukemia Diseases 0.000 description 2
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- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 239000000594 mannitol Substances 0.000 description 2
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- 239000000463 material Substances 0.000 description 2
- 229920003145 methacrylic acid copolymer Polymers 0.000 description 2
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Chemical compound C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
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- 235000002639 sodium chloride Nutrition 0.000 description 2
- 235000000346 sugar Nutrition 0.000 description 2
- 238000010998 test method Methods 0.000 description 2
- NOOLISFMXDJSKH-UTLUCORTSA-N (+)-Neomenthol Chemical compound CC(C)[C@@H]1CC[C@@H](C)C[C@@H]1O NOOLISFMXDJSKH-UTLUCORTSA-N 0.000 description 1
- NNJPGOLRFBJNIW-HNNXBMFYSA-N (-)-demecolcine Chemical compound C1=C(OC)C(=O)C=C2[C@@H](NC)CCC3=CC(OC)=C(OC)C(OC)=C3C2=C1 NNJPGOLRFBJNIW-HNNXBMFYSA-N 0.000 description 1
- ILFPCMXTASDZKM-YFKPBYRVSA-N (1s)-2-methylidene-3-oxocyclopentane-1-carboxylic acid Chemical compound OC(=O)[C@H]1CCC(=O)C1=C ILFPCMXTASDZKM-YFKPBYRVSA-N 0.000 description 1
- JNYAEWCLZODPBN-JGWLITMVSA-N (2r,3r,4s)-2-[(1r)-1,2-dihydroxyethyl]oxolane-3,4-diol Chemical compound OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O JNYAEWCLZODPBN-JGWLITMVSA-N 0.000 description 1
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 description 1
- PXRKCOCTEMYUEG-UHFFFAOYSA-N 5-aminoisoindole-1,3-dione Chemical compound NC1=CC=C2C(=O)NC(=O)C2=C1 PXRKCOCTEMYUEG-UHFFFAOYSA-N 0.000 description 1
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- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
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- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
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- 235000003343 Brassica rupestris Nutrition 0.000 description 1
- 241000219193 Brassicaceae Species 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- NOOLISFMXDJSKH-UHFFFAOYSA-N DL-menthol Natural products CC(C)C1CCC(C)CC1O NOOLISFMXDJSKH-UHFFFAOYSA-N 0.000 description 1
- NNJPGOLRFBJNIW-UHFFFAOYSA-N Demecolcine Natural products C1=C(OC)C(=O)C=C2C(NC)CCC3=CC(OC)=C(OC)C(OC)=C3C2=C1 NNJPGOLRFBJNIW-UHFFFAOYSA-N 0.000 description 1
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- 229940123414 Folate antagonist Drugs 0.000 description 1
- 102000001554 Hemoglobins Human genes 0.000 description 1
- 108010054147 Hemoglobins Proteins 0.000 description 1
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- 229930192392 Mitomycin Natural products 0.000 description 1
- NWIBSHFKIJFRCO-WUDYKRTCSA-N Mytomycin Chemical compound C1N2C(C(C(C)=C(N)C3=O)=O)=C3[C@@H](COC(N)=O)[C@@]2(OC)[C@@H]2[C@H]1N2 NWIBSHFKIJFRCO-WUDYKRTCSA-N 0.000 description 1
- 235000019502 Orange oil Nutrition 0.000 description 1
- 235000019483 Peanut oil Nutrition 0.000 description 1
- 108010058864 Phospholipases A2 Proteins 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 235000019485 Safflower oil Nutrition 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- 206010043276 Teratoma Diseases 0.000 description 1
- 241000271577 Trimeresurus Species 0.000 description 1
- JXLYSJRDGCGARV-WWYNWVTFSA-N Vinblastine Natural products O=C(O[C@H]1[C@](O)(C(=O)OC)[C@@H]2N(C)c3c(cc(c(OC)c3)[C@]3(C(=O)OC)c4[nH]c5c(c4CCN4C[C@](O)(CC)C[C@H](C3)C4)cccc5)[C@@]32[C@H]2[C@@]1(CC)C=CCN2CC3)C JXLYSJRDGCGARV-WWYNWVTFSA-N 0.000 description 1
- YKTSYUJCYHOUJP-UHFFFAOYSA-N [O--].[Al+3].[Al+3].[O-][Si]([O-])([O-])[O-] Chemical compound [O--].[Al+3].[Al+3].[O-][Si]([O-])([O-])[O-] YKTSYUJCYHOUJP-UHFFFAOYSA-N 0.000 description 1
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- 150000001298 alcohols Chemical class 0.000 description 1
- 229940100198 alkylating agent Drugs 0.000 description 1
- 239000002168 alkylating agent Substances 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
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- 229940045713 antineoplastic alkylating drug ethylene imines Drugs 0.000 description 1
- 239000007900 aqueous suspension Substances 0.000 description 1
- HFACYLZERDEVSX-UHFFFAOYSA-N benzidine Chemical compound C1=CC(N)=CC=C1C1=CC=C(N)C=C1 HFACYLZERDEVSX-UHFFFAOYSA-N 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
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- FUFJGUQYACFECW-UHFFFAOYSA-L calcium hydrogenphosphate Chemical compound [Ca+2].OP([O-])([O-])=O FUFJGUQYACFECW-UHFFFAOYSA-L 0.000 description 1
- MKJXYGKVIBWPFZ-UHFFFAOYSA-L calcium lactate Chemical compound [Ca+2].CC(O)C([O-])=O.CC(O)C([O-])=O MKJXYGKVIBWPFZ-UHFFFAOYSA-L 0.000 description 1
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Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
【発明の詳細な説明】
（技術分野）
本発明は、ドコサヘキサエノイル−リゾフォス７７チジ
ルコリン（ｄｏｃｏｓａｈｅｘａｅｎｏｙｌ−１ｙｓｏ
ｐｈｏｓｐｈａ−ｔｉｄｙｌ ｃｈｏｌｉｎｅ）を有効
成分とする制癌剤に関する。Detailed Description of the Invention (Technical Field) The present invention provides docosahexaenoyl-lysophos 77tidylcholine (docosahexaenoyl-lysophos).
The present invention relates to an anticancer agent containing phospha-tidyl choline as an active ingredient.
（発明の背景）
従来、癌化学療法剤として、アルキル化剤（ナイトクジ
エンマスタード類、エチレンイミン類、スルホン酸エス
テル類）、代謝拮抗物質（葉酸拮抗剤、プリン拮抗剤、
ピリミジン拮抗剤）、植物性核***等（コルセミド、ビ
ンブラスチン等）、抗生物質（ザルコマイシン、カルチ
ノフイリン、マイトマイシン等）、ホルモン類（副腎ス
テロイド、男性ホルモン、女性ホルモン）及びポルフィ
リン錯塩（マーフィリン、Ｃ０ＰＰ）等が用いられてい
る。しかしながら、その殆んどは、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。(Background of the Invention) Conventionally, cancer chemotherapy agents include alkylating agents (night compound mustards, ethyleneimines, sulfonic acid esters), antimetabolites (folate antagonists, purine antagonists,
pyrimidine antagonists), plant nuclear fission, etc. (colcemid, vinblastine, etc.), antibiotics (sarcomycin, cartinophilin, mitomycin, etc.), hormones (adrenal steroids, male hormones, female hormones), and porphyrin complex salts (marphyrin, C0PP) etc. are used. However, most of them are cytotoxic substances and exhibit serious side effects, so the development of anticancer agents with low toxicity and excellent anticancer activity is strongly desired.
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た結果、先にザリガニ生体中より
、奇形腫細胞や赤芽球性白血病細胞に対し強力な分化誘
導活性を示すフォスファチジルコリンを単離し、その構
造解析を行い、該物質が優れた制癌剤として用いうるこ
とを見出したく特開昭６０−１９９８２１号公報参照）
。With this in mind, the present inventors searched for a substance with low toxicity and anticancer properties, and as a result, they discovered that it has a strong ability to induce differentiation of teratoma cells and erythroblastic leukemia cells in living crayfish. We isolated active phosphatidylcholine, analyzed its structure, and discovered that this substance could be used as an excellent anticancer agent.
.
その後、更に研究を進め、該物質の各種誘導体の化学合
成あるいは半合成を行ってその制癌活性（分化誘導活性
）を調べたところ、ドコサヘキサエノイルーリゾフォス
ファチジルコリンが優れた活性を示すことを見出し、本
発明を完成した。After that, further research was carried out, and various derivatives of the substance were chemically synthesized or semi-synthesized and their anticancer activity (differentiation inducing activity) was investigated, and docosahexaenoyl lysophosphatidylcholine was found to have excellent activity. They discovered this and completed the present invention.
（発明、の目的）
本発明の目的は、ドコサヘキサエノイルーリゾフォスフ
ァチジルコリンを有効成分とする制癌剤を提供すること
にある。(Objective of the Invention) An object of the present invention is to provide an anticancer agent containing docosahexaenoyl lysophosphatidylcholine as an active ingredient.
（発明の構成） て合成することができる。(Structure of the invention) can be synthesized by
Ｄ−ＬＰＧの合成
■ ドコサヘキサエン酸（ＤＭＡ）１１．２ｇ（３４，
２ｍＭ）を脱水ジクｏｏメタン２８ｎ＋ｊ！に溶解しＮ
、Ｎ’−ジシクロへキシルカルボジイミド（ＤＣＣ）
３．４ ｇ （１６，３ｍＭ）を加えて室温で２４時間
反応させＤＭＡ無水物７．７ｇを得た。Synthesis of D-LPG■ Docosahexaenoic acid (DMA) 11.2g (34,
2mM) dehydrated oo methane 28n+j! Dissolved in N
, N'-dicyclohexylcarbodiimide (DCC)
3.4 g (16.3 mM) was added and reacted at room temperature for 24 hours to obtain 7.7 g of DMA anhydride.
■ ＤＭＡ無水物７．７ｇ （１２，１ｍＭ）と脱水ジ
クロロメタン２５ｍ１とグリセロホスホリルコリン（Ｇ
Ｐ Ｃ） １．２５ ｇ （４，８ｍＭ）と４−ジメ
チルアミノピリジン（ＤＭＡ Ｐ） ０．５８ ｇ （
４，８０ＩＭ）を加え常温で２４時間反応させた。反応
後濾別し脱溶媒して粗フォスファチジルコリン（ＰＣ）
を得た。■ 7.7 g of DMA anhydride (12.1 mM), 25 ml of dehydrated dichloromethane, and glycerophosphorylcholine (G
PC) 1.25 g (4,8mM) and 4-dimethylaminopyridine (DMAP) 0.58 g (
4,80 IM) was added and reacted at room temperature for 24 hours. After the reaction, the crude phosphatidylcholine (PC) is obtained by filtering and removing the solvent.
I got it.
■ 粗ＰＣをクロロホルム−メタノール混液に溶解し、
イオン交換樹脂アンバーライト２００Ｃを充填したカラ
ムに通して触媒を除去した。■ Dissolve crude PC in chloroform-methanol mixture,
The catalyst was removed by passing through a column packed with ion exchange resin Amberlite 200C.
■ 脱溶媒後、脱水冷アセトン１００ｍｊ！を添加し冷
凍庫に３時間放置したのち、３０００ＲＰＭＸＩＯ分間
遠心分離した。この操作を２回繰り返して脱溶媒後、微
黄色の油状物を得た。■ After removing the solvent, use 100mj of dehydrated cold acetone! was added and left in the freezer for 3 hours, followed by centrifugation at 3000 RPMXIO minutes. After repeating this operation twice to remove the solvent, a pale yellow oil was obtained.
■ 油状物をシリカゲル（富士ゲル社製 ＣＧ３）の中
圧カラム（２，２ｃｍＸ ３０ｃｍ）に付した。メタノ
ール−クロロホルム（０〜１００％）で展開した。クロ
ロホルム−メタノール（４： ＩＶ／Ｖ）の画分に１．
２−シトコサへキサエノイル・フォスファチジルコリン
（ＤＤ−ＰＣ）６．０ｇを得た。(2) The oil was applied to a medium pressure column (2.2 cm x 30 cm) of silica gel (CG3, manufactured by Fuji Gel). Developed with methanol-chloroform (0-100%). 1. to the chloroform-methanol (4: IV/V) fraction.
6.0 g of 2-cytocosahexaenoyl phosphatidylcholine (DD-PC) was obtained.
■ 得られたＤＤ−ＰＣ２，５ｇに脱水エーテル−脱水
メタノール（９８： ２ｖハ）とハブ毒ホスホリパーゼ
Ａ２ （Ｔｒｉｍｅｒｅｓｕｒｕｓ ｆｌａｖｏｖｉ
ｒｉｄｉｓ和光純薬工業社製）２５ｍｇと１００ｍＭ塩
化カルシウム溶液５０ｍ１と２００ｍＭ）リス−塩酸緩
衝液２００＋ｔ＋ｊ！を添加し３７℃で２４時間インキ
ュベートした。■ Dehydrated ether-dehydrated methanol (98:2v Ha) and Trimeresurus flavovi phospholipase A2 were added to 2.5 g of the obtained DD-PC.
ridis Wako Pure Chemical Industries, Ltd.) 25mg and 100mM calcium chloride solution 50ml and 200mM) Lis-HCl buffer 200+t+j! was added and incubated at 37°C for 24 hours.
■ Ｂｌｉｇｈ −Ｄｙｅｒ法により抽出し、脱溶媒後
、脱水冷アセトン１００ｍ１を添加して冷凍庫に３時間
放置した。放置後３０００ＲＰＭＸ１０分間遠心分離し
た。この操作を２回繰り返し、脱溶媒後、白色の油状物
を得た。(2) Extraction was carried out by the Bligh-Dyer method, and after removing the solvent, 100 ml of cold dehydrated acetone was added and the mixture was left in a freezer for 3 hours. After standing, it was centrifuged at 3000 RPMX for 10 minutes. This operation was repeated twice to obtain a white oil after removing the solvent.
■ 油状物をシリカゲル（富士ゲル社製 ＣＧ３）の中
圧カラム（２，２ｃｍＸ ３０ｃｍ）に付した。メタノ
ール−クロロホルム（０〜１００％）で展開した。クロ
ロホルム−メタノール（１： ４ｖ／ｖ）の画分にＤ−
ＬＰＧｌ、９ｇを得た。(2) The oil was applied to a medium pressure column (2.2 cm x 30 cm) of silica gel (CG3, manufactured by Fuji Gel). Developed with methanol-chloroform (0-100%). D- in the chloroform-methanol (1:4 v/v) fraction.
9 g of LPGl was obtained.
分析値は次の通りである。The analytical values are as follows.
ｌ） 物質の形状：白色の油状物
２）ＧＣ（キャピラリーガスクロマトグラフィー）によ
る脂肪酸組成分析
Ｃ２２：６ ９９．６％
３） ＨＰＬＣによるＤ−ＬＰＣ組成分析ＯＤＳカラ
ム、流速： ｌ＋ｎｆ／ｍｉｎ ＳＵＶ２０５ｎｍ：溶
出液：メタノール、単一ピーク。l) Shape of substance: white oil 2) Fatty acid composition analysis by GC (capillary gas chromatography) C22:6 99.6% 3) D-LPC composition analysis by HPLC ODS column, flow rate: l+nf/min SUV205nm: elution Liquid: methanol, single peak.
４） 質量分析： ＦＡＢ−ＭＳより分子量Ｍ５６５（
ＣＭ＋Ｈ）” ５６６）を有する。4) Mass spectrometry: Molecular weight M565 (
CM+H)” 566).
本発明の制癌剤は、経口及び非経口投与のいずれも使用
可能であり、経口投与する場合は、軟・硬カプセル剤又
は錠剤、顆粒剤、細粒剤、散剤として投与され、非経口
投与する場合は、水溶性懸濁液、油性製剤などの皮下或
いは静脈注射剤、点滴剤及び固体状又は懸濁粘稠液状と
して持続的な粘膜吸収が維持できるように小葉のような
剤型で投与され得る。The anticancer agent of the present invention can be administered either orally or parenterally; when administered orally, it is administered as a soft/hard capsule, tablet, granule, fine granule, or powder; when administered parenterally, can be administered in the form of subcutaneous or intravenous injections such as aqueous suspensions, oil-based preparations, infusions, and solid or suspended viscous liquid forms such as lobules to maintain sustained mucosal absorption. .
本発明の有効成分の製剤化は、界面活性剤、賦形剤、滑
沢剤、佐剤、及び必要に応じて腸溶性製剤とするために
医薬的に許容し得る被膜形成物質、コーティング助剤等
を用いて適宜行うことができ、その具体例を挙げれば、
次のとおりである。The active ingredients of the present invention are formulated using surfactants, excipients, lubricants, adjuvants, and, if necessary, pharmaceutically acceptable film-forming substances and coating aids to form enteric-coated formulations. This can be done as appropriate using, for example,
It is as follows.
本発明の組成物の崩壊、溶出を良好ならしめるために、
界面活性剤、例えばアルコール、エステル類、ポリエチ
レングリコール誘導体、ソルビタンの脂肪酸エステル類
、硫酸化脂肪アルコール類等の１種又は２種以上を添加
することができる。In order to improve the disintegration and elution of the composition of the present invention,
One or more surfactants such as alcohols, esters, polyethylene glycol derivatives, fatty acid esters of sorbitan, sulfated fatty alcohols, etc. can be added.
また、賦形剤として、例えば蔗糖、乳糖、デンプン、結
晶セルロース、マンニット、軟質無水珪酸、アルミン酸
マグネシウム、メタ珪酸アルミン酸マグネシウム、合成
珪酸アルミニウム、炭酸カルシウム、炭酸水素ナトリウ
ム、リン酸水素カルシウム、カルボキシメチルセルロー
スカルシウム等の１種又は２種以上を組合せて添加する
ことができる。In addition, as excipients, for example, sucrose, lactose, starch, crystalline cellulose, mannitol, soft silicic anhydride, magnesium aluminate, magnesium metasilicate aluminate, synthetic aluminum silicate, calcium carbonate, sodium hydrogen carbonate, calcium hydrogen phosphate, Carboxymethyl cellulose calcium and the like can be added alone or in combination of two or more.
滑沢剤としては、例えばステアリン酸マグネシウム、タ
ルク、硬化油等を１種又は２種以上添加することができ
、また矯味剤及び矯臭剤として、食塩、サッカリン、糖
、マンニット、オレンジ油カンゾウエキス、クエン酸、
ブドウ糖、メントール、ユーカリ油、リンゴ酸等の甘味
剤、香料、着色料、保存料等を含有させてもよい。As a lubricant, for example, one or more types of magnesium stearate, talc, hydrogenated oil, etc. can be added, and as a flavoring agent and a flavoring agent, salt, saccharin, sugar, mannitol, orange oil licorice extract, etc. can be added. ,citric acid,
Sweeteners such as glucose, menthol, eucalyptus oil, and malic acid, fragrances, coloring agents, preservatives, and the like may be included.
懸濁剤、潤滑剤の如き佐剤としては、例えばココナツト
油、オリーブ油、ゴマ油、落花生油、乳酸カルシウム、
ベニバナ油、大豆リン脂質等を含有させることができる
。Examples of adjuvants such as suspending agents and lubricants include coconut oil, olive oil, sesame oil, peanut oil, calcium lactate,
Safflower oil, soybean phospholipids, etc. can be contained.
また皮膜形成物質としては、セルロース、糖類等の炭水
化物誘導体として酢酸フタル酸セルロース（ＣＰＡ）、
またアクリル酸系共重合体、二塩基酸モノエステル類等
のポリビニル誘導体としてアクリル酸メチル・メタアク
リル酸共重合体、メタアクリル酸メチル・メタアクリル
酸共重合体が挙げられる。Film-forming substances include cellulose, cellulose acetate phthalate (CPA) as carbohydrate derivatives such as sugars,
Examples of polyvinyl derivatives such as acrylic acid copolymers and dibasic acid monoesters include methyl acrylate/methacrylic acid copolymers and methyl methacrylate/methacrylic acid copolymers.
また、上記皮膜形成物質をコーティングするに際し、通
常使用されるコーティング助剤、例えば可塑剤の他、コ
ーティング操作時の薬剤相互の付着防止のための各種添
加剤を添加することによって皮膜形成剤の性質を改良し
たり、コーティング操作をより容易ならしめることがで
きる。なお、有効成分を皮膜形成物質を用いてマイクロ
カプセル化してから賦形剤等を混合した剤型としても良
い。In addition, when coating the above-mentioned film-forming substances, in addition to commonly used coating aids such as plasticizers, the properties of the film-forming agent can be improved by adding various additives to prevent mutual adhesion of chemicals during coating operations. This can improve the coating process and make coating operations easier. In addition, a dosage form may be prepared in which the active ingredient is microencapsulated using a film-forming substance and then excipients and the like are mixed therein.
次に代表的な剤型における配合比は下記の通りである。Next, the compounding ratio in typical dosage forms is as follows.
有 効 成 分 ０．１〜９０ 重量％０．３〜１
５ 重量％賦 形 剤 １０〜９９．８
〃 ８５〜９９．４ 〃滑 沢 剤
Ｏ〜５０ 〃 Ｏ〜２０ 〃
界面活性剤 Ｏ〜５０〃０〜２０〃
皮膜形成物質 ０．１〜５０ 〃０．３〜２０〃
特に好ましい賦形剤は、乳糖、結晶セルロース、カルボ
キシメチルセルロースカルシウムである。Active ingredient 0.1-90 Weight% 0.3-1
5 wt% excipient 10-99.8
〃85～99.4 〃Lubricant
O~50 〃 O~20 〃
Surfactant O~50〃0~20〃 Film forming substance 0.1~50〃0.3~20〃
Particularly preferred excipients are lactose, crystalline cellulose, and calcium carboxymethyl cellulose.
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、投与経路、剤型などによって左右
されるが、一般に、経口投与の場合、大人では１日当り
、約０．０１〜１００ｍｇ／ｋｇ体重（小人では０．０
１〜６０ｍｇ／ｋｇ体重）の範囲で、その上限は好まし
くは約５０ｍｇ／ｋｇ体重、更に好ましくは約１０ｍｇ
／ｋｇ体重程度であり、非経口投与の場合、その上限は
約１０ｍｇ／ｋｇ体重程度であり、好ましくは５ｍｇ／
ｋｇ体重、更に好ましくは２０ｇ ／ ｋｇ体重が適当
である。In addition, the dosage is sufficient to effectively treat the target tumor, and depends on the symptoms of the tumor, route of administration, dosage form, etc., but in general, in the case of oral administration, approximately 0.0 .01-100mg/kg body weight (0.0 for dwarfs)
1 to 60 mg/kg body weight), and the upper limit is preferably about 50 mg/kg body weight, more preferably about 10 mg
/kg body weight, and in the case of parenteral administration, the upper limit is about 10 mg/kg body weight, preferably 5 mg/kg body weight.
kg body weight, more preferably 20 g/kg body weight is suitable.
次に、本発明化合物の制癌活性を確認した制癌性試験法
について述べる。Next, the anticancer activity test method for confirming the anticancer activity of the compound of the present invention will be described.
フレンド白血病細胞（マウス赤芽球性白血病細胞、Ｂ８
細胞）に対する試験を行った。ＨＡＭのＦ−１２培地（
ＧＩＢＣＯ製）に１５％の牛胎児血清及び６０ｍｇ／ｌ
のカナマイシンう加えたものに、２．５ Ｘ １０ ’
ｃｅｌｌ／ｍ ｊ２となるようにＢ８細胞を接種し、こ
れに所定量の被験化合物を加える（最終容量５ｍ１）。Friend leukemia cells (mouse erythroblastic leukemia cells, B8
A test was conducted on cells). HAM's F-12 medium (
GIBCO) with 15% fetal bovine serum and 60 mg/l
of kanamycin plus 2.5 x 10'
B8 cells are inoculated at cell/m j2, and a predetermined amount of the test compound is added thereto (final volume: 5 ml).
８．０％炭酸ガス中、３７℃で７日間培養した後、オル
キン（Ｏｒｋｉｎ）のベンジジン染色法により染色し、
染色された細胞数、即ち、赤血球への分化によりヘモグ
ロビンを生成するようになった細胞数を測定し、全細胞
に対する比率から分化誘導率を求めた。After culturing at 37°C for 7 days in 8.0% carbon dioxide gas, the cells were stained using Orkin's benzidine staining method.
The number of stained cells, that is, the number of cells that began to produce hemoglobin due to differentiation into red blood cells, was measured, and the differentiation induction rate was determined from the ratio to the total cells.
以下に、本発明を製剤例及び試験例によって具体的に説
明する。The present invention will be specifically explained below using formulation examples and test examples.
製剤例１ （注射・点滴剤）
化合物 Ｄ−ＬＰＣｌＯｍｇを含有するように粉末ぶど
う糖５ｇを加えてバイアルに無菌的に分配し、密封した
上、窒素、ヘリウム等の不活性ガスを封入して冷暗所に
保存した。使用前にエタノールに溶解し、０．８５％生
理的食塩水ｔｏｏｍ１を添加して静脈内注射剤とし、１
日、１０〜１００ｍ！！を症状に応じて静脈内注射又は
点滴で投与する。Formulation Example 1 (Injection/Drop) Add 5 g of powdered glucose to contain the compound D-LPClOmg, dispense into vials aseptically, seal them, fill with inert gas such as nitrogen or helium, and store in a cool, dark place. saved. Before use, dissolve in ethanol and add 0.85% physiological saline toom1 to make an intravenous injection.
Sun, 10-100m! ! Administer by intravenous injection or drip depending on the symptoms.
製剤例２（注射・点滴剤）
化合物Ｄ −Ｌ Ｐ’Ｃ２ｍｇを用いて、製剤例１と同
様の方法により軽症用静脈内注射剤とし、１日、１０〜
１００ｍｊ！を症状に応じて静脈内注射又は点滴で投与
する。Formulation Example 2 (Injection/Drop) Using 2 mg of the compound D-L P'C, an intravenous injection for mild symptoms was prepared in the same manner as Formulation Example 1, and administered for 10 to 1 day.
100mj! Administer by intravenous injection or drip depending on the symptoms.
製剤例３ （腸溶性カプセル剤）
化合物Ｄ−ＬＰＧ５ｇ、乳糖、２．４６ｇ及びヒドロキ
シプロピルセルロース０．０４ ｇを各々とり、よく混
合した後、常法１こ従って粒状に成形し、これをよく乾
燥して篩別してピン、ヒートシール包装などに適した顆
粒剤を製造した。次に、酢酸フタル酸セルロース０．５
ｇ及びヒドロキシプロピルセルロースフタレ−） ０
．５ ｇを溶解して被覆基材となし、前記顆粒を浮遊流
動させつつこの基材を被覆して腸溶性の顆粒剤とした。Formulation Example 3 (Enteric-coated capsules) After thoroughly mixing 5 g of Compound D-LPG, 2.46 g of lactose, and 0.04 g of hydroxypropyl cellulose, it was formed into granules according to the conventional method 1, and this was thoroughly dried. The mixture was then sieved to produce granules suitable for pin, heat-seal packaging, etc. Next, cellulose acetate phthalate 0.5
g and hydroxypropyl cellulose phthalate) 0
．． 5 g was dissolved to form a coated base material, and the granules were coated on this base material while floating and flowing to give enteric-coated granules.
この組成物をカプセルに充填して腸溶性カプセル製剤１
００個を製造する。Enteric-coated capsule preparation 1 by filling this composition into capsules
Manufacture 00 pieces.
試験例（制癌活性試験）
化合物Ｄ−ＬＰＧを用い、前記試験法により、フレンド
白血病（Ｂ８）細胞の分化誘導活性を調べた。その結果
を次に示す。Test Example (Anticancer Activity Test) Compound D-LPG was used to investigate the differentiation-inducing activity of Friend leukemia (B8) cells according to the test method described above. The results are shown below.
Claims (1)
有効成分とする制癌剤Anticancer drug containing docosahexaenoyl-lysophosphatidylcholine as an active ingredient
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2534288A JPH01203330A (en) | 1988-02-05 | 1988-02-05 | Carcinostatic agent |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2534288A JPH01203330A (en) | 1988-02-05 | 1988-02-05 | Carcinostatic agent |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH01203330A true JPH01203330A (en) | 1989-08-16 |
Family
ID=12163225
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2534288A Pending JPH01203330A (en) | 1988-02-05 | 1988-02-05 | Carcinostatic agent |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH01203330A (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1994012170A2 (en) * | 1992-11-24 | 1994-06-09 | Institut National De La Sante Et De La Recherche Medicale | Polyunsaturated fatty acid based drugs, in particular docosahexaenoic acid, for use as platelet aggregation inhibitors and against essential fatty acid deficiencies of the brain |
| FR2857265A1 (en) * | 2003-07-08 | 2005-01-14 | Clinigenetics | Medicaments for combating diseases involving matrix metalloproteases, TolR4 receptor and/or CD36, especially arteriosclerosis or hypercholesterolemia, containing docosahexaenoic acid esters |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5396311A (en) * | 1977-01-29 | 1978-08-23 | Toyama Chem Co Ltd | Anti-cander drugs containing lysolecithins |
| JPS54106430A (en) * | 1978-02-07 | 1979-08-21 | Toyama Chem Co Ltd | Novel preparation of lysophosphatidylcholine analog |
| JPS5649322A (en) * | 1979-09-14 | 1981-05-02 | Toyama Chem Co Ltd | Composition, carcinostatic, and immune reactivator containing lysolin lipid |
| JPS57145811A (en) * | 1982-02-01 | 1982-09-09 | Toyama Chem Co Ltd | Carcinostatic agent containing lysophospholipid and phospholipid and preparation thereof |
| JPS59501211A (en) * | 1982-07-06 | 1984-07-12 | マツクス−プランク−ゲゼルシヤフト ツ−ル フエルデルング デル ヴイツセンシヤフテン エ− フアウ | Novel glycerin derivatives for phospholipid synthesis |
-
1988
- 1988-02-05 JP JP2534288A patent/JPH01203330A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5396311A (en) * | 1977-01-29 | 1978-08-23 | Toyama Chem Co Ltd | Anti-cander drugs containing lysolecithins |
| JPS54106430A (en) * | 1978-02-07 | 1979-08-21 | Toyama Chem Co Ltd | Novel preparation of lysophosphatidylcholine analog |
| JPS5649322A (en) * | 1979-09-14 | 1981-05-02 | Toyama Chem Co Ltd | Composition, carcinostatic, and immune reactivator containing lysolin lipid |
| JPS57145811A (en) * | 1982-02-01 | 1982-09-09 | Toyama Chem Co Ltd | Carcinostatic agent containing lysophospholipid and phospholipid and preparation thereof |
| JPS59501211A (en) * | 1982-07-06 | 1984-07-12 | マツクス−プランク−ゲゼルシヤフト ツ−ル フエルデルング デル ヴイツセンシヤフテン エ− フアウ | Novel glycerin derivatives for phospholipid synthesis |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1994012170A2 (en) * | 1992-11-24 | 1994-06-09 | Institut National De La Sante Et De La Recherche Medicale | Polyunsaturated fatty acid based drugs, in particular docosahexaenoic acid, for use as platelet aggregation inhibitors and against essential fatty acid deficiencies of the brain |
| WO1994012170A3 (en) * | 1992-11-24 | 1994-07-21 | Inst Nat Sante Rech Med | Polyunsaturated fatty acid based drugs, in particular docosahexaenoic acid, for use as platelet aggregation inhibitors and against essential fatty acid deficiencies of the brain |
| FR2857265A1 (en) * | 2003-07-08 | 2005-01-14 | Clinigenetics | Medicaments for combating diseases involving matrix metalloproteases, TolR4 receptor and/or CD36, especially arteriosclerosis or hypercholesterolemia, containing docosahexaenoic acid esters |
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