JPH01252605A - 5-fluorouracil-carrying chitosan - Google Patents
5-fluorouracil-carrying chitosanInfo
- Publication number
- JPH01252605A JPH01252605A JP7818288A JP7818288A JPH01252605A JP H01252605 A JPH01252605 A JP H01252605A JP 7818288 A JP7818288 A JP 7818288A JP 7818288 A JP7818288 A JP 7818288A JP H01252605 A JPH01252605 A JP H01252605A
- Authority
- JP
- Japan
- Prior art keywords
- chitosan
- fluorouracil
- formula
- reacting
- antitumor activity
- 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
- 229920001661 Chitosan Polymers 0.000 title claims abstract description 28
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 claims abstract description 26
- 229960002949 fluorouracil Drugs 0.000 claims abstract description 25
- 150000001875 compounds Chemical class 0.000 claims description 13
- 239000000126 substance Substances 0.000 claims description 5
- 239000002246 antineoplastic agent Substances 0.000 claims description 4
- 239000005714 Chitosan hydrochloride Substances 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 230000000259 anti-tumor effect Effects 0.000 abstract description 11
- 231100000053 low toxicity Toxicity 0.000 abstract description 5
- 210000004027 cell Anatomy 0.000 abstract description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 abstract description 3
- 210000004881 tumor cell Anatomy 0.000 abstract description 3
- QIPKQEKUQASMNI-UHFFFAOYSA-N 5-hydroxy-1h-pyrimidin-2-one Chemical compound OC1=CN=C(O)N=C1 QIPKQEKUQASMNI-UHFFFAOYSA-N 0.000 abstract 1
- 239000005057 Hexamethylene diisocyanate Substances 0.000 abstract 1
- RRAMGCGOFNQTLD-UHFFFAOYSA-N hexamethylene diisocyanate Chemical compound O=C=NCCCCCCN=C=O RRAMGCGOFNQTLD-UHFFFAOYSA-N 0.000 abstract 1
- 229920002101 Chitin Polymers 0.000 description 11
- 241000699670 Mus sp. Species 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 201000011510 cancer Diseases 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 150000004676 glycans Chemical class 0.000 description 2
- 125000004836 hexamethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[*:1] 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 230000000704 physical effect Effects 0.000 description 2
- 229920001282 polysaccharide Polymers 0.000 description 2
- 239000005017 polysaccharide Substances 0.000 description 2
- 150000003222 pyridines Chemical class 0.000 description 2
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Inorganic materials [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 2
- WSWCOQWTEOXDQX-MQQKCMAXSA-M (E,E)-sorbate Chemical compound C\C=C\C=C\C([O-])=O WSWCOQWTEOXDQX-MQQKCMAXSA-M 0.000 description 1
- 101100005765 Arabidopsis thaliana CDF1 gene Proteins 0.000 description 1
- 101100007579 Arabidopsis thaliana CPP1 gene Proteins 0.000 description 1
- 241000238424 Crustacea Species 0.000 description 1
- IAYPIBMASNFSPL-UHFFFAOYSA-N Ethylene oxide Chemical compound C1CO1 IAYPIBMASNFSPL-UHFFFAOYSA-N 0.000 description 1
- 241000233866 Fungi Species 0.000 description 1
- 208000007093 Leukemia L1210 Diseases 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- 101100161696 Myxine glutinosa ache gene Proteins 0.000 description 1
- 239000000061 acid fraction Substances 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 231100000215 acute (single dose) toxicity testing Toxicity 0.000 description 1
- 231100000403 acute toxicity Toxicity 0.000 description 1
- 230000007059 acute toxicity Effects 0.000 description 1
- 238000011047 acute toxicity test Methods 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 150000001450 anions Chemical class 0.000 description 1
- 230000000340 anti-metabolite Effects 0.000 description 1
- 229940100197 antimetabolite Drugs 0.000 description 1
- 239000002256 antimetabolite Substances 0.000 description 1
- 239000012620 biological material Substances 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 230000000850 deacetylating effect Effects 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 1
- MSWZFWKMSRAUBD-IVMDWMLBSA-N glucosamine group Chemical group OC1[C@H](N)[C@@H](O)[C@H](O)[C@H](O1)CO MSWZFWKMSRAUBD-IVMDWMLBSA-N 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 230000003308 immunostimulating effect Effects 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 208000032839 leukemia Diseases 0.000 description 1
- 229920001542 oligosaccharide Polymers 0.000 description 1
- 150000002482 oligosaccharides Chemical class 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 238000006116 polymerization reaction Methods 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 229940075554 sorbate Drugs 0.000 description 1
- 125000006850 spacer group Chemical group 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 238000009966 trimming Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 230000004580 weight loss Effects 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Polysaccharides And Polysaccharide Derivatives (AREA)
Abstract
Description
【発明の詳細な説明】
（産業−にの利用分野）
本発明は、５−フルオロウラシル担持キトサンオリゴマ
ー、並びにその製造方法及び該５−フルオロウラシル担
持キｌ−サンからなる抗腫匹活性剤に関する。DETAILED DESCRIPTION OF THE INVENTION (Field of Industrial Application) The present invention relates to a 5-fluorouracil-supported chitosan oligomer, a method for producing the same, and an anti-tumor active agent comprising the 5-fluorouracil-supported chitosan oligomer.
（従来の技術）
キチンは、甲殻類や菌類の外骨格を形成する組織多糖で
セルロースと非常に良く似た化学構造及び物性を持ち、
地珠上では非常に豊富な資源てある。このキチンは強固
な結晶構造を持つため、溶解性や反応性に欠けるか、キ
チンを強アルカリ条件下で脱アセチル化したキトサンは
塩を作ると水溶性となり、またキチンをエチレンオキサ
イドでヒドロキシエチル化したグリコール化キチンも水
溶性となり、化学修飾が容易になる。(Prior art) Chitin is a tissue polysaccharide that forms the exoskeleton of crustaceans and fungi, and has a chemical structure and physical properties very similar to cellulose.
There are very rich resources on Earth. This chitin has a strong crystal structure, so it lacks solubility and reactivity, or chitosan, which is obtained by deacetylating chitin under strong alkaline conditions, becomes water-soluble when it is made into a salt, and chitin can also be hydroxyethylated with ethylene oxide. The resulting glycolized chitin also becomes water-soluble, making it easier to chemically modify it.
これらキチン及びその誘導体は、一般に毒性か低く、生
体内分解吸収性であるなどバイオマテリアルに適した性
質を数多く備えた高分子物質である。これらの中でも特
に部分Ｎ−アセチル化キチン又は部分Ｎ−アセチル化キ
トサンは白血病Ｌ１２１０脱水ガン細胞を選択的に凝集
させ、その増殖を阻害し、また、キチンの水溶性低級同
族体のＮ−アセチルキトオリゴ糖（特にヘキサオース）
は強い免疫賦活抗腫瘍活性を示すことか近年報告され、
キチン、キトサンが抗腫瘍活性を有する多糖として脚光
を浴びつつある（例えば特開昭５９−２７８２６号、同
６２−１２３１２３号）。このように、キチン、キトサ
ンは低毒性、生体内分解吸収性で腫瘍細胞への選択的集
積能を有しているのて、見方を変えれば、これらは高分
子医薬のキャリアーとしての条件を満たしていると言え
る。These chitins and their derivatives are polymeric substances that generally have many properties suitable for biomaterials, such as low toxicity and biodegradability and absorption. Among these, partially N-acetylated chitin or partially N-acetylated chitosan selectively aggregates leukemia L1210 dehydrated cancer cells and inhibits their proliferation. Oligosaccharides (especially hexaose)
It has been reported in recent years that it exhibits strong immunostimulatory antitumor activity.
Chitin and chitosan are attracting attention as polysaccharides having antitumor activity (for example, JP-A-59-27826 and JP-A-62-123123). In this way, chitin and chitosan have low toxicity, are biodegradable and absorbable, and have the ability to selectively accumulate in tumor cells, so from a different perspective, they meet the requirements as carriers for polymeric drugs. I can say that it is.
一方、５−フルオロウラシル（５ＦＵ）は１代謝拮抗阻
害剤として働く抗腫瘍剤で、強い抗腫瘍活性を有するが
同時に強い毒性があり、その副作用抑制か問題となって
いる。On the other hand, 5-fluorouracil (5FU) is an antitumor agent that acts as an antimetabolite inhibitor, and although it has strong antitumor activity, it is also highly toxic, and there is a problem in suppressing its side effects.
（発明が解決しようとする課題）
したかって本発明の目的はこのような抗腫瘍活性、低毒
性、生体内分解吸収性及び腫瘍細胞への選択的集積能を
有するキチン、キトサン化合物と抗腫瘍剤として有用な
５−ＦＵとを組合わせた新規な化合物を提供することに
ある。(Problems to be Solved by the Invention) Therefore, the purpose of the present invention is to provide chitin and chitosan compounds and antitumor agents that have such antitumor activity, low toxicity, biodegradability and absorption ability, and ability to selectively accumulate in tumor cells. The object of the present invention is to provide a novel compound in combination with 5-FU that is useful as a compound.
（課題を解決するための手段）
本発明者は、５ＦＵの副作用の軽減、薬効の持続性、タ
ーゲツティング、活性の増大を期待して、キチン誘導体
への共有結合による５ＦＵの担持を行い、高分子プロト
ラグ（ＭａｃｒｏｍｏｌｅｃｕｌａｒＰｒｏｄｒｕｇ）
の観点から、５ＦＵ担持の結合様式、スペイサ−の有無
、グリコール化するか否かか、抗腫瘍活性に及ぼす影響
について検討し、この検討過程において、疎水性スペー
サーとしてのへキサメチレン基を介したカルバモイル、
カルバモイル結合によるキトサンの２位へ５ＦＵが導入
された下記式（１）で表わされる５ＦＵ担持キトサンか
、５ＦＵの放出性に優れ、極めて優れた抗腫瘍活性を示
すことを見いたし、本発明をなすに至った。(Means for Solving the Problems) The present inventor carries 5FU by covalent bonding to a chitin derivative, expecting to reduce the side effects of 5FU, maintain drug efficacy, increase targeting, and increase activity. Macromolecular Prodrug
From the viewpoint of ,
It has been found that 5FU-supported chitosan represented by the following formula (1), in which 5FU is introduced into the 2-position of chitosan by a carbamoyl bond, has excellent release properties of 5FU and exhibits extremely excellent antitumor activity, and the present invention has been made based on this finding. reached.
すなわち、本発明は
（１）下記式（ｒ）で表わされる縁り返し単位を有する
５−フルオロウラシル担持キトサン、（ただし、ｍは２
〜６の整数を示す）
（２）上記（１）項のキトサンを含有する抗腫瘍剤、（
３）５−フルオロウラシルにアルキレンジイソシアネー
トを反応させて１式（ＩＩ）
Ｈ
（式中、ｍは２〜６の整数を示す。）
で表わされる化合物を得、これとキトサン塩酸塩とを反
応させることを特徴とする式（Ｉ）で表わされる繰り返
し単位を有する５−フルオロウラシル担持キトサンの製
造方法
を提供するものである。That is, the present invention provides (1) a 5-fluorouracil-supported chitosan having a turning unit represented by the following formula (r) (where m is 2
(indicates an integer of ~6) (2) An antitumor agent containing chitosan according to item (1) above, (
3) Reacting 5-fluorouracil with alkylene diisocyanate to obtain a compound represented by formula (II) H (in the formula, m represents an integer of 2 to 6), and reacting this with chitosan hydrochloride. The present invention provides a method for producing 5-fluorouracil-supported chitosan having a repeating unit represented by formula (I), characterized by:
本発明において式（Ｉ）で表わされる祿り返し単位中に
おいて＝（ＣＨ２）、−は疎水性のスペーサーである。In the present invention, =(CH2) and - in the trimming unit represented by formula (I) are hydrophobic spacers.
またそのキトサンにおいて重合度（ｎ）は２０〜５０か
好ましい。Further, the degree of polymerization (n) of the chitosan is preferably 20 to 50.
この５ＦＵ４ｆ！持キトサンは、そのままの形で癌細胞
に取り込まれ、そこで５ＦＵがリリースして、５ＦＵと
して作用し、キャリアーのキトサンは目的達成後分解、
吸収される。This 5FU4f! The carrier chitosan is taken up into cancer cells as it is, where 5FU is released and acts as 5FU, and the carrier chitosan is decomposed and decomposed after achieving its purpose.
Absorbed.
したがってその投与量は５ＦＵ換算で従来の５ＦＵとほ
ぼ同等になるようにするのか好′：＋′、１ノい。Therefore, the dosage should be approximately equivalent to the conventional 5FU in terms of 5FU.
（実施例） 次に本発明を実施例に基づきさらに詳細に説明する。(Example) Next, the present invention will be explained in more detail based on examples.
実施例１
（１）−１ｏｒ （１）−２
５ＦＵ］、 １．９ｇ（１５↓０１）とへキサメチ１
／ンシイソシアネ−１−２（１２，５ｍｍｏｌ）を脱水
ピリジン１００摺中、９０−１００°Ｃて３時間反応さ
せることにより、３て示１″化合物を得、これ？単離す
ることなく、溶液の形のままでギトサン塩酸塩４［君津
化学工業ｖ４製、粘度６．５ＣＰＳ（０，５％メタノー
ル中０．５％ａｔｆｆ：） （Ｍｎ ＝２００００と
推定される）コー０．８ｇを３．０謂のジメチルスルホ
キシｌ＝：（ＤＭＳＯ）に分散さセた溶液中に滴下ｌノ
、５０〜６０℃で２４時間攪拌後、反応混合液をアセト
ン中に投入し沈澱物を得た。これをピリジン、アセ１〜
ンで十分に洗浄して、目的の化合物（Ｉ）−１を得た。Example 1 (1)-1or (1)-2 5FU], 1.9g (15↓01) and hexamethylene 1
By reacting isocyanate-1-2 (12.5 mmol) in 100 ml of dehydrated pyridine at 90-100°C for 3 hours, the compound 1'' shown in 3 was obtained. Gitosan hydrochloride 4 [manufactured by Kimitsu Kagaku Kogyo V4, viscosity 6.5 CPS (0.5% atff: in 0.5% methanol) (estimated to be Mn = 20000) 0.8 g of 3.0 It was added dropwise to a solution of so-called dimethylsulfoxyl = (DMSO) and stirred at 50 to 60°C for 24 hours, and then the reaction mixture was poured into acetone to obtain a precipitate. Pyridine, ace1~
The target compound (I)-1 was obtained by washing thoroughly with water.
化合物（Ｉ）−１の物性は次の通りであった。The physical properties of compound (I)-1 were as follows.
Ｉｎ（ＫＢｒ ｄｉｓｋ） ｒｃ＋ａ当； ２８６０．
２９４０ ［（１’：１１２）６］ 。In (KBr disk) rc+a; 2860.
2940 [(1':112)6].
ｔ７５０（（：＝０１５ＦＵ） 、 １５７５（ＮｌＩ
ＣＯＮＩＩ）、１０８０（Ｃ−０−Ｃ）。t750((:=015FU), 1575(NlI
CONII), 1080 (C-0-C).
式（Ｂ−ｉは溶媒に不溶なため、３Ｎ−ＮａＯＨ溶液中
で２時間煮廓還流してカルバモイル結合を完全に加水分
解し、その溶液中に存在する５ＦＵＷ度を５Ｆ［Ｊアニ
オンとしてＵＶスベク１〜ル法て測定することにより、
（Ｉ）−１のグルコサミン・ユニット当りの５ＦＵの導
入率（Ｄ５Ｆ Ｕ ）を算出した。基準：５ＦＵ（５Ｆ
ｔＪアニオン）、入３Ｎ Ｎａ０１ｌ ＝２８２ｎｒｎ
、、３Ｎ Ｎａ０１ｌ ＝ｏ＋ａｘ
ｍａｘ６５００、Ｄ５
ＦＵ＝７．０％
水、有機溶媒に不溶。Since the formula (B-i is insoluble in the solvent, the carbamoyl bond is completely hydrolyzed by boiling and refluxing in a 3N-NaOH solution for 2 hours, and the 5FUW degree present in the solution is By measuring using the method 1 to 1,
The introduction rate of 5FU per glucosamine unit (D5F U ) of (I)-1 was calculated. Standard: 5FU (5F
tJ anion), 3N Na01l = 282nrn
,,3N Na01l=o+ax
max6500, D5
FU=7.0% Insoluble in water and organic solvents.
実施例２
５ＦＵ １ ３． １ ｇ（２，４ｍ鳳０１）とへキサ
メチレンジイソシアネ−ｈ ２ （２０ｍｍｏｌ）を脱
水ピリジン１００イ中９０ヘー１００℃で３峙間反応さ
せることにより、３で示す化合物を得、実施例１と同様
の方法で、分子縫の小さいキトサン塩酸ＰＩＸ４（Ｐｎ
＝３０）０．９８ｇと３を５０〜６０℃で２４時間反応
させることにより、目的の化合物（Ｉ）−２を得た。Example 2 5FU 1 3. By reacting 1 g (2,4m 01) and hexamethylene diisocyane-h2 (20 mmol) in 100 ml of dehydrated pyridine at 100° C. for 3 reactions, the compound shown in 3 was obtained, and the compound shown in Example 3 was obtained. Using the same method as in 1, chitosan hydrochloride PIX4 (Pn
=30) 0.98g and 3 were reacted at 50 to 60°C for 24 hours to obtain the target compound (I)-2.
Ｄ５ＦＵ＝１８％
Ｐｎ−＝３０
水、有機溶媒に不溶
実施例３ 抗腫瘍活性試験
ＣＤＦ１マウス（５退会）にＰ −３８８１ｙｍｐｈｏ
ｅｙｔｉｃＩｃｕｋｃ＋ｓｉａ （白血病）細胞をｔｘ
ｔｏ６個／マウスを腹腔内投与し、所定量の実施例２で
得た式（Ｉ）−１の化合物を翌日と５日目に腹腔内投与
した。D5FU=18% Pn-=30 Insoluble in water and organic solvent Example 3 Antitumor activity test P-3881ympho in CDF1 mice (5 withdrawals)
tx eyticIcukc+sia (leukemia) cells
To6 mice/mouse were intraperitoneally administered, and a predetermined amount of the compound of formula (I)-1 obtained in Example 2 was intraperitoneally administered on the next day and on the 5th day.
実験群には、■投与レベルに対しで各６匹を、対照群に
は３０匹を用いた。抗腫瘍活性の評価は、次式で第１表
に表わされる生存日数比率により行い、結果を第１表に
示す。For the experimental group, 6 animals were used for each dose level, and for the control group, 30 animals were used. The antitumor activity was evaluated using the survival days ratio shown in Table 1 using the following formula, and the results are shown in Table 1.
第 １ 表
このものは、水に不溶なのでツルベート（ｓｏｒｂａｔ
ｅ）８０を用いて懸濁溶液の形で投！ｊ−シた。Table 1 This substance is insoluble in water, so it is called sorbate.
e) Pour in the form of a suspension using 80! j-shita.
なお、Ｔ／Ｃの値か１２０以−Ｌの場合に、その試料は
活性かあると評価される。第１表で（１）のＴ／Ｃの値
かフリーの５ＦＵのそれより大きくなったことは、高分
子プロトラグとして注目に値する。Note that if the T/C value is 120 or more -L, the sample is evaluated to be active. It is noteworthy that the T/C value of (1) in Table 1 was greater than that of free 5FU as a polymeric protolog.
［急性毒性試験］
式（１）の繰り返し単位を有する本発明の化合物をマウ
スに投与したが、投与量が８００ ｍｇ／ ｋｇまては
、マウスの急激な体重減少は見られず、急性毒性はない
と判断てきる。従って、ＬＤ５０も８００ ｔｓｇ／
ｋｇ以上であると言える。[Acute toxicity test] The compound of the present invention having the repeating unit of formula (1) was administered to mice, but no rapid weight loss was observed in the mice up to a dose of 800 mg/kg, indicating no acute toxicity. I can conclude that there is no. Therefore, LD50 is also 800 tsg/
It can be said that it is more than kg.
［５ＦＵの放出挙動試験］
０．０１Ｎ−ＮａＯＨ１０，ｌＮ−ＨＣｌ、生理食塩水
あるいはリン酸緩衝液中、３７°Ｃて本発明の５ＦＵ担
持キトサンの加水分解を行った結果、このような ｉｎ
ｖｉｔｒｏにおいては、エステル、アミド及びカルバ
モイル結合は、アルカリ分解を受は易く、エーテル結合
は酸分数を受は易いことがわかった０式（１）で表わさ
れる縁り返し単位を有する化合物が加水分解を受けると
、フリーの５ＦＵかまずリリースしてくることがわかっ
た。なお、５ＦＵ以外に５ＦＵ−ＣＯＮＨ（ＣＨ２）６
ＮＨ２という５ＦＵ誘導体の形てのリリースユニントも
僅かに存在することが確認された。[5FU release behavior test] As a result of hydrolyzing the 5FU-supported chitosan of the present invention in 0.01N-NaOH10, IN-HCl, physiological saline, or phosphate buffer at 37°C, such in
In vitro, it was found that ester, amide, and carbamoyl bonds are easily susceptible to alkaline decomposition, and ether bonds are easily susceptible to acid fraction. When I received it, I found out that they would release the free 5FU first. In addition to 5FU, 5FU-CONH(CH2)6
It was also confirmed that a small amount of release unit in the form of a 5FU derivative called NH2 was present.
（発明の効果）
本発明の５ＦＵ担持キトサンは５ＦＵの放出性能か高く
、かつ、抗腫瘍活性も高く、毒性の少ない有用な化合物
である。(Effects of the Invention) The 5FU-supported chitosan of the present invention has high 5FU release performance, high antitumor activity, and is a useful compound with low toxicity.
Claims (4)
る５−フルオロウラシル担持キトサン。 ▲数式、化学式、表等があります▼（ I ） （ただし、ｍは２〜６の整数を示す）(1) 5-fluorouracil-supported chitosan having a repeating unit represented by the following formula (I). ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) (However, m indicates an integer from 2 to 6)
シル担持キトサン。(2) The 5-fluorouracil-supported chitosan according to claim 1, wherein m is 6.
ートを反応させて、式（II） ▲数式、化学式、表等があります▼・・・（II） （式中、ｍは２〜６の整数を示す。） で表わされる化合物を得、これとキトサン塩酸塩とを反
応させることを特徴とする式（ I ）で表わされる繰り
返し単位を有する請求項１項記載の５−フルオロウラシ
ル担持キトサンの製造方法。(4) By reacting alkylene diisocyanate with 5-fluorouracil, formula (II) ▲There are mathematical formulas, chemical formulas, tables, etc.▼...(II) (In the formula, m represents an integer from 2 to 6.) 2. The method for producing 5-fluorouracil-supported chitosan according to claim 1, which comprises obtaining a compound represented by the formula and reacting it with chitosan hydrochloride having a repeating unit represented by formula (I).
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP7818288A JPH01252605A (en) | 1988-04-01 | 1988-04-01 | 5-fluorouracil-carrying chitosan |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP7818288A JPH01252605A (en) | 1988-04-01 | 1988-04-01 | 5-fluorouracil-carrying chitosan |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH01252605A true JPH01252605A (en) | 1989-10-09 |
Family
ID=13654827
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP7818288A Pending JPH01252605A (en) | 1988-04-01 | 1988-04-01 | 5-fluorouracil-carrying chitosan |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH01252605A (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1992003480A1 (en) * | 1990-08-17 | 1992-03-05 | Drug Delivery System Institute, Ltd. | N-acetylcarboxymethylchitosan derivative and production thereof |
| JP2001031575A (en) * | 1999-07-16 | 2001-02-06 | Fujibio Co Ltd | Inhibition of side effect of 5-fluorouracil by chitin chitosan and formulation therefor |
| US7511023B2 (en) * | 2001-08-18 | 2009-03-31 | Korea Institute Of Science And Technology | Anticancer drug-chitosan complex forming self-aggregates and preparation method thereof |
-
1988
- 1988-04-01 JP JP7818288A patent/JPH01252605A/en active Pending
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1992003480A1 (en) * | 1990-08-17 | 1992-03-05 | Drug Delivery System Institute, Ltd. | N-acetylcarboxymethylchitosan derivative and production thereof |
| JP2001031575A (en) * | 1999-07-16 | 2001-02-06 | Fujibio Co Ltd | Inhibition of side effect of 5-fluorouracil by chitin chitosan and formulation therefor |
| US7511023B2 (en) * | 2001-08-18 | 2009-03-31 | Korea Institute Of Science And Technology | Anticancer drug-chitosan complex forming self-aggregates and preparation method thereof |
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