JPH029563B2 - - Google Patents
Info
- Publication number
- JPH029563B2 JPH029563B2 JP56118477A JP11847781A JPH029563B2 JP H029563 B2 JPH029563 B2 JP H029563B2 JP 56118477 A JP56118477 A JP 56118477A JP 11847781 A JP11847781 A JP 11847781A JP H029563 B2 JPH029563 B2 JP H029563B2
- Authority
- JP
- Japan
- Prior art keywords
- formula
- polymer
- group
- constituent
- integer
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
Links
- 229920000642 polymer Polymers 0.000 claims description 46
- 239000000126 substance Substances 0.000 claims description 23
- 239000000470 constituent Substances 0.000 claims description 17
- 231100000433 cytotoxic Toxicity 0.000 claims description 17
- 230000001472 cytotoxic effect Effects 0.000 claims description 17
- -1 alkylamine compound Chemical group 0.000 claims description 9
- 125000003277 amino group Chemical group 0.000 claims description 9
- 238000006116 polymerization reaction Methods 0.000 claims description 9
- 239000002246 antineoplastic agent Substances 0.000 claims description 7
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 7
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 7
- 125000001841 imino group Chemical group [H]N=* 0.000 claims description 7
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 7
- 230000000259 anti-tumor effect Effects 0.000 claims description 6
- 239000002168 alkylating agent Substances 0.000 claims description 4
- 229940100198 alkylating agent Drugs 0.000 claims description 4
- 230000000340 anti-metabolite Effects 0.000 claims description 4
- 239000002256 antimetabolite Substances 0.000 claims description 4
- 229940100197 antimetabolite Drugs 0.000 claims description 4
- 230000003115 biocidal effect Effects 0.000 claims description 4
- 150000001768 cations Chemical class 0.000 claims description 4
- 239000004480 active ingredient Substances 0.000 claims description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 3
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 150000003973 alkyl amines Chemical group 0.000 claims 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 24
- 238000006243 chemical reaction Methods 0.000 description 19
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 12
- 229920002643 polyglutamic acid Polymers 0.000 description 12
- 239000000243 solution Substances 0.000 description 12
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 10
- 239000003814 drug Substances 0.000 description 9
- 229940079593 drug Drugs 0.000 description 9
- 239000000203 mixture Substances 0.000 description 9
- 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 8
- 239000007787 solid Substances 0.000 description 8
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 7
- IERHLVCPSMICTF-CCXZUQQUSA-N [(2r,3s,4s,5r)-5-(4-amino-2-oxopyrimidin-1-yl)-3,4-dihydroxyoxolan-2-yl]methyl dihydrogen phosphate Chemical compound O=C1N=C(N)C=CN1[C@H]1[C@@H](O)[C@H](O)[C@@H](COP(O)(O)=O)O1 IERHLVCPSMICTF-CCXZUQQUSA-N 0.000 description 7
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 239000007788 liquid Substances 0.000 description 6
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 5
- 238000000862 absorption spectrum Methods 0.000 description 5
- 239000007864 aqueous solution Substances 0.000 description 5
- 230000008033 biological extinction Effects 0.000 description 5
- 238000002360 preparation method Methods 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- 159000000000 sodium salts Chemical class 0.000 description 5
- 125000001340 2-chloroethyl group Chemical group [H]C([H])(Cl)C([H])([H])* 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 229930192392 Mitomycin Natural products 0.000 description 4
- 238000010521 absorption reaction Methods 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 229960004857 mitomycin Drugs 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- 230000001988 toxicity Effects 0.000 description 4
- 231100000419 toxicity Toxicity 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- 241000699670 Mus sp. Species 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 238000011481 absorbance measurement Methods 0.000 description 3
- 150000001370 alpha-amino acid derivatives Chemical class 0.000 description 3
- 235000008206 alpha-amino acids Nutrition 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- 239000008187 granular material Substances 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- 150000004986 phenylenediamines Chemical class 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 230000004083 survival effect Effects 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- UHDGCWIWMRVCDJ-UHFFFAOYSA-N 1-beta-D-Xylofuranosyl-NH-Cytosine Natural products O=C1N=C(N)C=CN1C1C(O)C(O)C(CO)O1 UHDGCWIWMRVCDJ-UHFFFAOYSA-N 0.000 description 2
- REUUVTULEYHTCC-UHFFFAOYSA-N 2-n,2-n-bis(2-chloroethyl)benzene-1,2-diamine Chemical compound NC1=CC=CC=C1N(CCCl)CCCl REUUVTULEYHTCC-UHFFFAOYSA-N 0.000 description 2
- KQIGMPWTAHJUMN-UHFFFAOYSA-N 3-aminopropane-1,2-diol Chemical compound NCC(O)CO KQIGMPWTAHJUMN-UHFFFAOYSA-N 0.000 description 2
- UHDGCWIWMRVCDJ-YDKYIBAVSA-N 4-amino-1-[(2r,3s,4r,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]pyrimidin-2-one Chemical compound O=C1N=C(N)C=CN1[C@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O1 UHDGCWIWMRVCDJ-YDKYIBAVSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- 101100005765 Arabidopsis thaliana CDF1 gene Proteins 0.000 description 2
- 101100007579 Arabidopsis thaliana CPP1 gene Proteins 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- 229920000298 Cellophane Polymers 0.000 description 2
- 101710112752 Cytotoxin Proteins 0.000 description 2
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- 240000001090 Papaver somniferum Species 0.000 description 2
- 235000008753 Papaver somniferum Nutrition 0.000 description 2
- 239000000654 additive Substances 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 239000000969 carrier Substances 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- OPTASPLRGRRNAP-UHFFFAOYSA-N cytosine Chemical compound NC=1C=CNC(=O)N=1 OPTASPLRGRRNAP-UHFFFAOYSA-N 0.000 description 2
- 231100000599 cytotoxic agent Toxicity 0.000 description 2
- 239000002619 cytotoxin Substances 0.000 description 2
- 235000014113 dietary fatty acids Nutrition 0.000 description 2
- 239000003937 drug carrier Substances 0.000 description 2
- 239000003995 emulsifying agent Substances 0.000 description 2
- 239000000194 fatty acid Substances 0.000 description 2
- 229930195729 fatty acid Natural products 0.000 description 2
- 238000004108 freeze drying Methods 0.000 description 2
- 239000013067 intermediate product Substances 0.000 description 2
- SGDBTWWWUNNDEQ-LBPRGKRZSA-N melphalan Chemical compound OC(=O)[C@@H](N)CC1=CC=C(N(CCCl)CCCl)C=C1 SGDBTWWWUNNDEQ-LBPRGKRZSA-N 0.000 description 2
- 239000012457 nonaqueous media Substances 0.000 description 2
- 239000003921 oil Substances 0.000 description 2
- 235000019198 oils Nutrition 0.000 description 2
- 239000006187 pill Substances 0.000 description 2
- 230000000379 polymerizing effect Effects 0.000 description 2
- 239000003755 preservative agent Substances 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- 125000000467 secondary amino group Chemical group [H]N([*:1])[*:2] 0.000 description 2
- 235000002639 sodium chloride Nutrition 0.000 description 2
- 239000003381 stabilizer Substances 0.000 description 2
- URAYPUMNDPQOKB-UHFFFAOYSA-N triacetin Chemical compound CC(=O)OCC(OC(C)=O)COC(C)=O URAYPUMNDPQOKB-UHFFFAOYSA-N 0.000 description 2
- 239000000080 wetting agent Substances 0.000 description 2
- MTCFGRXMJLQNBG-REOHCLBHSA-N (2S)-2-Amino-3-hydroxypropansÀure Chemical compound OC[C@H](N)C(O)=O MTCFGRXMJLQNBG-REOHCLBHSA-N 0.000 description 1
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 description 1
- JVSFQJZRHXAUGT-UHFFFAOYSA-N 2,2-dimethylpropanoyl chloride Chemical compound CC(C)(C)C(Cl)=O JVSFQJZRHXAUGT-UHFFFAOYSA-N 0.000 description 1
- ABFYEILPZWAIBN-UHFFFAOYSA-N 3-(iminomethylideneamino)-n,n-dimethylpropan-1-amine;hydrochloride Chemical compound Cl.CN(C)CCCN=C=N ABFYEILPZWAIBN-UHFFFAOYSA-N 0.000 description 1
- 239000005995 Aluminium silicate Substances 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- LVGKNOAMLMIIKO-UHFFFAOYSA-N Elaidinsaeure-aethylester Natural products CCCCCCCCC=CCCCCCCCC(=O)OCC LVGKNOAMLMIIKO-UHFFFAOYSA-N 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 1
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 description 1
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 description 1
- 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 1
- 241001465754 Metazoa Species 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- WUGQZFFCHPXWKQ-UHFFFAOYSA-N Propanolamine Chemical compound NCCCO WUGQZFFCHPXWKQ-UHFFFAOYSA-N 0.000 description 1
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 239000002250 absorbent Substances 0.000 description 1
- 230000002745 absorbent Effects 0.000 description 1
- 150000008065 acid anhydrides Chemical class 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 235000004279 alanine Nutrition 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 235000012211 aluminium silicate Nutrition 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 229940024606 amino acid Drugs 0.000 description 1
- 235000001014 amino acid Nutrition 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 239000007900 aqueous suspension Substances 0.000 description 1
- VBICKXHEKHSIBG-UHFFFAOYSA-N beta-monoglyceryl stearate Natural products CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 description 1
- 239000004327 boric acid Substances 0.000 description 1
- 244000309464 bull Species 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 239000012830 cancer therapeutic Substances 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 239000003240 coconut oil Substances 0.000 description 1
- 235000019864 coconut oil Nutrition 0.000 description 1
- 239000008119 colloidal silica Substances 0.000 description 1
- 229920000547 conjugated polymer Polymers 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000002285 corn oil Substances 0.000 description 1
- 235000005687 corn oil Nutrition 0.000 description 1
- 229940104302 cytosine Drugs 0.000 description 1
- 238000000502 dialysis Methods 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- LVGKNOAMLMIIKO-QXMHVHEDSA-N ethyl oleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC LVGKNOAMLMIIKO-QXMHVHEDSA-N 0.000 description 1
- 229940093471 ethyl oleate Drugs 0.000 description 1
- 230000001747 exhibiting effect Effects 0.000 description 1
- 235000019197 fats Nutrition 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- IYWCBYFJFZCCGV-UHFFFAOYSA-N formamide;hydrate Chemical compound O.NC=O IYWCBYFJFZCCGV-UHFFFAOYSA-N 0.000 description 1
- 238000005227 gel permeation chromatography Methods 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 150000002314 glycerols Chemical class 0.000 description 1
- 239000001087 glyceryl triacetate Substances 0.000 description 1
- 235000013773 glyceryl triacetate Nutrition 0.000 description 1
- 239000012456 homogeneous solution Substances 0.000 description 1
- 229920001477 hydrophilic polymer Polymers 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 239000012155 injection solvent Substances 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- NLYAJNPCOHFWQQ-UHFFFAOYSA-N kaolin Chemical compound O.O.O=[Al]O[Si](=O)O[Si](=O)O[Al]=O NLYAJNPCOHFWQQ-UHFFFAOYSA-N 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 231100001231 less toxic Toxicity 0.000 description 1
- 208000032839 leukemia Diseases 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 229940057995 liquid paraffin Drugs 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 229960001924 melphalan Drugs 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 150000004712 monophosphates Chemical class 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 150000002895 organic esters Chemical class 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 description 1
- 229960005190 phenylalanine Drugs 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 239000003505 polymerization initiator Substances 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 125000001749 primary amide group Chemical group 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 125000003156 secondary amide group Chemical group 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000000661 sodium alginate Substances 0.000 description 1
- 235000010413 sodium alginate Nutrition 0.000 description 1
- 229940005550 sodium alginate Drugs 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 239000012064 sodium phosphate buffer Substances 0.000 description 1
- 239000003549 soybean oil Substances 0.000 description 1
- 235000012424 soybean oil Nutrition 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008223 sterile water Substances 0.000 description 1
- 239000003206 sterilizing agent Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 229960002622 triacetin Drugs 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- LADGBHLMCUINGV-UHFFFAOYSA-N tricaprin Chemical compound CCCCCCCCCC(=O)OCC(OC(=O)CCCCCCCCC)COC(=O)CCCCCCCCC LADGBHLMCUINGV-UHFFFAOYSA-N 0.000 description 1
- 229940093633 tricaprin Drugs 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
Description
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TECHNICAL FIELD The present invention relates to an antitumor agent containing a polymer bound to a cytotoxic substance such as an anticancer agent as an active ingredient, and a method for producing the same. By binding various drugs to polymeric carriers to make polymeric drugs, the hydrophilicity or hydrophobicity of the drug can be changed to improve absorption into the body or transfer to target organs. It is conceivable that it will be improved. Furthermore, since the drug is gradually dissociated and released from the polymeric carrier in the body, sustained release of drug efficacy over a long period of time and reduction in side effects can be expected. The present inventors have conducted extensive research into polymerizing cytotoxic substances such as anticancer agents in order to develop polymeric drugs that can be used as antitumor agents, and have arrived at the present invention. That is, the present invention provides a structural unit represented by the formula [] In [Formula [], Z represents a hydrogen atom or a monovalent cation. m represents an integer from 1 to 4. ] The constituent unit represented by the formula [] and In [Formula []], X represents a reactive residue of an alkylamine compound substituted with one or more hydroxyl groups. m represents an integer from 1 to 4. ] The constituent unit expressed by the formula [] and In [formula], Y represents an amino group- or imino-reactive residue of an antitumor alkylating agent, antimetabolite, or antibiotic containing an amino group or imino group in the molecule. m represents an integer from 1 to 4. ] Consists of the constituent unit represented by the formula [ ], In [Formula []], R represents a hydrogen atom, a methyl group, a benzyl group, or a hydroxymethyl group. ] The ratio of constituent units [ ], [ ] and [ ] is [ ] / [ ] + [ ] + [ ] = 0.05 to 0.95, and the constituent units [ ] are less than 40 mol% of the total constituent units,
It is a polymer bound to a cytotoxic substance with a degree of polymerization of 10 to 2000. In formula [], Z is a hydrogen atom or a monovalent cation, such as Na + , K + , NH 4 + . m is 1
It represents an integer of ~4, but m is preferably 1 or 2. The polymer of the present invention also includes, for example, a polymer in which m=1 and m=2. The preferred degree of polymerization is 10
~2000. The ratio of constituent units [ ], [ ] and [ ] is [ ] / [ ] + [ ] + [ ] = 0.05 to 0.95. In formula [], Y represents a cytotoxic substance containing an amino group or imino group in the molecule, ie, an amino group- or imino-reactive residue of an antitumor alkylating agent, antimetabolite, or antibiotic. A cytotoxic substance in the present invention refers to a substance that exhibits toxicity to cells as it is, or a substance that does not exhibit toxicity as it is but can be converted into a substance capable of exhibiting toxicity to cells in vivo. Examples of these are: p-[N,N-bis(2-chloroethyl)]phenylenediamine p-[bis(2-chloroethyl)amino]L-
Phenylalanine (Melphalan) 2-Amino-N-[p-bis(2-chloroethyl)amino]phenyl-3-hydroxypropionamide 1-(β-D-arabinofuranosyl)cytosine or its monophosphate 1-[5'-(n-aminoalkylphosphoryl)
-β-D-arabinofuranosyl]cytosines (n
=2~12) 1-[5'-(n-aminoalkylphosphoryl)
-2â²-deoxy-β-D-ribofuranosyl]-5
-Fluorouracils 2-Amino-N-[p-bis(2-chloroethyl)amino]phenyl-3-hydroxy-2-hydroxymethylpropionamide etc. In the present invention, the alkylamine compound substituted with one or more hydroxyl groups includes 2
-ethanolamine, 3-propanolamine,
4-butanolamine, 2,3-dihydroxy-
Propylamine and the like are preferably used, but are not limited thereto. In the polymer of the present invention, 40 mol% of the total structural units
Constituent units other than those represented by the formulas [], [], and [] may be included within the range below. Examples of these include α-glycine, alanine, phenylalanine, serine, etc. that do not have a carboxyl group (or its salt) in the α-position side chain.
-There are amino acids. Such a structural unit consisting of an α-amino acid does not participate in any way in binding with a cytotoxic substance, but it regulates the water solubility of a hydrophilic polymer and the lipid solubility and water solubility of a polymer obtained by binding a cytotoxic substance. It may be helpful. Therefore, if there is no particular need to adjust the fat solubility or water solubility, it is practically advantageous to use a product that does not contain such α-amino acid constituent units. The carboxyl terminal of the polymer of the present invention varies depending on the polymerization method. For example, when polymerizing α-amino acid N-carboxylic anhydride, if the polymerization initiator used is water, -COOH, and if ammonia is used, -COOH is used.
ãåŒãéå±ã¢ã«ã³ã©ãŒãã®å Žåã¯[Formula] In the case of metal alcoholate,
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ãïŒåæäžããçåæ¥æ°ã枬å®ããã[Formula] etc., but any physiologically harmless one may be used. The amine terminus is usually an amino group. The cytotoxic substance-bound polymer of the present invention has at least 60 mol% of the total structural units of the formula [] [Definitions of Z and m are the same as in the previous case. ] A polymer obtained by reacting a polymer consisting of the structural unit represented by the above with a cytotoxic substance containing an amino group or an imino group in the molecule, which has a primary or secondary amino group in the molecule. It can be obtained by reacting a water-soluble low molecular weight compound containing one or more hydroxyl groups. The reaction between the polymer of the present invention and a cytotoxic substance containing an amino group or imino group in the molecule is usually carried out in a homogeneous reaction system using water or an organic solvent such as dimethylformamide or dimethyl sulfoxide as a reaction solvent. For example, 1-ethyl-3-
The carboxyl groups in the polymer may be activated with (3-dimethylaminopropyl)carbodiimide hydrochloride or dicyclohexylcarbodiimide, or the carboxyl groups may be activated in the form of a mixed acid anhydride. Appropriate reaction temperature is -40 to 100°C and reaction time is 10 minutes to 10 days. The ratio of polymer to cytotoxic substance used varies depending on the desired degree of polymerization, but usually -COOZ in the polymer
An amount corresponding to 5 to 200% of the group is suitable. The desired polymer is obtained by removing low-molecular substances from the reaction mixture by dialysis, gel permeation chromatography, etc., and removing water by freeze-drying. Next, the obtained polymer is made into a homogeneous solution in water or dimethylformamide, etc., and a water-soluble low-molecular compound containing one primary or secondary amide group and one or more hydroxyl groups in the molecule is added. , for example, in the presence of a condensing agent such as 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride or dicyclohexylcarbodiimide. Appropriate reaction temperature is -40 to 100°C and reaction time is 10 minutes to 10 days. The ratio of polymer to cytotoxic substance used is
Although it varies depending on the desired degree of polymerization, an amount corresponding to 5 to 200% of the -COOZ groups in the polymer is usually suitable. In the above sequential reactions, the intermediate product (polymer) does not necessarily need to be isolated. That is, after reacting a cytotoxic substance containing an amino group or an imino group, one molecule is added to the same reaction system.
The reaction can also proceed by adding a water-soluble low molecule having one primary or secondary amino group and one or more hydroxyl groups and a condensing agent. The thus obtained polymer of the present invention is effective in treating leukemia and various malignant tumors. The compounds of the present invention are administered to patients by oral, subcutaneous, intramuscular, intravenous injection, suppositories, and other administration methods. For oral administration, solid or liquid preparations can be used. Examples of the preparation include tablets, pills, powders, granules, solutions, suspensions, and capsules. When preparing tablets, excipients such as lactose, starch, calcium carbonate, crystalline cellulose, or silicic acid; binders such as carboxymethylcellulose, methylcellulose, calcium phosphate, or polyvinylpyrrolidone; sodium alginate, Disintegrants such as sodium chloride, sodium lauryl sulfate and stearic acid monoglyceride; wetting agents such as glycerin; absorbents such as kaolin and colloidal silica; and additives such as talc and granular boric acid, etc., are used in formulations. be converted into Pills, powders, and granules are also formulated using the same additives as described above according to conventional methods. Liquid preparations such as solutions and suspensions are also formulated according to conventional methods. Examples of carriers used include glycerol esters such as tricaprin, triacetin, and iodized poppy oil fatty acid esters; water; alcohols such as ethanol; and oily bases such as liquid paraffin, coconut oil, soybean oil, sesame oil, and corn oil. . The above powders, granules, liquid preparations, etc. can also be contained in capsules made of gelatin or the like. Pharmaceutically acceptable carriers herein include stabilizers or preservatives. Formulations for parenteral administration are presented as sterile aqueous or non-aqueous solutions, suspensions, or emulsions. Non-aqueous solutions or suspensions include, for example, propylene glycol, polyethylene glycol or vegetable oils such as olive oil, ethyl oleate,
Injectable organic esters such as iodized poppy oil fatty acid esters are pharmaceutically acceptable carriers. Such formulations may also contain adjuvants such as preservatives, wetting agents, emulsifying agents, dispersing agents, and stabilizing agents. These solutions, suspensions, and emulsifiers can be sterilized by, for example, filtration through a bacteria retention filter, addition of a sterilizing agent, or irradiation. Alternatively, a sterile solid preparation can be prepared and used by dissolving it in sterile water or a sterile injection solvent immediately before use. The effective dosage of the antitumor agent of the present invention is determined based on age, gender,
It varies depending on the patient's condition, but generally 10 2 ~
It is recommended to administer around 10 5 ÎŒg/person/day. The toxicity of the cancer therapeutic agent of the present invention to experimental animals is as follows:
Although it depends on the type of cytotoxin it binds to, it is generally less toxic than the cytotoxin itself. For example, the LD50 value for mice of a polymer conjugated with AraC is 250
mg/Kg or more. The present invention will be explained in detail below with reference to Examples. Example 1 This example demonstrates the antitumor effect of the following reaction and product (polymer conjugated with a cytotoxic substance). (1) 705 mg of poly-L-glutamic acid sodium salt (molecular weight 21000, degree of polymerization 140) and 1-[5'-
(2-aminoethylphosphoryl)-β-D-arabinofuranomyl]cytosine (hereinafter AraCMP
(referred to as derivative) 502 mg (1.40 mmole) in 50 ml of water
and add 1N NaOH to bring the pH of the solution to 7.50.
And so. Next, 2.683g (14.0/mmole) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (condensing agent) was added, and 2.75g (14.0/mmole) was added.
Stir for hours. During this time, the pH of the solution tends to rise, so add 1NHCl dropwise to reach a pH of 7 to 7.6.
I continued to make adjustments. After the reaction was completed, the mixture was concentrated under reduced pressure at 40° to a volume of about 40 ml, and dialyzed in a cellophane tube at 4°C against pure water for 48 hours. The recovered liquid was freeze-dried to obtain 1114 g of flocculent white solid. bound in the resulting polymer
For convenience, the amount of AraCMP residues is calculated using the molecular extinction coefficient ε 273nm = 9000 (the Merck Index, 9th ed.
When the above sample was quantified, it was found that it contained 1.046 mmole (see page 2778). The reaction rate of Ara CMP was 74.7%. (2) Dissolve this substance in 50ml of water and add 503.4mg (8.25mmole) of 2-hydroxyethylamine to 1N.
Dissolve in 8.25ml of HCl and add, EDCIã»HCl3.16g
(16.5 mmole) and adjust the pH of the solution to 7.0 with 1NHCl.
The mixture was stirred for 4 hours. During this period, the PH tends to rise, so
1NHCl was added to react at pH 7.0 to 7.5. After the reaction was completed, the volume was concentrated under reduced pressure to 20 ml, and dialyzed against pure water at 4°C for 48 hours. The recovered liquid was freeze-dried to obtain 742 mg of flocculent solid. The amount of AraCMP residues contained in the obtained polymer was 0.654 mmole as determined by absorbance measurement at 273 nm. Poly-L-glutamate sodium salt has a pH of
At pH=4.0, precipitation occurred from aqueous solution, but on the other hand, the obtained polymer was water-soluble even at pH=4.0. This shows that many side chain carboxyl groups of poly-L-glutamic acid were hydroxyethylated. Furthermore, the binding rate of AraCMP residues in the obtained polymer was calculated as follows. Since AraCMP residue amount = 0.654 mmole (determined by ultraviolet absorbance measurement) and polymer weight = 742 mg, the molecular weight of the AraCMP-bound unit (formula []) is 469, and the 2-hydroxyethylamine-bound unit ( The molecular weight of formula []) is 172, so 469Ã0.654+172x=742
becomes. From this, x = 2.53 mmole (amount of hydroxyethylated units). Therefore, the binding rate of AraCMP = 0.654/2.53 + 0.654
=5), and 24 hours later, the test drug was administered once via IP, and the number of survival days was measured.
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i.v.ã§ïŒåæäžããçåæ¥æ°ã枬å®ããã[Table] It can be seen that the polymer of the present invention has a greater life prolonging effect than AraC. (ii) 1 à 105 L1210 cells were transferred to CDF1 mice (N
= 5), and 24 hours later, the test drug was administered.
It was administered once iv and the number of days of survival was measured.
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åæäžããçåæ¥æ°ã枬å®ããã[Table] Also in this case, the polymer of the present invention shows an excellent life prolonging effect. Example 2 This example demonstrates the following reactions and products. 100 mg of sodium salt of poly-L-glutamic acid (molecular weight 31000; degree of polymerization 240) and mitomycin
33mg of C in 0.025M sodium phosphate buffer (PH
7.24) Dissolved in 20ml. Next, 254 mg of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride was added and dissolved therein, and the mixture was stirred overnight in the dark. The reaction solution was then dialyzed against 0.9% NaCl for 24 hours and against pure water at 4°C for 24 hours.
By freeze-drying, 96.7 mg of a flocculent solid of mitomycin C-poly-L-glutamic acid conjugate, which is an intermediate product, was obtained. Dissolve this substance in 20ml of water, add 81mg of 2-hydroxyethylamine to 1N.
The mixture was dissolved in 1.33 ml of HCl, added with 509 mg of EDCI.HCl, and stirred for 4 hours. During this time, the pH tended to increase, so the pH was adjusted to 7.0 to 7.5 with 1NHCl. The reaction solution was then dialyzed against pure water at 4°C for 48 hours.
The recovered liquid was freeze-dried to obtain 105 mg of flocculent solid. Poly-L-glutamate sodium salt has PH=
On the other hand, the polymer obtained above was an aqueous solution even at PH=4.0. This indicates that many side chain carboxyl groups of poly-L-glutamic acid were hydroxyethylated. Further, the amount of mitomycin C residues bound to the obtained polymer was determined by measuring the ultraviolet absorption spectrum (in water) of the polymer. That is, the ultraviolet absorption spectrum has an absorption maximum at 360 nm based on the mitomycin C residue, confirming that the object of the present invention is formed, and the molecular extinction coefficient of the mitomycin C residue. For convenience, ε360nm=23000 (JSWebb et al., JACS,
84, p. 3185 (1962)), the amount of mitomycin and residues contained in 105 mg of the resulting mitomycin C-polymer conjugate was determined to be 29.7 ÎŒmole.
(equivalent to 9.93 mg). Also, the binding rate of MMC is
When calculated using the same method as in Example 1, it was 5.3%. Example 3 This example demonstrates the following reaction and product (cytotoxic substance conjugated polymer). Poly-L-glutamate sodium salt (molecular weight
21000, degree of polymerization 140) 100 mg and p-[N,N-bis(2-chloroethyl)]phenylenediamine hydrochloride
17.8 mg was dissolved in 20 ml of water, 130 mg of EDCI.HCl was added, and the mixture was stirred overnight. The reaction solution was then dialyzed against pure water at 4° C. for 48 hours and diaphragm-dried to yield 92 mg of the intermediate as a flocculent white solid. water this thing
Add 60 mg of 2,3-dihydroxypropylamine dissolved in 0.66 ml of 1N HCl,
Furthermore, 130 mg of EDCI/HCl was added and stirred overnight. The reaction solution was dialyzed against pure water at 4°C for 48 hours and then freeze-dried to obtain the target product, p-
122 mg of a polymer conjugate of [N,N-bis(2-chloroethyl)]phenylenediamine was obtained. Poly-L-glutamate sodium salt has PH=
The polymer obtained above was water-soluble even at pH=4.0, whereas it precipitated from an aqueous solution at pH=4.0. This shows that many side chain carboxyl groups of poly-L-glutamic acid were 2,3-dihydroxypropylaminated. Further, the amount of p-[N,N-bis(2-chloroethyl)]phenylenediamine residue bonded to the obtained polymer was determined by measuring the ultraviolet absorption spectrum of the polymer. That is, the ultraviolet absorption spectrum shows an absorption maximum based on the same residue at 275 nm, which confirms that the object of the present invention is formed, and the molecular extinction coefficient of the same residue is calculated as ε275 nm= 16200 (for convenience, the extinction coefficient of the conjugate of acetic acid and p-[N,N-bis(2-chloroethyl)]phenylenediamine was adopted), and the p contained in 122 mg of the obtained conjugate was
- The amount of [N,N-bis(2-chloroethyl)]phenylenediamine residue was determined to be 40 ÎŒmole.
(equivalent to 10.8 mg). Further, the binding rate was calculated in the same manner as in Example 1 and was 6.0%. Example 4 (1) Poly-L-glutamic acid (molecular weight 30000) 129
mg was dissolved in 30 ml of dry dimethylformamide, 121 mg of pivaloyl chloride and 100 mg of triethylamine were added under ice cooling, and the mixture was stirred for 40 minutes. Then,
1-(β-D-arabinofuranosyl)cytosine
A solution of 243 mg dissolved in 3 mg of dimethylformamide and 100 mg of triethylamine were added and stirred. After 20 minutes, the ice bath was removed, and the reaction was allowed to proceed at room temperature for 17 hours. Then, 2-hydroxyethylamine
61 mg was added and reacted for 2 hours. Thereafter, the reaction solution was added dropwise to 30 ml of ice water, and the resulting aqueous solution was dialyzed against water at 4° C. for 24 hours through a cellophane membrane. The dialysate was freeze-dried to obtain 205 mg of a flocculent solid of the following formula. The above-obtained polymer was water-soluble even at pH=4.0. This shows that many side chain carboxyl groups of poly-L-glutamic acid were hydroxyethylated. 247nm in ultraviolet absorption spectrum (UV)
By showing the characteristic absorption maximum of 1N-acylated AraC at 298 nm, it was confirmed that AraC is polymer-bonded with the 4N amino group. (M.
Akiyama et al., Chem.Pharm.Bull., vol. 26, 981
(1978)). The amount of AraC residues in the polymer is determined by setting the molecular extinction coefficient at 300 nm to 8000 for convenience (see the above literature).
When it was quantified, it was 0.18 mmole. Therefore,
The binding rate of AraC residues in the polymer was calculated as follows. Since AraC residue amount = 0.18 mmole (quantified by ultraviolet absorbance measurement) and polymer weight = 205 mg,
Furthermore, the molecular weight of the unit bound to AraC (formula []) is 354, and the molecular weight of the unit bound to 2-hydroxyethylamine (formula []) is 172, so 354Ã0.18+172x=205. From this, x = 0.82 mmole (amount of hydroxyethylated units). Therefore, the binding rate of AraC=0.18/0.82+0.18Ã100=18%. (2) Anti-tumor test 1Ã 105 L1210 cells were injected into CDF1 mice (N=
5), and 24 hours later, 1 dose of the study drug was administered ip.
The animals were administered twice, and the survival days were measured.
ãè¡šã
æ¬çºæã®éåäœã¯AraCã®å Žåããã延åœå¹
æã倧ã§ããããšããããã[Table] It can be seen that the polymer of the present invention has a greater life prolonging effect than AraC.
Claims (1)
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åäœã掻æ§æåãšããæè «çå€ã®è£œé æ³ã[Claims] 1. A structural unit represented by the formula [], In [Formula [], Z represents a hydrogen atom or a monovalent cation. m represents an integer of 1 to 4. ] The constituent unit represented by the formula [ ] and In [Formula []], X represents an alkylamine residue substituted with one or more hydroxyl groups. m represents an integer of 1 to 4. ] The constituent unit represented by the formula [ ] and In the formula [], Y represents an amino group- or imino-reactive residue of an antitumor alkylating agent, antimetabolite, or antibiotic containing an amino group or imino group in the molecule. m represents an integer of 1 to 4. ] Consisting of the constituent units represented by the formula [ ], In [Formula []], R represents a hydrogen atom, a methyl group, a benzyl group, or a hydroxymethyl group. ] The ratio of constituent units [ ], [ ] and [ ] is [ ] / [ ] + [ ] + [ ] = 0.05 to 0.95, and the constituent units [ ] are less than 40 mol% of the total constituent units,
An antitumor agent whose active ingredient is a polymer bound to a cytotoxic substance with a degree of polymerization of 10 to 2000. 2 At least 60 mol% of all structural units are of the formula [] In [Formula [], Z represents a hydrogen atom or a monovalent cation. m represents an integer of 1 to 4. ] Consisting of the constituent units represented by [ ], where the constituent unit [ ] is
When it is not 100 mol%, the remaining structural units are of the formula [] In [Formula []], R represents a hydrogen atom, a methyl group, a benzyl group, or a hydroxymethyl group. ] One polymer is obtained by reacting a polymer consisting of the structural unit represented by the following with an antitumor alkylating agent, antimetabolite, or antibiotic containing an amino group or imino group in the molecule. Alternatively, a method for producing an antitumor agent containing a polymer bound to a cytotoxic substance as an active ingredient, which comprises reacting an alkylamine compound substituted with a plurality of hydroxyl groups.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP56118477A JPS5821426A (en) | 1981-07-30 | 1981-07-30 | Polymer having joined cytotoxic substance and preparation thereof |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP56118477A JPS5821426A (en) | 1981-07-30 | 1981-07-30 | Polymer having joined cytotoxic substance and preparation thereof |
Publications (2)
Publication Number | Publication Date |
---|---|
JPS5821426A JPS5821426A (en) | 1983-02-08 |
JPH029563B2 true JPH029563B2 (en) | 1990-03-02 |
Family
ID=14737636
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP56118477A Granted JPS5821426A (en) | 1981-07-30 | 1981-07-30 | Polymer having joined cytotoxic substance and preparation thereof |
Country Status (1)
Country | Link |
---|---|
JP (1) | JPS5821426A (en) |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
IT1201474B (en) * | 1985-10-01 | 1989-02-02 | Vincenzo Zappia | MACROMOLECULARIZED DERIVATIVES OF CDP-COLINA, PROCEDURE FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS THAT CONTAIN THEM |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS5566352A (en) * | 1978-11-10 | 1980-05-19 | Matsushita Electric Works Ltd | Mouth washer |
JPS5629342A (en) * | 1979-08-17 | 1981-03-24 | Nec Corp | Manufacture of semiconductor device |
-
1981
- 1981-07-30 JP JP56118477A patent/JPS5821426A/en active Granted
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS5566352A (en) * | 1978-11-10 | 1980-05-19 | Matsushita Electric Works Ltd | Mouth washer |
JPS5629342A (en) * | 1979-08-17 | 1981-03-24 | Nec Corp | Manufacture of semiconductor device |
Also Published As
Publication number | Publication date |
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JPS5821426A (en) | 1983-02-08 |
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