CN100453118C - Antientity tumour medicinal composition containing topoenzyme inhibitor - Google Patents

Antientity tumour medicinal composition containing topoenzyme inhibitor Download PDF

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Publication number
CN100453118C
CN100453118C CNB2005100422362A CN200510042236A CN100453118C CN 100453118 C CN100453118 C CN 100453118C CN B2005100422362 A CNB2005100422362 A CN B2005100422362A CN 200510042236 A CN200510042236 A CN 200510042236A CN 100453118 C CN100453118 C CN 100453118C
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tumor
acid
entity
camptothecin
enzyme inhibitor
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CN1686552A (en
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孔庆忠
孙娟
孙静
孙宪德
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DASEN BIOLOGICAL PHARMACEUTICAL CO., LTD.
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Shandong Lanjin Pharmaceuticals Co Ltd
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Abstract

The present invention relates to a solid tumor resisting medicinal composition containing a topology enzyme inhibitor, which comprises anticancer effective components and medicinal supplementary materials, wherein the anticancer effective components comprise a topology enzyme inhibitor and topology enzyme inhibitor synergistic agents, and the topology enzyme inhibitor synergistic agents mainly comprise paclitaxel anticancer drugs, and/or anticancer antibiotics, and/or antimetabolita. The medicinal supplementary materials mainly comprise high molecular biologic capacitability polymers which can be degraded and absorbed, and in the degradation and absorption processes, the anticancer drug can be slowly released at part of a tumor, so that the systemic toxicity reaction of the drug is reduced obviously. Simultaneously, the effective drug concentration can be kept at part of the tumor. The composition is put at part of the tumor, the medicinal systemic toxicity reaction can be reduced, and simultaneously the drug concentration of part of the tumor can be enhanced in a selective mode. The treatment effect of non-operative treatment modes, such as chemotherapeutics, radiotherapy, etc., can be enhanced.

Description

A kind of entity-tumor-resistant medicine composition that contains topoenzyme inhibitor
(1) technical field
The present invention relates to a kind of topoenzyme inhibitor entity-tumor-resistant medicine composition that contains, belong to technical field of pharmaceuticals.
(2) background technology
Treatment for cancer mainly comprises methods such as operation, radiotherapy and chemotherapy.In used various chemotherapeutics, the action effect of topoenzyme inhibitor is comparatively obvious, has been widely used in multiple malignant tumor.Because topoenzyme inhibitor is by suppressing synthetic its antitumor action of bringing into play of RNA, and the DNA repair function in many tumor cells obviously increases after treatment, so effectively reduce or suppress the emphasis that the interior DNA repair function of tumor cell just becomes current research.
Recent findings, deactivation or suppress intracellular dna repair protein and can strengthen the sensitivity of part tumor cell to chemotherapy, referring to " O6-benzyl guanine analog is to the effect of human tumor cells to the cell toxicant sensitivity of alkylating agent " " cancer research " 51 phase 3367-3372 pages or leaves (1991) such as Doran (Dolan et al., Cancer Res., 51,3367-3372,1991)).Yet, blood vessel in the mesenchyma stroma of tumors, connective tissue, stromatin, fine micro protein and collagen protein etc. not only provide support and requisite nutrient substance for the growth of tumor cell, also influenced chemotherapeutics around tumor and infiltration and diffusion in the tumor tissues, " situation of extracellular matrix is to the influence of medicine running in the entity tumor " " cancer research " 60 phase 2497-503 page or leaf (2000) (Netti PA such as carry referring to the Buddhist nun, Cancer Res.2000,60 (9): 2497-503).Because entity tumor excessive expansion hypertrophy, the viscosity of matter was high than its normal surrounding tissue all between matter pressure, tissue elasticity pressure, fluid pressure reached therebetween, therefore, conventional chemotherapy, be difficult to tumor by local and form effective drug level, referring to " placing cisplatin adding system carmustine treatment rat brain tumor in the tumor " " surgery tumor magazine " 69 phase 76-82 pages or leaves (1998) (Kong Q et al., J Surg Oncol.1998 Oct such as Kong Qingzhongs; 69 (2): 76-82), improve the restriction that dosage is subjected to general reaction again merely.
In addition, the cancer drug therapy of low dosage not only can increase the Drug tolerance of cancerous cell, but also can promote the growth of its wettability "; referring to beam etc. " increased after the cancer therapy drug pulse screening human lung carcinoma cell Drug tolerance and external invade the profit ability and with the change of gene expression " " international journal of cancer " 111 phase 484-93 page or leaf (2004) (Liang Y; et al., Int J Cancer.2004; 111 (4): 484-93).
Because the principal element of decision therapeutic effect is the drug level of tumor by local and the tumor cell sensitivity to medicine.And the blood vessel in the mesenchyma stroma of tumors, connective tissue, stromatin, fine micro protein and collagen protein etc. not only provide support and requisite nutrient substance for the growth of tumor cell, have also influenced chemotherapeutics around tumor and infiltration and diffusion in the tumor tissues.
(3) summary of the invention
The present invention is directed to the deficiencies in the prior art, a kind of entity-tumor-resistant medicine composition is provided.
Entity-tumor-resistant medicine composition comprises anticancer effective component and pharmaceutic adjuvant, and wherein anticancer effective component is topoenzyme inhibitor and topoenzyme inhibitor synergist.Wherein, the topoenzyme inhibitor synergist mainly comprises one of paclitaxel kind anti-cancer drugs thing, antitumor antibiotics or antimetabolitas or combination.
The above topology enzyme inhibitor is selected from one of following or combination: Camptothecin (camptothecin, CPT), the derivant of Camptothecin, lurtotecan (Lurtotecan), topotecan (10-hydroxy-9-dimethylaminomethyl-(S)-camptothecin, topotecan), irinotecan (irinotecan, IRT).
The derivant of above-mentioned Camptothecin comprises: 9-nitro Camptothecin (9-nitrocamptothecin, 9NC), 7-ethyl-10-hydroxyl-Camptothecin (7-ethyl-10-hydroxy-camptothecin, SN-38), 7-ethyl-10-[4-(1-piperidino)-1-piperidino] and the carbonyl Camptothecin (7-ethyl-10-[4-(1-pyperidino)-1-piperidino] carbonyloxycamptothecin, CPT-11), 10-hydroxyl-Camptothecin (10-Hydroxycamptothecin, HCPT), Homocamptothecins (Homocamptothecins), MD-CPT (10,11-methylenedioxy, MD-CPT), (RS)-MD-CPT (10,11-MD-20 (RS)-CPT), (S)-MD-CPT glycinate (10,11-MD-20 (S)-CPT-glycinate ester (Gly) .HCl), 9-amino-(S)-MD-CPT glycinate (9-amino-10,11-MD-20 (S)-CPT-Gly), N-[2-(dimethylamino) ethyl] and pyridine-4-carboxylic acid amides (N-[2-(dimethylamino) ethyl] acridine-4-carboxamide, DACA) and the derivant of 5 or 7 replacements, podophyllotoxin (podophyllotoxin), etoposide (Etoposide, epipodophyllotoxins, etoposide, etoposide, VP-16), teniposide (Teniposide, teniposide, VM-26), Podophyllinic acid, podophyllotoxin, trihydroxy-isoflavone (Genistein), the 14-doxorubicin, amrubicin (Amrubicin), Ai Rou than star (4 '-(acridinylamino) methansulfon-m-anisidide (amsacrine, m-AMSA)), the nor-oxygen daunorubicin of 4-(4-demethoxydaunorubicin), detorubicin, 7-O-methyl Nuo Jia-4 '-epirubicin (7-o-methylnogallol-4 '-epiadriamycin), esorubicin (Esorubicin), carubicin, idarubicin (idarubicin, IDA), rodorubicin, leurubicin (Leurubicin), medorubicin, Nemorubicin (Nemorubicin), doxorubicin, N-trifluoro toxin-14-valerate (N-trifluoroacetyladriamycin-14-valerate, AD 32, valrubicin), 2-[4-(7-chloro-2-quinoxalinyl phenoxy base)-propanoic acid ((2-[4-(7-chloro-2-quinoxalinyloxyphenoxy)-propionicacid, XK469], zorubicin (Zorubicin), N-(2-ethyl chloride)-N-nitroso-group urea groups daunorubicin (N-(2-Chloroethyl)-N-nitrosoureidodaunorubicin, AD 312), pyrazoles [1,5-a] indole derivatives, as, but be not limited to, GS-2,-3,-4, GS-5; The dioxy piperazine oxazine derivatives, as, but be not limited to, (+)-1, two (3, the 5-dioxo piperazinyl) propane ((+)-1 of 2-, 2-bis (3,5-dioxopiperazinyl-1-yl) propane, ICRF-187) ,-2,3-two (3,5-dioxo piperazine-1-yl) butane (meso-2,3-bis (3,5-dioxopiperazine-1-yl) butane, ICRF-193), two dioxo piperazine (bisdioxopiperazine); Suramin (Suramin), deoxyguanosine (Deoxy guanosine), lithocholic acid (lithocholic acid, LCA) or Hydrazoic acid,sodium salt (sodium azide).
In the above topology enzyme inhibitor, serve as preferred than star, rodorubicin, leurubicin, zorubicin, N-trifluoro toxin-14-valerate, idarubicin with Camptothecin, hydroxy-camptothecin alkali, lurtotecan, topotecan, irinotecan, etoposide, teniposide, amrubicin, Ai Rou.
Topoenzyme inhibitor shared ratio in compositions is decided because of concrete condition, generally speaking, can be good with 1%-50% from 0.01%-99.99%, is best with 5%-30%.All be weight percentage.
Be selected from one of following or combination as the paclitaxel kind anti-cancer drugs thing (taxanes) of topoenzyme inhibitor synergist:
Paclitaxel (Paclitaxel, taxol, taxol), Docetaxel (Docetaxel, taxotere, docetaxel) and the derivant of paclitaxel, as, but be not limited to, 2 '-hydroxyl taxol (paclitaxel-2 '-hydroxy), 10-go the acetyl Baccatine III (10-deacetylbaccatin III, DAB), 14 beta-hydroxies-10-removes acetyl Baccatine III (14-OH-DAB), 9-dihydro-13-Baccatine III (DHB), IDN5109,10-removes acetyl taxol (10-deacetyltaxol), 7-table-taxol (7-epi-taxol), Tetraol, Baccatine III (baccatin III), Tetraol V, Semen Caesalpiniae Ramulus et folium taxi cuspidatae (Taxus brevifolia), ground hemlock (Taxus Canadensis), yew (Taxus baccata) and Chinese Ramulus et folium taxi cuspidatae (Taxus chinensis), pointed tooth Ramulus et folium taxi cuspidatae (Taxus cuspidata), cultivation Ramulus et folium taxi cuspidatae (Taxus X mediacultivars) ', Yunnan Ramulus et folium taxi cuspidatae Taxus yunnanensis) or Florida Ramulus et folium taxi cuspidatae (Taxus floridana).Above paclitaxel kind anti-cancer drugs thing also comprises their salt, as, but be not limited to sulfate, phosphate, hydrochlorate, Lactobionate, acetate, aspat, nitrate, citrate, purine or pyrimidine salt, succinate and maleate etc.
In above-mentioned paclitaxel kind anti-cancer drugs thing, serve as preferred with paclitaxel, Docetaxel (docetaxel) or 2 '-hydroxyl taxol.The content of above paclitaxel kind anti-cancer drugs thing in compositions is 1-50%.
Suppress by combining that RNA is synthetic to be used for the treatment of various cancers as the antitumor antibiotics of topoenzyme inhibitor synergist with DNA.
Antitumor antibiotics is selected from one of following or combination: carcinomycin, bleomycin (Bleomycin, Bleomycin A5, Pingyangmycin), (hydrochloric acid) bleomycin, zorbamycin, the piperazine bleomycin, sulphuric acid piperazine bleomycin, antibiotic 1588, bouvardin, clarithromycin (Clarithromycin), aklavine (Aclacinomycin A, aclarubicin, ACLA, aclarubicin), aklavine-B, 9-[4-(N-Methylacetamido)anilino, 9-(4-(N-Methylacetamido)anilino)-7-methyl-1H-imidazo(4,5-f)quinoline, kidamycin, acetylkitamycin (acetyl kidamycin), azotomycin (azotomycin), daunorubicin (daunorubicin, DNR, daunomycin, rubidomycin, daunorubicin, daunomycin), Diacetoxysciroenol (Diacetoxysciroenol), doxorubicin hydrochloride (doxorubicin, doxorubicin, adriamycin), triferricdoxorubicin, epirubicin (epiadriamycin) or epirubicin (Epirubicin), Valrubicin (valrubicin), pirarubicin, 7-O-methyl Nuo Jia-4 '-epirubicin (7-o-methylnogallol-4 '-epiadriamycin), diethoxy acetyl amycin, ciclamicin, mitomycin (Mitomycin), ametycin (mitomycin C), NSC-69529, actinomycin D (Dactinomycin), actinomycin C, cyclosporin A, Carzinocidin (carzinocidin), carzinophillin (carzinophylin), cardinophyllin, the tumor rhzomorph, carzinostatin (carzinostatin, carcinostain), neocarzinostain NCS (neocarzinostain), diazamycine (diazamycine), Macrocin (macrocin), macrocinomycin (macrocinomycin), dactinomycin, alanopsin, alazopeptin, the A Le lid, neothricin (neothricin, neothramycin), macromycin (macromomycin or macromycin), neothramycin A, nocardin (nocardin), nocardorubin. (nocardorubin), 2-[N-(2-amidinoethyl)carbamoyl (noformicin), nogalamycin (promise Garamycin, nogalamycin or nogaromycin), Mitochromine mitocromine B-35251 (mitochromine or mitocromine), polymyxin E (Polymyxin E), pirlimycin (Pirlimycin), dirithromycin (Dirithromycin), antramycin, oxalysine, duazomycin, Olivomycin, rufocromomycin, NSC-45384, streptozotocin, peplomycin, puromycin, sparsomycin, talisomycin, Anthrapyrazole, losoxantrone (Losoxantrone), mitoxantrone (Mitoxantrone), piroxantrone (Piroxantrone), teloxantrone (Teloxantrone), hydroxyl nitre D-glucosamine ring element, anthramycin (anthramycin, antramycin), methylanthramycin, Ai Fei ground can be peaceful, asperlin, (hydrochloric acid) Carrninomycin I, talisomycin, macromycin, O-Demethyldaunomycin, NSC-178248, chromomycin A3, chlorine assistant star (chlorozotocin), demethylrifampicin, ditrisarubicins, Hitachimycin, deoxycoformycin, puromycin, puromycin hydrochloride, rachelmycin, rebeccamycin, Sangivamycin, sarkomycin, sibiromycin, talisomycin, rice holder Zuro, selenazofurin, Antibiotic BMG-162aF2, spirogermanium hydrochloride, Spirogermanium, Spirophydantoin Mustard or stibcytostatum.
Above-mentioned antitumor antibiotics serves as preferred with bleomycin, daunomycin, aclarubicin, amycin, epirubicin, pirarubicin, Valrubicin, ametycin, actinomycin D, losoxantrone, mitoxantrone, piroxantrone, teloxantrone or chlorine assistant star.
Antimetabolitas as the topoenzyme inhibitor synergist can stop the synthetic of DNA in different links respectively, suppresses the cell division increment, and cell cycle and DNA are synthetic to play a role by influencing.
Antimetabolite is selected from one of following or combination: pemetrexed (Alimta), pemetrexed disodium, Rumi Qu Sai, doxifluridine (Doxifloridine, fortulon), the 5-doxifluridine, floxuridine (fluridine), propylthiouracil, fluorouracil (Fluoracil, Fluracil), the fluorobutane uracil, 5-fluorouracil (Fluorouracil, 5-FU), tegadifurum, the 5-fluoxydin, sulfomercaprine sodium, mercaptopurine (Mercaptopurine, happy disease is peaceful, 6-MP), mercapto miaow purine, Ismipur, the adenine hydrochlorate, Benin, thioguanine (thioguanine, 6-TG), sulfur crow purine, tisupurin, Hydrazinium sulfate, dianhydrogalactitol, Aziridinyl Benzoquinone, but sweet smell Luoning, isoeuxanthone, chalone, chlorine is bent phosphoric acid, clastoban, cycloleucine, look into the Chinese holly woods, methyl yellow is looked into the Chinese holly woods sourly, Bai Ruikuaer, oxipurinol, Australia Ma Lite, bromine crust acid (sodium), Brytoslatin-I, bromine urea glycosides, fluorine urea hexylamine, folic acid, methotrexate (methotrexate, MTX), 10-ethyl denitrification aminopterin (deaza-aminopterin), fluoromethotrexate, the dioxy methotrexate, 5, the 10-lonetrexol, N5-Methyltetrahydrohmofotic Acid, buthiopurin, his amide of Dinke, Guang azepine crow glycosides, carmofur (Carmofur), ftorafur (Tegafur, tegafur, FT-207), Tegafur-uracil mixt., 6-prenylindole, 6-thioinosine, UFT (Tegafur-Uracil, UFT), coralyne, N-foymylsarcolysin, ammonia (base) pterin (aminopterin), aminopterin sodium (Aminopterin Sodium), 8-azaguanine (8-azaguanine), 6-dimethylamino-8-azaadenosine, (nitro) imuran (azathioprine), uracil, 5-mercaptomethyluracil, azaserine (azaserine), Raltitrexed (Raltitrexed), nolatrexed dihydrochloride, sophoridine, formyl tetrahydrofolic acid, 5-methyltetrahydrohomofolate, Zoledronate, thunder accounts for for song, the temozolomide, bicalutamide, asparaginase (L-Asparaginase, left-handed asparagine), calcium levofolinate, calcium folinate (Calcium Levofolinate, calcium leucovorin), Quinespar, triazinate, trimetrexate, tramadol, the 5-chlorobarbituric acid, 5-diazonium uracil, piracetam, hycamtin, topotecan hydrochloride, ZD-9331, BHAC, SM108, cytosine arabinoside (cytosine arabinoside, Cytarabine (Ara-C)), ancitabine (cyclotidine, Cyclocytidine], hydroxyurea (Hydroxycarbamide, hydroxyurea), the hydroxyl guanidine, the 5-fluorouracil nucleoside, the 5-fluorouracil deoxynucleoside claims fluorouracil deoxynucleoside (floxuridine) again, glycerol Citrus chachiensis Hort. alkali, A Lei can loose, HCFU, 5 ' DFUR, TK-177, isoxazole acetic acid, aminoglutethimide (ethylbenzene amine piperidones, aminoglutethimidium, aminoglutethimide), amonafide, 5-chloro-5-deoxyarabinosylcytosine, atamestane, azacytidine (Azacitidine, 5-azacytidine, the atropic cytidine, AzGR), chloramphenalan (betamerphalan, Betamerphalan), decitabing, dexrazoxane (Dexrazoxane), crisnatol, cristatic acid, carat is sharp flat, the sharp guest of carat, galocitabine (Galocitabine), gemcitabine (Gemcitabine), ibacitabine (Ibacitabine), enocitabine (Enocitabine), ancitabine (Ancitabine), decitabine (Decitabine), flurocitabine (Flurocitabine), capecitabine (Capecitabine), enocitabine, his shore of imidazoles, the non-Shandong of Crane, the OK a karaoke club amide, carzolamide, carbazylquinone, CB-1-252, curcumin, the curcumin diketone, ketotrexate, trimetrexate, Si Poguning, deoxidation Si Poguning, naphthalene urea phosphamide, Ditercalinium Chloride, F-ara AMP-2, fluorine benzyl thiophene ketone, gamlogic acid, goserelin, nitrogen Chinese holly mountain range, Hellebrigenin, inosine dialdehyde, metoprine, mitobronitol (Dibromomannitol, Mitobronitol), mitolactol (Mitolactol), Ke is for ground, Persian, eriolangin, dopan (Chlorethylaminouracil, Dopan), Mei Luogerui, Methyl GAG, GR 30921X, mitotane, fazarabine (Fazarabine), fludarabine (fludarabine), cladribine (cladribine), pentoside (pentostatin), phenaline, benzene comes U.S. special, phosphemide, hair Buddhist nun azoles, Polyprenic Acid, Pteroylaspartic Acid, pteroyltriglutamic acid, fast rice tongue pool, riboprine, simtrazene, Schizophyllan, sodium bromebrate, Solvent Yellow 3, bent fourth sulphur ester, TEM, triaziquone, triciribine, TCN-P NSC-280594, triptolide, triptorelin, nine cloth Lip river azoles, UFT, vitamin B-17, Wei Maining, z-azepine adenosine, prick western cytidine, epipropidine [Epipropidine], the A Monuo phase, adozelesin (Adozelesin), acronine (Acronine), alanosine (Alanosine), ametantrone (Ametantrone), Anastrozole, the A Naxi army, anaxirone (Anaxirone), A Si Yin wakes up, acivicin (Acivicin), atevirdine [Atevirdine], idoxifene (idoxifene), AT-236, hold high and rather study carefully Ji, individual Lu Dabuxin, antineoplaston, antineoplastons, asaphan, Aspargus Granule, AT-346, Bai Ruikuaer (sodium), (hydrochloric acid) Orang Crush, granisetron, tropisetron, dacarbazine, ondansetron, thymosin, tramadol, imatinib mesylate, diclofenac, Thalidomide, the holder fluorine kills star, toremifene, ambroxol, lappaconitine, anti-general etc. because of, thymosin, flutamide, ethyliminum, amine benzene, neoquini oxydum, the N-methylformamide, the jail can reach azoles, NSC-56045, oxisuran, oxylycorine, paphencyl, it is fixed to moor damp Nip, the penberol, prospidine chloride, protoanemonin, good generation born of the same parents, retelliptine, Sensorad, M3, solapalmitine, solaziquonum, stibenemidine, Temozoromide, the many Shillongs of platform, thiaolivacine, bifurcation pyridine of nitre ammonia or SN-11841.
In above-mentioned antimetabolite with Ismipur, 5-fluorouracil (5-FU), pemetrexed, pemetrexed disodium, Rumi Qu Sai, doxifluridine, floxuridine, mercaptopurine, thioguanine, methotrexate, carmofur, ftorafur, galocitabine, ibacitabine, enocitabine, ancitabine, decitabine, flurocitabine, enocitabine, his shore of imidazoles, GR 30921X, mitotane, cytosine arabinoside, hydroxyurea, the 5-fluorouracil nucleoside, capecitabine, gemcitabine, fludarabine, thunder accounts for for song, Raltitrexed, the atropic cytidine, dexrazoxane, cladribine or pentoside are preferred.
To suppress RNA synthetic by combining with DNA for topoenzyme inhibitor in the entity-tumor-resistant medicine composition of the present invention, thereby be used for the treatment of various cancers, its synergist is used for the treatment of outside the various cancers, also can effectively reduce or suppress the DNA repair function in the tumor cell, and then increase the sensitivity of tumor cell topoenzyme inhibitor.
Topoenzyme inhibitor synergist shared percentage by weight in compositions is decided because of concrete condition, generally speaking, can be good with 1%-50% from 0.01%-80%, is best with 5%-30%.The weight ratio of topoenzyme inhibitor and topoenzyme inhibitor synergist is 1-9: 1 to 1: 1-9.
Pharmaceutic adjuvant of the present invention can be through enzyme, soda acid or tissue fluid hydrolysis or degraded.Described pharmaceutic adjuvant comprises one of following or its combination:
(1) biocompatibility polymer, comprise biodegradable or biological nondegradable polymer and composition thereof or copolymer, (2) water-soluble low-molecular chemical compound is or/and (3) are used to realize the suitable additive and the excipient of pharmaceutical dosage forms such as injection and slow releasing agent.
Above-mentioned biodegradable polymer comprises natural and/or synthetic polymer.Synthetic polymer as, but be not limited to, polyanhydrides, polyhydroxy acid, polyester (polyesters), polyamide (polyamides), polypeptide (polypeptides), polyactide (polylactides) is as polylactic acid (polylactic acid), polyactide and glycolide copolymer (as the copolymer (PLGA) of glycolic and lactic acid), poe (polyorthoesters), polyphosphazene (polyphosphazenes), to carboxy phenyl propane (p-CPP), certain herbaceous plants with big flowers diacid (sebacic acid), liposome, Polyethylene Glycol (polyglycolide) (polymer of hydroxyacetic acid and lactic acid), carboxylic acids (carboxylic acids), fatty acid (fatty acids), phospholipid (phospholipids), nucleic acid (nucleic acids), polyamino acid (polyamino acids), aminoacid such as phenylalanine (phenylalanine), tyrosine (tyrosine), different bright (isoleucine), polynucleotide (polynucleotides); Natural polymer as, but be not limited to, protein and polysaccharide (polysaccharides) comprise hyaluronic acid (hyaluronic acid), chondroitin sulfate (chondroitin sulfate), collagen protein, gelatin, albumin etc.Wherein, preferred polymer is polyactide, Polyethylene Glycol or polyactide and glycolide copolymer (as the copolymer (PLGA) of glycolic and lactic acid).
Above-mentioned polyanhydrides can be selected for use, but is not limited to, fragrant polyanhydride, aliphatic polyanhydride; Wherein fragrant polyanhydride will be separated slower, the fusing point height, and dissolubility is low in the organic solvent, however the copolymer of fragrant polyanhydride and aliphatic polyanhydride is comparatively desirable (United States Patent (USP) 4757128) but.Representative wherein is polifeprosan (to the copolymer of carboxy phenyl propane (p-CPP) and certain herbaceous plants with big flowers diacid (SA)), and is fragrant polyanhydride to carboxy phenyl propane, and the certain herbaceous plants with big flowers diacid then is the copolymer of an aromatic diacid and a fat diacid.The copolymer of available other fragrance or aliphatic polyanhydride has a detailed description in other United States Patent (USP) that (US 4857311; 4888176; 4789724).
Above-mentioned polyhydroxy acid can be selected for use, but is not limited to, the copolymer (PLGA) of mixture, glycolic and the lactic acid of polylactic acid (PLA), polyglycolic acid (PGA), polylactic acid (PLA) and polyglycolic acid.Above polyhydroxy acid can singly select or multiselect, and when singly selecting, the molecular weight of polylactic acid (PLA) can be, but is not limited to, 5000-100, and 000, but with 10,000-50000 is preferred, with 10,000-30000 is for most preferably; The molecular weight of polyglycolic acid can be, but is not limited to, 5000-100, and 000, but with 10,000-50000 is preferred, with 10,000-20000 is for most preferably; The molecular weight of the copolymer of glycolic and lactic acid (PLGA) can be, but is not limited to, 1000-100, and 000, but with 10,000-50000 is preferred; With 10,000-20000 is for most preferably; When multiselect, compound polymer or the copolymer formed with macromolecule polymer or different macromolecule polymer serve as preferred, with the compound polymer that contains different molecular weight polylactic acid or certain herbaceous plants with big flowers diacid or copolymer for most preferably, as, but be not limited to, molecular weight is 5000 to 10000 polylactic acid with molecular weight is that 20000 to 50000 polylactic acid mixes, molecular weight is 10000 to 20000 polylactic acid with molecular weight is that 30000 to 80000 PLGA mixes, molecular weight is that 5000 to 10000 polylactic acid mixes with the certain herbaceous plants with big flowers diacid, molecular weight is that 30000 to 80000 PLGA mixes with the certain herbaceous plants with big flowers diacid.When PLA and PGA mixing, its content percentage by weight is respectively 0.1-99.9% and 99.9-0.1%.Compositions can discharge effective ingredient by the mode of direct diffusion and/or degraded.Above molecular weight peak value scope is that GPC records.
The nondegradable polymer of above-mentioned biology comprises, but be not limited to: polyethylene propylene (polyvinyl propylene), polyvinylpyrrolidone (polyvinylpyrrolidone, PVP), organosilicon polymer, ethylene vinyl acetate copolymer (Ethelene-vinyl acetate copolymer, EVAc), polyacrylonitrile (polyacrylonitriles), polyurethanes (polyurethanes), silicone (silicone) and polyphosphazene (polyphosphazenes) etc.Compositions can discharge effective ingredient by the mode of direct diffusion.
For regulating other characteristic of drug releasing rate or change entity-tumor-resistant medicine composition of the present invention, can change the composition and the proportioning of monomer component or molecular weight, interpolation or the adjusting pharmaceutic adjuvant of polymer, add the water-soluble low-molecular chemical compound, as, but be not limited to various sugar and salt etc.Wherein sugar can be, but is not limited to, xylitol, oligosaccharide and chitin etc., and wherein salt can be but is not limited to, potassium salt or sodium salt etc.
The used pharmaceutic adjuvant of entity-tumor-resistant medicine composition of the present invention can be any or multiple material in the above-mentioned pharmaceutic adjuvant, but with the high molecular weight water soluble polymer is main separation, in various high molecular polymers, with polylactic acid, certain herbaceous plants with big flowers diacid, the mixture or the copolymer that contain the macromolecule polymer of polylactic acid or certain herbaceous plants with big flowers diacid is first-selection, mixture and copolymer can be selected from, but be not limited to the mixture or the copolymer of the mixture of PLA, PLGA, PLA and PLGA, certain herbaceous plants with big flowers diacid and fragrant polyanhydride or aliphatic polyanhydride.Polylactic acid (PLA) and polyglycolic acid the blend ratio be 10/90-90/10 (weight), 25/75-75/25 (weight) preferably.The method of blend is arbitrarily.Content when glycolic and lactic acid copolymerization is respectively percentage by weight 10-90% and 90-10%.The representative of fragrance polyanhydride is to carboxy phenyl propane (p-CPP), content during to carboxy phenyl propane (p-CPP) and the copolymerization of certain herbaceous plants with big flowers diacid is respectively percentage by weight 10-60% and 20-90%, the blend weight ratio is 10-40: 50-90, preferably weight ratio 15-30: 65-85.
Pharmaceutic adjuvant has a detailed description in " pharmaceutic adjuvant complete works " (the 123rd page, Sichuan science tech publishing house published in 1993, Luo Mingsheng and Gao Tianhui chief editor).In addition, Chinese patent (application number 96115937.5; 91109723.6; 9710703.3; 01803562.0) and U.S.'s patent of invention (patent No. 5,651,986) also enumerated some pharmaceutic adjuvants.Comprise filler, solubilizing agent, absorption enhancer, film former, gellant, system (or causing) hole agent, excipient or inhibitor.Above pharmaceutic adjuvant has has multiple action, and therefore the material of the same race that has is listed in different classifications.The available holder of composition for treating solid tumor of the present invention can be any or multiple material in the above-mentioned pharmaceutic adjuvant, and not exclusively comes the technical characterictic of limit combination according to its classification or definition.
The effective ingredient of entity-tumor-resistant medicine composition can be packaged in the whole pharmaceutic adjuvant equably, also can be packaged in carrier holder center or its surface; Can effective ingredient be discharged by direct diffusion or through mode or dual mode like this that polymer is degraded.In addition, the effective ingredient of composition for treating solid tumor also can be packaged in the liposome equably, or makes microsphere with art methods.
Characteristics of the present invention are that used pharmaceutic adjuvant removes the high molecular polymerization beyond the region of objective existence, also contain above-mentioned any one or multiple other pharmaceutic adjuvant.The pharmaceutic adjuvant that adds is referred to as additive.Additive can be divided into filler, porogen, excipient, dispersant, isotonic agent, preservative agent, inhibitor, solubilizing agent, absorption enhancer, film former, gellant etc. according to its function.
Pharmaceutic adjuvant also can be liquid, as, but be not limited to Oleum sesami, suspension, distilled water, physiology towards liquid and semisolid, as (but being not limited to) fruit jelly, paste, ointment etc., above-mentioned pharmaceutic adjuvant is applicable to the compositions that contains or do not contain additive.
Entity-tumor-resistant medicine composition of the present invention can be made into multiple dosage form.As, but be not limited to injection, muddy suspension, ointment, capsule, slow releasing agent, implant, implantation slow release agent etc.; Be different shape, as, but be not limited to granular, lamellar, sphere, bulk, needle-like, bar-shaped and membranaceous.In various dosage forms, based on agent for slow releasing in the body or implant.Above-mentioned dosage form and shape are applicable to the compositions that contains or do not contain additive.
Most preferred dosage form of the present invention is the implantation slow release agent that bio-capacitivity, degradable absorb, and can make different shape because of the clinical needs of difference.The packing method of its Main Ingredients and Appearance and step in United States Patent (USP) (US5651986) have a detailed description, comprise the some kinds of methods that prepare slow releasing preparation: as, but be not limited to, (i) carrier holder powder and medicament mixed be pressed into implant then, promptly so-called mixing method; (ii) carrier holder fusing, mix solid cooled then, promptly so-called fusion method mutually with medicine to be packaged; (iii) the carrier holder is dissolved in the solvent, medicine dissolution to be packaged or be scattered in the polymer solution, evaporating solvent then, the universe is dry, promptly so-called dissolution method; (iv) spray drying method; And (v) freeze-drying etc.Wherein dissolution method can be used for the manufacturing of microsphere, and anticancer pharmaceutical composition also can be packed in the liposome.
Because entity-tumor-resistant medicine composition of the present invention can make the action effect of methods such as conventional chemotherapy, immunization therapy, high thermal therapeutical, photochemical therapy, electrotherapy, Biotherapeutics, hormone therapy, magnetic therapy, ultrasonic therapeutic, radiotherapy and gene therapy strengthen.Therefore when local slow discharges, can share, thereby its anticancer effect is further strengthened with above-mentioned non-operative treatment.
Route of administration
Entity-tumor-resistant medicine composition of the present invention can be through various administrations, as in passages through which vital energy circulates, tremulous pulse, subcutaneous, muscle, Intradermal, intracavity, the tumor, tumor week etc.Route of administration depends on multiple factor, for obtaining valid density in position, tumor place, medicine can give through other number of ways, as arterial perfusion optionally, administration in the intra-bladder instillation (intracavitary), abdominal cavity (intraperitoneal) or thoracic cavity (intrapleural) and canalis spinalis.In number of ways, with topical, as with in selective arterial, the tumor, tumor week injection or be placed as the master, with in the tumor, the form that slowly discharges of tumor week or tumor chamber serve as preferably, can plant slow-releasing pump, slow releasing capsule, slow releasing agent, implant or sustained-release implant as selecting for use.With the tremulous pulse approach is good, directly is placed as the best in the tumor body.
Dosage
The consumption of cancer therapy drug depends on several factors, as, but be not limited to gross tumor volume, patient body weight, administering mode, disease progression situation and therapeutic response.Generally speaking, the topoenzyme inhibitor synergist can be 0.01-200 milligram/kg body weight, with 1-100 milligram/kg body weight is ideal, with 5-80 milligram/kg body weight for the most desirable, topoenzyme inhibitor can be 0.01-100 milligram/kg body weight, with 1-180 milligram/kg body weight is ideal, with 5-50 milligram/kg body weight for the most desirable.
Entity-tumor-resistant medicine composition of the present invention can be used to prepare the medicine of the various entity tumors for the treatment of people, house pet and animal, comprises former or cancer or sarcoma or the carcinosarcoma that shifts originating from brain, central nervous system, kidney, liver, gallbladder, incidence, oral cavity, thyroid, skin, mucosa, body of gland, blood vessel, osseous tissue, lymph node, lungs, esophagus, stomach, mammary gland, pancreas, eyes, nasopharynx part, uterus, ovary, endometrium, cervix uteri, prostate, bladder, colon, rectum.
Also can add other medicinal ingredient in the entity-tumor-resistant medicine composition of the present invention, as, but be not limited to antibiotics, antalgica, anticoagulant medicine, hemorrhage etc.Above medicinal ingredient can singly select or multiselect, can join the compositions that contains or do not contain additive, and its content is because of specifically deciding.
Above-mentioned effective ingredient is packaged in the pharmaceutic adjuvant, then topical application.Said composition can be through various administrations, with topical, as selective arterial injection and directly injection or be placed as goodly in the tumor body, wherein are released to the best with local slow again.When used the part, composition for treating solid tumor of the present invention can directly place around former or the entity tumor that shifts or in the tumor body, also can directly place former or all or part of excision of entity tumor shifted formed intracavity afterwards.
Entity-tumor-resistant medicine composition Main Ingredients and Appearance of the present invention is a holder with the bio-capacitivity material, so do not cause foreign body reaction.Support to place in the object back degradable and absorb, so no longer operation is taken out.Cause discharges contained drug at tumor by local, thereby optionally improves and prolong local drug concentration, can reduce the general toxic reaction that is caused by the conventional route administration simultaneously.
The characteristics of entity-tumor-resistant medicine composition technology of preparing of the present invention are topoenzyme inhibitor and/or its synergist are packaged in the pharmaceutic adjuvant, proportionally with active ingredient and pharmaceutic adjuvant dissolving, treat that abundant mixing is dry afterwards.Be shaped immediately after to be dried and sterilize packing.
Above topological enzyme suppresses and/or its synergist is local places, not only can overcome the toxic reaction that the whole body administration brings, and has solved the tumor by local drug level and cross the low and cell sensitive question to medicine.
By following test and embodiment the technology side of composition for treating solid tumor of the present invention is further described:
The external tumor-inhibiting action of test one, topological enzyme inhibition and/or its synergist.
Used tumor cell comprises CNS-1, C6,9L, gastric gland epithelial cancer (SA), bone tumor (BC), breast carcinoma (BA), pulmonary carcinoma (LH), papillary adenocarcinoma of thyroid (PAT), hepatocarcinoma etc.Following topological enzyme inhibition and/or its synergist are added in 24 hours the various tumor cells of In vitro culture by 10ug/ml concentration, continue to cultivate counting cells sum after 48 hours.Its tumor growth suppresses effect and is shown in Table 1.
Table 1
Oncocyte (A) (B) (C) (D) (E) (A) +(B) (A) +(C) (A) +(D) (A) +(E)
CNS 58％ 65％ 68％ 64％ 60％ 90％ 92％ 81％ 90％
C6 52％ 64％ 60％ 64％ 63％ 96％ 94％ 86％ 92％
SA 58％ 60％ 56％ 60％ 62％ 86％ 85％ 86％ 86％
BC 54％ 64％ 54％ 54％ 54％ 94％ 94％ 84％ 94％
BA 54％ 62％ 62％ 52％ 52％ 98％ 96％ 98％ 98％
LH 50％ 58％ 62％ 68％ 66％ 90％ 90％ 94％ 92％
PAT 64％ 54％ 64％ 66％ 69％ 94％ 94％ 94％ 94％
Annotate: (A): Camptothecin, topological enzyme suppresses; (B): paclitaxel, (C): Docetaxel, (D): amycin, (E): 5-fluorouracil.(B)-(E) be topological enzyme and suppress synergist, topological enzyme is suppressed all to have notable synergistic effect (P＜0.05).
The external tumor-inhibiting action of test two, topological enzyme inhibition and/or its synergist.
Used tumor cell is with test one.Following topological enzyme suppressed and/its synergist is added in 24 hours the various tumor cells of In vitro culture by 10ug/ml concentration, continues to cultivate counting cells sum after 48 hours.Its tumor growth suppresses effect and is shown in Table 2.
Table 2
Oncocyte (A) (B) (C) (D) (E) (A) +(B) (A) +(C) (A) +(D) (A) +(E)
CNS 68％ 64％ 66％ 64％ 60％ 90％ 92％ 80％ 94％
C6 62％ 64％ 60％ 64％ 63％ 96％ 94％ 86％ 92％
SA 58％ 60％ 56％ 60％ 62％ 86％ 85％ 86％ 86％
BC 54％ 64％ 54％ 54％ 54％ 94％ 94％ 84％ 94％
BA 54％ 62％ 62％ 52％ 52％ 98％ 96％ 98％ 98％
LH 60％ 58％ 62％ 68％ 66％ 90％ 90％ 94％ 92％
PAT 54％ 56％ 66％ 66％ 69％ 94％ 92％ 94％ 92％
Annotate: (A): topotecan, topological enzyme suppresses; (B): mitoxantrone, (C): ametycin, (D): epirubicin, (E): pemetrexed.(B)-(E) be topological enzyme and suppress synergist, topological enzyme is suppressed all to have notable synergistic effect (P＜0.05).
The external tumor-inhibiting action of test three, topological enzyme inhibition and/or its synergist.
Used tumor cell is with test one.Following topological enzyme inhibition and/or its synergist are added in 24 hours the various tumor cells of In vitro culture by 10ug/ml concentration, continue to cultivate counting cells sum after 48 hours.Its tumor growth suppresses effect and is shown in Table 3.
Table 3
Oncocyte (A) (B) (C) (D) (E) (A) +(B) (A) +(C) (A) +(D) (A) +(E)
CNS 68％ 64％ 66％ 64％ 60％ 90％ 92％ 80％ 94％
C6 62％ 64％ 60％ 64％ 63％ 96％ 94％ 86％ 92％
SA 58％ 60％ 56％ 60％ 62％ 86％ 85％ 86％ 86％
BC 54％ 64％ 54％ 54％ 54％ 94％ 94％ 84％ 94％
BA 54％ 62％ 62％ 52％ 52％ 98％ 96％ 98％ 98％
LH 60％ 58％ 62％ 68％ 66％ 90％ 90％ 94％ 92％
PAT 54％ 56％ 66％ 66％ 69％ 94％ 92％ 94％ 92％
Annotate: (A): irinotecan, topological enzyme suppresses; (B): bleomycin, (C): Ismipur, (D): Rumi Qu Sai, (E): methotrexate.(B)-(E) be topological enzyme and suppress synergist, topological enzyme is suppressed all to have notable synergistic effect (P＜0.05).
Above-mentioned experimental result shows that topological enzyme suppresses synergist topological enzyme is suppressed all to have the notable synergistic effect.Further test shows, other topoenzyme inhibitor synergist that the present invention is listed, as, carmofur, ftorafur, cytosine arabinoside, gemcitabine, thunder for song account for, Raltitrexed, dexrazoxane etc. suppress all to have the notable synergistic effect to hydroxy-camptothecin alkali, etoposide, teniposide, amrubicin, Ai Rou than topological enzymes such as star, rodorubicin, leurubicin, zorubicin, N-trifluoro toxin-14-valerate, idarubicin.Though be unexpected discovery the of the present invention, be of universal significance.
Tumor-inhibiting action in the body of test four, topoenzyme inhibitor and synergist thereof.
With the rat is subjects, with 2x10 5Individual tumor cell subcutaneous injection is in its hypochondrium, treats that tumor growth after 14 days is divided into it following 10 groups (seeing Table 4).First group is contrast, and the 2nd to 10 group is the treatment group.The dosage of topoenzyme inhibitor and synergist thereof is 5mg/kg.The treatment back was measured gross tumor volume size, relatively therapeutic effect (seeing Table 4) on the 30th day.
Table 4
Test group (n) Suffered treatment Gross tumor volume (cm 3) The P value
1(6) Contrast 62.5±12cm 3
2(6) Etoposide 46±11cm 3 ＜0.05
3(6) Methotrexate 41±8cm 3 ＜0.01
4(6) Paclitaxel 34±6cm 3 ＜0.01
5(6) Docetaxel 38±6.4cm 3 ＜0.01
6(6) 5-fluorouracil 36±6.8cm 3 ＜0.01
7(6) Etoposide+methotrexate 20±4.6cm 3 ＜0.001
8(6) Etoposide+paclitaxel 14±2.6cm 3 ＜0.001
9(6) Etoposide+Docetaxel 12±3.6cm 3 ＜0.001
10(6) Etoposide+5-fluorouracil 16±2.4cm 3 ＜0.001
Annotate: above topoenzyme inhibitor synergist all has notable synergistic effect (P＜0.001) to topoenzyme inhibitor.
Tumor-inhibiting action in the body of test five, topoenzyme inhibitor synergist and topoenzyme inhibitor.
With the rat is subjects, with 2x10 5Individual tumor cell subcutaneous injection treats that in its hypochondrium tumor growth was divided into 10 groups (seeing Table 5) with it after 14 days, and first group is contrast, and the 2nd to 10 group is the treatment group.The dosage of topoenzyme inhibitor synergist and topoenzyme inhibitor is 5mg/kg.The treatment back was measured gross tumor volume size, relatively therapeutic effect (seeing Table 5) on the 30th day.
Table 5
Test group (n) Suffered treatment Gross tumor volume (cm 3) The P value
1(6) Contrast 65±12cm 3
2(6) Teniposide 42±10cm 3 ＜0.05
3(6) Pemetrexed 43±8.4cm 3 ＜0.01
4(6) Rumi Qu Sai 36±6.2cm 3 ＜0.01
5(6) Carmofur 40±6.46cm 3 ＜0.01
6(6) Ftorafur 34±6.8cm 3 ＜0.01
7(6) Teniposide+pemetrexed 26±4.8cm 3 ＜0.001
8(6) Teniposide+Rumi Qu Sai 20±3.8cm 3 ＜0.001
9(6) Teniposide+carmofur 16±4.4cm 3 ＜0.001
10(6) Teniposide+ftorafur 14±2.2cm 3 ＜0.001
Above topoenzyme inhibitor synergist all has notable synergistic effect (P＜0.001) to topoenzyme inhibitor.
Tumor-inhibiting action in the body of test six, topoenzyme inhibitor synergist and topoenzyme inhibitor.
With the rat is subjects, with 2x10 5Individual tumor cell subcutaneous injection treats that in its hypochondrium tumor growth was divided into 10 groups (seeing Table 6) with it after 14 days, and first group is contrast, and the 2nd to 10 group is the treatment group.The dosage of topoenzyme inhibitor synergist and topoenzyme inhibitor is 5mg/kg.The treatment back was measured gross tumor volume size, relatively therapeutic effect (seeing Table 6) on the 30th day.
Table 6
Test group (n) Suffered treatment Gross tumor volume (cm 3) The P value
1(6) Contrast 66.5±13cm 3
2(6) Hydroxy-camptothecin alkali 42±8cm 3 ＜0.05
3(6) Cytosine arabinoside 45±8cm 3 ＜0.01
4(6) Gemcitabine 38±6cm 3 ＜0.01
5(6) Thunder accounts for for song 42±6.4cm 3 ＜0.01
6(6) Raltitrexed 40±6.8cm 3 ＜0.01
7(6) Hydroxy-camptothecin alkali+cytosine arabinoside 26±4.6cm 3 ＜0.001
8(6) Hydroxy-camptothecin alkali+gemcitabine 20±3.6cm 3 ＜0.001
9(6) Hydroxy-camptothecin alkali+thunder accounts for for song 18±4.6cm 3 ＜0.001
10(6) Hydroxy-camptothecin alkali+Raltitrexed 20±2.6cm 3 ＜0.001
Above topoenzyme inhibitor synergist all has notable synergistic effect (P＜0.001) to topoenzyme inhibitor.
Tumor-inhibiting action in the body of test seven, topoenzyme inhibitor synergist and topoenzyme inhibitor.
With the rat is subjects, with 2x10 5Individual tumor cell subcutaneous injection is in its hypochondrium, treats that tumor growth after 14 days is divided into it 10 groups (seeing Table 7).First group is contrast, and the 2nd to 10 group is the treatment group.The dosage of topoenzyme inhibitor synergist and topoenzyme inhibitor is 5mg/kg.The treatment back was measured gross tumor volume size, relatively therapeutic effect (seeing Table 7) on the 30th day.
Table 7
Test group (n) Suffered treatment Gross tumor volume (cm 3) The P value
1(6) Contrast 66.5±13cm 3
2(6) Idarubicin 42±11cm 3 ＜0.05
3(6) Amycin 42±6cm 3 ＜0.01
4(6) Daunomycin 48±86cm 3 ＜0.01
5(6) Aclarubicin 40±6.4cm 3 ＜0.01
6(6) Epirubicin 42±6.8cm 3 ＜0.01
7(6) Idarubicin+amycin 20±3.2cm 3 ＜0.001
8(6) Idarubicin+epirubicin 23±3.8cm 3 ＜0.001
9(6) Idarubicin+aclarubicin 18±4.4cm 3 ＜0.001
10(6) Idarubicin+daunomycin 20±2.2cm 3 ＜0.001
Above topoenzyme inhibitor synergist all has notable synergistic effect (P＜0.001) to topoenzyme inhibitor.
Tumor-inhibiting action in the body of test eight, topoenzyme inhibitor synergist and topoenzyme inhibitor.
With the rat is subjects, with 2x10 5Individual tumor cell subcutaneous injection is in its hypochondrium, treats that tumor growth after 14 days is divided into it following 10 groups (seeing Table 8).First group is contrast, and the 2nd to 10 group is the treatment group.The dosage of topoenzyme inhibitor synergist and topoenzyme inhibitor is 5mg/kg.The treatment back was measured gross tumor volume size, relatively therapeutic effect (seeing Table 8) on the 30th day.
Table 8
Test group (n) Suffered treatment Gross tumor volume (cm 3) The P value
1(6) Contrast 62.5±12cm 3
2(6) Ai Rou compares star 46±10cm 3 ＜0.05
3(6) Mitoxantrone 41±8cm 3 ＜0.01
4(6) Ametycin 34±6cm 3 ＜0.01
5(6) Valrubicin 38±6.4cm 3 ＜0.01
6(6) Pirarubicin 36±6.8cm 3 ＜0.01
7(6) Ai Rou is than star+mitoxantrone 20±4.6cm 3 ＜0.001
8(6) Ai Rou is than star+ametycin 14±3.6cm 3 ＜0.001
9(6) Ai Rou is than star+Valrubicin 12±4.6cm 3 ＜0.001
10(6) Ai Rou is than star+pirarubicin 14±2.6cm 3 ＜0.001
Above topoenzyme inhibitor synergist all has notable synergistic effect (P＜0.001) to topoenzyme inhibitor.
In a word, the topoenzyme inhibitor synergist among the present invention all has the notable synergistic effect to topoenzyme inhibitor.Therefore, the effective ingredient of entity-tumor-resistant medicine composition of the present invention is the associating of any one (or multiple) topoenzyme inhibitor synergist and any one (or multiple) topoenzyme inhibitor synergist or packs separately.The entity-tumor-resistant medicine composition that contains above effective ingredient can be made into any dosage form or shape, but serves as preferred with agent for slow releasing (or implant) type.
The preparation method of entity-tumor-resistant medicine composition of the present invention is as follows:
1. Chong pharmaceutic adjuvant is put into container, and it is even to add organic dissolution with solvents, and the not strict qualification of the amount of organic solvent is suitable fully to be dissolved as.
2. stating percentage by weight adds the anticancer active ingredient weigh and shakes up again.
3. remove organic solvent.Vacuum drying or cold drying all can.
4. dried solid composite is made different shape as required.
5. ray sterilizing (roentgendosis is different because of volume) is standby after the packing.Also available other method sterilization.
(4) specific embodiment
Embodiment 1.
With the 80mg molecular weight is that 10000 the polyglycolic acid and the copolymer (PLGA) of hydroxyacetic acid are put into container, adds 100 milliliters of dichloromethane, behind the dissolving mixing, adds 10mg teniposide and 10mg ametycin, shakes up the dry organic solvent of removing of final vacuum again.Dried solid composite is shaped immediately, and ray sterilizing after the packing must contain the entity-tumor-resistant medicine composition of 10% teniposide and 10% ametycin.All be weight percentage.The drug release time of this entity-tumor-resistant medicine composition in external normal saline is 15-20 days, is 30-40 days at the subcutaneous drug release time of mice.
Embodiment 2.
As described in embodiment 1, different is that contained anticancer effective component is:
(A) MD-CPT of 1-50%, (RS)-MD-CPT, (S)-the MD-CPT glycinate, 9-amino-(S)-the MD-CPT glycinate, lurtotecan, topotecan, Irinotecan, 9-nitro Camptothecin, hydroxy-camptothecin alkali, 7-ethyl-10-hydroxyl-Camptothecin, 7-ethyl-10-[4-(1-piperidino)-1-piperidino] the carbonyl Camptothecin, 10-hydroxyl-Camptothecin, Homocamptothecins, Camptothecin, N-[2-(dimethylamino) ethyl) bifurcation pyridine-4-carboxylic acid amides, podophyllotoxin, etoposide, teniposide, teniposide, Podophyllinic acid, podophyllotoxin, trihydroxy-isoflavone, amrubicin, daunorubicin, daunorubicin, the nor-oxygen daunorubicin of 4-, detorubicin, epirubicin, 7-O-methyl Nuo Jia-4 '-epirubicin, esorubicin, carubicin, idarubicin, rodorubicin, leurubicin, medorubicin, Nemorubicin, doxorubicin, N-trifluoro toxin-14-valerate, 2-[4-(7-chloro-2-quinoxalinyl phenoxy base]-propanoic acid, zorubicin, N-(2-ethyl chloride)-N-nitroso-group urea groups daunorubicin, (+)-1,2-two (3, the 5-dioxo piperazinyl) propane, between-2, two (3, the 5-dioxo piperazine-1-yl) butane of 3-, two dioxo piperazines, suramin, deoxyguanosine, the paclitaxel of lithocholic acid or Hydrazoic acid,sodium salt and 1-50%, docetaxel, 2 '-hydroxyl taxol, 10-removes the acetyl Baccatine III, 14 beta-hydroxies-10-removes the acetyl Baccatine III, 9-sodium catchol disulfonate 3-Baccatine III, 10-removes the acetyl taxol, 7-table-taxol, Tetraol, the combination of Baccatine III or Tetraol V; Or
(B) MD-CPT of 1-50%, (RS)-MD-CPT, (S)-the MD-CPT glycinate, 9-amino-(S)-the MD-CPT glycinate, lurtotecan, topotecan, Irinotecan, 9-nitro Camptothecin, hydroxy-camptothecin alkali, 7-ethyl-10-hydroxyl-Camptothecin, 7-ethyl-10-[4-(1-piperidino)-1-piperidino] the carbonyl Camptothecin, 10-hydroxyl-Camptothecin, Homocamptothecins, Camptothecin, N-[2-(dimethylamino) ethyl) bifurcation pyridine-4-carboxylic acid amides, podophyllotoxin, etoposide, teniposide, teniposide, Podophyllinic acid, podophyllotoxin, trihydroxy-isoflavone, amrubicin, daunorubicin, daunorubicin, the nor-oxygen daunorubicin of 4-, detorubicin, epirubicin, 7-O-methyl Nuo Jia-4 '-epirubicin, esorubicin, carubicin, idarubicin, rodorubicin, leurubicin, medorubicin, Nemorubicin, doxorubicin, N-trifluoro toxin-14-valerate, 2-[4-(7-chloro-2-quinoxalinyl phenoxy base]-propanoic acid, zorubicin, N-(2-ethyl chloride)-N-nitroso-group urea groups daunorubicin, (+)-1,2-two (3, the 5-dioxo piperazinyl) propane, between-2, two (3, the 5-dioxo piperazine-1-yl) butane of 3-, two dioxo piperazines, suramin, deoxyguanosine, lithocholic acid or Hydrazoic acid,sodium salt and with the bleomycin of 1-50%, daunomycin, aclarubicin, amycin, epirubicin, pirarubicin, Valrubicin, ametycin, actinomycin D, losoxantrone, mitoxantrone, piroxantrone, the combination of teloxantrone or chlorine assistant star; Or
(C) MD-CPT of 1-50%, (RS)-MD-CPT, (S)-the MD-CPT glycinate, 9-amino-(S)-the MD-CPT glycinate, lurtotecan, topotecan, Irinotecan, 9-nitro Camptothecin, hydroxy-camptothecin alkali, 7-ethyl-10-hydroxyl-Camptothecin, 7-ethyl-10-[4-(1-piperidino)-1-piperidino] the carbonyl Camptothecin, 10-hydroxyl-Camptothecin, Homocamptothecins, Camptothecin, N-[2-(dimethylamino) ethyl) bifurcation pyridine-4-carboxylic acid amides, podophyllotoxin, etoposide, teniposide, teniposide, Podophyllinic acid, podophyllotoxin, trihydroxy-isoflavone, amrubicin, daunorubicin, daunorubicin, the nor-oxygen daunorubicin of 4-, detorubicin, epirubicin, 7-O-methyl Nuo Jia-4 '-epirubicin, esorubicin, carubicin, idarubicin, rodorubicin, leurubicin, medorubicin, Nemorubicin, doxorubicin, N-trifluoro toxin-14-valerate, 2-[4-(7-chloro-2-quinoxalinyl phenoxy base]-propanoic acid, zorubicin, N-(2-ethyl chloride)-N-nitroso-group urea groups daunorubicin, (+)-1,2-two (3, the 5-dioxo piperazinyl) propane, between-2, two (3, the 5-dioxo piperazine-1-yl) butane of 3-, two dioxo piperazines, suramin, deoxyguanosine, lithocholic acid or Hydrazoic acid,sodium salt and with the Ismipur of 1-50%, 5-fluorouracil, pemetrexed, pemetrexed disodium, Rumi Qu Sai, doxifluridine, floxuridine, mercaptopurine, thioguanine, methotrexate, carmofur, ftorafur, galocitabine, ibacitabine, enocitabine, ancitabine, decitabine, flurocitabine, enocitabine, his shore of imidazoles, GR 30921X, mitotane, cytosine arabinoside, hydroxyurea, the 5-fluorouracil nucleoside, capecitabine, gemcitabine, fludarabine, thunder accounts for for song, Raltitrexed, the atropic cytidine, dexrazoxane, the combination of cladribine and pentoside.Below all be weight percentage.
Embodiment 3.
With the 80mg molecular weight is that 20000 the polyglycolic acid and the copolymer (PLGA) of hydroxyacetic acid are put into container, adds 100 milliliters of dichloromethane, behind the dissolving mixing, adds 10mg topotecan and 10mg amycin, shakes up the dry organic solvent of removing of final vacuum again.Dried solid composite is shaped immediately, and ray sterilizing after the packing must contain the entity-tumor-resistant medicine composition of 10% topotecan and 10% amycin.All be weight percentage.The drug release time of this entity-tumor-resistant medicine composition in external normal saline is 15-20 days, is 30-40 days at the subcutaneous drug release time of mice.
Embodiment 4.
As described in embodiment 3, different is that contained anticancer effective component is:
(a) Camptothecin of 5-30%, hydroxy-camptothecin alkali, lurtotecan, topotecan, irinotecan, etoposide, teniposide, amrubicin, Ai Rou compares star, rodorubicin, leurubicin, zorubicin, the paclitaxel of N-trifluoro toxin-14-valerate or idarubicin and 5-30%, docetaxel, 2 '-hydroxyl taxol, 10-removes the acetyl Baccatine III, 14 beta-hydroxies-10-removes the acetyl Baccatine III, 9-dihydroxy-13-Baccatine III, 10-removes the acetyl taxol, 7-table-taxol, Tetraol, the combination of Baccatine III or Tetraol V; Or
(b) Camptothecin of 5-30%, hydroxy-camptothecin alkali, lurtotecan, topotecan, irinotecan, etoposide, teniposide, amrubicin, Ai Rou compares star, rodorubicin, leurubicin, zorubicin, the bleomycin of N-trifluoro toxin-14-valerate or idarubicin and 5-30%, daunomycin, aclarubicin, amycin, epirubicin, pirarubicin, Valrubicin, ametycin, actinomycin D, losoxantrone, mitoxantrone, piroxantrone, the combination of teloxantrone or chlorine assistant star; Or
(c) Camptothecin of 5-30%, hydroxy-camptothecin alkali, lurtotecan, topotecan, irinotecan, etoposide, teniposide, amrubicin, Ai Rou compares star, rodorubicin, leurubicin, zorubicin, the Ismipur of N-trifluoro toxin-14-valerate or idarubicin and 5-30%, 5-fluorouracil, pemetrexed, pemetrexed disodium, Rumi Qu Sai, doxifluridine, floxuridine, mercaptopurine, thioguanine, methotrexate, carmofur, ftorafur, galocitabine, ibacitabine, enocitabine, ancitabine, decitabine, flurocitabine, enocitabine, his shore of imidazoles, GR 30921X, mitotane, cytosine arabinoside, hydroxyurea, the 5-fluorouracil nucleoside, capecitabine, gemcitabine, fludarabine, thunder accounts for for song, Raltitrexed, the atropic cytidine, dexrazoxane, the combination of cladribine and pentoside.Below all be weight percentage.
Embodiment 5.
80mg polifeprosan (to carboxy phenyl propane: certain herbaceous plants with big flowers diacid weight ratio is 20: 80) copolymer is put into container, add 100 milliliters of dichloromethane, behind the dissolving mixing, add 10mg Camptothecin and 10mg epirubicin, shake up the dry organic solvent of removing of final vacuum again.Dried solid composite is shaped immediately, and ray sterilizing after the packing must contain the entity-tumor-resistant medicine composition of 10% Camptothecin and 10% epirubicin.All be weight percentage.The drug release time of this entity-tumor-resistant medicine composition in external normal saline is 15-20 days, is 30-40 days at the subcutaneous drug release time of mice.
Embodiment 6.
As described in embodiment 5, different is that contained anticancer effective component is, all is weight percentage:
(a) combination of the paclitaxel of the Camptothecin of 5-30%, topotecan, irinotecan, etoposide, teniposide or idarubicin and 5-30%, docetaxel or 2 '-hydroxyl taxol; Or
(b) combination of the bleomycin of the Camptothecin of 5-30%, topotecan, irinotecan, etoposide, teniposide or idarubicin and 5-30%, daunomycin, aclarubicin, amycin, epirubicin, pirarubicin, Valrubicin, ametycin, actinomycin D, losoxantrone, mitoxantrone, piroxantrone, teloxantrone or chlorine assistant star; Or
(c) Ismipur of the Camptothecin of 5-30%, topotecan, irinotecan, etoposide, teniposide or idarubicin and 5-30%, 5-fluorouracil, pemetrexed, pemetrexed disodium, Rumi Qu Sai, methotrexate, carmofur, ftorafur, cytosine arabinoside, hydroxyurea, gemcitabine, fludarabine, thunder for bently account for, the combination of Raltitrexed, atropic cytidine, dexrazoxane or cladribine.
Embodiment 7.
(EVAc) puts into container with the 80mg ethylene vinyl acetate copolymer, add 100 milliliters of dichloromethane dissolving mixings after, adds 10 milligrams of irinotecans and 10mg mitoxantrone, shake up the dry removal of final vacuum organic solvent again.Dried solid composite is shaped immediately, and ray sterilizing after the packing must contain 10% irinotecan and 10% mitoxantrone entity-tumor-resistant medicine composition.All be weight percentage.The drug release time of this entity-tumor-resistant medicine composition in external normal saline is 15-20 days, is 30-40 days at the subcutaneous drug release time of mice.
Embodiment 8.
As described in embodiment 7, different is that contained anticancer effective component is:
(a) combination of the paclitaxel of the Camptothecin of 5-30%, topotecan, irinotecan, etoposide, teniposide or idarubicin and 5-30%, docetaxel or 2 '-hydroxyl taxol; Or
(b) combination of the bleomycin of the Camptothecin of 5-30%, topotecan, irinotecan, etoposide, teniposide or idarubicin and 5-30%, daunomycin, aclarubicin, amycin, epirubicin, pirarubicin, Valrubicin, ametycin, actinomycin D, losoxantrone, mitoxantrone, piroxantrone, teloxantrone or chlorine assistant star; Or
(c) Ismipur of the Camptothecin of 5-30%, topotecan, irinotecan, etoposide, teniposide or idarubicin and 5-30%, 5-fluorouracil, pemetrexed, pemetrexed disodium, Rumi Qu Sai, methotrexate, carmofur, ftorafur, cytosine arabinoside, hydroxyurea, gemcitabine, fludarabine, thunder for bently account for, the combination of Raltitrexed, atropic cytidine, dexrazoxane or cladribine.Below all be weight percentage.
Embodiment 9.
As described in embodiment 1,3,5 or 7, used pharmaceutic adjuvant is respectively one of following or its combination that different is:
A) molecular weight is the polylactic acid (PLA) of 5000-15000,10000-20000,20000-35000 or 30000-50000;
B) molecular weight is the polyglycolic acid of 5000-15000,10000-20000,25000-35000 or 30000-50000 and the copolymer of hydroxyacetic acid (PLGA);
C) ethylene vinyl acetate copolymer (EVAc);
D) to the copolymer (polifeprosan) of carboxy phenyl propane and certain herbaceous plants with big flowers diacid, to carboxy phenyl propane: certain herbaceous plants with big flowers diacid weight ratio is 10: 90,20: 80,30: 70,40: 60,50: 50 or 60: 40;
E) xylitol, oligosaccharide, chitin, potassium salt, sodium salt, hyaluronic acid, collagen protein, gelatin or albumin.
Embodiment 10.
As described in embodiment 1,3,5 or 7, anticancer effective component that different is is one of following:
(a) combination of 10% etoposide and 10% 5-fluorouracil;
(b) combination of 10% etoposide and 10% methotrexate;
(c) combination of 10% etoposide and 10% gemcitabine;
(d) combination of 10% etoposide and 10% pemetrexed;
(e) combination of 10% etoposide and 10% amycin;
(f) combination of 10% etoposide and 10% epirubicin;
(g) combination of 10% etoposide and 10% pirarubicin;
(h) combination of 10% etoposide and 10% ametycin;
(i) combination of 10% etoposide and 10% mitoxantrone;
(j) combination of 10% etoposide and 10% paclitaxel;
(k) combination of 10% cisplatin and 10% docetaxel;
(l) combination of 10% etoposide and 2 '-hydroxyl paclitaxel of 10%.
More than be weight percentage.
Embodiment 11. is composition for treating solid tumor inside and outside release characteristics relatively
Get the composition for treating solid tumor among the embodiment 10, be placed in the room temperature normal saline and soak, survey the different time release amount of medicine, calculate external accumulative total and discharge percent (%).It is subcutaneous to be put in white mice, regularly takes out and surveys medicament contg, according to the residual drug amount, calculates the interior accumulative total of body and discharges percent (%).The result shows, the different pharmaceutical release in vitro no significant difference that tries discharged the about 20%, the 14th day and discharges 85-90% in first day.Try to discharge in the different pharmaceutical body also no significant difference, discharged the about 10%, 28th day and discharge more than 98% in first day.But the inside and outside discharges notable difference is arranged, release in vitro is fast than being released in the body.Can keep one month in vivo.

Claims (3)

1. entity-tumor-resistant medicine composition, comprise anticancer effective component and pharmaceutic adjuvant, it is characterized in that anticancer effective component is topoisomerase enzyme inhibitor and the medicine that strengthens the topoisomerase enzyme inhibitor effect, wherein, the medicine of enhancing topoisomerase enzyme inhibitor effect is selected from the paclitaxel kind anti-cancer drugs thing;
The anticancer effective component of described entity-tumor-resistant medicine composition is:
The paclitaxel of the Camptothecin of 5-30% or etoposide and 5-30% or the combination of docetaxel;
Below all be weight percentage;
Described pharmaceutic adjuvant is selected from one of following or its combination:
A) molecular weight is the polylactic acid of 5000-15000,10000-20000,20000-35000 or 30000-50000;
B) molecular weight is the polylactic acid of 5000-15000,10000-20000,25000-35000 or 30000-50000 and the copolymer of hydroxyacetic acid;
C) ethylene vinyl acetate copolymer; Or
D) to the copolymer of carboxy phenyl propane and decanedioic acid, to carboxy phenyl propane: the decanedioic acid weight ratio is 10: 90,20: 80,30: 70,40: 60,50: 50 or 60: 40;
E) xylitol, oligosaccharide, chitin, hyaluronic acid, collagen protein, gelatin or albumin.
2. entity-tumor-resistant medicine composition according to claim 1 is characterized in that this anti-cancer composition is suspension, slow releasing agent, implant or implantation slow release agent.
3. the application of the described a kind of entity-tumor-resistant medicine composition of claim 1 is used to prepare the medicine for the treatment of gastric gland epithelial cancer, bone tumor, breast carcinoma, pulmonary carcinoma, papillary adenocarcinoma of thyroid or hepatocarcinoma.
CNB2005100422362A 2005-04-06 2005-04-06 Antientity tumour medicinal composition containing topoenzyme inhibitor Expired - Fee Related CN100453118C (en)

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Non-Patent Citations (13)

* Cited by examiner, † Cited by third party
Title
《盐酸拓扑替康、紫杉醇及顺铂对人卵巢癌细胞株OC3体外作用的实验研究》. 刘冠媛等.现代妇产科进展，第12卷第1期. 2003
《盐酸拓扑替康、紫杉醇及顺铂对人卵巢癌细胞株OC3体外作用的实验研究》. 刘冠媛等. 现代妇产科进展，第12卷第1期. 2003 *
《药剂学》. 毕殿洲主编，全文，人民卫生出版社. 2001 *
《药剂辅料大全》. 罗明生主编，全文，四川科学技术出版社. 1995 《药剂学》. 毕殿洲主编，全文，人民卫生出版社. 2001
《药剂辅料大全》. 罗明生主编，全文，四川科学技术出版社. 1995 *
以羟基喜树碱为主联合治疗中晚期恶性肿瘤50例近期疗效观察. 张定清.肿瘤防治杂志，第12卷第2期. 2005
以羟基喜树碱为主联合治疗中晚期恶性肿瘤50例近期疗效观察. 张定清. 肿瘤防治杂志，第12卷第2期. 2005 *
抗肿瘤药物研究应用进展. 冯威健.河北医药，第24卷第11期. 2002
抗肿瘤药物研究应用进展. 冯威健. 河北医药，第24卷第11期. 2002 *
拓扑替康在临床应用的研究进展. 张秀国，雍政，张谦.中国新药与临床杂志，第22卷第11期. 2003
拓扑替康在临床应用的研究进展. 张秀国，雍政，张谦. 中国新药与临床杂志，第22卷第11期. 2003 *
羟基喜树碱、依托泊苷、5－氟尿嘧啶联合治疗老年人晚期胃癌40例. 徐千朗，吉学源.中国癌症杂志，第10卷第3期. 2000
羟基喜树碱、依托泊苷、5－氟尿嘧啶联合治疗老年人晚期胃癌40例. 徐千朗，吉学源. 中国癌症杂志，第10卷第3期. 2000 *

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