CN100500212C - Anti entity tumour medicinal composition - Google Patents

Anti entity tumour medicinal composition Download PDF

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Publication number
CN100500212C
CN100500212C CNB200510042263XA CN200510042263A CN100500212C CN 100500212 C CN100500212 C CN 100500212C CN B200510042263X A CNB200510042263X A CN B200510042263XA CN 200510042263 A CN200510042263 A CN 200510042263A CN 100500212 C CN100500212 C CN 100500212C
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China
Prior art keywords
combination
paclitaxel
fluorouracil
tumor
amycin
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CN1686545A (en
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孔庆忠
孙娟
陈颖
杨健
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DASEN BIOLOGICAL PHARMACEUTICAL CO., LTD.
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Shandong Lanjin Pharmaceuticals Co Ltd
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Abstract

A composite medicine for treating solid tumor by locally putting it in the tumor is composed of the active anticancer component chosen from anticancer taxol-type medicine, antineoplastic antibiotic and antimetabolitic medicine, and the medicinal auxiliary (biocompatible and biodegrable high-molecular polymer).

Description

A kind of entity-tumor-resistant medicine composition
(1) technical field
The present invention relates to a kind of entity-tumor-resistant medicine composition, belong to technical field of pharmaceuticals.
(2) background technology
The treatment of entity tumor mainly comprises methods such as operation, radiotherapy and chemotherapy.Wherein, chemotherapy plays important effect.In used various chemotherapeutics, the action effect of paclitaxel kind anti-cancer drugs thing, antitumor antibiotics and antimetabolitas etc. is comparatively obvious, has been widely used in multiple malignant tumor.Yet single medicine is easy to cause the generation of Drug tolerance.
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.
A kind of entity-tumor-resistant medicine composition, comprise anticancer effective component and pharmaceutic adjuvant, wherein anticancer effective component is (A) paclitaxel kind anti-cancer drugs thing, (B) antitumor antibiotics or (C) combination of any two or more composition in the antimetabolitas.
Above-mentioned paclitaxel kind anti-cancer drugs thing (taxanes) is selected from one of following or combination:
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-removes 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), cultivate Ramulus et folium taxi cuspidatae (Taxus X media cultivars), Yunnan Ramulus et folium taxi cuspidatae Taxus yunnanensis) or Florida Ramulus et folium taxi cuspidatae (Taxus floridana), or their salt, as, but be not limited to sulfate, phosphate, hydrochlorate, Lactobionate, acetate, aspat, nitrate, citrate, purine or pyrimidine salt, succinate or maleate.
Above-mentioned paclitaxel kind anti-cancer drugs thing serves as preferred with paclitaxel, Docetaxel (docetaxel) or 2 '-hydroxyl taxol.The shared percentage by weight of above paclitaxel kind anti-cancer drugs thing in compositions decided because of concrete condition, generally speaking, from 0.01%-80%, is good with 1%-50%, is the best with 5%-20%.
Antitumor antibiotics suppresses by combining with DNA that RNA is synthetic to be used for the treatment of various cancers.
Above-mentioned 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 (mitochromineor 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 and chlorine assistant star, its shared percentage by weight in compositions is decided because of concrete condition, generally speaking, from 0.01%-80%, with 1%-50% is good, is the best with 5%-20%.
Antimetabolitas 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.
Above-mentioned 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, the fluorine urea is amine, 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.
Above antimetabolitas is 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.
Above antimetabolitas 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 the best with 5%-30%.
Pharmaceutic adjuvant of the present invention can be through enzyme, soda acid or tissue fluid hydrolysis or degraded, 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 (carboxyl ic acids), fatty acid (fatty acids), phospholipid (phospholipids), nucleic acid (nucleic acids), polyamino acid (polyamino acids), aminoacid such as phenylalanine (phenylalanine), tyrosine (tyrosine), different bright (i soleucine), 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 (US4857311 in other United States Patent (USP); 4888176; 4789724).
Above-mentioned polyhydroxy acid can be selected for use: the copolymer (PLGA) of mixture, glycolic and the lactic acid of polylactic acid (PLA), polyglycolic acid (PGA), polylactic acid and polyglycolic acid.Above polyhydroxy acid can singly select or multiselect, and when singly selecting, the molecular weight of polylactic acid can be, and 5000～100,000, with 10,000～50,000 is preferred, with 10,000～30,000 for most preferably; The molecular weight of polyglycolic acid can be, but is not limited to, and 5000～100,000, but with 10,000～50,000 is preferred, and with 10,000～20,000 for most preferably; The molecular weight of the copolymer of glycolic and lactic acid can be, but is not limited to, and 1000～100,000, but with 10,000～50,000 is preferred; With 10,000～20,000 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 or salt etc.Wherein sugar can be, but is not limited to, xylitol, oligosaccharide or 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 fruit jelly, paste or ointment, 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, can be 0.01-200 milligram/kg body weight, is ideal with 1-100 milligram/kg body weight, with 5-80 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 drug packages in 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.
Entity-tumor-resistant medicine composition of the present invention is local to be placed, not only can overcome the toxic reaction that the whole body administration brings, and solved routine treatment the tumor by local drug level that should rise cross low or cell to the insensitive problem of medicine.
By following test and embodiment the technology side of composition for treating solid tumor of the present invention is further described:
Test one, paclitaxel kind anti-cancer drugs thing and antitumor antibiotics external presses down the tumor potentiation.
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 paclitaxel kind anti-cancer drugs thing and antitumor antibiotics 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 56％ 65％ 68％ 64％ 60％ 91％ 92％ 83％ 91％
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 62％ 54％ 64％ 66％ 69％ 94％ 94％ 94％ 92％
Annotate: (A): paclitaxel; (B)-(E) be respectively amycin, epirubicin, ametycin and mitoxantrone.The result shows that paclitaxel all has notable synergistic effect (P＜0.05) to the examination antitumor antibiotics.
Test two, paclitaxel kind anti-cancer drugs thing and antimetabolitas external presses down the tumor potentiation.
Used tumor cell is with test one.Following paclitaxel kind anti-cancer drugs thing and antimetabolitas 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 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): docetaxel is the paclitaxel kind anti-cancer drugs thing; (B)-(E) be respectively 5-fluorouracil, pemetrexed, methotrexate and cytosine arabinoside.The result shows that paclitaxel all has notable synergistic effect (P＜0.05) to the examination antimetabolitas.
Test three, antitumor antibiotics and antimetabolitas external presses down the tumor potentiation.
Used tumor cell is with test one.Following antitumor antibiotics and antimetabolitas 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 58％ 64％ 66％ 64％ 60％ 90％ 92％ 80％ 90％
C6 60％ 64％ 60％ 64％ 63％ 96％ 94％ 86％ 92％
SA 58％ 60％ 56％ 60％ 62％ 86％ 85％ 86％ 88％
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 52％ 56％ 66％ 66％ 69％ 94％ 92％ 94％ 94％
Annotate: (A): amycin: antitumor antibiotics; (B)-(E) be respectively Ismipur, Rumi Qu Sai, methotrexate and Raltitrexed.The result shows that antitumor antibiotics (amycin) all has notable synergistic effect (P＜0.05) to the examination antimetabolitas.
Above-mentioned experimental result shows that paclitaxel kind anti-cancer drugs thing, antitumor antibiotics and antimetabolitas all have obviously potentiation mutually.Further test shows, 2 '-hydroxyl taxol to bleomycin, daunomycin, aclarubicin, epirubicin, pirarubicin, Valrubicin, actinomycin D, losoxantrone, mitoxantrone, piroxantrone, teloxantrone or chlorine assistant magnitude antitumor antibiotics and Rumi Qu Sai, carmofur, ftorafur, hydroxyurea, fludarabine, thunder for song account for, antimetabolitases such as Raltitrexed, atropic cytidine, dexrazoxane and cladribine all have obviously potentiation mutually.
Bleomycin, daunomycin, epirubicin, pirarubicin, Valrubicin, actinomycin D, losoxantrone, piroxantrone, teloxantrone or chlorine assistant magnitude antitumor antibiotics and Ismipur, 5-fluorouracil, pemetrexed, pemetrexed disodium, Rumi Qu Sai, methotrexate, carmofur, ftorafur, cytosine arabinoside, hydroxyurea, gemcitabine, fludarabine, thunder accounts for for song, Raltitrexed, the atropic cytidine, antimetabolitas such as dexrazoxane or cladribine all has obviously potentiation mutually.This unexpected discovery of the present invention is of universal significance.Inhibition test has illustrated this potentiation more in its body.
Tumor-inhibiting action in the body of test four, paclitaxel kind anti-cancer drugs thing and antitumor antibiotics.
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 4).First group is contrast, and the 2nd to 10 group is the treatment group.The dosage of paclitaxel kind anti-cancer drugs thing and antitumor antibiotics 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) Paclitaxel 42±10cm 3 <0.05
3(6) Amycin 43±11cm 3 <0.01
4(6) Epirubicin 36±6cm 3 <0.01
5(6) Ametycin 39±6.4cm 3 <0.01
6(6) Mitoxantrone 38±6.8cm 3 <0.01
7(6) Paclitaxel+amycin 24±4.6cm 3 <0.001
8(6) Paclitaxel+epirubicin 18±2.6cm 3 <0.001
9(6) Paclitaxel+ametycin 16±3.6cm 3 <0.001
10(6) Paclitaxel+mitoxantrone 18±2.4cm 3 <0.001
Paclitaxel all has notable synergistic effect (P＜0.001) to the examination antitumor antibiotics.
Tumor-inhibiting action in the body of test five, paclitaxel kind anti-cancer drugs thing and antimetabolitas.
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 5).First group is contrast, and the 2nd to 10 group is the treatment group.The dosage of paclitaxel kind anti-cancer drugs thing and antimetabolitas 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) Docetaxel 42±10cm 3 <0.05
3(6) 5-fluorouracil 43±8.4cm 3 <0.01
4(6) Rumi Qu Sai 36±6.2cm 3 <0.01
5(6) Methotrexate 40±6.46cm 3 <0.01
6(6) Ftorafur 34±6.8cm 3 <O.01
7(6) Docetaxel+5-fluorouracil 26±4.8cm 3 <0.001
8(6) Docetaxel+Rumi Qu Sai 22±3.8cm 3 <0.001
9(6) Docetaxel+methotrexate 14±2.4cm 3 <0.001
10(6) Docetaxel+cytosine arabinoside 18±2.2cm 3 <0.001
Above docetaxel is the paclitaxel kind anti-cancer drugs thing, and the examination antimetabolitas is all had notable synergistic effect (P＜0.001).
Tumor-inhibiting action in the body of test six, antitumor antibiotics and antimetabolitas.
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 6).First group is contrast, and the 2nd to 10 group is the treatment group.The dosage of antitumor antibiotics and antimetabolitas 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) Amycin 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) Amycin+cytosine arabinoside 26±4.6cm 3 <0.001
8(6) Amycin+gemcitabine 20±3.6cm 3 <0.001
9(6) Amycin+thunder accounts for for song 18±4.6cm 3 <0.001
10(6) Amycin+Raltitrexed 20±2.6cm 3 <0.001
Above amycin is an antitumor antibiotics, and the examination antimetabolitas is all had notable synergistic effect (P＜0.001).
Tumor-inhibiting action in the body of test seven, antitumor antibiotics and antimetabolitas.
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 7).First group is contrast, and the 2nd to 10 group is the treatment group.The dosage of antitumor antibiotics and antimetabolitas 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) Pemetrexed 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) Pemetrexed+amycin 20±3.2cm 3 <0.001
8(6) Pemetrexed+epirubicin 23±3.8cm 3 <0.001
9(6) Pemetrexed+aclarubicin 18±4.4cm 3 <0.001
10(6) Pemetrexed+daunomycin 20±2.2cm 3 <0.001
Above pemetrexed is an antimetabolitas, and the examination antitumor antibiotics is all had notable synergistic effect (P＜0.001).
Tumor-inhibiting action in the body of test eight, paclitaxel kind anti-cancer drugs thing, antitumor antibiotics and antimetabolitas
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 8 groups (seeing Table 8).First group is contrast, and the 2nd to 10 group is the treatment group.The dosage of paclitaxel, antitumor antibiotics and antimetabolitas 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 82±16cm 3
2(6) Paclitaxel 66±12cm 3 <0.05
3(6) Amycin 61±10cm 3 <0.01
4(6) 5-FU 64±11cm 3 <0.01
5(6) Paclitaxel+amycin 28±6.4cm 3 <0.01
6(6) Paclitaxel+5-fluorouracil 26±6.2cm 3 <0.01
7(6) Amycin+5-fluorouracil 24±4.6cm 3 <0.01
8(6) Paclitaxel+amycin+5-FU 8±1.6cm 3 <0.001
Above result shows: paclitaxel, antitumor antibiotics (amycin) and antimetabolitas (5-FU) all have obviously potentiation (P＜0.001) mutually.
Therefore, the effective ingredient of entity-tumor-resistant medicine composition of the present invention is the associating of any one or multiple and/or any one or multiple antitumor antibiotics and/or any one or multiple antimetabolitas.The entity-tumor-resistant medicine composition that contains above effective ingredient can be made into any dosage form or shape, but with agent for slow releasing or to implant dosage form serve as preferred.
The preparation method of entity-tumor-resistant medicine composition of the present invention is as follows:
1. the pharmaceutic adjuvant of weighing is put into container, 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. adding the anticancer active ingredient of weighing by above-mentioned percentage by weight shakes up again.
3. removal 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 paclitaxel 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% paclitaxel and 10% amycin.All be weight percentage.
Embodiment 2. is as described in the embodiment 1, and different is that contained anticancer effective component is:
The paclitaxel of 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 bleomycin of Baccatine III or Tetraol V and 1-50%, daunomycin, aclarubicin, amycin, epirubicin, pirarubicin, Valrubicin, ametycin, actinomycin D, losoxantrone, mitoxantrone, piroxantrone, the combination of teloxantrone or chlorine assistant star.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 docetaxel and 10mg5-fluorouracil, 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% docetaxel and 10%5-fluorouracil.All be weight percentage.
Embodiment 4. is as described in the embodiment 3, and different is that contained anticancer effective component is:
The paclitaxel of 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 Ismipur of Baccatine III or Tetraol V and 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.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 methotrexate 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% methotrexate and 10% epirubicin.All be weight percentage.
Embodiment 6. is as described in the embodiment 5, and different is that contained anticancer effective component is:
The bleomycin of 1-50%, daunomycin, aclarubicin, amycin, epirubicin, pirarubicin, Valrubicin, ametycin, actinomycin D, losoxantrone, mitoxantrone, piroxantrone, the Ismipur of teloxantrone or chlorine assistant star and 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.All be weight percentage.
Embodiment 7.
(EVAc) puts into container with the 70mg ethylene vinyl acetate copolymer, add 100 milliliters of dichloromethane dissolving mixings after, adds 10 milligrams of paclitaxels and 10mg amycin and 10mg 5-fluorouracil, 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% paclitaxel and 10% amycin and 10%5-fluorouracil entity-tumor-resistant medicine composition.All be weight percentage.
Embodiment 8. is as described in the embodiment 7, and different is that contained anticancer effective component is:
The paclitaxel of 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 bleomycin of Baccatine III or Tetraol V and 1-50%, daunomycin, aclarubicin, amycin, epirubicin, pirarubicin, Valrubicin, ametycin, actinomycin D, losoxantrone, mitoxantrone, piroxantrone, the Ismipur of teloxantrone or chlorine assistant star and 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 9.
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 gemcitabine and 10mg mitoxantrone, 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% gemcitabine and 10% mitoxantrone.All be weight percentage.
Embodiment 10. is as described in the embodiment 9, and different is that contained anticancer effective component is:
(a) combination of the bleomycin of the paclitaxel of 2-30%, docetaxel or 2 '-hydroxyl taxol and 2-30%, daunomycin, aclarubicin, amycin, epirubicin, pirarubicin, Valrubicin, ametycin, actinomycin D, losoxantrone, mitoxantrone, piroxantrone, teloxantrone or chlorine assistant star; Or
(b) Ismipur of the paclitaxel of 2-30%, docetaxel or 2 '-hydroxyl taxol and 2-30%, 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; Or
(c) bleomycin of 5-30%, daunomycin, aclarubicin, amycin, epirubicin, pirarubicin, Valrubicin, ametycin, actinomycin D, losoxantrone, mitoxantrone, piroxantrone, the Ismipur of teloxantrone or chlorine assistant star and 2-30%, 5-fluorouracil, pemetrexed, pemetrexed disodium, Rumi Qu Sai, methotrexate, carmofur, ftorafur, cytosine arabinoside, hydroxyurea, gemcitabine, fludarabine, thunder accounts for for song, Raltitrexed, the atropic cytidine, the combination of dexrazoxane or cladribine.Below all be weight percentage.
Embodiment 11. is as described in the embodiment 9, and different is that contained anticancer effective component is:
(a) combination of the bleomycin of the paclitaxel of 2-30%, docetaxel or 2 '-hydroxyl taxol and 2-30%, daunomycin, aclarubicin, amycin, epirubicin, pirarubicin, Valrubicin, ametycin, actinomycin D, losoxantrone, mitoxantrone, piroxantrone, teloxantrone or chlorine assistant star; Or
(b) Ismipur of the paclitaxel of 2-30%, docetaxel or 2 '-hydroxyl taxol and 2-30%, 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; Or
(c) bleomycin of 2-30%, daunomycin, aclarubicin, amycin, epirubicin, pirarubicin, Valrubicin, ametycin, actinomycin D, losoxantrone, mitoxantrone, piroxantrone, the Ismipur of teloxantrone or chlorine assistant star and 2-30%, 5-fluorouracil, pemetrexed, pemetrexed disodium, Rumi Qu Sai, methotrexate, carmofur, ftorafur, cytosine arabinoside, hydroxyurea, gemcitabine, fludarabine, thunder accounts for for song, Raltitrexed, the atropic cytidine, the combination of dexrazoxane or cladribine.
Below all be weight percentage.
Embodiment 12. is as described in the embodiment 9, and different is that contained anticancer effective component is:
(a) combination of the bleomycin of the paclitaxel of 5-20%, docetaxel or 2 '-hydroxyl taxol and 5-20%, daunomycin, aclarubicin, amycin, epirubicin, pirarubicin, Valrubicin, ametycin, actinomycin D, losoxantrone, mitoxantrone, piroxantrone, teloxantrone or chlorine assistant star; Or
(b) Ismipur of the paclitaxel of 5-20%, docetaxel or 2 '-hydroxyl taxol and 5-20%, 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; Or
(c) bleomycin of 5-20%, daunomycin, aclarubicin, amycin, epirubicin, pirarubicin, Valrubicin, ametycin, actinomycin D, losoxantrone, mitoxantrone, piroxantrone, the Ismipur of teloxantrone or chlorine assistant star and 5-20%, 5-fluorouracil, pemetrexed, pemetrexed disodium, Rumi Qu Sai, methotrexate, carmofur, ftorafur, cytosine arabinoside, hydroxyurea, gemcitabine, fludarabine, thunder accounts for for song, Raltitrexed, the atropic cytidine, the combination of dexrazoxane or cladribine.
Below all be weight percentage.
Embodiment 13.
70mg polifeprosan (to carboxy phenyl propane: certain herbaceous plants with big flowers diacid weight ratio is 30:70) copolymer is put into container, after adding 100 milliliters of dichloromethane dissolving mixings, add 10 milligrams of docetaxels and 10mg mitoxantrone and 10mg methotrexate, 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 10% docetaxel and 10% mitoxantrone and 10% methotrexate entity-tumor-resistant medicine composition.All be weight percentage.Embodiment 14. is as described in the embodiment 13, and different is that contained anticancer effective component is:
The paclitaxel of 2-30%, the bleomycin of docetaxel or 2 '-hydroxyl taxol and 5-30%, daunomycin, aclarubicin, amycin, epirubicin, pirarubicin, Valrubicin, ametycin, actinomycin D, losoxantrone, mitoxantrone, piroxantrone, the Ismipur of teloxantrone or chlorine assistant star and 5-30%, 5-fluorouracil, pemetrexed, pemetrexed disodium, Rumi Qu Sai, methotrexate, carmofur, ftorafur, cytosine arabinoside, hydroxyurea, gemcitabine, fludarabine, thunder accounts for for song, Raltitrexed, the atropic cytidine, the combination of dexrazoxane or cladribine.Below all be weight percentage.Embodiment 15. is as described in embodiment 1,3,5,7,9 or 13, 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 30000-80000;
B) molecular weight is the polyglycolic acid of 5000-15000,10000-20000,25000-35000 or 30000-80000 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 16. is as described in embodiment 1,3,5 or 7, and anticancer effective component that different is is one of following:
(a) combination of 10% paclitaxel and 10% 5-fluorouracil;
(b) combination of 10% paclitaxel and 10% methotrexate;
(c) combination of 10% paclitaxel and 10% gemcitabine;
(d) combination of 10% paclitaxel and 10% mitoxantrone;
(e) combination of 10% paclitaxel and 10% amycin;
(f) combination of 10% paclitaxel and 10% epirubicin;
(g) combination of 10% 5-fluorouracil and 10% mitoxantrone;
(h) combination of 10% 5-fluorouracil and 10% amycin;
(i) combination of 10% 5-fluorouracil and 10% ametycin;
(j) combination of 10% amycin and 10% ametycin;
(k) 10% 5-fluorouracil and 10% paclitaxel and the combination of 10% ametycin;
The combination of (1) 10% 5-fluorouracil and 10% paclitaxel and 10% amycin.
More than be weight percentage.
Embodiment 17. is composition for treating solid tumor inside and outside release characteristics relatively
Get each composition for treating solid tumor among the embodiment 10, be placed on respectively 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 (5)

1. entity-tumor-resistant medicine composition, comprise anticancer effective component and medicinal slow-release auxiliary material, it is characterized in that this entity-tumor-resistant medicine composition is the implantation slow release agent, anticancer effective component is (A) paclitaxel kind anti-cancer drugs thing, (B) antitumor antibiotics or (C) combination of any two or more composition in the antimetabolitas;
Described paclitaxel kind anti-cancer drugs thing is selected from one of following or combination: paclitaxel, docetaxel, 2 '-hydroxyl taxol, 10-go acetyl Baccatine III, 14 beta-hydroxies-10-to go acetyl Baccatine III, 9-sodium catchol disulfonate 3-Baccatine III, 10-to remove acetyl taxol, 7-table-taxol, Tetraol, Baccatine III or Tetraol V;
Described antitumor antibiotics is selected from one of following or combination: bleomycin, daunomycin, aclarubicin, amycin, epirubicin, pirarubicin, Valrubicin, ametycin, actinomycin D, losoxantrone, mitoxantrone, piroxantrone, teloxantrone or chlorine assistant star;
Described antimetabolitas is selected from one of following or combination: Ismipur, 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, cladribine or pentoside;
Described medicinal slow-release auxiliary material is selected from one of following or its combination:
A) molecular weight is the polylactic acid of 5000-15000,10000-20000,20000-35000 or 30000-80000;
B) molecular weight is the polyglycolic acid of 5000-15000,10000-20000,25000-35000 or 30000-80000 and the copolymer of hydroxyacetic acid;
C) ethylene vinyl acetate copolymer;
D) to the copolymer of carboxy phenyl propane and decanedioic acid, to carboxy phenyl propane: the decanedioic acid percentage by weight 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. the entity-tumor-resistant medicine composition according to claim 1 is characterized in that the effective ingredient of this anti-cancer composition is:
(a) combination of the bleomycin of the paclitaxel of 2-30%, docetaxel or 2 '-hydroxyl taxol and 2-30%, daunomycin, aclarubicin, amycin, epirubicin, pirarubicin, Valrubicin, ametycin, actinomycin D, losoxantrone, mitoxantrone, piroxantrone, teloxantrone or chlorine assistant star; Or
(b) Ismipur of the paclitaxel of 2-30%, docetaxel or 2 '-hydroxyl taxol and 2-30%, 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; Or
(c) bleomycin of 5-30%, daunomycin, aclarubicin, amycin, epirubicin, pirarubicin, Valrubicin, ametycin, actinomycin D, losoxantrone, mitoxantrone, piroxantrone, the Ismipur of teloxantrone or chlorine assistant star and 2-30%, 5-fluorouracil, pemetrexed, pemetrexed disodium, Rumi Qu Sai, methotrexate, carmofur, ftorafur, cytosine arabinoside, hydroxyurea, gemcitabine, fludarabine, thunder accounts for for song, Raltitrexed, the atropic cytidine, the combination of dexrazoxane or cladribine; Or
(d) Ismipur of Camptothecin, topotecan, irinotecan, etoposide, teniposide or the idarubicin of the paclitaxel of 2-30%, docetaxel or 2 '-hydroxyl taxol and 5-30% 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.
3. the entity-tumor-resistant medicine composition according to claim 1 is characterized in that the effective ingredient of this anti-cancer composition is:
(a) 5-fluorouracil of the paclitaxel of 5-20% or docetaxel and 5-20%, pemetrexed, Rumi Qu Sai, methotrexate, carmofur, ftorafur, cytosine arabinoside, gemcitabine, fludarabine, thunder account for or the combination of Raltitrexed for bent; Or
(b) combination of the amycin of the paclitaxel of 5-20% or docetaxel and 5-20%, epirubicin, pirarubicin, Valrubicin, ametycin, actinomycin D or mitoxantrone; Or
(c) combination of the 5-fluorouracil of the amycin of 5-20%, epirubicin, pirarubicin, Valrubicin, ametycin or mitoxantrone and 5-20%, pemetrexed, the bent plug of Rumi or methotrexate; Or
(d) combination of the 5-fluorouracil of the amycin of the paclitaxel of 5-20% and 5-20%, epirubicin, ametycin or mitoxantrone and 5-20% or methotrexate;
Below all be weight percentage.
4. the entity-tumor-resistant medicine composition according to claim 1, the effective ingredient that it is characterized in that this anti-cancer composition are one of following:
(a) combination of 10% paclitaxel and 10% 5-fluorouracil;
(b) combination of 10% paclitaxel and 10% methotrexate;
(c) combination of 10% paclitaxel and 10% gemcitabine;
(d) combination of 10% paclitaxel and 10% mitoxantrone;
(e) combination of 10% paclitaxel and 10% amycin;
(f) combination of 10% paclitaxel and 10% epirubicin;
(g) combination of 10% 5-fluorouracil and 10% mitoxantrone;
(h) combination of 10% 5-fluorouracil and 10% amycin;
(i) combination of 10% 5-fluorouracil and 10% ametycin;
(j) combination of 10% amycin and 10% ametycin;
(k) 10% 5-fluorouracil and 10% paclitaxel and the combination of 10% ametycin;
(l) 10% 5-fluorouracil and 10% paclitaxel and the combination of 10% amycin;
More than be weight percentage.
5. the application of the described entity-tumor-resistant medicine composition of claim 1 is used to prepare the medicine that treatment originates from cancer, sarcoma or the carcinosarcoma of people and animal 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 or rectum former or secondary.
CNB200510042263XA 2005-04-06 2005-04-06 Anti entity tumour medicinal composition Expired - Fee Related CN100500212C (en)

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CN1349406A (en) * 1999-04-29 2002-05-15 法玛西雅厄普约翰公司 Combined preparations comprising morpholine anthracyclines and anticancer agent

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Publication number Priority date Publication date Assignee Title
CN1349406A (en) * 1999-04-29 2002-05-15 法玛西雅厄普约翰公司 Combined preparations comprising morpholine anthracyclines and anticancer agent

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