CN100340297C - Anticarcinogenic internal implant agent - Google Patents

Anticarcinogenic internal implant agent Download PDF

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Publication number
CN100340297C
CN100340297C CNB2005100424349A CN200510042434A CN100340297C CN 100340297 C CN100340297 C CN 100340297C CN B2005100424349 A CNB2005100424349 A CN B2005100424349A CN 200510042434 A CN200510042434 A CN 200510042434A CN 100340297 C CN100340297 C CN 100340297C
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China
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anticancer
tumor
carmustine
lomustine
cancer therapy
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CN1679950A (en
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孔庆忠
孙娟
张红军
宋邦强
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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 an anticancer internal implanted agent which belongs to the technical field of anticancer drugs. Anticancer effective components comprise nitrosyl compound sulfaurea anticancer drugs and nitrosyl compound sulfaurea anticancer drug synergistic agents, wherein the nitrosyl compound sulfaurea anticancer drug synergistic agents comprise nitrogen mustard compounds, antimitotic drugs and anti-metabolism anticancer drugs. The pharmaceutical combination can effectively suppress the DNA repair function in tumor cells, and can reduce the tolerance of the tumor cells for the anticancer drugs. 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 drugs can be slowly released at part of a tumor, so that the systemic toxicity reactions of the drugs are reduced obviously. Simultaneously, the effective drug concentration can be kept at part of the tumor. The anticancer internal implant agent is put at part of the tumor, the systemic toxicity reactions of the anticancer drugs can be reduced, and simultaneously the drug concentration of part of the tumor can be improved in a selective mode. The treatment effect of non-operative treatment modes, such as chemotherapeutics, radiotherapy, etc., can be enhanced.

Description

Anticarcinogenic internal implant agent
(1) technical field
The present invention relates to a kind of Anticarcinogenic internal implant agent, belong to technical field of pharmaceuticals.
(2) background technology
The treatment of entity tumor mainly comprises methods such as operation, radiotherapy and chemotherapy.In used various chemotherapeutics, the action effect of nitrosourea cancer therapy drug is comparatively obvious, has been widely used in multiple malignant tumor.Yet, discover that further the DNA repair function in many tumor cells obviously increases after treatment.The latter often causes the enhancing of tumor cell to the toleration of nitrosourea cancer therapy drug, consequently treatment failure.
Recent findings, many medicines can increase the sensitivity of tumor cell to the nitrosourea cancer therapy drug, referring to " 06-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, simple raising dosage is subjected to the restriction of general reaction again, 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).In addition, the cancer drug therapy of low dosage not only can increase the Drug tolerance of cancerous cell, but also can promote its wettability growth, 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 Anticarcinogenic internal implant agent is provided.
Anticarcinogenic internal implant agent of the present invention comprises anticancer effective component and pharmaceutic adjuvant, and anticancer effective component is nitrosourea cancer therapy drug and nitrosourea cancer therapy drug synergist.Wherein nitrosourea cancer therapy drug synergist comprises nitrogen mustards chemical compound, anti-mitosis medicine and anti-metabolism anticarcinogen.
Available nitrosourea medicament is; but be not limited to; alestramustine (Alestramustine); streptozocin (streptozotocin; STZ); atrimustine (Atrimustine); ambamustine (Ambamustine); nimustine (ACNU; Nimustine); bendamustine (Bendamustine); ditiomustine (Ditiomustine); bofumustine (Bofumustine); carmustine (carmustine; BCNU; carmustine); elmustine (Elmustine); ecomustine (Ecomustine); galamustine (Galamustine; GCNU); fotemustine (Fotemustine); estramustine (Estramustine); hemustine heCNU He (hemustine; heCNU); pentamustine (Pentamustine; Neptamustine); mannomustine (Mannomustine; MCNU); lomustine (lomustine; CCNU; lomustine; chlorethyl cyclohexyl nitrosourea); methyl lomustine (methyl-CCNU); semustine (Semustine; CH3-CCNU; Me-CCNU); Ranimustine (Ranimustine); prednimustine (Prednimustine); uracil mustard (Uramustine, Uracil Mustard); Sarmustine SarCNU (SarCNU); tauromustine (Tauromustine); tallimustine (Tailimustine) and spiromustine (Spiromustine) etc.
Above nitrosourea medicament also comprises its salt, as, but be not limited to sulfate, phosphate, hydrochlorate, Lactobionate, acetate, aspat, nitrate, citrate, purine or pyrimidine salt, succinate and maleate etc.
Nitrosourea medicament and salt thereof can singly select or multiselect, but serve as preferred with streptozocin (STZ), estramustine, semustine, Sarmustine SarCNU, nimustine, lomustine and carmustine.
Described chlormethine series pharmaceuticals is selected from, but be not limited to, mechlorethaminoxide (Mechlorethaminoxide), glyforfin (Glyfosfin), chlornaphazine (Chlornaphazine), chlormethine (Mustine, Mechlorethamine, Chlormethine), nitrocaphane (Nitrocaphane, nitrocaphanum, AT-1258), betamerphalan (Betamerphalan), ocaphane (Ocaphane), the card mustard, methoxymerphalan (Methoxymerphalan), AGN 1414, trichlormethine (Trimustine), desmofosfamide, ocaphane (Ocaphane), Am, Thyminalkylamine, uracil mustard, imidazole mustard, mannomustin, mannomustine, 1-(2-Chloroethyl)-3-neopentyl-1-nitrosourea, nitro can moisten, novoembichin, AT 581., phenesterine, PM, the tower chlorethyl cyclohexyl nitrosourea, 2, 2', 2''-Trichlorotriethylamine, the chlormethine uracil, uraphetinum.
Above chlormethine series pharmaceuticals also comprises its salt, as, but be not limited to sulfate, phosphate, hydrochlorate, Lactobionate, acetate, aspat, nitrate, citrate, purine or pyrimidine salt, succinate and maleate etc.
Chlormethine series pharmaceuticals and salt thereof can singly select or multiselect.But with chlormethine, methoxymerphalan, nitrocaphanum, mustine hydrochlcride, Thyminalkylamine, uracil mustard, imidazole mustard, mannomustin, mannomustine and chlormethine uracil serves as preferred.
Described anti-mitosis medicine will make tumor cell stop at the different links of cell cycle.This type of medicine can be, but be not limited to cytochalasin (podophyllotoxin), Datelliptium Chloride, ellipticine, 2-Methylellipticine, mitoclomine (Mitoclomine), mitoflaxone (Mitoflaxone), mitoguazone (Mitoguazone), mitonafide (Mitonafide), mitopodozide (Mitopodozide), mitoquidone (Mitoquidone), mitosper (Mitosper), mitotane (Mitotane), mitotenamine (Mitotenamine), mitozolomide (Mitozolomide), Flavone acetic acid, colchisal (colchisal) and other colchium salts; Colchiceinamide (Colchiceinamide), colchicine (Colchicine), 7-acetamido-10-hydroxy-1,2,3-trimethoxy-6,7-dihydrobenzo[a (colchiceine), sulfo--colchicine (thio-colchicine), Demecolcine (Demecolcine), Colchiceinamidum, Colchicine, B cytochalasin B (cytochalasins) is (as A-E, H, J), okadaic acid, carbaryl (sevin, carbaryl), naphthols (naphthol), alpha-Naphthol (1-naphthol), betanaphthol (2-naphthol), alpha-phosphate naphthols (1-naphthylphosphate), malonate, acodazole (Acodazole), procodazole (Procodazole), giracodazole (Giracodazole), nocodazole (nocodazole), malonic acid or malonate.
Antimetabolitas is selected from following one or more: 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 (CalciumLevofolinate, 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-mentioned antimetabolitas is preferred: Ismipur, 5-fluorouracil (5-FU), pemetrexed, pemetrexed disodium, Rumi Qu Sai, doxifluridine, floxuridine, mercaptopurine, thioguanine, methotrexate, 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, cladribine or pentoside.
Nitre ureas cancer therapy drug can be from 0.01%-99.99% at the content of Anticarcinogenic internal implant agent, with 1%-50% is good, with 5%-30% is best, and nitrogen mustards chemical compound, anti-mitosis medicine and anti-metabolism anticarcinogen shared ratio in compositions is also decided because of concrete condition, can be from 0.01%-99.99%, with 1%-50% is good, is best with 5%-30%.All be weight percentage.
Chlormethine series pharmaceuticals is better to the therapeutic effect of entity tumor in the present composition, and anti-mitosis medicine can will make tumor cell stop at the different links of cell cycle.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.
Pharmaceutic adjuvant of the present invention 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), poe (polyorthoesters), polyphosphazene (polyphosphazenes), to carboxy phenyl propane (p-CPP), certain herbaceous plants with big flowers diacid (sebacic acid) etc.; Natural polymer as, but be not limited to, protein and polysaccharide comprise hyaluronic acid, collagen protein, gelatin, albumin etc.
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 hydroxy carboxylic acid of polylactic acid (PLA), polyglycolic acid (PGA), polylactic acid (PLA) and polyglycolic acid; When PLA and PLGA mixing, its content percentage by weight is respectively 0.1-99.9% and 99.9-0.1%.The molecular weight of polylactic 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 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; Above polyhydroxy acid can singly select or multiselect.When singly selecting, serve as preferred with the copolymer (PLGA) of polylactic acid (PLA) or hydroxy carboxylic acid and glycolic, the molecular weight of copolymer can be, but is not limited to, 1000-100,000, 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.The indication molecular weight is the molecular weight peak value scope for being recorded by GPC all.
The nondegradable polymer of above-mentioned biology comprises, but be not limited to: organosilicon polymer, ethylene vinyl acetate copolymer (Ethelene-vinyl acetate copolymer, EVAc), polyacrylonitrile (polyacrylonitriles), polyurethanes (polyurethanes) 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 Anticarcinogenic internal implant agent 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 and sodium salt etc.
The used pharmaceutic adjuvant of Anticarcinogenic internal implant agent 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 PLGA, glycolic and hydroxy carboxylic acid, certain herbaceous plants with big flowers diacid and fragrant polyanhydride or aliphatic polyanhydride.The blend ratio of glycolic and hydroxy carboxylic acid is 10/90-90/10 (weight), preferably 25/75-75/25 (weight).The method of blend is arbitrarily.Content when glycolic and hydroxy carboxylic 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 10-90% and 90-10%, the blend weight ratio is 10/90-90/10, preferably weight ratio 25/75-75/25.
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 adjuvant.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 Anticarcinogenic internal implant agent 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 Anticarcinogenic internal implant agent 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 Anticarcinogenic internal implant agent 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.
Anticarcinogenic internal implant agent 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, sustained-release implant etc.; Be different shape, as, but be not limited to granular, lamellar, sphere, bulk, needle-like, bar-shaped and membranaceous.In various dosage forms, serve as preferred with the sustained release profile in vivo test implant.Above-mentioned dosage form and shape are applicable to the compositions that contains or do not contain additive.
Because Anticarcinogenic internal implant agent 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.
When share with above-mentioned non-operative treatment, Anticarcinogenic internal implant agent of the present invention can be used simultaneously with non-operative treatment, also can use in non-operative treatment is implemented a few days ago, and its purpose is to strengthen as far as possible the sensitivity of tumor.There is potentiation significantly to act between the inhomogeneity cancer therapy drug, thereby provides a kind of more effective new method, have very high clinical value and remarkable economical and social benefit for effecting a radical cure former of various human bodies and animal and shifting entity tumor.
Route of administration
Anticarcinogenic internal implant agent of the present invention can be used through various approach, as in tremulous pulse, subcutaneous, muscle, Intradermal, intracavity, the tumor, tumor week etc.Whether route of administration depends on multiple factor, as position, tumor place, perform the operation or transfer, gross tumor volume size, tumor classification, patient age, health, bearing status and requirement etc.For obtain active drug concentration in position, tumor place, arterial perfusion optionally, intra-bladder instillation (intracavitary), (intraspinal) administration in abdominal cavity (intraperitoneal) or thoracic cavity (intrapleural) and the canalis spinalis, but also place in the internal organs, as in the enteric cavity, in the intravesical, uterine cavity, in intravaginal, gastric and the esophagus etc.In number of ways, with topical, as based in selective arterial, the tumor, tumor week injection, with in the tumor, the form that slowly discharges of tumor week or tumor chamber serve as preferably, can plant slow-releasing pump and slow releasing capsule or sustained release profile in vivo test implant as selecting for use.
When with topical, as with in the tumor, the form that slowly discharges of tumor week or tumor chamber serve as preferably, during topical also can with systemic chemotherapy or radiotherapy use in conjunction.
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.But its principle is at the repair ability that can reduce tumor cell, when increasing the chemotherapy action effect and the toxic reaction of not obvious increase medicine.
The effective dose of nitrosourea cancer therapy drug is 0.01-200 milligram/kg body weight, is ideal with 1-30 milligram/kg body weight, with 2-20 milligram/kg body weight for the most desirable; The effective dose of nitrogen mustards chemical compound is 0.01-80 milligram/kg body weight, is ideal with 1-50 milligram/kg body weight, with 2-10 milligram/kg body weight for the most desirable; The effective dose of anti-mitosis medicine and anti-metabolism anticarcinogen all can be 0.01-80 milligram/kg body weight, is ideal with 1-50 milligram/kg body weight, with 2-10 milligram/kg body weight for the most desirable.The content in compositions of nitrosourea cancer therapy drug is 1%-50%, and the content of other medicines also can be 1%-50%,
Anticarcinogenic internal implant agent of the present invention can be used for the treatment of the entity tumors such as various cancers, sarcoma or carcinosarcoma of people, house pet and various animals, 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 this Anticarcinogenic internal implant agent, 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.
Dosage form
Anticarcinogenic internal implant agent of the present invention can be made into different shape, and wherein the content of active ingredient is decided because of different needs.Can be made into various dosage forms, as, but be not limited to injection, muddy suspension, ointment, capsule, implant, slow releasing agent and implantation slow release agent etc.; Be different shape, as, but be not limited to granular, lamellar, sphere, bulk, needle-like, bar-shaped and membranaceous; Can be good with the tremulous pulse approach through various administrations, directly be placed as the best in the tumor body.Most preferred dosage form is the implantation slow release agent that bio-capacitivity, degradable absorb, and can make different shape because of the clinical needs of difference.Available arbitrary method preparation.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 packaged in the liposome.
The characteristics of Anticarcinogenic internal implant agent technology of preparing of the present invention be with all kinds of cancer therapy drugs separately or packaged in combination in the carrier holder, according to a certain percentage with active ingredient and carrier holder dissolving (or mixing), the drying of bleeding (or tabletting) is shaped and the sterilization packing.Can control its release time by technology such as layering packings when packing simultaneously.Its principle is when alleviating drug toxicity as far as possible, strengthens the action effect between various medicines most effectively.
Anticarcinogenic internal implant agent of the present invention can be used by many schemes.Above-mentioned effective ingredient can be packaged in the pharmaceutic adjuvant, then topical application.Said composition can with topical, wherein be released to the best with local slow again as injection in selective arterial injection and the direct tumor body for good through various administrations.When used the part, compositions 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.
Anticarcinogenic internal implant agent 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.
Test one, nitrosourea cancer therapy drug and synergist thereof are to the inhibitory action of tumor cell in vitro growth.
For the mutual potentiation of checking nitrosourea cancer therapy drug and synergist thereof used, this test comprises CNS-1, C6, gastric gland epithelial cancer (SA), bone tumor (BC), breast carcinoma (BA), pulmonary carcinoma (LH), papillary adenocarcinoma of thyroid (PAT), hepatocarcinoma etc. with the tumor cell of multiple In vitro culture.The inhomogeneity cancer therapy drug is pressed the combination shown in the table 1, and cancer therapy drug is added in 24 hours the various tumor cells of In vitro culture by the concentration of 10ug/ml, continue to cultivate after 48 hours the counting cells sum and calculates its suppression ratio to growth of tumour cell (%).
Table 1
Oncocyte (A) (B) (C) (D) (E) (A) +(B)NU (A) +(C) (A) +(D) (A) +(E)
CNS 64％ 60％ 62％ 60％ 62％ 96％ 94％ 92％ 95％
C6 62％ 64％ 66％ 60％ 66％ 94％ 94％ 96％ 90％
SA 60％ 60％ 68％ 56％ 58％ 92％ 90％ 86％ 96％
BC 52％ 64％ 64％ 54％ 64％ 84％ 94％ 94％ 95％
BA 50％ 62％ 68％ 62％ 58％ 82％ 89％ 96％ 92％
LH 62％ 58％ 62％ 62％ 62％ 92％ 88％ 92％ 92％
PAT 58％ 56％ 64％ 66％ 64％ 92％ 96％ 94％ 94％
Explain: (A): CCNU is the nitrosourea cancer therapy drug; (B): methoxymerphalan is the nitrogen mustards chemical compound; (C) colchicine and (D) nocodazole be anti-mitosis medicine; (E): 5-fluorouracil is the anti-metabolism anticarcinogen.
Test two, nitrosourea cancer therapy drug and synergist thereof are to the inhibitory action of tumor cell in vitro growth.
According to testing a described method comparison nitrosourea cancer therapy drug and synergist thereof inhibitory action to the tumor cell in vitro growth.The results are shown in Table 2.
Table 2
Oncocyte (A) (B) (C) (D) (E) (A) +(B)NU (A) +(C) (A) +(D) (A) +(E)
CNS 60％ 64％ 62％ 66％ 62％ 96％ 94％ 92％ 93％
C6 56％ 64％ 66％ 60％ 56％ 94％ 94％ 96％ 91％
SA 68％ 60％ 68％ 56％ 58％ 92％ 90％ 86％ 96％
BC 64％ 64％ 64％ 54％ 64％ 84％ 94％ 94％ 94％
BA 58％ 62％ 68％ 62％ 58％ 82％ 90％ 96％ 92％
LH 62％ 58％ 62％ 62％ 62％ 92％ 88％ 92％ 92％
PAT 62％ 56％ 64％ 66％ 64％ 92％ 96％ 94％ 90％
Explain: (A): be ACNU, belong to the nitrosourea cancer therapy drug; (B): mechlorethaminoxide is the nitrogen mustards chemical compound; (C): betanaphthol, anti-mitosis medicine; (D) pemetrexed and (E) Rumi Qu Sai be the anti-metabolism anticarcinogen.
Test three, according to test one described method relatively nitrosourea cancer therapy drug and synergist thereof to the inhibitory action of tumor cell in vitro growth.The results are shown in Table 3.
Table 3
Oncocyte (A) (B) (C) (D) (E) (A) +(B)NU (A) +(C) (A) +(D) (A) +(E)
CNS 54％ 64％ 62％ 66％ 62％ 86％ 94％ 92％ 93％
C6 56％ 64％ 66％ 60％ 58％ 94％ 94％ 96％ 91％
SA 60％ 60％ 68％ 56％ 58％ 92％ 90％ 86％ 96％
BC 64％ 64％ 64％ 54％ 54％ 84％ 94％ 94％ 94％
BA 58％ 62％ 68％ 62％ 58％ 82％ 92％ 96％ 92％
LH 62％ 60％ 62％ 62％ 52％ 92％ 88％ 92％ 92％
PAT 63％ 56％ 64％ 66％ 64％ 92％ 96％ 94％ 94％
Explain: (A): SarCNU is the nitrosourea cancer therapy drug; (B): giracodazole, anti-mitosis medicine; (C) gemcitabine and (D) decitabine and (E) flurocitabine be the anti-metabolism anticarcinogen.
Test four, according to test one described method relatively nitrosourea cancer therapy drug and synergist thereof to the inhibitory action of tumor cell in vitro growth.The results are shown in Table 4.
Table 4
Oncocyte (A) (B) (C) (D) (E) (A) +(B)NU (A) +(C) (A) +(D) (A) +(E)
CNS 52％ 60％ 62％ 66％ 52％ 86％ 94％ 92％ 93％
C6 56％ 64％ 66％ 60％ 88％ 94％ 94％ 96％ 91％
SA 62％ 62％ 68％ 56％ 58％ 92％ 90％ 86％ 96％
BC 64％ 64％ 64％ 54％ 64％ 84％ 94％ 94％ 94％
BA 56％ 62％ 68％ 62％ 58％ 82％ 92％ 96％ 92％
LH 62％ 60％ 62％ 62％ 62％ 92％ 88％ 92％ 93％
PAT 60％ 58％ 64％ 66％ 64％ 92％ 96％ 94％ 94％
Explain: (A): carmustine is the nitrosourea cancer therapy drug; (B): acodazole, anti-mitosis medicine; (C) methotrexate and (D) carmofur and (E) ftorafur be the anti-metabolism anticarcinogen.
In test one to four, selected for use nimustine (ACNU), carmustine (BCNU), semustine (CCNU) and Sarmustine SarCNU (SarCNU) etc. to be the nitrosourea cancer therapy drug of representative; Methoxymerphalan and mechlorethaminoxide are the nitrogen mustards chemical compound; Betanaphthol, colchicine, giracodazole, acodazole and nocodazole etc. are the anti-mitosis medicine of representative; 5-fluorouracil, pemetrexed, Rumi Qu Sai, gemcitabine, decitabine, flurocitabine, methotrexate, carmofur and ftorafur etc. are the anti-metabolism anticarcinogen of representative.With its inhibitory action of cellular assay such as CNS-1, C6, gastric gland epithelial cancer (SA), bone tumor (BC), breast carcinoma (BA), pulmonary carcinoma (LH), papillary adenocarcinoma of thyroid (PAT), hepatocarcinoma to tumor growth.The result shows, growth all has the obvious suppression effect to used cancer therapy drug to cultured tumor cells in vitro when 5-10ul/ml concentration, but the two has obvious synergistic effect when share.
Test five, nitrosourea cancer therapy drug and synergist thereof are to the inhibitory action of tumor cell in vitro growth
With the rat is subjects, with 2 * 10 5Individual tumor cell subcutaneous injection is in its hypochondrium, treats that tumor growth is divided into it following 10 groups (seeing Table 5) at random after 14 days.All medicines are all placed in tumor, and dosage 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 80±20cm 3
2(6) (A) carmustine 32±4.3cm 3 ＜0.05
3(6) (B) methoxymerphalan 56±12.2cm 3 ＜0.01
4(6) (C) colchicine 52±13.0cm 3 ＜0.01
5(6) (D) 5-fluorouracil 60±14cm 3 ＜0.01
6(6) (E) pemetrexed 50±13.6cm 3 ＜0.01
7(6) (A)+(B) 21±5.6cm 3 ＜0.001
8(6) (A)+(C) 20±4.6cm 3 ＜0.001
9(6) (A)+(D) 21±3.6cm 3 ＜0.001
10(6) (A)+(E) 18±3.0cm 3 ＜0.001
Explain: (A): carmustine is the nitrosourea cancer therapy drug; (B): methoxymerphalan is the nitrogen mustards chemical compound; (C): colchicine is anti-mitosis medicine; (D) 5-fluorouracil and (E) pemetrexed be the anti-metabolism anticarcinogen.
Test six, nitrosourea cancer therapy drug and synergist thereof are to the inhibitory action of tumor cell in vitro growth
With the rat is subjects, with 2 * 10 5Individual tumor cell subcutaneous injection is in its hypochondrium, treats that tumor growth is divided into it following 10 groups (seeing Table 6) at random after 14 days.All medicines are all placed in tumor, and dosage 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 78±18cm 3
2(6) (A) nimustine 36±10.3cm 3 ＜0.05
3(6) (B) giracodazole 58±12.5cm 3 ＜0.01
4(6) (C) methotrexate 40±11.6cm 3 ＜0.01
5(6) (D) gemcitabine 42±10cm 3 ＜0.01
6(6) (E) Rumi Qu Sai 22±13.8cm 3 ＜0.01
7(6) (A)+(B) 18±6.6cm 3 ＜0.001
8(6) (A)+(C) 20±3.6cm 3 ＜0.001
9(6) (B)+(D) 16±2.6cm 3 ＜0.001
10(6) (B)+(E) 18±3.0cm 3 ＜0.001
Explain: (A): nimustine is the nitrosourea cancer therapy drug; (B): giracodazole is anti-mitosis medicine; (C) methotrexate, (D) gemcitabine and (E) Rumi Qu Sai be the anti-metabolism anticarcinogen.
The result of the test of test 5 to 6 shows, compares with matched group, and above-mentioned all kinds of cancer therapy drugs are used separately all has obvious inhibitory action (P＜0.05) to tumor growth in vivo.And use in conjunction has obvious synergistic effect (P＜0.001).
In a word, a few kind anti-cancer drugs things used among the present invention all have significantly potentiation mutually to the nitrosourea cancer therapy drug, and are of universal significance.This is unexpected discovery the of the present invention.Therefore, effective ingredient nitrosourea cancer therapy drug of the present invention can be any one or more than one composition combination in nitrogen mustards chemical compound, anti-mitosis medicine or the anti-metabolism anticarcinogen with its synergist, thereby constitutes major technique feature of the present invention.
The Anticarcinogenic internal implant agent that contains above effective ingredient can be made into any dosage form or shape, but is preferred with the agent for slow releasing.
The preparation method of Anticarcinogenic internal implant agent of the present invention is as follows:
1. the pharmaceutic adjuvant of weighing is put into container, add the certain amount of organic solvent dissolving evenly, the not strict qualification of the amount of organic solvent, suitable fully to be dissolved as.
2. adding the anticancer active ingredient of weighing shakes up again.The usage ratio of anticancer active ingredient and pharmaceutic adjuvant is decided because of specific requirement.
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
The present invention will be further described below by embodiment, but be not limited thereto.
Embodiment one:
The pharmaceutic adjuvant (molecular weight is 10000 polylactic acid (PLGA)) of (80mg) of will weighing is put into container, after adding certain amount of organic solvent dissolving mixing (being as the criterion) with abundant dissolving, add 10 milligrams of carmustines and 10mg methoxymerphalan, shake up the dry organic solvent of removing of final vacuum again.Dried solid composite is shaped immediately, and ray sterilizing after the packing obtains Anticarcinogenic internal implant agent and contains 10% carmustine and 10% methoxymerphalan.
Embodiment two:
Make Anticarcinogenic internal implant agent by above-mentioned flow process and embodiment one described method, institute's difference is that contained anticancer effective component is:
The alestramustine of 1-50%; streptozocin; atrimustine; ambamustine; nimustine; bendamustine; ditiomustine; bofumustine; carmustine; elmustine; ecomustine; CNCC; galamustine; fotemustine; estramustine; hemustine heCNU He; pentamustine; mannomustine; lomustine; methyl lomustine; semustine; Ranimustine; prednimustine; Sarmustine SarCNU; uracil mustard; tauromustine; the methoxymerphalan of tallimustine or spiromustine and 1-50%; nitrocaphanum; mechlorethaminoxide; glyforfin; chlornaphazine; mustine hydrochlcride; betamerphalan; ocaphane; the card mustard; AGN 1414; trichlormethine; desmofosfamide; ocaphane; Am; Thyminalkylamine; uracil mustard; imidazole mustard; mannomustin; mannomustine; 1-(2-Chloroethyl)-3-neopentyl-1-nitrosourea; nitro can moisten; novoembichin; AT 581.; phenesterine; PM; the tower chlorethyl cyclohexyl nitrosourea; 2, 2', 2''-Trichlorotriethylamine; the combination of chlormethine uracil or uraphetinum.
Embodiment three:
The pharmaceutic adjuvant (molecular weight is 25000 polylactic acid (PLGA)) of (80mg) of will weighing is put into container, after adding certain amount of organic solvent dissolving mixing (being as the criterion) with abundant dissolving, add 10mg nimustine and 10 milligrams of nocodazoles, shake up the dry organic solvent of removing of final vacuum again.Dried solid composite is shaped immediately, and ray sterilizing after the packing obtains Anticarcinogenic internal implant agent and contains 10% nimustine and 10% milligram of nocodazole.
Embodiment four:
Make Anticarcinogenic internal implant agent by above-mentioned flow process and embodiment three described methods, institute's difference is that contained anticancer effective component is:
The alestramustine of 1-50%; streptozocin; atrimustine; ambamustine; nimustine; bendamustine; ditiomustine; bofumustine; carmustine; elmustine; ecomustine; CNCC; galamustine; fotemustine; estramustine; hemustine heCNU He; pentamustine; mannomustine; lomustine; methyl lomustine; semustine; Ranimustine; prednimustine; Sarmustine SarCNU; uracil mustard; tauromustine; the cytochalasin of tallimustine or spiromustine and 1-50%; Datelliptium Chloride; ellipticine; 2-Methylellipticine; mitoclomine; mitoflaxone; mitoguazone; mitonafide; mitopodozide; mitoquidone; mitosper; mitotane; mitotenamine; mitozolomide; Flavone acetic acid; colchicine; Salicylate; colchiceinamide; colchicine; 7-acetamido-10-hydroxy-1,2,3-trimethoxy-6,7-dihydrobenzo[a; sulfo--colchicine; Demecolcine; Colchiceinamidum; Colchicine; 7-acetamido-10-hydroxy-1,2,3-trimethoxy-6,7-dihydrobenzo[a; sulfo--colchicine; Demecolcine; Colchiceinamidum; Colchicine; B cytochalasin B; carbaryl; naphthols; alpha-Naphthol; betanaphthol; the alpha-phosphate naphthols; acodazole; procodazole; giracodazole; nocodazole; the combination of malonic acid or malonate.
Embodiment five:
The pharmaceutic adjuvant (molecular weight is 15000 EVAc) of (80mg) of will weighing is put into container, after adding certain amount of organic solvent dissolving mixing (being as the criterion) with abundant dissolving, add 10mg estramustine and 10 milligrams of 5-fluorouracil, shake up the dry organic solvent of removing of final vacuum again.Dried solid composite is shaped immediately, and ray sterilizing after the packing obtains Anticarcinogenic internal implant agent and contains 10% estramustine and 10%5-fluorouracil.
Embodiment six:
Make Anticarcinogenic internal implant agent by above-mentioned flow process and embodiment five described methods, institute's difference is that contained anticancer effective component is:
The alestramustine of percentage by weight 1-50%; streptozocin; atrimustine; ambamustine; nimustine; bendamustine; ditiomustine; bofumustine; carmustine; elmustine; ecomustine; CNCC; galamustine; fotemustine; estramustine; hemustine heCNU He; pentamustine; mannomustine; lomustine; methyl lomustine; semustine; Ranimustine; prednimustine; Sarmustine SarCNU; uracil mustard; tauromustine; the Ismipur of tallimustine or spiromustine and percentage by weight 1-50%; 5-fluorouracil; pemetrexed; pemetrexed disodium; Rumi Qu Sai; mercaptopurine; thioguanine; methotrexate; carmofur; ftorafur; cytosine arabinoside; hydroxyurea; the 5-fluorouracil nucleoside; galocitabine; gemcitabine; ibacitabine; enocitabine; ancitabine; decitabine; flurocitabine; capecitabine; enocitabine; his shore of imidazoles; GR 30921X; mitotane; fludarabine; the combination of cladribine or pentoside.
Embodiment seven:
With the pharmaceutic adjuvant molecular weight of the 70mg that weighs is that 20000 EVAc puts into container, after adding certain amount of organic solvent dissolving mixing (being as the criterion) with abundant dissolving, add 15mg Sarmustine SarCNU and 15 milligrams of methotrexates, shake up the dry organic solvent of removing of final vacuum again.Dried solid composite is shaped immediately, and ray sterilizing after the packing obtains Anticarcinogenic internal implant agent and contains 15% carmustine and 15% methotrexate.All be weight percentage.
Embodiment eight:
As described in embodiment seven, anticancer effective component that different is is one of following:
A) combination of methoxymerphalan, nitrocaphanum or the mechlorethaminoxide of the nimustine of 5-30%, carmustine, lomustine, methyl lomustine, female semustine, semustine, Sarmustine SarCNU or streptozocin and 5-30%; Or
B) combination of the Ismipur of the nimustine of 5-30%, carmustine, lomustine, methyl lomustine, female semustine, semustine, Sarmustine SarCNU or streptozocin and 5-30%, 5-fluorouracil, mercaptopurine, thioguanine, methotrexate, carmofur, ftorafur, cytosine arabinoside, hydroxyurea, 5-fluorouracil nucleoside, galocitabine, gemcitabine, capecitabine, GR 30921X, mitotane, fludarabine, cladribine or pentoside; Or
C) combination of cytochalasin, mitoclomine, mitoflaxone, colchicine, Demecolcine, alpha-Naphthol, betanaphthol, acodazole, procodazole, giracodazole, nocodazole or the malonic acid of the nimustine of 5-30%, carmustine, lomustine, methyl lomustine, female semustine, semustine, Sarmustine SarCNU or streptozocin and 5-30%.
Below all be weight percentage.
Embodiment nine:
Be 35000 polylactic acid (PLGA) with the pharmaceutic adjuvant molecular weight of the 80mg that weighs) put into container, after adding certain amount of organic solvent dissolving mixing (being as the criterion) with abundant dissolving, add 10mg estramustine and 10 milligrams of nocodazoles, shake up the dry organic solvent of removing of final vacuum again.Dried solid composite is shaped immediately, and ray sterilizing after the packing obtains Anticarcinogenic internal implant agent and contains 10% nimustine and 10% milligram of nocodazole.All be weight percentage.
Embodiment ten:
As described in embodiment nine, anticancer effective component that different is is one of following:
A) combination of methoxymerphalan, nitrocaphanum or the mechlorethaminoxide of the nimustine of 5-30%, carmustine, lomustine, methyl lomustine, female semustine, semustine, Sarmustine SarCNU or streptozocin and 5-30%; Or
B) combination of the Ismipur of the nimustine of 5-30%, carmustine, lomustine, methyl lomustine, female semustine, semustine, Sarmustine SarCNU or streptozocin and 5-30%, 5-fluorouracil, mercaptopurine, thioguanine, methotrexate, carmofur, ftorafur, cytosine arabinoside, hydroxyurea, 5-fluorouracil nucleoside, galocitabine, gemcitabine, capecitabine, GR 30921X, mitotane, fludarabine, cladribine or pentoside; Or
C) combination of cytochalasin, mitoclomine, mitoflaxone, colchicine, Demecolcine, alpha-Naphthol, betanaphthol, acodazole, procodazole, giracodazole, nocodazole or the malonic acid of the nimustine of 5-30%, carmustine, lomustine, methyl lomustine, female semustine, semustine, Sarmustine SarCNU or streptozocin and 5-30%.
Below all be weight percentage.
Embodiment 11:
Pharmaceutic adjuvant-polifeprosan of the 80mg that weighs (to carboxy phenyl propane (p-CPP): certain herbaceous plants with big flowers diacid (SA) is 20: 80) is put into container, after adding certain amount of organic solvent dissolving mixing (being as the criterion) with abundant dissolving, add 10mg carmustine and 10 milligrams of 5-fluorouracil, shake up the dry organic solvent of removing of final vacuum again.Dried solid composite is shaped immediately, and ray sterilizing after the packing obtains Anticarcinogenic internal implant agent and contains 10% carmustine and 10% milligram of 5-fluorouracil.All be weight percentage.
Embodiment 12:
As described in embodiment 11, anticancer effective component that different is is one of following:
A) combination of methoxymerphalan, nitrocaphanum or the mechlorethaminoxide of the nimustine of 5-30%, carmustine, lomustine, methyl lomustine, female semustine, semustine, Sarmustine SarCNU or streptozocin and 5-30%; Or
B) combination of the Ismipur of the nimustine of 5-30%, carmustine, lomustine, methyl lomustine, female semustine, semustine, Sarmustine SarCNU or streptozocin and 5-30%, 5-fluorouracil, mercaptopurine, thioguanine, methotrexate, carmofur, ftorafur, cytosine arabinoside, hydroxyurea, 5-fluorouracil nucleoside, galocitabine, gemcitabine, capecitabine, GR 30921X, mitotane, fludarabine, cladribine or pentoside; Or
C) combination of cytochalasin, mitoclomine, mitoflaxone, colchicine, Demecolcine, alpha-Naphthol, betanaphthol, acodazole, procodazole, giracodazole, nocodazole or the malonic acid of the nimustine of 5-30%, carmustine, lomustine, methyl lomustine, female semustine, semustine, Sarmustine SarCNU or streptozocin and 5-30%.
Below all be weight percentage.
Embodiment 13:
By the Anticarcinogenic internal implant agent that the foregoing description one to 12 described method is made, institute's difference is that used pharmaceutic adjuvant is selected from one of following or its combination:
A) molecular weight is the polylactic acid (PLA) of 5000-15000,10000-20000,25000-35000 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) polifeprosan is (to carboxy phenyl propane (p-CPP): certain herbaceous plants with big flowers diacid (SA) copolymer), be 10: 90,20: 80,30: 70,40: 60,50: 50 or 60: 40 to the weight ratio of carboxy phenyl propane (p-CPP) and certain herbaceous plants with big flowers diacid (SA);
E) xylitol, oligosaccharide, chitin, potassium salt, sodium salt, hyaluronic acid, collagen protein, gelatin or albumin.
Embodiment 14:
Make Anticarcinogenic internal implant agent by embodiment one described method, but different is that contained anticancer effective component is:
(a) 10% carmustine and 10% methoxymerphalan; Or
(b) 10% carmustine and 10%6-purinethol; Or
(c) 10% carmustine and 10%5-fluorouracil; Or
(d) 10% carmustine and 10% methotrexate; Or
(e) 10% carmustine and 10% carmofur; Or
(f) 10% carmustine and 10% ftorafur; Or
(g) 10% carmustine and 10% giracodazole; Or
(h) combination of 10% carmustine and 10% nocodazole.
Below all be weight percentage.
Embodiment 15: the Anticarcinogenic internal implant agent extracorporeal releasing characteristic relatively
Pastille polymer among the embodiment 14 is placed in the room temperature normal saline soaks, survey the burst size of different time medicine (carmustine), and calculate accumulative total and discharge percent (%).Be shown in Table 7.
Table 7
The pastille polymer 1 day 3 days 5 days 7 days 14 days
(a) (b) (c) (d) (e) (f) (g) (h) 19 20 21 21 21 23 22 23 40 39 41 42 41 39 41 42 59 61 61 61 61 60 62 58 78 78 72 81 71 79 78 82 92 88 89 89 86 92 90 91
Embodiment 16: the Anticarcinogenic internal implant agent extracorporeal releasing characteristic relatively
It is subcutaneous that pastille polymer among the embodiment 14 is put in white mice, regularly takes out and measure medicament contg, according to the residual drug amount, and calculates accumulative total and discharge percent (%).Be shown in Table 8.
Table 8
Embodiment 1 day 3 days 5 days 7 days 14 days 21 days 28 days
(a) (b) (c) (d) (e) (f) (g) (h) 9 12 11 14 9 15 11 14 27 21 22 20 21 19 20 21 33 33 33 29 31 29 33 31 50 52 51 48 49 58 56 51 78 72 73 72 79 70 75 66 92 92 91 89 94 84 88 84 97 96 95 94 99 94 97 97
As can be seen from Table 7, 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.
By table on 8 as can be seen, institute try to discharge in the different pharmaceutical body also no significant difference, and release in first day release in the about 10%, 28th day is more than 95%.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, external then about 15 days.
As mentioned above, Anticarcinogenic internal implant agent can be made various dosage forms with existing method, and therefore, above embodiment only is used for explanation, and is not limitation application of the present invention.

Claims (3)

1. Anticarcinogenic internal implant agent, anticancer effective component and pharmaceutic adjuvant by effective anticancer are formed, it is characterized in that anticancer effective component is nitrosourea cancer therapy drug and nitrosourea cancer therapy drug synergist, wherein nitrosourea cancer therapy drug synergist is by one of nitrogen mustards chemical compound, anti-mitosis medicine and anti-metabolism anticarcinogen or combinations thereof, and pharmaceutic adjuvant is that molecular weight is 10000 polylactic acid;
The nitrosourea cancer therapy drug is selected from streptozocin, nimustine, carmustine, elmustine, ecomustine, CNCC, fotemustine, hemustine heCNU He, pentamustine, lomustine, semustine, Ranimustine, Sarmustine SarCNU, uracil mustard, tauromustine or spiromustine;
The nitrogen mustards chemical compound is selected from nitrocaphanum, mechlorethaminoxide, glyforfin, chlornaphazine, mustine hydrochlcride, desmofosfamide, ocaphane, Thyminalkylamine, imidazole mustard, novoembichin, phenesterine, PM or uraphetinum;
Anti-mitosis medicine is selected from cytochalasin, mitoclomine, mitoflaxone, mitoguazone, mitonafide, mitopodozide, mitozolomide, colchicine, 7-acetamido-10-hydroxy-1,2,3-trimethoxy-6,7-dihydrobenzo[a, Demecolcine, Colchiceinamidum, acodazole, giracodazole or nocodazole;
Antimetabolitas is selected from one or more in mercaptopurine, pemetrexed, thioguanine, methotrexate, carmofur, ftorafur, cytosine arabinoside, hydroxyurea, galocitabine, gemcitabine, enocitabine, ancitabine, decitabine, flurocitabine, capecitabine and the cladribine.
2. Anticarcinogenic internal implant agent according to claim 1 is characterized in that anticancer effective component is:
A) combination of nimustine, carmustine, lomustine, semustine, Sarmustine SarCNU or streptozocin and nitrocaphanum or mechlorethaminoxide; Or
B) combination of nimustine, carmustine, lomustine, semustine, Sarmustine SarCNU or streptozocin and mercaptopurine, thioguanine, methotrexate, carmofur, ftorafur, cytosine arabinoside, hydroxyurea, galocitabine, gemcitabine, capecitabine or cladribine; Or
C) combination of nimustine, carmustine, lomustine, semustine, Sarmustine SarCNU or streptozocin and cytochalasin, mitoclomine, mitoflaxone, colchicine, Demecolcine, acodazole, giracodazole or nocodazole.
3. the described Anticarcinogenic internal implant agent of claim 1 is used to prepare the medicine that treatment originates from cancer, sarcoma or the carcinosarcoma of brain, central nervous system, kidney, liver, gallbladder, incidence, oral cavity, thyroid, skin, mucosa, blood vessel, osseous tissue, lymph node, lungs, esophagus, stomach, mammary gland, pancreas, eyes, nasopharynx part, uterus, ovary, prostate, bladder, colon or rectum former or secondary.
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