CN100431608C - Anti entity tumour medicinal composition containing tetrazine kind compound - Google Patents

Anti entity tumour medicinal composition containing tetrazine kind compound Download PDF

Info

Publication number
CN100431608C
CN100431608C CNB2005100422625A CN200510042262A CN100431608C CN 100431608 C CN100431608 C CN 100431608C CN B2005100422625 A CNB2005100422625 A CN B2005100422625A CN 200510042262 A CN200510042262 A CN 200510042262A CN 100431608 C CN100431608 C CN 100431608C
Authority
CN
China
Prior art keywords
temozolomide
combination
mitozolomide
procarbazine
tetrazine
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Fee Related
Application number
CNB2005100422625A
Other languages
Chinese (zh)
Other versions
CN1686555A (en
Inventor
孔庆忠
孙娟
赵云峰
张楠
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
DASEN BIOLOGICAL PHARMACEUTICAL CO., LTD.
Original Assignee
Shandong Lanjin Pharmaceuticals Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Shandong Lanjin Pharmaceuticals Co Ltd filed Critical Shandong Lanjin Pharmaceuticals Co Ltd
Priority to CNB2005100422625A priority Critical patent/CN100431608C/en
Publication of CN1686555A publication Critical patent/CN1686555A/en
Application granted granted Critical
Publication of CN100431608C publication Critical patent/CN100431608C/en
Expired - Fee Related legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Landscapes

  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

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

Description

A kind of entity-tumor-resistant medicine composition that contains tetrazine kind compound
(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
Treatment for cancer mainly comprises methods such as operation, radiotherapy and chemotherapy.In used various chemotherapeutics, the action effect of tetrazine kind compound is comparatively obvious, has been widely used in multiple malignant tumor.Because topoenzyme inhibitor is by suppressing synthetic its antitumor action of bringing into play of RNA, and the DNA repair function in many tumor cells obviously increases after treatment, so effectively reduce or suppress the emphasis that the interior DNA repair function of tumor cell just becomes current research.
Recent findings, deactivation or suppress intracellular dna repair protein and can strengthen the sensitivity of part tumor cell to chemotherapy, referring to " 6-benzyl guanine analog is to the effect of human tumor cells to the cell toxicant sensitivity of alkylating agent " " cancer research " 51 phase 3367-3372 pages or leaves (1991) such as Doran (Dolan et al., Cancer Res., 51,3367-3372,1991)).Yet, blood vessel in the mesenchyma stroma of tumors, connective tissue, stromatin, fine micro protein and collagen protein etc. not only provide support and requisite nutrient substance for the growth of tumor cell, also influenced chemotherapeutics around tumor and infiltration and diffusion in the tumor tissues, " situation of extracellular matrix is to the influence of medicine running in the entity tumor " " cancer research " 60 phase 2497-503 page or leaf (2000) (Netti PA such as carry referring to the Buddhist nun, Cancer Res.2000,60 (9): 2497-503).Because entity tumor excessive expansion hypertrophy, the viscosity of matter was high than its normal surrounding tissue all between matter pressure, tissue elasticity pressure, fluid pressure reached therebetween, therefore, conventional chemotherapy, be difficult to tumor by local and form effective drug level, referring to " placing cisplatin adding system carmustine treatment rat brain tumor in the tumor " " surgery tumor magazine " 69 phase 76-82 pages or leaves (1998) (Kong Q et al., J Surg Oncol.1998 Oct such as Kong Qingzhongs; 69 (2): 76-82), improve the restriction that dosage is subjected to general reaction again merely.
In addition, the cancer drug therapy of low dosage not only can increase the Drug tolerance of cancerous cell, but also can promote the growth of its wettability "; referring to beam etc. " increased after the cancer therapy drug pulse screening human lung carcinoma cell Drug tolerance and external invade the profit ability and with the change of gene expression " " international journal of cancer " 111 phase 484-93 page or leaf (2004) (Liang Y; et al., Int J Cancer.2004; 111 (4): 484-93).
Because the principal element of decision therapeutic effect is the drug level of tumor by local and the tumor cell sensitivity to medicine.And the blood vessel in the mesenchyma stroma of tumors, connective tissue, stromatin, fine micro protein and collagen protein etc. not only provide support and requisite nutrient substance for the growth of tumor cell, have also influenced chemotherapeutics around tumor and infiltration and diffusion in the tumor tissues.
(3) summary of the invention
The present invention is directed to the deficiencies in the prior art, a kind of entity-tumor-resistant medicine composition is provided.
A kind of entity-tumor-resistant medicine composition comprises anticancer effective component and pharmaceutic adjuvant, and wherein anticancer effective component is tetrazine kind compound and tetrazine kind compound synergist.Wherein, the tetrazine kind compound synergist is one of paclitaxel kind anti-cancer drugs thing, antitumor antibiotics or antimetabolitas or combination.
Above-mentioned tetrazine kind compound is selected from one of following or combination: imidazo tetrazine (imidazotetrazine), imidazopyrazine (imidazopyrazine), 1H-imidazo [b] piperazine (1H-imidazo[b] pyrazine), imidazopyridine (imidazopyridine), 1H-imidazo [1,2-a] pyridine (1H-imidazo[1,2-a] pyridinum), procarbazine (procarbazine, PCB), mitozolomide (mitozolomide, MTZ), dacarbazine (dacarbazine, DCB), temozolomide (Temozolomide or8-Carbamoyl-3-methylimidazo[5,1-d]-1,2,3, and analog or derivant such as 4-carboxyl temozolomide [4--carbonyl] temozolomide 5-tetrazin-4 (3H)-one or NSC 362856)), 3-N-methyl temozolomide [3-N-methyl] temozolomide), the pyrroles [2,1-d] [1,2,3,5] tetrazine-4 (3H)-temozolomide (Pyrrolo[2,1-d] [1,2,3,5] tetrazine-4 (3H)-ones), the pyrroles [2,1-d] [1,2,3,5] tetrazine 10a-o (Pyrrolo[2,1-d] [1,2,3,5] tetrazinones 10a-o), temozolomide's roguing azepine derivatives such as 5-(3-N-methyl three nitrogen-1-yl)-imidazo-4-carboxylic acid amides (MTIC, 5-(3-N-methyltriazen-1-yl)-imidazole-4-carboxamide), 8-nitro-3-methyl-phendioxin, 2,3,5-four azatropylidene 4-temozolomide (8-nitro-3-methyl-benzo-1,2,3,5-tetrazepin-4 (3H)-one, NIME), 3,5-dimethyl-pyrido-1,2,3,5-four azatropylidenes-4-temozolomide (3,5-dimethyl-pyrido-1,2,3,5-tetrazepin-4-one, PYRZ) or 3-(2-ethyl chloride)-N, N dimethyl-4-oxygen-3,4-glyoxalidine [5,1-d]-1,2,3,5-tetrazine-8-carboxylic acid amides (3-(2-chloroethyl)-N, N-dimethyl-4-oxo-3,4-dihydroimidazo[5,1-d]-1,2,3,5-tetrazine-8-carboxamide, CDODTC).
Above-mentioned tetrazine kind compound is preferred with imidazo tetrazine, imidazopyrazine, 1H-imidazo [b] piperazine, imidazopyridine, 1H-imidazo [1,2-a] pyridine, procarbazine, mitozolomide, dacarbazine or temozolomide.
Tetrazine kind compound shared ratio in compositions is decided because of concrete condition, generally speaking, can be good with 1%-50% from 0.01%-80%, is best with 5%-30%.All be weight percentage.
Be selected from one of following or combination as the paclitaxel kind anti-cancer drugs thing (taxanes) of tetrazine kind compound synergist:
Paclitaxel (Paclitaxel, taxol, taxol), Docetaxel (Docetaxel, taxotere, docetaxel) and the derivant of paclitaxel, as, but be not limited to, 2 '-hydroxyl paclitaxel (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), 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 paclitaxel.The content 0.01%-80% of above paclitaxel kind anti-cancer drugs thing in compositions is good with 1%-50%, is best with 5%-30%.
Suppress by combining that RNA is synthetic to be used for the treatment of various cancers as the antitumor antibiotics of tetrazine kind compound synergist with DNA.
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 (mitochromine or mitocromine), polymyxin E (Polymyxin E), pirlimycin (Pirlimycin), dirithromycin (Dirithromycin), antramycin, oxalysine, duazomycin, Olivomycin, rufocromomycin, NSC-45384, streptozotocin, peplomycin, puromycin, sparsomycin, talisomycin, Anthrapyrazole, losoxantrone (Losoxantrone), mitoxantrone (Mitoxantrone), piroxantrone (Piroxantrone), teloxantrone (Teloxantrone), hydroxyl nitre D-glucosamine ring element, anthramycin (anthramycin, antramycin), methylanthramycin, Ai Fei ground can be peaceful, asperlin, (hydrochloric acid) Carrninomycin I, talisomycin, macromycin, O-Demethyldaunomycin, NSC-178248, chromomycin A3, chlorine assistant star (chlorozotocin), demethylrifampicin, ditrisarubicins, Hitachimycin, deoxycoformycin, puromycin, puromycin hydrochloride, rachelmycin, rebeccamycin, Sangivamycin, sarkomycin, sibiromycin, talisomycin, rice holder Zuro, selenazofurin, Antibiotic BMG-162aF2, spirogermanium hydrochloride, Spirogermanium, Spirophydantoin Mustard or stibcytostatum.
Above-mentioned antitumor antibiotics serves as preferred with bleomycin, daunomycin, aclarubicin, amycin, epirubicin, pirarubicin, Valrubicin, ametycin, actinomycin D, losoxantrone, mitoxantrone, piroxantrone, teloxantrone and chlorine assistant star.
The content 0.01%-80% of above antitumor antibiotics in compositions is good with 1%-50%, is best with 5%-30%.
Antimetabolitas as the tetrazine kind compound synergist can stop the synthetic of DNA in different links respectively, suppresses the cell division increment, and cell cycle and DNA are synthetic to play a role by influencing.
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, fluorine urea hexylamine, folic acid, methotrexate (methotrexate, MTX), 10-ethyl denitrification aminopterin (deaza-aminopterin), fluoromethotrexate, the dioxy methotrexate, 5, the 10-lonetrexol, N5-Methyltetrahydrohmofotic Acid, buthiopurin, his amide of Dinke, Guang azepine crow glycosides, carmofur (Carmofur), ftorafur (Tegafur, tegafur, FT-207), Tegafur-uracil mixt., 6-prenylindole, 6-thioinosine, UFT (Tegafur-Uracil, UFT), coralyne, N-foymylsarcolysin, ammonia (base) pterin (aminopterin), aminopterin sodium (Aminopterin Sodium), 8-azaguanine (8-azaguanine), 6-dimethylamino-8-azaadenosine, (nitro) imuran (azathioprine), uracil, 5-mercaptomethyluracil, azaserine (azaserine), Raltitrexed (Raltitrexed), nolatrexed dihydrochloride, sophoridine, formyl tetrahydrofolic acid, 5-methyltetrahydrohomofolate, Zoledronate, thunder accounts for for song, the temozolomide, bicalutamide, asparaginase (L-Asparaginase, left-handed asparagine), calcium levofolinate, calcium folinate (Calcium Levofolinate, calcium leucovorin), Quinespar, triazinate, trimetrexate, tramadol, the 5-chlorobarbituric acid, 5-diazonium uracil, piracetam, hycamtin, topotecan hydrochloride, ZD-9331, BHAC, SM108, cytosine arabinoside (cytosine arabinoside, Cytarabine (Ara-C)), ancitabine (cyclotidine, Cyclocytidine), hydroxyurea (Hydroxycarbamide, hydroxyurea), the hydroxyl guanidine, the 5-fluorouracil nucleoside, the 5-fluorouracil deoxynucleoside claims fluorouracil deoxynucleoside (floxuridine) again, glycerol Citrus chachiensis Hort. alkali, A Lei can loose, HCFU, 5 ' DFUR, TK-177, isoxazole acetic acid, aminoglutethimide (ethylbenzene amine piperidones, aminoglutethimidium, aminoglutethimide), amonafide, 5-chloro-5-deoxyarabinosylcytosine, atamestane, azacytidine (Azacitidine, 5-azacytidine, the atropic cytidine, AzGR), chloramphenalan (betamerphalan, Betamerphalan), decitabing, dexrazoxane (Dexrazoxane), crisnatol, cristatic acid, carat is sharp flat, the sharp guest of carat, galocitabine (Galocitabine), gemcitabine [Gemcitabine], ibacitabine (Ibacitabine), enocitabine (Enocitabine), ancitabine (Ancitabine), decitabine (Decitabine), flurocitabine (Flurocitabine), capecitabine (Capecitabine), enocitabine, his shore of imidazoles, the non-Shandong of Crane, the OK a karaoke club amide, carzolamide, carbazylquinone, CB-1-252, curcumin, the curcumin diketone, ketotrexate, trimetrexate, Si Poguning, deoxidation Si Poguning, naphthalene urea phosphamide, Ditercalinium Chloride, F-ara AMP-2, fluorine benzyl thiophene ketone, gamlogic acid, goserelin, nitrogen Chinese holly mountain range, Hellebrigenin, inosine dialdehyde, metoprine, mitobronitol (Dibromomannitol, Mitobronitol), mitolactol (Mitolactol), Ke is for ground, Persian, eriolangin, dopan (Chlorethylaminouracil, Dopan), Mei Luogerui, Methyl GAG, GR 30921X, mitotane, fazarabine (Fazarabine), fludarabine (fludarabine), cladribine (cladribine), pentoside (pentostatin), phenaline, benzene comes U.S. special, phosphemide, hair Buddhist nun azoles, Polyprenic Acid, Pteroylaspartic Acid, pteroyltriglutamic acid, fast rice tongue pool, riboprine, simtrazene, Schizophyllan, sodium bromebrate, Solvent Yellow 3, bent fourth sulphur ester, TEM, triaziquone, triciribine, TCN-P NSC-280594, triptolide, triptorelin, nine cloth Lip river azoles, UFT, vitamin B-17, Wei Maining, z-azepine adenosine, prick western cytidine, epipropidine (Epipropidine), the A Monuo phase, adozelesin (Adozelesin), acronine (Acronine), alanosine (Alanosine), ametantrone (Ametantrone), Anastrozole, the A Naxi army, anaxirone (Anaxirone), A Si Yin wakes up, acivicin (Acivicin), atevirdine (Atevirdine), idoxifene (idoxifene), AT-236, hold high and rather study carefully Ji, individual Lu Dabuxin, antineoplaston, antineoplastons, asaphan, Aspargus Granule, AT-346, Bai Ruikuaer, Bipenquinate Sodium, Bisantrene Hydrochloride, 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.
The content of above antimetabolitas in compositions can be good with 1%-50% from 0.01%-80%, is best with 5%-30%.
Tetrazine kind compound synergist shared percentage by weight in compositions is decided because of concrete condition, generally speaking, can be good with 1%-50% from 0.01%-80%, is best with 5%-30%.The weight ratio of tetrazine kind compound and tetrazine kind compound synergist is 1-9: 1 to 1: 1-9.
Pharmaceutic adjuvant of the present invention can be through enzyme, soda acid or tissue fluid hydrolysis or degraded, comprises one of following or its combination:
(1) biocompatibility polymer, comprise biodegradable or biological nondegradable polymer and composition thereof or copolymer, (2) water-soluble low-molecular chemical compound is or/and (3) are used to realize the suitable additive and the excipient of pharmaceutical dosage forms such as injection and slow releasing agent.
Above-mentioned biodegradable polymer comprises natural and/or synthetic polymer.Synthetic polymer as, but be not limited to, polyanhydrides, polyhydroxy acid, polyester (polyesters), polyamide (polyamides), polypeptide (polypeptides), polyactide (polylactides) is as polylactic acid (polylactic acid), polyactide and glycolide copolymer (as the copolymer (PLGA) of glycolic and lactic acid), poe (polyorthoesters), polyphosphazene (polyphosphazenes), to carboxy phenyl propane (p-CPP), certain herbaceous plants with big flowers diacid (sebacic acid), liposome, Polyethylene Glycol (polyglycolide) (polymer of hydroxyacetic acid and lactic acid), carboxylic acids (carboxylic acids), fatty acid (fatty acids) phospholipid (phospholipids), nucleic acid (nucleic acids), polyamino acid (polyamino acids), aminoacid such as phenylalanine (phenylalanine), tyrosine (tyrosine), different bright (isoleucine), polynucleotide (polynucleotides); Natural polymer as, but be not limited to, protein and polysaccharide (polysaccharides) comprise hyaluronic acid (hyaluronic acid), chondroitin sulfate (chondroitin sulfate), collagen protein, gelatin, albumin etc.Wherein, preferred polymer is polyactide, Polyethylene Glycol or polyactide and glycolide copolymer (as the copolymer (PLGA) of glycolic and lactic acid).
Above-mentioned polyanhydrides can be selected for use, but is not limited to, fragrant polyanhydride, aliphatic polyanhydride; Wherein fragrant polyanhydride will be separated slower, the fusing point height, and dissolubility is low in the organic solvent, however the copolymer of fragrant polyanhydride and aliphatic polyanhydride is comparatively desirable (United States Patent (USP) 4757128) but.Representative wherein is polifeprosan (to the copolymer of carboxy phenyl propane (p-CPP) and certain herbaceous plants with big flowers diacid (SA)), and is fragrant polyanhydride to carboxy phenyl propane, and the certain herbaceous plants with big flowers diacid then is the copolymer of an aromatic diacid and a fat diacid.The copolymer of available other fragrance or aliphatic polyanhydride has a detailed description in other United States Patent (USP) that (US 4857311; 4888176; 4789724).
Above-mentioned polyhydroxy acid can be selected for use: 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, and 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 its method is arbitrarily, and anticancer pharmaceutical composition also can be packed in the liposome.
Because entity-tumor-resistant medicine composition of the present invention can make the action effect of methods such as conventional chemotherapy, immunization therapy, high thermal therapeutical, photochemical therapy, electrotherapy, Biotherapeutics, hormone therapy, magnetic therapy, ultrasonic therapeutic, radiotherapy and gene therapy strengthen.Therefore when local slow discharges, can share, thereby its anticancer effect is further strengthened with above-mentioned non-operative treatment.
Route of administration
Entity-tumor-resistant medicine composition of the present invention can be through various administrations, as in passages through which vital energy circulates, tremulous pulse, subcutaneous, muscle, Intradermal, intracavity, the tumor, tumor week etc.Route of administration depends on multiple factor, for obtaining valid density in position, tumor place, medicine can give through other number of ways, as arterial perfusion optionally, administration in the intra-bladder instillation (intracavitary), abdominal cavity (intraperitoneal) or thoracic cavity (intrapleural) and canalis spinalis.In number of ways, with topical, as with in selective arterial, the tumor, tumor week injection or be placed as the master, with in the tumor, the form that slowly discharges of tumor week or tumor chamber serve as preferably, can plant slow-releasing pump, slow releasing capsule, slow releasing agent, implant or sustained-release implant as selecting for use.With the tremulous pulse approach is good, directly is placed as the best in the tumor body.
Dosage
The consumption of cancer therapy drug depends on several factors, as, but be not limited to gross tumor volume, patient body weight, administering mode, disease progression situation and therapeutic response.Generally speaking, the topoenzyme inhibitor synergist can be 0.01-200 milligram/kg body weight, with 1-100 milligram/kg body weight is ideal, with 5-80 milligram/kg body weight for the most desirable, topoenzyme inhibitor can be 0.01-100 milligram/kg body weight, with 1-180 milligram/kg body weight is ideal, with 5-50 milligram/kg body weight for the most desirable.
Entity-tumor-resistant medicine composition of the present invention can be used to prepare the medicine of the various entity tumors for the treatment of people, house pet and animal, comprises former or cancer or sarcoma or the carcinosarcoma that shifts originating from brain, central nervous system, kidney, liver, gallbladder, incidence, oral cavity, thyroid, skin, mucosa, body of gland, blood vessel, osseous tissue, lymph node, lungs, esophagus, stomach, mammary gland, pancreas, eyes, nasopharynx part, uterus, ovary, endometrium, cervix uteri, prostate, bladder, colon, rectum.
Also can add other medicinal ingredient in the entity-tumor-resistant medicine composition of the present invention, as, but be not limited to antibiotics, antalgica, anticoagulant medicine, hemorrhage etc.Above medicinal ingredient can singly select or multiselect, can join the compositions that contains or do not contain additive, and its content is because of specifically deciding.
Above-mentioned effective ingredient is packaged in the pharmaceutic adjuvant, then topical application.Said composition can be through various administrations, with topical, as selective arterial injection and directly injection or be placed as goodly in the tumor body, wherein are released to the best with local slow again.When used the part, composition for treating solid tumor of the present invention can directly place around former or the entity tumor that shifts or in the tumor body, also can directly place former or all or part of excision of entity tumor shifted formed intracavity afterwards.
Entity-tumor-resistant medicine composition Main Ingredients and Appearance of the present invention is a holder with the bio-capacitivity material, so do not cause foreign body reaction.Support to place in the object back degradable and absorb, so no longer operation is taken out.Discharge contained drug at tumor by local, optionally improve 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 tetrazine kind compound and/or its synergist are packaged in the pharmaceutic adjuvant, proportionally with active ingredient and pharmaceutic adjuvant dissolving, treat that abundant mixing is dry afterwards.Be shaped immediately after to be dried and sterilize packing.
Above tetrazine kind compound synergist and/or its synergist are local to be placed, not only can overcome the toxic reaction that the whole body administration brings, and has solved the tumor by local drug level and cross the low and cell sensitive question to medicine.
The external tumor-inhibiting action of test one, tetrazine kind compound and synergist thereof.
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.With following tetrazine kind compound synergist and and synergist be 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 50％ 65％ 68％ 64％ 60％ 90％ 92％ 81％ 93％
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％ 90％ 92％ 93％ 90％
Annotate: (A): procarbazine, tetrazine kind compound; (B): paclitaxel, (C): Docetaxel, (D): amycin, (E): 5-fluorouracil.(B)-(E) be the tetrazine kind compound synergist, tetrazine kind compound is all had notable synergistic effect (P＜0.05).
The external tumor-inhibiting action of test two, tetrazine kind compound and synergist thereof.
Used tumor cell is with test one.Following tetrazine kind compound and synergist thereof 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 58％ 54％ 56％ 62％ 60％ 92％ 92％ 80％ 92％
C6 56％ 46％ 50％ 64％ 63％ 94％ 94％ 86％ 90％
SA 52％ 56％ 58％ 60％ 64％ 86％ 85％ 86％ 88％
BC 52％ 48％ 64％ 56％ 54％ 94％ 94％ 84％ 94％
BA 50％ 52％ 60％ 52％ 52％ 98％ 96％ 48％ 96％
LH 61％ 48％ 64％ 68％ 66％ 92％ 90％ 94％ 92％
PAT 50％ 46％ 62％ 64％ 66％ 92％ 92％ 94％ 94％
Annotate: (A): imidazo tetrazine, tetrazine kind compound; (B): mitoxantrone, (C): ametycin, (D): epirubicin, (E): pemetrexed.(B)-(E) be the tetrazine kind compound synergist, tetrazine kind compound is all had notable synergistic effect (P＜0.05).
The external tumor-inhibiting action of test three, tetrazine kind compound and synergist thereof.
Used tumor cell is with test one.Following tetrazine kind compound and/or its synergist are added in 24 hours the various tumor cells of In vitro culture by 10ug/ml concentration, continue to cultivate counting cells sum after 48 hours.Its tumor growth suppresses effect and is shown in Table 3.
Table 3
Oncocyte (A) (B) (C) (D) (E) (A) +(B) (A) +(C) (A) +(D) (A) +(E)
CNS 68％ 64％ 66％ 64％ 60％ 90％ 92％ 80％ 94％
C6 62％ 64％ 60％ 64％ 63％ 96％ 94％ 86％ 92％
SA 58％ 60％ 56％ 60％ 62％ 86％ 85％ 86％ 86％
BC 54％ 64％ 54％ 54％ 54％ 94％ 94％ 84％ 94％
BA 54％ 62％ 62％ 52％ 52％ 98％ 96％ 98％ 98％
LH 60％ 58％ 62％ 68％ 66％ 90％ 90％ 94％ 92％
PAT 54％ 56％ 66％ 66％ 69％ 94％ 92％ 94％ 92％
Annotate: (A): mitozolomide, tetrazine kind compound; (B): bleomycin, (C): Ismipur, (D): Rumi Qu Sai, (E): methotrexate.(B)-(E) be the tetrazine kind compound synergist, tetrazine kind compound is all had notable synergistic effect (P＜0.05).
Above-mentioned experimental result shows that the tetrazine kind compound synergist all has the notable synergistic effect to tetrazine kind compound.Further test shows, other tetrazine kind compound synergist that the present invention is listed, as, carmofur, ftorafur, cytosine arabinoside, gemcitabine, thunder accounts for for song, Raltitrexed, dexrazoxane, amycin, epirubicin, pirarubicin, Valrubicin, ametycin, actinomycin D, losoxantrone, mitoxantrone, paclitaxel, docetaxel and 2 '-hydroxyl paclitaxels etc. are to imidazopyrazine, 1H-imidazo [b] piperazine, imidazopyridine, 1H-imidazo [1,2-a] pyridine, tetrazine kind compound such as dacarbazine and temozolomide all has the notable synergistic effect, though be unexpected discovery the of the present invention, be of universal significance.
Tumor-inhibiting action in the body of test four, tetrazine kind compound and synergist thereof.
With the rat is subjects, with 2x10 5Individual tumor cell subcutaneous injection is in its hypochondrium, treats that tumor growth after 14 days is divided into it 10 groups (seeing Table 4).First group is contrast, and the 2nd to 10 group is the treatment group.The dosage of tetrazine kind compound and synergist thereof is 5mg/kg, and the percentage composition in pharmaceutical composition is 5-20%.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) Procarbazine 42±10cm 3 ＜0.05
3(6) Methotrexate 401±9cm 3 ＜0.01
4(6) Paclitaxel 34±6cm 3 ＜0.01
5(6) Docetaxel 38±6.4cm 3 ＜0.01
6(6) 5-fluorouracil 36±6.8cm 3 ＜0.01
7(6) Procarbazine+methotrexate 22±4.8cm 3 ＜0.001
8(6) Procarbazine+paclitaxel 16±2.8cm 3 ＜0.001
9(6) Procarbazine+Docetaxel 14±3.6cm 3 ＜0.001
10(6) Procarbazine+5-fluorouracil 16±2.8cm 3 ＜0.001
Above tetrazine kind compound synergist all has notable synergistic effect (P＜0.001) to tetrazine kind compound (procarbazine).
Tumor-inhibiting action in the body of test five, tetrazine kind compound and synergist thereof.
Test method and grouping experiment four together, the dosage of tetrazine kind compound and synergist thereof is 5mg/kg, and the percentage composition in pharmaceutical composition is 10-20%.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 67±12cm 3
2(6) The temozolomide 40±11cm 3 ＜0.05
3(6) Pemetrexed 42±8.2cm 3 ＜0.01
4(6) Rumi Qu Sai 34±6.0cm 3 ＜0.01
5(6) Carmofur 41±6.6cm 3 ＜0.01
6(6) Ftorafur 36±7cm 3 ＜0.01
7(6) Temozolomide+pemetrexed 22±5cm 3 ＜0.001
8(6) Temozolomide+Rumi Qu Sai 24±5.8cm 3 ＜0.001
9(6) Temozolomide+carmofur 14±4.0cm 3 ＜0.001
10(6) Temozolomide+ftorafur 12±2.0cm 3 ＜0.001
Above tetrazine kind compound synergist all has notable synergistic effect (P＜0.001) to tetrazine kind compound.
Tumor-inhibiting action in the body of test six, tetrazine kind compound and synergist thereof.
Test method and grouping experiment four together, the dosage of tetrazine kind compound and synergist thereof is 5mg/kg, and the percentage composition in pharmaceutical composition is 15-25%.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±13cm 3
2(6) Mitozolomide 40±8cm 3 ＜0.05
3(6) Cytosine arabinoside 45±6cm 3 ＜0.01
4(6) Gemcitabine 36±4cm 3 ＜0.01
5(6) Thunder accounts for for song 40±6cm 3 ＜0.01
6(6) Raltitrexed 42±6.4cm 3 ＜0.01
7(6) Mitozolomide+cytosine arabinoside 24±4.4cm 3 ＜0.001
8(6) Mitozolomide+gemcitabine 20±3.6cm 3 ＜0.001
9(6) Mitozolomide+thunder accounts for for song 18±4.0cm 3 ＜0.001
10(6) Mitozolomide+Raltitrexed 16±1.6cm 3 ＜0.001
Above tetrazine kind compound synergist all has notable synergistic effect (P＜0.001) to tetrazine kind compound (mitozolomide).
Tumor-inhibiting action in the body of test seven, tetrazine kind compound and synergist thereof.
Test method and grouping experiment four together, the dosage of tumor-inhibiting action is 5mg/kg in the body of tetrazine kind compound and synergist thereof, and the percentage composition in pharmaceutical composition is 5-20%.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 62.5±12cm 3
2(6) Dacarbazine 42±10cm 3 ＜0.05
3(6) Amycin 42±8cm 3 ＜0.01
4(6) Daunomycin 48±9cm 3 ＜0.01
5(6) Aclarubicin 40±6.4cm 3 ＜0.01
6(6) Epirubicin 42±6.8cm 3 ＜0.01
7(6) Dacarbazine+amycin 18±3.8cm 3 ＜0.001
8(6) Dacarbazine+epirubicin 23±4.2cm 3 ＜0.001
9(6) Dacarbazine+aclarubicin 18±4.4cm 3 ＜0.001
10(6) Dacarbazine+daunomycin 22±3.4cm 3 ＜0.001
Above tetrazine kind compound synergist all has notable synergistic effect (P＜0.001) to tetrazine kind compound (dacarbazine).
Tumor-inhibiting action in the body of test eight, tetrazine kind compound and synergist thereof.
Test method with the grouping with the experiment four, tetrazine kind compound and synergist thereof dosage be 5mg/kg, the percentage composition in pharmaceutical composition is 7.5-15%.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 66.5±13cm 3
2(6) Imidazopyridine 44±10cm 3 ＜0.05
3(6) Mitoxantrone 41±8cm 3 ＜0.01
4(6) Ametycin 34±6cm 3 ＜0.01
5(6) Valrubicin 38±6.4cm 3 ＜0.01
6(6) Pirarubicin 36±6.8cm 3 ＜0.01
7(6) Imidazopyridine+mitoxantrone 22±4.6cm 3 ＜0.001
8(6) Imidazopyridine+ametycin 16±3.6cm 3 ＜0.001
9(6) Imidazopyridine+Valrubicin 14±4.6cm 3 ＜0.001
10(6) Imidazopyridine+pirarubicin 18±3.6cm 3 ＜0.001
Above tetrazine kind compound synergist all has notable synergistic effect (P＜0.001) to tetrazine kind compound (imidazopyridine).
To sum up, the tetrazine kind compound synergist among the present invention all has the notable synergistic effect to tetrazine kind compound.The effective ingredient of entity-tumor-resistant medicine composition of the present invention is the associating of any one or multiple tetrazine kind compound synergist and any one or multiple tetrazine kind compound synergist or packing separately.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 procarbazine and 10mg ametycin, shakes up the dry organic solvent of removing of final vacuum again.Dried solid composite is shaped immediately, and ray sterilizing after the packing must contain the entity-tumor-resistant medicine composition of 10% procarbazine and 10% ametycin.All be weight percentage.The drug release time of this entity-tumor-resistant medicine composition in external normal saline is 15-20 days, is 30-40 days at the subcutaneous drug release time of mice.
Embodiment 2. is as described in the embodiment 1, and different is that contained anticancer effective component is:
(A) procarbazine of 1-50%, mitozolomide, dacarbazine, the temozolomide, the imidazo tetrazine, imidazopyrazine, 1H-imidazo [b] piperazine, imidazopyridine, 1H-imidazo [1,2-a] pyridine, 4-carboxyl temozolomide, 3-N-methyl temozolomide, the pyrroles [2,1-d] [1,2,3,5] tetrazine-4 (3H)-temozolomide, the pyrroles [2,1-d] [1,2,3,5] tetrazine 10a-o, 5-(3-N-methyl three nitrogen-1-yl)-imidazo-4-carboxylic acid amides, 8-nitro-3-methyl-phendioxin, 2,3,5-four azatropylidenes-4-temozolomide, 3,5-dimethyl-pyrido-1,2,3,5-four azatropylidenes-4-temozolomide or 3-(2-ethyl chloride)-N, N dimethyl-4-oxygen-3,4-glyoxalidine [5,1-d]-1,2,3,5-tetrazine-8-carboxylic acid amides, 5-(triazenyl) imidazoles-4-carboxylic acid amides, the paclitaxel of 3-aminobenzene amide or 6-aminonicotinamide and 1-50%, docetaxel, 2 '-hydroxyl taxol, 10-removes the acetyl Baccatine III, 14 beta-hydroxies-10-removes the acetyl Baccatine III, 9-sodium catchol disulfonate 3-Baccatine III, 10-removes the acetyl taxol, 7-table-taxol, Tetraol, the combination of Baccatine III or Tetraol V; Or
(B) procarbazine of 1-50%, mitozolomide, dacarbazine, the temozolomide, the imidazo tetrazine, imidazopyrazine, 1H-imidazo [b] piperazine, imidazopyridine, 1H-imidazo [1,2-a] pyridine, 4-carboxyl temozolomide, 3-N-methyl temozolomide, the pyrroles [2,1-d] [1,2,3,5] tetrazine-4 (3H)-temozolomide, the pyrroles [2,1-d] [1,2,3,5] tetrazine 10a-o, 5-(3-N-methyl three nitrogen-1-yl)-imidazo-4-carboxylic acid amides, 8-nitro-3-methyl-phendioxin, 2,3,5-four azatropylidenes-4-temozolomide, 3,5-dimethyl-pyrido-1,2,3,5-four azatropylidenes-4-temozolomide or 3-(2-ethyl chloride)-N, N dimethyl-4-oxygen-3,4-glyoxalidine [5,1-d]-1,2,3,5-tetrazine-8-carboxylic acid amides, 5-(triazenyl) imidazoles-4-carboxylic acid amides, the bleomycin of 3-aminobenzene amide or 6-aminonicotinamide and 1-50%, daunomycin, aclarubicin, amycin, epirubicin, pirarubicin, Valrubicin, ametycin, actinomycin D, losoxantrone, mitoxantrone, piroxantrone, the combination of teloxantrone or chlorine assistant star; Or
(C) procarbazine of 1-50%, mitozolomide, dacarbazine, the temozolomide, the imidazo tetrazine, imidazopyrazine, 1H-imidazo [b] piperazine, imidazopyridine, 1H-imidazo [1,2-a] pyridine, 4-carboxyl temozolomide, 3-N-methyl temozolomide, the pyrroles [2,1-d] [1,2,3,5] tetrazine-4 (3H)-temozolomide, the pyrroles [2,1-d] [1,2,3,5] tetrazine 10a-o, 5-(3-N-methyl three nitrogen-1-yl)-imidazo-4-carboxylic acid amides, 8-nitro-3-methyl-phendioxin, 2,3,5-four azatropylidenes-4-temozolomide, 3,5-dimethyl-pyrido-1,2,3,5-four azatropylidenes-4-temozolomide or 3-(2-ethyl chloride)-N, N dimethyl-4-oxygen-3,4-glyoxalidine [5,1-d]-1,2,3,5-tetrazine-8-carboxylic acid amides, 5-(triazenyl) imidazoles-4-carboxylic acid amides, the Ismipur of 3-aminobenzene amide or 6-aminonicotinamide 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 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 mitozolomide 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% mitozolomide and 10% amycin.All be weight percentage.The drug release time of this entity-tumor-resistant medicine composition in external normal saline is 15-20 days, is 30-40 days at the subcutaneous drug release time of mice.
Embodiment 4. is as described in the embodiment 3, and different is that contained anticancer effective component is:
(a) combination of the paclitaxel of the procarbazine of 5-30%, mitozolomide, dacarbazine, temozolomide, imidazo tetrazine or imidazopyrazine and 5-30%, docetaxel or 2 '-hydroxyl taxol; Or
(b) combination of the bleomycin of the procarbazine of 5-30%, mitozolomide, dacarbazine, temozolomide, imidazo tetrazine or imidazopyrazine and 5-30%, daunomycin, aclarubicin, amycin, epirubicin, pirarubicin, Valrubicin, ametycin, actinomycin D, losoxantrone, mitoxantrone, piroxantrone, teloxantrone or chlorine assistant star; Or
(c) procarbazine of 5-30%, mitozolomide, dacarbazine, the temozolomide, the Ismipur of imidazo tetrazine or imidazopyrazine and 5-30%, 5-fluorouracil, pemetrexed, pemetrexed disodium, Rumi Qu Sai, methotrexate, carmofur, ftorafur, galocitabine, ibacitabine, enocitabine, ancitabine, decitabine, flurocitabine, enocitabine, his shore of imidazoles, GR 30921X, mitotane, cytosine arabinoside, hydroxyurea, the 5-fluorouracil nucleoside, capecitabine, gemcitabine, fludarabine, thunder accounts for for song, Raltitrexed, the atropic cytidine, dexrazoxane, the combination of cladribine and pentoside.Below all be weight percentage.
Embodiment 5.
80mg polifeprosan (to carboxy phenyl propane: certain herbaceous plants with big flowers diacid weight ratio is 20: 80) copolymer is put into container, add 100 milliliters of dichloromethane, behind the dissolving mixing, add 10mg temozolomide 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% temozolomide and 10% epirubicin.All be weight percentage.The drug release time of this entity-tumor-resistant medicine composition in external normal saline is 15-20 days, is 30-40 days at the subcutaneous drug release time of mice.
Embodiment 6. is as described in the embodiment 5, and different is that contained anticancer effective component is:
(a) combination of the paclitaxel of the procarbazine of 5-30%, mitozolomide, dacarbazine, temozolomide, imidazo tetrazine or imidazopyrazine and 5-30%, docetaxel or 2 '-hydroxyl taxol; Or
(b) combination of the bleomycin of the procarbazine of 5-30%, mitozolomide, dacarbazine, temozolomide, imidazo tetrazine or imidazopyrazine and 5-30%, daunomycin, aclarubicin, amycin, epirubicin, pirarubicin, Valrubicin, ametycin, actinomycin D, losoxantrone, mitoxantrone, piroxantrone, teloxantrone or chlorine assistant star; Or
(c) Ismipur of the procarbazine of 5-30%, mitozolomide, dacarbazine, temozolomide, imidazo tetrazine or imidazopyrazine and 5-30%, 5-fluorouracil, pemetrexed, pemetrexed disodium, Rumi Qu Sai, methotrexate, carmofur, ftorafur, cytosine arabinoside, hydroxyurea, gemcitabine, fludarabine, thunder for bently account for, the combination of Raltitrexed, atropic cytidine, dexrazoxane or cladribine.Below all be weight percentage.
Embodiment 7.
(EVAc) puts into container with the 80mg ethylene vinyl acetate copolymer, add 100 milliliters of dichloromethane dissolving mixings after, adds 10 milligrams of dacarbazines and 10mg mitoxantrone, shake up the dry removal of final vacuum organic solvent again.Dried solid composite is shaped immediately, and ray sterilizing after the packing must contain 10% dacarbazine and 10% mitoxantrone entity-tumor-resistant medicine composition.All be weight percentage.The drug release time of this entity-tumor-resistant medicine composition in external normal saline is 15-20 days, is 30-40 days at the subcutaneous drug release time of mice.
Embodiment 8. is identical as embodiment 7, but different is that contained anticancer effective component is:
(a) combination of the paclitaxel of the procarbazine of 5-30%, mitozolomide, dacarbazine, temozolomide, imidazo tetrazine or imidazopyrazine and 5-30%, docetaxel or 2 '-hydroxyl taxol; Or
(b) combination of the bleomycin of the procarbazine of 5-30%, mitozolomide, dacarbazine, temozolomide, imidazo tetrazine or imidazopyrazine and 5-30%, daunomycin, aclarubicin, amycin, epirubicin, pirarubicin, Valrubicin, ametycin, actinomycin D, losoxantrone, mitoxantrone, piroxantrone, teloxantrone or chlorine assistant star; Or
(c) Ismipur of the procarbazine of 5-30%, mitozolomide, dacarbazine, temozolomide, imidazo tetrazine or imidazopyrazine and 5-30%, 5-fluorouracil, pemetrexed, pemetrexed disodium, Rumi Qu Sai, methotrexate, carmofur, ftorafur, cytosine arabinoside, hydroxyurea, gemcitabine, fludarabine, thunder for bently account for, the combination of Raltitrexed, atropic cytidine, dexrazoxane or cladribine.Below all be weight percentage.
Embodiment 9. is as described in embodiment 1,3,5 or 7, used pharmaceutic adjuvant is respectively one of following or its combination that different is:
A) molecular weight is the polylactic acid (PLA) of 5000-15000,10000-20000,20000-35000 or 35000-80000;
B) molecular weight is the polyglycolic acid of 5000-15000,10000-20000,20000-35000 or 35000-80000 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 10. 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% procarbazine, mitozolomide or temozolomide and 10% 5-fluorouracil;
(b) combination of 10% procarbazine, mitozolomide or temozolomide and 10% methotrexate;
(c) combination of 10% procarbazine, mitozolomide or temozolomide and 10% gemcitabine;
(d) combination of 10% procarbazine, mitozolomide or temozolomide and 10% pemetrexed;
(e) combination of 10% procarbazine, mitozolomide or temozolomide and 10% amycin;
(f) combination of 10% procarbazine, mitozolomide or temozolomide and 10% epirubicin;
(g) combination of 10% procarbazine, mitozolomide or temozolomide and 10% pirarubicin;
(h) combination of 10% procarbazine, mitozolomide or temozolomide and 10% ametycin;
(i) combination of 10% procarbazine, mitozolomide or temozolomide and 10% mitoxantrone;
(j) combination of 10% procarbazine, mitozolomide or temozolomide and 10% paclitaxel;
(k) combination of 10% procarbazine, mitozolomide or temozolomide and 10% docetaxel; Or
(l) combination of 10% procarbazine, mitozolomide or temozolomide and 2 '-hydroxyl paclitaxel of 10%.
More than be weight percentage.
Embodiment 11. is composition for treating solid tumor inside and outside release characteristics relatively
Get the composition for treating solid tumor among the embodiment 10, be placed 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 (4)

1. an entity-tumor-resistant medicine composition comprises anticancer effective component and slow-release auxiliary material, it is characterized in that said composition is the implantation slow release agent; Anticancer effective component is tetrazine kind compound and tetrazine kind compound synergist, and wherein, the tetrazine kind compound synergist is one of paclitaxel kind anti-cancer drugs thing, antitumor antibiotics or antimetabolitas or combination;
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 35000-80000;
B) molecular weight is the polyglycolic acid of 5000-15000,10000-20000,20000-35000 or 35000-80000 and the copolymer of hydroxyacetic acid;
C) ethylene vinyl acetate copolymer; Or
D) to the copolymer 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, hyaluronic acid, collagen protein, gelatin or albumin;
Tetrazine class medicine is selected from one of following or combination: procarbazine, mitozolomide, dacarbazine, the temozolomide, the imidazo tetrazine, imidazopyrazine, 1H-imidazo [b] piperazine, imidazopyridine, 1H-imidazo [1,2-a] pyridine, 4-carboxyl temozolomide, 3-N-methyl temozolomide, the pyrroles [2,1-d] [1,2,3,5] tetrazine-4 (3H)-temozolomide, the pyrroles [2,1-d] [1,2,3,5] tetrazine 10a-o, 5-(3-N-methyl three nitrogen-1-yl)-imidazo-4-carboxylic acid amides, 8-nitro-3-methyl-phendioxin, 2,3,5-four azatropylidenes-4-temozolomide, 3,5-dimethyl-pyrido-1,2,3,5-four azatropylidenes-4-temozolomide or 3-(2-ethyl chloride)-N, N dimethyl-4-oxygen-3,4-glyoxalidine [5,1-d]-1,2,3,5-tetrazine-8-carboxylic acid amides, 5-(triazenyl) imidazoles-4-carboxylic acid amides, 3-aminobenzene amide or 6-aminonicotinamide;
The 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;
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;
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.
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 paclitaxel of the procarbazine of 5-30%, mitozolomide, dacarbazine, temozolomide, imidazo tetrazine or imidazopyrazine and 5-30%, docetaxel or 2 '-hydroxyl taxol; Or
(b) combination of the bleomycin of the procarbazine of 5-30%, mitozolomide, dacarbazine, temozolomide, imidazo tetrazine or imidazopyrazine and 5-30%, daunomycin, aclarubicin, amycin, epirubicin, pirarubicin, Valrubicin, ametycin, actinomycin D, losoxantrone, mitoxantrone, piroxantrone, teloxantrone or chlorine assistant star; Or
(c) procarbazine of 5-30%, mitozolomide, dacarbazine, the temozolomide, the Ismipur of imidazo tetrazine or imidazopyrazine and 5-30%, 5-fluorouracil, pemetrexed, pemetrexed disodium, Rumi Qu Sai, 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.
3. 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% procarbazine, mitozolomide or temozolomide and 10% 5-fluorouracil;
(b) combination of 10% procarbazine, mitozolomide or temozolomide and 10% methotrexate;
(c) combination of 10% procarbazine, mitozolomide or temozolomide and 10% gemcitabine;
(d) combination of 10% procarbazine, mitozolomide or temozolomide and 10% pemetrexed;
(e) combination of 10% procarbazine, mitozolomide or temozolomide and 10% amycin;
(f) combination of 10% procarbazine, mitozolomide or temozolomide and 10% epirubicin;
(g) combination of 10% procarbazine, mitozolomide or temozolomide and 10% pirarubicin;
(h) combination of 10% procarbazine, mitozolomide or temozolomide and 10% ametycin;
(i) combination of 10% procarbazine, mitozolomide or temozolomide and 10% mitoxantrone;
(j) combination of 10% procarbazine, mitozolomide or temozolomide and 10% paclitaxel;
(k) combination of 10% procarbazine, mitozolomide or temozolomide and 10% docetaxel; Or
(l) combination of 10% procarbazine, mitozolomide or temozolomide and 2 '-hydroxyl paclitaxel of 10%;
More than be weight percentage.
4. 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.
CNB2005100422625A 2005-04-06 2005-04-06 Anti entity tumour medicinal composition containing tetrazine kind compound Expired - Fee Related CN100431608C (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CNB2005100422625A CN100431608C (en) 2005-04-06 2005-04-06 Anti entity tumour medicinal composition containing tetrazine kind compound

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CNB2005100422625A CN100431608C (en) 2005-04-06 2005-04-06 Anti entity tumour medicinal composition containing tetrazine kind compound

Publications (2)

Publication Number Publication Date
CN1686555A CN1686555A (en) 2005-10-26
CN100431608C true CN100431608C (en) 2008-11-12

Family

ID=35304597

Family Applications (1)

Application Number Title Priority Date Filing Date
CNB2005100422625A Expired - Fee Related CN100431608C (en) 2005-04-06 2005-04-06 Anti entity tumour medicinal composition containing tetrazine kind compound

Country Status (1)

Country Link
CN (1) CN100431608C (en)

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1600307A (en) * 2002-09-29 2005-03-30 天津市金士力药物研究开发有限公司 Control releasing administration system for temozolomide

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1600307A (en) * 2002-09-29 2005-03-30 天津市金士力药物研究开发有限公司 Control releasing administration system for temozolomide

Also Published As

Publication number Publication date
CN1686555A (en) 2005-10-26

Similar Documents

Publication Publication Date Title
CN100500219C (en) Anti tumour medicinal composition containing platinum compound
CN100350974C (en) Anticarcinogen composition
CN100374160C (en) Anti-cancer medicine composition containing antimetabolite
CN100500218C (en) Anti tumour medicinal composition
CN100500212C (en) Anti entity tumour medicinal composition
CN100431606C (en) Anti-cancer medicine composition
CN1923173B (en) Anti-cancer drugs slow release agent comprising anticancer antibiotics and synergist thereof
CN1846672A (en) Anticancer medicine composition containing antimetabolite
CN100500216C (en) Anti entity tumour medicinal composition containing dichloro ethamine kind drug
CN100431608C (en) Anti entity tumour medicinal composition containing tetrazine kind compound
CN100453118C (en) Antientity tumour medicinal composition containing topoenzyme inhibitor
CN100998553A (en) Compound anticarcinogen slow-release preparation containing vasoinhibitor
CN100563711C (en) A kind of slow-releasing anticarcinogen injection
CN101244272B (en) Anti-solid tumors pharmaceutical combination containing topological enzyme inhibitor
CN101637444B (en) Anti-cancer drug slow release injection containing gemcitabine
CN1857723A (en) Slow released anticancer medicine preparation with both amrubicin and its synergist
CN101371821A (en) Anti-cancer medicine composition containing metabolism-resistance medicament
CN100431605C (en) Anticarcinogen composition
CN101327185A (en) Anticancer sustained-release implantation agent
CN101244271A (en) Anti-solid tumors pharmaceutical combination containing topological enzyme inhibitor
CN100340297C (en) Anticarcinogenic internal implant agent
CN101066452A (en) Solid tumor treating medicine composition containing
CN101066451A (en) Solid tumor treating medicine composition containing dicloethamine
CN1923284A (en) Anti-cancer drug slow release injection and uses thereof
CN101357135A (en) Anti-cancer medicine composition containing anti-metabolism medicine

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
C10 Entry into substantive examination
SE01 Entry into force of request for substantive examination
C14 Grant of patent or utility model
GR01 Patent grant
C56 Change in the name or address of the patentee
CP02 Change in the address of a patent holder

Address after: High tech Zone Tianchen road Ji'nan City, Shandong province 250101 No. 1750

Co-patentee after: Kong Qingzhong

Patentee after: Shandong Lanjin Pharmaceuticals Co., Ltd.

Address before: 250100 No. 69, building 7, Pioneer Park, Huayang Road, Ji'nan hi tech Development Zone, Shandong, -802

Co-patentee before: Kong Qingzhong

Patentee before: Shandong Lanjin Pharmaceuticals Co., Ltd.

ASS Succession or assignment of patent right

Free format text: FORMER OWNER: KONG QINGZHONG

Owner name: SHANDONG ENDUO BIOLOGICAL PHARMACEUTICAL CO., LTD.

Free format text: FORMER OWNER: SHANDONG LANJIN BIOENGINEERING CO., LTD.

Effective date: 20110314

C41 Transfer of patent application or patent right or utility model
COR Change of bibliographic data

Free format text: CORRECT: ADDRESS; FROM: 250101 NO. 1750, TIANCHEN ROAD, HIGH-TECH. ZONE, JI'NAN CITY, SHANDONG PROVINCE TO: 250101 ROOM 201, NO. 1750, TIANCHEN ROAD, HIGH-TECH. ZONE, JI'NAN CITY, SHANDONG PROVINCE

TR01 Transfer of patent right

Effective date of registration: 20110314

Address after: High tech Zone Tianchen road Ji'nan City, Shandong province 250101 No. 1750 Room 201

Patentee after: Shandong many biological pharmaceutical Co., Ltd.

Address before: High tech Zone Tianchen road Ji'nan City, Shandong province 250101 No. 1750

Co-patentee before: Kong Qingzhong

Patentee before: Shandong Lanjin Pharmaceuticals Co., Ltd.

C56 Change in the name or address of the patentee

Owner name: DASEN BIOPHARMACEUTICAL CO., LTD.

Free format text: FORMER NAME: SHANDONG ENDUO BIOLOGICAL PHARMACEUTICAL CO., LTD.

CP01 Change in the name or title of a patent holder

Address after: High tech Zone Tianchen road Ji'nan City, Shandong province 250101 No. 1750 Room 201

Patentee after: DASEN BIOLOGICAL PHARMACEUTICAL CO., LTD.

Address before: High tech Zone Tianchen road Ji'nan City, Shandong province 250101 No. 1750 Room 201

Patentee before: Shandong many biological pharmaceutical Co., Ltd.

CF01 Termination of patent right due to non-payment of annual fee

Granted publication date: 20081112

Termination date: 20160406

CF01 Termination of patent right due to non-payment of annual fee