CN1923173B - Anti-cancer drugs slow release agent comprising anticancer antibiotics and synergist thereof - Google Patents

Anti-cancer drugs slow release agent comprising anticancer antibiotics and synergist thereof Download PDF

Info

Publication number
CN1923173B
CN1923173B CN200610200173A CN200610200173A CN1923173B CN 1923173 B CN1923173 B CN 1923173B CN 200610200173 A CN200610200173 A CN 200610200173A CN 200610200173 A CN200610200173 A CN 200610200173A CN 1923173 B CN1923173 B CN 1923173B
Authority
CN
China
Prior art keywords
injection
release
tumor
slow
antitumor antibiotic
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
CN200610200173A
Other languages
Chinese (zh)
Other versions
CN1923173A (en
Inventor
孔庆新
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.)
Shandong Lanjin Pharmaceuticals Co Ltd
Original Assignee
Jinan Kangquan Medicine Science and Technology 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 Jinan Kangquan Medicine Science and Technology Co Ltd filed Critical Jinan Kangquan Medicine Science and Technology Co Ltd
Priority to CN200610200173A priority Critical patent/CN1923173B/en
Publication of CN1923173A publication Critical patent/CN1923173A/en
Application granted granted Critical
Publication of CN1923173B publication Critical patent/CN1923173B/en
Expired - Fee Related legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Landscapes

  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

Disclosed is an anticancer slow release agent which comprises slow release microspheres and dissolvent, wherein the slow release microballoons comprise anti-cancer active constituents and slow release auxiliary materials, the dissolvent being specific dissolvent containing suspension adjuvant. The anticancer antibiotics are selected from Idarubicin, Valtaxin, Pirarubicin and Mitoxantrone, The anti-metabolite drugs are selected from Pemetrexed, Carmustine, Tegafur, Zalcitabine, Emtritabine, Galocitabine, Ibacitabine, Ancitabine, Decitabine, Flurocitabine, Enocitabine, Imidazoletabine, Capecittabine, Gemcitabine, Fludrarbine, Raltitrexed, Dexrazoxane, Cladribine, Nolatrexed and folic acid, The slow release auxiliary materials are selected from EVAc, Polifeprosan, sebacylic acid copolymer, lactic acid, the viscosity of the suspension adjuvant is 100-3000cp (at 25-30 deg C), and is selected from sodium carboxymethylcellulose. The slow release microspheres can also be prepared into slow release implanting agent for injection or placement in or around tumor.

Description

The anticancer medicine slow-release preparation containing of a kind of anticancer antibiotics and synergist thereof
(1) technical field
The present invention relates to the anticancer medicine slow-release preparation containing of a kind of anticancer antibiotics and synergist thereof, belong to technical field of pharmaceuticals.Particularly, the invention provides a kind of compound anti-cancer medicinal slow release agent that contains antitumor antibiotic and/or its synergist, be mainly slow releasing injection and sustained-release implant.
(2) background technology
As a kind of chemotherapeutics commonly used, antitumor antibiotic has been widely used in the treatment of multiple malignant tumor, and action effect is comparatively obvious.Yet its beat all general toxicity has greatly limited the application of this medicine.Blood vessel in the mesenchyma stroma of tumors, connective tissue, stromatin, fibrin and collagen protein etc. not only provide support and requisite nutrient substance for the growth of tumor cell, also influenced chemotherapeutics around tumor and the infiltration in the tumor tissues and diffusion (carry and to wait " situation of extracellular matrix to entity tumor in the medicine influence of turning round " " cancer research " 60 phase 2497-503 page or leaf (2000) (Netti PA 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 is difficult to tumor by local and forms 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.1998Oct such as Kong Qingzhongs; 69 (2): 76-82), improve the restriction that dosage is subjected to general reaction again merely.Pharmaceutical topical application may solve the problem (Chinese patent) of drug level to a certain extent, yet operation techniques such as medicine implantation are complicated, traumatic big, the various complication such as, infection hemorrhage, immunity reduction, also can cause or quicken the diffusion and the transfer of tumor except that easily causing.In addition, the preparation of perioperatively itself and expensive expense usually influence its effective enforcement.
In addition, the DNA repair function in many tumor cells obviously increases after chemotherapy.The latter often causes the enhancing of tumor cell to the toleration of cancer therapy drug, consequently treatment failure.
In addition, the cancer drug therapy of low dosage not only can increase the Drug tolerance of cancerous cell, but also can promote its infiltrative growth " (referring to beam etc. " increased the Drug tolerance of human lung carcinoma cell and external wetting capacity after the cancer therapy drug pulse screening and with the change of gene expression " " international journal of cancer " 111 phase 484-93 page or leaf (2004) (Liang Y; etal., Int J Cancer.2004; 111 (4): 484-93).
Therefore, be convenient to keep high drug level and increase tumor cell the preparation and the method for the sensitivity of medicine just become an important subject at tumor by local.
(3) summary of the invention
The present invention is directed to the deficiencies in the prior art, a kind of slow releasing injection that contains antitumor antibiotic and/or its synergist is provided.
Antitumor antibiotic is mainly used in entity tumors such as the treatment cerebral tumor, ovarian cancer, pulmonary carcinoma abroad as a kind of new cancer therapy drug.Yet tangible general toxicity has greatly limited the application of this medicine in application process.
The present invention finds that medicine that has and antitumor antibiotic share its antitumaous effect is strengthened mutually, and its synergistic mechanism remains further to be studied.Below the antitumor antibiotic antitumaous effect will be increased mutually medicine be referred to as the antitumor antibiotic synergist; In addition, antitumor antibiotic and/or its synergist are made drug level that anticancer medicine slow-release preparation containing (being mainly slow releasing injection and sustained-release implant) not only can greatly improve tumor by local, reduce the drug level of medicine in blood circulation, are reduced the toxicity of medicine to normal structure, can also greatly make things convenient for the medicine injection, reduce operation technique complication, reduce patient's expense.The above unexpected main contents of the present invention of finding to constitute.
Anti-cancer medicine sustained-release injection of the present invention is made up of sustained-release micro-spheres and solvent.Particularly, this slow-releasing anticarcinogen injection is grouped into by following one-tenth:
(A) sustained-release microparticle, the one-tenth following by percentage by weight is grouped into:
Biological effective components 0.5-60%
Slow-release auxiliary material 41-99.9%
Suspending agent 0.0-30%
(B) solvent is divided into common solvent and special solvent.
Wherein, anticancer effective component is the compound anti-cancer medicine of antitumor antibiotic and/or its synergist, and the antitumor antibiotic synergist is selected from antimetabolitas; Slow-release auxiliary material is selected from polifeprosan, bis-fatty acid and decanedioic acid copolymer (PFAD-SA)], one of copolymer (PLGA), xylitol, oligosaccharide, chrondroitin, chitin, hyaluronic acid, collagen protein, gelatin and white tempera of poly-(erucic acid dimer-decanedioic acid) [P (EAD-SA)], poly-(fumaric acid-decanedioic acid) [P (FA-SA)], ethylene vinyl acetate copolymer (EVAc), polylactic acid (PLA), polyglycolic acid and hydroxyacetic acid or its combination; Suspending agent is selected from one of sodium carboxymethyl cellulose, (iodine) glycerol, simethicone, propylene glycol, carbomer, mannitol, sorbitol, surfactant, soil temperature 20, soil temperature 40 and soil temperature 80 or its combination.
Antitumor antibiotics class drug main will be selected from carcinomycin, bleomycin (Bleomycin, Bleomycin A5, Pingyangmycin), (hydrochloric acid) bleomycin, zorbamycin, the piperazine bleomycin, sulphuric acid piperazine bleomycin, antibiotic 1588, bouvardin, kidamycin, acetylkitamycin (acetyl kidamycin), azotomycin (azotomycin), daunorubicin (rubidomycin, daunomycin, daunomycin), doxorubicin hydrochloride (adriamycin), triferricdoxorubicin, epirubicin (epiadriamycin), 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, 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, 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, stibcytostatum, aclarubicin (aklavine, Aclacinomycin A), aklavine-B, darubicin (Idarubicin Hydrochloride, darubicin), Diacetoxysciroenol (Diacetoxysciroenol), clarithromycin (Clarithromycin), 9-[4-(N-Methylacetamido)anilino, 9-(4-(N-Methylacetamido)anilino)-7-methyl-1H-imidazo(4,5-f)quinoline, doxorubicin (doxorubicin), epirubicin (Epirubicin), valrubicin (valrubicin), pirarubicin, Anthrapyrazole, losoxantrone (Losoxantrone), mitoxantrone (Mitoxantrone), piroxantrone (Piroxantrone), teloxantrone (Teloxantrone), chlorine assistant star (chlorozotocin).
More than in the above antitumor antibiotics, with bleomycin, daunomycin, amycin, triferricdoxorubicin, epirubicin, 7-O-methyl Nuo Jia-4 '-epirubicin, diethoxy acetyl amycin, ametycin, actinomycin D, nocardin, nocardorubin., 2-[N-(2-amidinoethyl)carbamoyl, nogalamycin, Mitochromine mitocromine B-35251, polymyxin E, pirlimycin, dirithromycin, antramycin, peplomycin, puromycin, sparsomycin, anthramycin, Carrninomycin I, puromycin, aclarubicin, aklavine-B, darubicin, Diacetoxysciroenol, clarithromycin, 9-[4-(N-Methylacetamido)anilino, 9-(4-(N-Methylacetamido)anilino)-7-methyl-1H-imidazo(4,5-f)quinoline, doxorubicin, epirubicin, valrubicin, pirarubicin, Anthrapyrazole, losoxantrone, mitoxantrone, piroxantrone, teloxantrone, chlorine assistant star is preferred.
Above antitumor antibiotics medicine also comprises its salt, as, but be not limited to sulfate, phosphate, hydrochlorate, Lactobionate, acetate, aspat, nitrate, citrate, purine or pyrimidine salt, succinate or maleate.
Above-mentioned antitumor antibiotic shared ratio in compositions is decided because of concrete condition, can be 0.1%-50%, is good with 1%-40%, and 5%-30% is best.
Antimetabolitas can stop the synthetic of DNA in different links respectively, suppresses cell division propagation, and cell cycle and DNA are synthetic to play a role by influencing.Antimetabolitas is selected from one of following or combination: comprise, pemetrexed (Alimta), pemetrexed disodium, Rumi Qu Sai, doxifluridine (Doxifloridine, fortulon), the 5-doxifluridine, floxuridine (fluridine), propylthiouracil, fluorouracil (Fluoracil, Fluracil), the fluorobutane uracil, 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, 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 the fluorouracil deoxynucleoside 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, zalcitabine, emtricitabine, galocitabine (Galocitabine), gemcitabine (Gemcitabine), ibacitabine (Ibacitabine), enocitabine (Enocitabine), ancitabine (Ancitabine), decitabine (Decitabine), flurocitabine (Flurocitabine), capecitabine (Capecitabine), 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, rice holder quinone, 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, 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, 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, the pyridine of nitre ammonia bifurcation, 2-Amino-6-methyl-5-(pyridin-4-ylsulfanyl)-3H-quinazolin-4-one (nolatrexed dihydrochlormide) or SN-11841.
Above-mentioned antimetabolitas with his shore of pemetrexed, pemetrexed disodium, Rumi Qu Sai, carmofur, ftorafur, temozolomide, zalcitabine, emtricitabine, galocitabine, ibacitabine, ancitabine, decitabine, flurocitabine, enocitabine, imidazoles, capecitabine, gemcitabine, fludarabine, thunder for song account for, Raltitrexed, dexrazoxane, cladribine or 2-Amino-6-methyl-5-(pyridin-4-ylsulfanyl)-3H-quinazolin-4-one serve as preferred.
The percentage by weight of above-mentioned antimetabolitas in compositions is good from 0.01%-99.99% with 1%-50%, is best with 5%-30%.
Anticancer effective component is mainly antitumor antibiotic and/or its synergist.When the cancer therapy drug in the medicament slow-release microsphere only is antitumor antibiotic or antitumor antibiotic synergist, slow-releasing anticarcinogen injection is mainly used in the antitumor antibiotic of other approach application of increase or the action effect of antitumor antibiotic synergist, or is used for the potentiation to radiotherapy or other therapies.When the cancer therapy drug in the medicament slow-release microsphere only was antitumor antibiotic or its synergist, the application of slow-releasing anticarcinogen injection and potentiation mode were:
(1) contain the slow releasing injection local injection of antitumor antibiotic, other approach of antitumor antibiotic synergist are used;
(2) local injection contains the slow releasing injection of antitumor antibiotic synergist, and other approach are used antitumor antibiotic;
(3) local injection contains the slow releasing injection and the slow releasing injection that contains the antitumor antibiotic synergist of antitumor antibiotic; Or
(4) local injection contains the slow releasing injection of antitumor antibiotic and synergist.
The slow-releasing anticarcinogen injection of topical application also is used for the potentiation to radiotherapy or other therapies.Other approach refer to, but, be not limited to tremulous pulse, vein, abdominal cavity, subcutaneous, intracavitary administration.
The percentage by weight of cancer therapy drug in medicament slow-release microsphere is 0.5%-60%, is good with 2%-40%, is best with 5%-30%.The weight ratio of antitumor antibiotic and antitumor antibiotic synergist is 1-9: 1 to 1: 1-9.With 1-2: 1 serves as preferred.
Anticancer effective component and percentage by weight in the slow-releasing anticarcinogen injection microsphere of the present invention are preferably as follows:
(a) bleomycin of 1-40%, daunomycin, amycin, triferricdoxorubicin, epirubicin, 7-O-methyl Nuo Jia-4 '-epirubicin, diethoxy acetyl amycin, ametycin, actinomycin D, nocardin, nocardorubin., 2-[N-(2-amidinoethyl)carbamoyl, nogalamycin, Mitochromine mitocromine B-35251, polymyxin E, pirlimycin, dirithromycin, antramycin, peplomycin, puromycin, sparsomycin, anthramycin, Carrninomycin I, puromycin, aclarubicin, aklavine-B, darubicin, Diacetoxysciroenol, clarithromycin, 9-[4-(N-Methylacetamido)anilino, 9-(4-(N-Methylacetamido)anilino)-7-methyl-1H-imidazo(4,5-f)quinoline, doxorubicin, epirubicin, valrubicin, pirarubicin, Anthrapyrazole, losoxantrone, mitoxantrone, piroxantrone, teloxantrone or chlorine assistant star;
(b) Ismipur of 1-50%, pemetrexed, pemetrexed disodium, Rumi Qu Sai, doxifluridine, floxuridine, mercaptopurine, thioguanine, carmofur, ftorafur, zalcitabine, emtricitabine, galocitabine, ibacitabine, ancitabine, decitabine, flurocitabine, enocitabine, his shore of imidazoles, rice holder quinone, mitotane, cytosine arabinoside, hydroxyurea, the 5-fluorouracil nucleoside, capecitabine, gemcitabine, fludarabine, thunder accounts for for song, Raltitrexed, dexrazoxane, cladribine, 2-Amino-6-methyl-5-(pyridin-4-ylsulfanyl)-3H-quinazolin-4-one or pentoside; Or
(c) 1-40% bleomycin, daunomycin, amycin, triferricdoxorubicin, epirubicin, 7-O-methyl Nuo Jia-4 '-epirubicin, diethoxy acetyl amycin, ametycin, actinomycin D, nocardin, nocardorubin., 2-[N-(2-amidinoethyl)carbamoyl, nogalamycin, Mitochromine mitocromine B-35251, polymyxin E, pirlimycin, dirithromycin, antramycin, peplomycin, puromycin, sparsomycin, anthramycin, Carrninomycin I, puromycin, aclarubicin, aklavine-B, darubicin, Diacetoxysciroenol, clarithromycin, 9-[4-(N-Methylacetamido)anilino, 9-(4-(N-Methylacetamido)anilino)-7-methyl-1H-imidazo(4,5-f)quinoline, doxorubicin, epirubicin, valrubicin, pirarubicin, Anthrapyrazole, losoxantrone, mitoxantrone, piroxantrone, the Ismipur of teloxantrone or chlorine assistant star and 1-50%, 5-fluorouracil, pemetrexed, pemetrexed disodium, Rumi Qu Sai, doxifluridine, floxuridine, mercaptopurine, thioguanine, methotrexate, carmofur, ftorafur, zalcitabine, emtricitabine, galocitabine, ibacitabine, ancitabine, decitabine, flurocitabine, enocitabine, his shore of imidazoles, rice holder quinone, mitotane, cytosine arabinoside, hydroxyurea, the 5-fluorouracil nucleoside, capecitabine, gemcitabine, fludarabine, thunder accounts for for song, Raltitrexed, dexrazoxane, cladribine, the combination of 2-Amino-6-methyl-5-(pyridin-4-ylsulfanyl)-3H-quinazolin-4-one or pentoside.
One of the copolymer (PLGA) of the preferred polylactic acid of slow-release auxiliary material (PLA), polyglycolic acid and hydroxyacetic acid, ethylene vinyl acetate copolymer (EVAc), polifeprosan, bis-fatty acid and decanedioic acid copolymer, poly-(erucic acid dimer-decanedioic acid) copolymer, poly-(fumaric acid-decanedioic acid) copolymer or its combination.
When selecting the copolymer (PLGA) of polylactic acid (PLA), polyglycolic acid (PGA), polylactic acid (PLA) and mixture, glycolic and the hydroxy carboxylic acid of polyglycolic acid for use, PLA and PLGA content percentage by weight are respectively 0.1-99.9% and 99.9-0.1%.The molecular weight peak value of polylactic acid can be, but is not limited to, 5000-100, and 000, but with 20,000-60,000 is preferred, with 30,000-50,000 for most preferably; The molecular weight of polyglycolic acid can be, but is not limited to, 5000-100, and 000, but with 20,000-60,000 is preferred, with 30,000-50,000 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, 5000-100,000, but with 20,000-60,000 be preferably, with 30,000-50,000 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 decanedioic acid or copolymer for most preferably, as, but be not limited to, molecular weight is 1000 to 30000 polylactic acid with molecular weight is that 20000 to 50000 polylactic acid mixes, molecular weight is 10000 to 30000 polylactic acid with molecular weight is that 30000 to 80000 PLGA mixes, molecular weight is that 20000 to 30000 polylactic acid mixes with decanedioic acid, molecular weight is that 30000 to 80000 PLGA mixes with decanedioic acid.
In various high molecular polymers, with polylactic acid, decanedioic acid, 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, 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 polifeprosan [poly-(1,3-two (to the carboxyl phenoxy group) propane-decanedioic acid) (p (CPP-SA)), bis-fatty acid-decanedioic acid copolymer (PFAD-SA)], poly-(erucic acid dimer-decanedioic acid) [P (EAD-SA)] and poly-(fumaric acid-decanedioic acid) [P (FA-SA)] etc.Content during to carboxylic phenoxypropane (p-CPP) and decanedioic acid copolymerization is respectively percentage by weight 10-60% and 20-90%, and the blend weight ratio is 10-40: 50-90, preferably weight ratio 15-30: 65-85.
Except that above-mentioned adjuvant, also can select for use other materials to see the United States Patent (USP) (patent No. 4757128; 4857311; 4888176; 4789724) and in " pharmaceutic adjuvant complete works " (the 123rd page, Sichuan science tech publishing house published in 1993, Luo Mingsheng and Gao Tianhui chief editor) have a detailed description.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 blocker etc.
For regulating drug releasing rate or changing other characteristic 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, (sulphuric acid) chrondroitin and chitin etc., and wherein salt can be, but is not limited to, potassium salt and sodium salt etc.
In the slow releasing injection, drug sustained release system can be made into microsphere, sub-micro ball, microemulsion, nanosphere, granule or spherical piller, makes the injection use then with after the injection solvent mixes.In various slow releasing injection, serve as preferred with the suspension type slow releasing injection, the suspension type slow releasing injection is the preparation that the drug sustained release system that will contain anticancer component is suspended in gained in the injection, used adjuvant is a kind of or its combination in the above-mentioned slow-release auxiliary material, and used solvent is common solvent or the special solvent that contains suspending agent.Common solvent is, but is not limited to the buffer that distilled water, water for injection, physiology are prepared towards liquid, dehydrated alcohol or various salt.The purpose of suspending agent is the pastille microsphere that effectively suspends, thereby is beneficial to the usefulness of injection.
Suspending agent is selected from one of sodium carboxymethyl cellulose, (iodine) glycerol, simethicone, propylene glycol, carbomer, mannitol, sorbitol, surfactant, soil temperature 20, soil temperature 40 and soil temperature 80 or its combination.
The content of suspending agent in common solvent is decided because of its characteristic, can be 0.1-30% and decides because of concrete condition.Consisting of of preferred suspending agent:
A) 0.5-5% sodium carboxymethyl cellulose+0.1-0.5% soil temperature 80; Or
B) 5-20% mannitol+0.1-0.5% soil temperature 80; Or.
C) 0.5-5% sodium carboxymethyl cellulose+5-20% sorbitol+0.1-0.5% soil temperature 80.
The kind of solvent is then depended in the preparation of solvent, and common solvent has commercially available, also can make by oneself, and as distilled water, water for injection, physiology buffer towards liquid, dehydrated alcohol or the preparation of various salt, but must be in strict accordance with related standards.Special solvent need be considered the kind of suspending agent and the medicine that composition, solvent suspended, composition, character and the requirement thereof of sustained-release micro-spheres (or microcapsule) and the preparation method of injection, as sodium carboxymethyl cellulose (1.5%)+mannitol and/or sorbitol (15%) and/or soil temperature 80 (0.1%) are dissolved in the normal saline mutually deserved solvent, viscosity is at 10cp-650cp (20 ℃-30 ℃ time).
The present invention finds to influence medicine and/or sustained-release micro-spheres suspends and/or the key factor of injection is the viscosity of solvent, and viscosity is big more, and suspension effect is good more, and syringeability is strong more.This unexpected one of main index characteristic of the present invention of finding to have constituted.The viscosity of solvent depends on the viscosity of suspending agent, and the viscosity of suspending agent is 100cp-3000cp (20 ℃-30 ℃ time), preferred 1000cp-3000cp (20 ℃-30 ℃ time), most preferably 1500cp-3000cp (20 ℃-30 ℃ time).According to the viscosity of the prepared solvent of this condition is 10cp-650cp (20 ℃-30 ℃ time), preferred 20cp-650cp (20 ℃-30 ℃ time), most preferably 60cp-650cp (20 ℃-30 ℃ time).
The preparation of injection has several different methods, and a kind of is that the sustained-release microparticle (A) of suspending agent for " 0 " directly mixed in special solvent, obtains corresponding sustained-release microparticle injection; Another kind is that suspending agent is not mixed in special solvent or common solvent for the sustained-release microparticle (A) of " 0 ", obtains corresponding sustained-release microparticle injection; Another is that sustained-release microparticle (A) is mixed in common solvent, adds the suspending agent mixing then, obtains corresponding sustained-release microparticle injection.Except, also can earlier sustained-release microparticle (A) be mixed and in special solvent, make corresponding suspension, with the moisture in ways such as the vacuum drying removal suspension, special solvent of reuse or common solvent suspendible obtain corresponding sustained-release microparticle injection afterwards then.Above method just is illustrative rather than definitive thereof the present invention.It should be noted that suspended drug or sustained-release micro-spheres (or microcapsule) concentration in injection decide because of specifically needing, can be, but be not limited to, 10-400mg/ml, but be preferably with 30-300mg/ml, with 50-200mg/ml most preferably.The viscosity of injection is 50cp-1000cp (20 ℃-30 ℃ time), preferred 100cp-1000cp (20 ℃-30 ℃ time), most preferably 200cp-650cp (20 ℃-30 ℃ time).So viscosity is applicable to 18-22 injection needle and special bigger (to 3 millimeters) injection needle of internal diameter.
The preparation method of slow releasing injection is arbitrarily, available some kinds of methods preparation: as, but be not limited to, mixing method, fusion method, dissolution method, spray drying method for preparation microsphere, dissolution method are made micropowder, liposome bag medicine method and emulsion process etc. in conjunction with freezing (drying) comminuting method.Serve as preferred wherein with dissolution method (being the solvent volatility process), seasoning, spray drying method and emulsion process.Microsphere then can be used for preparing above-mentioned various slow releasing injection, and its method is arbitrarily.The particle size range of used microsphere can be between 5-400um, serving as preferred between the 10-300um, with between the 20-200um for most preferably.
Microsphere also can be used for preparing other slow releasing injection, as gel injection, block copolymer micelle injection.Wherein, block copolymer micelle is formed in aqueous solution by hydrophobic-hydrophilic block copolymers, has spherical inner core-shell mechanism, and hydrophobic block forms kernel, and hydrophilic block forms shell.The carrier micelle injection enters the purpose that reaches control drug release or targeted therapy in the body.Used pharmaceutical carrier is above-mentioned any one or its combination.Wherein preferred molecular weight is the hydrophilic block of the Polyethylene Glycol (PEG) of 1000-15000 as the micelle copolymer, and preferred biological degradation polyalcohol (as PLA, polylactide, polycaprolactone and copolymer thereof (molecular weight 1500-25000)) is as the hydrophobic block of micelle copolymer.The particle size range of block copolymer micelle can be between 10-300um, between the 20-200um serving as preferred.Gel injection system is dissolved in some amphipathic solvent with biological degradation polyalcohol (as PLA, PLGA or DL-LA and epsilon-caprolactone copolymer), adds medicine miscible with it (or suspendible) back again and forms flowability gel preferably, can be through tumor week or intratumor injection.In case inject, amphipathic solvent diffuses to body fluid very soon, the moisture in the body fluid then infiltrates gel, makes polymer cure, slowly discharges medicine.
Sustained-release micro-spheres also can be used for preparing sustained-release implant, used pharmaceutic adjuvant 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.
Another form of anticancer medicine slow-release preparation containing of the present invention is that anticancer medicine slow-release preparation containing is a sustained-release implant.The effective ingredient of anticancer implant 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 and/or the mode of degrading through polymer.
The characteristics of sustained-release implant are that used slow-release auxiliary material removes the high molecular polymerization beyond the region of objective existence, also contain above-mentioned any one or multiple other adjuvant.The pharmaceutic adjuvant that adds is referred to as additive.Additive can be divided into filler, porogen, excipient, dispersant, isotonic agent, preservative agent, blocker, solubilizing agent, absorption enhancer, film former, gellant etc. according to its function.
The Main Ingredients and Appearance of sustained-release implant can be made into multiple dosage form.As, but be not limited to capsule, slow releasing agent, implant, slow releasing agent implant etc.; Be multiple shape, as, but be not limited to granule, pill, tablet, powder, granule, sphere, bulk, needle-like, bar-shaped, column and membranaceous.In various dosage forms, serve as preferred slowly to discharge implant in the body.
The main anticancer active ingredient of sustained-release implant and the percentage composition in implant are preferably as follows:
(a) nocardin of 1-40%, nocardorubin., 2-[N-(2-amidinoethyl)carbamoyl, nogalamycin, Mitochromine mitocromine B-35251, polymyxin E, pirlimycin, dirithromycin, antramycin, peplomycin, puromycin, sparsomycin, anthramycin, Carrninomycin I, puromycin, aclarubicin, aklavine-B, darubicin, Diacetoxysciroenol, clarithromycin, 9-[4-(N-Methylacetamido)anilino, 9-(4-(N-Methylacetamido)anilino)-7-methyl-1H-imidazo(4,5-f)quinoline, doxorubicin, epirubicin, valrubicin, pirarubicin, Anthrapyrazole, losoxantrone, mitoxantrone, piroxantrone, teloxantrone or chlorine assistant star;
(b) pemetrexed of 1-50%, pemetrexed disodium, Rumi Qu Sai, doxifluridine, floxuridine, mercaptopurine, thioguanine, carmofur, ftorafur, zalcitabine, emtricitabine, galocitabine, ibacitabine, ancitabine, decitabine, flurocitabine, enocitabine, his shore of imidazoles, rice holder quinone, mitotane, the 5-fluorouracil nucleoside, capecitabine, gemcitabine, fludarabine, thunder accounts for for song, Raltitrexed, dexrazoxane, cladribine or 2-Amino-6-methyl-5-(pyridin-4-ylsulfanyl)-3H-quinazolin-4-one; Or
(c) 1-40% bleomycin, daunomycin, amycin, triferricdoxorubicin, epirubicin, 7-O-methyl Nuo Jia-4 '-epirubicin, diethoxy acetyl amycin, ametycin, actinomycin D, nocardin, nocardorubin., 2-[N-(2-amidinoethyl)carbamoyl, nogalamycin, Mitochromine mitocromine B-35251, polymyxin E, pirlimycin, dirithromycin, antramycin, peplomycin, puromycin, sparsomycin, anthramycin, Carrninomycin I, puromycin, aclarubicin, aklavine-B, darubicin, Diacetoxysciroenol, clarithromycin, 9-[4-(N-Methylacetamido)anilino, 9-(4-(N-Methylacetamido)anilino)-7-methyl-1H-imidazo(4,5-f)quinoline, doxorubicin, epirubicin, valrubicin, pirarubicin, Anthrapyrazole, losoxantrone, mitoxantrone, piroxantrone, the Ismipur of teloxantrone or chlorine assistant star and 1-50%, 5-fluorouracil, pemetrexed, pemetrexed disodium, Rumi Qu Sai, doxifluridine, floxuridine, mercaptopurine, thioguanine, carmofur, ftorafur, zalcitabine, emtricitabine, galocitabine, ibacitabine, ancitabine, decitabine, flurocitabine, enocitabine, his shore of imidazoles, rice holder quinone, mitotane, the 5-fluorouracil nucleoside, capecitabine, gemcitabine, fludarabine, thunder accounts for for song, Raltitrexed, dexrazoxane, the combination of cladribine or 2-Amino-6-methyl-5-(pyridin-4-ylsulfanyl)-3H-quinazolin-4-one.
The most preferred dosage form of sustained-release implant is that the slow releasing agent that biocompatibility, degradable absorb is implanted, and can make different shape and various dosage form 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, drying, promptly so-called dissolution method; (iv) spray drying method; And (v) freeze-drying etc.
Route of administration depends on multiple factor, for obtain valid density in former or position, metastatic tumour place, medicine can give through number of ways, as in subcutaneous, intracavity (in abdominal cavity, thoracic cavity and canalis spinalis), the tumor, in all injections of tumor or placement, selective arterial injection, the lymph node and injection in the bone marrow.With in selective arterial injection, intracavity, the tumor, tumor week injection or be placed as preferred.When the cancer therapy drug in the medicament slow-release microsphere only is antitumor antibiotic or its synergist, the application of anti-cancer sustained-released implantation agent and the same slow releasing injection of potentiation mode.
The present invention can be used to prepare the pharmaceutical preparation of the various tumors for the treatment of people and animal, be mainly slow releasing injection or sustained-release implant, the indication tumor comprises former or cancer or sarcoma or the carcinosarcoma that shifts that originates 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 slow releasing injection that the present invention is made or the sustained-release implant, as, but be not limited to antibiotics, antalgica, anticoagulant medicine, hemorrhage etc.
By following test and embodiment technical method of the present invention is further described:
The local drug concentration of antitumor antibiotic relatively after test 1, the different modes administration
With the rat is subjects, with 2 * 10 5Individual prostate tumor cells subcutaneous injection is in its hypochondrium, treats behind tumor growth to 1 cm diameter its grouping.Every group of dosage is the 5mg/kg valrubicin.Measure antitumor antibiotic content (%) in the different time tumor.The result shows, the local drug concentration significant difference of antitumor antibiotic after different modes is used, topical can obviously improve and effectively keep the active drug concentration at position, tumor place, and is wherein best with the effect of placing sustained-release implant in the tumor, secondly is the intratumor injection slow releasing injection.This discovery constitutes key character of the present invention.Following relevant inhibition test has further confirmed this point.
Tumor-inhibiting action relatively in the body after test 2, the different modes administration
With the rat is subjects, with 2 * 10 5Individual prostate tumor cells subcutaneous injection is in its hypochondrium, treats behind tumor growth to 0.5 cm diameter its grouping.Every group of dosage is 5mg/kg amycin and 2mg/kgO6-BG.The treatment back was measured gross tumor volume size, relatively therapeutic effect on the 10th day.The result shows, the tumor-inhibiting action significant difference of antitumor antibiotic after different modes is used, and topical can obviously improve its tumor-inhibiting action, and is wherein best with the effect of placing sustained-release implant in the tumor, secondly is the intratumor injection slow releasing injection.Good effect not only, toxic and side effects is also little.
Test 3, contain tumor-inhibiting action in the body of antitumor antibiotic and antitumor antibiotic synergist (slow releasing injection)
With the rat is subjects, with 2 * 10 5Individual pancreatic tumor cell subcutaneous injection is in its hypochondrium, treats that tumor growth after 14 days is divided into it following 10 groups (seeing Table 1).First group is contrast, and the 2nd to 10 group is the treatment group, and medicine is through intratumor injection.Dosage is 5mg/kg.The treatment back was measured gross tumor volume size, relatively therapeutic effect (seeing Table 1) on the 10th day.
Table 1
Test group (n) Suffered treatment Gross tumor volume (cm 3) The P value
1(6) Contrast 62±8
2(6) Pemetrexed 48±5.0 ＜0.05
3(6) Amycin 44±2.0 ＜0.01
4(6) Epirubicin 34±2.0 ＜0.01
5(6) Darubicin 36±3.2 ＜0.01
6(6) Valrubicin 30±3.0 ＜0.01
Test group (n) Suffered treatment Gross tumor volume (cm 3) The P value
7(6) Pemetrexed+amycin 22±2.8 ＜0.001
8(6) Pemetrexed+epirubicin 20±3.4 ＜0.001
9(6) Pemetrexed+darubicin 20±3.2 ＜0.001
10(6) Pemetrexed+valrubicin 16±2.0 ＜0.001
Above result shows, growth all has the obvious suppression effect to kinds of tumor cells when this concentration is used separately for used antitumor antibiotics (amycin, epirubicin, darubicin, valrubicin) and antitumor antibiotic synergist-pemetrexed, can show significant potentiation when use in conjunction.
The tumor-inhibiting action of test 4, antitumor antibiotic and antitumor antibiotic synergist (slow releasing injection)
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.Antitumor antibiotic and antitumor antibiotic 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 growth of tumour cell suppresses effect and is shown in Table 2.
Table 2
Oncocyte Carmofur Ametycin Actinomycin D Mitoxantrone Carmofur+ametycin Carmofur+actinomycin D Carmofur+mitoxantrone
CNS 58％ 56％ 64％ 66％ 96％ 88％ 86％
C6 60％ 64％ 60％ 64％ 90％ 86％ 92％
SA 52％ 62％ 56％ 62％ 86％ 94％ 90％
BC 54％ 64％ 54％ 64％ 90％ 86％ 80％
BA 52％ 60％ 62％ 60％ 92％ 92％ 88％
LH 56％ 58％ 62％ 58％ 90％ 90％ 82％
PAT 60％ 58％ 62％ 56％ 94％ 90％ 78％
Above result shows, growth all has the obvious suppression effect to kinds of tumor cells when this concentration is used separately for used antitumor antibiotics (ametycin, actinomycin D, mitoxantrone) and antitumor antibiotic synergist-carmofur, can show significant potentiation when use in conjunction.Same potentiation also sees bleomycin, daunomycin, amycin, triferricdoxorubicin, epirubicin, 7-O-methyl Nuo Jia-4 '-epirubicin, diethoxy acetyl amycin, ametycin, actinomycin D, nocardin, nocardorubin., 2-[N-(2-amidinoethyl)carbamoyl, nogalamycin, Mitochromine mitocromine B-35251, polymyxin E, pirlimycin, dirithromycin, antramycin, peplomycin, puromycin, sparsomycin, anthramycin, Carrninomycin I or puromycin and Ismipur, pemetrexed disodium, Rumi Qu Sai, doxifluridine, floxuridine, mercaptopurine, thioguanine, carmofur, zalcitabine, emtricitabine, galocitabine, ibacitabine, ancitabine, flurocitabine, enocitabine, his shore of imidazoles, rice holder quinone, mitotane, hydroxyurea, the 5-fluorouracil nucleoside, thunder accounts for for song, dexrazoxane, the combination of 2-Amino-6-methyl-5-(pyridin-4-ylsulfanyl)-3H-quinazolin-4-one or pentoside.
The tumor-inhibiting action of test 5, antitumor antibiotic and antitumor antibiotic synergist (slow releasing injection)
With the rat is subjects, with 2 * 10 5Individual tumor cell of liver subcutaneous injection is in its hypochondrium, treats that tumor growth after 14 days is divided into it following 10 groups (seeing Table 3).First group is contrast, and the 2nd to 10 group is the treatment group, and sustained-release implant is placed in tumor.Dosage is 5mg/kg.The treatment back was measured gross tumor volume size, relatively therapeutic effect (seeing Table 3) on the 10th day.
Table 3
Test group (n) Suffered treatment Gross tumor volume (cm 3) The P value
1(6) Contrast 70±10
2(6) 2-Amino-6-methyl-5-(pyridin-4-ylsulfanyl)-3H-quinazolin-4-one 58±5.0 ＜0.05
3(6) Antitumor antibiotic 50±4.0 ＜0.01
4(6) 2-Amino-6-methyl-5-(pyridin-4-ylsulfanyl)-3H-quinazolin-4-one+antitumor antibiotic 34±2.4 ＜0.001
5(6) Pemetrexed 46±3.0 ＜0.01
6(6) Pemetrexed+antitumor antibiotic 32±3.0 ＜0.001
7(6) Enocitabine 50±2.6 ＜0.01
8(6) Enocitabine+antitumor antibiotic 24±2.0 ＜0.001
9(6) Carmofur 56±4.8 ＜0.01
10(6) Carmofur+antitumor antibiotic 20±2.0 ＜0.001
Above result shows, growth all has the obvious suppression effect to kinds of tumor cells when this concentration is used separately for used antitumor antibiotic thing synergist-pirarubicin and antitumor antibiotic thing synergist-antimetabolitas (2-Amino-6-methyl-5-(pyridin-4-ylsulfanyl)-3H-quinazolin-4-one, pemetrexed, enocitabine, carmofur), can show significant potentiation when use in conjunction.
The tumor-inhibiting action of test 6, antitumor antibiotic and antitumor antibiotic synergist (slow releasing injection)
With the rat is subjects, with 2 * 10 5Individual prostate tumor cells subcutaneous injection is in its hypochondrium, treats that tumor growth after 14 days is divided into it negative control (blank), single therapy group (antitumor antibiotic or antitumor antibiotic synergist) and therapeutic alliance group (antitumor antibiotic and antitumor antibiotic synergist).The medicine antitumor antibiotic is through intratumor injection, antitumor antibiotic synergist lumbar injection.Dosage is 5mg/kg.The treatment back was measured the gross tumor volume size on the 10th day, made relatively therapeutic effect (seeing Table 4) of index with inhibition rate of tumor growth.
Table 4
Test group (n) Suffered treatment Tumor control rate (%) The P value
1(6) Contrast -
2(6) Antitumor antibiotic 44 ＜0.05
3(6) Ftorafur 46 ＜0.01
4(6) Decitabine 44 ＜0.01
5(6) Cytosine arabinoside 50 ＜0.01
6(6) Capecitabine 42 ＜0.01
7(6) Antitumor antibiotic+ftorafur 80 ＜0.001
8(6) Antitumor antibiotic+decitabine 86 ＜0.001
9(6) Antitumor antibiotic+cytosine arabinoside 94 ＜0.001
10(6) Antitumor antibiotic+capecitabine 90 ＜0.001
Above result shows, growth all has the obvious suppression effect to kinds of tumor cells when this concentration is used separately for used antitumor antibiotic (valrubicin) and antitumor antibiotic synergist-antimetabolitas (ftorafur, decitabine, cytosine arabinoside, capecitabine), can show significant potentiation when use in conjunction.
The tumor-inhibiting action of test 7, antitumor antibiotic and antitumor antibiotic synergist (slow releasing injection)
With the rat is subjects, with 2 * 10 5Individual breast tumor cell subcutaneous injection is in its hypochondrium, treats that tumor growth after 14 days is divided into it negative control (blank), single therapy group, therapeutic alliance group.Antitumor antibiotic is through the injection of tumor week, the intravenous injection of antitumor antibiotic synergist.Medicine is through intratumor injection.Dosage is 5mg/kg.The treatment back was measured the gross tumor volume size on the 10th day, made relatively therapeutic effect (seeing Table 5) of index with inhibition rate of tumor growth.
Table 5
Test group (n) Suffered treatment Tumor control rate (%) The P value
1(6) Contrast -
2(6) Antitumor antibiotic 58 ＜0.05
3(6) Gemcitabine 50 ＜0.01
4(6) Fludarabine 40 ＜0.01
5(6) Raltitrexed 44 ＜0.01
Test group (n) Suffered treatment Tumor control rate (%) The P value
6(6) Cladribine 48 ＜0.01
7(6) Antitumor antibiotic+gemcitabine 84 ＜0.001
8(6) Antitumor antibiotic+fludarabine 88 ＜0.001
9(6) Antitumor antibiotic+Raltitrexed 90 ＜0.001
10(6) Antitumor antibiotic+cladribine 92 ＜0.001
Above result shows, growth all has the obvious suppression effect to kinds of tumor cells when this concentration is used separately for used antitumor antibiotic (epirubicin) and antitumor antibiotic synergist-antimetabolitas (gemcitabine, fludarabine, Raltitrexed, cladribine), can show significant potentiation when use in conjunction.
The tumor-inhibiting action of test 8, antitumor antibiotic and antitumor antibiotic synergist (sustained-release implant)
With the rat is subjects, with 2 * 10 5Individual breast tumor cell subcutaneous injection is in its hypochondrium, treats that tumor growth after 14 days is divided into it negative control (blank), single therapy group, therapeutic alliance group.Sustained-release implant is placed in tumor.Dosage is 5mg/kg.The treatment back was measured the gross tumor volume size on the 10th day, made relatively therapeutic effect (seeing Table 6) of index with inhibition rate of tumor growth.
Table 6
Test group (n) Suffered treatment Tumor control rate (%) The P value
1(6) Contrast -
2(6) Antitumor antibiotic 58 ＜0.05
3(6) Zalcitabine 52 ＜0.05
4(6) Emtricitabine 54 ＜0.05
5(6) Galocitabine 60 ＜0.05
6(6) Ibacitabine 62 ＜0.01
7(6) Antitumor antibiotic+zalcitabine 88 ＜0.01
8(6) Antitumor antibiotic+emtricitabine 86 ＜0.01
9(6) Antitumor antibiotic+galocitabine 92 ＜0.01
10(6) Antitumor antibiotic+ibacitabine 94 ＜0.001
Above result shows, growth all has the obvious suppression effect to kinds of tumor cells when this concentration is used separately for used antitumor antibiotic (doxorubicin) and antitumor antibiotic synergist (zalcitabine, emtricitabine, galocitabine, ibacitabine), can show significant potentiation when use in conjunction when use in conjunction.Potentiation is in 50-90% (P＜0.01).Same potentiation also sees aclarubicin, aklavine-B, darubicin, Diacetoxysciroenol, clarithromycin, 9-[4-(N-Methylacetamido)anilino, 9-(4-(N-Methylacetamido)anilino)-7-methyl-1H-imidazo(4,5-f)quinoline, doxorubicin, epirubicin, valrubicin, pirarubicin, Anthrapyrazole, losoxantrone, mitoxantrone, piroxantrone, teloxantrone or chlorine assistant star and Ismipur, 5-fluorouracil, pemetrexed, pemetrexed disodium, Rumi Qu Sai, doxifluridine, floxuridine, mercaptopurine, thioguanine, carmofur, ftorafur, zalcitabine, emtricitabine, galocitabine, ibacitabine, ancitabine, decitabine, flurocitabine, enocitabine, his shore of imidazoles, rice holder quinone, mitotane, hydroxyurea, the 5-fluorouracil nucleoside, capecitabine, gemcitabine, fludarabine, thunder accounts for for song, Raltitrexed, dexrazoxane, the associating of cladribine or 2-Amino-6-methyl-5-(pyridin-4-ylsulfanyl)-3H-quinazolin-4-one.
The tumor-inhibiting action of test 9, antitumor antibiotic and antitumor antibiotic synergist (sustained-release implant)
By the tumor-inhibiting action of test 8 described methods mensuration antitumor antibiotics and antitumor antibiotic synergist (sustained-release implant), its inhibition rate of tumor growth sees Table 7.
Table 7
Test group (n) Suffered treatment Tumor control rate (%) The P value
1(6) Contrast -
2(6) Antitumor antibiotic 50 ＜0.05
3(6) Ancitabine 48 ＜0.01
4(6) Flurocitabine 56 ＜0.01
5(6) Enocitabine 48 ＜0.01
6(6) His shore of imidazoles 48 ＜0.01
7(6) Antitumor antibiotic+ancitabine 80 ＜0.001
8(6) Antitumor antibiotic+enocitabine 82 ＜0.001
9(6) Antitumor antibiotic+vinorelbine 90 ＜0.001
10(6) His shore of antitumor antibiotic+imidazoles 92 ＜0.001
Above result shows, growth all has the obvious suppression effect to kinds of tumor cells when this concentration is used separately, can show significant potentiation when use in conjunction for used antitumor antibiotic (Ai Rou is than star) and antitumor antibiotic synergist (ancitabine, flurocitabine, enocitabine, imidazoles he shore).Same potentiation also sees the combination of platinum in heptan, lobaplatin, nedaplatin, oxaliplatin, DNA-2114 or enloplatin and Vinmegallate, vinleurosine, vinleucinol, vinglycinate, vinfosiltine, vinformide, vinflunine, vinepidine, vinzolidine, vintriptol, vinrosidine, monocrotaline or cephalotaxin.
The tumor-inhibiting action of test 10, antitumor antibiotic synergist (slow releasing injection)
Measure the tumor-inhibiting action of antitumor antibiotic synergists (slow releasing injection) by test 7 described methods, the result shows and is selected from bleomycin, daunomycin, clarithromycin, dactinomycin, amrubicin, Ai Rou compares star, detorubicin, esorubicin, carubicin, rodorubicin, leurubicin, medorubicin, Nemorubicin, zorubicin, aclarubicin, pirarubicin, losoxantrone, piroxantrone, the antitumor antibiotic of teloxantrone or chlorine assistant star can significantly strengthen Ismipur, pemetrexed disodium, Rumi Qu Sai, doxifluridine, floxuridine, mercaptopurine, thioguanine, carmofur, zalcitabine, emtricitabine, galocitabine, ibacitabine, ancitabine, flurocitabine, enocitabine, his shore of imidazoles, rice holder quinone, mitotane, hydroxyurea, the 5-fluorouracil nucleoside, thunder accounts for for song, dexrazoxane, the effect of 2-Amino-6-methyl-5-(pyridin-4-ylsulfanyl)-3H-quinazolin-4-one or pentoside.
The tumor-inhibiting action of test 11, antitumor antibiotic and antitumor antibiotic synergist (sustained-release implant)
Measure the tumor-inhibiting action of antitumor antibiotic and antitumor antibiotic synergist (sustained-release implant) by test 8 described methods, the result shows and is selected from bleomycin, daunomycin, clarithromycin, dactinomycin, amrubicin, Ai Rou compares star, detorubicin, esorubicin, carubicin, rodorubicin, leurubicin, medorubicin, Nemorubicin, zorubicin, aclarubicin, pirarubicin, losoxantrone, piroxantrone, the antitumor antibiotic of teloxantrone or chlorine assistant star can significantly strengthen the tumor killing effect of long antitumor antibiotic, and potentiation is in 45-90% (P＜0.05).
The tumor-inhibiting action of test 12, antitumor antibiotic and antitumor antibiotic synergist (slow releasing injection)
Measure the tumor-inhibiting action of antitumor antibiotics and antitumor antibiotic synergist (slow releasing injection) by test 7 described methods, the result shows and is selected from Ismipur, pemetrexed disodium, Rumi Qu Sai, doxifluridine, floxuridine, mercaptopurine, thioguanine, carmofur, zalcitabine, emtricitabine, galocitabine, ibacitabine, ancitabine, flurocitabine, enocitabine, his shore of imidazoles, rice holder quinone, mitotane, hydroxyurea, the 5-fluorouracil nucleoside, thunder accounts for for song, dexrazoxane, 2-Amino-6-methyl-5-(pyridin-4-ylsulfanyl)-3H-quinazolin-4-one or pentoside can significantly strengthen long amrubicin, Ai Rou compares star, detorubicin, esorubicin, carubicin, rodorubicin, leurubicin, medorubicin, Nemorubicin, zorubicin, aclarubicin, pirarubicin, losoxantrone, piroxantrone, the tumor killing effect of teloxantrone or chlorine assistant star.
In a word, growth all had the obvious suppression effect to kinds of tumor cells when above-mentioned antitumor antibiotic and/or various antitumor antibiotic synergist were used separately, can show significant potentiation when use in conjunction.Therefore, effective ingredient of the present invention is above-mentioned any one antitumor antibiotic and/or any one antitumor antibiotic synergist.The medicine that contains above effective ingredient can be made into sustained-release micro-spheres, and then makes slow releasing injection or sustained-release implant, serves as preferred with the suspensoid injectio that is combined to form with the special solvent that contains suspending agent wherein.
Slow releasing injection or sustained-release implant also can be further specified by following embodiment.Just the invention will be further described for the foregoing description and following examples, is not its content and use are imposed any restrictions.
(4) specific embodiment
Embodiment 1.
90,90,80 milligrams of polifeprosans (to carboxy phenyl propane (p-CPP): certain herbaceous plants with big flowers diacid (SA) is 20: 80) copolymer is put into 3 containers respectively, all add 100 milliliters of dichloromethane, add medicine (10mg pemetrexed, 10mg amycin, 10mg pemetrexed and 10mg amycin) after the dissolving mixing, again shake up the back contains 10% pemetrexed, 10% amycin, 10% pemetrexed and 10% amycin with spray drying method for preparation medicine injectable microsphere, then microsphere is suspended in the normal saline that contains 15% mannitol, makes corresponding suspension type slow releasing injection.The drug release time of gained slow releasing injection in external normal saline is 10-15 days, is about 20-30 days at the subcutaneous drug release time of mice.
Embodiment 2.
The method step that is processed into slow releasing injection is identical with embodiment 1, but different is that contained anticancer effective component and percentage by weight thereof are:
(a) bleomycin of 5-30%, daunomycin, amycin, triferricdoxorubicin, epirubicin, 7-O-methyl Nuo Jia-4 '-epirubicin, diethoxy acetyl amycin, ametycin, actinomycin D, nocardin, nocardorubin., 2-[N-(2-amidinoethyl)carbamoyl, nogalamycin, Mitochromine mitocromine B-35251, polymyxin E, pirlimycin, dirithromycin, antramycin, peplomycin, puromycin, sparsomycin, anthramycin, Carrninomycin I, puromycin, aclarubicin, aklavine-B, darubicin, Diacetoxysciroenol, clarithromycin, 9-[4-(N-Methylacetamido)anilino, 9-(4-(N-Methylacetamido)anilino)-7-methyl-1H-imidazo(4,5-f)quinoline, doxorubicin, epirubicin, valrubicin, pirarubicin, Anthrapyrazole, losoxantrone, mitoxantrone, piroxantrone, teloxantrone or chlorine assistant star;
(b) Ismipur of 5-40%, pemetrexed, pemetrexed disodium, Rumi Qu Sai, doxifluridine, floxuridine, mercaptopurine, thioguanine, carmofur, ftorafur, zalcitabine, emtricitabine, galocitabine, ibacitabine, ancitabine, decitabine, flurocitabine, enocitabine, his shore of imidazoles, rice holder quinone, mitotane, cytosine arabinoside, hydroxyurea, the 5-fluorouracil nucleoside, capecitabine, gemcitabine, fludarabine, thunder accounts for for song, Raltitrexed, dexrazoxane, cladribine, 2-Amino-6-methyl-5-(pyridin-4-ylsulfanyl)-3H-quinazolin-4-one or pentoside; Or
(c) 5-30% bleomycin, daunomycin, amycin, triferricdoxorubicin, epirubicin, 7-0-methyl Nuo Jia-4 '-epirubicin, diethoxy acetyl amycin, ametycin, actinomycin D, nocardin, nocardorubin., 2-[N-(2-amidinoethyl)carbamoyl, nogalamycin, Mitochromine mitocromine B-35251, polymyxin E, pirlimycin, dirithromycin, antramycin, peplomycin, puromycin, sparsomycin, anthramycin, Carrninomycin I, puromycin, aclarubicin, aklavine-B, darubicin, Diacetoxysciroenol, clarithromycin, 9-[4-(N-Methylacetamido)anilino, 9-(4-(N-Methylacetamido)anilino)-7-methyl-1H-imidazo(4,5-f)quinoline, doxorubicin, epirubicin, valrubicin, pirarubicin, Anthrapyrazole, losoxantrone, mitoxantrone, piroxantrone, the Ismipur of teloxantrone or chlorine assistant star and 5-40%, 5-fluorouracil, pemetrexed, pemetrexed disodium, Rumi Qu Sai, doxifluridine, floxuridine, mercaptopurine, thioguanine, methotrexate, carmofur, ftorafur, zalcitabine, emtricitabine, galocitabine, ibacitabine, ancitabine, decitabine, flurocitabine, enocitabine, his shore of imidazoles, rice holder quinone, mitotane, cytosine arabinoside, hydroxyurea, the 5-fluorouracil nucleoside, capecitabine, gemcitabine, fludarabine, thunder accounts for for song, Raltitrexed, dexrazoxane, cladribine, the combination of 2-Amino-6-methyl-5-(pyridin-4-ylsulfanyl)-3H-quinazolin-4-one or pentoside.
Embodiment 3.
The method step that is processed into slow releasing injection is identical with embodiment 1, but different is that used slow-release auxiliary material is polylactic acid (PLA), and its molecular weight peak value is 30000-50000; Contained anticancer effective component and percentage by weight thereof are:
(a) Ismipur of 5-40%, pemetrexed, pemetrexed disodium, Rumi Qu Sai, doxifluridine, floxuridine, mercaptopurine, thioguanine, carmofur, ftorafur, zalcitabine, emtricitabine, galocitabine, ibacitabine, ancitabine, decitabine, flurocitabine, enocitabine, his shore of imidazoles, rice holder quinone, mitotane, cytosine arabinoside, hydroxyurea, the 5-fluorouracil nucleoside, capecitabine, gemcitabine, fludarabine, thunder accounts for for song, Raltitrexed, dexrazoxane, cladribine, 2-Amino-6-methyl-5-(pyridin-4-ylsulfanyl)-3H-quinazolin-4-one or pentoside; Or
(b) bleomycin of 5-30%, daunomycin, amycin, triferricdoxorubicin, epirubicin, 7-O-methyl Nuo Jia-4 '-epirubicin, diethoxy acetyl amycin, ametycin, actinomycin D, nocardin, nocardorubin., 2-[N-(2-amidinoethyl)carbamoyl, nogalamycin, Mitochromine mitocromine B-35251, polymyxin E, pirlimycin, dirithromycin, antramycin, peplomycin, puromycin, sparsomycin, anthramycin, Carrninomycin I, puromycin, aclarubicin, aklavine-B, darubicin, Diacetoxysciroenol, clarithromycin, 9-[4-(N-Methylacetamido)anilino, 9-(4-(N-Methylacetamido)anilino)-7-methyl-1H-imidazo(4,5-f)quinoline, doxorubicin, epirubicin, valrubicin, pirarubicin, Anthrapyrazole, losoxantrone, mitoxantrone, piroxantrone, teloxantrone or chlorine assistant star;
(c) bleomycin of 5-30%, daunomycin, amycin, triferricdoxorubicin, epirubicin, 7-O-methyl Nuo Jia-4 '-epirubicin, diethoxy acetyl amycin, ametycin, actinomycin D, nocardin, nocardorubin., 2-[N-(2-amidinoethyl)carbamoyl, nogalamycin, Mitochromine mitocromine B-35251, polymyxin E, pirlimycin, dirithromycin, antramycin, peplomycin, puromycin, sparsomycin, anthramycin, Carrninomycin I, puromycin, aclarubicin, aklavine-B, darubicin, Diacetoxysciroenol, clarithromycin, 9-[4-(N-Methylacetamido)anilino, 9-(4-(N-Methylacetamido)anilino)-7-methyl-1H-imidazo(4,5-f)quinoline, doxorubicin, epirubicin, valrubicin, pirarubicin, Anthrapyrazole, losoxantrone, mitoxantrone, piroxantrone, the Ismipur of teloxantrone or chlorine assistant star and 5-40%, 5-fluorouracil, pemetrexed, pemetrexed disodium, Rumi Qu Sai, doxifluridine, floxuridine, mercaptopurine, thioguanine, methotrexate, carmofur, ftorafur, zalcitabine, emtricitabine, galocitabine, ibacitabine, ancitabine, decitabine, flurocitabine, enocitabine, his shore of imidazoles, rice holder quinone, mitotane, cytosine arabinoside, hydroxyurea, the 5-fluorouracil nucleoside, capecitabine, gemcitabine, fludarabine, thunder accounts for for song, Raltitrexed, dexrazoxane, cladribine, the combination of 2-Amino-6-methyl-5-(pyridin-4-ylsulfanyl)-3H-quinazolin-4-one or pentoside.
Embodiment 4.
The method step that is processed into slow releasing injection is identical with embodiment 1, but different is that used slow-release auxiliary material is the copolymer (PLGA) of polyglycolic acid and hydroxyacetic acid, and wherein, the ratio of polyglycolic acid and hydroxyacetic acid is 50-50; Contained anticancer effective component and percentage by weight thereof are:
(a) his shore of the pemetrexed of 5-40%, pemetrexed disodium, Rumi Qu Sai, thioguanine, carmofur, ftorafur, zalcitabine, emtricitabine, galocitabine, ibacitabine, ancitabine, decitabine, flurocitabine, enocitabine, imidazoles, capecitabine, gemcitabine, fludarabine, thunder for song account for, Raltitrexed, dexrazoxane, cladribine or 2-Amino-6-methyl-5-(pyridin-4-ylsulfanyl)-3H-quinazolin-4-one; Or
(b) aclarubicin of 5-30%, darubicin, 9-(4-(N-Methylacetamido)anilino)-7-methyl-1H-imidazo(4,5-f)quinoline, doxorubicin, epirubicin, valrubicin, pirarubicin, Anthrapyrazole, losoxantrone, mitoxantrone, piroxantrone, teloxantrone or chlorine assistant star;
(c) bleomycin of 5-30%, daunomycin, amycin, triferricdoxorubicin, epirubicin, 7-O-methyl Nuo Jia-4 '-epirubicin, diethoxy acetyl amycin, ametycin, actinomycin D, nocardin, nocardorubin., 2-[N-(2-amidinoethyl)carbamoyl, nogalamycin, Mitochromine mitocromine B-35251, polymyxin E, pirlimycin, dirithromycin, antramycin, peplomycin, puromycin, sparsomycin, anthramycin, Carrninomycin I, puromycin, aclarubicin, aklavine-B, darubicin, Diacetoxysciroenol, clarithromycin, 9-[4-(N-Methylacetamido)anilino, 9-(4-(N-Methylacetamido)anilino)-7-methyl-1H-imidazo(4,5-f)quinoline, doxorubicin, epirubicin, valrubicin, pirarubicin, Anthrapyrazole, losoxantrone, mitoxantrone, piroxantrone, the Ismipur of teloxantrone or chlorine assistant star and 5-40%, 5-fluorouracil, pemetrexed, pemetrexed disodium, Rumi Qu Sai, doxifluridine, floxuridine, mercaptopurine, thioguanine, methotrexate, carmofur, ftorafur, zalcitabine, emtricitabine, galocitabine, ibacitabine, ancitabine, decitabine, flurocitabine, enocitabine, his shore of imidazoles, rice holder quinone, mitotane, cytosine arabinoside, hydroxyurea, the 5-fluorouracil nucleoside, capecitabine, gemcitabine, fludarabine, thunder accounts for for song, Raltitrexed, dexrazoxane, cladribine, the combination of 2-Amino-6-methyl-5-(pyridin-4-ylsulfanyl)-3H-quinazolin-4-one or pentoside.
Embodiment 5.
(EVAc) puts into container with the 70mg ethylene vinyl acetate copolymer, after adding 100 milliliters of dichloromethane dissolving mixings, add 20 milligrams of gemcitabines and 10 milligrams of valrubicins, shake up the back contains 20% gemcitabine and 10% valrubicin with spray drying method for preparation injectable microsphere again.Then microsphere is suspended in the injection that contains the 5-15% sorbitol, makes corresponding suspension type slow releasing injection.The drug release time of this slow releasing injection in external normal saline is 10-15 days, is about 20-30 days at the subcutaneous drug release time of mice.
Embodiment 6.
The method step that is processed into slow releasing injection is identical with embodiment 5, but different is that contained anticancer effective component is:
(a) his shore of the pemetrexed of 5-40%, pemetrexed disodium, Rumi Qu Sai, thioguanine, carmofur, ftorafur, zalcitabine, emtricitabine, galocitabine, ibacitabine, ancitabine, decitabine, flurocitabine, enocitabine, imidazoles, capecitabine, gemcitabine, fludarabine, thunder for song account for, Raltitrexed, dexrazoxane, cladribine or 2-Amino-6-methyl-5-(pyridin-4-ylsulfanyl)-3H-quinazolin-4-one;
(b) aclarubicin of 5-30%, darubicin, 9-(4-(N-Methylacetamido)anilino)-7-methyl-1H-imidazo(4,5-f)quinoline, doxorubicin, epirubicin, valrubicin, pirarubicin, Anthrapyrazole, losoxantrone, mitoxantrone, piroxantrone, teloxantrone or chlorine assistant star; Or
(c) bleomycin of 5-30%, daunomycin, amycin, ametycin, actinomycin D, aclarubicin, darubicin, 9-(4-(N-Methylacetamido)anilino)-7-methyl-1H-imidazo(4,5-f)quinoline, doxorubicin, epirubicin, valrubicin, pirarubicin, Anthrapyrazole, losoxantrone, mitoxantrone, piroxantrone, the Ismipur of teloxantrone or chlorine assistant star and 5-40%, pemetrexed, pemetrexed disodium, Rumi Qu Sai, thioguanine, carmofur, ftorafur, zalcitabine, emtricitabine, galocitabine, ibacitabine, ancitabine, decitabine, flurocitabine, enocitabine, his shore of imidazoles, capecitabine, gemcitabine, fludarabine, thunder accounts for for song, Raltitrexed, dexrazoxane, the combination of cladribine or 2-Amino-6-methyl-5-(pyridin-4-ylsulfanyl)-3H-quinazolin-4-one.
Embodiment 7.
70mg polifeprosan (to carboxy phenyl propane (p-CPP): certain herbaceous plants with big flowers diacid (SA) is 20: 80) copolymer is put into container, add 100 milliliters of dichloromethane, behind the dissolving mixing, add 20mg 2-Amino-6-methyl-5-(pyridin-4-ylsulfanyl)-3H-quinazolin-4-one and 10mg pirarubicin, shake up the back contains 20% 2-Amino-6-methyl-5-(pyridin-4-ylsulfanyl)-3H-quinazolin-4-one and 10% pirarubicin with spray drying method for preparation injectable microsphere again.Microsphere is suspended in the normal saline that contains 1.5% sodium carboxymethyl cellulose and 0.5% Tween 80 then, makes corresponding suspension type slow releasing injection.The drug release time of this slow releasing injection in external normal saline is 10-15 days, is about 20-30 days at the subcutaneous drug release time of mice.
Embodiment 8.
The method step that is processed into slow releasing injection is identical with embodiment 7, but different is that contained anticancer effective component is:
(a) his shore of the pemetrexed of 10-40%, pemetrexed disodium, Rumi Qu Sai, thioguanine, carmofur, ftorafur, zalcitabine, emtricitabine, galocitabine, ibacitabine, ancitabine, decitabine, flurocitabine, enocitabine, imidazoles, capecitabine, gemcitabine, fludarabine, thunder for song account for, Raltitrexed, dexrazoxane, cladribine or 2-Amino-6-methyl-5-(pyridin-4-ylsulfanyl)-3H-quinazolin-4-one;
(b) aclarubicin of 5-30%, darubicin, 9-(4-(N-Methylacetamido)anilino)-7-methyl-1H-imidazo(4,5-f)quinoline, doxorubicin, epirubicin, valrubicin, pirarubicin, Anthrapyrazole, losoxantrone, mitoxantrone, piroxantrone, teloxantrone or chlorine assistant star; Or
(c) aclarubicin of 5-30%, darubicin, 9-(4-(N-Methylacetamido)anilino)-7-methyl-1H-imidazo(4,5-f)quinoline, doxorubicin, epirubicin, valrubicin, pirarubicin, Anthrapyrazole, losoxantrone, mitoxantrone, piroxantrone, the pemetrexed of teloxantrone or chlorine assistant star and 5-40%, pemetrexed disodium, Rumi Qu Sai, thioguanine, carmofur, ftorafur, zalcitabine, emtricitabine, galocitabine, ibacitabine, ancitabine, decitabine, flurocitabine, enocitabine, his shore of imidazoles, capecitabine, gemcitabine, fludarabine, thunder accounts for for song, Raltitrexed, dexrazoxane, the combination of cladribine or 2-Amino-6-methyl-5-(pyridin-4-ylsulfanyl)-3H-quinazolin-4-one.
Embodiment 9
70mg polifeprosan (to carboxy phenyl propane (p-CPP): certain herbaceous plants with big flowers diacid (SA) is 20: 80) copolymer is put into container, add 100 milliliters of dichloromethane, behind the dissolving mixing, add 20mg gemcitabine and 10mg ametycin, shake up the back contains 20% gemcitabine and 10% ametycin with spray drying method for preparation injectable microsphere again.Then microsphere is suspended in the normal saline that contains 1.5% sodium carboxymethyl cellulose and 15% sorbitol and 0.2% Tween 80, makes corresponding suspension type slow releasing injection.The drug release time of this slow releasing injection in external normal saline is 10-15 days, is about 20-30 days at the subcutaneous drug release time of mice.
Embodiment 10
The method step that is processed into slow releasing injection is identical with embodiment 9, but different is that contained anticancer effective component is:
The 5-30% bleomycin, daunomycin, clarithromycin, dactinomycin, amrubicin, Ai Rou compares star, detorubicin, esorubicin, carubicin, rodorubicin, leurubicin, medorubicin, Nemorubicin, zorubicin, aclarubicin, doxorubicin, epirubicin, darubicin, pirarubicin, valrubicin, ametycin, actinomycin D, losoxantrone, mitoxantrone, piroxantrone, the Ismipur of teloxantrone or chlorine assistant star and 5-30%, pemetrexed, pemetrexed disodium, Rumi Qu Sai, doxifluridine, floxuridine, mercaptopurine, thioguanine, carmofur, ftorafur, zalcitabine, emtricitabine, galocitabine, ibacitabine, ancitabine, decitabine, flurocitabine, enocitabine, his shore of imidazoles, rice holder quinone, mitotane, cytosine arabinoside, hydroxyurea, the 5-fluorouracil nucleoside, capecitabine, gemcitabine, fludarabine, thunder accounts for for song, Raltitrexed, dexrazoxane, cladribine, the combination of 2-Amino-6-methyl-5-(pyridin-4-ylsulfanyl)-3H-quinazolin-4-one or pentoside.
Embodiment 11
70mg polifeprosan (to carboxy phenyl propane (p-CPP): certain herbaceous plants with big flowers diacid (SA) is 20: 80) copolymer is put into container, add 100 milliliters of dichloromethane, behind the dissolving mixing, add 10mg doxorubicin and 20mg capecitabine, shake up the back contains 10% doxorubicin and 20% capecitabine with spray drying method for preparation injectable microsphere again.Then microsphere is made corresponding sustained-release implant through pressed disc method.The drug release time of this sustained-release implant in external normal saline is 10-15 days, is about 30-40 days at the subcutaneous drug release time of mice.
Embodiment 12
The method step that is processed into sustained-release implant is identical with embodiment 11, but different is that contained anticancer effective component is:
The 5-30% bleomycin, daunomycin, clarithromycin, dactinomycin, amrubicin, Ai Rou compares star, detorubicin, esorubicin, carubicin, rodorubicin, leurubicin, medorubicin, Nemorubicin, zorubicin, aclarubicin, doxorubicin, epirubicin, darubicin, pirarubicin, valrubicin, ametycin, actinomycin D, losoxantrone, mitoxantrone, piroxantrone, the Ismipur of teloxantrone or chlorine assistant star and 5-30%, pemetrexed, pemetrexed disodium, Rumi Qu Sai, doxifluridine, floxuridine, mercaptopurine, thioguanine, carmofur, ftorafur, zalcitabine, emtricitabine, galocitabine, ibacitabine, ancitabine, decitabine, flurocitabine, enocitabine, his shore of imidazoles, rice holder quinone, mitotane, cytosine arabinoside, hydroxyurea, the 5-fluorouracil nucleoside, capecitabine, gemcitabine, fludarabine, thunder accounts for for song, Raltitrexed, dexrazoxane, cladribine, the combination of 2-Amino-6-methyl-5-(pyridin-4-ylsulfanyl)-3H-quinazolin-4-one or pentoside.
Embodiment 13
With 70mg molecular weight peak value 85000 polylactic acid (PLGA, 50: 50) put into container, add 100 milliliters of dichloromethane, behind the dissolving mixing, add 10mg darubicin and 20mg cladribine, shake up the back contains 10% darubicin and 20% cladribine with spray drying method for preparation injectable microsphere again.Then microsphere is made corresponding sustained-release implant through pressed disc method.The drug release time of this sustained-release implant in external normal saline is 10-15 days, is about 35-50 days at the subcutaneous drug release time of mice.
Embodiment 14
Be processed into the method step and the embodiment 11 of sustained-release implant, 13 is identical, but different is that contained anticancer effective component is: the bleomycin of 5-30%, daunomycin, clarithromycin, dactinomycin, amrubicin, Ai Rou compares star, detorubicin, esorubicin, carubicin, rodorubicin, leurubicin, medorubicin, Nemorubicin, zorubicin, aclarubicin, doxorubicin, epirubicin, darubicin, pirarubicin, valrubicin, ametycin, actinomycin D, losoxantrone, mitoxantrone, piroxantrone, the pemetrexed of teloxantrone or chlorine assistant star and 5-30%, pemetrexed disodium, Rumi Qu Sai, carmofur, ftorafur, zalcitabine, emtricitabine, galocitabine, ibacitabine, ancitabine, decitabine, flurocitabine, enocitabine, his shore of imidazoles, capecitabine, gemcitabine, fludarabine, thunder accounts for for song, Raltitrexed, dexrazoxane, the combination of cladribine or 2-Amino-6-methyl-5-(pyridin-4-ylsulfanyl)-3H-quinazolin-4-one.
Embodiment 15.
70mg bis-fatty acid and decanedioic acid copolymer are put into container, add 100 milliliters of dichloromethane, behind the dissolving mixing, add 15mg pemetrexed and 15mg zorubicin, shake up the dry organic solvent of removing of final vacuum again.Dried pastille solid composite freezing and pulverizing is made the micropowder that contains 10% pemetrexed and 10% zorubicin, be suspended in then in the normal saline that contains 1.5% sodium carboxymethyl cellulose, make corresponding suspension type slow releasing injection.The drug release time of this slow releasing injection in external normal saline is 10-15 days, is about 20-30 days at the subcutaneous drug release time of mice.
Embodiment 16
The method step that is processed into slow releasing injection is identical with embodiment 15, but different is that contained anticancer effective component and percentage by weight thereof are:
The pemetrexed of 5-30%, pemetrexed disodium, Rumi Qu Sai, carmofur, ftorafur, zalcitabine, emtricitabine, galocitabine, ibacitabine, ancitabine, decitabine, flurocitabine, enocitabine, his shore of imidazoles, rice holder quinone, mitotane, capecitabine, gemcitabine, fludarabine, thunder accounts for for song, Raltitrexed, dexrazoxane, cladribine, the bleomycin of 2-Amino-6-methyl-5-(pyridin-4-ylsulfanyl)-3H-quinazolin-4-one or pentoside and 5-30%, daunomycin, clarithromycin, dactinomycin, amrubicin, Ai Rou compares star, detorubicin, esorubicin, carubicin, rodorubicin, leurubicin, medorubicin, Nemorubicin, zorubicin, aclarubicin, doxorubicin, epirubicin, darubicin, pirarubicin, valrubicin, ametycin, actinomycin D, losoxantrone, mitoxantrone, the combination of piroxantrone or teloxantrone.
Embodiment 17.
With 70mg molecular weight peak value is that 30000 poly-(erucic acid dimer-decanedioic acid) copolymer (20: 80) is put into container, add 100 milliliters of dichloromethane, behind the dissolving mixing, add 15mg cisplatin and 15mg vinorelbine, shake up the dry organic solvent of removing of final vacuum again.Dried pastille solid composite freezing and pulverizing is made the micropowder that contains 10% cisplatin and 10% vinorelbine, be suspended in then in the normal saline that contains 1.5% sodium carboxymethyl cellulose, make corresponding suspension type slow releasing injection.The drug release time of this slow releasing injection in external normal saline is 10-15 days, is about 20-30 days at the subcutaneous drug release time of mice.
Embodiment 18.
The method step that is processed into slow releasing injection is identical with embodiment 17, and used slow-release auxiliary material is poly-(fumaric acid-decanedioic acid) copolymer (30: 70) but different is, contained anticancer effective component and percentage by weight thereof are:
The aclarubicin of 5-30%, amycin, epirubicin, darubicin, pirarubicin, valrubicin, ametycin, actinomycin D, losoxantrone, mitoxantrone, the pemetrexed of piroxantrone or teloxantrone and 5-30%, pemetrexed disodium, Rumi Qu Sai, doxifluridine, floxuridine, mercaptopurine, thioguanine, carmofur, ftorafur, zalcitabine, emtricitabine, galocitabine, ibacitabine, ancitabine, decitabine, flurocitabine, enocitabine, his shore of imidazoles, rice holder quinone, mitotane, cytosine arabinoside, hydroxyurea, capecitabine, gemcitabine, fludarabine, thunder accounts for for song, Raltitrexed, dexrazoxane, cladribine, the combination of 2-Amino-6-methyl-5-(pyridin-4-ylsulfanyl)-3H-quinazolin-4-one or pentoside.
Embodiment 19
The method step that is processed into slow releasing agent is identical with embodiment 1-18, but different is used slow-release auxiliary material is one of following or its combination:
A) the molecular weight peak value is the polylactic acid (PLA) of 5000-30000,30000-50000,50000-100000 or 100000-150000;
B) the molecular weight peak value is the polyglycolic acid of 5000-30000,30000-50000,50000-100000 or 100000-150000 and the copolymer of hydroxyacetic acid (PLGA), and wherein, the ratio of polyglycolic acid and hydroxyacetic acid is 50-95: 50-50;
C) ethylene vinyl acetate copolymer (EVAc);
D) polifeprosan, to carboxy phenyl propane (p-CPP): certain herbaceous plants with big flowers diacid (SA) is 10: 0,20: 0,30: 70,40: 0,50: 50 or 60: 40;
E) bis-fatty acid and decanedioic acid copolymer;
F) poly-(erucic acid dimer-decanedioic acid) copolymer;
G) poly-(fumaric acid-decanedioic acid) copolymer;
H) xylitol, oligosaccharide, chrondroitin, chitin, potassium salt, sodium salt, hyaluronic acid, collagen protein, gelatin or white tempera.
Embodiment 20
The method step that is processed into slow releasing injection is identical with embodiment 1-19, but different is used suspending agent is respectively one of following or its combination:
A) 0.5-3.0% carboxymethyl cellulose (sodium);
B) 5-15% mannitol;
C) 5-15% sorbitol;
D) 0.1-1.5% surfactant;
E) 0.1-0.5% polysorbas20.
Embodiment 21
The method step that is processed into sustained-release implant is identical with embodiment 11-13, but different is that contained anticancer effective component is:
(a) nocardin of 1-40%, nocardorubin., 2-[N-(2-amidinoethyl)carbamoyl, nogalamycin, Mitochromine mitocromine B-35251, polymyxin E, pirlimycin, dirithromycin, antramycin, peplomycin, puromycin, sparsomycin, anthramycin, Carrninomycin I, puromycin, aclarubicin, aklavine-B, darubicin, Diacetoxysciroenol, clarithromycin, 9-[4-(N-Methylacetamido)anilino, 9-(4-(N-Methylacetamido)anilino)-7-methyl-1H-imidazo(4,5-f)quinoline, doxorubicin, epirubicin, valrubicin, pirarubicin, Anthrapyrazole, losoxantrone, mitoxantrone, piroxantrone, teloxantrone or chlorine assistant star;
(b) pemetrexed of 1-50%, pemetrexed disodium, Rumi Qu Sai, doxifluridine, floxuridine, mercaptopurine, thioguanine, carmofur, ftorafur, zalcitabine, emtricitabine, galocitabine, ibacitabine, ancitabine, decitabine, flurocitabine, enocitabine, his shore of imidazoles, rice holder quinone, mitotane, the 5-fluorouracil nucleoside, capecitabine, gemcitabine, fludarabine, thunder accounts for for song, Raltitrexed, dexrazoxane, cladribine or 2-Amino-6-methyl-5-(pyridin-4-ylsulfanyl)-3H-quinazolin-4-one; Or
(c) 1-40% bleomycin, daunomycin, amycin, triferricdoxorubicin, epirubicin, 7-0-methyl Nuo Jia-4 '-epirubicin, diethoxy acetyl amycin, ametycin, actinomycin D, nocardin, nocardorubin., 2-[N-(2-amidinoethyl)carbamoyl, nogalamycin, Mitochromine mitocromine B-35251, polymyxin E, pirlimycin, dirithromycin, antramycin, peplomycin, puromycin, sparsomycin, anthramycin, Carrninomycin I, puromycin, aclarubicin, aklavine-B, darubicin, Diacetoxysciroenol, clarithromycin, 9-[4-(N-Methylacetamido)anilino, 9-(4-(N-Methylacetamido)anilino)-7-methyl-1H-imidazo(4,5-f)quinoline, doxorubicin, epirubicin, valrubicin, pirarubicin, Anthrapyrazole, losoxantrone, mitoxantrone, piroxantrone, the Ismipur of teloxantrone or chlorine assistant star and 1-50%, 5-fluorouracil, pemetrexed, pemetrexed disodium, Rumi Qu Sai, doxifluridine, floxuridine, mercaptopurine, thioguanine, carmofur, ftorafur, zalcitabine, emtricitabine, galocitabine, ibacitabine, ancitabine, decitabine, flurocitabine, enocitabine, his shore of imidazoles, rice holder quinone, mitotane, the 5-fluorouracil nucleoside, capecitabine, gemcitabine, fludarabine, thunder accounts for for song, Raltitrexed, dexrazoxane, the combination of cladribine or 2-Amino-6-methyl-5-(pyridin-4-ylsulfanyl)-3H-quinazolin-4-one.
Above embodiment only is used for explanation, and is not limitation application of the present invention.
The present invention disclosed and the protection the content see claim.

Claims (2)

1. anticancer medicine slow-release preparation containing that contains antitumor antibiotic and synergist thereof is characterized in that this anticancer medicine slow-release preparation containing is a slow releasing injection, is grouped into by following one-tenth:
(1) anticancer effective component is that 10% pemetrexed and 10% amycin, slow-release auxiliary material are 80% pair of carboxy phenyl propane in the sustained-release micro-spheres: decanedioic acid is 20: 80 a polifeprosan, and solvent is the normal saline that contains 15% mannitol; Or
(2) anticancer effective component is that 20% 2-Amino-6-methyl-5-(pyridin-4-ylsulfanyl)-3H-quinazolin-4-one and 10% pirarubicin, slow-release auxiliary material are 70% pair of carboxy phenyl propane in the sustained-release micro-spheres: decanedioic acid is 20: 80 a polifeprosan, and solvent is the normal saline that contains 1.5% sodium carboxymethyl cellulose and 0.5% Tween 80;
Percentage ratio in the sustained-release micro-spheres is weight percentage.
2. the slow-releasing anticarcinogen injection according to claim 1, it is characterized in that sustained-release micro-spheres in the slow-releasing anticarcinogen injection also is used for the preparation treatment and originates from people and animal brain, the central nervous system, kidney, liver, gallbladder, incidence, the oral cavity, thyroid, skin, mucosa, body of gland, blood vessel, osseous tissue, lymph node, lungs, esophagus, stomach, mammary gland, pancreas, eyes, nasopharynx part, the uterus, ovary, endometrium, cervix uteri, prostate, bladder, former or the cancer of secondary of colon or rectum, the sustained-release implant of sarcoma or carcinosarcoma is in tumor or tumor week injection or place administration.
CN200610200173A 2006-02-24 2006-02-24 Anti-cancer drugs slow release agent comprising anticancer antibiotics and synergist thereof Expired - Fee Related CN1923173B (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN200610200173A CN1923173B (en) 2006-02-24 2006-02-24 Anti-cancer drugs slow release agent comprising anticancer antibiotics and synergist thereof

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN200610200173A CN1923173B (en) 2006-02-24 2006-02-24 Anti-cancer drugs slow release agent comprising anticancer antibiotics and synergist thereof

Publications (2)

Publication Number Publication Date
CN1923173A CN1923173A (en) 2007-03-07
CN1923173B true CN1923173B (en) 2010-05-19

Family

ID=37816117

Family Applications (1)

Application Number Title Priority Date Filing Date
CN200610200173A Expired - Fee Related CN1923173B (en) 2006-02-24 2006-02-24 Anti-cancer drugs slow release agent comprising anticancer antibiotics and synergist thereof

Country Status (1)

Country Link
CN (1) CN1923173B (en)

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103142491B (en) * 2013-02-06 2015-07-15 广东先强药业有限公司 Vidarabine monophosphate microsphere drug delivery system and preparation method thereof
BR112018002399A2 (en) 2015-08-06 2018-09-25 Chimerix, Inc. pyrrolopyrimidine nucleosides and analogs thereof, useful as antiviral agents
WO2019060692A1 (en) 2017-09-21 2019-03-28 Chimerix, Inc. MORPHIC FORMS OF 4-AMINO-7-(3,4-DIHYDROXY-5-(HYDROXYMETHYL)TETRAHYDROFURAN-2-YL)-2-METHYL-7H-PYRROLO[2,3-d]PYRIMIDINE-5-CARBOXAMIDE AND USES THEREOF

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1356892A (en) * 1999-05-17 2002-07-03 埃迪克埃迪法姆药品实验室 Use of biodegradable microspheres for delivery of anticancer for treatment of glioblastoma
CN1586624A (en) * 2004-06-30 2005-03-02 中国人民解放军南京军区福州总医院 Water soluble chitose intervention embolism chemical therapeutic medicine slow release gel microball
CN1839843A (en) * 2006-01-18 2006-10-04 济南帅华医药科技有限公司 Fluorouracil slow release injection
CN1846678A (en) * 2006-01-18 2006-10-18 济南帅华医药科技有限公司 Slow-released anticancer injection
CN1846670A (en) * 2006-01-09 2006-10-18 济南帅华医药科技有限公司 Anticancer implant

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1356892A (en) * 1999-05-17 2002-07-03 埃迪克埃迪法姆药品实验室 Use of biodegradable microspheres for delivery of anticancer for treatment of glioblastoma
CN1586624A (en) * 2004-06-30 2005-03-02 中国人民解放军南京军区福州总医院 Water soluble chitose intervention embolism chemical therapeutic medicine slow release gel microball
CN1846670A (en) * 2006-01-09 2006-10-18 济南帅华医药科技有限公司 Anticancer implant
CN1839843A (en) * 2006-01-18 2006-10-04 济南帅华医药科技有限公司 Fluorouracil slow release injection
CN1846678A (en) * 2006-01-18 2006-10-18 济南帅华医药科技有限公司 Slow-released anticancer injection

Also Published As

Publication number Publication date
CN1923173A (en) 2007-03-07

Similar Documents

Publication Publication Date Title
CN101336899A (en) Anticancer sustained-released injection containing taxane
CN1923173B (en) Anti-cancer drugs slow release agent comprising anticancer antibiotics and synergist thereof
CN100374160C (en) Anti-cancer medicine composition containing antimetabolite
CN100500219C (en) Anti tumour medicinal composition containing platinum compound
CN100998553A (en) Compound anticarcinogen slow-release preparation containing vasoinhibitor
CN1861055A (en) Composite slow-releasing anticarcinogen injection contg. platinum compounds
CN1923171B (en) Compound recipe anti-cancer drugs slow release agent comprising anticancer antibiotics and synergist thereof
CN100563711C (en) A kind of slow-releasing anticarcinogen injection
CN100431606C (en) Anti-cancer medicine composition
CN100500218C (en) Anti tumour medicinal composition
CN100500212C (en) Anti entity tumour medicinal composition
CN1846672A (en) Anticancer medicine composition containing antimetabolite
CN1857723A (en) Slow released anticancer medicine preparation with both amrubicin and its synergist
CN101327185A (en) Anticancer sustained-release implantation agent
CN1927175B (en) Compound recipe anticancer slow release injection comprising tetrazole violet
CN100453118C (en) Antientity tumour medicinal composition containing topoenzyme inhibitor
CN1973820A (en) Anticancer composition containing Sirolimus and its application
CN100500216C (en) Anti entity tumour medicinal composition containing dichloro ethamine kind drug
CN1923284A (en) Anti-cancer drug slow release injection and uses thereof
CN1846670A (en) Anticancer implant
CN101244272B (en) Anti-solid tumors pharmaceutical combination containing topological enzyme inhibitor
CN101352413A (en) Compound anticancer sustained-release injection containing clofarabine
CN101371821A (en) Anti-cancer medicine composition containing metabolism-resistance medicament
CN100431608C (en) Anti entity tumour medicinal composition containing tetrazine kind compound
CN101327186A (en) Anticancer implantation agent

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

Patentee after: Jinan Kangquan Medicine Sci. & Tech. Co., Ltd.

Address before: 206, room 2, building 19, Pioneer Park, No. 250100 Huaneng Road, Shandong, Ji'nan

Patentee before: Jinan Kangquan Medicine Sci. & Tech. Co., Ltd.

ASS Succession or assignment of patent right

Owner name: SHANDONG LANJIN BIOENGINEERING CO., LTD.

Free format text: FORMER OWNER: JINAN KANGQUAN MEDICINE SCI. + TECH. CO., LTD.

Effective date: 20120807

C41 Transfer of patent application or patent right or utility model
TR01 Transfer of patent right

Effective date of registration: 20120807

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

Patentee after: Shandong Lanjin Pharmaceuticals Co., Ltd.

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

Patentee before: Jinan Kangquan Medicine Sci. & Tech. Co., Ltd.

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

Granted publication date: 20100519

Termination date: 20160224

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