CN1923284A - Anti-cancer drug slow release injection and uses thereof - Google Patents
Anti-cancer drug slow release injection and uses thereof Download PDFInfo
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- CN1923284A CN1923284A CN 200510044524 CN200510044524A CN1923284A CN 1923284 A CN1923284 A CN 1923284A CN 200510044524 CN200510044524 CN 200510044524 CN 200510044524 A CN200510044524 A CN 200510044524A CN 1923284 A CN1923284 A CN 1923284A
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Abstract
Disclosed is an anticancer medicinal injection and its use, which comprises slow release microballoons including anticancer active constituents and slow release auxiliary materials and dissolvent, the anticancer active constituents being platinum-group compounds, anti-metabolism, anti-cancer drugs, anticancer antibiotics or topoisomerase inhibitor, the slow release auxiliary materials are selected from polylactic acid, polyglycolic acid and glycolic acid copolymer, which can slowly release the anti-cancer medicament onto tumor partially during the degradation and absorption process, thus the whole body toxicity reaction is reduced appreciably , and the effective medicinal concentration can be sustained to the tumor partially. The suspending agent is selected from sodium carboxymethylcellulose and mannitol. The injection can lower down the whole body toxicity reaction of the anti-cancer medicament, selectively increase the tumor local medicinal concentration, and improve the treatment effect of the non-operative treatment methods such as chemotherapy, medicament and radiation.
Description
(1) technical field
The present invention relates to a kind of anti-cancer medicine sustained-release injection and application thereof, belong to technical field of pharmaceuticals.
(2) background technology
Treatment for cancer mainly comprises methods such as operation, radiotherapy and chemotherapy.Wherein, the action effect of chemotherapy is comparatively obvious, has been widely used in multiple malignant tumor.Yet, further discover, blood vessel in the mesenchyma stroma of tumors, connective tissue, stromatin, fine micro protein and collagen protein etc. not only provide support and requisite nutrient substance for the growth of tumor cell, also influenced chemotherapeutics around tumor and 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, be difficult to tumor by local and form effective drug level, referring to " placing cisplatin adding system carmustine treatment rat brain tumor in the tumor " " surgery tumor magazine " 1998 69 phase 76-82 pages or leaves (Kong Q et al., J Surg Oncol.1998 Oct such as Kong Qingzhongs; 69 (2): 76-82), improve the restriction that dosage is subjected to general reaction again merely.Medicine is implanted the problem may solve drug level to a certain extent, yet medicine implant surgery operation is complicated, and is traumatic big, the various complication such as, infection hemorrhage except that easily causing, immunity reduction, also can cause or quicken the diffusion and the transfer of tumor.In addition, the preparation of perioperatively itself and rehabilitation require usually to influence the enforcement and the process of conventional therapies such as radiotherapy and chemotherapy.
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 the growth of its wettability "; referring to beam etc. " increased after the cancer therapy drug pulse screening human lung carcinoma cell Drug tolerance and external invade the profit ability and with the change of gene expression " " international journal of cancer " 2004 111 phase 484-93 page or leaf (Liang Y; etal., Int J Cancer.2004; 111 (4): 484-93).Therefore, keep high drug level and increase tumor cell at tumor by local the sensitivity of medicine is just become an important subject.
(3) summary of the invention
The present invention is directed to the deficiencies in the prior art, a kind of anti-cancer medicine sustained-release injection is provided.
Anti-cancer medicine sustained-release injection of the present invention comprises sustained-release microparticle and solvent, and composition is as follows:
(A) sustained-release microparticle anticancer effective component and slow-release auxiliary material are formed, and anticancer effective component is the chemotherapeutics and/or the chemical-therapy synergistic agent of effective anticancer;
(B) solvent is for common solvent or contain the special solvent of suspending agent.
Wherein, chemotherapeutics is selected from platinum-like compounds, anti-metabolism anticarcinogen and/or antitumor antibiotic, and chemical-therapy synergistic agent is selected from topoenzyme inhibitor; Slow-release auxiliary material is selected from one of copolymer (PLGA), ethylene vinyl acetate copolymer (EVAc), polifeprosan, xylitol, oligosaccharide, chrondroitin, chitin, potassium salt, sodium salt, hyaluronic acid, collagen protein, gelatin and white tempera of polylactic acid (PLA), polyglycolic acid and hydroxyacetic acid or its combination.
Suspending agent is selected from one of sodium carboxymethyl cellulose, carboxymethyl cellulose, glycerol, iodine glycerol, simethicone, propylene glycol, carbomer, mannitol, sorbitol, surfactant, polysorbas20, polysorbate40 and Tween 80 or its combination.
The decapacitation of chemical-therapy synergistic agent topoenzyme inhibitor suppresses can also increase the sensitivity of tumor cell to chemotherapeutics outside the tumor growth; Slow-release auxiliary material is used as the carrier holder of medicine, thereby the local concentration of medicine is improved and kept to the rate of release of may command medicine and time; Suspending agent helps the suspension of slow releasing pharmaceutical and then makes things convenient for drug administration by injection.
In described chemotherapeutics, platinum-like compounds is selected from cisplatin, carboplatin, heptan platinum, DNA-2114, enloplatin (Enloplatin), sulfatodiamino cyclohexane platinum (ring ethylenediamine platinic sulfate), Spiroplatin (spiral shell sulphur platinum amine), dexormaplatin (Dexormaplatin), iproplatin (Iproplatin), lobaplatin (Lobaplatin), rice platinum (Miboplatin), nedaplatin (Nedaplatin), ormaplatin (Ormaplatin), oxaliplatin (Oxaliplatin, Oxaloplatin), sebriplatin (Sebriplatin), in a kind of or number in spiroplatin (Spiroplatin) and the zeniplatin (Zeniplatin), wherein with cisplatin, carboplatin, heptan platinum, enloplatin, dexormaplatin, lobaplatin, ormaplatin or oxaliplatin are preferred.
In described chemotherapeutics, antimetabolite is selected from doxifluridine (Doxifloridine, fortulon), the 5-doxifluridine, floxuridine (fluridine), propylthiouracil, fluorouracil (Fluoracil, Fluracil), the fluorobutane uracil, tegadifurum, the 5-fluoxydin, sulfomercaprine sodium, mercapto miaow purine, Ismipur, the adenine hydrochlorate, Benin, sulfur crow purine, tisupurin, Hydrazinium sulfate, dianhydrogalactitol, Aziridinyl Benzoquinone, but sweet smell Luoning, isoeuxanthone, chalone, chlorine is bent phosphoric acid, clastoban, cycloleucine, look into the Chinese holly woods, methyl yellow is looked into the Chinese holly woods sourly, Bai Ruikuaer, oxipurinol, Australia Ma Lite, bromine crust acid (sodium), Brytoslatin-I, bromine urea glycosides, fluorine urea hexylamine, folic acid, methotrexate (methotrexate, MTX), 10-ethyl denitrification aminopterin (deaza-aminopterin), fluoromethotrexate, the dioxy methotrexate, 5, the 10-lonetrexol, N5-Methyltetrahydrohmofotic Acid, buthiopurin, his amide of Dinke, Guang azepine crow glycosides, carmofur (Carmofur), Tegafur-uracil mixt., 6-prenylindole, 6-thioinosine, UFT (UFT), coralyne, N-foymylsarcolysin, ammonia (base) pterin, aminopterin sodium, the 8-azaguanine, 6-dimethylamino-8-azaadenosine, (nitro) imuran, uracil, 5-mercaptomethyluracil, azaserine, pemetrexed (Alimta), Raltitrexed (Raltitrexed), thunder accounts for for song, nolatrexed dihydrochloride, sophoridine, formyl tetrahydrofolic acid, 5-methyltetrahydrohomofolate, Zoledronate, the temozolomide, bicalutamide, asparaginase (L-Asparaginase, left-handed asparagine), calcium levofolinate, calcium folinate (calcium leucovorin), Quinespar, triazinate, trimetrexate, tramadol, the 5-chlorobarbituric acid, 5-diazonium uracil, piracetam, hycamtin, topotecan hydrochloride, cytosine arabinoside (Ara-C), ancitabine, the hydroxyl guanidine, the 5-fluorouracil nucleoside, 5-fluorouracil deoxynucleoside (claiming the fluorouracil deoxynucleoside again), glycerol Citrus chachiensis Hort. alkali, A Lei can loose, isoxazole acetic acid, aminoglutethimide (ethylbenzene amine piperidones, aminoglutethimidium, aminoglutethimide), amonafide, 5-chloro-5-deoxyarabinosylcytosine, atamestane, azacytidine (Azacitidine, 5-azacytidine, the atropic cytidine, AzGR), chloramphenalan (betamerphalan, Betamerphalan), decitabing, dexrazoxane (Dexrazoxane), crisnatol, cristatic acid, carat is sharp flat, the sharp guest of carat, galocitabine (Galocitabine), gemcitabine (Gemcitabine), ibacitabine (Ibacitabine), enocitabine (Enocitabine), ancitabine (Ancitabine), decitabine (Decitabine), flurocitabine (Flurocitabine), capecitabine (Capecitabine), enocitabine, his shore of imidazoles, the non-Shandong of Crane, the OK a karaoke club amide, carzolamide, carbazylquinone, CB-1-252, curcumin, the curcumin diketone, ketotrexate, trimetrexate, Si Poguning, deoxidation Si Poguning, naphthalene urea phosphamide, Ditercalinium Chloride, F-ara AMP-2, fluorine benzyl thiophene ketone, gamlogic acid, goserelin, nitrogen Chinese holly mountain range, Hellebrigenin, inosine dialdehyde, metoprine, mitobronitol, mitolactol (Mitolactol), Ke is for ground, Persian, eriolangin, dopan (Chlorethylaminouracil, Dopan), Mei Luogerui, Methyl GAG, GR 30921X, mitotane, fazarabine (Fazarabine), fludarabine (fludarabine), cladribine (cladribine), pentoside, phenaline, benzene comes U.S. special, phosphemide, hair Buddhist nun azoles, Polyprenic Acid, Pteroylaspartic Acid, pteroyltriglutamic acid, fast rice tongue pool, riboprine, simtrazene, Schizophyllan, sodium bromebrate, Solvent Yellow 3, bent fourth sulphur ester, TEM, triaziquone, triciribine, TCN-P NSC-280594, triptolide, triptorelin, nine cloth Lip river azoles, UFT, vitamin B-17, Wei Maining, z-azepine adenosine, prick western cytidine, epipropidine [Epipropidine], the A Monuo phase, adozelesin (Adozelesin), acronine (Acronine), alanosine (Alanosine), ametantrone (Ametantrone), Anastrozole, the A Naxi army, anaxirone (Anaxirone), A Si Yin wakes up, acivicin (Acivicin), atevirdine (Atevirdine), idoxifene (idoxifene), AT-236, hold high and rather study carefully Ji, individual Lu Dabuxin, antineoplaston, antineoplastons, asaphan, Aspargus Granule, AT-346, Bai Ruikuaer (sodium), (hydrochloric acid) Orang Crush, granisetron, tropisetron, dacarbazine, ondansetron, thymosin, tramadol, imatinib mesylate, diclofenac, Thalidomide, the holder fluorine kills star, toremifene, ambroxol, lappaconitine, anti-general etc. because of, thymosin, flutamide, ethyliminum, amine benzene, neoquini oxydum, the N-methylformamide, the jail can reach azoles, NSC-56045, oxisuran, oxylycorine, paphencyl, it is fixed to moor damp Nip, the penberol, prospidine chloride, protoanemonin, good generation born of the same parents, retelliptine, Sensorad, M3, solapalmitine, solaziquonum, stibenemidine, Temozoromide, the many Shillongs of platform, thiaolivacine, the pyridine of nitre ammonia bifurcation, SN-11841,5-fluorouracil (5-FU), (happy disease is peaceful for mercaptopurine, 6-MP), thioguanine (6-TG), ftorafur (Tegafur, tegafur, FT-207) one or more and in the hydroxyurea.With Ismipur, 5-fluorouracil (5-FU), methotrexate, pemetrexed, Raltitrexed, thunder for song account for, his shore of carmofur, ftorafur, galocitabine, ibacitabine, enocitabine, ancitabine, decitabine, flurocitabine, enocitabine, imidazoles, GR 30921X, mitotane, cytosine arabinoside, hydroxyurea, 5-fluorouracil nucleoside, capecitabine, gemcitabine, fludarabine, cladribine, idoxifene and pentoside serve as preferred.
In described chemotherapeutics, antitumor antibiotics is selected from doxorubicin hydrochloride, epirubicin or epirubicin (Epirubicin), mitomycin, ametycin, NSC-69529, actinomycin D, actinomycin C, mitoxantrone (MTX), dactinomycin, daunorubicin (DNR) or daunorubicin or rubidomycin, bleomycin (Bleomycin A5, Pingyangmycin), (hydrochloric acid) bleomycin, zorbamycin, cyclosporin A and neocarzinostain NCS (neocarzinostain), 7-O-methyl Nuo Jia-4 '-epirubicin (mDox), clarithromycin, aklavine (ACLA, aclarubicin), aklavine-B, amrubicin, 4 '-(Radix Cochleariae officinalis biphenyl ammonia anisidide) (m-AMSA), the nor-oxygen daunorubicin of 4-, detorubicin, epirubicin, esorubicin, carubicin, idarubicin (IDA), rodorubicin, leurubicin, medorubicin, Nemorubicin, doxorubicin, pirarubicin, pirarubicin, Valrubicin (N-trifluoro toxin-14-valerate), 2-[4-(7-chloro-2-quinoxalinyl phenoxy base)-propanoic acid (XK469), zorubicin, N-(2-ethyl chloride)-N-nitroso-group urea groups daunorubicin (AD 312), Anthrapyrazole, losoxantrone (Losoxantrone), piroxantrone (Piroxantrone), teloxantrone (Teloxantrone), carcinomycin, Bleomycin, Pelomecin Sulfate, antibiotic 1588, bouvardin, 9-[4-(N-Methylacetamido)anilino, 9-(4-(N-Methylacetamido)anilino)-7-methyl-1H-imidazo(4,5-f)quinoline, kidamycin, acetylkitamycin (acetyl kidamycin), azotomycin (azotomycin), Diacetoxysciroenol (Diacetoxysciroenol), triferricdoxorubicin, diethoxy acetyl amycin, ciclamicin, Carzinocidin (carzinocidin), carzinophillin (carzinophylin), cardinophyllin, the tumor rhzomorph, carzinostatin (carzinostatin, carcinostain), diazamycine (diazamycine), Macrocin (macrocin), macrocinomycin (macrocinomycin), 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 ornogaromycin), 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, chlorine assistant star (chlorozotocin), demethylrifampicin, ditrisarubicins, Hitachimycin, deoxycoformycin, puromycin, puromycin hydrochloride, rachelmycin, rebeccamycin, Sangivamycin, sarkomycin, sibiromycin, talisomycin, rice holder Zuro, selenazofurin, Antibiotic BMG-162aF2, spirogermanium hydrochloride, Spirogermanium, in the antitumor antibiotic such as Spirophydantoin Mustard and stibcytostatum one or more.
More than preferred doxorubicin hydrochloride, epirubicin, mitomycin, ametycin, NSC-69529, actinomycin D, mitoxantrone, dactinomycin, daunorubicin, bleomycin, (hydrochloric acid) bleomycin, aclarubicin, amrubicin, detorubicin, epirubicin, esorubicin, carubicin, idarubicin, rodorubicin, leurubicin, medorubicin, Nemorubicin, doxorubicin, pirarubicin, pirarubicin, Valrubicin, zorubicin, Anthrapyrazole, losoxantrone, piroxantrone, teloxantrone, 9-(4-(N-Methylacetamido)anilino)-7-methyl-1H-imidazo(4,5-f)quinoline, diethoxy acetyl amycin, carzinostatin or neothricin.
Topoenzyme inhibitor is selected from lurtotecan (Lurtotecan) in described chemical-therapy synergistic agent, irinotecan (irinotecan, IRT), podophyllotoxin (podophyllotoxin), etoposide (Etoposide, epipodophyllotoxins, etoposide, etoposide, VP-16), teniposide (Teniposide, teniposide, VM-26), Podophyllinic acid, podophyllotoxin, trihydroxy-isoflavone (Genistein), suramin (Suramin), deoxyguanosine (Deoxyguanosine), lithocholic acid (lithocholic acid, LCA) or Hydrazoic acid,sodium salt (sodiumazide), Camptothecin (camptothecin, CPT), 9-nitro Camptothecin (9-nitrocamptothecin, 9NC), 7-ethyl-10-hydroxyl-Camptothecin (SN-38), 7-ethyl-10-[4-(1-piperidino)-1-piperidino] carbonyl Camptothecin (CPT-11), 10-hydroxyl-Camptothecin (HCPT), Homocamptothecins (Homocamptothecins), MD-CPT (MD-CPT), (RS)-MD-CPT (10,11-MD-20 (RS)-CPT), (S)-MD-CPT glycinate (10,11-MD-20 (S)-CPT-glycinate ester (Gly) .HCl), 9-amino-(S)-MD-CPT glycinate (9-amino-10,11-MD-20 (S)-CPT-Gly), topotecan (10-hydroxy-9-dimethylaminomethyl-(S)-camptothecin, topotecan), (+)-1,2-two (3, the 5-dioxo piperazinyl) propane ((+)-1,2-bis (3,5-dioxopiperazinyl-1-yl) propane, ICRF-187), between-2, two (3, the 5-dioxo piperazine-1-yl) butane (ICRF-193) of 3-, two dioxo piperazines, N-[2-(dimethylamino) ethyl] pyridine-4-carboxylic acid amides (DACA) and derivant thereof.
The above topology enzyme inhibitor can singly select or multiselect.Be preferably as follows: lurtotecan, irinotecan, etoposide, teniposide, Camptothecin, 9-nitro Camptothecin (9NC), topotecan, 7-ethyl-10-hydroxyl-Camptothecin (SN-38), 7-ethyl-10-[4-(1-piperidino)-1-piperidino] carbonyl Camptothecin (CPT-11), 10-hydroxyl-Camptothecin (HCPT), (+)-1,2-two (3, the 5-dioxo piperazinyl) propane (ICRF-187), between-2, two (3, the 5-dioxo piperazine-1-yl) butane (ICRF-193) of 3-and pair dioxo piperazine or N-[2-(dimethylamino) ethyl) in pyridine-4-carboxylic acid amides (DACA) one or more.
The percentage by weight of anticancer effective component is 0.5%-60% in sustained-release microparticle, is good with 2%-40%, is best with 5%-30%.
Anticancer effective component in the slow-releasing anticarcinogen injection microgranule of the present invention is preferably as follows, and all is weight percentage:
(a) cisplatin of 1-40%, carboplatin, heptan platinum, DNA-2114, enloplatin, Spiroplatin, dexormaplatin, iproplatin, lobaplatin, rice platinum, nedaplatin, ormaplatin, oxaliplatin, sebriplatin, spiroplatin or zeniplatin; Or
(b) Ismipur of 1-40%, 5-fluorouracil, methotrexate, pemetrexed, Raltitrexed, thunder for song account for, his shore of carmofur, ftorafur, galocitabine, ibacitabine, enocitabine, ancitabine, decitabine, flurocitabine, enocitabine, imidazoles, GR 30921X, mitotane, cytosine arabinoside, hydroxyurea, 5-fluorouracil nucleoside, capecitabine, gemcitabine, fludarabine, cladribine or idoxifene; Or
(c) doxorubicin hydrochloride of 1-40%, epirubicin, ametycin, actinomycin D, mitoxantrone, dactinomycin, daunorubicin, (hydrochloric acid) bleomycin, aclarubicin, amrubicin, detorubicin, epirubicin, esorubicin, carubicin, idarubicin, rodorubicin, leurubicin, medorubicin, Nemorubicin, doxorubicin, pirarubicin, Valrubicin, zorubicin, Anthrapyrazole, losoxantrone, piroxantrone, teloxantrone, 9-(4-(N-Methylacetamido)anilino)-7-methyl-1H-imidazo(4,5-f)quinoline, diethoxy acetyl amycin, carzinostatin or neothricin; Or
(d) lurtotecan of 1-40%, irinotecan, etoposide, teniposide, Camptothecin, 9-nitro Camptothecin or topotecan; Or
(e) combination of the lurtotecan of the cisplatin of 1-40%, carboplatin or oxaliplatin and 1-40%, irinotecan, etoposide, teniposide, Camptothecin, 9-nitro Camptothecin or topotecan; Or
(f) Ismipur of 1-40%, 5-fluorouracil, methotrexate, pemetrexed, Raltitrexed, thunder accounts for for song, carmofur, ftorafur, galocitabine, ibacitabine, enocitabine, ancitabine, decitabine, flurocitabine, enocitabine, his shore of imidazoles, GR 30921X, mitotane, cytosine arabinoside, hydroxyurea, the 5-fluorouracil nucleoside, capecitabine, gemcitabine, fludarabine, the lurtotecan of cladribine or idoxifene and 1-40%, irinotecan, etoposide, teniposide, Camptothecin, the combination of 9-nitro Camptothecin or topotecan; Or
(g) doxorubicin hydrochloride of 1-40%, epirubicin, ametycin, actinomycin D, mitoxantrone, aclarubicin, amrubicin, detorubicin, epirubicin, esorubicin, carubicin, idarubicin, rodorubicin, leurubicin, medorubicin, Nemorubicin, doxorubicin, pirarubicin, Valrubicin, zorubicin, Anthrapyrazole, losoxantrone, the lurtotecan of piroxantrone or teloxantrone and 1-40%, irinotecan, etoposide, teniposide, Camptothecin, the combination of 9-nitro Camptothecin or topotecan.
The percentage by weight of slow-release auxiliary material in sustained-release microparticle is 40-99.5%, 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) and polifeprosan or its combination.
Polylactic acid in the above-mentioned slow-release auxiliary material (PLA) molecular weight peak value can be, but is not limited to 5,000～100,000, and with 20,000～60,000 is preferred, and with 30,000～50,000 for most preferably; The molecular weight of polyglycolic acid (PGA) can be, but is not limited to 5,000～100,000, and with 20,000～60,000 is preferred, and with 30,000～50,000 for most preferably; The molecular weight of the copolymer of polyglycolic acid and hydroxyacetic acid (PLGA) can be, but is not limited to 5,000～100,000, but with 20,000～60, and 000 is preferred, and with 30,000～50,000 for most preferably; The blend weight ratio of glycolic and hydroxyacetic acid is 10/90-90/10, polifeprosan (poly-(1,3-two (to the carboxyl phenoxy group) propane-decanedioic acid) in, to the weight ratio 10/90-90/10 of carboxy phenyl propane (p-CPP) with certain herbaceous plants with big flowers diacid (SA), preferred 20/80-75/25.
Common solvent is selected from distilled water, water for injection, physiology towards liquid, dehydrated alcohol, phosphate or carbonate buffer solution.
The content of suspending agent is 0.1-30% volume weight percentage ratio in the special solvent, is preferably as follows:
A) 0.5-5% sodium carboxymethyl cellulose and 0.1-0.5% Tween 80; Or
B) 5-20% mannitol and 0.1-0.5% Tween 80; Or.
C) 0.5-5% sodium carboxymethyl cellulose, 5-20% sorbitol and 0.1-0.5% Tween 80.
The above-mentioned volume weight percentage ratio that is contains the weight of suspending agent in the common solvent of unit volume, as g/ml, and kg/l.Down together.
The sustained-release microparticle of above-mentioned slow releasing injection can prepare with some kinds of methods, as, but be not limited to (i) fusion method: pharmaceutic adjuvant is directly pulverized with medicine mixed, melt, cool off the preparation slow-releasing granules then; (ii) dissolution method: pharmaceutic adjuvant and medicine dissolution in organic solvent, remove solvent then and prepare sustained-release micro-spheres; (iii) spray drying method for preparation microsphere; (iv) freezing (drying) comminuting method is made micropowder; (v) dissolution method is made micropowder in conjunction with freezing (drying) comminuting method; (vi) liposome bag medicine method and (vii) preparation such as emulsion process sustained-release micro-spheres.The particle size range of made microsphere can be at 5-400um, is preferred with 10-300um, with 20-200um for most preferably.
Sustained-release microparticle can be different shape, as, but be not limited to microgranule, granule, spherical piller, microsphere or micropowder.Be to regulate drug releasing rate, the composition and the proportioning that can change the monomer component of polymer or molecular weight, interpolation or regulate pharmaceutic adjuvant are added any one or multiple other pharmaceutic adjuvant 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, and its content is decided because of concrete condition.Slow release or pharmaceutic adjuvant are in Luo Mingsheng and Gao Tianhui chief editor's " pharmaceutic adjuvant complete works " the 123rd page, had a detailed description in " pharmaceutics " People's Health Publisher in May, 85 version of chief editors such as Sichuan science tech publishing house in March, 1993 version and Tu Xide, 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 enumerate some pharmaceutic adjuvant, comprised filler, solubilizing agent, absorption enhancer, film former, gellant, system (or causing) hole agent, cross-linking agent, the binding agent, excipient or blocker.Above pharmaceutic adjuvant has has multiple action, and therefore the material of the same race that has is listed in different classifications.The available holder of the present invention can be any or multiple material in the above-mentioned pharmaceutic adjuvant, and not exclusively comes the technical characterictic of limit combination according to its classification or definition.
Slow-releasing system can separate the packing respectively of independent sterilization back, storage, suspendible, injection again during use with the injection system; Also slow-releasing system can be mixed back sterilization, packing with a certain proportion of suspending agent, it is suspended in the common solvent or special solvent of the packing of separately sterilizing during use.Used common solvent refers to clinical injection commonly used, as, but be not limited to, the buffer that distilled water, water for injection, physiology are prepared towards liquid, dehydrated alcohol or various salt is as phosphate or carbonate buffer solution etc.Special solvent is the common solvent that contains a kind of or several suspending agents; Slow-releasing system is sterilized after also can being suspended in the injection system, packing, and the time spent direct injection can add a certain amount of antiseptic in such cases.
Slow releasing injection of the present invention can be further divided into gel-type slow releasing injection, solution-type slow releasing injection, suspension type slow releasing injection, microcapsule-type slow releasing injection, microspheric slow releasing injection, block copolymer micelle injection or liposome slow releasing injection.More than in the multiple slow releasing injection, preferred suspension type slow releasing injection, gel-type slow releasing injection, microspheric slow releasing injection, block copolymer micelle injection.
Wherein, the suspension type slow releasing injection is the preparation that the sustained-release microparticle that will contain anticancer component is suspended in gained in the injection.Gel-type slow releasing injection system is dissolved in some amphipathic solvent with biological degradation polyalcohol (as PLA, PLGA or DL-LA and epsilon-caprolactone copolymer), add medicine miscible with it (or suspendible) back again and form 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.The microspheric slow releasing injection comprises microparticulate preparations such as microsphere, sub-micro ball, microemulsion, nanosphere, liposome or gel, and used pharmaceutical carrier is above-mentioned any one or its combination.The block copolymer micelle injection 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 1,000-15,000 Polyethylene Glycol (PEG) are as the hydrophilic block of micelle copolymer, and preferred biological degradation polyalcohol is (as PLA, polylactide, polycaprolactone and copolymer thereof (molecular weight 1,500-25,000) as the hydrophobic block of micelle copolymer.The particle size range of block copolymer micelle can be at 10-300um, between the 20-200um serving as preferred.
In above-mentioned all kinds of slow releasing injection with the suspension type slow releasing injection for most preferably, the suspension type slow releasing injection is the preparation that the sustained-release microparticle 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.The mode that suspends is divided into multiple, but based on following three kinds, the one, the sustained-release microparticle of pastille is packed with suspending agent, before injection, it is suspended in the common solvent, i.e. " sustained-release microparticle and suspending agent+common solvent " scheme; The 2nd, the sustained-release microparticle of pastille is packed separately, before injection, it is suspended in the special solvent, i.e. " sustained-release microparticle+special solvent " scheme; The 3rd, with the packing of behind suspending agent and common solvent suspendible, sterilizing of the sustained-release microparticle of pastille, time spent direct injection.
The used pharmaceutic adjuvant of slow releasing injection is above-mentioned a kind of or several adjuvants, can import in the body cavity, in the tumor or tumor all; The gel-type slow releasing injection is biological degradation polyalcohol PLA, PLGA, hyaluronic acid, chrondroitin, collagen protein, gelatin, albumin etc. to be dissolved with the amphiphilic solvent phase make polymer solution, make after miscible with medicine then, be fruit jelly shape, paste or ointment isogel type; The solution-type slow releasing injection can be selected vegetable oil for use, as, but be not limited to, iodine glycerol, certain herbaceous plants with big flowers acid esters, carnic acid, Oleum sesami, Oleum Ricini, Oleum Glycines, Semen arachidis hypogaeae wet goods are made holder; The suspension type slow releasing injection also can be with medicine separately or be packaged in and make oil suspension after the high molecular polymer, medicine and macromolecular compound be combined into the indissoluble salt suspensoid or with the suspension of medicine and reactant salt formation drug salts crystalline solid.
Slow-releasing anticarcinogen injection of the present invention is intracavitary administration agent, intratumor injection agent, all injections of tumor or selective arterial injection, and intracavitary administration comprises in intraperitoneal, the thoracic cavity and injection through vertebral canal.It can also be in the lymph node and the interior injection of bone marrow.
Because the present invention can make the action effect of methods such as conventional chemotherapy, immunization therapy, high thermal therapeutical, photochemical therapy, electrotherapy, Biotherapeutics, hormone therapy, magnetic therapy, ultrasonic therapeutic, radiotherapy and gene therapy strengthen.Therefore when local slow discharges, can share, thereby its anticancer effect is further strengthened with above-mentioned non-operative treatment.When share with above-mentioned non-operative treatment, the present invention can use simultaneously with non-operative treatment, also can use in non-operative treatment is implemented a few days ago, and its purpose is to strengthen as far as possible the sensitivity of tumor.
Route of administration depends on multiple factor, for obtaining 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, the selective arterial injection of tumor, lymph node and injection in the bone marrow.With in selective arterial, intracavity, the tumor, tumor week injection serves as preferred.
The present invention can be used to prepare the medicine of the various tumors for the treatment of people and animal, be mainly slow releasing injection, 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 the made slow releasing injection of the present invention, as, but be not limited to antibiotics, antalgica, anticoagulant medicine, hemorrhage, antitumor antibiotic etc.
By following test excellent results of the present invention is further described.
Test 1, topoenzyme inhibitor press down the potentiation of tumor to platinum-like compounds
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.Topoenzyme inhibitor and platinum-like compounds are added in 24 hours the various tumor cells of In vitro culture by the 10ug/ml drug level, continue to cultivate counting cells sum after 48 hours.Its growth of tumour cell suppresses effect and is shown in Table 1.
Table 1
| Oncocyte | Cisplatin | Carboplatin | Camptothecin | Cisplatin+Camptothecin | Carboplatin+Camptothecin | Oxaliplatin | Etoposide | Oxaliplatin+etoposide |
| CNS | 68％ | 64％ | 66％ | 84％ | 90％ | 56％ | 58％ | 86％ |
| C6 | 62％ | 64％ | 60％ | 84％ | 96％ | 60％ | 68％ | 94％ |
| SA | 58％ | 60％ | 56％ | 90％ | 86％ | 56％ | 62％ | 92％ |
| BC | 54％ | 64％ | 54％ | 84％ | 94％ | 64％ | 64％ | 82％ |
| BA | 54％ | 62％ | 62％ | 92％ | 98％ | 62％ | 62％ | 90％ |
| LH | 60％ | 58％ | 62％ | 88％ | 90％ | 62％ | 58％ | 84％ |
| PAT | 54％ | 56％ | 66％ | 86％ | 94％ | 56％ | 58％ | 88％ |
Above result shows, growth all has the obvious suppression effect to kinds of tumor cells when this concentration is used separately for used various topoenzyme inhibitor (Camptothecin and etoposide) and platinum-like compounds, when use in conjunction, topoenzyme inhibitor can significantly strengthen the tumor-inhibiting action of platinum-like compounds.
Test 2, topoenzyme inhibitor slow releasing injection are to pressing down the potentiation of tumor in the platinum-like compounds slow releasing injection body
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 2).First group is contrast, and the 2nd to 10 group is the treatment group, and slow releasing injection is through intratumor injection.Drug dose is 5mg/kg.The treatment back was measured gross tumor volume size, relatively therapeutic effect (seeing Table 2) on the 10th day.
Table 2
| Test group (n) | Suffered treatment | Gross tumor volume (cm 3) | The P value |
| 1(6) | Contrast | 88±2 | |
| 2(6) | Oxaliplatin | 48±5.3 | ＜0.05 |
| 3(6) | Irinotecan | 58±2.3 | ＜0.01 |
| 4(6) | Oxaliplatin+irinotecan | 36±2.4 | ＜0.001 |
| 5(6) | Heptan platinum | 48±3.0 | ＜0.01 |
| 6(6) | Teniposide | 44±3.0 | ＜0.01 |
| 7(6) | Heptan platinum+teniposide | 20±2.0 | ＜0.001 |
| 8(6) | Enloplatin | 32±3.6 | ＜0.01 |
| 9(6) | Camptothecin | 34±3.8 | ＜0.01 |
| 10(6) | Enloplatin+Camptothecin | 18±2.6 | ＜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 various topoenzyme inhibitor (irinotecan and teniposide) and platinum-like compounds, when use in conjunction, topoenzyme inhibitor can significantly strengthen the tumor-inhibiting action of platinum-like compounds.
Test 3, topoenzyme inhibitor slow releasing injection are to pressing down the potentiation of tumor in the antimetabolic kind anti-cancer drugs slow releasing injection body
With the rat is subjects, and 2 * 105 pancreatic tumor cell subcutaneous injections in its hypochondrium, are treated 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 medicine is through intratumor injection.Drug dose 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 | 28±2 | |
| 2(6) | 5-FU | 46±5.3 | ＜0.05 |
| 3(6) | Lurtotecan | 58±2.3 | ＜0.01 |
| 4(6) | The 5-FU+ lurtotecan | 38±2.4 | ＜0.001 |
| 5(6) | Methotrexate | 50±3.0 | ＜0.01 |
| 6(6) | Teniposide | 46±3.0 | ＜0.01 |
| 7(6) | Methotrexate+teniposide | 22±2.0 | ＜0.001 |
| 8(6) | Pemetrexed | 34±3.6 | ＜0.01 |
| 9(6) | Camptothecin | 36±3.8 | ＜0.01 |
| 10(6) | Pemetrexed+Camptothecin | 16±2.4 | ＜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 various topoenzyme inhibitor (lurtotecan, teniposide and Camptothecin) and anti-metabolism anticarcinogen (5-FU, methotrexate and pemetrexed), when use in conjunction, topoenzyme inhibitor can significantly strengthen the tumor-inhibiting action of anti-metabolism anticarcinogen.
Test 4, topoenzyme inhibitor slow releasing injection are to pressing down the potentiation of tumor in the anticancer antibiotic sustained release injection body
With the rat is subjects, with 2 * 10
5Individual breast tumor cell subcutaneous injection treats that in its hypochondrium tumor growth was divided into following 10 groups with it after 14 days, saw Table 4.First group is contrast, and the 2nd to 10 group is the treatment group, and medicine is through intratumor injection, and drug dose is 5mg/kg.The treatment back was measured gross tumor volume size, relatively therapeutic effect (seeing Table 4) on the 10th day.
Table 4
| Test group (n) | Suffered treatment | Gross tumor volume (cm 3) | The P value |
| 1(6) | Contrast | 88±2 | |
| 2(6) | Amycin | 58±5.8 | ＜0.05 |
| 3(6) | Irinotecan | 52±4.3 | ＜0.01 |
| 4(6) | Amycin+irinotecan | 36±2.4 | ＜0.001 |
| 5(6) | Ametycin | 58±3.0 | ＜0.01 |
| 6(6) | Topotecan | 44±3.0 | ＜0.01 |
| 7(6) | Ametycin+topotecan | 20±2.0 | ＜0.001 |
| 8(6) | Mitoxantrone | 52±3.6 | ＜0.01 |
| 9(6) | The nitro Camptothecin | 34±3.8 | ＜0.01 |
| 10(6) | Mitoxantrone+nitro Camptothecin | 28±2.6 | ＜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 various topoenzyme inhibitor (irinotecan, topotecan and nitro Camptothecin) and antitumor antibiotic (amycin, ametycin and mitoxantrone), when use in conjunction, topoenzyme inhibitor can significantly strengthen the tumor-inhibiting action of antitumor antibiotic.
In a word, growth all has the obvious suppression effect to used various medicines to kinds of tumor cells when this concentration is used separately, and when use in conjunction, topoenzyme inhibitor can significantly strengthen the tumor-inhibiting action of platinum-like compounds, anti-metabolism anticarcinogen or antitumor antibiotic.Therefore, effective ingredient of the present invention is the combination of any one topoenzyme inhibitor and any one platinum-like compounds, anti-metabolism anticarcinogen or antitumor antibiotic.The medicine that contains above effective ingredient can be made into sustained-release micro-spheres and dosage form slow releasing injection arbitrarily, serves as preferred with the suspensoid injectio that is combined to form with the special solvent that contains suspending agent wherein.
(4) specific embodiment
Below each embodiment, the content of suspending agent is volume weight percentage ratio in the special solvent, promptly contains the weight of suspending agent in the common solvent of unit volume, as g/ml, kg/l.The content of anticancer effective component all is weight percentage in the sustained-release microparticle.
Embodiment 1.
With 90mg molecular weight peak value is that 25000 polylactic acid (PLGA, 75: 25) is put into container, adds 100 milliliters of dichloromethane, behind the dissolving mixing, adds the 10mg oxaliplatin, shakes 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% oxaliplatin, 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 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 is:
Cisplatin, carboplatin, heptan platinum, DNA-2114, enloplatin, sulfatodiamino cyclohexane platinum, Spiroplatin, dexormaplatin, oxaliplatin, iproplatin, lobaplatin, rice platinum, nedaplatin, ormaplatin, sebriplatin, spiroplatin or zeniplatin.
Embodiment 3.
80mg polifeprosan (to carboxy phenyl propane: certain herbaceous plants with big flowers diacid weight ratio is 20: 80) copolymer is put into container, add 100 milliliters of dichloromethane, behind the dissolving mixing, add the 20mg5-fluorouracil, shake up the back contains the 20%5-fluorouracil with spray drying method for preparation injectable microsphere again.Then microsphere is suspended in the normal saline that contains 15% mannitol, 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 20-30 days at the subcutaneous drug release time of mice.
Embodiment 4
The method step that is processed into slow releasing injection is identical with embodiment 5, but different is that contained anticancer effective component is:
20% Ismipur, 5-fluorouracil, methotrexate, pemetrexed, Raltitrexed, thunder for song account for, his shore of carmofur, ftorafur, galocitabine, ibacitabine, enocitabine, ancitabine, decitabine, flurocitabine, enocitabine, imidazoles, GR 30921X, mitotane, cytosine arabinoside, hydroxyurea, 5-fluorouracil nucleoside, capecitabine, gemcitabine, fludarabine, cladribine or idoxifene
Embodiment 5. spray drying method for preparation
With 90mg molecular weight peak value is that 25000 polylactic acid (PLA) is put into container, add 100 milliliters of dichloromethane dissolving mixings after, adds 10 milligrams of doxorubicin hydrochlorides, shake up the injectable microsphere that afterwards contains 10 doxorubicin hydrochlorides again with spray drying method for preparation.Microsphere is suspended in the injection that contains 15% sorbitol 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 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:
10% epirubicin, ametycin, actinomycin D, mitoxantrone, dactinomycin, daunorubicin, (hydrochloric acid) bleomycin, aclarubicin, amrubicin, detorubicin, epirubicin, esorubicin, carubicin, idarubicin, rodorubicin, leurubicin, medorubicin, Nemorubicin, doxorubicin, pirarubicin, Valrubicin, zorubicin, Anthrapyrazole, losoxantrone, piroxantrone, teloxantrone, 9-(4-(N-Methylacetamido)anilino)-7-methyl-1H-imidazo(4,5-f)quinoline, diethoxy acetyl amycin, carzinostatin or neothricin;
Embodiment 7.
80mg polifeprosan (to carboxy phenyl propane: certain herbaceous plants with big flowers diacid weight ratio is 20: 80) copolymer is put into container, add 100 milliliters of dichloromethane, behind the dissolving mixing, add the 20mg Camptothecin, shake up the back contains 20% Camptothecin 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 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: 20% lurtotecan, irinotecan, etoposide, teniposide, Camptothecin, 9-nitro Camptothecin or topotecan.
Embodiment 9.
70mg polifeprosan (to carboxy phenyl propane: certain herbaceous plants with big flowers diacid weight ratio is 30: 70) copolymer is put into container, add 100 milliliters of dichloromethane, behind the dissolving mixing, add 20mg Camptothecin and 10mg cisplatin, shake up the back contains 20% Camptothecin and 10% cisplatin 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 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 combination of 10% cisplatin, carboplatin or oxaliplatin and 20% lurtotecan, irinotecan, etoposide, teniposide, Camptothecin, 9-nitro Camptothecin or topotecan.
Embodiment 11.
70mg polifeprosan (to carboxy phenyl propane: certain herbaceous plants with big flowers diacid weight ratio is 40: 60) copolymer is put into container, add 100 milliliters of dichloromethane, behind the dissolving mixing, add 10mg hydroxy-camptothecin alkali and 20mg methotrexate, shake up the back contains 10% hydroxy-camptothecin alkali and 20% methotrexate 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.
Embodiment 12.
The method step that is processed into slow releasing injection is identical with embodiment 11, but different is that contained anticancer effective component is: 10% Ismipur, 5-fluorouracil, methotrexate, pemetrexed, Raltitrexed, thunder accounts for for song, carmofur, ftorafur, galocitabine, ibacitabine, enocitabine, ancitabine, decitabine, flurocitabine, enocitabine, his shore of imidazoles, GR 30921X, mitotane, cytosine arabinoside, hydroxyurea, the 5-fluorouracil nucleoside, capecitabine, gemcitabine, fludarabine, cladribine or idoxifene and 20% lurtotecan, irinotecan, etoposide, teniposide, Camptothecin, the combination of 9-nitro Camptothecin or topotecan.
Embodiment 13.
With 70mg molecular weight peak value 45000 polylactic acid (PLGA, 75: 25) put into container, add 100 milliliters of dichloromethane, behind the dissolving mixing, add 10mg doxorubicin hydrochloride and 20mg Camptothecin, shake up the back contains 10% doxorubicin hydrochloride and 20% Camptothecin 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.
Embodiment 14.
The method step that is processed into slow releasing injection is identical with embodiment 13, but different is that contained anticancer effective component is: 10% doxorubicin hydrochloride, epirubicin, ametycin, actinomycin D, mitoxantrone, aclarubicin, amrubicin, detorubicin, epirubicin, esorubicin, carubicin, idarubicin, rodorubicin, leurubicin, medorubicin, Nemorubicin, doxorubicin, pirarubicin, Valrubicin, zorubicin, Anthrapyrazole, losoxantrone, the lurtotecan of piroxantrone or teloxantrone and 1-40%, irinotecan, etoposide, teniposide, Camptothecin, the combination of 9-nitro Camptothecin or topotecan.
Embodiment 15.
The method step that is processed into slow releasing injection is identical with embodiment 1-14, but different is used slow-release auxiliary material is one of following or its combination:
A) molecular weight is the polylactic acid (PLA) of 5000-15000,10000-20000,20000-35000 or 30000-50000;
B) molecular weight is the polyglycolic acid of 5000-15000,10000-20000,20000-35000 or 30000-50000 and the copolymer of hydroxyacetic acid (PLGA), and wherein, the ratio of polyglycolic acid and hydroxyacetic acid is 50-95: 50-5;
C) ethylene vinyl acetate copolymer (EVAc);
D) weight ratio 10: 90,20: 80,30: 70,40: 60,50: 50 or 60: 40 to carboxy phenyl propane (p-CPP): certain herbaceous plants with big flowers diacid (SA) copolymer (polifeprosan);
E) xylitol, oligosaccharide, chrondroitin, chitin, potassium salt, sodium salt, hyaluronic acid, collagen protein, gelatin or white tempera.
Embodiment 16.
The method step that is processed into slow releasing injection is identical with embodiment 1-15, but different is used suspending agent is respectively one of following or its combination:
A) 0.5-3.0% carboxymethyl cellulose or sodium carboxymethyl cellulose;
B) 5-15% mannitol;
C) 5-15% sorbitol;
D) 0.1-1.5% surfactant;
E) 0.1-0.5% polysorbas20.
Claims (11)
1. an anti-cancer medicine sustained-release injection comprises sustained-release microparticle and solvent, it is characterized in that composition is as follows:
(A) sustained-release microparticle anticancer effective component and slow-release auxiliary material are formed, and anticancer effective component is the chemotherapeutics and/or the chemical-therapy synergistic agent of effective anticancer;
(B) solvent is for common solvent or contain the special solvent of suspending agent;
Wherein, chemotherapeutics is selected from platinum-like compounds, anti-metabolism anticarcinogen and/or antitumor antibiotic, and chemical-therapy synergistic agent is selected from topoenzyme inhibitor; Slow-release auxiliary material is selected from one of copolymer, ethylene vinyl acetate copolymer, polifeprosan, xylitol, oligosaccharide, chrondroitin, chitin, potassium salt, sodium salt, hyaluronic acid, collagen protein, gelatin and white tempera of polylactic acid, polyglycolic acid and hydroxyacetic acid or its combination; Suspending agent is selected from one of sodium carboxymethyl cellulose, carboxymethyl cellulose, glycerol, iodine glycerol, simethicone, propylene glycol, carbomer, mannitol, sorbitol, polysorbas20, polysorbate40 and Tween 80 or its combination.
2. anti-cancer medicine sustained-release injection according to claim 1 is characterized in that described platinum-like compounds is selected from cisplatin, carboplatin, heptan platinum, DNA-2114, enloplatin, sulfatodiamino cyclohexane platinum, Spiroplatin, dexormaplatin, iproplatin, lobaplatin, rice platinum, nedaplatin, ormaplatin, oxaliplatin, sebriplatin, spiroplatin or zeniplatin.
3. anti-cancer medicine sustained-release injection according to claim 1, it is characterized in that described anti-metabolism anticarcinogen be selected from Ismipur, 5-fluorouracil, methotrexate, pemetrexed, Raltitrexed, thunder for song account for, his shore of carmofur, ftorafur, galocitabine, ibacitabine, enocitabine, ancitabine, decitabine, flurocitabine, enocitabine, imidazoles, GR 30921X, mitotane, cytosine arabinoside, hydroxyurea, 5-fluorouracil nucleoside, capecitabine, gemcitabine, fludarabine, cladribine or idoxifene.
4. anti-cancer medicine sustained-release injection according to claim 1 is characterized in that described antitumor antibiotic is selected from doxorubicin hydrochloride, epirubicin, ametycin, actinomycin D, mitoxantrone, dactinomycin, daunorubicin, (hydrochloric acid) bleomycin, aclarubicin, amrubicin, detorubicin, epirubicin, esorubicin, carubicin, idarubicin, rodorubicin, leurubicin, medorubicin, Nemorubicin, doxorubicin, pirarubicin, Valrubicin, zorubicin, Anthrapyrazole, losoxantrone, piroxantrone, teloxantrone, 9-(4-(N-Methylacetamido)anilino)-7-methyl-1H-imidazo(4,5-f)quinoline, diethoxy acetyl amycin, carzinostatin or neothricin.
5. anti-cancer medicine sustained-release injection according to claim 1 is characterized in that described topoenzyme inhibitor is selected from lurtotecan, irinotecan, etoposide, teniposide, Camptothecin, 9-nitro Camptothecin or topotecan.
6. anti-cancer medicine sustained-release injection according to claim 1 is characterized in that described anticancer effective component is:
(A) cisplatin of 1-40%, carboplatin, heptan platinum, DNA-2114, enloplatin, Spiroplatin, dexormaplatin, iproplatin, lobaplatin, rice platinum, nedaplatin, ormaplatin, oxaliplatin, sebriplatin, spiroplatin or zeniplatin; Or
(B) Ismipur of 1-40%, 5-fluorouracil, methotrexate, pemetrexed, Raltitrexed, thunder for song account for, his shore of carmofur, ftorafur, galocitabine, ibacitabine, enocitabine, ancitabine, decitabine, flurocitabine, enocitabine, imidazoles, GR 30921X, mitotane, cytosine arabinoside, hydroxyurea, 5-fluorouracil nucleoside, capecitabine, gemcitabine, fludarabine, cladribine or idoxifene; Or
(C) doxorubicin hydrochloride of 1-40%, epirubicin, ametycin, actinomycin D, mitoxantrone, dactinomycin, daunorubicin, Bleocin Hydrochloride, bleomycin, aclarubicin, amrubicin, detorubicin, epirubicin, esorubicin, carubicin, idarubicin, rodorubicin, leurubicin, medorubicin, Nemorubicin, doxorubicin, pirarubicin, Valrubicin, zorubicin, Anthrapyrazole, losoxantrone, piroxantrone, teloxantrone, 9-(4-(N-Methylacetamido)anilino)-7-methyl-1H-imidazo(4,5-f)quinoline, diethoxy acetyl amycin, carzinostatin or neothricin; Or
(D) lurtotecan of 1-40%, irinotecan, etoposide, teniposide, Camptothecin, 9-nitro Camptothecin or topotecan; Or
(E) combination of the lurtotecan of the cisplatin of 1-40%, carboplatin or oxaliplatin and 1-40%, irinotecan, etoposide, teniposide, Camptothecin, 9-nitro Camptothecin or topotecan; Or
(F) Ismipur of 1-40%, 5-fluorouracil, methotrexate, pemetrexed, Raltitrexed, thunder accounts for for song, carmofur, ftorafur, galocitabine, ibacitabine, enocitabine, ancitabine, decitabine, flurocitabine, enocitabine, his shore of imidazoles, GR 30921X, mitotane, cytosine arabinoside, hydroxyurea, the 5-fluorouracil nucleoside, capecitabine, gemcitabine, fludarabine, the lurtotecan of cladribine or idoxifene and 1-40%, irinotecan, etoposide, teniposide, Camptothecin, the combination of 9-nitro Camptothecin or topotecan; Or
(G) doxorubicin hydrochloride of 1-40%, epirubicin, ametycin, actinomycin D, mitoxantrone, aclarubicin, amrubicin, detorubicin, epirubicin, esorubicin, carubicin, idarubicin, rodorubicin, leurubicin, medorubicin, Nemorubicin, doxorubicin, pirarubicin, Valrubicin, zorubicin, Anthrapyrazole, losoxantrone, the lurtotecan of piroxantrone or teloxantrone and 1-40%, irinotecan, etoposide, teniposide, Camptothecin, the combination of 9-nitro Camptothecin or topotecan;
Below all be weight percentage.
7. anti-cancer medicine sustained-release injection according to claim 1 is characterized in that described slow-release auxiliary material is one of following:
A) the molecular weight peak value of polylactic acid (PLA) is 5000-15000,10000-20000,20000-35000 or 30000-50000;
B) the molecular weight of copolymer peak value of polyglycolic acid and hydroxyacetic acid is 5000-15000,10000-20000,20000-35000 or 30000-50000, and wherein, the ratio of polyglycolic acid and hydroxyacetic acid is 50-95: 50-5;
C) in the polifeprosan to carboxy phenyl propane: certain herbaceous plants with big flowers diacid weight ratio is 10: 90,20: 80,30: 70,40: 60,50: 50 or 60: 40.
8. anti-cancer medicine sustained-release injection according to claim 1 is characterized in that used suspending agent is respectively one of following:
A) 0.5-3.0% carboxymethyl cellulose or sodium carboxymethyl cellulose;
B) 5-15% mannitol;
C) 5-15% sorbitol;
D) 0.1-0.5% polysorbas20; Or
E) glycerol, iodine glycerol, simethicone, propylene glycol or carbomer.
9. anti-cancer medicine sustained-release injection according to claim 1 is characterized in that used suspending agent is one of following:
A) 0.5-5% sodium carboxymethyl cellulose and 0.1-0.5% Tween 80; Or
B) 5-20% mannitol and 0.1-0.5% Tween 80; Or
C) 0.5-5% sodium carboxymethyl cellulose, 5-20% sorbitol and 0.1-0.5% Tween 80.
10. slow-releasing anticarcinogen injection according to claim 1 is characterized in that, is intracavitary administration agent, intratumor injection agent, all injections of tumor or selective arterial injection.
11. the anti-cancer medicine sustained-release injection that claim 1 is described is used to prepare the suspensoid injectio that treatment originates from cancer, sarcoma or the carcinosarcoma of people and animal brain, central nervous system, kidney, liver, gallbladder, incidence, oral cavity, thyroid, skin, mucosa, body of gland, blood vessel, osseous tissue, lymph node, lungs, esophagus, stomach, mammary gland, pancreas, eyes, nasopharynx part, uterus, ovary, endometrium, cervix uteri, prostate, bladder, colon or rectum former or secondary.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200510044524 CN1923284A (en) | 2005-08-30 | 2005-08-30 | Anti-cancer drug slow release injection and uses thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200510044524 CN1923284A (en) | 2005-08-30 | 2005-08-30 | Anti-cancer drug slow release injection and uses thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1923284A true CN1923284A (en) | 2007-03-07 |
Family
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 200510044524 Pending CN1923284A (en) | 2005-08-30 | 2005-08-30 | Anti-cancer drug slow release injection and uses thereof |
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| Country | Link |
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| CN (1) | CN1923284A (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008138758A1 (en) * | 2007-05-11 | 2008-11-20 | Nerviano Medical Sciences S.R.L. | Pharmaceutical composition of an anthracycline |
| CN107412725A (en) * | 2009-12-22 | 2017-12-01 | 武田药品工业株式会社 | Sustained release preparation |
-
2005
- 2005-08-30 CN CN 200510044524 patent/CN1923284A/en active Pending
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008138758A1 (en) * | 2007-05-11 | 2008-11-20 | Nerviano Medical Sciences S.R.L. | Pharmaceutical composition of an anthracycline |
| US8940334B2 (en) | 2007-05-11 | 2015-01-27 | Nerviano Medical Sciences S.R.L. | Pharmaceutical composition of an anthracycline |
| CN107412725A (en) * | 2009-12-22 | 2017-12-01 | 武田药品工业株式会社 | Sustained release preparation |
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