(3) summary of the invention
The present invention is directed to the deficiencies in the prior art, a kind of anticancer pharmaceutical composition is provided.
Anticancer pharmaceutical composition of the present invention comprises that the anticancer effective component and the pharmaceutic adjuvant of effective anticancer, anticancer effective component are (A) antimetabolitas and (B) guanine or guanine analog.
Above-mentioned antimetabolite is selected from, but be not limited to, 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 (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), 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 Levofolinate, calcium leucovorin), Quinespar, triazinate, trimetrexate, tramadol, the 5-chlorobarbituric acid, 5-diazonium uracil, piracetam, hycamtin, topotecan hydrochloride, cytosine arabinoside (cytosine arabinoside, Cytarabine (Ara-C)), ancitabine (cyclotidine, Cyclocytidine), the hydroxyl guanidine, the 5-fluorouracil nucleoside, the 5-fluorouracil deoxynucleoside claims fluorouracil deoxynucleoside (floxuridine) again, glycerol Citrus chachiensis Hort. alkali, A Lei can loose, isoxazole acetic acid, aminoglutethimide (ethylbenzene amine piperidones, aminoglutethimidium, aminoglutethimide), amonafide, 5-chloro-5-deoxyarabinosylcytosine, atamestane, azacytidine (Azacitidine, 5-azacytidine, the atropic cytidine, AzGR), chloramphenalan (betamerphalan, Betamerphalan), decitabing, dexrazoxane (Dexrazoxane), crisnatol, cristatic acid, carat is sharp flat, the sharp guest of carat, galocitabine (Galocitabine), gemcitabine (Gemcitabine), ibacitabine (Ibacitabine), enocitabine (Enocitabine), ancitabine (Ancitabine), decitabine (Decitabine), flurocitabine (Flurocitabine), capecitabine (Capecitabine), enocitabine, his shore of imidazoles, the non-Shandong of Crane, the OK a karaoke club amide, carzolamide, carbazylquinone, CB-1-252, curcumin, the curcumin diketone, ketotrexate, trimetrexate, Si Poguning, deoxidation Si Poguning, naphthalene urea phosphamide, Ditercalinium Chloride, F-ara AMP-2, fluorine benzyl thiophene ketone, gamlogic acid, goserelin, nitrogen Chinese holly mountain range, Hellebrigenin, inosine dialdehyde, metoprine, mitobronitol (Dibromomannitol, Mitobronitol), mitolactol (Mitolactol), Ke is for ground, Persian, eriolangin, dopan (Chlorethylaminouracil, Dopan), Mei Luogerui, Methyl GAG, GR 30921X, mitotane, fazarabine (Fazarabine), fludarabine (fludarabine), cladribine (cladribine), pentoside (pentostatin), phenaline, benzene comes U.S. special, phosphemide, hair Buddhist nun azoles, Polyprenic Acid, Pteroylaspartic Acid, pteroyltriglutamic acid, fast rice tongue pool, riboprine, simtrazene, Schizophyllan, sodium bromebrate, Solvent Yellow 3, bent fourth sulphur ester, TEM, triaziquone, triciribine, TCN-P NSC-280594, triptolide, triptorelin, nine cloth Lip river azoles, UFT, vitamin B-17, Wei Maining, z-azepine adenosine, prick western cytidine, epipropidine (Epipropidine), the A Monuo phase, adozelesin (Adozelesin), acronine (Acronine), alanosine (Alanosine), ametantrone (Ametantrone), Anastrozole, the A Naxi army, anaxirone (Anaxirone), A Si Yin wakes up, acivicin (Acivicin), atevirdine (Atevirdine), idoxifene (idoxifene), AT-236, hold high and rather study carefully Ji, individual Lu Dabuxin, antineoplaston, antineoplastons, asaphan, Aspargus Granule, AT-346, Bai Ruikuaer (sodium), (hydrochloric acid) Orang Crush, granisetron, tropisetron, dacarbazine, ondansetron, thymosin, tramadol, imatinib mesylate, diclofenac, Thalidomide, the holder fluorine kills star, toremifene, ambroxol, lappaconitine, anti-general etc. because of, thymosin, flutamide, ethyliminum, amine benzene, neoquini oxydum, the N-methylformamide, the jail can reach azoles, NSC-56045, oxisuran, oxylycorine, paphencyl, it is fixed to moor damp Nip, the penberol, prospidine chloride, protoanemonin, good generation born of the same parents, retelliptine, Sensorad, M3, solapalmitine, solaziquonum, stibenemidine, Temozoromide, the many Shillongs of platform, thiaolivacine, the pyridine of nitre ammonia bifurcation, SN-11841,5-fluorouracil (Fluorouracil, 5-FU), mercaptopurine (Mercaptopurine, happy disease is peaceful, 6-MP), thioguanine (thioguanine, 6-TG), ftorafur (Tegafur, tegafur, FT-207) and hydroxyurea (Hydroxycarbamide, hydroxyurea) etc.
Above-mentioned antimetabolitas optional one or more.With his shore of Ismipur, 5-fluorouracil (5-FU), doxifluridine, floxuridine, mercaptopurine, thioguanine, methotrexate, carmofur, ftorafur, galocitabine, ibacitabine, enocitabine, ancitabine, decitabine, flurocitabine, enocitabine, imidazoles, GR 30921X, mitotane, cytosine arabinoside, hydroxyurea, 5-fluorouracil nucleoside, capecitabine, gemcitabine, fludarabine, cladribine and pentoside serves as preferred.
Above-mentioned guanine or guanine analog are selected from; but be not limited to; 2-amino-6-oxypurine (2-amino-6-oxypurine); guanine (guanine); benzyl guanine (benzylguanine); O6-benzyl guanine (O6-BG); O6-butyl guanine (O6-butylguanines); O6-methyl guanine (O6-MG); O6-alkyl guanine (O6-Alkylguanine); O6-benzyl-2 '-deoxyguanosine (O6-benzyl-2 '-deoxyguanosine); 8-amino-O6-benzyl guanine (8-Amino-O.sup.6-benzylguanine); 8-methyl-O6-benzyl guanine (8-methyl-O.sup.6-benzylguanine); 8-hydroxyl-O6-benzyl guanine (8-hydroxy-O.sup.6-benzylguanine); 8-bromo-O6-benzyl guanine (8-bromo-O.sup.6-benzylguanine); 8-oxygen-O6-benzyl guanine (8-Oxo-O.sup.6-benzylguanine); 8-trifluoromethyl-O6-benzyl guanine (8-trifluoromethyl-O.sup.6-benzylguanine); O6-benzyl uric acid (O.sup.6-Benzyluricacid); O6-benzyl xanthine (O.sup.6-Benzylxanthine); O6-benzyl-2-fluorine hypoxanthine (O.sup.6-Benzyl-2-fluorohypoxanthine); Diacetyl-O.sup.6-benzyl-8-oxoguanine (Diacetyl-O.sup.6-benzyl-8-oxoguanine); O6-benzyl-8-methyl guanine (O.sup.6-Benzyl-8-methylguanine); O6-benzyl-8-oxo guanine (O.sup.6-Benzyl-8-oxoguanine); O6-benzyl-8-bromination guanine (O.sup.6-Benzyl-8-bromoguanine); O6-benzyl-8-trifluoromethyl guanine (O.sup.6-Benzyl-8-trifluoromethylguanine); O6-benzyl-N2-methyl guanine (O.sup.6-benzyl-N.sup.2-methylguanine); O6-benzyl-N2N2-dimethylguanine (O.sup.6-benzyl-N.sup.2; N.sup.2-dimethylguanine); O6-benzyl-8-trifluoromethyl-9-methyl guanine (O.sup.6-benzyl-8-trifluoromethyl-9-methylguanine); O6-benzyl-8-bromo-9-methyl guanine (O.sup.6-benzyl-8-bromo-9-methylguanine); O6-benzyl-8-bromo-9-pivaloyl oxygen methyl guanine (O.sup.6-benzyl-8-bromo-9-(pivaloyloxymethyl) guanine); O6-benzyl-7-pivaloyl oxygen methyl guanine (O.sup.6-benzyl-7-(pivaloyloxymethyl) guanine); O6-benzyl-8-bromo-7-pivaloyl oxygen methyl guanine (O.sup.6-benzyl-8-bromo-7-(pivaloyloxymethyl) guanine); 8-azepine-O6-benzyl-7-pivaloyl oxygen methyl guanine (8-Aza-O.sup.6-benzyl-9-(pivaloyloxymethyl) guanine); 8-azepine-O6-benzyl-7-pivaloyl oxygen methyl guanine (8-Aza-O.sup.6-benzyl-7-(pivaloyloxymethyl) guanine); 8-azepine-O6-benzyl guanine (8-Aza-O.sup.6-benzylguanine); 8-azepine-O6-benzyl-9-methyl guanine (8-Aza-O.sup.6-benzyl-9-methylguanine); N.sup.2-Acetyl-O.sup.6-benzyl-8-oxoguanine (N.sup.2-Acetyl-O.sup.6-benzyl-8-oxoguanine); O6-benzyl-N2-methyl guanine (O.sup.6-Benzyl-N.sup.2-methylguanine); O6-benzyl-N2 N2-dimethylguanine (O.sup.6-Benzyl-N.sup.2; N.sup.2-dimethylguanine); 2-amino-6-chloro-8-methyl purine (2-Amino-6-chloro-8-methylpurine); 2; 8-diaminourea-6-chloropurine (2; 8-Diamino-6-chloropurine); O6-benzyl-N2-guanosine (O6-benzyl-N2-acetylguanosine); O6-benzyl-9-cyano group guanine (O6-benzyl-9-cyanomethylguanine (CMBG)); N (7)-methyl guanine (N (7)-methylguanine); O6-benzyl-N2-guanosine (O6-benzylguanosine (BGS)); O6-cycloalkyl guanine (O (6)-cycloalkyl guanines); O6-pi-allyl guanine (O (6)-allylguanine); O6-(2-oxyalkyl guanine (O (6)-(2-oxoalkyl) guanine); O6-cycloalkenyl guanine (O (6)-Cycloalkenylguanines; O6-CAG); 1-cyclobutane methyl guanine (1-cyclobutenylmethylguanine; CBMG); 1-cyclopentenyl methyl guanine (1-cyclopentenyl methylguanine; CPMG) and 6-bromothen base guanine (O (6)-(4-bromothenyl) guanine, O6-BTG).
The derivant of above-mentioned guanine, guanine derivatives, guanine analog or guanine analog also comprises their salt, as, but be not limited to sulfate, phosphate, hydrochlorate, Lactobionate, acetate, aspat, nitrate, citrate, purine or pyrimidine salt, succinate and maleate etc.
Above guanine or guanine analog can singly select or multiselect.With O6-benzyl guanine, O6-butyl guanine, O6-methyl guanine, O6-alkyl guanine, O6-benzyl-2 '-deoxyguanosine, 8-amino-O6-benzyl guanine, 8-methyl-O6-benzyl guanine, 8-hydroxyl-O6-benzyl guanine, 8-bromo-O6-benzyl guanine and 8-oxygen-O6-benzyl guanine serves as preferred.
The content of antimetabolitas in compositions can be from 0.01%-99.99%, with 1%-50% is good, with 2%-40% is best, and guanine derivatives or guanine analog shared ratio in compositions is also decided because of concrete condition, can be from 0.01%-99.99%, with 1%-50% is good, is best with 2%-40%.Below all be weight percentage.
Pharmaceutic adjuvant comprises one of following or its combination:
(1) biocompatibility polymer, comprise biodegradable or biological nondegradable polymer and composition thereof or copolymer, (2) water-soluble low-molecular chemical compound is or/and (3) are used to realize the suitable additive and the excipient of pharmaceutical dosage forms such as injection and slow releasing agent.
Above-mentioned biodegradable polymer comprises natural and/or synthetic polymer.Synthetic polymer as, but be not limited to polyanhydrides, polyhydroxy acid, polyester (polyesters), polyamide (polyamides), poe (polyorthoesters), polyphosphazene (polyphosphazenes), to carboxy phenyl propane (p-CPP), certain herbaceous plants with big flowers diacid (sebacic acid), polifeprosan (to the copolymer of carboxy phenyl propane and certain herbaceous plants with big flowers diacid) etc.; Natural polymer as, but be not limited to, protein and polysaccharide comprise hyaluronic acid, collagen protein, gelatin, albumin, Fibrinogen and agarose etc.
Above-mentioned polyanhydrides can be selected for use, but is not limited to, fragrant polyanhydride, aliphatic polyanhydride; Wherein fragrant polyanhydride will be separated slower, the fusing point height, and dissolubility is low in the organic solvent, however the copolymer of fragrant polyanhydride and aliphatic polyanhydride is comparatively desirable (United States Patent (USP) 4757128) but.Representative wherein is polifeprosan (to the copolymer of carboxy phenyl propane (p-CPP) and certain herbaceous plants with big flowers diacid (SA)), and is fragrant polyanhydride to carboxy phenyl propane, and the certain herbaceous plants with big flowers diacid then is the copolymer of an aromatic diacid and a fat diacid.The copolymer of available other fragrance or aliphatic polyanhydride has a detailed description in other United States Patent (USP) that (US 4857311; 4888176; 4789724).
Above-mentioned polyhydroxy acid can be selected for use, but is not limited to, the copolymer (PLGA) of mixture, glycolic and the hydroxy carboxylic acid of polylactic acid (PLA), polyglycolic acid (PGA), polylactic acid (PLA) and polyglycolic acid; When PLA and PLGA mixing, its content percentage by weight is respectively 0.1-99.9% and 99.9-0.1%.The molecular weight of polylactic acid can be, but is not limited to, 5000-100, and 000, but with 10,000-50000 is preferred, with 10,000-20000 is for most preferably; The molecular weight of polyglycolic acid can be, but is not limited to, 5000-100, and 000, but with 10,000-50000 is preferred, with 10,000-20000 is for most preferably; Above polyhydroxy acid can singly select or multiselect.When singly selecting, serve as preferred with the copolymer (PLGA) of polylactic acid (PLA) or hydroxy carboxylic acid and glycolic, the molecular weight of copolymer can be, but is not limited to, 1000-100,000, but with 10,000-50000 is preferred; With 10,000-20000 is for most preferably; When multiselect, compound polymer or the copolymer formed with macromolecule polymer or different macromolecule polymer serve as preferred, with the compound polymer that contains different molecular weight polylactic acid or certain herbaceous plants with big flowers diacid or copolymer for most preferably, as, but be not limited to, molecular weight is 5000 to 10000 polylactic acid with molecular weight is that 20000 to 50000 polylactic acid mixes, molecular weight is 10000 to 20000 polylactic acid with molecular weight is that 30000 to 80000 PLGA mixes, molecular weight is that 5000 to 10000 polylactic acid mixes with the certain herbaceous plants with big flowers diacid, molecular weight is that 30000 to 80000 PLGA mixes with the certain herbaceous plants with big flowers diacid.The indication molecular weight is the molecular weight peak value scope for being recorded by GPC all.
The nondegradable polymer of above-mentioned biology comprises, but be not limited to: organosilicon polymer, ethylene vinyl acetate copolymer (Ethelene-vinyl acetate copolymer, EVAc), polyacrylonitrile (polyacrylonitriles), polyurethanes (polyurethanes) and polyphosphazene (polyphosphazenes) etc.Compositions can discharge effective ingredient by the mode of direct diffusion.
For regulating other characteristic of drug releasing rate or change anticancer pharmaceutical composition of the present invention, can change the composition and the proportioning of monomer component or molecular weight, interpolation or the adjusting pharmaceutic adjuvant of polymer, add the water-soluble low-molecular chemical compound, as, but be not limited to various sugar and salt etc.Wherein sugar can be, but is not limited to, xylitol, oligosaccharide and chitin etc., and wherein salt can be but is not limited to, potassium salt and sodium salt etc.
The used pharmaceutic adjuvant of anticancer pharmaceutical composition of the present invention can be any or multiple material in the above-mentioned pharmaceutic adjuvant, but with the high molecular weight water soluble polymer is main separation, in various high molecular polymers, with polylactic acid, certain herbaceous plants with big flowers diacid, the mixture or the copolymer that contain the macromolecule polymer of polylactic acid or certain herbaceous plants with big flowers diacid is first-selection, mixture and copolymer can be selected from, but be not limited to the mixture or the copolymer of the mixture of PLGA, glycolic and hydroxy carboxylic acid, certain herbaceous plants with big flowers diacid and fragrant polyanhydride or aliphatic polyanhydride.The blend ratio of glycolic and hydroxy carboxylic acid is 10/90-90/10 (weight), preferably 25/75-75/25 (weight).The method of blend is arbitrarily.Content when glycolic and hydroxy carboxylic acid copolymerization is respectively percentage by weight 10-90% and 90-10%.The representative of fragrance polyanhydride is to carboxy phenyl propane (p-CPP), content during to carboxy phenyl propane (p-CPP) and the copolymerization of certain herbaceous plants with big flowers diacid is respectively percentage by weight 10-60% and 20-90%, the blend weight ratio is 10-40: 50-90, preferably weight ratio 15-30: 65-85.
Pharmaceutic adjuvant has a detailed description in " pharmaceutic adjuvant complete works " (the 123rd page, Sichuan science tech publishing house published in 1993, Luo Mingsheng and Gao Tianhui chief editor).In addition, Chinese patent (application number 96115937.5; 91109723.6; 9710703.3; 01803562.0) and U.S.'s patent of invention (patent No. 5,651,986) also enumerated some pharmaceutic adjuvant.Comprise filler, solubilizing agent, absorption enhancer, film former, gellant, system (or causing) hole agent, excipient or inhibitor.Above pharmaceutic adjuvant has has multiple action, and therefore the material of the same race that has is listed in different classifications.The available holder of composition for treating solid tumor of the present invention can be any or multiple material in the above-mentioned pharmaceutic adjuvant, and not exclusively comes the technical characterictic of limit combination according to its classification or definition.
The effective ingredient of anticancer pharmaceutical composition can be packaged in the whole pharmaceutic adjuvant equably, also can be packaged in carrier holder center or its surface; Can effective ingredient be discharged by direct diffusion or through mode or dual mode like this that polymer is degraded.In addition, the effective ingredient of anticancer pharmaceutical composition also can be packaged in the liposome equably, or makes microsphere with art methods.
Characteristics of the present invention are that used pharmaceutic adjuvant removes the high molecular polymerization beyond the region of objective existence, also contain above-mentioned any one or multiple other pharmaceutic adjuvant.The pharmaceutic adjuvant that adds is referred to as additive.Additive can be divided into filler, porogen, excipient, dispersant, isotonic agent, preservative agent, inhibitor, solubilizing agent, absorption enhancer, film former, gellant etc. according to its function.
Pharmaceutic adjuvant also can be liquid, as, but be not limited to Oleum sesami, suspension, distilled water, physiology towards liquid and semisolid, as (but being not limited to) fruit jelly, paste, ointment etc., above-mentioned pharmaceutic adjuvant is applicable to the compositions that contains or do not contain additive.
Entity-tumor-resistant medicine composition of the present invention can be made into multiple dosage form.As, but be not limited to injection, muddy suspension, ointment, capsule, slow releasing agent, implant, implantation slow release agent etc.; Be different shape, as, but be not limited to granular, lamellar, sphere, bulk, needle-like, bar-shaped and membranaceous.In various dosage forms, based on agent for slow releasing in the body or implant.Above-mentioned dosage form and shape are applicable to the compositions that contains or do not contain additive.
Because anticancer pharmaceutical composition of the present invention can make the action effect of methods such as conventional chemotherapy, immunization therapy, high thermal therapeutical, photochemical therapy, electrotherapy, Biotherapeutics, hormone therapy, magnetic therapy, ultrasonic therapeutic, radiotherapy and gene therapy strengthen.Therefore when local slow discharges, can share, thereby its anticancer effect is further strengthened with above-mentioned non-operative treatment.
When share with above-mentioned non-operative treatment, anticancer pharmaceutical composition of the present invention can be used simultaneously with non-operative treatment, also can use in non-operative treatment is implemented a few days ago, and its purpose is to strengthen as far as possible the sensitivity of tumor.Guanine derivatives, guanine analog have obvious synergistic effect to antimetabolitas, thereby provide a kind of more effective new method for effecting a radical cure former of various human bodies and animal and shifting entity tumor, have very high clinical value and remarkable economical and social benefit.
Route of administration
Anticancer pharmaceutical composition of the present invention can be used through various approach, as in passages through which vital energy circulates, tremulous pulse, subcutaneous, muscle, Intradermal, intracavity, the tumor, tumor week etc.Route of administration depends on multiple factor, for obtaining valid density in position, tumor place, medicine can give through other number of ways, as arterial perfusion optionally, administration in the intra-bladder instillation (intracavitary), abdominal cavity (intraperitoneal) or thoracic cavity (intrapleural) and canalis spinalis.In number of ways, with topical, as based in selective arterial, the tumor, tumor week injection, with in the tumor, the form that slowly discharges of tumor week or tumor chamber serve as preferably, can plant slow-releasing pump, slow releasing capsule, slow releasing agent, implant or sustained release profile in vivo test implant as selecting for use.
When used the part, anticancer pharmaceutical composition of the present invention can directly place around former or the entity tumor that shifts or in the tumor body, also can directly place former or all or part of excision of entity tumor shifted formed intracavity afterwards.
Dosage
The consumption of cancer therapy drug depends on several factors, as, but be not limited to gross tumor volume, patient body weight, administering mode, disease progression situation and therapeutic response.But its principle is to reduce the repair ability of tumor cell to DNA, increases the action effect of therapies such as chemotherapy.The effective dose of guanine or guanine analog is 0.01-80 milligram/kg body weight, is ideal with 1-50 milligram/kg body weight, with 2-10 milligram/kg body weight for the most desirable.And the effective dose of antimetabolitas is 0.01-200 milligram/kg body weight, is ideal with 1-30 milligram/kg body weight, with 2-20 milligram/kg body weight for the most desirable.When guanine or guanine analog and antimetabolitas use in conjunction, the ratio of the two can be arbitrarily, but is good with 1: 9 to 9: 1, and 3: 7 to 7: 3 is best.
Anticancer pharmaceutical composition of the present invention can be used to prepare the medicine of the various entity tumors for the treatment of the people, comprises former or cancer or sarcoma or the carcinosarcoma that shifts originating from brain, central nervous system, kidney, liver, gallbladder, incidence, oral cavity, thyroid, skin, mucosa, body of gland, blood vessel, osseous tissue, lymph node, lungs, esophagus, stomach, mammary gland, pancreas, eyes, nasopharynx part, uterus, ovary, endometrium, cervix uteri, prostate, bladder, colon, rectum.
Anticancer pharmaceutical composition of the present invention also can be used for the treatment of the various entity tumors of house pet and animal, and when being used for the treatment of the various entity tumor of house pet and animal, the material of species specificity is preferably selected in the active ingredient of anticancer pharmaceutical composition of the present invention for use.
Also can add other medicinal ingredient in the anticancer pharmaceutical composition of the present invention, as, but be not limited to antibiotics, antalgica, anticoagulant medicine, hemorrhage etc.Above medicinal ingredient can singly select or multiselect, can join the compositions that contains or do not contain additive, and its content is because of specifically deciding.
Anticancer pharmaceutical composition Main Ingredients and Appearance of the present invention is a holder with the bio-capacitivity material, so do not cause foreign body reaction.Support to place in the object back degradable and absorb, so no longer operation is taken out.Cause discharges contained drug at tumor by local, thereby optionally improves and prolong local drug concentration, can reduce the general toxic reaction that is caused by the conventional route administration simultaneously.
Anticancer pharmaceutical composition can be made into various dosage forms, as, but be not limited to injection, muddy suspension, ointment, capsule, slow releasing agent, implant and implantation slow release agent etc.; Be different shape, as, but be not limited to granular, lamellar, sphere, bulk, needle-like, bar-shaped and membranaceous; Can be good with the tremulous pulse approach through various administrations, directly be placed as the best in the tumor body.Most preferred dosage form of the present invention is slow releasing agent, implant or the implantation slow release agent that bio-capacitivity, degradable absorb.The packing method of its Main Ingredients and Appearance and step in United States Patent (USP) (US5651986) have a detailed description, comprise the some kinds of methods that prepare slow releasing preparation: as, but be not limited to, (i) carrier holder powder and medicament mixed be pressed into implant then, promptly so-called mixing method; (ii) carrier holder fusing, mix solid cooled then, promptly so-called fusion method mutually with medicine to be packaged; (iii) the carrier holder is dissolved in the solvent, medicine dissolution to be packaged or be scattered in the polymer solution, evaporating solvent then, the universe is dry, promptly so-called dissolution method; (iv) spray drying method; And (v) freeze-drying etc.Wherein dissolution method can be used for the manufacturing of microsphere, and anticancer pharmaceutical composition also can be packaged in the liposome.
The characteristics of anticancer pharmaceutical composition technology of preparing of the present invention be with guanine derivatives or guanine analog and antimetabolitas separately or packaged in combination in pharmaceutic adjuvant, proportionally with active ingredient and pharmaceutic adjuvant dissolving, it is dry afterwards to wait to fill part mixing.Be shaped immediately after to be dried and sterilize packing.
Above guanine or guanine analog can be in various degree inhibition or reduce the activity of tumor cell DNA repairase, experiment in vivo and vitro of the present invention is found its notable synergistic effect to antimetabolitas.When the two associating topical application, especially local the placement not only can overcome the toxic reaction that the whole body administration brings, and solved the tumor by local drug level and cross the low and cell sensitive question to medicine.
Test one, guanine or guanine analog are to the inhibitory action of growth of tumour cell
As mentioned above, in the tumor cell activity of DNA repairase increase be its to the tolerific main cause of antimetabolitas, therefore, guanine derivatives can strengthen the inhibitory action of antimetabolitas to growth of tumour cell.This experiment is a subjects with pulmonary carcinoma (LH) tumor cell, adding concentration in 24 hours tumor cell of In vitro culture is the guanine derivatives of 5mM/ml and the 5-fluorouracil of 5mM/ml (5-FU), continues to cultivate the inhibitory action that detects after 48 hours growth of tumour cell.Suppressing effect (%) is shown in Table 1.
Table 1
The D guanine derivatives | The inhibitory rate of cell growth (%) that does not add 5-FU | The inhibitory rate of cell growth (%) that adds 5-FU |
O6-benzyl guanine O6-butyl guanine O6-methyl guanine O6-alkyl guanine | 40 38 50 51 | 84 88 90 80 |
Annotate: the suppression ratio to the growth of pulmonary carcinoma (LH) cell when 5-FU uses separately is 59%.As can be seen from the above table, the guanine derivatives that tries all has the notable synergistic effect to 5-FU, more than 80%.
Test two, guanine derivatives are to the inhibitory action of growth of tumour cell
Method according to test one detects the potentiation of different guanine derivatives to methotrexate, and breast carcinoma (BA) inhibitory rate of cell growth (%) is shown in Table 2.
Table 2
Guanine derivatives | The inhibitory rate of cell growth (%) that does not add methotrexate | The inhibitory rate of cell growth (%) that adds methotrexate |
O6-benzyl guanine O6-butyl guanine O6-methyl guanine O6-alkyl guanine | 50 40 40 34 | 92 90 94 90 |
Annotate: the suppression ratio to the growth of pulmonary carcinoma (LH) cell when methotrexate is used separately is 59%.As can be seen from the above table, the guanine derivatives that tries all has the notable synergistic effect to methotrexate, more than 90%.
Test three, guanine derivatives are to the inhibitory action of growth of tumour cell
Method according to test one detects the potentiation of different guanine derivatives to ftorafur, and liver cancer cell growth suppression ratio (%) is shown in Table 3.
Table 3
Guanine derivatives | The inhibitory rate of cell growth (%) that does not add ftorafur | The inhibitory rate of cell growth (%) that adds ftorafur |
O6-benzyl guanine O6-butyl guanine O6-methyl guanine O6-alkyl guanine | 40 38 50 58 | 88 90 90 92 |
Annotate: the suppression ratio to the growth of pulmonary carcinoma (LH) cell when using ftorafur separately is 56%.As can be seen from the above table, the guanine derivatives that tries all has the notable synergistic effect to ftorafur, more than 90%.
Test four, guanine derivatives are to the inhibitory action of growth of tumour cell
Method according to test one detects the potentiation of different guanine derivatives to gemcitabine, and brain tumor cell growth inhibition ratio (%) is shown in Table 4.
Table 4
Guanine derivatives | The inhibitory rate of cell growth (%) that does not add gemcitabine | The inhibitory rate of cell growth (%) that adds gemcitabine |
O6-benzyl guanine O6-butyl guanine O6-methyl guanine O6-alkyl guanine | 50 40 40 34 | 90 90 88 90 |
Annotate: the suppression ratio to the growth of pulmonary carcinoma (LH) cell when using gemcitabine separately is 56%.As can be seen from the above table, the guanine derivatives that tries has the notable synergistic effect to gemcitabine, more than 90%.
Test five, guanine derivatives are to the inhibitory action of growth of tumour cell
Method according to test one detects the potentiation of different guanine derivatives to cytosine arabinoside, and pancreatic cancer cell growth inhibition ratio (%) is shown in Table 5.
Table 5
Guanine derivatives | The inhibitory rate of cell growth (%) that does not add cytosine arabinoside | The inhibitory rate of cell growth (%) that adds cytosine arabinoside |
O6-benzyl guanine O6-butyl guanine O6-methyl guanine O6-alkyl guanine | 50 51 48 38 | 88 90 88 90 |
Annotate: the suppression ratio to the growth of pulmonary carcinoma (LH) cell when using cytosine arabinoside separately is 56%.As can be seen from the above table, the guanine derivatives that tries has the notable synergistic effect to cytosine arabinoside, more than 88%.
Test six, guanine derivatives are to the inhibitory action of growth of tumour cell
Method according to test one detects the potentiation of different guanine derivatives to cladribine, and stomach cancer cell growth inhibition ratio (%) is shown in Table 6.
Table 6
Guanine derivatives | The inhibitory rate of cell growth (%) that does not add cladribine | The inhibitory rate of cell growth (%) that adds cladribine |
O6-benzyl guanine O6-butyl guanine O6-methyl guanine O6-alkyl guanine | 34 40 40 50 | 90 90 94 89 |
Annotate: the suppression ratio to the growth of pulmonary carcinoma (LH) cell when using cladribine separately is 56%.As can be seen from the above table, the guanine derivatives that tries has the notable synergistic effect to cladribine, more than 89%.
Test one to six result shows that used guanine derivatives and various antimetabolitas all have the obvious suppression effect to growth of tumour cell under used concentration, but the two has obvious synergistic effect when share.
According to detecting with quadrat method, with comprising 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.) different tumor cells, effect to different guanine derivatives and other antimetabolitas compares, found that, be of universal significance.
Tumor-inhibiting action in the body of test seven, guanine derivatives and antimetabolitas.
With the rat is subjects, with 2 * 10
5Individual tumor cell subcutaneous injection is in its hypochondrium, treats that tumor growth after 14 days is divided into it following 10 groups (seeing Table 7).First group is contrast, and the 2nd to 10 group is the treatment group, and wherein, the 2nd group is O6-benzyl guanine (O6-BG), and the 3rd to 6 group is respectively 5-fluorouracil, methotrexate, carmofur and gemcitabine.The the 7th to 10 group of associating that is respectively O6-BG and 5-fluorouracil, methotrexate, carmofur and gemcitabine.All medicines are all through intratumor injection, and dosage is 5mg/kg.The treatment back was measured gross tumor volume size, relatively therapeutic effect (seeing Table 7) on the 30th day.
Table 7
Test group (n) | Suffered treatment | Gross tumor volume (cm
3)
| The P value |
1(6) | Contrast | 78.5±13.3 | |
2(6) | O6-BG | 62±12.3 | <0.05 |
3(6) | 5-FU | 52±10.5 | <0.01 |
4(6) | Methotrexate | 42±8.6 | <0.01 |
5(6) | Carmofur | 40±7.4 | <0.01 |
6(6) | Gemcitabine | 42±7.6 | <0.01 |
7(6) | O6-BG+5-FU | 22±5.6 | <0.001 |
8(6) | The O6-BG+ methotrexate | 23±5.6 | <0.001 |
9(6) | The O6-BG+ carmofur | 20±4.6 | <0.001 |
10(6) | The O6-BG+ gemcitabine | 18±3.6 | <0.001 |
Annotate: O6-benzyl guanine (O6-BG) is a guanine derivatives, and 5-fluorouracil, methotrexate, carmofur and gemcitabine are antimetabolitas.
Tumor-inhibiting action in the body of test eight, guanine derivatives and antimetabolitas.
With the rat is subjects, with 2 * 10
5Individual tumor cell subcutaneous injection is in its hypochondrium, treats that tumor growth after 14 days is divided into it following 10 groups (seeing Table 8).First group is contrast, and the 2nd to 10 group is the treatment group, and wherein, the 2nd group is O6-butyl guanine (O6-bG), and the 3rd to 6 group is respectively Ismipur, doxifluridine, floxuridine, mercaptopurine.The the 7th to 10 group of associating that is respectively O6-bG and Ismipur, doxifluridine, floxuridine and mercaptopurine.All medicines are all through intratumor injection, and dosage is 5mg/kg.The treatment back was measured gross tumor volume size, relatively therapeutic effect (seeing Table 8) on the 30th day.
Table 8
Test group (n) | Suffered treatment | Gross tumor volume (cm
3)
| The P value |
1(6) | Contrast | 88±14 | |
2(6) | O6-bG | 50±12.3 | <0.05 |
3(6) | Ismipur | 58±10.3 | <0.01 |
4(6) | Doxifluridine | 56±10.4 | <0.01 |
5(6) | Floxuridine | 48±8.0 | <0.01 |
6(6) | Mercaptopurine | 44±6.0 | <0.01 |
7(6) | The O6-bG+6-purinethol | 32±4.3 | <0.001 |
8(6) | The O6-bG+ doxifluridine | 30±3.6 | <0.001 |
9(6) | The O6-bG+ floxuridine | 22±3.2 | <0.001 |
10(6) | The O6-bG+ mercaptopurine | 18±1.0 | <0.001 |
Annotate: O6-butyl guanine (O6-bG) is a guanine derivatives, and Ismipur, doxifluridine, floxuridine, mercaptopurine are antimetabolitas.
Tumor-inhibiting action in the body of test nine, guanine derivatives and antimetabolitas.
With the rat is subjects, with 2 * 10
5Individual tumor cell subcutaneous injection is in its hypochondrium, treats that tumor growth after 14 days is divided into it following 10 groups (seeing Table 9).First group is contrast, and the 2nd to 10 group is the treatment group, and wherein, the 2nd group is O6-methyl guanine (O6-MG), and the 3rd to 6 group is respectively thioguanine, ftorafur, galocitabine, ibacitabine.The the 7th to 10 group of associating that is respectively O6-MG and thioguanine, ftorafur, galocitabine, ibacitabine.All medicines are all placed in tumor, and dosage is 5mg/kg.The treatment back was measured gross tumor volume size, relatively therapeutic effect (seeing Table 9) on the 30th day.
Table 9
Test group (n) | Suffered treatment | Gross tumor volume (cm
3)
| The P value |
1(6) | Contrast | 82.5±15.0 | |
2(6) | O6-MG | 64.0±13 | <0.05 |
3(6) | Thioguanine | 62±12.3 | <0.01 |
4(6) | Ftorafur | 46±8.4 | <0.01 |
5(6) | Galocitabine | 48±8.0 | <0.01 |
6(6) | Ibacitabine | 40±7.0 | <0.01 |
7(6) | The O6-MG+ thioguanine | 39±6.0 | <0.001 |
8(6) | The O6-MG+ ftorafur | 27±5.6 | <0.001 |
9(6) | The O6-MG+ galocitabine | 22±3.0 | <0.001 |
10(6) | The O6-MG+ ibacitabine | 19±2.6 | <0.001 |
Annotate: O6-methyl guanine (O6-MG) is a guanine derivatives, and thioguanine, ftorafur, galocitabine, ibacitabine are antimetabolitas.
Tumor-inhibiting action in the body of test ten, guanine derivatives and antimetabolitas.
With the rat is subjects, with 2 * 10
5Individual tumor cell subcutaneous injection is in its hypochondrium, treats that tumor growth after 14 days is divided into it following 10 groups (seeing Table 10).First group is contrast, and the 2nd to 10 group is the treatment group, and wherein, the 2nd group is O6-alkyl guanine (O6-AG), and the 3rd to 6 group is respectively Ismipur, doxifluridine, floxuridine, mercaptopurine.The the 7th to 10 group of associating that is respectively O6-AG and Ismipur, doxifluridine, floxuridine and mercaptopurine.All medicines are all through intratumor injection, and dosage is 5mg/kg.The treatment back was measured gross tumor volume size, relatively therapeutic effect (seeing Table 10) on the 30th day.
Table 10
Test group (n) | Suffered treatment | Gross tumor volume (cm
3)
| The P value |
1(6) | Contrast | 88±14 | |
2(6) | O6-AG | 50±12.3 | <0.05 |
3(6) | Ismipur | 58±10.3 | <0.01 |
4(6) | Doxifluridine | 56±10.4 | <0.01 |
5(6) | Floxuridine | 48±8.0 | <0.01 |
6(6) | Mercaptopurine | 44±6.0 | <0.01 |
7(6) | The O6-AG+6-purinethol | 32±4.3 | <0.001 |
8(6) | The O6-AG+ doxifluridine | 30±3.6 | <0.001 |
9(6) | The O6-AG+ floxuridine | 22±3.2 | <0.001 |
10(6) | The O6-AG+ mercaptopurine | 18±1.0 | <0.001 |
Annotate: O6-alkyl guanine (O6-AG) is a guanine derivatives, and Ismipur, doxifluridine, floxuridine, mercaptopurine are antimetabolitas.
Test seven to ten result shows that used guanine derivatives, guanine analog or derivatives thereof and various antimetabolitas all have the obvious suppression effect to growth of tumour cell when this concentration, but the two has obvious synergistic effect when share.
The present invention be processed into anticancer pharmaceutical composition preparation method as follows:
1. the pharmaceutic adjuvant of weighing is put into container, add the certain amount of organic solvent dissolving evenly, the not strict qualification of the amount of organic solvent, suitable fully to be dissolved as.
2. adding the anticancer active ingredient of weighing shakes up again.The usage ratio of anticancer active ingredient and pharmaceutic adjuvant is decided because of specific requirement.
3. removal organic solvent.Vacuum drying or cold drying all can.
4. dried solid composite is made different shape as required.
5. ray sterilizing (roentgendosis is different because of volume) is standby after the packing.Also available other method sterilization.
In a word, above-mentioned listed various guanines or the guanine analog activity that all can suppress transmethylase.Experimental result also shows the potentiation to listed antimetabolitas of guanine among the present invention or guanine analog.Therefore, the effective ingredient of anticancer compound of the present invention is the associating of any one or multiple guanine or guanine analog and any one or multiple antimetabolitas.
The anticancer pharmaceutical composition that contains above effective ingredient can be made into any dosage form or shape, but is preferred with the agent for slow releasing, wherein is implanted into agent for most preferably with body.
(4) specific embodiment
Below by embodiment the present invention further is illustrated, but is not limited thereto.
Embodiment 1.
80mg pharmaceutic adjuvant ethylene vinyl acetate copolymer (EVAc) is put into container, add 100 milliliters of dichloromethane dissolving mixings after, add 10mg O6-benzyl guanine and 10mg 5-fluorouracil, shake up the dry organic solvent of removing of final vacuum again.Dried solid composite is shaped immediately, and ray sterilizing after the packing must contain the anticancer pharmaceutical composition of percentage by weight 10%O6-benzyl guanine and 10%5-fluorouracil, and body is implanted into agent.The drug release time of this anticancer pharmaceutical composition in external normal saline is 14-24 days, is 20-35 days at the subcutaneous drug release time of mice.All be weight percentage.
Embodiment 2.
As described in embodiment 1, different is that anticancer effective component is:
The Ismipur of 1-50%; 5-fluorouracil; mercaptopurine; thioguanine; methotrexate; carmofur; ftorafur; cytosine arabinoside; hydroxyurea; the 5-fluorouracil nucleoside; galocitabine; gemcitabine; ibacitabine; enocitabine; ancitabine; decitabine; flurocitabine; capecitabine; enocitabine; his shore of imidazoles; GR 30921X; mitotane; fludarabine; the benzyl guanine of cladribine and pentoside and 1-50%; O6-benzyl guanine; O6-butyl guanine; the O6-methyl guanine; O6-alkyl guanine; 2-amino-6-oxypurine; O6-benzyl 2 '-deoxyguanosine; guanine (guanine); 8-amino-O6-benzyl guanine; 8-methyl-O6-benzyl guanine; 8-hydroxyl-O6-benzyl guanine; 8-bromo-O6-benzyl guanine; 8-oxygen-O6-benzyl guanine; 8-trifluoromethyl-O6-benzyl guanine; O6-benzyl uric acid; O6-benzyl xanthine; O6-benzyl-2-fluorine hypoxanthine; Diacetyl-O.sup.6-benzyl-8-oxoguanine; O6-benzyl-8-methyl guanine; O6-benzyl-8-oxo guanine; O6-benzyl-8-bromination guanine; 6-benzyl-8-trifluoromethyl guanine; O6-benzyl-N2-methyl guanine; O6-benzyl-N2N2-dimethylguanine; O6-benzyl-8-trifluoromethyl-9-methyl guanine; O6-benzyl-8-bromo-9-methyl guanine; O6-benzyl-8-bromo-9-pivaloyl oxygen methyl guanine; O6-benzyl-7-pivaloyl oxygen methyl guanine; O6-benzyl-8-bromo-7-pivaloyl oxygen methyl guanine; 8-azepine-O6-benzyl-7-pivaloyl oxygen methyl guanine; 8-azepine-O6-benzyl-7-pivaloyl oxygen methyl guanine; 8-azepine-O6-benzyl guanine; 8-azepine-O6-benzyl-9-methyl guanine; or N.sup.2-Acetyl-O.sup.6-benzyl-8-oxoguanine; O6-benzyl-N2-methyl guanine; O6-benzyl-N2N2-dimethylguanine; 2-amino-6-chloro-8-methyl purine; 2,8-diaminourea-6-chloropurine; O6-benzyl-N2-guanosine; N (7)-methyl guanine; O6-benzyl-9-cyano group guanine; O6-benzyl-N2-guanosine; O6-cycloalkenyl guanine; 1-cyclobutane methyl guanine; the combination of 1-cyclopentenyl methyl guanine and O6-bromothen base guanine.Below all be weight percentage.
Embodiment 3.
With the 80mg molecular weight is that 10000 PLGA (copolymer of hydroxyacetic acid and glycolic) puts into container, add 100 milliliters of dichloromethane, behind the dissolving mixing, add 10mg O6-butyl guanine and 10mg methotrexate, shake up the dry organic solvent of removing of final vacuum again.Dried solid composite is shaped immediately, and ray sterilizing after the packing must contain the anticancer pharmaceutical composition of percentage by weight 10% methotrexate and 10%O6-butyl guanine, and body is implanted into agent.The drug release time of this anticancer pharmaceutical composition in external normal saline is 15-20 days, is 30-40 days at the subcutaneous drug release time of mice.
Embodiment 4.
As described in embodiment 3, different is that effective ingredient is:
The O6-benzyl guanine of 1-50%, O6-butyl guanine, the Ismipur of O6-methyl guanine or O6-alkyl guanine and 1-50%, 5-fluorouracil, mercaptopurine, thioguanine, methotrexate, carmofur, ftorafur, cytosine arabinoside, hydroxyurea, the 5-fluorouracil nucleoside, galocitabine, gemcitabine, ibacitabine, enocitabine, ancitabine, decitabine, flurocitabine, capecitabine, enocitabine, his shore of imidazoles, GR 30921X, mitotane, fludarabine, the combination of cladribine or pentoside.All be weight percentage.
Embodiment 5.
With the 80mg polifeprosan (to carboxy phenyl propane (p-CPP): certain herbaceous plants with big flowers diacid (SA) copolymer) put into container, add 100 milliliters of dichloromethane, behind the dissolving mixing, add 10mgO6-methyl guanine and 10mg cladribine, shake up the dry organic solvent of removing of final vacuum again.Dried solid composite is shaped immediately, and ray sterilizing after the packing must contain the anticancer pharmaceutical composition of percentage by weight 10%O6-methyl guanine and 10% cladribine, and body is implanted into agent.The drug release time of this anticancer pharmaceutical composition in external normal saline is 15-20 days, is 30-40 days at the subcutaneous drug release time of mice.All be weight percentage.
Embodiment 6.
As described in embodiment 5, different is that effective ingredient is:
The O6-benzyl guanine of 2-40%, O6-butyl guanine, the Ismipur of O6-methyl guanine or O6-alkyl guanine and 2-40%, 5-fluorouracil, mercaptopurine, thioguanine, methotrexate, carmofur, ftorafur, cytosine arabinoside, hydroxyurea, the 5-fluorouracil nucleoside, galocitabine, gemcitabine, ibacitabine, enocitabine, ancitabine, decitabine, flurocitabine, capecitabine, enocitabine, his shore of imidazoles, GR 30921X, mitotane, fludarabine, the combination of cladribine or pentoside.All be weight percentage.
Embodiment 7.
With the 80mg molecular weight is that 30000 PLGA (copolymer of hydroxyacetic acid and glycolic) puts into container, add 100 milliliters of dichloromethane, behind the dissolving mixing, add 10mgO6-alkyl guanine and 10mg gemcitabine, shake up the dry organic solvent of removing of final vacuum again.Dried solid composite is shaped immediately, and ray sterilizing after the packing must contain the anticancer pharmaceutical composition of percentage by weight 10%O6-alkyl guanine and 10% gemcitabine, and body is implanted into agent.The drug release time of this anticancer pharmaceutical composition in external normal saline is 15-20 days, is 30-40 days at the subcutaneous drug release time of mice.All be weight percentage.
Embodiment 8.
As described in embodiment 5, different is that effective ingredient is as follows:
(a) combination of his shore of the Ismipur of the O6-benzyl guanine of 2-40% and 2-40%, 5-fluorouracil, mercaptopurine, thioguanine, methotrexate, carmofur, ftorafur, cytosine arabinoside, hydroxyurea, 5-fluorouracil nucleoside, galocitabine, gemcitabine, ibacitabine, enocitabine, ancitabine, decitabine, flurocitabine, capecitabine, enocitabine, imidazoles, GR 30921X, mitotane, fludarabine, cladribine or pentoside; Or
(b) combination of his shore of the Ismipur of the O6-butyl guanine of 2-40% and 2-40%, 5-fluorouracil, mercaptopurine, thioguanine, methotrexate, carmofur, ftorafur, cytosine arabinoside, hydroxyurea, 5-fluorouracil nucleoside, galocitabine, gemcitabine, ibacitabine, enocitabine, ancitabine, decitabine, flurocitabine, capecitabine, enocitabine, imidazoles, GR 30921X, mitotane, fludarabine, cladribine or pentoside; Or
(c) combination of his shore of the Ismipur of the O6-methyl guanine of 2-40% and 2-40%, 5-fluorouracil, mercaptopurine, thioguanine, methotrexate, carmofur, ftorafur, cytosine arabinoside, hydroxyurea, 5-fluorouracil nucleoside, galocitabine, gemcitabine, ibacitabine, enocitabine, ancitabine, decitabine, flurocitabine, capecitabine, enocitabine, imidazoles, GR 30921X, mitotane, fludarabine, cladribine or pentoside; Or
(d) combination of his shore of the Ismipur of the O6-alkyl guanine of 2-40% and 2-40%, 5-fluorouracil, mercaptopurine, thioguanine, methotrexate, carmofur, ftorafur, cytosine arabinoside, hydroxyurea, 5-fluorouracil nucleoside, galocitabine, gemcitabine, ibacitabine, enocitabine, ancitabine, decitabine, flurocitabine, capecitabine, enocitabine, imidazoles, GR 30921X, mitotane, fludarabine, cladribine or pentoside.
Below all be weight percentage.
Embodiment 9.
As described in embodiment 1,3 or 5, different is used pharmaceutic adjuvant is following one of a)-e):
A) molecular weight is the polylactic acid (PLA) of 5000-15000,10000-20000,25000-35000 or 30000-50000;
B) molecular weight is the polyglycolic acid of 5000-15000,10000-20000,25000-35000 or 30000-50000 and the copolymer of hydroxyacetic acid (PLGA);
C) ethylene vinyl acetate copolymer (EVAc);
D) to carboxy phenyl propane (p-CPP): certain herbaceous plants with big flowers diacid (SA) copolymer (polifeprosan) polymer, to carboxy phenyl propane: certain herbaceous plants with big flowers diacid weight ratio is 10: 90,20: 80,30: 70,40: 60,50: 50 or 60: 40;
E) xylitol, oligosaccharide, chitin, potassium salt, sodium salt, hyaluronic acid, collagen protein, gelatin or albumin.
As mentioned above, the preparation method of anticancer pharmaceutical composition of the present invention can be selected as the case may be.Anticancer pharmaceutical composition can be made various dosage forms with existing method, and therefore, above embodiment only is used for explanation, and is not limitation application of the present invention.