CN1299773C - Anti-cancer medicine composition - Google Patents

Abstract

The present invention relates to an anticancer medical composition which belongs to the technical field of drugs. The present invention is composed of pharmaceutic supplementary materials and topology enzyme inhibitors packaged in the pharmaceutic supplementary materials, wherein the topology enzyme inhibitors can suppress DNA repair functions in cells and can reduce the tolerance of tumor cells to nitrosourea anticancer drugs; the pharmaceutic supplementary materials mainly adopt soluble biologic macromolecule polymers which can be degraded and absorbed, and in a degradation and absorption process, the anticancer drugs can be slowly released locally at tumors, so the systemic toxicity reactions of human bodies are reduced obviously; simultaneously, the tumors can locally keep effective drug concentration. The anticancer medical composition also contains the nitrosourea anticancer drugs. The composition is put locally at the tumors, the systemic toxicity reactions of the nitrosourea anticancer drugs and/or the topology enzyme inhibitors can be reduced, and simultaneously, the local drug concentration of the tumors can be improved in a selective mode. The treatment effect of non-operative treatments, such as chemotherapeutics, radiotherapy, etc., can be enhanced.

Description

A kind of anticancer pharmaceutical composition

(1) technical field

The present invention relates to a kind of anticancer pharmaceutical composition, belong to technical field of pharmaceuticals.

(2) background technology

The treatment of entity tumor mainly comprises methods such as operation, radiotherapy and chemotherapy.In used various chemotherapeutics, the action effect of nitrosourea cancer therapy drug is comparatively obvious, has been widely used in multiple malignant tumor.Yet, discover that further the DNA repair function in many tumor cells obviously increases after treatment.The latter often causes the enhancing of tumor cell to the toleration of nitrosourea cancer therapy drug, consequently treatment failure.

Recent findings, deactivation or suppress intracellular dna repair protein can strengthen the part tumor cell to the sensitivity of chemotherapy (referring to " 06-benzyl guanine analog is to the effect of human tumor cells to the cell toxicant sensitivity of alkylating agent " " cancer research " 51 phase 3367-3372 pages or leaves (1991) such as Doran (Dolan et al., Cancer Res., 51,3367-3372,1991)).Yet, blood vessel in the mesenchyma stroma of tumors, connective tissue, stromatin, fine micro protein and collagen protein etc. not only provide support and requisite nutrient substance for the growth of tumor cell, also influenced chemotherapeutics around tumor and 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 " 69 phase 76-82 pages or leaves (1998) (Kong Q et al., J Surg Oncol.1998 Oct such as Kong Qingzhongs; 69 (2): 76-82), improve the restriction that dosage is subjected to general reaction again merely.

Therefore, a concrete theme of the present invention is an anticancer pharmaceutical composition, because the principal element of decision therapeutic effect is the drug level of tumor by local and the tumor cell sensitivity to medicine.And the blood vessel in the mesenchyma stroma of tumors, connective tissue, stromatin, fine micro protein and collagen protein etc. not only provide support and requisite nutrient substance for the growth of tumor cell, have also influenced chemotherapeutics around tumor and infiltration and diffusion in the tumor tissues.

(3) summary of the invention

The present invention is directed to the deficiencies in the prior art, a kind of anticancer pharmaceutical composition is provided.

Anticancer pharmaceutical composition of the present invention comprises anticancer effective component and pharmaceutic adjuvant, and anticancer effective component is:

Topoenzyme inhibitor 0.01-50% and

Nitrosourea cancer therapy drug 0.00-40%

Below all be weight percentage.

The topoenzyme inhibitor decapacitation suppresses can also increase the sensitivity of tumor cell to the nitrosourea cancer therapy drug outside the tumor growth.

Described topoenzyme inhibitor comprises, but be not limited to, and Camptothecin (camptothecin, CPT), lurtotecan [Lurtotecan], topotecan (10-hydroxy-9-dimethylaminomethyl-(S)-camptothecin, topotecan), irinotecan (irinotecan, IRT).

Topoenzyme inhibitor also comprises the derivant of Camptothecin: 9-nitro Camptothecin (9-nitrocamptothecin, 9NC), 7-ethyl-10-hydroxyl-Camptothecin (7-ethyl-10-hydroxy-camptothecin, SN-38), 7-ethyl-10-[4-(1-piperidino)-1-piperidino] and the carbonyl Camptothecin (7-ethyl-10-[4-(1-pyperidino)-1-piperidino] carbonyloxycamptothecin, CPT-11), 10-hydroxyl-Camptothecin (10-Hydroxycamptothecin, HCPT), Homocamptothecins (Homocamptothecins), MD-CPT (10,11-methylenedioxy, 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), pyridine-4-carboxylic acid amides N-[2-(dimethylamino) ethyl) (N-[2-(dimethylamino) ethyl] acridine4-carboxamide, DACA) and the derivant of 5 or 7 replacements, podophyllotoxin (podophyllotoxin), etoposide (Etoposide, epipodophyllotoxins, etoposide, etoposide, VP-16), teniposide (Teniposide, teniposide, VM-26), Podophyllinic acid, podophyllotoxin, trihydroxy-isoflavone (Genistein).

Topoenzyme inhibitor also comprises amycin (adriamycin, Doxorubicin, the 14-doxorubicin), aklavine (Aclacinomycin A, aclarubicin, ACLA, aclarubicin), amrubicin (Amrubicin), 4 '-(acridinylamino) methansulfon-m-anisidide (m-AMSA), daunorubicin (daunorubicin, DNR) or daunorubicin (Daunorubicin) or rubidomycin, amsacrine (mAMSA), the nor-oxygen daunorubicin of 4-(4-demethoxydaunorubicin), detorubicin, epirubicin (epiadriamycin, eDox), 7-O-methyl Nuo Jia-4 '-epirubicin (7-o-methylnogallol-4 '-epiadriamycin), epirubicin (Epirubicin), esorubicin (Esorubicin), carubicin, idarubicin (idarubicin, IDA), rodorubicin, leurubicin (Leurubicin), medorubicin, merbarone, Nemorubicin (Nemorubicin), doxorubicin, pirarubicin (Pirarubicin), N-trifluoro toxin-14-valerate (N-trifluoroacetyladriamycin-14-valerate, AD 32, valrubicin), 2-[4-(7-chloro-2-quinoxalinyl phenoxy base]-propanoic acid ((2-[4-(7-chloro-2-quinoxalinyloxyphenoxy]-propionicacid, XK469), zorubicin (Zorubicin), N-(2-ethyl chloride)-N-nitroso-group urea groups daunorubicin (N-(2-Chloroethyl)-N-nitrosoureidodaunorubicin, AD 312), mitoxantrone (mitroxantrone ormitoxantrone, MTX).

Topoenzyme inhibitor also comprises pyrazoles [1,5-a] indole derivatives, as, but be not limited to GS-2 ,-3 ,-4, GS-5; The dioxy piperazine oxazine derivatives, as, but be not limited to, (+)-1, two (3, the 5-dioxo piperazinyl) propane ((+)-1 of 2-, 2-bis (3,5-dioxopiperazinyl-1-yl) propane, ICRF-187) ,-2,3-two (3,5-dioxo piperazine-1-yl) butane (meso-2,3-bis (3,5-dioxopiperazine-1-yl) butane, ICRF-193), two dioxo piperazine (bisdioxopiperazine); Suramin (Suramin), deoxyguanosine (Deoxyguanosine), lithocholic acid (lithocholic acid, LCA) or Hydrazoic acid,sodium salt (sodium azide) etc.

In the above topology enzyme inhibitor, serve as preferred with Camptothecin, lurtotecan, topotecan, irinotecan, etoposide (VP-16), teniposide (VM-26), amycin (Dox), epirubicin, epirubicin, pirarubicin, mitoxantrone, N-trifluoro toxin-14-valerate, idarubicin.

Topoenzyme inhibitor shared ratio in compositions is decided because of concrete condition, generally speaking, can be good with 1%-50% from 0.01%-99.99%, is best with 2%-30%.All be weight percentage.

Described nitrosourea medicament is; but be not limited to; alestramustine (Alestramustine); streptozocin (streptozotocin; STZ); atrimustine (Atrimustine); ambamustine (Ambamustine); nimustine (ACNU; Nimustine); bendamustine (Bendamustine); ditiomustine (Ditiomustine); bofumustine (Bofumustine); carmustine (carmustine; BCNU; carmustine); elmustine (Elmustine); ecomustine (Ecomustine); galamustine (Galamustine; GCNU); fotemustine (Fotemustine); estramustine (Estramustine); hemustine heCNU He (hemustine; heCNU); pentamustine (Pentamustine; Neptamustine); mannomustine (Mannomustine; MCNU); lomustine (lomustine; CCNU; lomustine; chlorethyl cyclohexyl nitrosourea); methyl lomustine (methyl-CCNU); semustine (Semustine; CH3-CCNU; Me-CCNU); Ranimustine (Ranimustine); prednimustine (Prednimustine); uracil mustard (Uramustine, Uracil Mustard); Sarmustine SarCNU (SarCNU); tauromustine (Tauromustine); tallimustine (Tallimustine) and spiromustine (Spiromustine) etc.Above nitrosourea medicament also comprises its salt, as, but be not limited to sulfate, phosphate, hydrochlorate, Lactobionate, acetate, aspat, nitrate, citrate, purine or pyrimidine salt, succinate and maleate etc.

Above-mentioned nitrosourea medicament and salt thereof can singly select or multiselect, serve as preferred with streptozocin (STZ), estramustine, semustine, nimustine, lomustine, Sarmustine SarCNU, methyl lomustine and carmustine.

The content of nitrosourea cancer therapy drug in compositions can be good with 1%-50% from 0.01%-99.99%, is best with 2%-30%.Below all be weight percentage.

Above-mentioned anticancer effective component is a Camptothecin; hydroxy-camptothecin alkali; teniposide; Irinotecan; pirarubicin; doxorubicin; idarubicin; etoposide; topotecan; teniposide; epirubicin; N-trifluoro toxin-14-valerate or idarubicin and alestramustine; streptozocin; atrimustine; ambamustine; nimustine; bendamustine; ditiomustine; bofumustine; carmustine; elmustine; ecomustine; CNCC; galamustine; fotemustine; estramustine; hemustine heCNU He; pentamustine; mannomustine; lomustine; methyl lomustine; semustine; Ranimustine; prednimustine; uracil mustard; Sarmustine SarCNU; tauromustine; the combination of tallimustine or spiromustine.

Above-mentioned anticancer effective component is preferably, and all is weight percentage:

A) 1-40% Camptothecin and 5-20% carmustine,

Or

B) 1-45% amycin and 5-20% carmustine,

Or

C) 2-40% epirubicin and 5-20% carmustine,

Or

D) 2-40% Irinotecan and 5-20% carmustine,

Or

E) 5-25% etoposide and 5-20% carmustine,

Or

F) 2-35% pirarubicin and 5-20% carmustine,

Or

G) 2-40% epirubicin and 5-20% carmustine,

Or

H) 2-40% hydroxy-camptothecin alkali and 5-20% carmustine,

Or

I) 2-40% doxorubicin and 5-20% carmustine,

Or

J) 2-40% idarubicin and 5-20% carmustine.

K) combination of Camptothecin and nimustine, semustine, lomustine, methyl lomustine, streptozocin or estramustine;

Or

L) combination of amycin and nimustine, semustine, lomustine, Sarmustine SarCNU, streptozocin or estramustine;

Or

M) combination of epirubicin and nimustine, semustine, lomustine, Sarmustine SarCNU, streptozocin or estramustine;

Or

N) combination of Irinotecan and nimustine, semustine, lomustine, Sarmustine SarCNU, streptozocin or estramustine;

Or

O) combination of etoposide and nimustine, semustine, lomustine, Sarmustine SarCNU, streptozocin or estramustine;

Or

P) combination of pirarubicin and nimustine, semustine, lomustine, Sarmustine SarCNU, streptozocin or estramustine;

Or

Q) combination of epirubicin and nimustine, semustine, lomustine, Sarmustine SarCNU, streptozocin or estramustine;

Or

R) combination of doxorubicin and nimustine, semustine, lomustine, Sarmustine SarCNU, streptozocin or estramustine;

Or

S) combination of idarubicin and nimustine, semustine, lomustine, Sarmustine SarCNU, streptozocin or estramustine;

Or

T) combination of hydroxy-camptothecin alkali and nimustine, semustine, lomustine, Sarmustine SarCNU, streptozocin or estramustine.

It is one of following that pharmaceutic adjuvant comprises:

(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 (sebacicacid) etc.; Natural polymer as, but be not limited to, protein and polysaccharide comprise hyaluronic acid, collagen protein, gelatin, albumin etc.

Above-mentioned polyanhydrides can be selected for use, but is not limited to, fragrant polyanhydride, aliphatic polyanhydride; Wherein fragrant polyanhydride will be separated slower, the fusing point height, and dissolubility is low in the organic solvent, however the copolymer of fragrant polyanhydride and aliphatic polyanhydride is comparatively desirable (United States Patent (USP) 4757128) but.Its representative 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), as 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 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 anti-cancer 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 anti-cancer 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.

Anticancer pharmaceutical composition of the present invention can be made into multiple dosage form.As, but be not limited to injection, suspension, ointment, capsule and slow releasing 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.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.Topoenzyme inhibitor has obvious synergistic effect to the nitrosourea cancer therapy drug, 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 vein, tremulous pulse, subcutaneous, muscle, Intradermal, intracavity, the tumor, tumor week etc.Whether route of administration depends on multiple factor, as position, tumor place, perform the operation or transfer, gross tumor volume size, tumor classification, patient age, health, bearing status and requirement etc.For obtain active drug concentration in position, tumor place, arterial perfusion optionally, intra-bladder instillation (intracavitary), (intraspinal) administration in abdominal cavity (intraperitoneal) or thoracic cavity (intrapleural) and the canalis spinalis, but also place in the internal organs, as in the enteric cavity, in the intravesical, uterine cavity, in intravaginal, gastric and the esophagus etc.。In number of ways, with topical, as based in selective arterial, the tumor, tumor week injection, with in the tumor, the form that slowly discharges of tumor week or tumor chamber serve as preferably, can plant slow-releasing pump and slow releasing capsule or sustained release profile in vivo test implant as selecting for use.

When the effective ingredient of anticancer pharmaceutical composition is topoenzyme inhibitor, said composition is based on 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, and the nitrosourea cancer therapy drug can be through administrations such as vein, tremulous pulse, abdominal cavity or thoracic cavities.

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 topoenzyme inhibitor 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.Topoenzyme inhibitor shared ratio in compositions is decided because of concrete condition, can be good with 1%-80% from 0.01%-99.99%, is best with 2%-40%.All be weight percentage.

When used the part, its blood level maintained reduced levels, and concentration maintains higher level in the tumor.

When topoenzyme inhibitor and nitrosourea cancer therapy drug use in conjunction, the ratio of the two can be 1: 9 to 9: 1, the effective dose of topoenzyme inhibitor 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 nitrosourea cancer therapy drug is 0.01-200 milligram/kg body weight, is ideal with 1-30 milligram/kg body weight, with 2-20 milligram/kg body weight for the most desirable.The content in compositions of nitrosourea cancer therapy drug is 0.1%-40%, and the content of topoenzyme inhibitor is 0.1%-30%, all is weight percentage.

Anticancer pharmaceutical composition of the present invention can be used to prepare the medicine of the entity tumors such as various cancers, sarcoma or carcinosarcoma for the treatment of people, house pet and various animals, comprises former or cancer or sarcoma or the carcinosarcoma that shifts originating from brain, central nervous system, kidney, liver, gallbladder, incidence, oral cavity, thyroid, skin, mucosa, body of gland, blood vessel, osseous tissue, lymph node, lungs, esophagus, stomach, mammary gland, pancreas, eyes, nasopharynx part, uterus, ovary, endometrium, cervix uteri, prostate, bladder, colon, rectum.

Also can add other medicinal ingredient in this anticancer pharmaceutical composition, as, but be not limited to antibiotics, antalgica, anticoagulant medicine, hemorrhage etc.Above medicinal ingredient can singly select or multiselect, can join the compositions that contains or do not contain additive, and its content is because of specifically deciding.

Above-mentioned effective ingredient is packaged in the pharmaceutic adjuvant, then topical application.Said composition can with topical, wherein be released to the best with local slow again as injection in selective arterial injection and the direct tumor body for good through various administrations.When used the part, 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.

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 different shape, and wherein the content of active ingredient is decided because of different needs.Can be good with 1%-80% from 0.1%-99.9%, be best with 5%-40%.All be weight percentage.This anticancer pharmaceutical composition can be made into various dosage forms, as, but be not limited to injection, suspension, ointment, capsule, and implantation slow release agent etc.; Be different shape, as, but be not limited to granular, lamellar, sphere, bulk, needle-like, bar-shaped and film sample; 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 the implantation slow release agent that bio-capacitivity, degradable absorb, and can make different shape because of the clinical needs of difference.The packing method of its Main Ingredients and Appearance and step in United States Patent (USP) (US5651986) have a detailed description, comprise the some kinds of methods that prepare slow releasing preparation: as, but be not limited to, (i) carrier holder powder and medicament mixed be pressed into implant then, promptly so-called mixing method; (ii) carrier holder fusing, mix solid cooled then, promptly so-called fusion method mutually with medicine to be packaged; (iii) the carrier holder is dissolved in the solvent, medicine dissolution to be packaged or be scattered in the polymer solution, evaporating solvent then, the universe is dry, promptly so-called dissolution method.Wherein dissolution method can be in order to the manufacturing of microsphere, and its method is arbitrarily, and anticancer pharmaceutical composition also can be packed in the liposome.

The characteristics of anticancer pharmaceutical composition technology of preparing of the present invention be with nitrosourea cancer therapy drug and topoenzyme inhibitor separately or packaged in combination in pharmaceutic adjuvant, according to a certain percentage with active ingredient and pharmaceutic adjuvant dissolving, wait to fill part mixing after the universe dry.Treat that the universe is shaped immediately after dry and sterilizes packing.

Above topoenzyme inhibitor 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 the nitrosourea cancer therapy drug.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.

The external tumor-inhibiting action of test one, topoenzyme inhibitor and nitrosourea cancer therapy drug.

Used tumor cell comprises CNS-1, C6, gastric gland epithelial cancer (SA), bone tumor (BC), breast carcinoma (BA), pulmonary carcinoma (LH), papillary adenocarcinoma of thyroid (PAT), hepatocarcinoma etc.Following topoenzyme inhibitor and nitrosourea cancer therapy drug are added in 24 hours the various tumor cells of In vitro culture by 10ug/ml concentration, continue to cultivate counting cells sum after 48 hours.Its tumor growth suppresses effect and is shown in Table 1.

Table 1

Oncocyte	VP- 16	BCNU	VP-16 +BCNU OX	ACN U	VP-16+ ACNU	CCN U	VP-1 6+ CCN U	GCN U	VP-16 +GCNU
										CNS C6 SA BC BA LH PAT	66％ 62％ 60％ 52％ 50％ 62％ 55％	64％ 64％ 60％ 64％ 62％ 58％ 56％	92％ 96％ 88％ 94％ 98％ 92％ 94％	66％ 60％ 56％ 54％ 62％ 62％ 66％	96％ 94％ 92％ 84％ 82％ 92％ 92％	64％ 64％ 60％ 54％ 52％ 68％ 66％	92％ 96％ 86％ 94％ 96％ 92％ 94％	66％ 60％ 66％ 64％ 62％ 62％ 66％	96％ 94％ 92％ 84％ 82％ 92％ 93％

Explain: VP-16: etoposide is topoenzyme inhibitor; BCNU, ACNU, CCNU, GCNU are respectively carmustine, nimustine, lomustine and galamustine, are the nitrosourea cancer therapy drug.

The external tumor-inhibiting action of test two, topoenzyme inhibitor and nitrosourea cancer therapy drug.

With used tumor cell in the test one, topoenzyme inhibitor and nitrosourea cancer therapy drug are added in 24 hours the various tumor cells of In vitro culture by 10ug/ml concentration, continue to cultivate counting cells sum after 48 hours.Its tumor growth suppresses effect and is shown in Table 2.

Table 2

Oncocyte

Dox

Al

Dox +Al

At

Dox +At

Am

Dox +Am

Be

Dox +Be

CNS C6 SA BC BA LH PAT

68％ 62％ 56％ 54％ 57％ 62％ 52％

64％ 66％ 60％ 56％ 52％ 66％ 66％

92％ 96％ 88％ 94％ 96％ 90％ 96％

67％ 60％ 58％ 54％ 62％ 68％ 66％

96％ 98％ 90％ 84％ 80％ 90％ 98％

65％ 64％ 68％ 64％ 68％ 50％ 56％

94％ 96％ 86％ 90％ 98％ 92％ 94％

64％ 60％ 68％ 64％ 56％ 70％ 76％

98％ 94％ 92％ 86％ 82％ 90％ 96％

Explain: Dox: amycin is topoenzyme inhibitor, i.e. nitrosourea cancer therapy drug synergist; Al: alestramustine, At: atrimustine, Am: ambamustine, Be: bendamustine.And alestramustine, atrimustine, ambamustine, bendamustine are the nitrosourea cancer therapy drug.

The external tumor-inhibiting action of test three, topoenzyme inhibitor and nitrosourea cancer therapy drug.

With used tumor cell in the test one, topoenzyme inhibitor and nitrosourea cancer therapy drug are added in 24 hours the various tumor cells of In vitro culture by 10ug/ml concentration, continue to cultivate counting cells sum after 48 hours.Its tumor growth suppresses effect and is shown in Table 3.

Table 3

Oncocyte	CPT	Di	CPT +Di	Bo	CPT +Bo	El	CPT +El	Ec	CPT +Ec
										CNS C6 SA BC BA LH PAT	69％ 62％ 56％ 54％ 57％ 62％ 53％	64％ 66％ 60％ 56％ 52％ 66％ 66％	92％ 96％ 88％ 94％ 96％ 90％ 96％	67％ 60％ 58％ 54％ 62％ 68％ 66％	96％ 98％ 90％ 84％ 80％ 90％ 98％	65％ 64％ 68％ 64％ 68％ 50％ 56％	94％ 96％ 690％ 90％ 92％ 92％ 94％	64％ 60％ 58％ 64％ 66％ 60％ 66％	94％ 94％ 92％ 86％ 82％ 90％ 96％

Explain: CPT: Camptothecin is a topoenzyme inhibitor, i.e. nitrosourea cancer therapy drug synergist; Di: ditiomustine; Bo: bofumustine; El: elmustine; Ec: ecomustine.And ditiomustine, bofumustine, elmustine and ecomustine are the nitrosourea cancer therapy drug.

The external tumor-inhibiting action of test four, topoenzyme inhibitor and nitrosourea cancer therapy drug.

With used tumor cell in the test one, topoenzyme inhibitor and nitrosourea cancer therapy drug are added in 24 hours the various tumor cells of In vitro culture by 10ug/ml concentration, continue to cultivate counting cells sum after 48 hours.Its tumor growth suppresses effect and is shown in Table 4.

Table 4

Oncocyte	eDox	Fo	eDox +Fo	Es	eDox +Es	He	eDox +He	Ne	eDox +Ne
										CNS C6	56％ 52％	68％ 76％	98％ 96％	68％ 62％	98％ 98％	68％ 64％	98％ 96％	64％ 60％	96％ 90％

SA BC BA LH PAT

46％ 58％ 57％ 60％ 56％

60％ 66％ 58％ 68％ 66％

88％ 94％ 96％ 98％ 96％

58％ 54％ 68％ 68％ 68％

90％ 84％ 88％ 90％ 98％

68％ 60％ 68％ 50％ 58％

94％ 94％ 92％ 93％ 94％

48％ 54％ 76％ 70％ 66％

95％ 88％ 82％ 92％ 92％

Explain: eDox: epirubicin is topoenzyme inhibitor, i.e. nitrosourea cancer therapy drug synergist; Fo: fotemustine; Es: estramustine; He: hemustine heCNU He; Ne: pentamustine.And fotemustine, estramustine, hemustine heCNU He and pentamustine are the nitrosourea cancer therapy drug.

The external tumor-inhibiting action of test five, topoenzyme inhibitor and nitrosourea cancer therapy drug.

With used tumor cell in the test one, following topoenzyme inhibitor and nitrosourea cancer therapy drug are added in 24 hours the various tumor cells of In vitro culture by 10ug/ml concentration, continue to cultivate counting cells sum after 48 hours.Its tumor growth suppresses effect and is shown in Table 5.

Table 5

Oncocyte	Topo	Ma	Topo +Ma	Met	Topo +Met	Se	Topo +Se	Ra	Topo +Ra
										CNS C6 SA BC BA LH PAT	67％ 62％ 56％ 54％ 57％ 62％ 54％	64％ 66％ 60％ 56％ 52％ 66％ 66％	92％ 96％ 88％ 94％ 96％ 90％ 96％	67％ 60％ 58％ 54％ 62％ 68％ 66％	96％ 98％ 90％ 84％ 80％ 90％ 98％	65％ 64％ 68％ 64％ 68％ 50％ 56％	94％ 96％ 86％ 90％ 98％ 92％ 94％	64％ 60％ 58％ 64％ 66％ 60％ 66％	96％ 94％ 92％ 86％ 82％ 90％ 98％

Explain: Topo: topotecan; Ma: mannomustine; Met: methyl lomustine; Se: semustine; Ra: Ranimustine.Wherein topotecan is a topoenzyme inhibitor, i.e. nitrosourea cancer therapy drug synergist, and mannomustine, methyl lomustine, semustine and Ranimustine are the nitrosourea cancer therapy drug.

The external tumor-inhibiting action of test six, topoenzyme inhibitor and nitrosourea cancer therapy drug.

With used tumor cell in the test one, following topoenzyme inhibitor and nitrosourea cancer therapy drug are added in 24 hours the various tumor cells of In vitro culture by 10ug/ml concentration, continue to cultivate counting cells sum after 48 hours.Its tumor growth suppresses effect and is shown in Table 6.

Table 6

Oncocyte	Epi	Pr	Epi +Pr	Ur	Epi +Ur	Ta	Epi +Ta	Sp	Epi +Sp
										CNS C6 SA BC	64％ 62％ 56％ 54％	64％ 66％ 60％ 56％	92％ 96％ 88％ 94％	67％ 60％ 58％ 54％	96％ 98％ 90％ 84％	65％ 64％ 68％ 64％	94％ 96％ 92％ 90％	64％ 60％ 58％ 64％	94％ 94％ 92％ 86％

BA LH PAT

57％ 62％ 44％

52％ 66％ 66％

96％ 90％ 96％

62％ 68％ 66％

80％ 90％ 98％

68％ 50％ 56％

88％ 82％ 84％

66％ 60％ 66％

82％ 90％ 96％

Explain: Epi: epirubicin; Pr: prednimustine; Ur: uracil mustard; Ta: tallimustine; Sp: spiromustine.Wherein Epi is a topoenzyme inhibitor, i.e. nitrosourea cancer therapy drug synergist, and prednimustine, uracil mustard, tallimustine and spiromustine are the nitrosourea cancer therapy drug.

Test is 1 to 6 result show, growth all has the obvious suppression effect to cultured tumor cells in vitro when this concentration for used topoenzyme inhibitor and various nitrosourea cancer therapy drug, but the two has obvious synergistic effect when share.

Tumor-inhibiting action in the body of test seven, topoenzyme inhibitor and nitrosourea cancer therapy drug.

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 6).First group is contrast, and the 2nd to 10 group is the treatment group, and wherein, the 2nd group is idarubicin (IDA), and the 3rd to 6 group is respectively BCNU (carmustine), ACNU, CCNU and estramustine.The the 7th to 10 group is respectively IDA and BCNU, ACNU, CCNU and the female not associating of department.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) 2(6) 3(6) 4(6) 5(6) 6(6) 7(6) 8(6) 9(6) 10(6)	Contrast IDA ACNU BCNU CCNU Estramustine IDA+ACNU IDA+BCNU IDA+CCNU IDA+ Estramustine	78.5±23cm 3 62±4.3cm 3 50±2.5cm 3 40±3.6cm 3 42±4cm 3 42±3.8cm 3 22±3.6cm 3 20±3.6cm 3 20±3.6cm 3 18±3.6cm 3	＜0.05 ＜0.01 ＜0.01 ＜0.01 ＜0.01 ＜0.001 ＜0.001 ＜0.001 ＜0.001

IDA is a topoenzyme inhibitor, and BCNU, ACNU, CCNU and estramustine are the nitrosourea cancer therapy drug.

Tumor-inhibiting action in the body of test eight, topoenzyme inhibitor and nitrosourea cancer therapy drug.

With the rat is subjects, with 2 * 10 ⁵Individual tumor cell (hepatocarcinoma) 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 topoenzyme inhibitor, and the 3rd to 6 group is respectively BCNU (carmustine), ACNU, CCNU and estramustine.The the 7th to 10 group of associating that is respectively topoenzyme inhibitor and BCNU, ACNU, CCNU and estramustine.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) 2(6)	Contrast IRT	80±21cm 3 60±4.5cm 3	＜0.05

3(6) 4(6) 5(6) 6(6) 7(6) 8(6) 9(6) 10(6)

ACNU BCNU CCNU Estramustine IRT+ACNU IRT+BCNU IRT+CCNU IRT+ Estramustine

50±2.5cm 3 44±3.2cm 3 48±3.6cm 3 40±3.8cm 3 30±3.2cm 3 34±3.6cm 3 22±3.2cm 3 20±3.4cm 3

＜0.01 ＜0.01 ＜0.01 ＜0.01 ＜0.001 ＜0.001 ＜0.001 ＜0.001

Explain: IRT: Irinotecan be topoenzyme inhibitor, and BCNU, ACNU, CCNU and estramustine is the nitrosourea cancer therapy drug.

Tumor-inhibiting action in the body of test nine, topoenzyme inhibitor and nitrosourea cancer therapy drug.

With the rat is subjects, with 2 * 10 ⁵Individual tumor cell (breast carcinoma) subcutaneous injection is in its hypochondrium, treats that tumor growth after 14 days is divided into it following 10 groups (seeing Table 9).The 1st group is contrast, and the 2nd to 10 group is the treatment group, and wherein, the 2nd group is topoenzyme inhibitor; The the 3rd to 6 group is respectively the nitrosourea cancer therapy drug.The the 7th to 10 group of associating that is respectively topoenzyme inhibitor and different nitrosourea cancer therapy drugs.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) 2(6) 3(6) 4(6) 5(6) 6(6) 7(6) 8(6) 9(6) 10(6)	Contrast AD 32 Fotemustine Semustine Tauromustine spiromustine AD 32+ Fotemustine AD 32+ Semustine AD 32+ Tauromustine AD 32+ spiromustines	78.5±23cm 3 56±3.3cm 3 41±2.3cm 3 42±3.6cm 3 44±3.4cm 3 44±3.8cm 3 20±3.6cm 3 24±3.6cm 3 26±3.6cm 3 25±3.6cm 3	＜0.05 ＜0.01 ＜0.01 ＜0.01 ＜0.01 ＜0.001 ＜0.001 ＜0.001 ＜0.001

Remarks: AD 32:N-trifluoro toxin-14-valerate be topoenzyme inhibitor, and fotemustine, semustine, tauromustine and spiromustine is the nitrosourea cancer therapy drug.

The result of the test of test 7 to 9 shows, compares with matched group, and topoenzyme inhibitor and nitrosourea cancer therapy drug are used separately all has obvious inhibitory action (P＜0.05) to tumor growth in vivo.And use in conjunction has obvious synergistic effect (P＜0.001).

Test ten, topical application topoenzyme inhibitor are to the potentiation of nitrosourea cancer therapy drug.

With the rat is subjects, with 2 * 10 ⁵Individual sarcoma cell (S180) 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 lurtotecan (Lur), and the 3rd to 6 group is respectively BCNU (carmustine), ACNU, CCNU and estramustine.The the 7th to 10 group is respectively Lur and BCNU, ACNU, CCNU and the female not associating of department.BCNU (carmustine), ACNU, CCNU and estramustine.Topoenzyme inhibitor is placed in tumor, and the nitrosourea cancer therapy drug in one day after lumbar injection, all drug doses are 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) 2(6) 3(6) 4(6) 5(6) 6(6) 7(6) 8(6) 9(6) 10(6)	Contrast Lur ACNU BCNU CCNU Estramustine Lur+ACNU Lur+BCNU Lur+CCNU Lur+ Estramustine	86±20cm 3 66±4.3cm 3 40±2.3cm 3 33±3.6cm 3 34±3.4cm 3 32±3.8cm 3 26±3.6cm 3 25±3.6cm 3 18±3.6cm 3 26±3.6cm 3	＜0.05 ＜0.01 ＜0.01 ＜0.01 ＜0.01 ＜0.001 ＜0.001 ＜0.001 ＜0.001

Remarks: Lur: lurtotecan is topoenzyme inhibitor, i.e. nitrosourea cancer therapy drug synergist; And BCNU, ACNU, CCNU and estramustine are the nitrosourea cancer therapy drug.

Test 11, topical application topoenzyme inhibitor and nitrosourea cancer therapy drug be to the inhibitory action of tumor.

According to testing nine described methods comparison topoenzyme inhibitors and nitrosourea cancer therapy drug tumor-inhibiting action to the intestinal cancer growth.First group is contrast, and the 2nd to 10 group is the treatment group, and wherein, the 2nd group is BCNU (carmustine), and the 3rd to 6 group is respectively topotecan (Topo), Camptothecin (CPT), etoposide (VP-16) and amycin (Dox).The the 7th to 10 group of associating that is respectively BCNU and topotecan, Camptothecin, etoposide and amycin.All medicines are all placed in tumor, and slow releasing preparation is made according to technology of the present invention.Slow releasing preparation weight is 30 milligrams, and all content of medicines are 12%.The treatment back was measured gross tumor volume size, relatively therapeutic effect (seeing Table 11) on the 30th day.

Table 11

Test group (n)	Suffered treatment	Gross tumor volume (cm 3)	The P value
				1(6) 2(6) 3(6) 4(6) 5(6) 6(6) 7(6) 8(6) 9(6) 10(6)	Contrast BCNU Topo CPT VP-16 Dox BCNU+Topo BCNU+CPT BCNU+VP-16 BCNU+Dox	69.5±23cm 3 36±5.8cm 3 39±2.3cm 3 36±3.6cm 3 34±3.4cm 3 30±3.8cm 3 12±3.6cm 3 12±3.6cm 3 16±3.6cm 3 12±3.6cm 3	＜0.05 ＜0.01 ＜0.01 ＜0.01 ＜0.01 ＜0.001 ＜0.001 ＜0.001 ＜0.001

Test 12, topical application topoenzyme inhibitor and nitrosourea cancer therapy drug be to the inhibitory action of tumor.

According to testing nine described methods comparison topoenzyme inhibitors and nitrosourea cancer therapy drug tumor-inhibiting action to the intestinal cancer growth.First group is contrast, and the 2nd to 10 group is the treatment group, and wherein, the 2nd group is CCNU (lomustine), and the 3rd to 6 group is respectively teniposide (VM-26), epirubicin (eDox), epirubicin (Epi), idarubicin (IDA).The the 7th to 10 group of associating that is respectively CCNU and teniposide, epirubicin, epirubicin, idarubicin.All medicines are all placed in tumor, and slow releasing preparation is made according to technology of the present invention.Slow releasing preparation weight is 30 milligrams, and all content of medicines are 12%.The treatment back was measured gross tumor volume size, relatively therapeutic effect (seeing Table 12) on the 30th day.

Table 12

Test group (n)	Suffered treatment	Gross tumor volume (cm 3)	The P value
				1(6) 2(6) 3(6) 4(6) 5(6) 6(6) 7(6) 8(6) 9(6) 10(6)	Contrast CCNU VM-26 eDox Epi IDA CCNU+VM-26 CCNU+eDox CCNU+Epi CCNU+IDA	67.5±23cm 3 36±5.8cm 3 38±2.3cm 3 30±3.6cm 3 34±3.4cm 3 30±3.8cm 3 10±3.6cm 3 12±3.6cm 3 16±3.6cm 3 12±3.6cm 3	＜0.05 ＜0.01 ＜0.01 ＜0.01 ＜0.01 ＜0.001 ＜0.001 ＜0.001 ＜0.001

Remarks: teniposide (VM-26), epirubicin (eDox), epirubicin (Epi), idarubicin (IDA) are topoenzyme inhibitor.

More than test (ten to 12) result shows that compare with matched group, topoenzyme inhibitor and the independent application of nitrosourea cancer therapy drug all have certain tumor-inhibiting action (P＜0.05).Yet use in conjunction has obvious synergistic effect (P＜0.001).Similar potentiation also sees the associating of other topoenzyme inhibitor and other nitrosourea cancer therapy drug.

In a word, the topoenzyme inhibitor in the bright anticancer pharmaceutical composition of the present invention all has obvious synergistic effect to listed nitrosourea cancer therapy drug, and explanation is of universal significance.Therefore, the effective ingredient of anticancer compound of the present invention is any one (or multiple) topoenzyme inhibitor or any one (or multiple) topoenzyme inhibitor and or any one (or multiple) nitrosourea cancer therapy drug.

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.

The preparation method of anticancer pharmaceutical composition of the present invention is as follows:

1. the pharmaceutic adjuvant of weighing is put into container, add the certain amount of organic solvent dissolving evenly, the not strict qualification of the amount of organic solvent, suitable fully to be dissolved as.

2. adding the anticancer active ingredient of weighing shakes up again.The usage ratio of medicine and pharmaceutic adjuvant is decided because of specific requirement.

3. removal organic solvent.Vacuum drying or cold drying all can.

4. dried solid composite is made different shape as required.

5. ray sterilizing (roentgendosis is different because of volume) is standby after the packing.Also available other method sterilization.

(4) specific embodiment

The present invention is processed into anticancer pharmaceutical composition and further is illustrated by following examples, but is not limited thereto.

Embodiment one:

With the 90mg molecular weight is that 20000 polylactic acid (PLA) is put into container, add 100 milliliters of dichloromethane dissolving mixings after, add the anticancer active ingredient of 10mg (epirubicin), shake up the dry organic solvent of removing of final vacuum again.Dried solid composite is shaped immediately, and ray sterilizing after the packing obtains containing the anticancer pharmaceutical composition of 10% epirubicin.Anticancer pharmaceutical composition is prevented in white mice subcutaneous, regularly taken out and survey medicament contg,, and calculate accumulative total and discharge percent (%) according to the residual drug amount.Found that medicine evenly discharged 80-95% in 30 days.All be weight percentage.

Embodiment two:

The method step that is processed into anticancer pharmaceutical composition is identical with embodiment one, but contained effective ingredient is one of following combination:

(1) MD-CPT, (RS)-MD-CPT, (S)-MD-CPT glycinate, 9-amino-(S)-MD-CPT glycinate, lurtotecan, topotecan, Irinotecan, 9-nitro Camptothecin, hydroxy-camptothecin alkali, 7-ethyl-10-hydroxyl-Camptothecin, 7-ethyl-10-[4-(1-piperidino)-1-piperidino] carbonyl Camptothecin, 10-hydroxyl-Camptothecin, Homocamptothecins or Camptothecin;

(2) N-[2-(dimethylamino) ethyl) bifurcation pyridine 4-carboxylic acid amides, podophyllotoxin, teniposide, teniposide, Podophyllinic acid, podophyllotoxin, trihydroxy-isoflavone, amycin, aclarubicin, amrubicin, daunorubicin, daunorubicin, the nor-oxygen daunorubicin of 4-or detorubicin;

(3) epirubicin, 7-O-methyl Nuo Jia-4 '-epirubicin, epirubicin, esorubicin, carubicin, idarubicin, rodorubicin, leurubicin, medorubicin, Nemorubicin, doxorubicin, pirarubicin, N-trifluoro toxin-14-valerate, 2-[4-(7-chloro-2-quinoxalinyl phenoxy base]-propanoic acid, zorubicin, N-(2-ethyl chloride)-N-nitroso-group urea groups daunorubicin, (+)-1,2-two (3, the 5-dioxo piperazinyl) propane, between-2, two (3, the 5-dioxo piperazine-1-yl) butane of 3-, two dioxo piperazines, suramin, deoxyguanosine, lithocholic acid or Hydrazoic acid,sodium salt.

Embodiment three:

The method step that is processed into anticancer pharmaceutical composition is identical with embodiment one, but used pharmaceutic adjuvant is respectively one of following combination:

A) molecular weight is the polylactic acid (PLA) of 5000-15000,10000-20000,25000-35000 or 30000-50000;

B) molecular weight is the polyglycolic acid of 5000-15000,10000-20000,25000-35000 or 30000-50000 and the copolymer of hydroxyacetic acid (PLGA);

C) ethylene vinyl acetate copolymer (EVAc);

D) 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) all is weight percentage.

Embodiment four:

With the 80mg molecular weight is that 10000 polylactic acid (PLGA) is put into container, add 100 milliliters of dichloromethane dissolving mixings after, add 5mg etoposide and 15mg carmustine, shake up the dry organic solvent of removing of final vacuum again.Dried solid composite is shaped immediately, and ray sterilizing after the packing obtains anticancer pharmaceutical composition and contains 5% etoposide and 15% carmustine.The pastille complex is prevented in little under Corium Mus, is regularly taken out and survey medicament contg that according to the residual drug amount, and calculating accumulative total discharges percent (%).Found that medicine evenly discharged 90-95% in 30 days.All be weight percentage.

Embodiment five:

The method step that is processed into anticancer pharmaceutical composition is identical with embodiment four, but contained effective ingredient is one of following combination, all is weight percentage:

(a) 15% carmustine and 5% MD-CPT, (RS)-MD-CPT, (S)-MD-CPT glycinate, 9-amino-(S)-MD-CPT glycinate, lurtotecan, topotecan, Irinotecan, 9-nitro Camptothecin, hydroxy-camptothecin alkali, 7-ethyl-10-hydroxyl-Camptothecin, 7-ethyl-10-[4-(1-piperidino)-1-piperidino] carbonyl Camptothecin, 10-hydroxyl-Camptothecin, Homocamptothecins or Camptothecin;

(b) 15% carmustine and 5% N-[2-(dimethylamino) ethyl) bifurcation pyridine-4-carboxylic acid amides, podophyllotoxin, teniposide, teniposide, Podophyllinic acid, podophyllotoxin, trihydroxy-isoflavone, amycin, aclarubicin, amrubicin, daunorubicin, daunorubicin, the nor-oxygen daunorubicin of 4-or detorubicin;

(c) 15% carmustine and 5% epirubicin, 7-O-methyl Nuo Jia-4 '-epirubicin, epirubicin, esorubicin, carubicin, idarubicin, rodorubicin, leurubicin, medorubicin, Nemorubicin, doxorubicin, pirarubicin, N-trifluoro toxin-14-valerate, 2-[4-(7-chloro-2-quinoxalinyl phenoxy base]-propanoic acid, zorubicin, N-(2-ethyl chloride)-N-nitroso-group urea groups daunorubicin, (+)-1,2-two (3, the 5-dioxo piperazinyl) propane, between-2, two (3, the 5-dioxo piperazine-1-yl) butane of 3-, two dioxo piperazines, suramin, deoxyguanosine, lithocholic acid or Hydrazoic acid,sodium salt.

Embodiment six:

The method step that is processed into anticancer pharmaceutical composition is identical with embodiment four, but contained effective ingredient is one of following combination, all is weight percentage:

(a) 15% nimustine and 5% MD-CPT, (RS)-MD-CPT, (S)-MD-CPT glycinate, 9-amino-(S)-MD-CPT glycinate, lurtotecan, topotecan, Irinotecan, 9-nitro Camptothecin, hydroxy-camptothecin alkali, 7-ethyl-10-hydroxyl-Camptothecin, 7-ethyl-10-[4-(1-piperidino)-1-piperidino] carbonyl Camptothecin, 10-hydroxyl-Camptothecin, Homocamptothecins or Camptothecin;

(b) 15% nimustine and 5% N-[2-(dimethylamino) ethyl) bifurcation pyridine-4-carboxylic acid amides, podophyllotoxin, teniposide, teniposide, Podophyllinic acid, podophyllotoxin, trihydroxy-isoflavone, amycin, aclarubicin, amrubicin, daunorubicin, daunorubicin, the nor-oxygen daunorubicin of 4-or detorubicin;

(c) 15% nimustine and 5% epirubicin, 7-O-methyl Nuo Jia-4 '-epirubicin, epirubicin, esorubicin, carubicin, idarubicin, rodorubicin, leurubicin, medorubicin, Nemorubicin, doxorubicin, pirarubicin, N-trifluoro toxin-14-valerate, 2-[4-(7-chloro-2-quinoxalinyl phenoxy base]-propanoic acid, zorubicin, N-(2-ethyl chloride)-N-nitroso-group urea groups daunorubicin, (+)-1,2-two (3, the 5-dioxo piperazinyl) propane, between-2, two (3, the 5-dioxo piperazine-1-yl) butane of 3-, two dioxo piperazines, suramin, deoxyguanosine, lithocholic acid or Hydrazoic acid,sodium salt.

Embodiment seven:

The method step that is processed into anticancer pharmaceutical composition is identical with embodiment one, but contained effective ingredient is one of following combination, all is weight percentage:

(a) 15% lomustine and 5% MD-CPT, (RS)-MD-CPT, (S)-MD-CPT glycinate, 9-amino-(S)-MD-CPT glycinate, lurtotecan, topotecan, Irinotecan, 9-nitro Camptothecin, hydroxy-camptothecin alkali, 7-ethyl-10-hydroxyl-Camptothecin, 7-ethyl-10-[4-(1-piperidino)-1-piperidino] carbonyl Camptothecin, 10-hydroxyl-Camptothecin, Homocamptothecins or Camptothecin;

(b) 15% lomustine and 5% N-[2-(dimethylamino) ethyl) bifurcation pyridine-4-carboxylic acid amides, podophyllotoxin, teniposide, teniposide, Podophyllinic acid, podophyllotoxin, trihydroxy-isoflavone, amycin, aclarubicin, amrubicin, daunorubicin, daunorubicin, the nor-oxygen daunorubicin of 4-or detorubicin;

(c) 15% lomustine and 5% epirubicin, 7-O-methyl Nuo Jia-4 '-epirubicin, epirubicin, esorubicin, carubicin, idarubicin, rodorubicin, leurubicin, medorubicin, Nemorubicin, doxorubicin, pirarubicin, N-trifluoro toxin-14-valerate, 2-[4-(7-chloro-2-quinoxalinyl phenoxy base]-propanoic acid, zorubicin, N-(2-ethyl chloride)-N-nitroso-group urea groups daunorubicin, (+)-1,2-two (3, the 5-dioxo piperazinyl) propane, between-2, two (3, the 5-dioxo piperazine-1-yl) butane of 3-, two dioxo piperazines, suramin, deoxyguanosine, lithocholic acid or Hydrazoic acid,sodium salt.

Embodiment eight:

The 80mg ethylene vinyl acetate copolymer is put into container, add 100 milliliters of dichloromethane dissolving mixings after, add 10mg topoenzyme inhibitor and 10mg nitrosourea cancer therapy drug, shake up the dry organic solvent of removing of final vacuum again.Dried solid composite is shaped immediately, and ray sterilizing after the packing obtains anticancer pharmaceutical composition and contains 10% nitrosourea cancer therapy drug and 15% topoenzyme inhibitor.The pastille complex is prevented in white mice subcutaneous, regularly taken out and survey medicament contg,, and calculate accumulative total and discharge percent (%) according to the residual drug amount.Found that medicine evenly discharged 90-95% in 30 days.Below all be weight percentage.

Embodiment nine:

The method step that is processed into anticancer pharmaceutical composition is identical with embodiment eight; nitrosourea cancer therapy drug in the contained effective ingredient is an alestramustine; streptozocin; atrimustine; ambamustine; carmustine; nimustine; bendamustine; ditiomustine; bofumustine; elmustine; ecomustine; CNCC; galamustine; fotemustine; estramustine; hemustine heCNU He; pentamustine; mannomustine; lomustine; methyl lomustine; semustine; Ranimustine; SarCNU; prednimustine; uracil mustard; tauromustine; tallimustine or spiromustine; and topoenzyme inhibitor is a MD-CPT; (RS)-MD-CPT; (S)-the MD-CPT glycinate; 9-amino-(S)-the MD-CPT glycinate; lurtotecan; topotecan; Irinotecan; 9-nitro Camptothecin; hydroxy-camptothecin alkali; 7-ethyl-10-hydroxyl-Camptothecin; 7-ethyl-10-[4-(1-piperidino)-1-piperidino] the carbonyl Camptothecin; 10-hydroxyl-Camptothecin; Homocamptothecins; Camptothecin; N-[2-(dimethylamino) ethyl) bifurcation pyridine-4-carboxylic acid amides; podophyllotoxin; teniposide; teniposide; Podophyllinic acid; podophyllotoxin; trihydroxy-isoflavone; amycin; aclarubicin; amrubicin; daunorubicin; daunorubicin; the nor-oxygen daunorubicin of 4-; detorubicin; epirubicin; 7-O-methyl Nuo Jia-4 '-epirubicin; epirubicin; esorubicin; carubicin; idarubicin; rodorubicin; leurubicin; medorubicin; Nemorubicin; doxorubicin; pirarubicin; N-trifluoro toxin-14-valerate; 2-[4-(7-chloro-2-quinoxalinyl phenoxy base]-propanoic acid; zorubicin; N-(2-ethyl chloride)-N-nitroso-group urea groups daunorubicin; mitoxantrone; (+)-1; 2-two (3; the 5-dioxo piperazinyl) propane; between-2; two (3, the 5-dioxo piperazine-1-yl) butane of 3-; two dioxo piperazines; suramin; deoxyguanosine; lithocholic acid or Hydrazoic acid,sodium salt.

Embodiment ten:

The method step that is processed into anticancer pharmaceutical composition is identical with embodiment eight, and contained effective ingredient is:

A) 1-40% Camptothecin and 5-20% carmustine, or

B) 1-45% amycin and 5-20% carmustine, or

C) 2-40% epirubicin and 5-20% carmustine, or

D) 2-40% Irinotecan and 5-20% carmustine, or

E) 5-25% etoposide and 5-20% carmustine, or

F) 2-35% pirarubicin and 5-20% carmustine, or

G) 2-40% epirubicin and 5-20% carmustine, or

H) 2-40% hydroxy-camptothecin alkali and 5-20% carmustine, or

I) 2-40% doxorubicin and 5-20% carmustine, or

J) 2-40% idarubicin and 5-20% carmustine.

Below all be weight percentage.

Embodiment 11:

As embodiment eight, different is that contained effective ingredient is:

A) combination of Camptothecin and nimustine, semustine, lomustine, methyl lomustine, Sarmustine SarCNU, streptozocin or estramustine; Or

B) or the combination of amycin and nimustine, semustine, lomustine, methyl lomustine, Sarmustine SarCNU, streptozocin or estramustine; Or

C) combination of epirubicin and nimustine, semustine, lomustine, methyl lomustine, Sarmustine SarCNU, streptozocin or estramustine; Or

D) combination of Irinotecan and nimustine, semustine, lomustine, methyl lomustine, Sarmustine SarCNU, streptozocin or estramustine; Or

E) combination of etoposide and nimustine, semustine, lomustine, methyl lomustine, Sarmustine SarCNU, Sarmustine SarCNU, streptozocin or estramustine; Or

F) combination of pirarubicin and nimustine, semustine, lomustine, methyl lomustine, Sarmustine SarCNU, streptozocin or estramustine; Or

G) combination of epirubicin and nimustine, semustine, lomustine, methyl lomustine, Sarmustine SarCNU, streptozocin or estramustine; Or

H) combination of doxorubicin and nimustine, semustine, lomustine, methyl lomustine, Sarmustine SarCNU, streptozocin or estramustine; Or

I) combination of idarubicin and nimustine, semustine, lomustine, methyl lomustine, Sarmustine SarCNU, streptozocin or estramustine; Or

J) combination of hydroxy-camptothecin alkali and nimustine, semustine, lomustine, methyl lomustine, Sarmustine SarCNU, streptozocin or estramustine.

Test 13, different embodiment medicine extracorporeal releasing characteristic relatively

Anticancer pharmaceutical composition in the foregoing description ten is placed in the room temperature normal saline soaks, survey the different time release amount of medicine, and calculate accumulative total and discharge percent (%).Be shown in Table 13.

Table 13

Embodiment ten	1 day	3 days	5 days	7 days	14
						A B C D E F G H I J	22 20 19 21 20 23 22 23 24 23	38 39 40 40 41 39 41 42 43 42	59 60 61 61 61 63 62 59 60 59	78 76 72 81 70 79 78 81 82 80	90 85 89 88 86 92 90 90 92 90

Test 14, release characteristics is relatively in the different embodiment medicine body

Anticancer pharmaceutical composition in the foregoing description ten is prevented in white mice subcutaneous, regularly taken out and measure medicament contg,, and calculate accumulative total and discharge percent (%) according to the residual drug amount.Be shown in Table 14.

Table 14

Embodiment ten	1 day	3 days	5 days	7 days	14	21	28 days
								A B C D E F G H I J	10 14 13 12 10 13 12 13 12 10	29 21 22 20 21 19 20 21 21 21	31 33 32 29 30 29 31 31 30 29	50 52 51 48 49 58 56 51 53 50	78 72 73 70 79 70 75 66 68 67	96 94 94 96 94 94 93 94 94 93	99 98 98 99 99 99 98 99 98 97

As can be seen from Table 13, the different pharmaceutical release in vitro no significant difference that tries discharged the about 20%, the 14th day and discharges 85-90 in first day.

As can be seen from Table 14, try to discharge in the different pharmaceutical body also no significant difference, discharged the about 10%, 28th day and discharge more than 98% in first day.But the inside and outside discharges notable difference is arranged, release in vitro is fast than being released in the body.Can keep one month in vivo, external then about 15 days.

Claims (2)

1. an anticancer pharmaceutical composition comprises anticancer effective component and pharmaceutic adjuvant, it is characterized in that, described pharmaceutic adjuvant is a slow-release auxiliary material, and anticancer effective component is:

1) Camptothecin and carmustine, weight ratio are 1～40: 10,

2) amycin and carmustine, weight ratio are 1～45: 10,

3) Irinotecan and carmustine, weight ratio are 1～20: 5, or

4) etoposide and carmustine, weight ratio are 1～5: 2.

2, the described application of anticancer pharmaceutical composition in preparation treatment cancer drug of claim 1.