CN100340296C - Anticarcinogenic internal implant agent - Google Patents

Anticarcinogenic internal implant agent Download PDF

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Publication number
CN100340296C
CN100340296C CNB2005100424334A CN200510042433A CN100340296C CN 100340296 C CN100340296 C CN 100340296C CN B2005100424334 A CNB2005100424334 A CN B2005100424334A CN 200510042433 A CN200510042433 A CN 200510042433A CN 100340296 C CN100340296 C CN 100340296C
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anticancer
tumor
paclitaxel
internal implant
drug
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CN1679949A (en
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孔庆忠
孙娟
于建江
孙宪德
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DASEN BIOLOGICAL PHARMACEUTICAL CO., LTD.
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Shandong Lanjin Pharmaceuticals Co Ltd
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Abstract

The present invention relates to an anticancer internal implanted agent which belongs to the technical field of anticancer drugs. The anticancer internal implanted agent comprises medicinal supplementary materials and anticancer effective components packaged in the medicinal supplementary materials, wherein the anticancer effective components comprise nitrosyl compound sulfaurea anticancer drugs and anticancer drug synergistic agents. The anticancer drug synergistic agents are selected from one kind or the combination of platinum compounds, paclitaxel anticancer drugs and plant alkaloid. The composition can effectively suppress the DNA repair function in tumor cells and can also reduce the tolerance of the tumor cells for the anticancer drugs. The medicinal supplementary materials mainly comprise high molecular biologic capacitability polymers which can be degraded and absorbed, and in the degradation and absorption processes, the anticancer drug can be slowly released at part of a tumor, so that the systemic toxicity reaction of the drug is reduced obviously. Simultaneously, the effective drug concentration can be kept at part of the tumor. The anticancer internal implant agent is put at part of the tumor, the systemic toxicity reaction of the anticancer drug can be reduced, and simultaneously the drug concentration of part of the tumor can be enhanced in a selective mode. The treatment effect of non-operative treatment modes, such as chemotherapeutics, radiotherapy, etc., can be enhanced.

Description

A kind of Anticarcinogenic internal implant agent
(1) technical field
The present invention relates to a kind of Anticarcinogenic internal implant agent, belong to technical field of pharmaceuticals.
(2) background technology
The treatment of entity tumor mainly comprises methods such as operation, radiotherapy and chemotherapy.In the middle of used various treatments, chemotherapy is safer reliable, has been widely used in multiple malignant tumor.Wherein, chemotherapeutics comparatively commonly used is the nitrosourea cancer therapy drug.Yet, discover that further the DNA in many tumor cells repairs and other autoprotection function obviously increases, and then the toleration that shows as used medicine strengthens after the chemotherapeutics treatment.The latter often causes the enhancing of tumor cell to the toleration of other cancer therapy drug, and consequently treatment is difficult more, finally causes the treatment failure.
Recent findings, combined chemotherapy can deactivation or is suppressed the function of intracellular dna repair protein, thereby strengthen the sensitivity of part tumor cell to chemotherapy, comprising the nitrosourea cancer therapy drug, referring to " O6-benzyl guanine analog is to the effect of human tumor cells to the cell toxicant sensitivity of alkylating agent " " cancer research " 51 phase 3367-3372 pages or leaves (1991) such as Doran (Dolan et al., Cancer Res., 51,3367-3372,1991).Yet, blood vessel in the mesenchyma stroma of tumors, connective tissue, stromatin, fine micro protein and collagen protein etc. not only provide support and requisite nutrient substance for the growth of tumor cell, also influenced chemotherapeutics around tumor and infiltration and diffusion in the tumor tissues, " situation of extracellular matrix is to the influence of medicine running in the entity tumor " " cancer research " 60 phase 2497-503 page or leaf (2000) (Netti PA such as carry referring to the Buddhist nun, Cancer Res.2000,60 (9): 2497-503).Because entity tumor excessive expansion hypertrophy, the viscosity of matter was high than its normal surrounding tissue all between matter pressure, tissue elasticity pressure, fluid pressure reached therebetween, therefore, conventional chemotherapy, be difficult to tumor by local and form effective drug level, simple raising dosage is subjected to the restriction of general reaction again, 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).In addition, the cancer drug therapy of low dosage not only can increase the Drug tolerance of cancerous cell, but also can promote the growth of its wettability "; referring to beam etc. " increased after the cancer therapy drug pulse screening human lung carcinoma cell Drug tolerance and external invade the profit ability and with the change of gene expression " " international journal of cancer " 111 phase 484-93 page or leaf (2004) (Liang Y; et al., Int J Cancer.2004; 111 (4): 484-93).
Because the principal element of decision therapeutic effect is except that the sensitivity of tumor cell to medicine, more crucial is the drug level of tumor by local.Because blood vessel, connective tissue, stromatin, fine micro protein and collagen protein etc. in the mesenchyma stroma of tumors, have also influenced chemotherapeutics not only for the growth of tumor cell provides support and requisite nutrient substance 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 Anticarcinogenic internal implant agent is provided.
Anticarcinogenic internal implant agent of the present invention comprises the anticancer effective component and the pharmaceutic adjuvant of effective anticancer, and anticancer effective component is nitrosourea cancer therapy drug and nitrosourea cancer therapy drug synergist.Nitrosourea cancer therapy drug synergist is selected from one of platinum-like compounds, paclitaxel kind anti-cancer drugs thing or plant alkaloid or combination.
Nitrosourea medicament is selected from following one or more: 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; 81); 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, UracilMustard); Sarmustine SarCNU (SarCNU); tauromustine (Tauromustine); tallimustine (Tallimustine) or spiromustine (Spiromustine) etc.
Above nitrosourea medicament 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 nitrosourea medicament and salt thereof can singly select or multiselect, but serve as preferred with streptozocin (STZ), estramustine, nimustine, lomustine and carmustine.
The weight percent content of above nitrosourea cancer therapy drug in Anticarcinogenic internal implant agent is 0.01%-99.99%, is good with 1%-50%, is best with 2%-30%,
Above-mentioned platinum-like compounds and analog thereof or derivant are selected from, as, but be not limited to, cisplatin (cisplatin, DDP), carboplatin (Carboplatin, carboplatin), heptan platinum, DNA-2114, enloplatin (Enloplatin), sulfatodiamino cyclohexane platinum (ring ethylenediamine platinic sulfate), Spiroplatin (spiral shell sulphur platinum amine), dexormaplatin (Dexormaplatin), iproplatin (Iproplatin), lobaplatin (Lobaplatin), rice platinum (Miboplatin), nedaplatin (Nedaplatin), ormaplatin (Ormaplatin), oxaliplatin (Oxaliplatin, Oxaloplatin), sebriplatin (Sebriplatin), spiroplatin (Spiroplatin) or zeniplatin (Zeniplatin) etc.Above platinum-like compounds can singly select or multiselect, serves as preferred with cisplatin, carboplatin, dexormaplatin and oxaliplatin.The weight percent content of above platinum-like compounds in Anticarcinogenic internal implant agent is 1-35%.
Paclitaxel kind anti-cancer drugs thing (taxanes) is selected from, as, but be not limited to, taxol (Paclitaxel, taxol, taxol), Docetaxel (Docetaxel, taxotere, docetaxel) and the derivant of paclitaxel, as, but be not limited to, 2 '-hydroxyl taxol (paclitaxel-2 '-hydroxy), 10-go the acetyl Baccatine III (10-deacetylbaccatin III, DAB), 14 beta-hydroxies-10-removes acetyl Baccatine III (14-OH-DAB), 9-dihydro-13-Baccatine III (DHB), IDN5109,10-removes acetyl taxol (10-deacetyl taxol), 7-table-taxol (7-epi-taxol), Tetraol, Baccatine III (baccatin III), Tetraol V, Semen Caesalpiniae Ramulus et folium taxi cuspidatae (Taxus brevifolia), ground hemlock (Taxus Canadensis), yew (Taxus baccata) and Chinese Ramulus et folium taxi cuspidatae (Taxus chinensis), pointed tooth Ramulus et folium taxi cuspidatae (Taxus cuspidata), cultivate Ramulus et folium taxi cuspidatae (Taxus X media cultivars), Yunnan Ramulus et folium taxi cuspidatae Taxusyunnanensis) and Florida Ramulus et folium taxi cuspidatae (Taxus floridana) etc.Above paclitaxel kind anti-cancer drugs thing 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 paclitaxel kind anti-cancer drugs thing and salt thereof can singly select or multiselect.With taxol (Paclitaxel, taxol) and Docetaxel (Docetaxel, docetaxel) be preferred.The weight percent content of above paclitaxel kind anti-cancer drugs thing in Anticarcinogenic internal implant agent is 1-35%.
Plant alkaloid is the anti-tumor botanical that derives from plant, be selected from, but be not limited to, vinblastine, leurosidine, the Changchun indole, the Changchun chlormethine, the oxo bridge vinblastine, vincristine (Vincristine, leurocristine), Podophyllinic Acid (mitopodozide), (sulphuric acid) vincristine, vincaleucoblastine (Vinblastine), the tartaric acid F 81097, the tartaric acid leurosine, leurosine, the tartaric acid catharanthine, Hainanensine, Hainanolide, vinpocetine, vinorelbine (Vinorelbine, Vinorebine), Vinorelbine monotartrate, the two tartrates of vinorelbine, Vinorelbine tartrate, Vinmegallate (Vinmegallate), vinleurosine (Vinleurosine), vinleucinol (Vinleucinol), vinglycinate (Vinglycinate), Deacetylvincaleucoblastine 4-(N,N-dimethylglycinate) sesquisulfate, virosine, vinfosiltine (Vinfosiltine), vinformide (Vinformide), vinflunine (Vinflunine), vinepidine (Vinepidine), vindesine (Vindesine, vindesine), vinzolidine (Vinzolidine), vintriptol (Vintriptol), vinrosidine (Vinrosidine), oxymatrine, cephalotaxin (Cephalotaxin), 3(R)-Deoxyharringtonine, homoharringtonine (Homoharringtonine), aranotin, monocrotaline (Monocrotaline), maitansine, elliptinium acetate, total alkaloid of harmaline, heart chrysanthemum lactone, Mei Dengsu, rubescensine A, pretazettine, tazettine before the hydrochloric acid, procarbazine, procarbazine hydrochloride, thalictrine, thalidasine, 2,3,5,6-tetramethoxyphenanthro[9,10:6',7', tylophorimidine or white cottonrose hibiscus alkali etc.
Above plant alkaloid cancer therapy drug also comprises their salt, as, but be not limited to sulfate, phosphate, hydrochlorate, Lactobionate, acetate, aspat, nitrate, citrate, purine or pyrimidine salt, tartrate, succinate or maleate etc.
Above plant alkaloid and salt thereof can singly select or multiselect.With vincristine, vincaleucoblastine, vinorelbine and cephalotaxin serves as preferred.The weight percent content of above plant alkaloid in Anticarcinogenic internal implant agent is 1-35%.
Above-mentioned nitrosourea cancer therapy drug synergist shared ratio in Anticarcinogenic internal implant agent is decided because of concrete condition, can be good with 1%-35% from 0.01%-99.99%, is best with 2%-20%.
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 (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.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 Anticarcinogenic internal implant agent 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 Anticarcinogenic internal implant agent 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 10-90% and 90-10%, the blend weight ratio is 10/90-90/10, preferably weight ratio 25/75-75/25.
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 Anticarcinogenic internal implant agent 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 Anticarcinogenic internal implant agent 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 Anticarcinogenic internal implant agent 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 fruit jelly, paste, ointment etc., above-mentioned pharmaceutic adjuvant is applicable to the compositions that contains or do not contain additive.
Anticarcinogenic internal implant agent 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, sustained-release implant etc.; Be different shape, as, but be not limited to granular, lamellar, sphere, bulk, needle-like, bar-shaped and membranaceous.In various dosage forms, serve as preferred with the sustained release profile in vivo test implant.Above-mentioned dosage form and shape are applicable to the compositions that contains or do not contain additive.
Because Anticarcinogenic internal implant agent 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, Anticarcinogenic internal implant agent 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.There is potentiation significantly to act between the inhomogeneity cancer therapy drug, thereby provides a kind of more effective new method, have very high clinical value for effecting a radical cure former of various human bodies and animal and shifting entity tumor.
Route of administration
Anticarcinogenic internal implant agent of the present invention can be used through various approach, as in 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 with topical, as with in the tumor, the form that slowly discharges of tumor week or tumor chamber serve as preferably, during topical also can with systemic chemotherapy or radiotherapy use in conjunction.
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 at the repair ability that can reduce tumor cell, when increasing the chemotherapy action effect and the toxic reaction of not obvious increase medicine.
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 effective dose of nitrosourea cancer therapy drug synergist 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.
Anticarcinogenic internal implant agent of the present invention can be used for the treatment of the entity tumors such as various cancers, sarcoma or carcinosarcoma 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 Anticarcinogenic internal implant agent, 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.
Anticarcinogenic internal implant agent of the present invention can be used in the following manner.
Above-mentioned effective ingredient is packaged in the pharmaceutic adjuvant, then topical application.Good as injecting or be placed as in selective arterial injection and the direct tumor body, wherein be released to the best with local slow again.When use the part, 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.
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.
Anticarcinogenic internal implant agent can be made into different shape, and wherein the content of active ingredient is decided because of different needs.Can be made into various dosage forms, wherein most preferably dosage form is the implantation slow release agent that bio-capacitivity, degradable absorb, and can make different shape because of the clinical needs of difference.The packing method of its Main Ingredients and Appearance and step in United States Patent (USP) (US5651986) have a detailed description, comprise the some kinds of methods that prepare slow releasing preparation: as, but be not limited to, (i) carrier holder powder and medicament mixed be pressed into implant then, promptly so-called mixing method; (ii) carrier holder fusing, mix solid cooled then, promptly so-called fusion method mutually with medicine to be packaged; (iii) the carrier holder is dissolved in the solvent, medicine dissolution to be packaged or be scattered in the polymer solution, evaporating solvent then, the universe is dry, promptly so-called dissolution method: (iv) spray drying method; And (v) freezing and pulverizing method.Wherein dissolution method can be in order to the manufacturing of microsphere, and its method is arbitrarily, and Anticarcinogenic internal implant agent also can be packed in the liposome.
The characteristics of technology of preparing of the present invention are with drug packages that in pharmaceutic adjuvant proportionally with active ingredient and pharmaceutic adjuvant dissolving, the universe is dry afterwards to wait to fill part mixing.Treat that the universe is shaped immediately after dry and sterilizes packing.
The associating of above cancer therapy drug can be in various degree inhibition or reduce the activity of tumor cell DNA repairase, experiment in vivo and vitro of the present invention finds that its use in conjunction has the notable synergistic effect.Place when the part, not only can overcome the toxic reaction that the whole body administration brings, and solved the tumor by local drug level and cross low and cell sensitive question medicine.
Test one, nitrosourea cancer therapy drug and synergist thereof are to the inhibitory action of tumor cell in vitro growth.
For the mutual potentiation of checking inhomogeneity cancer therapy drug used, this test 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. with the tumor cell of multiple In vitro culture.The inhomogeneity cancer therapy drug is pressed the combination shown in the table 1, and cancer therapy drug is added in 24 hours the various tumor cells of In vitro culture by the concentration of 10ug/ml, continue to cultivate after 48 hours the counting cells sum and calculates its suppression ratio to growth of tumour cell (%).
Table 1
Oncocyte (A) (B) (C) (D) (E) (A) +(B) (A) +(C) (A) +(D) (A) +(E)
CNS 62％ 64％ 62％ 66％ 52％ 96％ 94％ 92％ 92％
C6 62％ 64％ 66％ 60％ 56％ 94％ 94％ 96％ 90％
SA 60％ 60％ 68％ 56％ 58％ 92％ 90％ 86％ 96％
BC 52％ 64％ 64％ 54％ 54％ 84％ 94％ 94％ 94％
BA 50％ 62％ 68％ 62％ 88％ 82％ 89％ 96％ 92％
LH 62％ 58％ 62％ 62％ 62％ 92％ 88％ 92％ 92％
PAT 58％ 56％ 64％ 66％ 64％ 92％ 96％ 94％ 92％
Explain: (A): BCNU is the nitrosourea cancer therapy drug; (B): oxaliplatin is platinum-like compounds; (C): docetaxel; Be the paclitaxel kind anti-cancer drugs thing; (D) vinorelbine and (E) vincristine be plant alkaloid.
Test two, detect nitrosourea cancer therapy drug and synergist thereof inhibitory action to the tumor cell in vitro growth by test one described method.The results are shown in Table 2.
Table 2
Oncocyte (A) (B) (C) (D) (E) (A) +(B) (A) +(C) (A) +(D) (A) +(E)
CNS 62％ 64％ 62％ 66％ 92％ 96％ 94％ 92％ 95％
C6 56％ 64％ 66％ 60％ 96％ 94％ 94％ 96％ 94％
SA 68％ 60％ 68％ 56％ 88％ 92％ 90％ 86％ 92％
BC 64％ 64％ 64％ 54％ 94％ 84％ 94％ 94％ 84％
BA 58％ 62％ 68％ 62％ 98％ 82％ 90％ 96％ 82％
LH 62％ 58％ 62％ 62％ 92％ 92％ 88％ 92％ 92％
PAT 64％ 56％ 64％ 66％ 94％ 92％ 96％ 94％ 95％
Explain: (A): ACNU is the nitrosourea cancer therapy drug; (B): cisplatin is platinum-like compounds; (C) paclitaxel and (D) docetaxel be the paclitaxel kind anti-cancer drugs thing; (E) vinorelbine is a plant alkaloid.
Test three, detect nitrosourea cancer therapy drug and synergist thereof inhibitory action to the tumor cell in vitro growth by test one described method.The results are shown in Table 3.
Table 3
Oncocyte (A) (B) (C) (D) (E) (A) +(C) (A) +(D) (A) +(C) (A) +(E)
CNS 52％ 64％ 62％ 66％ 42％ 86％ 94％ 92％ 92％
C6 56％ 64％ 66％ 60％ 48％ 94％ 94％ 96％ 87％
SA 60％ 60％ 68％ 56％ 58％ 92％ 90％ 86％ 85％
BC 64％ 64％ 64％ 54％ 54％ 84％ 94％ 94％ 84％
BA 58％ 62％ 68％ 62％ 48％ 82％ 92％ 96％ 82％
LH 62％ 60％ 62％ 62％ 52％ 92％ 88％ 92％ 92％
PAT 60％ 56％ 64％ 66％ 44％ 92％ 96％ 94％ 905％
Explain: (A): SarCNU is the nitrosourea cancer therapy drug; (B): carboplatin is platinum-like compounds; (C): paclitaxel and (D) docetaxel be the paclitaxel kind anti-cancer drugs thing; () vincaleucoblastine is plant alkaloid.
Test four, detect nitrosourea cancer therapy drug and synergist thereof inhibitory action to the tumor cell in vitro growth by test one described method.The results are shown in Table 4.
Table 4
Oncocyte (A) (B) (C) (D) (E) (A) +(B) (A) +(C) (A) +(D) (A) +(E)
CNS 62％ 64％ 62％ 66％ 52％ 96％ 94％ 92％ 92％
C6 62％ 64％ 66％ 60％ 56％ 94％ 94％ 96％ 90％
SA 60％ 60％ 68％ 56％ 58％ 92％ 90％ 86％ 96％
BC 52％ 64％ 64％ 54％ 54％ 84％ 94％ 94％ 94％
BA 50％ 62％ 68％ 62％ 88％ 82％ 89％ 96％ 92％
LH 62％ 58％ 62％ 62％ 62％ 92％ 88％ 92％ 92％
PAT 58％ 56％ 64％ 66％ 64％ 92％ 96％ 94％ 92％
Explain: (A): CCNU is the nitrosourea cancer therapy drug; (B): oxaliplatin is platinum-like compounds; (C) paclitaxel (D) docetaxel is the paclitaxel kind anti-cancer drugs thing; (E) vinorelbine is a plant alkaloid.
The result of test 1 to 4 shows, growth all has the obvious suppression effect to used cancer therapy drug to cultured tumor cells in vitro when 5-10ul/ml concentration, and used platinum-like compounds, paclitaxel kind anti-cancer drugs thing and plant alkaloid all have obvious synergistic effect (P＜0.001) to the nitrosourea cancer therapy drug.
Test five, nitrosourea cancer therapy drug and synergist thereof are to the inhibitory action of tumor cell in vitro growth.
With the rat is subjects, with 2 * 10 5Individual tumor cell subcutaneous injection is in its hypochondrium, treats that tumor growth is divided into it following 10 groups (seeing Table 5) at random after 14 days.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 5) on the 30th day.
Table 5
Test group (n) Suffered treatment Gross tumor volume (cm 3) The P value
1(6) Contrast 88.5±23cm 3
2(6) (A) carmustine 52±14.3cm 3 ＜0.05
3(6) (B) cisplatin 58±12.5cm 3 ＜0.01
4(6) (C) paclitaxel 40±13.6cm 3 ＜0.01
5(6) (D) Vinorebine 42±14cm 3 ＜0.01
6(6) (E) vincaleucoblastine 22±8cm 3 ＜0.01
7(6) (A)+(B) 21±6cm 3 ＜0.001
8(6) (A)+(C) 20±6cm 3 ＜0.001
9(6) (A)+(D) 20±4.6cm 3 ＜0.001
10(6) (A)+(E) 18±3.6cm 3 ＜0.001
Test six, detect nitrosourea cancer therapy drug and synergist thereof inhibitory action to the interior tumor cell growth by test five described methods.The results are shown in Table 6.
Table 6
Test group (n) Suffered treatment Gross tumor volume (cm 3) The P value
1(6) Contrast 82±21cm 3
2(6) (A) nimustine 50±13cm 3 ＜0.05
3(6) (B) oxaliplatin 58±15cm 3 ＜0.01
4(6) (C) docetaxel 40±13.6cm 3 ＜0.01
5(6) (D) vincaleucoblastine 42±14cm 3 ＜0.01
6(6) (E) paclitaxel 22±8cm 3 ＜0.01
7(6) (A)+(B) 21±6cm 3 ＜0.001
8(6) (A)+(C) 20±5cm 3 ＜0.001
9(6) (A)+(D) 20±4cm 3 ＜0.001
10(6) (A)+(E) 12±3.6cm 3 ＜0.001
The result of the test of test 5 to 6 shows, compares with matched group, and above-mentioned all kinds of cancer therapy drugs are used separately all has obvious inhibitory action (P＜0.05) to tumor growth in vivo.And used platinum-like compounds, paclitaxel kind anti-cancer drugs thing and plant alkaloid all have obvious synergistic effect (P＜0.001) to the nitrosourea cancer therapy drug.
In a word, platinum-like compounds, paclitaxel kind anti-cancer drugs thing and plant alkaloid used among the present invention all have obvious synergistic effect to the nitrosourea cancer therapy drug, are unexpected discoveries the of the present invention, but the tool universal meaning.Therefore, effective ingredient nitrosourea cancer therapy drug of the present invention can with the combination of any one or multiple composition in platinum-like compounds, paclitaxel kind anti-cancer drugs thing and the plant alkaloid, this is a major technique feature of the present invention.Two or more not only potentiation mutually of cancer therapy drug associating, the DNA that also can suppress effectively and destroy in the tumor cell repairs and other autoprotection function, and then increases the therapeutic effect of cancer therapy drug.Body is implanted into agent can slowly be released to tumor by local with cancer therapy drug in the process of its degraded and absorbed, therefore also can keep active drug concentration in tumor by local when obviously reducing its general toxic reaction.Anticarcinogenic internal implant agent of the present invention can be made into any dosage form or shape, but serves as preferred with the agent for slow releasing type.
The preparation method of Anticarcinogenic internal implant agent of the present invention can be any means of the prior art, and one of them 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 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.
(4) specific embodiment
Embodiment one:
With the 80mg molecular weight is that 10000 the polyglycolic acid and the copolymer (PLGA) of hydroxyacetic acid are put into container, add certain amount of organic solvent dissolving mixing after, adds 10 milligrams of carmustines and 10mg oxaliplatin, shake up the dry removal of final vacuum organic solvent again.Dried solid composite is shaped immediately, and ray sterilizing after the packing obtains Anticarcinogenic internal implant agent and contains 10% carmustine and 10% oxaliplatin.All be weight percentage.
Embodiment two:
Make Anticarcinogenic internal implant agent by embodiment one described method, but different is that contained anticancer effective component is:
(a) alestramustine of 1-35%, 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 cisplatin of tallimustine or spiromustine and 1-35%, carboplatin, heptan platinum, DNA-2114, enloplatin, sulfatodiamino cyclohexane platinum, Spiroplatin, dexormaplatin, iproplatin, lobaplatin, rice platinum, nedaplatin, ormaplatin, oxaliplatin, sebriplatin, the combination of spiroplatin or zeniplatin; Or
(b) alestramustine of 1-35%, 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 paclitaxel of tallimustine or spiromustine and 1-35%, docetaxel, 2 '-hydroxyl taxol, 10-removes the acetyl Baccatine III, 14 beta-hydroxies-10-removes the acetyl Baccatine III, the 9-dihydro-13-Baccatine III, IDN5109,10-removes the acetyl taxol, 7-table-taxol, Tetraol, Baccatine III or Tetraol V; Or
(c) alestramustine of 1-35%; streptozocin; atrimustine; ambamustine; Ni Moketing; 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 leurosidine of tallimustine or spiromustine and 1-35%; the Changchun indole; the Changchun chlormethine; the oxo bridge vinblastine; vincristine; Podophyllinic Acid; (sulphuric acid) vincristine; vincaleucoblastine; the tartaric acid F 81097; the tartaric acid leurosine; leurosine; the tartaric acid catharanthine; Hainanensine; Hainanolide; vinpocetine; vinorelbine; liquor epinephrinae bitartratis ophthalmicus; vinorelbine; the two tartrates of vinorelbine; Vinorelbine tartrate; Vinmegallate; vinleurosine; vinleucinol; vinglycinate; Deacetylvincaleucoblastine 4-(N,N-dimethylglycinate) sesquisulfate; virosine; vinfosiltine; vinformide; vinflunine; vinepidine; vindesine; vinzolidine; vintriptol; vinrosidine; oxymatrine; cephalotaxin; 3(R)-Deoxyharringtonine; homoharringtonine; aranotin; monocrotaline; maitansine; elliptinium acetate; total alkaloid of harmaline; heart chrysanthemum lactone; Mei Dengsu; rubescensine A; pretazettine; tazettine before the hydrochloric acid; procarbazine; procarbazine hydrochloride; thalictrine; thalidasine; 2,3,5,6-tetramethoxyphenanthro[9,10:6',7'; the combination of tylophorimidine or white cottonrose hibiscus alkali.
Below all be weight percentage.
Embodiment three:
(EVAc) puts into container with the 80mg ethylene vinyl acetate copolymer, adds 100 milliliters of dichloromethane, behind the dissolving mixing, adds 10mg nimustine and 10 milligrams of Vinorebine, shakes up the dry organic solvent of removing of final vacuum again.Dried solid composite is shaped immediately, and ray sterilizing after the packing obtains Anticarcinogenic internal implant agent and contains 10% nimustine and 10% Vinorebine.All be weight percentage.
Embodiment four:
As described in embodiment three, anticancer effective component that different is is one of following:
(a) combination of the cisplatin of the carmustine of 5-25% and 5-15%, carboplatin, oxaliplatin, vincaleucoblastine, vincristine, vinorelbine, docetaxel or paclitaxel;
(b) combination of the cisplatin of the nimustine of 5-25% and 5-15%, carboplatin, oxaliplatin, vincaleucoblastine, vincristine, vinorelbine, docetaxel or paclitaxel;
(c) combination of the cisplatin of the Sarmustine SarCNU of 5-25% and 5-15%, carboplatin, oxaliplatin, vincaleucoblastine, vincristine, vinorelbine, docetaxel or paclitaxel; Or
(d) combination of the cisplatin of the Sarmustine SarCNU of 5-25% and 5-15%, carboplatin, oxaliplatin, vincaleucoblastine, vincristine, vinorelbine, docetaxel or paclitaxel.
Below all be weight percentage.
Embodiment five:
With the 80mg molecular weight is that 15000 polylactic acid (PLGA) is put into container, adds 100 milliliters of dichloromethane, behind the dissolving mixing, adds 10mg carmustine and 10 milligrams of docetaxels, shakes up the dry organic solvent of removing of final vacuum again.Dried solid composite is shaped immediately, and ray sterilizing after the packing obtains Anticarcinogenic internal implant agent and contains 10% carmustine and 10% docetaxel.All be weight percentage.
Embodiment six:
As described in embodiment five, anticancer effective component that different is is one of following:
(a) combination of the cisplatin of the carmustine of 5-25% and 5-15%, carboplatin, oxaliplatin, vincaleucoblastine, vincristine, vinorelbine, docetaxel or paclitaxel;
(b) combination of the cisplatin of the nimustine of 5-25% and 5-15%, carboplatin, oxaliplatin, vincaleucoblastine, vincristine, vinorelbine, docetaxel or paclitaxel;
(c) combination of the cisplatin of the Sarmustine SarCNU of 5-25% and 5-15%, carboplatin, oxaliplatin, vincaleucoblastine, vincristine, vinorelbine, docetaxel or paclitaxel; Or
(d) combination of the cisplatin of the Sarmustine SarCNU of 5-25% and 5-15%, carboplatin, oxaliplatin, vincaleucoblastine, vincristine, vinorelbine, docetaxel or paclitaxel.
Below all be weight percentage.
Embodiment seven:
70mg polifeprosan (to carboxy phenyl propane: the certain herbaceous plants with big flowers diacid is 20: 80) is put into container, add 100 milliliters of dichloromethane, behind the dissolving mixing, add 15mg carmustine and 15 milligrams of paclitaxels, shake up the dry organic solvent of removing of final vacuum again.With the tabletting shaping immediately of dried solid composite, ray sterilizing after the packing obtains Anticarcinogenic internal implant agent and contains 15% carmustine and 15% paclitaxel.All be weight percentage.
Embodiment eight:
As described in embodiment seven, anticancer effective component that different is is one of following:
(a) combination of the cisplatin of the carmustine of 5-25% and 5-15%, carboplatin, oxaliplatin, vincaleucoblastine, vincristine, vinorelbine, docetaxel or paclitaxel;
(b) combination of the cisplatin of the nimustine of 5-25% and 5-15%, carboplatin, oxaliplatin, vincaleucoblastine, vincristine, vinorelbine, docetaxel or paclitaxel;
(c) combination of the cisplatin of the Sarmustine SarCNU of 5-25% and 5-15%, carboplatin, oxaliplatin, vincaleucoblastine, vincristine, vinorelbine, docetaxel or paclitaxel; Or
(d) combination of the cisplatin of the Sarmustine SarCNU of 5-25% and 5-15%, carboplatin, oxaliplatin, vincaleucoblastine, vincristine, vinorelbine, docetaxel or paclitaxel.
Below all be weight percentage.
Embodiment nine:
With the 80mg molecular weight is that 30000 polylactic acid (PLGA) is put into container, adds 100 milliliters of dichloromethane, behind the dissolving mixing, adds 10mg nimustine and 10 milligrams of docetaxels, shakes up the dry organic solvent of removing of final vacuum again.Dried solid composite is shaped immediately, and ray sterilizing after the packing obtains Anticarcinogenic internal implant agent and contains 10% nimustine and 10% docetaxel.All be weight percentage.
Embodiment ten:
Make Anticarcinogenic internal implant agent as method as described in the embodiment nine, anticancer effective component that different is is one of following:
(a) combination of the cisplatin of the carmustine of 5-25% and 5-15%, carboplatin, oxaliplatin, vincaleucoblastine, vincristine, vinorelbine, docetaxel or paclitaxel;
(b) combination of the cisplatin of the nimustine of 5-25% and 5-15%, carboplatin, oxaliplatin, vincaleucoblastine, vincristine, vinorelbine, docetaxel or paclitaxel;
(c) combination of the cisplatin of the Sarmustine SarCNU of 5-25% and 5-15%, carboplatin, oxaliplatin, vincaleucoblastine, vincristine, vinorelbine, docetaxel or paclitaxel; Or
(d) combination of the cisplatin of the Sarmustine SarCNU of 5-25% and 5-15%, carboplatin, oxaliplatin, vincaleucoblastine, vincristine, vinorelbine, docetaxel or paclitaxel.
Below all be weight percentage.
Embodiment 11:
Make Anticarcinogenic internal implant agent by embodiment one to ten described method, different is, and that used pharmaceutic adjuvant is respectively is one of following:
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), to carboxy phenyl propane: certain herbaceous plants with big flowers diacid weight ratio is 90: 10,80: 20,70: 30,60: 40,50: 50 or 40: 60 to polifeprosan;
E) hyaluronic acid, collagen protein, gelatin, albumin xylitol, oligosaccharide, chitin, potassium salt or sodium salt.
Embodiment 12:
Make Anticarcinogenic internal implant agent by embodiment five described methods, that anticancer effective component is is one of following but different is:
(a) 10% carmustine and 10% cisplatin;
(b) 10% carmustine and 10% carboplatin;
(c) 10% carmustine and 10% oxaliplatin;
(d) 10% carmustine and 10% vincaleucoblastine;
(e) 10% carmustine and 10% vincristine;
(f) 10% carmustine and 10% vinorelbine;
(g) 10% carmustine and 10% docetaxel; Or
(h) 10% carmustine and 10% paclitaxel;
Below all be weight percentage.
Embodiment 13: the Anticarcinogenic internal implant agent extracorporeal releasing characteristic relatively
Anticarcinogenic internal implant agent among the embodiment 12 is placed in the room temperature normal saline soaks, survey the burst size of different time medicine (carmustine), and calculate accumulative total and discharge percent (%).Be shown in Table 7.
Table 7
The pastille polymer 1 day 3 days 5 days 7 days 14 days
(a) (b) (c) (d) (e) (f) (g) (h) 22 20 21 21 20 23 22 23 40 39 40 40 41 39 41 42 59 60 61 61 61 63 62 59 78 76 72 81 70 79 78 81 90 88 89 88 86 92 90 90
Embodiment 14: release characteristics relatively in the Anticarcinogenic internal implant agent body
It is subcutaneous that Anticarcinogenic internal implant agent among the embodiment 12 is put in white mice, regularly takes out and measure medicament contg, according to the residual drug amount, and calculates accumulative total and discharge percent (%).Be shown in Table 8.
Table 8
Embodiment 1 day 3 days 5 days 7 days 14 days 21 days 28 days
(a) (b) 10 14 29 21 31 33 50 52 78 72 90 90 96 96
(c) (d) (e) (f) (g) (h) 13 12 10 13 12 13 22 20 21 19 20 21 32 29 30 29 31 31 51 48 49 58 56 51 73 70 79 70 75 66 91 88 94 84 86 84 97 94 99 94 98 96
As can be seen from Table 7, 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.
By table on 8 as can be seen, institute try to discharge in the different pharmaceutical body also no significant difference, and release in first day release in the about 10%, 28th day is more than 95%.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 external about 15 days in vivo.
As mentioned above, Anticarcinogenic internal implant agent can be made various dosage forms with existing method.Above embodiment only is used for explanation, and is not limitation application of the present invention.

Claims (3)

1. Anticarcinogenic internal implant agent, anticancer effective component and pharmaceutic adjuvant by effective anticancer are formed, it is characterized in that anticancer effective component is nitrosourea cancer therapy drug and nitrosourea cancer therapy drug synergist, the molecular weight that pharmaceutic adjuvant absorbs for the bio-capacitivity degradable is 15000 polylactic acid;
Described nitrosourea cancer therapy drug synergist is one of platinum-like compounds, paclitaxel kind anti-cancer drugs thing or plant alkaloid or combination;
Described nitrosourea cancer therapy drug is selected from one or more of streptozocin, nimustine, carmustine, elmustine, ecomustine, CNCC, fotemustine, hemustine heCNU He, pentamustine, lomustine, semustine, Ranimustine, uracil mustard, Sarmustine SarCNU, tauromustine or spiromustine, and its content in Anticarcinogenic internal implant agent is 1-50%;
Described platinum-like compounds is selected from one of cisplatin, carboplatin, heptan platinum, DNA-2114, enloplatin, sulfatodiamino cyclohexane platinum, Spiroplatin, dexormaplatin, iproplatin, lobaplatin, rice platinum, nedaplatin, ormaplatin, oxaliplatin, sebriplatin, spiroplatin or zeniplatin or combination, and the weight percent content of platinum-like compounds in Anticarcinogenic internal implant agent is 1-35%;
Described paclitaxel kind anti-cancer drugs thing is selected from paclitaxel, docetaxel, 10-and goes acetyl Baccatine III, 10-to go one of acetyl taxol, Tetraol or Baccatine III or combination, and the weight percent content of above paclitaxel kind anti-cancer drugs thing in Anticarcinogenic internal implant agent is 1-35%;
Described plant alkaloid is selected from vinblastine, vincristine, vincristine sulfate, the tartaric acid F 81097, the tartaric acid leurosine, leurosine, the tartaric acid catharanthine, vinpocetine, vinorelbine, Vinorelbine tartrate, Vinmegallate, vinleurosine, vinleucinol, vinglycinate, Deacetylvincaleucoblastine 4-(N,N-dimethylglycinate) sesquisulfate, vinfosiltine, vinformide, vinflunine, vinepidine, vindesine, vinzolidine, one of vintriptol or vinrosidine or combination, the weight percent content of above plant alkaloid in Anticarcinogenic internal implant agent is 1-35%;
The percentage by weight sum of anticancer effective component and pharmaceutic adjuvant is 100%.
2. Anticarcinogenic internal implant agent according to claim 1 is characterized in that anticancer effective component is one of following;
(a) combination of the cisplatin of the carmustine of 5-25% and 5-15%, carboplatin, oxaliplatin, vincristine, vinorelbine, docetaxel or paclitaxel; Or
(b) combination of the cisplatin of the nimustine of 5-25% and 5-15%, carboplatin, oxaliplatin, vincristine, vinorelbine, docetaxel or paclitaxel; Or
(c) combination of the cisplatin of the Sarmustine SarCNU of 5-25% and 5-15%, carboplatin, oxaliplatin, vincristine, vinorelbine, docetaxel or paclitaxel;
Below all be weight percentage.
3. the described Anticarcinogenic internal implant agent of claim 1 is used to prepare the medicine that treatment originates from cancer, sarcoma or the carcinosarcoma of people and animal brain, central nervous system, kidney, liver, gallbladder, incidence, oral cavity, thyroid, skin, mucosa, blood vessel, osseous tissue, lymph node, lungs, esophagus, stomach, mammary gland, pancreas, eyes, nasopharynx part, uterus, ovary, prostate, bladder, colon or rectum former or secondary.
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