CN100569288C - A kind of entity-tumor-resistant medicine composition - Google Patents
A kind of entity-tumor-resistant medicine composition Download PDFInfo
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- CN100569288C CN100569288C CNB2007101127387A CN200710112738A CN100569288C CN 100569288 C CN100569288 C CN 100569288C CN B2007101127387 A CNB2007101127387 A CN B2007101127387A CN 200710112738 A CN200710112738 A CN 200710112738A CN 100569288 C CN100569288 C CN 100569288C
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Abstract
A kind of entity-tumor-resistant medicine composition.Comprise anticancer effective component and pharmaceutic adjuvant, anticancer effective component is dichloro ethamine kind drug and dichloro ethamine kind drug synergist.The dichloro ethamine kind drug synergist is mainly platinum-like compounds, tetrazine class medicine and/or topoenzyme inhibitor, and pharmaceutic adjuvant is mainly the macromolecule polymer that the bio-capacitivity degradable absorbs, in the process of its degraded and absorbed, cancer therapy drug slowly can be released to tumor by local, therefore when obviously reducing its general toxic reaction, also can keep active drug concentration in tumor by local.Tumor by local is placed the general toxic reaction that said composition not only can reduce medicine, can also optionally improve the drug level of tumor by local simultaneously, strengthens the therapeutic effect of non-operative treatment such as chemotherapeutics and radiotherapy.
Description
The application is dividing an application of 200510042235.8 patent applications of the same name, April 6 2005 applying date.
(1) technical field
The present invention relates to a kind of entity-tumor-resistant medicine composition, belong to technical field of pharmaceuticals.
(2) background technology
Treatment for cancer mainly comprises methods such as operation, radiotherapy and chemotherapy.In used various chemotherapeutics, the action effect of dichloro ethamine kind drug is comparatively obvious, has been widely used in multiple malignant tumor.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, 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.
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).
(3) summary of the invention
The present invention is directed to the deficiencies in the prior art, a kind of entity-tumor-resistant medicine composition is provided.
Entity-tumor-resistant medicine composition of the present invention comprises anticancer effective component and pharmaceutic adjuvant, and wherein anticancer effective component is for being dichloro ethamine kind drug and dichloro ethamine kind drug synergist.Wherein the dichloro ethamine kind drug synergist is one of platinum-like compounds, tetrazine kind compound or topoenzyme inhibitor or combination.
Dichloro ethamine kind drug (bischloroethylamines) is selected from one of following or combination:
Chlorambucil (chlorambucil, chlorambucil), cyclophosphamide (Cyclophosphamide, CTX), 4H-peroxide cyclophosphamide (4H-CTX), ifosfamide (Ifosfamide, Isophosphamide), three mustard cyclophosphamide, sufosfamide (Sufosfamide), defosfamide (Defosfamide), Mafosfamide (Mafosfamide), perfosfamide (Perfosfamide), trofosfamide (Trofosfamide), thiocarzolamide, melphalan (Melphalan), metamelfalan (Metamelfalan), methoxymerphalan (Methoxymerphalan), formylmerphalan (Formylmerphalan), hexamethylmelamine (hexamethylmelamine), Ametantrone, Thymopentin, clomifene, letrozole, disodium cantharidinate, cantharidin (cantharidine), sodium cantharidinate, N-methylcantharidimide, N-hydroxycantharidin, norcantharidin (Norcantharidin), thiocolciran, sarcolysine, methasquin, NSC-1895, mannomustine (Mannosulfan), treosulfan (Treosulfan), ritrosulfan (Ritrosulfan), an improsulfan (Improsulfan), Z 7557, Spirobromin, d-mannitobusulphan, cis-diamminetetrachloroplatinum, enpromate, epipropidine, ethoxene, bimolane, second hydroxyl urea, ethyliminum, etoglucid (etoglucid, Ethoglucid, Etoglucid), benefit hair phosphorus ammonium, E39, pipobroman (pipobroman, Pipobroman), piposulfan (A-20968, Piposulfan), Li Chuikexin, Dup 942, Dup 942, NSC 122402, radioplex, rofecoxib, taxodione, trimethylolmelamine, urethane, Zorubicin Hydrochloride, RP-22050, triethylenemelaine (triethylenemelamine), epoxypiperazine (epoxypiperazine), benzene assistant TEPA (Benzodepa), Phopurine (Pumitepa), meturedepa (Meturedepa), Ah bundle's TEPA (Aza-TEPA), urethimine (Uredepa) or their salt.
The salt of above dichloro ethamine kind drug is sulfate, phosphate, hydrochlorate, Lactobionate, acetate, aspat, nitrate, citrate, purine or pyrimidine salt, succinate or maleate.
Above dichloro ethamine kind drug can singly select or multiselect, but serves as preferred with Chlorambucil, cyclophosphamide, ifosfamide, melphalan, 4H-peroxide cyclophosphamide, methoxymerphalan, hexamethylmelamine, letrozole, cantharidin, norcantharidin or Ah bundle's TEPA.
The percentage by weight of dichloro ethamine kind drug in compositions is good from 0.01%-99.99% with 1%-50%, is best with 5%-30%.
As the platinum-like compounds of dichloro ethamine kind drug synergist, be selected from one of following or combination:
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).
Above platinum-like compounds with cisplatin, carboplatin, dexormaplatin, heptan platinum and oxaliplatin serve as preferred.
The percentage by weight of above-mentioned platinum-like compounds in compositions can be 0.1%-60%, is good with 1%-30%, and 5%-20% is best.
Be selected from one of following or combination as the tetrazine kind compound of dichloro ethamine kind drug synergist:
Imidazo tetrazine (imidazotetrazine), imidazopyrazine (imidazopyrazine), 1H-imidazo [b] piperazine (1H-imidazo[b] pyrazine), imidazopyridine (imidazopyridine), 1H-imidazo [1,2-a] pyridine (1H-imidazo[1,2-a] pyridinum), procarbazine (procarbazine, PCB), mitozolomide (mitozolomide), dacarbazine (dacarbazine, DCB), temozolomide (Temozolomide or 8-Carbamoyl-3-methylimidazo[5,1-d]-1,2,3, and analog or derivant such as 4-carboxyl temozolomide [4--carbonyl] temozolomide 5-tetrazin-4 (3H)-one or NSC 362856)), 3-N-methyl temozolomide [3-N-methyl] temozolomide), the pyrroles [2,1-d] [1,2,3,5] tetrazine-4 (3H)-temozolomide (Pyrrolo[2,1-d] [1,2,3,5] tetrazine-4 (3H)-ones), the pyrroles [2,1-d] [1,2,3,5] tetrazine 10a-o (Pyrrolo[2,1-d] [1,2,3,5] tetrazinones 10a-o), temozolomide's roguing azepine derivatives such as 5-(3-N-methyl three nitrogen-1-yl)-imidazo-4-carboxylic acid amides (MTIC, 5-(3-N-methyltriazen-1-yl)-imidazole-4-carboxamide), 8-nitro-3-methyl-phendioxin, 2,3,5-four azatropylidenes-4-temozolomide (8-nitro-3-methyl-benzo-1,2,3,5-tetrazepin-4 (3H)-one, NIME), 3,5-dimethyl-pyrido-1,2,3,5-four azatropylidenes-4-temozolomide (3,5-dimethyl-pyrido-1,2,3,5-tetrazepin-4-one, PYRZ) or 3-(2-ethyl chloride)-N, N dimethyl-4-oxygen-3,4-glyoxalidine [5,1-d]-1,2,3,5-tetrazine-8-carboxylic acid amides (3-(2-chloroethyl)-N, N-dimethyl-4-oxo-3,4-dihydroimidazo[5,1-d]-1,2,3,5-tetrazine-8-carboxamide, CDODTC).
Above-mentioned tetrazine kind compound can singly select or multiselect, but is preferred with imidazo tetrazine, imidazopyrazine, 1H-imidazo [b] piperazine, imidazopyridine, 1H-imidazo [1,2-a] pyridine, procarbazine, mitozolomide, dacarbazine or temozolomide.
Tetrazine kind compound shared ratio in compositions is decided because of concrete condition, generally speaking, can be good with 1%-50% from 0.01%-80%, is best with 5%-30%.All be weight percentage.
Be selected from one of following or combination as the topoenzyme inhibitor of dichloro ethamine kind drug synergist:
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] acridine-4-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), the 14-doxorubicin, amrubicin (Amrubicin), Ai Rou than star (4 '-(acridinylamino) methansulfon-m-anisidide (amsacrine, m-AMSA)), the nor-oxygen daunorubicin of 4-(4-demethoxydaunorubicin), detorubicin, 7-O-methyl Nuo Jia-4 '-epirubicin (7-o-methylnogallol-4 '-epiadriamycin), esorubicin (Esorubicin), carubicin, idarubicin (idarubicin, IDA), rodorubicin, leurubicin (Leurubicin), medorubicin, Nemorubicin (Nemorubicin), doxorubicin, 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), 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).
In the above topology enzyme inhibitor, serve as preferred than star, rodorubicin, leurubicin, zorubicin, N-trifluoro toxin-14-valerate, idarubicin with Camptothecin, hydroxy-camptothecin alkali, lurtotecan, topotecan, irinotecan, etoposide, teniposide, amrubicin, Ai Rou.
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 5%-30%.All be weight percentage.
Dichloro ethamine kind drug synergist shared percentage by weight in compositions is decided because of concrete condition, generally speaking, can be good with 1%-50% from 0.01%-80%, is best with 5%-30%.The weight ratio of dichloro ethamine kind drug and its synergist is 1-9: 1 to 1: 1-9.
Pharmaceutic adjuvant of the present invention is can be through enzyme, soda acid or tissue fluid hydrolysis or degraded.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
Polyamide (polyamides), polypeptide (polypeptides), polyactide (polylactides) are as polylactic acid (polylactic acid), polyactide and glycolide copolymer (as the copolymer (PLGA) of glycolic and lactic acid), poe (polyorthoesters), polyphosphazene (polyphosphazenes), to carboxy phenyl propane (p-CPP), certain herbaceous plants with big flowers diacid
Liposome, Polyethylene Glycol (polyglycolide) (polymer of hydroxyacetic acid and lactic acid), carboxylic acids (carboxylic acids), fatty acid (fatty acids), phospholipid (phospholipids), nucleic acid (nucleic acids), polyamino acid (polyamino acids), aminoacid such as phenylalanine (phenylalanine), tyrosine (tyrosine), different bright (isoleucine), polynucleotide (polynucleotides); Natural polymer as, but be not limited to, protein and polysaccharide (polysaccharides) comprise hyaluronic acid (hyaluronic acid), chondroitin sulfate (chondroitin sulfate), collagen protein, gelatin, albumin etc.Wherein, preferred polymer is polyactide, Polyethylene Glycol or polyactide and glycolide copolymer (as the copolymer (PLGA) of glycolic and lactic acid).
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 lactic acid of polylactic acid (PLA), polyglycolic acid (PGA), polylactic acid (PLA) and polyglycolic acid.Above polyhydroxy acid can singly select or multiselect, and when singly selecting, the molecular weight of polylactic acid (PLA) can be, but is not limited to, 5000-100, and 000, but with 10,000-50000 is preferred, with 10,000-30000 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; The molecular weight of the copolymer of glycolic and lactic acid (PLGA) can be, but is not limited to, 1000-100, and 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.When PLA and PGA mixing, its content percentage by weight is respectively 0.1-99.9% and 99.9-0.1%.Compositions can discharge effective ingredient by the mode of direct diffusion and/or degraded.Above molecular weight peak value scope is that GPC records.
The nondegradable polymer of above-mentioned biology comprises, but be not limited to: polyethylene propylene (polyvinyl propylene), polyvinylpyrrolidone (polyvinylpyrrolidone, PVP), organosilicon polymer, ethylene vinyl acetate copolymer (Ethelene-vinyl acetate copolymer, EVAc), polyacrylonitrile (polyacrylonitriles), polyurethanes (polyurethanes), silicone (silicone) 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 entity-tumor-resistant medicine 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 or 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 or sodium salt etc.
The used pharmaceutic adjuvant of entity-tumor-resistant medicine 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 PLA, PLGA, PLA and PLGA, certain herbaceous plants with big flowers diacid and fragrant polyanhydride or aliphatic polyanhydride.Polylactic acid (PLA) and polyglycolic acid the blend ratio be 10/90-90/10 (weight), 25/75-75/25 (weight) preferably.The method of blend is arbitrarily.Content when glycolic and lactic acid copolymerization is respectively percentage by weight 10-90% and 90-10%.The representative of fragrance polyanhydride is to carboxy phenyl propane (p-CPP), content during to carboxy phenyl propane (p-CPP) and the copolymerization of certain herbaceous plants with big flowers diacid is respectively percentage by weight 10-60% and 20-90%, the blend weight ratio is 10-40: 50-90, preferably weight ratio 15-30: 65-85.
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 adjuvants.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 entity-tumor-resistant medicine 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 composition for treating solid tumor also can be packaged in the liposome equably, or makes microsphere with art methods.
Characteristics of the present invention are that used pharmaceutic adjuvant removes the high molecular polymerization beyond the region of objective existence, also contain above-mentioned any one or multiple other pharmaceutic adjuvant.The pharmaceutic adjuvant that adds is referred to as additive.Additive can be divided into filler, porogen, excipient, dispersant, isotonic agent, preservative agent, inhibitor, solubilizing agent, absorption enhancer, film former, gellant etc. according to its function.
Pharmaceutic adjuvant also can be liquid, as, but be not limited to Oleum sesami, suspension, distilled water, physiology towards liquid and semisolid, as (but being not limited to) fruit jelly, paste, ointment etc., above-mentioned pharmaceutic adjuvant is applicable to the compositions that contains or do not contain additive.
Entity-tumor-resistant medicine composition of the present invention can be made into multiple dosage form.As, but be not limited to injection, muddy suspension, ointment, capsule, slow releasing agent, implant, implantation slow release agent etc.; Be different shape, as, but be not limited to granular, lamellar, sphere, bulk, needle-like, bar-shaped and membranaceous.In various dosage forms, based on agent for slow releasing in the body or implant.Above-mentioned dosage form and shape are applicable to the compositions that contains or do not contain additive.
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, drying, promptly so-called dissolution method; (iv) spray drying method; And (v) freeze-drying etc.Wherein dissolution method can be used for the manufacturing of microsphere, and anticancer pharmaceutical composition also can be packed in the liposome.
Because entity-tumor-resistant medicine 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.
Route of administration
Entity-tumor-resistant medicine composition of the present invention can be through various administrations, as in passages through which vital energy circulates, tremulous pulse, subcutaneous, muscle, Intradermal, intracavity, the tumor, tumor week etc.Route of administration depends on multiple factor, for obtaining valid density in position, tumor place, medicine can give through other number of ways, as arterial perfusion optionally, administration in the intra-bladder instillation (intracavitary), abdominal cavity (intraperitoneal) or thoracic cavity (intrapleural) and canalis spinalis.In number of ways, with topical, as with in selective arterial, the tumor, tumor week injection or be placed as the master, with in the tumor, the form that slowly discharges of tumor week or tumor chamber serve as preferably, can plant slow-releasing pump, slow releasing capsule, slow releasing agent, implant or sustained-release implant as selecting for use.With the tremulous pulse approach is good, directly is placed as the best in the tumor body.
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.Generally speaking, the dichloro ethamine kind drug synergist can be 0.01-200 milligram/kg body weight, with 1-100 milligram/kg body weight is ideal, with 5-80 milligram/kg body weight for the most desirable, dichloro ethamine kind drug can be 0.01-100 milligram/kg body weight, with 1-180 milligram/kg body weight is ideal, with 5-50 milligram/kg body weight for the most desirable.
Entity-tumor-resistant medicine composition of the present invention can be used to prepare the medicine of the various entity tumors for the treatment of people, house pet and animal, 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 the entity-tumor-resistant medicine composition of the present invention, as, but be not limited to antibiotics, antalgica, anticoagulant medicine, hemorrhage etc.Above medicinal ingredient can singly select or multiselect, can join the compositions that contains or do not contain additive, and its content is because of specifically deciding.
Above-mentioned effective ingredient is packaged in the pharmaceutic adjuvant, then topical application.Said composition can be through various administrations, with topical, as selective arterial injection and directly injection or be placed as goodly in the tumor body, wherein are released to the best with local slow again.When used the part, composition for treating solid tumor 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.
Entity-tumor-resistant medicine 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.
The characteristics of entity-tumor-resistant medicine composition technology of preparing of the present invention are dichloro ethamine kind drug and/or its synergist are packaged in the pharmaceutic adjuvant, proportionally with active ingredient and pharmaceutic adjuvant dissolving, treat that abundant mixing is dry afterwards.Be shaped immediately after to be dried and sterilize packing.
Above dichloro ethamine kind drug and/or its synergist are local to be placed, not only can overcome the toxic reaction that the whole body administration brings, and has solved the tumor by local drug level and cross the low and cell sensitive question to medicine.
By following test and embodiment the technology side of composition for treating solid tumor of the present invention is further described:
The external tumor-inhibiting action of test one, dichloro ethamine kind drug and synergist thereof.
Used tumor cell comprises the cerebral tumor (C6), gastric gland epithelial cancer (SA), bone tumor (BC), breast carcinoma (BA), pulmonary carcinoma (LH), papillary adenocarcinoma of thyroid (PAT), hepatocarcinoma etc.To be added in 24 hours the various tumor cells of In vitro culture by 10ug/ml concentration with dichloro ethamine kind drug and synergist thereof, continue to cultivate counting cells sum after 48 hours.Its tumor growth suppresses effect and is shown in Table 1.
Table 1
| Oncocyte | (A) | (B) | (C) | (D) | (E) | (A) +(B) | (A) +(C) | (A) +(D) | (A) +(E) |
| C6 | 62％ | 54％ | 64％ | 66％ | 69％ | 94％ | 94％ | 94％ | 92％ |
| SA | 58％ | 60％ | 56％ | 60％ | 62％ | 86％ | 85％ | 86％ | 86％ |
| BC | 54％ | 64％ | 54％ | 54％ | 54％ | 94％ | 94％ | 84％ | 94％ |
| BA | 54％ | 62％ | 62％ | 52％ | 52％ | 98％ | 96％ | 98％ | 98％ |
| LH | 50％ | 58％ | 62％ | 68％ | 66％ | 90％ | 90％ | 94％ | 90％ |
| PAT | 63％ | 54％ | 64％ | 66％ | 69％ | 94％ | 94％ | 90％ | 93％ |
Annotate: (A): Chlorambucil, dichloro ethamine kind drug; (B): cisplatin, (C): mitozolomide, (D): Camptothecin, (E): hydroxy-camptothecin alkali; (B)-(E) be the dichloro ethamine kind drug synergist, dichloro ethamine kind drug (Chlorambucil) is all had notable synergistic effect (P＜0.05).
The external tumor-inhibiting action of test two, dichloro ethamine kind drug and synergist thereof.
Used tumor cell is with test one.Following dichloro ethamine kind drug and synergist thereof 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 | (A) | (B) | (C) | (D) | (E) | (A) +(B) | (A) +(C) | (A) +(D) | (A) +(E) |
| CNS | 60％ | 64％ | 66％ | 64％ | 60％ | 90％ | 92％ | 80％ | 90％ |
| C6 | 62％ | 64％ | 60％ | 64％ | 63％ | 96％ | 94％ | 86％ | 92％ |
| SA | 58％ | 60％ | 56％ | 60％ | 62％ | 86％ | 85％ | 86％ | 86％ |
| BC | 54％ | 64％ | 54％ | 54％ | 54％ | 94％ | 94％ | 84％ | 94％ |
| BA | 54％ | 62％ | 62％ | 52％ | 52％ | 98％ | 96％ | 98％ | 98％ |
| LH | 60％ | 58％ | 62％ | 68％ | 66％ | 90％ | 90％ | 94％ | 92％ |
| PAT | 58％ | 56％ | 66％ | 66％ | 69％ | 94％ | 92％ | 94％ | 90％ |
Annotate: (A): melphalan, dichloro ethamine kind drug; (B): carboplatin, (C): procarbazine, (D): irinotecan; (E): topotecan.(B)-(E) be the dichloro ethamine kind drug synergist, dichloro ethamine kind drug is all had notable synergistic effect (P＜0.05).
The external tumor-inhibiting action of test three, dichloro ethamine kind drug and synergist thereof.
Used tumor cell is with test one.Following dichloro ethamine kind drug and synergist thereof 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 | (A) | (B) | (C) | (D) | (E) | (A) +(B) | (A) +(C) | (A) +(D) | (A) +(E) |
| C6 | 56％ | 64％ | 60％ | 64％ | 63％ | 92％ | 92％ | 86％ | 90％ |
| SA | 58％ | 60％ | 56％ | 60％ | 62％ | 86％ | 85％ | 86％ | 86％ |
| BC | 54％ | 64％ | 54％ | 54％ | 54％ | 94％ | 94％ | 84％ | 94％ |
| BA | 54％ | 62％ | 62％ | 52％ | 52％ | 92％ | 94％ | 94％ | 96％ |
| LH | 60％ | 58％ | 62％ | 68％ | 66％ | 90％ | 90％ | 94％ | 92％ |
| PAT | 52％ | 56％ | 66％ | 66％ | 69％ | 92％ | 90％ | 90％ | 92％ |
Annotate: (A): 4H-peroxide cyclophosphamide, dichloro ethamine kind drug; (B): oxaliplatin, (C): the temozolomide, (D): etoposide, (E): teniposide.(B)-(E) be the dichloro ethamine kind drug synergist, dichloro ethamine kind drug is all had notable synergistic effect (P＜0.05).
Above-mentioned experimental result shows that the dichloro ethamine kind drug synergist all has the notable synergistic effect to dichloro ethamine kind drug.Further test shows, other synergist that the present invention is listed, as, dexormaplatin,
Heptan platinumThe imidazo tetrazine, imidazopyrazine, 1H-imidazo [b] piperazine, imidazopyridine, 1H-imidazo [1,2-a] pyridine, dacarbazine, lurtotecan, amrubicin, Ai Rou compares star, rodorubicin, leurubicin, zorubicin, N-trifluoro toxin-14-valerate and idarubicin etc. are to cyclophosphamide, ifosfamide, sufosfamide, defosfamide, Mafosfamide, perfosfamide, metamelfalan, methoxymerphalan, hexamethylmelamine, Ametantrone, clomifene, letrozole, cantharidin, triethylenemelaine, epoxypiperazine, benzene assistant TEPA, Phopurine, meturedepa, dichloro ethamine kind drugs such as Ah bundle's TEPA or urethimine all have the notable synergistic effect.Though be unexpected discovery the of the present invention, be of universal significance.
Tumor-inhibiting action in the body of test four, dichloro ethamine kind drug and synergist thereof.
With the rat is subjects, with 2x10
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 4).First group is contrast, and the 2nd to 10 group is the treatment group.Dichloro ethamine kind drug and synergist thereof dosage be 5mg/kg, its percentage by weight shared in pharmaceutical composition is 5-20%.The treatment back was measured gross tumor volume size, relatively therapeutic effect (seeing Table 4) on the 30th day.
Table 4
| Test group (n) | Suffered treatment | Gross tumor volume (cm 3) | The P value |
| 1(6) | Contrast | 64±12cm 3 | |
| 2(6) | Letrozole | 44±10cm 3 | ＜0.05 |
| 3(6) | Cisplatin | 44±108cm 3 | ＜0.01 |
| 4(6) | Mitozolomide | 34±6cm 3 | ＜0.01 |
| 5(6) | Camptothecin | 38±6.4cm 3 | ＜0.01 |
| 6(6) | Hydroxy-camptothecin alkali | 36±6.8cm 3 | ＜0.01 |
| 7(6) | Letrozole+cisplatin | 20±5cm 3 | ＜0.001 |
| 8(6) | Letrozole+mitozolomide | 16±2.6cm 3 | ＜0.001 |
| 9(6) | Letrozole+Camptothecin | 16±3.2cm 3 | ＜0.001 |
| 10(6) | Letrozole+hydroxy-camptothecin alkali | 14±2.2cm 3 | ＜0.001 |
Above dichloro ethamine kind drug synergist all has notable synergistic effect (P＜0.001) to dichloro ethamine kind drug.
Tumor-inhibiting action in the body of test five, dichloro ethamine kind drug and synergist thereof.
With the rat is subjects, with 2x10
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 5).First group is contrast, and the 2nd to 10 group is the treatment group.The dosage of dichloro ethamine kind drug and synergist thereof is 5mg/kg, and its percentage by weight shared in pharmaceutical composition is 10-20%.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 | 65±12cm 3 | |
| 2(6) | Ah bundle's TEPA | 40±8cm 3 | ＜0.05 |
| 3(6) | Carboplatin | 43±8.4cm 3 | ＜0.01 |
| 4(6) | Procarbazine | 36±4.2cm 3 | ＜0.01 |
| 5(6) | Irinotecan | 40±5.4cm 3 | ＜0.01 |
| 6(6) | Topotecan | 34±6.0cm 3 | ＜0.01 |
| 7(6) | Ah bundle's TEPA+carboplatin | 26±4.8cm 3 | ＜0.001 |
| 8(6) | Ah bundle's TEPA+procarbazine | 20±3.8cm 3 | ＜0.001 |
| 9(6) | Ah bundle's TEPA+irinotecan | 12±2.4cm 3 | ＜0.001 |
| 10(6) | Ah bundle's TEPA+topotecan | 14±2.0cm 3 | ＜0.001 |
Above dichloro ethamine kind drug synergist all has notable synergistic effect (P＜0.001) to dichloro ethamine kind drug.
Tumor-inhibiting action in the body of test six, dichloro ethamine kind drug and synergist thereof.
With the rat is subjects, with 2x10
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.The dosage of dichloro ethamine kind drug and synergist thereof is 5mg/kg, and its percentage by weight shared in pharmaceutical composition is 5-20%.The treatment back was measured gross tumor volume size, relatively therapeutic effect (seeing Table 6) on the 30th day.
Table 6
| Test group (n) | Suffered treatment | Gross tumor volume (cm 3) | The P value |
| 1(6) | Contrast | 60±10cm 3 | |
| 2(6) | Melphalan | 42±6cm 3 | ＜0.05 |
| 3(6) | Oxaliplatin | 45±8cm 3 | ＜0.01 |
| 4(6) | The temozolomide | 38±6cm 3 | ＜0.01 |
| 5(6) | Etoposide | 42±6.4cm 3 | ＜0.01 |
| 6(6) | Teniposide | 40±6.8cm 3 | ＜0.01 |
| 7(6) | Melphalan+oxaliplatin | 26±4.6cm 3 | ＜0.001 |
| 8(6) | Melphalan+temozolomide | 20±3.6cm 3 | ＜0.001 |
| 9(6) | Melphalan+etoposide | 18±4.6cm 3 | ＜0.001 |
| 10(6) | Melphalan+teniposide | 20±2.6cm 3 | ＜0.001 |
Above dichloro ethamine kind drug synergist all has notable synergistic effect (P＜0.001) to dichloro ethamine kind drug.
Tumor-inhibiting action in the body of test seven, dichloro ethamine kind drug and synergist thereof.
With the rat is subjects, with 2x10
5Individual tumor cell subcutaneous injection is in its hypochondrium, treats that tumor growth after 14 days is divided into it following 10 groups (seeing Table 7).First group is contrast, and the 2nd to 10 group is the treatment group.The dosage of dichloro ethamine kind drug and synergist thereof is 5mg/kg, and its percentage by weight shared in pharmaceutical composition is 15-25%.The treatment back was measured gross tumor volume size, relatively therapeutic effect (seeing Table 7) on the 30th day.
Table 7
| Test group (n) | Suffered treatment | Gross tumor volume (cm 3) | The P value |
| 1(6) | Contrast | 50±10cm 3 | |
| 2(6) | Defosfamide | 32±8cm 3 | ＜0.05 |
| 3(6) | Heptan platinum | 30±6cm 3 | ＜0.01 |
| 4(6) | The imidazo tetrazine | 28±8cm 3 | ＜0.01 |
| 5(6) | Amrubicin | 30±6cm 3 | ＜0.01 |
| 6(6) | Dacarbazine | 32±6.8cm 3 | ＜0.01 |
| 7(6) | Defosfamide+ Heptan platinum | 14±3.2cm 3 | ＜0.001 |
| 8(6) | Defosfamide+imidazo tetrazine | 12±2.8cm3 | ＜0.001 |
| 9(6) | Defosfamide+amrubicin | 10±2.4cm3 | ＜0.001 |
| 10(6) | Defosfamide+dacarbazine | 12±1.2cm3 | ＜0.001 |
Above dichloro ethamine kind drug synergist all has notable synergistic effect (P＜0.001) to dichloro ethamine kind drug.
Tumor-inhibiting action in the body of test eight, dichloro ethamine kind drug and synergist thereof.
With the rat is subjects, with 2x10
5Individual tumor cell subcutaneous injection is in its hypochondrium, treats that tumor growth after 14 days is divided into it following 10 groups (seeing Table 8).First group is contrast, and the 2nd to 10 group is the treatment group.The dosage of dichloro ethamine kind drug and synergist thereof is 5mg/kg, and its percentage by weight shared in pharmaceutical composition is 5-15%.The treatment back was measured gross tumor volume size, relatively therapeutic effect (seeing Table 8) on the 30th day.
Table 8
| Test group (n) | Suffered treatment | Gross tumor volume (cm 3) | The P value |
| 1(6) | Contrast | 52±11cm 3 | |
| 2(6) | Urethimine | 36±8cm 3 | ＜0.05 |
| 3(6) | Imidazopyridine | 31±8cm 3 | ＜0.01 |
| 4(6) | Lurtotecan | 34±6cm 3 | ＜0.01 |
| 5(6) | Ai Rou compares star | 38±6.4cm 3 | ＜0.01 |
| 6(6) | Pirarubicin | 36±6.8cm 3 | ＜0.01 |
| 7(6) | Urethimine+imidazopyridine | 20±4.6cm 3 | ＜0.001 |
| 8(6) | Urethimine+lurtotecan | 20±3.6cm 3 | ＜0.001 |
| 9(6) | Urethimine+Ai Rou compares star | 14±3.6cm 3 | ＜0.001 |
| 10(6) | Urethimine+idarubicin | 12±2.6cm 3 | ＜0.001 |
Above dichloro ethamine kind drug synergist all has notable synergistic effect (P＜0.001) to dichloro ethamine kind drug.
In a word, the dichloro ethamine kind drug synergist among the present invention all has the notable synergistic effect to dichloro ethamine kind drug.Therefore, the effective ingredient of entity-tumor-resistant medicine composition of the present invention is the associating of any one (or multiple) dichloro ethamine kind drug synergist and any one (or multiple) dichloro ethamine kind drug or packs separately.The entity-tumor-resistant medicine composition that contains above effective ingredient can be made into any dosage form or shape, but serves as preferred with agent for slow releasing (or implant) type.
The preparation method of entity-tumor-resistant medicine composition of the present invention is as follows:
1. the pharmaceutic adjuvant of weighing is put into container, and it is even to add organic dissolution with solvents, and the not strict qualification of the amount of organic solvent is suitable fully to be dissolved as.
2. above-mentioned percentage by weight adds the anticancer active ingredient of weighing and shakes up again.
3. remove organic solvent.Vacuum drying or cold drying all can.
4. dried solid composite is made different shape.
5. ray sterilizing (roentgendosis is different because of volume) is standby after the packing.Also available other method sterilization.
(4) specific embodiment
Embodiment 1.
With 80mg molecular weight peak value is that the polyglycolic acid of 10000-20000 and the copolymer of hydroxyacetic acid (PLGA) are put into container, add 100 milliliters of dichloromethane, behind the dissolving mixing, add 10mg4H-peroxide cyclophosphamide and 10mg cisplatin ametycin, shake up the dry organic solvent of removing of final vacuum again.Dried solid composite is shaped immediately, and ray sterilizing after the packing must contain the entity-tumor-resistant medicine composition of 10%4H-peroxide cyclophosphamide and 10% cisplatin.All be weight percentage.The drug release time of this entity-tumor-resistant medicine composition in external normal saline is 15-20 days, is 30-40 days at the subcutaneous drug release time of mice.
Embodiment 2.
The method step that is processed into entity-tumor-resistant medicine composition is identical with embodiment 1, but different is that contained anticancer effective component is:
(A) Chlorambucil of 1-50%, cyclophosphamide, ifosfamide, 4H-peroxide cyclophosphamide, three mustard cyclophosphamide, sufosfamide, defosfamide, Mafosfamide, perfosfamide, trofosfamide, thiocarzolamide, melphalan, metamelfalan, methoxymerphalan, formylmerphalan, hexamethylmelamine, Ametantrone, Thymopentin, clomifene, letrozole, disodium cantharidinate, cantharidin, sodium cantharidinate, N-methylcantharidimide, N-hydroxycantharidin, norcantharidin, thiocolciran, sarcolysine, methasquin, NSC-1895, mannomustine, treosulfan, ritrosulfan, an improsulfan, Z 7557, Spirobromin, d-mannitobusulphan, cis-diamminetetrachloroplatinum, enpromate, epipropidine, ethoxene, bimolane, second hydroxyl urea, ethyliminum, etoglucid, benefit hair phosphorus ammonium, E39, pipobroman, piposulfan, Li Chuikexin, Dup 942, Dup 942, NSC 122402, radioplex, rofecoxib, taxodione, trimethylolmelamine, urethane, Zorubicin Hydrochloride, RP-22050, triethylenemelaine, epoxypiperazine, benzene assistant TEPA, Phopurine, meturedepa, the cisplatin of Ah bundle's TEPA or urethimine and 1-50%, 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) Chlorambucil of 1-50%, cyclophosphamide, ifosfamide, 4H-peroxide cyclophosphamide, three mustard cyclophosphamide, sufosfamide, defosfamide, Mafosfamide, perfosfamide, trofosfamide, thiocarzolamide, melphalan, metamelfalan, methoxymerphalan, formylmerphalan, hexamethylmelamine, Ametantrone, Thymopentin, clomifene, letrozole, disodium cantharidinate, cantharidin, sodium cantharidinate, N-methylcantharidimide, N-hydroxycantharidin, norcantharidin, thiocolciran, sarcolysine, methasquin, NSC-1895, mannomustine, treosulfan, ritrosulfan, an improsulfan, Z 7557, Spirobromin, d-mannitobusulphan, cis-diamminetetrachloroplatinum, enpromate, epipropidine, ethoxene, bimolane, second hydroxyl urea, ethyliminum, etoglucid, benefit hair phosphorus ammonium, E39, pipobroman, piposulfan, Li Chuikexin, Dup 942, Dup 942, NSC 122402, radioplex, rofecoxib, taxodione, trimethylolmelamine, urethane, Zorubicin Hydrochloride, RP-22050, triethylenemelaine, epoxypiperazine, benzene assistant TEPA, Phopurine, meturedepa, the procarbazine of Ah bundle's TEPA or urethimine and 1-50%, mitozolomide, dacarbazine, the temozolomide, the imidazo tetrazine, imidazopyrazine, 1H-imidazo [b] piperazine, imidazopyridine, 1H-imidazo [1,2-a] pyridine, 4-carboxyl temozolomide, 3-N-methyl temozolomide, the pyrroles [2,1-d] [1,2,3,5] tetrazine-4 (3H)-temozolomide, the pyrroles [2,1-d] [1,2,3,5] tetrazine 10a-o, 5-(3-N-methyl three nitrogen-1-yl)-imidazo-4-carboxylic acid amides, 8-nitro-3-methyl-phendioxin, 2,3,5-four azatropylidenes-4-temozolomide, 3,5-dimethyl-pyrido-1,2,3,5-four azatropylidenes-4-temozolomide or 3-(2-ethyl chloride)-N, N dimethyl-4-oxygen-3,4-glyoxalidine [5,1-d]-1,2,3,5-tetrazine-8-carboxylic acid amides, 5-(triazenyl) imidazoles-4-carboxylic acid amides, the combination of 3-aminobenzene amide or 6-aminonicotinamide; Or
(C) Chlorambucil of 1-50%, cyclophosphamide, ifosfamide, 4H-peroxide cyclophosphamide, three mustard cyclophosphamide, sufosfamide, defosfamide, Mafosfamide, perfosfamide, trofosfamide, thiocarzolamide, melphalan, metamelfalan, methoxymerphalan, formylmerphalan, hexamethylmelamine, Ametantrone, Thymopentin, clomifene, letrozole, disodium cantharidinate, cantharidin, sodium cantharidinate, N-methylcantharidimide, N-hydroxycantharidin, norcantharidin, thiocolciran, sarcolysine, methasquin, NSC-1895, mannomustine, treosulfan, ritrosulfan, an improsulfan, Z 7557, Spirobromin, d-mannitobusulphan, cis-diamminetetrachloroplatinum, enpromate, epipropidine, ethoxene, bimolane, second hydroxyl urea, ethyliminum, etoglucid, benefit hair phosphorus ammonium, E39, pipobroman, piposulfan, Li Chuikexin, Dup 942, Dup 942, NSC 122402, radioplex, rofecoxib, taxodione, trimethylolmelamine, urethane, Zorubicin Hydrochloride, RP-22050, triethylenemelaine, epoxypiperazine, benzene assistant TEPA, Phopurine, meturedepa, the MD-CPT of Ah bundle's TEPA or urethimine and 1-50%, (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, etoposide, teniposide, teniposide, Podophyllinic acid, podophyllotoxin, trihydroxy-isoflavone, amrubicin, daunorubicin, daunorubicin, the nor-oxygen daunorubicin of 4-, detorubicin, epirubicin, 7-O-methyl Nuo Jia-4 '-epirubicin, esorubicin, carubicin, idarubicin, rodorubicin, leurubicin, medorubicin, Nemorubicin, doxorubicin, 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, the combination of lithocholic acid or Hydrazoic acid,sodium salt.Below all be weight percentage.
Embodiment 3.
With 80mg molecular weight peak value is that the polyglycolic acid of 20000-30000 and the copolymer of hydroxyacetic acid (PLGA) are put into container, add 100 milliliters of dichloromethane, behind the dissolving mixing, add 10mg melphalan and 10mg mitozolomide, shake up the dry organic solvent of removing of final vacuum again.Dried solid composite is shaped immediately, and ray sterilizing after the packing makes the entity-tumor-resistant medicine composition that contains 10% melphalan and 10% mitozolomide.All be weight percentage.The drug release time of this entity-tumor-resistant medicine composition in external normal saline is 15-20 days, is 30-40 days at the subcutaneous drug release time of mice.
Embodiment 4.
As described in embodiment 3, different is that contained anticancer effective component is:
(a) cisplatin of the Chlorambucil of 5-30%, cyclophosphamide, ifosfamide, 4H-peroxide cyclophosphamide, sufosfamide, defosfamide, Mafosfamide, perfosfamide, melphalan, metamelfalan, methoxymerphalan, hexamethylmelamine, Ametantrone, clomifene, letrozole, cantharidin, etoglucid, triethylenemelaine, epoxypiperazine, benzene assistant TEPA, Phopurine, meturedepa, Ah bundle's TEPA or urethimine and 5-30%, carboplatin, heptan platinum or oxaliplatin combination; Or
(b) Chlorambucil of 5-30%, cyclophosphamide, ifosfamide, 4H-peroxide cyclophosphamide, sufosfamide, defosfamide, Mafosfamide, perfosfamide, melphalan, metamelfalan, methoxymerphalan, hexamethylmelamine, Ametantrone, clomifene, letrozole, cantharidin, etoglucid, triethylenemelaine, epoxypiperazine, benzene assistant TEPA, Phopurine, meturedepa, the procarbazine of Ah bundle's TEPA or urethimine and 5-30%, mitozolomide, dacarbazine, the temozolomide, the imidazo tetrazine, imidazopyrazine, 1H-imidazo [b] piperazine, imidazopyridine, the combination of 3-aminobenzene amide or 6-aminonicotinamide; Or
(c) Chlorambucil of 5-30%, cyclophosphamide, ifosfamide, 4H-peroxide cyclophosphamide, sufosfamide, defosfamide, Mafosfamide, perfosfamide, melphalan, metamelfalan, methoxymerphalan, hexamethylmelamine, Ametantrone, clomifene, letrozole, cantharidin, etoglucid, triethylenemelaine, epoxypiperazine, benzene assistant TEPA, Phopurine, meturedepa, the lurtotecan of Ah bundle's TEPA or urethimine and 5-30%, topotecan, Irinotecan, 9-nitro Camptothecin, hydroxy-camptothecin alkali, Camptothecin, etoposide, teniposide, amrubicin, daunorubicin, daunorubicin, detorubicin, esorubicin, carubicin, idarubicin, rodorubicin, leurubicin, medorubicin, Nemorubicin, the combination of doxorubicin or zorubicin.Below all be weight percentage.
Embodiment 5.
80mg polifeprosan (to carboxy phenyl propane: certain herbaceous plants with big flowers diacid weight ratio is 40: 60) copolymer is put into container, add 100 milliliters of dichloromethane, behind the dissolving mixing, add 10mg cantharidin and 10mg topotecan, shake up the dry organic solvent of removing of final vacuum again.Dried solid composite is shaped immediately, and ray sterilizing after the packing must contain the entity-tumor-resistant medicine composition of 10% cantharidin and 10% topotecan.All be weight percentage.The drug release time of this entity-tumor-resistant medicine composition in external normal saline is 15-20 days, is 30-40 days at the subcutaneous drug release time of mice.
Embodiment 6.
As described in embodiment 5, different is that contained anticancer effective component is:
(a) cisplatin of the Chlorambucil of 5-30%, cyclophosphamide, ifosfamide, 4H-peroxide cyclophosphamide, sufosfamide, defosfamide, Mafosfamide, perfosfamide, melphalan, metamelfalan, methoxymerphalan, hexamethylmelamine, Ametantrone, clomifene, letrozole, cantharidin, etoglucid, triethylenemelaine, epoxypiperazine, benzene assistant TEPA, Phopurine, meturedepa, Ah bundle's TEPA or urethimine and 5-30%, carboplatin, heptan platinum or oxaliplatin combination; Or
(b) Chlorambucil of 5-30%, cyclophosphamide, ifosfamide, 4H-peroxide cyclophosphamide, sufosfamide, defosfamide, Mafosfamide, perfosfamide, melphalan, metamelfalan, methoxymerphalan, hexamethylmelamine, Ametantrone, clomifene, letrozole, cantharidin, etoglucid, triethylenemelaine, epoxypiperazine, benzene assistant TEPA, Phopurine, meturedepa, the procarbazine of Ah bundle's TEPA or urethimine and 5-30%, mitozolomide, dacarbazine, temozolomide's combination; Or
(c) Chlorambucil of 5-30%, cyclophosphamide, ifosfamide, 4H-peroxide cyclophosphamide, sufosfamide, defosfamide, Mafosfamide, perfosfamide, melphalan, metamelfalan, methoxymerphalan, hexamethylmelamine, Ametantrone, clomifene, letrozole, cantharidin, etoglucid, triethylenemelaine, epoxypiperazine, benzene assistant TEPA, Phopurine, meturedepa, the topotecan of Ah bundle's TEPA or urethimine and 5-30%, Irinotecan, 9-nitro Camptothecin, hydroxy-camptothecin alkali, Camptothecin, etoposide, the combination of teniposide or idarubicin.Below all be weight percentage.
Embodiment 7.
(EVAc) puts into container with the 80mg ethylene vinyl acetate copolymer, add 100 milliliters of dichloromethane dissolving mixings after, adds 10 milligrams of etoglucid and 10mg etoposide, shake up the dry removal of final vacuum organic solvent again.Dried solid composite is shaped immediately, and ray sterilizing after the packing must contain 10% etoglucid and 10% etoposide entity-tumor-resistant medicine composition.All be weight percentage.The drug release time of this entity-tumor-resistant medicine composition in external normal saline is 15-20 days, is 30-40 days at the subcutaneous drug release time of mice.
Embodiment 8.
As described in embodiment 7, different is that contained anticancer effective component is:
(a) cisplatin of the Chlorambucil of 5-30%, cyclophosphamide, ifosfamide, 4H-peroxide cyclophosphamide, melphalan, methoxymerphalan, hexamethylmelamine and 5-30%, carboplatin, heptan platinum or oxaliplatin combination; Or
(b) procarbazine of the Chlorambucil of 5-30%, cyclophosphamide, ifosfamide, 4H-peroxide cyclophosphamide, melphalan, methoxymerphalan, hexamethylmelamine and 5-30%, mitozolomide, dacarbazine, temozolomide's combination; Or
(c) combination of the topotecan of the Chlorambucil of 5-30%, cyclophosphamide, ifosfamide, 4H-peroxide cyclophosphamide, melphalan, methoxymerphalan, hexamethylmelamine and 5-30%, Irinotecan, 9-nitro Camptothecin, hydroxy-camptothecin alkali, Camptothecin, etoposide, teniposide or idarubicin.Below all be weight percentage.
Embodiment 9.
As described in embodiment 1,3,5 or 7, used pharmaceutic adjuvant is respectively one of following or its combination that different is:
A) molecular weight is 5000-15000,10000-20000,20000-30000, the polylactic acid of 20000-35000 or 35000-80000 (PLA);
B) molecular weight is 5000-15000,10000-20000,20000-30000,30000-40000, the polyglycolic acid of 40000-50000 or 50000-80000 and the copolymer of hydroxyacetic acid (PLGA);
C) ethylene vinyl acetate copolymer (EVAc);
D) to the copolymer (polifeprosan) of carboxy phenyl propane and certain herbaceous plants with big flowers diacid, to carboxy phenyl propane: certain herbaceous plants with big flowers diacid weight ratio is 10: 90,20: 80,30: 70,40: 60,50: 50 or 60: 40;
E) xylitol, oligosaccharide, chitin, potassium salt, sodium salt, hyaluronic acid, collagen protein, gelatin or albumin.
Embodiment 10.
As described in embodiment 1,3,5 or 7, anticancer effective component that different is is one of following:
(a) combination of 10% Chlorambucil, 4H-peroxide cyclophosphamide, melphalan, methoxymerphalan or hexamethylmelamine and 10% cisplatin;
(b) combination of 10% Chlorambucil, 4H-peroxide cyclophosphamide, melphalan, methoxymerphalan or hexamethylmelamine and 10% procarbazine;
(c) combination of 10% Chlorambucil, 4H-peroxide cyclophosphamide, melphalan, methoxymerphalan or hexamethylmelamine and 10% mitozolomide;
(d) 10% Chlorambucil, 4H-peroxide cyclophosphamide, melphalan, methoxymerphalan or hexamethylmelamine and 10% temozolomide's combination;
(e) combination of 10% Chlorambucil, 4H-peroxide cyclophosphamide, melphalan, methoxymerphalan or hexamethylmelamine and 10% topotecan;
(f) combination of 10% Chlorambucil, 4H-peroxide cyclophosphamide, melphalan, methoxymerphalan or hexamethylmelamine and 10% Irinotecan;
(g) combination of 10% Chlorambucil, 4H-peroxide cyclophosphamide, melphalan, methoxymerphalan or hexamethylmelamine and 10% hydroxy-camptothecin alkali;
(h) combination of 10% Chlorambucil, 4H-peroxide cyclophosphamide, melphalan, methoxymerphalan or hexamethylmelamine and 10% Camptothecin;
(i) combination of 10% Chlorambucil, 4H-peroxide cyclophosphamide, melphalan, methoxymerphalan or hexamethylmelamine and 10% etoposide;
(j) combination of 10% Chlorambucil, 4H-peroxide cyclophosphamide, melphalan, methoxymerphalan or hexamethylmelamine and 10% teniposide;
(k) combination of 10% Chlorambucil, 4H-peroxide cyclophosphamide, melphalan, methoxymerphalan or hexamethylmelamine and 10% idarubicin;
(l) combination of 10% Chlorambucil, 4H-peroxide cyclophosphamide, melphalan, methoxymerphalan or hexamethylmelamine and 10% oxaliplatin.
More than be weight percentage.
Embodiment 11. is composition for treating solid tumor inside and outside release characteristics relatively
Get the composition for treating solid tumor among the embodiment 10, be placed in the room temperature normal saline and soak, survey the different time release amount of medicine, calculate external accumulative total and discharge percent (%).It is subcutaneous to be put in white mice, regularly takes out and surveys medicament contg, according to the residual drug amount, calculates the interior accumulative total of body and discharges percent (%).The result shows, the different pharmaceutical release in vitro no significant difference that tries discharged the about 20%, the 14th day and discharges 88-94% in first day.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.
Claims (1)
1. an entity-tumor-resistant medicine composition is made up of anticancer effective component and slow-release auxiliary material, it is characterized in that said composition is the implantation slow release agent; Anticancer effective component is dichloro ethamine kind drug and dichloro ethamine kind drug synergist, and wherein, the dichloro ethamine kind drug synergist is a topoenzyme inhibitor;
The effective ingredient of anti-cancer composition is one of following:
(a) combination of 10% Chlorambucil and 10% hydroxy-camptothecin alkali;
(b) combination of 10% Chlorambucil and 10% Camptothecin;
(c) combination of 10%4H-peroxide cyclophosphamide or melphalan and 10% etoposide;
(d) combination of 10%4H-peroxide cyclophosphamide or melphalan and 10% teniposide;
More than be weight percentage;
Slow-release auxiliary material is selected from one of following or its combination:
A) ethylene vinyl acetate copolymer; Or
B) to the copolymer of carboxy phenyl propane and decanedioic acid, to carboxy phenyl propane: the decanedioic acid weight ratio is 40: 60.
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