CN1311872C - Anticancer combination of medication - Google Patents
Anticancer combination of medication Download PDFInfo
- Publication number
- CN1311872C CN1311872C CNB2004100758379A CN200410075837A CN1311872C CN 1311872 C CN1311872 C CN 1311872C CN B2004100758379 A CNB2004100758379 A CN B2004100758379A CN 200410075837 A CN200410075837 A CN 200410075837A CN 1311872 C CN1311872 C CN 1311872C
- Authority
- CN
- China
- Prior art keywords
- colchicine
- pharmaceutical composition
- tumor
- anticancer
- nocodazole
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
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Abstract
The present invention relates to an anticancer medical composition, which belongs to the technical field of drugs. The present invention comprises pharmaceutic supplementary materials and antimitotic drugs, wherein the antimitotic drugs can suppress hyperplasia of tumors; the pharmaceutic supplementary materials are mainly high molecular biologic capacitability polymers which can be degraded and absorbed, and in a degradation and absorption process, the antimitotic drugs can be slowly released locally at the tumors, so the systemic toxicity reactions of human bodies are reduced obviously; simultaneously, the tumors can locally keep effective drug concentration. The composition is put locally at the tumors, the local drug concentration of the tumors can be improved in a selective mode, and the treatment effect of non-operative treatments, such as chemotherapeutics, radiotherapy, etc., can be enhanced.
Description
(1) technical field
The present invention relates to a kind of anticancer pharmaceutical composition, belong to technical field of pharmaceuticals.
(2) background technology
The treatment of entity tumor mainly comprises methods such as operation, radiotherapy and chemotherapy.In used various chemotherapeutics, the action effect of anti-mitosis medicine is comparatively obvious, has been widely used in multiple malignant tumor.Yet, further discover, 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 is difficult to tumor by local and forms 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) (KongQ 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.
(3) summary of the invention
The present invention is directed to the deficiencies in the prior art, a kind of anticancer pharmaceutical composition is provided.
Anticancer pharmaceutical composition comprises anticancer effective component and pharmaceutic adjuvant, and wherein, anticancer effective component is an anti-mitosis medicine.Anti-mitosis medicine is selected from one of following or its combination:
Cytochalasin (podophyllotoxin), Datelliptium Chloride, ellipticine, 2-Methylellipticine, mitoclomine (Mitoclomine), mitoflaxone [Mitoflaxone], mitoguazone [Mitoguazone], mitonafide [Mitonafide], mitopodozide [Mitopodozide], mitoquidone [Mitoquidone], mitosper [Mitosper], mitotane [Mitotane], mitotenamine [Mitotenamine], mitozolomide [Mitozolomide], Flavone acetic acid, colchicine, Salicylate (colchisal), colchiceinamide [Colchiceinamide], colchicine [Colchicine], 7-acetamido-10-hydroxy-1,2,3-trimethoxy-6,7-dihydrobenzo[a (colchiceine), sulfo--colchicine (thio-colchicine), Demecolcine [Demecolcine], Colchiceinamidum, Colchicine, B cytochalasin B (cytochalasins) is (as A-E, H, J), carbaryl (sevin, carbaryl), naphthols (naphthol), alpha-Naphthol (1-naphthol), betanaphthol (2-naphthol), alpha-phosphate naphthols (1-naphthylphosphate), acodazole (Acodazole), procodazole [Procodazole], giracodazole [Giracodazole], nocodazole (nocodazole), malonic acid (malonate) or malonate.
Anti-mitosis medicine will make tumor cell stop at the different links of cell cycle.Anti-mitosis medicine shared percentage by weight in compositions is also decided because of concrete condition, can be 0.01%-80%, is good with 1%-50%, is best with 2%-30%.
Anti-mitosis medicine in the anticancer pharmaceutical composition of the present invention is preferably as follows, and all is weight percentage:
(a) cytochalasin of 0.01%-10%, Datelliptium Chloride, ellipticine, 2-Methylellipticine, the mitoclomine mitoflaxone, mitoguazone, mitonafide, mitopodozide, mitoquidone, mitosper, mitotane, mitotenamine, mitozolomide, Flavone acetic acid, colchicine, Salicylate, colchiceinamide, colchicine, 7-acetamido-10-hydroxy-1,2,3-trimethoxy-6,7-dihydrobenzo[a, sulfo--colchicine, Demecolcine, Colchiceinamidum, Colchicine, 7-acetamido-10-hydroxy-1,2,3-trimethoxy-6,7-dihydrobenzo[a, sulfo--colchicine, Demecolcine, Colchiceinamidum, Colchicine, B cytochalasin B, carbaryl, naphthols, alpha-Naphthol, betanaphthol, the alpha-phosphate naphthols, acodazole, procodazole, giracodazole, nocodazole or malonic acid (salt); Perhaps
(b) 5%-20% cytochalasin, Datelliptium Chloride, ellipticine, 2-Methylellipticine, the mitoclomine mitoflaxone, mitoguazone, mitonafide, mitopodozide, mitoquidone, mitosper, mitotane, mitotenamine, mitozolomide, Flavone acetic acid, colchicine, Salicylate, colchiceinamide, colchicine, 7-acetamido-10-hydroxy-1,2,3-trimethoxy-6,7-dihydrobenzo[a, sulfo--colchicine, Demecolcine, Colchiceinamidum, Colchicine, 7-acetamido-10-hydroxy-1,2,3-trimethoxy-6,7-dihydrobenzo[a, sulfo--colchicine, Demecolcine, Colchiceinamidum, Colchicine, B cytochalasin B, carbaryl, naphthols, alpha-Naphthol, betanaphthol, the alpha-phosphate naphthols, acodazole, procodazole, giracodazole, nocodazole or malonic acid (salt); Perhaps
(c) 15%-30% cytochalasin, Datelliptium Chloride, ellipticine, 2-Methylellipticine, the mitoclomine mitoflaxone, mitoguazone, mitonafide, mitopodozide, mitoquidone, mitosper, mitotane, mitotenamine, mitozolomide, Flavone acetic acid, colchicine, Salicylate, colchiceinamide, colchicine, 7-acetamido-10-hydroxy-1,2,3-trimethoxy-6,7-dihydrobenzo[a, sulfo--colchicine, Demecolcine, Colchiceinamidum, Colchicine, 7-acetamido-10-hydroxy-1,2,3-trimethoxy-6,7-dihydrobenzo[a, sulfo--colchicine, Demecolcine, Colchiceinamidum, Colchicine, B cytochalasin B, carbaryl, naphthols, alpha-Naphthol, betanaphthol, the alpha-phosphate naphthols, acodazole, procodazole, giracodazole, nocodazole or malonic acid (salt)
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 (poiyamides), poe (polyorthoesters), polyphosphazene (polyphosphazenes), to carboxy phenyl propane (p-CPP), certain herbaceous plants with big flowers diacid (sebacicacid), polifeprosan (to the copolymer of carboxy phenyl propane and certain herbaceous plants with big flowers diacid) etc.; Natural polymer as, but be not limited to, protein and polysaccharide comprise hyaluronic acid, collagen protein, gelatin, albumin 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 nondegradable polymer of above-mentioned biology comprises, but be not limited to: organosilicon polymer, ethylene vinyl acetate copolymer (Ethelene-vinyl acetate copolymer, EVAc), polyacrylonitrile (polyacrylonitriles), polyurethanes (polyurethanes) and polyphosphazene (polyphosphazenes) etc.Compositions can discharge effective ingredient by the mode of direct diffusion.
For regulating other characteristic of drug releasing rate or change anticancer pharmaceutical composition of the present invention, can change the composition and the proportioning of monomer component or molecular weight, interpolation or the adjusting pharmaceutic adjuvant of polymer, add the water-soluble low-molecular chemical compound, as, but be not limited to various sugar and salt etc.Wherein sugar can be, but is not limited to, xylitol, oligosaccharide and chitin etc., and wherein salt can be but is not limited to, potassium salt and sodium salt etc.
The used pharmaceutic adjuvant of anticancer pharmaceutical composition of the present invention can be any or multiple material in the above-mentioned pharmaceutic adjuvant, but with the high molecular weight water soluble polymer is main separation, in various high molecular polymers, with polylactic acid, certain herbaceous plants with big flowers diacid, the mixture or the copolymer that contain the macromolecule polymer of polylactic acid or certain herbaceous plants with big flowers diacid is first-selection, mixture and copolymer can be selected from, but be not limited to the mixture or the copolymer of the mixture of PLGA, glycolic and hydroxy carboxylic acid, certain herbaceous plants with big flowers diacid and fragrant polyanhydride or aliphatic polyanhydride.The blend ratio of glycolic and hydroxy carboxylic acid is 10/90-90/10 (weight), preferably 25/75-75/25 (weight).The method of blend is arbitrarily.Content when glycolic and hydroxy carboxylic acid copolymerization is respectively percentage by weight 10-90% and 90-10%.The representative of fragrance polyanhydride is to carboxy phenyl propane (p-CPP), content during to carboxy phenyl propane (p-CPP) and the copolymerization of certain herbaceous plants with big flowers diacid is respectively percentage by weight 10-60% and 20-90%, the blend weight ratio is 10-40: 50-90, preferably weight ratio 15-30: 65-85.
Pharmaceutic adjuvant has a detailed description in " pharmaceutic adjuvant complete works " (the 123rd page, Sichuan science tech publishing house published in 1993, Luo Mingsheng and Gao Tianhui chief editor).In addition, Chinese patent (application number 96115937.5; 91109723.6; 9710703.3; 01803562.0) and U.S.'s patent of invention (patent No. 5,651,986) also enumerated some pharmaceutic adjuvant.Comprise filler, solubilizing agent, absorption enhancer, film former, gellant, system (or causing) hole agent, excipient or inhibitor.Above pharmaceutic adjuvant has has multiple action, and therefore the material of the same race that has is listed in different classifications.The available holder of composition for treating solid tumor of the present invention can be any or multiple material in the above-mentioned pharmaceutic adjuvant, and not exclusively comes the technical characterictic of limit combination according to its classification or definition.
The effective ingredient of anticancer pharmaceutical composition can be packaged in the whole pharmaceutic adjuvant equably, also can be packaged in carrier holder center or its surface; Can effective ingredient be discharged by direct diffusion or through mode or dual mode like this that polymer is degraded.In addition, the effective ingredient of anticancer pharmaceutical composition also can be packaged in the liposome equably, or makes microsphere with art methods.
Characteristics of the present invention are that used pharmaceutic adjuvant removes the high molecular polymerization beyond the region of objective existence, also contain above-mentioned any one or multiple other pharmaceutic adjuvant.The pharmaceutic adjuvant that adds is referred to as additive.Additive can be divided into filler, porogen, excipient, dispersant, isotonic agent, preservative agent, inhibitor, solubilizing agent, absorption enhancer, film former, gellant etc. according to its function.
Pharmaceutic adjuvant also can be liquid, as, but be not limited to Oleum sesami, suspension, distilled water, physiology towards liquid and semisolid, as (but being not limited to) fruit jelly, paste, ointment etc., above-mentioned pharmaceutic adjuvant is applicable to the compositions that contains or do not contain additive.
Anticancer pharmaceutical composition of the present invention can be made into multiple dosage form.As, but be not limited to injection, muddy suspension, ointment, capsule, implant, slow releasing agent and implantation slow release agent etc.; Be different shape, as, but be not limited to granular, lamellar, sphere, bulk, needle-like, bar-shaped and mould shape.In various dosage forms, serve as preferred with implant, slow releasing agent and implantation slow release agent.Above-mentioned dosage form and shape are applicable to the compositions that contains or do not contain additive.
Because anticancer pharmaceutical composition of the present invention can make the action effect of methods such as conventional chemotherapy, immunization therapy, high thermal therapeutical, photochemical therapy, electrotherapy, Biotherapeutics, hormone therapy, magnetic therapy, ultrasonic therapeutic, radiotherapy and gene therapy strengthen.Therefore when local slow discharges, can share, thereby its anticancer effect is further strengthened with above-mentioned non-operative treatment.
Route of administration
Anticancer pharmaceutical composition of the present invention can be used through various approach, as in passages through which vital energy circulates, tremulous pulse, subcutaneous, muscle, Intradermal, intracavity, the tumor, tumor week etc.Route of administration depends on multiple factor, for obtaining valid density in position, tumor place, medicine can give through other number of ways, as arterial perfusion optionally, administration in the intra-bladder instillation (intracavitary), abdominal cavity (intraperitoneal) or thoracic cavity (intrapleural) and canalis spinalis.In number of ways, with topical, as based in selective arterial, the tumor, tumor week injection, with in the tumor, the form that slowly discharges of tumor week or tumor chamber serve as preferably, can plant slow-releasing pump and slow releasing capsule as selecting for use, body is implanted into agent, sustained-release implant.
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 effective dose commonly used 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.Percentage by weight shared in compositions is decided because of concrete condition, can be good with 1%-50% from 0.01%-80%, is best with 2%-30%.Below all be weight percentage.
Anticancer pharmaceutical composition of the present invention can be used to prepare the various entity tumors for the treatment of the people, comprises former or the cancer of transfer or the medicine of sarcoma or carcinosarcoma originating from brain, central nervous system, kidney, liver, gallbladder, incidence, oral cavity, thyroid, skin, mucosa, body of gland, blood vessel, osseous tissue, lymph node, lungs, esophagus, stomach, mammary gland, pancreas, eyes, nasopharynx part, uterus, ovary, endometrium, cervix uteri, prostate, bladder, colon, rectum.
Anticancer pharmaceutical composition of the present invention also can be used for the treatment of the various entity tumors of house pet and animal, and when being used for the treatment of the various entity tumor of house pet and animal, the material of species specificity is preferably selected in the active ingredient of anticancer pharmaceutical composition of the present invention for use.
Also can add other medicinal ingredient in the anticancer pharmaceutical composition of the present invention, as, but be not limited to antibiotics, antalgica, anticoagulant medicine, hemorrhage etc.Above medicinal ingredient can singly select or multiselect, can join the compositions that contains or do not contain additive, and its content is because of specifically deciding.
Anticancer pharmaceutical composition of the present invention can be used in the following manner.
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 implant with the part again and slowly are released to the best.When used the part, anticancer pharmaceutical composition of the present invention can directly place around former or the entity tumor that shifts or in the tumor body, also can directly place former or all or part of excision of entity tumor shifted formed intracavity afterwards.
Anticancer pharmaceutical composition Main Ingredients and Appearance of the present invention is a holder with the bio-capacitivity material, so do not cause foreign body reaction.Support to place in the object back degradable and absorb, so no longer operation is taken out.Cause discharges contained drug at tumor by local, thereby optionally improves and prolong local drug concentration, can reduce the general toxic reaction that is caused by the conventional route administration simultaneously.
Anticancer pharmaceutical composition can be made into different shape, and wherein the content of active ingredient is decided because of different needs.Can be good with 1%-50% from 0.1%-80%, be best with 2%-30%.This anticancer pharmaceutical composition can be made into various dosage forms, as, but be not limited to injection, muddy suspension, ointment, capsule, implant, slow releasing agent and implantation slow release agent etc.; Be different shape, as, but be not limited to graininess, lamellar, sphere, bulk, needle-like, bar-shaped or mould shape; Can be good with the tremulous pulse approach through various administrations, directly be placed as the best in the tumor body.Most preferred dosage form of the present invention is the implantation slow release agent that bio-capacitivity, degradable absorb, and can make different shape because of the clinical needs of difference.The packing method of its Main Ingredients and Appearance and step in United States Patent (USP) (US5651986) have a detailed description, comprise the some kinds of methods that prepare slow releasing preparation: as, but be not limited to, (i) carrier holder powder and medicament mixed be pressed into implant then, promptly so-called mixing method; (ii) carrier holder fusing, mix solid cooled then, promptly so-called fusion method mutually with medicine to be packaged; (iii) the carrier holder is dissolved in the solvent, medicine dissolution to be packaged or be scattered in the polymer solution, evaporating solvent then, the universe is dry, promptly so-called dissolution method; (iii) the carrier holder is dissolved in the solvent, medicine dissolution to be packaged or be scattered in the polymer solution, evaporating solvent then, the universe is dry, promptly so-called dissolution method; (iv) spray drying method; And (v) freeze-drying etc.Wherein dissolution method can be in order to the manufacturing of microsphere, and its method is arbitrarily, and composition for treating solid tumor also can be packed in the liposome.
The characteristics of anticancer pharmaceutical composition technology of preparing of the present invention are one or more anti-mitosis medicines are packaged in the pharmaceutic adjuvant, and 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 local placement not only can overcome the toxic reaction that the whole body administration brings, and solved the tumor by local drug level and cross the low and cell sensitive question to medicine.
The present invention be processed into anticancer pharmaceutical composition preparation method as follows:
1. the pharmaceutic adjuvant of weighing is put into container, add the certain amount of organic solvent dissolving evenly, the not strict qualification of the amount of organic solvent, suitable fully to be dissolved as.
2. adding the anticancer active ingredient of weighing shakes up again.The usage ratio of anticancer active ingredient and pharmaceutic adjuvant is decided because of specific requirement.Active ingredient percentage by weight 0.01%-80%.
3. removal organic solvent.Vacuum drying, cold drying or cold drying all can.
4. dried solid composite is made different shape as required.
5. ray sterilizing (roentgendosis is different because of volume) is standby after the packing.Also available other method sterilization.
In a word, the anticancer pharmaceutical composition that contains above effective ingredient can be made into any dosage form or shape, the effective ingredient of anticancer compound is any one (or multiple) anti-mitosis medicine, but serving as preferred with implant, agent for slow releasing and implantation agent for slow releasing.
(4) specific embodiment
The present invention is processed into anticancer pharmaceutical composition and further is illustrated by following examples, but is not limited thereto.
Embodiment 1.
It with the 90mg molecular weight 10000 the PLGA (copolymer of hydroxyacetic acid and glycolic, hydroxyacetic acid and glycolic weight ratio 25: 75) put into container, add 100 milliliters of dichloromethane, behind the dissolving mixing, add the 10mg nocodazole, shake up the dry organic solvent of removing of final vacuum again.Dried solid composite is shaped immediately, and ray sterilizing after the packing must contain the anticancer pharmaceutical composition of percentage by weight 10% nocodazole.
Embodiment 2.
The method step that is processed into anticancer pharmaceutical composition is identical with embodiment 1, and different is that contained effective ingredient is:
The cytochalasin of 0.01%-10%, Datelliptium Chloride, ellipticine, 2-Methylellipticine, mitoclomine, mitoflaxone, mitoguazone, mitonafide, mitopodozide, mitoquidone, mitosper, mitotane, mitotenamine, mitozolomide, Flavone acetic acid, colchicine, Salicylate, colchiceinamide, colchicine, 7-acetamido-10-hydroxy-1,2,3-trimethoxy-6,7-dihydrobenzo[a, sulfo--colchicine, Demecolcine, Colchiceinamidum, Colchicine, 7-acetamido-10-hydroxy-1,2,3-trimethoxy-6,7-dihydrobenzo[a, sulfo--colchicine, Demecolcine, Colchiceinamidum, Colchicine, B cytochalasin B, carbaryl, naphthols, alpha-Naphthol, betanaphthol, the alpha-phosphate naphthols, acodazole, procodazole, giracodazole or malonic acid (salt).More than be weight percentage.
Embodiment 3.
80mg pharmaceutic adjuvant ethylene vinyl acetate copolymer (EVAc) is put into container, add 100 milliliters of dichloromethane dissolving mixings after, add the 20mg betanaphthol, shake up the dry organic solvent of removing of final vacuum again.Dried solid composite is shaped immediately, and ray sterilizing after the packing must contain the anticancer pharmaceutical composition of percentage by weight 20% betanaphthol.The drug release time of this anticancer pharmaceutical composition in external normal saline is 14-24 days, is 20-35 days at the subcutaneous drug release time of mice.
Embodiment 4.
The method step that is processed into anticancer pharmaceutical composition is identical with embodiment 3, and different is that contained effective ingredient is the cytochalasin of 5%-20%, Datelliptium Chloride, ellipticine, 2-Methylellipticine, mitoclomine, mitoflaxone, mitoguazone, mitonafide, mitopodozide, mitoquidone, mitosper, mitotane, mitotenamine, mitozolomide, Flavone acetic acid, colchicine, Salicylate, colchiceinamide, colchicine, 7-acetamido-10-hydroxy-1,2,3-trimethoxy-6,7-dihydrobenzo[a, sulfo--colchicine, Demecolcine, Colchiceinamidum, Colchicine, 7-acetamido-10-hydroxy-1,2,3-trimethoxy-6,7-dihydrobenzo[a, sulfo--colchicine, Demecolcine, Colchiceinamidum, Colchicine, B cytochalasin B, carbaryl, naphthols, alpha-Naphthol, the alpha-phosphate naphthols, acodazole, procodazole, giracodazole, nocodazole or malonic acid (salt).More than be weight percentage.
Embodiment 5.
70mg polifeprosan (to carboxy phenyl propane: certain herbaceous plants with big flowers diacid copolymer, weight ratio 40: 60) is put into container, add 100 milliliters of dichloromethane dissolving mixings after, add the 30mg B cytochalasin B, shake up the dry organic solvent of removing of final vacuum again.Dried solid composite is shaped immediately, and ray sterilizing after the packing must contain the anticancer pharmaceutical composition of percentage by weight 30% B cytochalasin B.The drug release time of this anticancer pharmaceutical composition in external normal saline is 15-25 days, is 25-40 days at the subcutaneous drug release time of mice.
Embodiment 6.
The method step that is processed into anticancer pharmaceutical composition is identical with embodiment 5, and the effective ingredient that different is wherein is respectively the 15%-30% cytochalasin, Datelliptium Chloride, ellipticine, 2-Methylellipticine, mitoclomine, mitoflaxone, mitoguazone, mitonafide, mitopodozide, mitoquidone, mitosper, mitotane, mitotenamine, mitozolomide, Flavone acetic acid, colchicine, Salicylate, colchiceinamide, colchicine, 7-acetamido-10-hydroxy-1,2,3-trimethoxy-6,7-dihydrobenzo[a, sulfo--colchicine, Demecolcine, Colchiceinamidum, Colchicine, 7-acetamido-10-hydroxy-1,2,3-trimethoxy-6,7-dihydrobenzo[a, sulfo--colchicine, Demecolcine, Colchiceinamidum, Colchicine, carbaryl, naphthols, alpha-Naphthol, betanaphthol, the alpha-phosphate naphthols, acodazole, procodazole, giracodazole, nocodazole or malonic acid (salt).More than be weight percentage.
Embodiment 7.
The method step that is processed into anticancer pharmaceutical composition is identical with embodiment 1,3 or 5, but used pharmaceutic adjuvant be following one of a)-e) or its combination:
A) molecular weight is the polylactic acid (PLA) of 5000-15000,10000-20000,25000-35000 or 30000-50000;
B) molecular weight is the polyglycolic acid of 5000-15000,10000-20000,25000-35000 or 30000-50000 and the copolymer of hydroxyacetic acid (PLGA);
C) ethylene vinyl acetate copolymer (EVAc);
D) to carboxy phenyl propane (p-CPP): certain herbaceous plants with big flowers diacid (SA) copolymer (polifeprosan), to carboxy phenyl propane (p-CPP): certain herbaceous plants with big flowers diacid (SA) is 10: 90,20: 80,30: 70,40: 60,50: 50 or 60: 40.All be weight percentage;
E) xylitol, oligosaccharide, chitin, potassium salt, sodium salt, hyaluronic acid, collagen protein, gelatin or albumin.
Embodiment 8.
With the 80mg polifeprosan (to carboxy phenyl propane (p-CPP): certain herbaceous plants with big flowers diacid (sA) copolymer) put into container, after adding 100 milliliters of dichloromethane dissolving mixings, add 10mg B cytochalasin B and 10mg alpha-Naphthol, shake up the dry organic solvent of removing of final vacuum again.Dried solid composite is shaped immediately, and ray sterilizing after the packing must contain the anticancer pharmaceutical composition of percentage by weight 10% B cytochalasin B and 10% alpha-Naphthol.The drug release time of this anticancer pharmaceutical composition in external normal saline is 15-25 days, is 30-40 days at the subcutaneous drug release time of mice.
Embodiment 9.
Method step is identical with embodiment 8, and the effective ingredient that different is wherein is respectively:
(a) cytochalasin of 1%-50%, Datelliptium Chloride, ellipticine, 2-Methylellipticine, mitoclomine, mitoflaxone, mitoguazone, mitonafide, mitopodozide or mitoquidone, mitosper, mitotane, mitotenamine, the colchicine of mitozolomide or Flavone acetic acid and 1%-50%, Salicylate, colchiceinamide, 7-acetamido-10-hydroxy-1,2,3-trimethoxy-6,7-dihydrobenzo[a, sulfo--colchicine, Demecolcine, Colchiceinamidum, Colchicine, 7-acetamido-10-hydroxy-1,2,3-trimethoxy-6,7-dihydrobenzo[a, sulfo--colchicine, Demecolcine, Colchiceinamidum, Colchicine, B cytochalasin B, carbaryl, naphthols, alpha-Naphthol, betanaphthol, the alpha-phosphate naphthols, acodazole, procodazole, giracodazole, the combination of nocodazole or malonic acid (salt);
(b) colchicine of 1%-50%, Salicylate, colchiceinamide, 7-acetamido-10-hydroxy-1,2,3-trimethoxy-6,7-dihydrobenzo[a, sulfo--colchicine, Demecolcine, Colchiceinamidum, Colchicine, 7-acetamido-10-hydroxy-1,2,3-trimethoxy-6,7-dihydrobenzo[a, sulfo--colchicine, Demecolcine, Colchiceinamidum, Colchicine, mitoclomine, mitoflaxone, mitoguazone, mitonafide, mitopodozide or mitoquidone, mitosper, mitotane, mitotenamine, the cytochalasin of mitozolomide or Flavone acetic acid and 1%-50%, Datelliptium Chloride, ellipticine, 2-Methylellipticine, B cytochalasin B, carbaryl, naphthols, alpha-Naphthol, betanaphthol, the alpha-phosphate naphthols, acodazole, procodazole, giracodazole, the combination of nocodazole or malonic acid (salt).
Below all be weight percentage.
Tumor-inhibiting action in the body of embodiment 10. anti-mitosis medicines.
With the white mice is subjects, with 2 * 10
5Individual tumor cell subcutaneous injection is in its hypochondrium, treats that tumor growth after 7 days is divided into it following 10 groups (seeing Table 1).First group is contrast, and the 2nd to 10 group is the treatment group, and wherein, the 2nd to 4 group is colchicine, and the 5th to 7 group is nocodazole, and the 8th to 10 group is alpha-Naphthol.Medicine is placed (itp) respectively in lumbar injection (ip), intratumor injection (it) and tumor.Local colchicine, nocodazole and the alpha-Naphthol of placing is selected from embodiment 4,2 and 6 respectively, and the percentage by weight of medicine in implant is respectively 10%, 20% and 30%.The treatment back was measured gross tumor volume size, relatively therapeutic effect (seeing Table 1) on the 10th day.
Table 1
| Test group (n) | Suffered treatment | Gross tumor volume (cm 3) | The P value |
| 1(6) 2(6) 3(6) 4(6) 5(6) 6(6) 7(6) 8(6) 9(6) 10(6) | Contrast colchicin (ip) colchicin (it) colchicin (itp) nocodazole (ip) nocodazole (it) nocodazole (itp) alpha-Naphthol (ip) alpha-Naphthol (it) alpha-Naphthol (itp) | 60.5±10.5 24±5.0 14±3.5 10±1.8 22±4.3 16±4.6 10±1.6 20±2.6 14±1.6 5±0.6 | ＜0.05 ＜0.01 ＜0.01 ＜0.01 ＜0.01 ＜0.001 ＜0.001 ＜0.001 ＜0.001 |
Tumor-inhibiting action in the body of embodiment 11. anti-mitosis medicines.
EXPERIMENTAL DESIGN is with embodiment 10, and local nocodazole, betanaphthol and the B cytochalasin B of placing is selected from embodiment 1,3 and 5 respectively, and the percentage by weight of medicine in implant is respectively 10%, 20% and 30%, (seeing Table 2).First group is contrast, and the 2nd to 10 group is the treatment group, and wherein, the 2nd to 4 group is nocodazole, and the 5th to 7 group is betanaphthol, and the 8th to 10 group is B cytochalasin B.Medicine is placed (itp) respectively in lumbar injection (ip), intratumor injection (it) and tumor.The treatment back was measured gross tumor volume size, relatively therapeutic effect (seeing Table 2) on the 10th day.
Table 2
| Test group (n) | Suffered treatment | Gross tumor volume (cm 3) | The P value |
| 1(6) 2(6) 3(6) 4(6) 5(6) 6(6) 7(6) 8(6) 9(6) 10(6) | Contrast nocodazole (ip) nocodazole (it) nocodazole (itp) betanaphthol (ip) betanaphthol (it) betanaphthol (itp) B cytochalasin B (ip) B cytochalasin B (it) B cytochalasin B (itp) | 76±13 45±6.2 38±4.0 28±2.6 54±6.0 32±3.2 18±2.2 53±5.8 22±3.0 10±1.6 | ＜0.05 ＜0.01 ＜0.01 ＜0.01 ＜0.01 ＜0.001 ＜0.001 ＜0.001 ＜0.001 |
Tumor-inhibiting action in the body of embodiment 12. anti-mitosis medicines.
EXPERIMENTAL DESIGN is with embodiment 10, and the local medicine of placing is that 10% naphthols, 20% giracodazole and 30% mitotenamine are respectively from embodiment 2,4 and 6.First group is contrast, and the 2nd to 10 group is the treatment group, and wherein, the 2nd to 4 group is vinorelbine, and the 5th to 7 group is naphthols, and the 8th to 10 group is mitotenamine.Medicine is placed (itp) respectively in lumbar injection (ip), intratumor injection (it) and tumor.The treatment back was measured gross tumor volume size, relatively therapeutic effect (seeing Table 3) on the 10th day.
Table 3
| Test group (n) | Suffered treatment | Gross tumor volume (cm 3) | The P value |
| 1(6) 2(6) 3(6) 4(6) 5(6) 6(6) 7(6) 8(6) 9(6) 10(6) | Contrast vinorelbine (ip) vinorelbine (ip) vinorelbine (ip) Vinmegallate (ip) Vinmegallate (ip) Vinmegallate (ip) Mitotenamine (ip) Mitotenamine (it) Mitotenamine (itp) | 74±10 48±6.6 39±4.1 28±2.2 54±7.0 36±3.0 17±2.2 42±6.6 20±2.6 12±1.6 | ＜0.05 ＜0.01 ＜0.01 ＜0.01 ＜0.01 ＜0.001 ＜0.001 ＜0.001 ＜0.001 |
The result of embodiment 10 to 12 shows that used various anti-mitosis medicines all have the obvious suppression effect to growth of tumour cell when this concentration, but comparatively obvious with local application's effect, wherein locally places that to be that tumor is implanted into the most effective.Local placement not only can suppress tumor growth effectively, and can significantly reduce the general toxic reaction of medicine, and selected anti-mitosis medicine is of universal significance.
The result of embodiment 10 to 12 shows that tumor by local placement anti-mitosis medicine has obvious superiority, be further clear and definite slow release effect of the present invention, selected the copolymer (PLGA of polyglycolic acid and hydroxyacetic acid respectively for use, molecular weight is 10000), ethylene vinyl acetate copolymer (EVAc) and polifeprosan (to carboxy phenyl propane (p-CPP) and certain herbaceous plants with big flowers diacid (SA) copolymer) be that pharmaceutic adjuvant, gravimetry percentage ratio are the release conditions of 20% anti-mitosis medicine.The result shows that the drug release time of this anticancer pharmaceutical composition in external normal saline is 15-20 days, is about 30-40 days at the subcutaneous drug release time of mice.Therefore the obvious tumor-inhibiting action that this anticancer pharmaceutical composition is described is mainly from its medicament slow release characteristic, and the latter is apparent at the superiority of keeping aspect the local drug concentration, and to selected anti-mitosis medicine tool universal meaning.Wherein PLGA is excellent than EVAc or polifeprosan.
As mentioned above, the preparation method of anticancer pharmaceutical composition of the present invention can be selected as the case may be.Anticancer pharmaceutical composition can be made various dosage forms with existing method, and therefore, above embodiment only is used for explanation, and is not limitation application of the present invention.Said composition except that independent application, also can with many treatment measure use in conjunction: as with use in conjunction such as radiotherapy, high thermal therapeutical, immunization therapy, phototherapy, electrotherapy.The local placement used said composition has uniqueness as synergist advantage and very high clinical value.When said composition and other treatment measure use in conjunction, said composition can be simultaneously or prior to other treatment measure.
Claims (3)
1, a kind of anticancer pharmaceutical composition, comprise anticancer effective component and pharmaceutic adjuvant, it is characterized in that this pharmaceutical composition is a sustained-release implant, described anticancer effective component is an anti-mitosis medicine, the percentage by weight of anti-mitosis medicine in compositions is 0.01-30%, and anti-mitosis medicine is selected from one of following or its combination:
The alpha-phosphate naphthols, alpha-Naphthol, betanaphthol, acodazole, procodazole, giracodazole, carbaryl, 2-Methylellipticine, sulfo--colchicine, Datelliptium Chloride, mitoguazone, mitopodozide, mitoquidone, the mitoclomine mitoflaxone, mitotenamine, mitonafide, Flavone acetic acid, mitosper, mitotane, mitozolomide, naphthols, nocodazole, the nocodazole malonic acid, the nocodazole malonate, colchiceinamide, Demecolcine, colchicine, Colchicine, Colchicum autumnale phthalein amine, 7-acetamido-10-hydroxy-1,2,3-trimethoxy-6,7-dihydrobenzo[a, Salicylate, cytochalasin, ellipticine, B cytochalasin B;
Described pharmaceutic adjuvant is a slow-release auxiliary material, selects for use one of following:
(1) molecular weight is 5000-15000,10000-20000, the polyglycolic acid of 25000-35000 or 30000-50000 and the copolymer of hydroxyacetic acid;
(2) ethylene vinyl acetate copolymer;
(3) to carboxy phenyl propane: the certain herbaceous plants with big flowers diacid copolymer, to carboxy phenyl propane: the certain herbaceous plants with big flowers diacid is 10: 90,20: 80,30: 70,40: 60,50: 50 or 60: 40; Be weight ratio.
2, the anticancer pharmaceutical composition according to claim 1 is characterized in that in this anti-cancer composition tumor or all placements of tumor.
3, the anticancer pharmaceutical composition according to claim 1 is characterized in that this entity-tumor-resistant medicine composition is graininess, lamellar, sphere, bulk, needle-like, bar-shaped or membranaceous.
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5250563A (en) * | 1991-09-25 | 1993-10-05 | Merck & Co., Inc. | Inhibitors of HIV protease |
| CN1192142A (en) * | 1995-08-03 | 1998-09-02 | 普罗克特和甘保尔公司 | Use of 1H-1,2,4-triazole derivatives for inhibiting the growth of cancers |
| CN1275377A (en) * | 2000-04-29 | 2000-12-06 | 孔庆忠 | Anticancer medicine composition |
| US6326402B1 (en) * | 1998-08-12 | 2001-12-04 | Octamer, Inc. | Methods for treating viral infections using a compound capable of inhibiting microtubules |
| CN1533765A (en) * | 2003-03-31 | 2004-10-06 | 清华大学 | Preparaton method of anticancer medicine colchicin microsphere freeze dried agent |
-
2004
- 2004-12-29 CN CNB2004100758379A patent/CN1311872C/en not_active Expired - Fee Related
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5250563A (en) * | 1991-09-25 | 1993-10-05 | Merck & Co., Inc. | Inhibitors of HIV protease |
| CN1192142A (en) * | 1995-08-03 | 1998-09-02 | 普罗克特和甘保尔公司 | Use of 1H-1,2,4-triazole derivatives for inhibiting the growth of cancers |
| US6326402B1 (en) * | 1998-08-12 | 2001-12-04 | Octamer, Inc. | Methods for treating viral infections using a compound capable of inhibiting microtubules |
| CN1275377A (en) * | 2000-04-29 | 2000-12-06 | 孔庆忠 | Anticancer medicine composition |
| CN1533765A (en) * | 2003-03-31 | 2004-10-06 | 清华大学 | Preparaton method of anticancer medicine colchicin microsphere freeze dried agent |
Non-Patent Citations (1)
| Title |
|---|
| 抗癌活性物质鬼臼类木脂素的研究进展 刘长军，侯嵩生，天然产物研究与开发，第9卷第3期 1997 * |
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