CN1660438A - Slow released anticancer combination of medication embedded the interior of the body - Google Patents
Slow released anticancer combination of medication embedded the interior of the body Download PDFInfo
- Publication number
- CN1660438A CN1660438A CN 200410075840 CN200410075840A CN1660438A CN 1660438 A CN1660438 A CN 1660438A CN 200410075840 CN200410075840 CN 200410075840 CN 200410075840 A CN200410075840 A CN 200410075840A CN 1660438 A CN1660438 A CN 1660438A
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- Prior art keywords
- pharmaceutical composition
- anticancer
- anticancer pharmaceutical
- tumor
- copolymer
- Prior art date
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Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
A slowly-releasing anticanser composite medicine implanted in human body is composed of the anticancer medicine prepared from implantation agent, slowly releasing agent and dichloroethane-kind medicine for suppressing the growth of tumor cells and the medicinal additive chosen from biocompatible and biodegradable polymer for slowly releasing said anticancer medicine toward tumor.
Description
(1) technical field
The present invention relates to a kind of anticancer pharmaceutical composition that implants and slowly discharge, 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 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 the infiltration in the tumor tissues and diffusion (carry and to wait " situation of extracellular matrix to entity tumor in the medicine influence of turning round " " cancer research " 60 phase 2497-503 page or leaf (2000) (Netti PA referring to the Buddhist nun, Cancer Res.2000,60 (9): 2497-503).Because entity tumor excessive expansion hypertrophy, the viscosity of matter was high than its normal surrounding tissue all between matter pressure, tissue elasticity pressure, fluid pressure reached therebetween, therefore, conventional chemotherapy, be difficult to tumor by local and form effective drug level (referring to " placing cisplatin adding system carmustine treatment rat brain tumor in the tumor " " surgery tumor magazine " 69 phase 76-82 pages or leaves (1998) (Kong Q et al., J Surg Oncol.1998Oct 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, particularly is anticancer implant.
Anticancer pharmaceutical composition of the present invention comprises anticancer effective component and pharmaceutic adjuvant, and wherein anticancer effective component is dichloro ethamine kind drug (bischloroethylamines).
Above-mentioned dichloro ethamine kind drug is selected from ifosfamide (Ifosfamide, Isophosphamide), three mustard cyclophosphamide, sufosfamide (Sufosfamide), defosfamide (Defosfamide), Mafosfamide [Mafosfamide], perfosfamide (Perfosfamide), trofosfamide [Trofosfamide], thiocarzolamide, formylmerphalan (Formylmerphalan), 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), benzodepa (Benzodepa), pumitepa (Pumitepa), meturedepa (Meturedepa), azatepa (Aza-TEPA) or urethimine (Uredepa).
Above dichloro ethamine kind drug can singly select or multiselect, serves as preferred with ifosfamide, letrozole, cantharidin, norcantharidin, azatepa, percentage by weight 5%-30%.
The percentage by weight of above-mentioned dichloro ethamine kind drug in compositions is good from 0.01%-99.99% with 1%-50%, is best with 5%-30%.
Pharmaceutic adjuvant of the present invention 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/or the excipient of pharmaceutical dosage forms such as injection and slow releasing agent.
Above-mentioned biodegradable polymer comprises natural and/or synthetic polymer.Synthetic polymer as, but be not limited to polyanhydrides, polyhydroxy acid, polyester (polyesters), polyamide (polyamides), poe (polyorthoesters), polyphosphazene (polyphosphazenes), to carboxy phenyl propane (p-CPP), certain herbaceous plants with big flowers diacid (sebacicacid) etc.; Natural polymer as, but be not limited to, protein and polysaccharide comprise hyaluronic acid, collagen protein, gelatin, albumin etc.
Above-mentioned polyanhydrides can be selected for use, but is not limited to, fragrant polyanhydride, aliphatic polyanhydride; Wherein fragrant polyanhydride will be separated slower, the fusing point height, and dissolubility is low in the organic solvent, however the copolymer of fragrant polyanhydride and aliphatic polyanhydride is comparatively desirable (United States Patent (USP) 4757128) but.Representative wherein is polifeprosan (to the copolymer of carboxy phenyl propane (p-CPP) and certain herbaceous plants with big flowers diacid (SA)), and is fragrant polyanhydride to carboxy phenyl propane, and the certain herbaceous plants with big flowers diacid then is the copolymer of an aromatic diacid and a fat diacid.The copolymer of available other fragrance or aliphatic polyanhydride has a detailed description (US 485731l in other United States Patent (USP); 4888l76; 4789724).
Above-mentioned polyhydroxy acid can be selected for use, but is not limited to, the copolymer (PLGA) of copolymer, glycolic and the hydroxy carboxylic acid of mixture, lactic acid and the glycolic 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 implant 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.
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.
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 anticancer implant 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.
Preferred pharmaceutic adjuvant is one of following:
A) molecular weight is the polylactic acid (PLA) of 5000-15000,10000-20000,25000-35000 or 30000-50000;
B) molecular weight is the lactic acid of 5000-15000,10000-20000,25000-35000 or 30000-50000 and the copolymer of glycolic (PLGA);
C) ethylene vinyl acetate copolymer (EVAc);
D) 10: 90,20: 80,30: 70,40: 60,50: 50 or 60: 40 to carboxy phenyl propane (p-CPP): certain herbaceous plants with big flowers diacid (SA) copolymer (polifeprosan) all is weight percentage;
E) xylitol, oligosaccharide, chitin, potassium salt, sodium salt, hyaluronic acid, collagen protein, gelatin or albumin.
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 or sustained release profile in vivo test implant as selecting for use.
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.Effective dose 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.Wherein the content of active ingredient in pharmaceutical composition is decided because of different needs, can be good with 1%-50% from 0.1%-99.9%, is best with 5%-30%.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 to prepare the medicine of the various entity tumors for the treatment of house pet and animal, 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.
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.
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.In various dosage forms, based on agent for slow releasing in the body; 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; (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.
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 discharging, local slow can share with above-mentioned non-operative treatment.When share with above-mentioned non-operative treatment, anticancer implant of the present invention can be used simultaneously with non-operative treatment, also can use in non-operative treatment is implemented a few days ago, and its purpose is to strengthen as far as possible the sensitivity of tumor.
The anticancer anticancer pharmaceutical composition topical application of the present invention, especially local the placement not only can overcome the toxic reaction that the whole body administration brings, and solved the tumor by local drug level and cross the low and cell sensitive question to medicine.
The preparation method of anticancer pharmaceutical composition of the present invention is as follows:
1. the pharmaceutic adjuvant of weighing is put into container, add the certain amount of organic solvent dissolving evenly, the not strict qualification of the amount of organic solvent, suitable fully to be dissolved as.
2. adding the anticancer active ingredient of weighing shakes up again.The usage ratio of anticancer active ingredient and pharmaceutic adjuvant is decided because of specific requirement.
3. removal organic solvent.Vacuum drying or cold drying all can.
4. dried solid composite is made different shape as required.
5. ray sterilizing (roentgendosis is different because of volume) is standby after the packing.Also available other method sterilization.
In a word, the effective ingredient of anticancer pharmaceutical composition of the present invention is the associating of above-mentioned any one (or multiple) dichloro ethamine kind drug or packs separately.The anticancer pharmaceutical composition that contains above effective ingredient can be made into any dosage form or shape, but serves as preferred with the agent for slow releasing type, as implant, slow releasing agent and implantation slow release agent etc.
(4) specific embodiment
Embodiment 1.
With the 90mg molecular weight is that 10000 polylactic acid (PLA) is put into container, adds 100 milliliters of dichloromethane, behind the dissolving mixing, adds the 10mg ifosfamide, shakes 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% ifosfamide.The drug release time of anticancer pharmaceutical 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 anticancer pharmaceutical composition is identical with embodiment 1, and different is that contained effective ingredient is:
The three mustard cyclophosphamide of percentage by weight 5-30%, sufosfamide, defosfamide, Mafosfamide, perfosfamide, trofosfamide, thiocarzolamide, formylmerphalan, 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, benzodepa, pumitepa, meturedepa, azatepa or urethimine.
Embodiment 3.
With the 80mg molecular weight is that 10000 the polyglycolic acid and the copolymer (PLGA) of hydroxyacetic acid are put into container, adds 100 milliliters of dichloromethane, behind the dissolving mixing, adds the 20mg letrozole, shakes 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% letrozole.The drug release time of this anticancer pharmaceutical composition in external normal saline is 15-20 days, is 30-40 days at the subcutaneous drug release time of mice.
Embodiment 4.
The method step that is processed into anticancer pharmaceutical composition is identical with embodiment 3, and different is that contained effective ingredient is:
The 5-30% ifosfamide, three mustard cyclophosphamide, sufosfamide, defosfamide, Mafosfamide, perfosfamide, trofosfamide, thiocarzolamide, formylmerphalan, Ametantrone, Thymopentin, clomifene, 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, benzodepa, pumitepa, meturedepa, azatepa or urethimine.
Embodiment 5.
With the 70mg polifeprosan (to carboxy phenyl propane (p-CPP): certain herbaceous plants with big flowers diacid (SA) 20: 80) put into container, add 100 milliliters of dichloromethane, behind the dissolving mixing, add the 30mg sodium cantharidinate, 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% sodium cantharidinate.The drug release time of this anticancer pharmaceutical composition in external normal saline is 15-20 days, is 30-40 days at the subcutaneous drug release time of mice.
Embodiment 6.
The method step that is processed into anticancer pharmaceutical composition is identical with embodiment 5, and different is that contained anticancer effective component is:
The 1-50% ifosfamide, three mustard cyclophosphamide, sufosfamide, defosfamide, Mafosfamide, perfosfamide, trofosfamide, thiocarzolamide, formylmerphalan, Ametantrone, Thymopentin, clomifene, letrozole, disodium cantharidinate, cantharidin, 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, benzodepa, pumitepa, meturedepa, azatepa or urethimine.
Embodiment 7.
(EVAc) puts into container with the 80mg pharmaceutic adjuvant, add 100 milliliters of dichloromethane dissolving mixings after, add the 20mg azatepa, 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% azatepa.The drug release time of this anticancer pharmaceutical composition in external normal saline is 15-20 days, is 30-40 days at the subcutaneous drug release time of mice.
Embodiment 8.
The method step that is processed into anticancer pharmaceutical composition is identical with embodiment 7, and the effective ingredient that different is wherein is:
The ifosfamide of percentage by weight 1-50%, three mustard cyclophosphamide, sufosfamide, defosfamide, Mafosfamide, perfosfamide, trofosfamide, thiocarzolamide, formylmerphalan, Ametantrone, Thymopentin, clomifene, letrozole, disodium cantharidinate, cantharidin, 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, benzodepa, pumitepa, meturedepa or urethimine.
Embodiment 9.
The method step that is processed into anticancer pharmaceutical composition is with embodiment 1,3,5 or 7, and different is, and that used pharmaceutic adjuvant is respectively is one of following:
A) molecular weight is the polylactic acid (PLA) of 5000-15000,10000-20000,25000-35000 or 30000-50000;
B) molecular weight is the lactic acid of 5000-15000,10000-20000,25000-35000 or 30000-50000 and the copolymer of glycolic (PLGA);
C) ethylene vinyl acetate copolymer (EVAc);
D) 10: 90,20: 80,30: 70,40: 60,50: 50 or 60: 40 to carboxy phenyl propane (p-CPP): certain herbaceous plants with big flowers diacid (SA) copolymer (polifeprosan) all is weight percentage;
E) xylitol, oligosaccharide, chitin, potassium salt, sodium salt, hyaluronic acid, collagen protein, gelatin or albumin.
As mentioned above, the preparation method of anticancer pharmaceutical composition of the present invention is arbitrary suitable prior art, can be made into various dosage forms, and therefore, above embodiment only is used for explanation, and is not limitation application of the present invention.
Above-mentioned anticancer pharmaceutical composition can be placed on tumor by local and be used for the treatment of above-mentioned people and the various entity tumors of animal, as, the cerebral tumor, breast carcinoma, multiple myeloma, the esophageal carcinoma, pulmonary carcinoma, gastroenteric tumor, hepatocarcinoma, ovarian cancer, central nerve neuroma, leukemia, colorectal cancer, cancer of pancreas, bone tumor, cervical cancer, carcinoma of prostate etc.Also can be used as the synergist of other treatment as system's chemotherapy or radiotherapy.
Embodiment 10. contains the interior tumor-inhibiting action of body of the anticancer pharmaceutical composition of dichloro ethamine kind drug.
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 ifosfamide, and the 5th to 7 group is letrozole, and the 8th to 10 group is sodium cantharidinate.Medicine is placed (itp) respectively in lumbar injection (ip), intratumor injection (it) and tumor.Local ifosfamide, letrozole and the sodium cantharidinate 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%.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) | Contrast | 65.5±11.5 | |
| 2(6) | Ifosfamide (ip) | 26±5.0 | ??＜0.05 |
| 3(6) | Ifosfamide (it) | 16±3.5 | ??＜0.01 |
| 4(6) | Ifosfamide (itp) | 11±1.8 | ??＜0.01 |
| 5(6) | Letrozole (ip) | 20±4.3 | ??＜0.01 |
| 6(6) | Letrozole (it) | 14±4.6 | ??＜0.01 |
| 7(6) | Letrozole (itp) | 10±1.6 | ??＜0.001 |
| 8(6) | Sodium cantharidinate (ip) | 20±2.0 | ??＜0.001 |
| 9(6) | Sodium cantharidinate (it) | 12±1.6 | ??＜0.001 |
| 10(6) | Sodium cantharidinate (itp) | 6±0.8 | ??＜0.001 |
Embodiment 11. contains the interior tumor-inhibiting action of body of the anticancer pharmaceutical composition of dichloro ethamine kind drug.
EXPERIMENTAL DESIGN is with embodiment 10, and local etoglucid, pipobroman and the benzodepa of placing is selected from embodiment 2,4 and 6 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 etoglucid, and the 5th to 7 group is pipobroman, and the 8th to 10 group is benzodepa.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) | Contrast | ????78±13 | |
| 2(6) | Etoglucid (ip) | ????40±6.2 | ??＜0.05 |
| 3(6) | Etoglucid (it) | ????36±4.0 | ??＜0.01 |
| 4(6) | Etoglucid (itp) | ????26±2.6 | ??＜0.01 |
| 5(6) | Pipobroman (ip) | ????52±6.0 | ??＜0.01 |
| ??6(6) | Pipobroman (it) | ????30±3.2 | ??＜0.01 |
| ??7(6) | Pipobroman (itp) | ????16±2.2 | ??＜0.001 |
| ??8(6) | Benzodepa (ip) | ????40±5.8 | ??＜0.001 |
| ??9(6) | Benzodepa (it) | ????20±3.0 | ??＜0.001 |
| ??10(6) | Benzodepa (itp) | ????11±1.6 | ??＜0.001 |
Embodiment 12. contains the interior tumor-inhibiting action of body of the anticancer pharmaceutical composition of dichloro ethamine kind drug.
EXPERIMENTAL DESIGN is with embodiment 10, and the local medicine of placing is that 10% piposulfan, 20% epoxypiperazine and 30% meturedepa 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 piposulfan, and the 5th to 7 group is epoxypiperazine, and the 8th to 10 group is meturedepa.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) | Contrast | ????74±10 | |
| 2(6) | Piposulfan (ip) | ????48±6.6 | ??＜0.05 |
| 3(6) | Piposulfan (it) | ????39±4.1 | ??＜0.01 |
| 4(6) | Piposulfan (itp) | ????28±2.2 | ??＜0.01 |
| 5(6) | Epoxypiperazine (ip) | ????54±7.0 | ??＜0.01 |
| 6(6) | Epoxypiperazine (it) | ????36±3.0 | ??＜0.01 |
| 7(6) | Epoxypiperazine (itp) | ????17±2.2 | ??＜0.001 |
| 8(6) | Meturedepa (ip) | ????42±6.6 | ??＜0.001 |
| 9(6) | Meturedepa (it) | ????20±2.6 | ??＜0.001 |
| 10(6) | Meturedepa (itp) | ????12±1.6 | ??＜0.001 |
The result of embodiment 10 to 12 shows, the used various anticancer pharmaceutical composition that contains dichloro ethamine kind drug all has the obvious suppression effect to growth of tumour cell when examination concentration, but comparatively obvious with local application's effect, wherein locally place 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 dichloro ethamine kind drug is of universal significance.
The result of embodiment 10 to 12 shows that tumor by local placement dichloro ethamine kind drug has obvious superiority, has obtained beyond thought effect.Be the slow release effect of further clear and definite anticancer pharmaceutical composition of the present invention to dichloro ethamine kind drug, the present invention has 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% dichloro ethamine kind drug.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 dichloro ethamine kind drug 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.
Claims (10)
1. anticancer pharmaceutical composition, comprise anticancer effective component and pharmaceutic adjuvant, it is characterized in that anticancer effective component is a dichloro ethamine kind drug, dichloro ethamine kind drug is selected from ifosfamide, three mustard cyclophosphamide, sufosfamide, defosfamide, Mafosfamide, perfosfamide, trofosfamide, thiocarzolamide, formylmerphalan, 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, benzodepa, pumitepa, meturedepa, in azatepa or the urethimine one or more.
2. the anticancer pharmaceutical composition according to claim 1 is characterized in that the percentage by weight of dichloro ethamine kind drug in compositions is 1-50%.
3. the anticancer pharmaceutical composition according to claim 1 is characterized in that dichloro ethamine kind drug is ifosfamide, letrozole, cantharidin, norcantharidin or the azatepa of percentage by weight 5%-30%.
4. the anticancer pharmaceutical composition according to claim 1 is characterized in that pharmaceutic adjuvant is selected from macromolecule polymer and composition thereof or copolymer.
5. the anticancer pharmaceutical composition according to claim 3, it is characterized in that the macromolecule polymer be selected from polylactic acid, hydroxyacetic acid, glycolic, ethylene vinyl acetate, to carboxy phenyl propane, certain herbaceous plants with big flowers diacid.
6. the anticancer implant according to claim 1 is characterized in that used pharmaceutic adjuvant is respectively one of following:
A) molecular weight is the polylactic acid of 5000-15000,10000-20000,25000-35000 or 30000-50000;
B) molecular weight is the lactic acid of 5000-15000,10000-20000,25000-35000 or 30000-50000 and the copolymer of glycolic;
C) ethylene vinyl acetate copolymer;
D) 10: 90,20: 80,30: 70,40: 60,50: 50 or 60: 40 to carboxy phenyl propane: the certain herbaceous plants with big flowers diacid copolymer all is weight percentage;
E) xylitol, oligosaccharide, chitin, potassium salt, sodium salt, hyaluronic acid, collagen protein, gelatin or albumin.
7. the anticancer pharmaceutical composition according to claim 1 is characterized in that, the interior or all placements of tumor of this entity-tumor-resistant medicine composition tumor.
8. the anticancer pharmaceutical composition according to claim 1 is characterized in that said composition is suspension, implant, slow releasing agent or implantation slow release agent.
9. the anticancer pharmaceutical composition according to claim 1 is characterized in that said composition makes graininess, lamellar, sphere, bulk, needle-like, bar-shaped or mould shape.
10. the application of the described anticancer pharmaceutical composition of claim 1 is used to prepare the medicine that treatment originates from cancer, sarcoma or the carcinosarcoma of people and animal brain, central nervous system, kidney, liver, gallbladder, incidence, oral cavity, thyroid, skin, mucosa, 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 or rectum former or secondary.
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| CN100421672C (en) * | 2006-03-02 | 2008-10-01 | 上海慈瑞医药科技有限公司 | Compound lentinan preparation for antitumour and its preparing method |
| CN101130057B (en) * | 2007-07-06 | 2011-04-27 | 复旦大学 | Long-acting implantation agent of pentapeptide for thymus gland and method of producing the same |
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| CN1385154A (en) * | 2001-05-15 | 2002-12-18 | 中国人民解放军第二军医大学 | Slow-releasing injection type demehylcantharidin for antitumor |
| CN1418622A (en) * | 2002-12-19 | 2003-05-21 | 王登之 | Demethyl catharidine lipid for treating malignant tumour, and its prepn. method |
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| CN100421672C (en) * | 2006-03-02 | 2008-10-01 | 上海慈瑞医药科技有限公司 | Compound lentinan preparation for antitumour and its preparing method |
| CN101130057B (en) * | 2007-07-06 | 2011-04-27 | 复旦大学 | Long-acting implantation agent of pentapeptide for thymus gland and method of producing the same |
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