CN1679948A - Anticarcinogenic internal implant agent - Google Patents
Anticarcinogenic internal implant agent Download PDFInfo
- Publication number
- CN1679948A CN1679948A CN 200510042432 CN200510042432A CN1679948A CN 1679948 A CN1679948 A CN 1679948A CN 200510042432 CN200510042432 CN 200510042432 CN 200510042432 A CN200510042432 A CN 200510042432A CN 1679948 A CN1679948 A CN 1679948A
- Authority
- CN
- China
- Prior art keywords
- internal implant
- anticarcinogenic internal
- implant agent
- anticancer
- agent
- 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.)
- Pending
Links
Abstract
An anticancer in vivo implant applied locally is prepared from the anticancer nitrosourea-type medicine, the anticancer synergist chosen from bichloroethanamine-type alkylating agent, anticancer antibiotic, and hormone-type anticancer medicine, and the biocompatible and biodegradable high-molecular polymer as medicinal additive.
Description
(1) technical field
The present invention relates to a kind of Anticarcinogenic internal implant agent, belong to the cancer therapy drug technical field.
(2) background technology
The treatment of entity tumor mainly comprises methods such as operation, radiotherapy and chemotherapy.In used various chemotherapeutics, the action effect of nitrosourea cancer therapy drug is comparatively obvious, has been widely used in multiple malignant tumor.Yet, discover that further the DNA repair function in many tumor cells obviously increases after treatment.The latter often causes the enhancing of tumor cell to the toleration of nitrosourea cancer therapy drug, consequently treatment failure.
Recent findings, many medicines can increase the sensitivity of tumor cell to the nitrosourea cancer therapy drug, referring to " O6-benzyl guanine analog is to the effect of human tumor cells to the cell toxicant sensitivity of alkylating agent " " cancer research " 51 phase 3367-3372 pages or leaves (1991) such as Doran (Dolan et al., Cancer Res., 51,3367-3372,1991).Yet, blood vessel in the mesenchyma stroma of tumors, connective tissue, stromatin, fine micro protein and collagen protein etc. not only provide support and requisite nutrient substance for the growth of tumor cell, also influenced chemotherapeutics around tumor and infiltration and diffusion in the tumor tissues, " situation of extracellular matrix is to the influence of medicine running in the entity tumor " " cancer research " 60 phase 2497-503 page or leaf (2000) (Netti PA such as carry referring to the Buddhist nun, Cancer Res.2000,60 (9): 2497-503).Because entity tumor excessive expansion hypertrophy, the viscosity of matter was high than its normal surrounding tissue all between matter pressure, tissue elasticity pressure, fluid pressure reached therebetween, therefore, and conventional chemotherapy, be difficult to tumor by local and form effective drug level, improve the restriction that dosage is subjected to general reaction again merely.Referring to " placing cisplatin adding system carmustine treatment rat brain tumor in the tumor " " surgery tumor magazine " 69 phase 76-82 pages or leaves (1998) (Kong Q et al., J Surg Oncol.1998 Oct such as Kong Qingzhongs; 69 (2): 76-82).In addition, the cancer drug therapy of low dosage not only can increase the Drug tolerance of cancerous cell, but also can promote the growth of its wettability "; referring to beam etc. " increased after the cancer therapy drug pulse screening human lung carcinoma cell Drug tolerance and external invade the profit ability and with the change of gene expression " " international journal of cancer " 111 phase 484-93 page or leaf (2004) (Liang Y; etal., Int J Cancer.2004; 111 (4): 484-93).
Because the principal element of decision therapeutic effect is the drug level of tumor by local and the tumor cell sensitivity to medicine.And the blood vessel in the mesenchyma stroma of tumors, connective tissue, stromatin, fine micro protein and collagen protein etc. not only provide support and requisite nutrient substance for the growth of tumor cell, have also influenced chemotherapeutics around tumor and infiltration and diffusion in the tumor tissues.
(3) summary of the invention
The present invention is directed to the deficiencies in the prior art, a kind of Anticarcinogenic internal implant agent is provided.
Anticarcinogenic internal implant agent of the present invention contains nitrosourea cancer therapy drug and synergist thereof, and the latter can suppress and destroy the DNA repair function in the tumor cell effectively, and then increases the therapeutic effect of nitrosourea cancer therapy drug.
Anticarcinogenic internal implant agent of the present invention comprises the anticancer effective component and the pharmaceutic adjuvant of effective anticancer, and wherein anticancer effective component is nitrosourea cancer therapy drug and nitrosourea cancer therapy drug synergist.The nitrosourea medicament synergist comprises one or more of dichloro ethamine kind alkylating agent, antitumor antibiotics or steroids anti-cancer drugs.
Nitrosourea medicament is selected from following one or more; alestramustine (Alestramustine); streptozocin (streptozotocin; STZ); atrimustine (Atrimustine); ambamustine (Ambamustine); nimustine (ACNU; Nimustine); bendamustine (Bendamustine); ditiomustine (Ditiomustine); bofumustine (Bofumustine); carmustine (carmustine; BCNU; carmustine); elmustine (Elmustine); ecomustine (Ecomustine); galamustine (Galamustine; GCNU); fotemustine (Fotemustine); estramustine (Estramustine; 81); hemustine heCNU He (hemustine; heCNU); pentamustine (Pentamustine; Neptamustine); mannomustine (Mannomustine; MCNU); lomustine (lomustine; CCNU; lomustine; chlorethyl cyclohexyl nitrosourea); methyl lomustine (methyl-CCNU); semustine (Semustine; CH3-CCNU; Me-CCNU); Ranimustine (Ranimustine); prednimustine (Prednimustine); uracil mustard (Uramustine, Uracil Mustard); Sarmustine SarCNU (SarCNU); tauromustine (Tauromustine); tallimustine (Tallimustine) and spiromustine (Spiromustine) etc.Above nitrosourea medicament also comprises its salt, as, but be not limited to sulfate, phosphate, hydrochlorate, Lactobionate, acetate, aspat, nitrate, citrate, purine or pyrimidine salt, succinate and maleate etc.
The preferred streptozocin of above-mentioned nitrosourea medicament (STZ), estramustine, nimustine, lomustine or carmustine.
Above-mentioned pair of chlorethamin (bischloroethylamines) class medicine is selected from following one or more:
Chlorambucil (chlorambucil, chlorambucil), cyclophosphamide (Cyclophosphamide), ifosfamide (Ifosfamide, Isophosphamide), 4H-peroxide cyclophosphamide, three mustard cyclophosphamide, sufosfamide (Sufosfamide), defosfamide (Defosfamide), Mafosfamide [Mafosfamide], perfosfamide (Perfosfamide), trofosfamide [Trofosfamide], thiocarzolamide, melphalan (Melphalan), metamelfalan (Metamelfalan), methoxymerphalan (Methoxymerphalan) and formylmerphalan (Formylmerphalan).Dichloro ethamine kind drug also comprises the medicine with similar structures or function, as, but be not limited to, 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), benzodepa (Benzodepa), pumitepa (Pumitepa), meturedepa (Meturedepa), azatepa (Aza-TEPA) or urethimine (Uredepa).
Above dichloro ethamine kind drug also comprises their salt, as, but be not limited to sulfate, phosphate, hydrochlorate, Lactobionate, acetate, aspat, nitrate, citrate, purine or pyrimidine salt, succinate and maleate etc.
Above dichloro ethamine kind drug is preferably with Chlorambucil, cyclophosphamide, ifosfamide, melphalan, 4H-peroxide cyclophosphamide, methoxymerphalan, hexamethylmelamine, letrozole, cantharidin, norcantharidin or azatepa.
Antitumor antibiotics suppresses by combining with DNA that RNA is synthetic to be used for the treatment of various cancers, and antitumor antibiotics is selected from following one or more:
Carcinomycin, bleomycin (Bleomycin, Bleomycin A5, Pingyangmycin), (hydrochloric acid) bleomycin, zorbamycin, Bleomycin, Pelomecin Sulfate, antibiotic 1588, bouvardin, clarithromycin (Clarithromycin), aklavine (Aclacinomycin A, aclarubicin), aklavine-B, 9-[4-(N-Methylacetamido)anilino, 9-(4-(N-Methylacetamido)anilino)-7-methyl-1H-imidazo(4,5-f)quinoline, kidamycin, acetylkitamycin (acetyl kidamycin), azotomycin (azotomycin), daunomycin (rubidomycin, daunorubicin, daunomycin), Diacetoxysciroenol (Diacetoxysciroenol), doxorubicin hydrochloride (doxorubicin, doxorubicin, adriamycin), triferricdoxorubicin, epirubicin (epiadriamycin) or epirubicin (Epirubicin), Valrubicin (valrubicin), pirarubicin, 7-O-methyl Nuo Jia-4 '-epirubicin (7-o-methylnogallol-4 '-epiadriamycin), diethoxy acetyl amycin, ciclamicin, mitomycin (Mitomycin), ametycin (mitomycin C), NSC-69529, actinomycin D (Dactinomycin), actinomycin C, cyclosporin A, Carzinocidin (carzinocidin), carzinophillin (carzinophylin), cardinophyllin, the tumor rhzomorph, carzinostatin (carzinostatin, carcinostain), neocarzinostain NCS (neocarzinostain), diazamycine (diazamycine), Macrocin (macrocin), macrocinomycin (macrocinomycin), dactinomycin, alanopsin, alazopeptin, the A Le lid, neothricin (neothricin, neothramycin), macromycin (macromomycin or macromycin), neothramycin A, nocardin (nocardin), nocardorubin. (nocardorubin), 2-[N-(2-amidinoethyl)carbamoyl (noformicin), nogalamycin (promise Garamycin, nogalamycin or nogaromycin), Mitochromine mitocromine B-35251 (mitochromine or mitocromine), polymyxin E (PolymyxinE), pirlimycin (Pirlimycin), dirithromycin (Dirithromycin), antramycin, oxalysine, duazomycin, Olivomycin, rufocromomycin, NSC-45384, streptozotocin, peplomycin, puromycin, sparsomycin, talisomycin, Anthrapyrazole, losoxantrone [Losoxantrone], mitoxantrone (Mitoxantrone), piroxantrone [Piroxantrone], teloxantrone [Teloxantrone], hydroxyl nitre D-glucosamine ring element, anthramycin (anthramycin, antramycin), methylanthramycin, Ai Fei ground can be peaceful, asperlin, (hydrochloric acid) Carrninomycin I, talisomycin, macromycin, O-Demethyldaunomycin, NSC-178248, chromomycin A3, chlorine assistant star (chlorozotocin), demethylrifampicin, ditrisarubicins, Hitachimycin, deoxycoformycin, puromycin, puromycin hydrochloride, rachelmycin, rebeccamycin, Sangivamycin, sarkomycin, sibiromycin, talisomycin, rice holder Zuro, selenazofurin, Antibiotic BMG-162aF2, spirogermanium hydrochloride, Spirogermanium, Spirophydantoin Mustard or stibcytostatum.
The preferred bleomycin of above-mentioned antitumor antibiotics, daunomycin, amycin, epirubicin, pirarubicin, ametycin, losoxantrone, mitoxantrone, piroxantrone, teloxantrone or chlorine assistant star.
Steroids anti-cancer drugs is that steroid hormone and hormone are robbed anti-agent, is used to regulate the hypertrophy of the tumor that some hormone relies on.This type of medicine is many according to its functional classification, as, but be not limited to adrenocortical hormone, estrogen, progestogen, estrogen antagonist, androgen antagonist.Steroids anti-cancer drugs is selected from following one or more among the present invention:
Anastrozole (anastrozole); idoxifene (idoxifene); Miproxifene (Miproxifene); tamoxifen (tamoxifen; tamoxifen); 4-monohydroxy tamoxifen (trans-4-monohydroxytamoxifen; OH-TAM); former times sweet smell (keoxifene not; LY156758); ICI-M 164384 (ICI164384; the 7-alpha-alkyl amide analogue of estradiol); 7-α-[9-(4; 4; 5; 5; 5-five fluorine amyl group sulfinyls) nonyl] female steroid-1; 3; 5 (10)-triolefins-3; 17 β diphenol (anticancer steroid alkene phenol; fulvestrant; 7alpha-[9-(4; 4; 5; 5; 5-pentafluoropentyl sulfinyl) nonyl] estra-1; 3; 5 (10)-triene-3; 17 beta-diol; ICI 182780); 4-trans-Hydroxytamoxifen (4-hydroxytamoxifen); γ-linoleic acid (gamma-linolenic acid); 2-methoxyestradiol (2-methoxyestradiol); moxestrol (moxestrol); 4-trans-Hydroxytamoxifen (4-hydroxytamoxifen); clofenotane (dichlorodiphenyltrichloroethane; o; p '-dichlorodiphenyltrichloroethane; o; p '-DDT); benzene hexachloride (benzene hexachloride; Gamma Hexaochlorocyclohexane; beta-hexachlorocyclohexane; beta-HCH); thunder is former times sweet smell (raloxifene) not; diethylstilbestrol (diethylstilbestrol); estradiol (estradiol); 6-(10-hydroxy-6-oxo-trans-1-undecenyl)-.beta.-resorcylic acid lactone (zearalenone); estrone (estrone); 17 alpha-estradiols (17alpha-estradiol); estradiol (estriol); 2-hydroxyestrone (2-hydroxyestrone); 5; 7; 4 trihydroxy-isoflavones (genistein); Progesterone; mepitiostane (Mepitiostane); androgen; (.+-.)-Pyridoglutethimide; rubitecan; Acapodene; Drogenil (Flutamide; flutamide); overstate single silicon indigo plant; bicalutamide (Casodex); aminoglutethimide (Aminoglutethimide, aminoglutethimidium); betamethasone benzoate; calusterone; megestrol; datiscoside; epitiostanol; the female sweet smell of bromine vinegar ethane; hisphen or testolactone.
The preferred Anastrozole of above steroids anti-cancer drugs, idoxifene, Miproxifene, tamoxifen, 4-monohydroxy tamoxifen (OH-TAM), not former times sweet smell, ICI-M 164384, anticancer steroid alkene phenol, 4-trans-Hydroxytamoxifen, Drogenil, megestrol or bicalutamide.
Above steroids anti-cancer drugs can be used for the tumor that various hormones rely on, but different pharmaceutical has relative tumor-selective, as, tamoxifen, (.+-.)-Pyridoglutethimide, rubitecan, Acapodenes etc. mainly rely on estrogenic tumor in order to treatment, as breast carcinoma and carcinoma of endometrium; Drogenil, overstate that single silicon indigo plant and bicalutamide mainly rely on androgenic tumor in order to treatment, as carcinoma of prostate; Aminoglutethimide is then in order to treatment breast carcinoma, carcinoma of prostate and carcinoma of endometrium.
The nitrosourea cancer therapy drug can be good with 1%-50% from 0.01%-99.99% at the weight percent content of Anticarcinogenic internal implant agent, is best with 2%-30%.Nitrosourea cancer therapy drug synergist is decided because of concrete condition at the content of Anticarcinogenic internal implant agent, and percentage by weight can be good with 1%-30% from 0.01%-99.99%, is best with 5%-25%.
Pharmaceutic adjuvant commonly used 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.In the available pharmaceutic adjuvant of the present invention and not exclusively limit the technical characterictic of implant according to its classification or definition, pharmaceutic adjuvant can be above-mentioned any or multiple material.
Pharmaceutic adjuvant mainly is selected from the biocompatibility polymer, comprises biodegradable or biological nondegradable polymer.
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), poly-phosphide (polyphosphazenes), to carboxy phenyl propane (p-CPP), certain herbaceous plants with big flowers diacid (sebacic acid, SA) etc.; Natural polymer as, but be not limited to, protein and polysaccharide comprise hyaluronic acid, collagen protein, gelatin, albumin etc.
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 the copolymer to carboxy phenyl propane (p-CPP) and certain herbaceous plants with big flowers diacid, as polifeprosan 20, 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 (US4857311 in other United States Patent (USP); 4888176; 4789724).
Polyhydroxy acid can be selected for use, but is not limited to, the copolymer (PLGA) 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 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 polylactic acid (PLA) or lactic acid and ethanol copolymer (PLGA), the molecular weight of copolymer can be, but is not limited to, 1000-100,000, but with 10,000-50,000 is preferred; With 10,000-20,000 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 5,000 to 10,000 polylactic acid and molecular weight are 20,000 to 50,000 polylactic acid mixing, molecular weight is 10,000 to 20,000 polylactic acid and molecular weight are 30,000 to 80,000 PLGA mixing, molecular weight is 5,000 to 10,000 polylactic acid mixes with the certain herbaceous plants with big flowers diacid, molecular weight is that 30,000 to 80,000 PLGA mixes with the certain herbaceous plants with big flowers diacid.The indication molecular weight is the molecular weight peak value scope for being recorded by GPC all.
Biological nondegradable polymer comprises, but be not limited to: organosilicon polymer, ethylene vinyl acetate (Ethelene-vinyl acetate copolymer, EVAc), polyacrylonitrile (polyacrylonitriles), polyurethane (polyurethanes), poly-phosphide (polyphosphazenes) etc.Compositions can discharge effective ingredient by the mode of direct diffusion.
Be main separation with the high molecular weight water soluble polymer in the used pharmaceutic adjuvant of Anticarcinogenic internal implant agent of the present invention, 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 lactic acid and ethanol copolymer, lactic acid and glycolic, certain herbaceous plants with big flowers diacid and fragrant polyanhydride or aliphatic polyanhydride.The blend ratio of lactic acid and ethanol copolymer is 10/90-90/10 (weight), serves as preferred with 25/75-75/25 (weight), and 50/50 for the most preferred.The method of blend is arbitrarily.Content when lactic acid and glycolic copolymerization is respectively 10-90% and 90-10%.The representative of fragrance polyanhydride is to carboxy phenyl propane (p-CPP), and the content during to carboxy phenyl propane (p-CPP) and the copolymerization of certain herbaceous plants with big flowers diacid is respectively 10-90% and 90-10%, and the blend ratio is 10/90-90/10 (weight), preferably 25/75-75/25 (weight).
The effective ingredient of Anticarcinogenic internal implant agent can be packaged in the whole carrier holder 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 ready-made any means.
For regulating other characteristic of drug releasing rate or change Anticarcinogenic internal implant agent of the present invention, can change the composition and the proportioning of monomer component or molecular weight, interpolation or the adjusting pharmaceutic adjuvant of polymer, add the water-soluble low-molecular chemical compound, as, but be not limited to various sugar and salt etc.Wherein sugar can be but is not limited to, xylitol, oligosaccharide and chitin etc., and wherein salt can be but is not limited to, potassium salt and sodium salt etc.
The characteristics of this technical characterictic are that used pharmaceutical carrier holder removes the high molecular polymerization beyond the region of objective existence, also contains above-mentioned any one (or individual) or multiple (or a plurality of) 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.
Anticarcinogenic internal implant agent of the present invention can be made into multiple dosage form.As, but be not limited to injection, muddy suspension, ointment, capsule and slow releasing agent etc.; Be different shape, as, but be not limited to granular, lamellar, sphere, bulk, needle-like, bar-shaped and membranaceous.In various dosage forms, based on agent for slow releasing in the body.Above-mentioned dosage form and shape are applicable to the compositions that contains or do not contain additive.
Another technical characterictic of anti-cancer composition of the present invention is that said composition comprises effective ingredient, carrier holder and additive.
Wherein effective ingredient can be packed separately or packaged in combination, and the carrier holder removes and can be the biocompatibility polymer, comprises a kind of or several above-mentioned biodegradable or biological nondegradable polymers.
Anticarcinogenic internal implant agent of the present invention can be used simultaneously or in the non-operative treatment other day with non-operative treatment such as conventional chemotherapy, immunization therapy, high thermal therapeutical, photochemical therapy, electrotherapy, Biotherapeutics, hormone therapy, magnetic therapy, ultrasonic therapeutic, radiotherapy and gene therapies.
Route of administration
Anticarcinogenic internal implant agent of the present invention can be used through various approach, as in tremulous pulse, subcutaneous, muscle, Intradermal, intracavity, the tumor, tumor week etc.Whether route of administration depends on multiple factor, as position, tumor place, perform the operation or transfer, gross tumor volume size, tumor classification, patient age, health, bearing status and requirement etc.For obtain active drug concentration in position, tumor place, arterial perfusion optionally, intra-bladder instillation (intracavitary), (intraspinal) administration in abdominal cavity (intraperitoneal) or thoracic cavity (intrapleural) and the canalis spinalis, but also place in the internal organs, as in the enteric cavity, in the intravesical, uterine cavity, in intravaginal, gastric and the esophagus etc.In number of ways, with topical, as based in selective arterial, the tumor, tumor week injection, with in the tumor, the form that slowly discharges of tumor week or tumor chamber serve as preferably, can plant slow-releasing pump, slow releasing capsule, slow releasing agent, implant and sustained-release implant as selecting for use.
Dosage
The consumption of cancer therapy drug depends on several factors, as, but be not limited to gross tumor volume, patient body weight, administering mode, disease progression situation and therapeutic response.But its principle is at the repair ability that can reduce tumor cell, when increasing the chemotherapy action effect and the toxic reaction of not obvious increase medicine.
The effective dose of nitrosourea cancer therapy drug is 0.01-200 milligram/kg body weight, is ideal with 1-30 milligram/kg body weight, with 2-20 milligram/kg body weight for the most desirable; Nitrosourea cancer therapy drug synergist Anticarcinogenic internal implant agent effective dose decide because of concrete condition, can be ideal with 1-30 milligram/kg body weight from 0.01-200 milligram/kg body weight, with 2-20 milligram/kg body weight for the most desirable.
Anticarcinogenic internal implant agent of the present invention can be used for the treatment of the entity tumors such as various cancers, sarcoma or carcinosarcoma of people, house pet and various animals, comprises former or cancer or sarcoma or the carcinosarcoma that shifts originating from brain, central nervous system, kidney, liver, gallbladder, incidence, oral cavity, thyroid, skin, mucosa, body of gland, blood vessel, osseous tissue, lymph node, lungs, esophagus, stomach, mammary gland, pancreas, eyes, Folium Nicotianae preparatum portion, uterus, ovary, endometrium, cervix uteri, prostate, bladder, colon, rectum.Therefore, the application of Anticarcinogenic internal implant agent of the present invention is the above-mentioned various preparations that are used to make the above-mentioned tumor of treatment.
Also can add other medicinal ingredient in this Anticarcinogenic internal implant agent, as, but be not limited to antibiotics, antalgica, anticoagulant medicine, hemorrhage etc.Above medicinal ingredient can singly select or multiselect, can join the compositions that contains or do not contain additive, and its content is because of specifically deciding.
The dosage form of Anticarcinogenic internal implant agent
Anticarcinogenic internal implant agent of the present invention can be made into different shape, and wherein the content of active ingredient is decided because of different needs.Can be made into various dosage forms, 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 film sample; Can be good with the tremulous pulse approach through various administrations, directly be placed as the best in the tumor body.Most preferred dosage form is the implantation slow release agent that bio-capacitivity, degradable absorb, and can make different shape because of the clinical needs of difference.Available arbitrary method preparation.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 used for the manufacturing of microsphere, and anticancer pharmaceutical composition also can be packaged in the liposome.
The characteristics of Anticarcinogenic internal implant agent technology of preparing of the present invention be with all kinds of cancer therapy drugs separately or packaged in combination in the carrier holder, according to a certain percentage with active ingredient and carrier holder dissolving (or mixing), the drying of bleeding (or tabletting) is shaped and the sterilization packing.Can control its release time by technology such as layering packings when packing simultaneously.Its principle is when alleviating drug toxicity as far as possible, strengthens the action effect between various medicines most effectively.
Anticarcinogenic internal implant agent of the present invention can be used by many schemes.Above-mentioned effective ingredient can be packaged in the pharmaceutic adjuvant, then topical application.Said composition can with topical, wherein be released to the best with local slow again as injection in selective arterial injection and the direct tumor body for good through various administrations.When used the part, compositions 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.
Anticarcinogenic internal implant agent 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.
Test one, nitrosourea cancer therapy drug and synergist thereof are to the inhibitory action of tumor cell in vitro growth.
For the mutual potentiation of checking nitrosourea cancer therapy drug and synergist thereof used, this test comprises CNS-1, C6, gastric gland epithelial cancer (SA), bone tumor (BC), breast carcinoma (BA), pulmonary carcinoma (LH), papillary adenocarcinoma of thyroid (PAT), hepatocarcinoma etc. with the tumor cell of multiple In vitro culture.The inhomogeneity cancer therapy drug is pressed the combination shown in the table 1, and cancer therapy drug is added in 24 hours the various tumor cells of In vitro culture by the concentration of 10ug/ml, continue to cultivate after 48 hours the counting cells sum and calculates its suppression ratio to growth of tumour cell (%).
Table 1
| Oncocyte | BCNU | Mel | Dox | Epi | Tam | BCNU +Mel | BCNU +Dox | BCNU +Epi | BCNU +Tam |
| CNS | 66％ | 60％ | 62％ | 60％ | 52％ | 96％ | 94％ | 92％ | 96％ |
| C6 | 62％ | 64％ | 66％ | 60％ | 66％ | 94％ | 94％ | 96％ | 90％ |
| SA | 60％ | 60％ | 68％ | 56％ | 58％ | 92％ | 90％ | 86％ | 96％ |
| BC | 52％ | 64％ | 64％ | 54％ | 64％ | 84％ | 94％ | 94％ | 94％ |
| BA | 50％ | 62％ | 68％ | 62％ | 58％ | 82％ | 89％ | 96％ | 92％ |
| LH | 62％ | 58％ | 62％ | 62％ | 52％ | 92％ | 88％ | 92％ | 92％ |
| PAT | 55％ | 56％ | 64％ | 66％ | 64％ | 92％ | 96％ | 94％ | 96％ |
Explain: BCNU: be the nitrosourea cancer therapy drug; Mel: be melphalan, belong to the dichloro ethamine kind alkylating agent; The Dox-amycin, the Epi-epirubicin is antitumor antibiotic; Tam: tamoxifen is steroids anti-cancer drugs.
Test two, according to test one described method relatively nitrosourea cancer therapy drug and synergist thereof to the inhibitory action of tumor cell in vitro growth.The results are shown in Table 2.
Table 2
| Oncocyte | (A) | (B) | (C) | (D) | (E) | (A) +(B) | (A) +(C) | (A) +(D) | (A) +(E) |
| CNS | 62％ | 64％ | 62％ | 66％ | 62％ | 96％ | 94％ | 92％ | 96％ |
| C6 | 56％ | 64％ | 66％ | 60％ | 56％ | 94％ | 94％ | 96％ | 91％ |
| SA | 68％ | 60％ | 68％ | 56％ | 58％ | 92％ | 90％ | 86％ | 96％ |
| BC | 64％ | 64％ | 64％ | 54％ | 64％ | 84％ | 94％ | 94％ | 94％ |
| BA | 58％ | 62％ | 68％ | 62％ | 58％ | 82％ | 90％ | 96％ | 92％ |
| LH | 62％ | 58％ | 62％ | 62％ | 62％ | 92％ | 88％ | 92％ | 92％ |
| PAT | 64％ | 56％ | 64％ | 66％ | 64％ | 92％ | 96％ | 94％ | 94％ |
Explain: (A): be ACNU, belong to the nitrosourea cancer therapy drug; (B): cyclophosphamide is the dichloro ethamine kind alkylating agent; (C): pirarubicin, antitumor antibiotic; (D): anticancer steroid alkene phenol and (E): Drogenil is steroids anti-cancer drugs.
Test three, according to test one described method relatively nitrosourea cancer therapy drug and synergist thereof to the inhibitory action of tumor cell in vitro growth.The results are shown in Table 3.
Table 3
| Oncocyte | (A) | (B) | (C) | (D) | (E) | (A) +(B) | (A) +(C) | (A) +(D) | (A) +(E) |
| CNS | 52％ | 64％ | 62％ | 66％ | 62％ | 86％ | 94％ | 92％ | 91％ |
| C6 | 56％ | 64％ | 66％ | 60％ | 58％ | 94％ | 94％ | 96％ | 91％ |
| SA | 60％ | 60％ | 68％ | 56％ | 58％ | 92％ | 90％ | 86％ | 96％ |
| BC | 64％ | 64％ | 64％ | 54％ | 54％ | 84％ | 94％ | 94％ | 94％ |
| BA | 58％ | 62％ | 68％ | 62％ | 58％ | 82％ | 92％ | 96％ | 92％ |
| LH | 62％ | 60％ | 62％ | 62％ | 52％ | 92％ | 88％ | 92％ | 92％ |
| PAT | 60％ | 56％ | 64％ | 66％ | 64％ | 92％ | 96％ | 94％ | 91％ |
Explain: (A): CCNU is the nitrosourea cancer therapy drug; (B): 4H-peroxide cyclophosphamide is the dichloro ethamine kind alkylating agent; (C): ametycin, (D): mitoxantrone and (E): piroxantrone is antitumor antibiotic.
Test four, according to test one described method relatively nitrosourea cancer therapy drug and synergist thereof to the inhibitory action of tumor cell in vitro growth.The results are shown in Table 4.
Table 4
| Oncocyte | (A) | (B) | (C) | (D) | (E) | (A) +(B) | (A) +(C) | (A) +(D) | (A) +(E) |
| CNS | 50％ | 60％ | 62％ | 66％ | 52％ | 86％ | 94％ | 92％ | 91％ |
| C6 | 56％ | 64％ | 66％ | 60％ | 88％ | 94％ | 94％ | 96％ | 91％ |
| SA | 62％ | 62％ | 68％ | 56％ | 58％ | 92％ | 90％ | 86％ | 96％ |
| BC | 64％ | 64％ | 64％ | 54％ | 64％ | 84％ | 94％ | 94％ | 94％ |
| BA | 56％ | 62％ | 68％ | 62％ | 58％ | 82％ | 92％ | 96％ | 92％ |
| LH | 62％ | 60％ | 62％ | 62％ | 62％ | 92％ | 88％ | 92％ | 92％ |
| PAT | 62％ | 58％ | 64％ | 66％ | 64％ | 92％ | 96％ | 94％ | 91％ |
Explain: (A): carmustine is the nitrosourea cancer therapy drug; (B): 4H-peroxide cyclophosphamide is the dichloro ethamine kind alkylating agent; (C): epirubicin, (D): mitoxantrone and (E): piroxantrone is antitumor antibiotic.
Test five, according to test one described method relatively nitrosourea cancer therapy drug and synergist thereof to the inhibitory action of tumor cell in vitro growth.The results are shown in Table 5.
Table 5
| Oncocyte | (A) | (B) | (C) | (D) | (E) | (A) +(B) | (A) +(C) | (A) +(D) | (A) +(E) |
| CNS | 52％ | 60％ | 62％ | 66％ | 92％ | 86％ | 94％ | 90％ | 90％ |
| C6 | 56％ | 64％ | 66％ | 60％ | 88％ | 94％ | 960 | 96％ | 91％ |
| SA | 62％ | 62％ | 68％ | 56％ | 88％ | 92％ | 90％ | 88％ | 94％ |
| BC | 64％ | 64％ | 64％ | 54％ | 94％ | 84％ | 94％ | 94％ | 94％ |
| BA | 56％ | 62％ | 68％ | 62％ | 98％ | 82％ | 92％ | 96％ | 92％ |
| LH | 62％ | 60％ | 62％ | 62％ | 92％ | 92％ | 88％ | 92％ | 92％ |
| PAT | 60％ | 58％ | 64％ | 66％ | 94％ | 92％ | 96％ | 96％ | 95％ |
Explain: (A): SarCNU is the nitrosourea cancer therapy drug; (B): letrozole is the dichloro ethamine kind alkylating agent; (C): epirubicin, (D): mitoxantrone and (E): piroxantrone is antitumor antibiotic.
In test 1 to 5, selected for use nimustine (ACNU), carmustine (BCNU), semustine (CCNU) and Sarmustine SarCNU (SarCNU) etc. to be the nitrosourea cancer therapy drug of representative; Dichloro ethamine kind alkylating agents such as cyclophosphamide, 4H-peroxide cyclophosphamide, melphalan and letrozole; Steroids anti-cancer drugs such as tamoxifen and anticancer steroid alkene phenol; Be the antitumor antibiotic of representative with amycin, epirubicin, pirarubicin, ametycin, epirubicin, mitoxantrone, piroxantrone etc.With its inhibitory action of cellular assay such as CNS-1, C6, gastric gland epithelial cancer (SA), bone tumor (BC), breast carcinoma (BA), pulmonary carcinoma (LH), papillary adenocarcinoma of thyroid (PAT), hepatocarcinoma to tumor growth.The result shows, growth all has the obvious suppression effect to used cancer therapy drug to cultured tumor cells in vitro when 5-10ul/ml concentration, but the two has obvious synergistic effect when share.
Test six, comparison nitrosourea cancer therapy drug and synergist thereof are to the inhibitory action of interior tumor cell growth.
With the rat is subjects, with 2 * 10
5Individual tumor cell subcutaneous injection is in its hypochondrium, treats that tumor growth is divided into it following 10 groups (seeing Table 6) at random after 14 days.All medicines are all placed in tumor, and dosage is 5mg/kg.The treatment back was measured gross tumor volume size, relatively therapeutic effect (seeing Table 6) on the 30th day.
Table 6
| Test group (n) | Suffered treatment | Gross tumor volume (cm 3) | The P value |
| 1(6) | Contrast | 88.5±14cm 3 | |
| 2(6) | (A) carmustine | 32±8cm 3 | ＜0.05 |
| 3(6) | (B) melphalan | 56±12cm 3 | ＜0.01 |
| 4(6) | (C) amycin | 42±10cm 3 | ＜0.01 |
| 5(6) | (D) epirubicin | 40±8cm 3 | ＜0.01 |
| 6(6) | (E) tamoxifen | 50±11cm 3 | ＜0.01 |
| 7(6) | (A)+(B) | 21±4.6cm 3 | ＜0.001 |
| 8(6) | (A)+(C) | 21±3.6cm 3 | ＜0.001 |
| 9(6) | (A)+(D) | 21±3.6cm 3 | ＜0.001 |
| 10(6) | (A)+(E) | 18±3.0cm 3 | ＜0.001 |
Explain: (A): carmustine is the nitrosourea cancer therapy drug; (B): melphalan is the dichloro ethamine kind alkylating agent; (C) amycin and (D) epirubicin be antitumor antibiotic; (E): tamoxifen is steroids anti-cancer drugs.
The inhibitory action that test seven, the combination of inhomogeneity cancer therapy drug are grown to interior tumor cell.
With the rat is subjects, with 2 * 10
5Individual tumor cell subcutaneous injection is in its hypochondrium, treats that tumor growth is divided into it following 10 groups (seeing Table 7) at random after 14 days.All medicines are all placed in tumor, and dosage is 5mg/kg.The treatment back was measured gross tumor volume size, relatively therapeutic effect (seeing Table 7) on the 30th day.
Table 7
| Test group (n) | Suffered treatment | Gross tumor volume (cm 3) | The P value |
| 1(6) | Contrast | 80.5±21cm 3 | |
| 2(6) | (A) nimustine | 32±5.3cm 3 | ＜0.05 |
| 3(6) | (B) ifosfamide | 48±6.5cm 3 | ＜0.01 |
| 4(6) | (C) ametycin | 40±6.6cm 3 | ＜0.01 |
| 5(6) | (D) pirarubicin | 42±6cm 3 | ＜0.01 |
| 6(6) | (E) Drogenil | 38±5.8cm 3 | ＜0.01 |
| 7(6) | (A)+(B) | 21±3.8cm 3 | ＜0.001 |
| 8(6) | (A)+(C) | 20±3.6cm 3 | ＜0.001 |
| 9(6) | (A)+(D) | 20±2.6cm 3 | ＜0.001 |
| 10(6) | (A)+(E) | 18±3.4cm 3 | ＜0.001 |
Explain: (A): nimustine is the nitrosourea cancer therapy drug; (B): ifosfamide is the dichloro ethamine kind alkylating agent; (C) ametycin and (D) pirarubicin be antitumor antibiotic; (E): Drogenil is steroids anti-cancer drugs.
Test eight, according to test one described method relatively nitrosourea cancer therapy drug and synergist thereof to the inhibitory action of interior tumor cell growth.The results are shown in Table 8.
Table 8
| Test group (n) | Suffered treatment | Gross tumor volume (cm 3) | The P value |
| 1(6) | Contrast | 80.5±21cm 3 | |
| 2(6) | (A) Sarmustine SarCNU | 32±5.3cm 3 | ＜0.05 |
| 3(6) | (B) 4H-peroxide cyclophosphamide | 48±6.5cm 3 | ＜0.01 |
| 4(6) | (C) mitoxantrone | 40±6.6cm 3 | ＜0.01 |
| 5(6) | (D) pirarubicin | 42±6cm 3 | ＜0.01 |
| 6(6) | (E) Drogenil | 38±5.8cm 3 | ＜0.01 |
| 7(6) | (A)+(B) | 21±3.8cm 3 | ＜0.001 |
| 8(6) | (A)+(C) | 20±3.6cm 3 | ＜0.001 |
| 9(6) | (A)+(D) | 20±2.6cm 3 | ＜0.001 |
| 10(6) | (A)+(E) | 18±3.4cm 3 | ＜0.001 |
Explain: (A): Sarmustine SarCNU is the nitrosourea cancer therapy drug; (B): 4H-peroxide cyclophosphamide is the dichloro ethamine kind alkylating agent; (C) mitoxantrone and (D) pirarubicin be antitumor antibiotic; (E): Drogenil is steroids anti-cancer drugs.
The result of the test of test 6 to 8 shows, compares with matched group, and above-mentioned all kinds of cancer therapy drugs are used separately all has obvious inhibitory action (P＜0.05) to tumor growth in vivo.And has obvious synergistic effect (P＜0.001) when nitrosourea cancer therapy drug and dichloro ethamine kind alkylating agent, antitumor antibiotic or steroids anti-cancer drugs use in conjunction.
In a word, have obvious synergistic effect when nitrosourea cancer therapy drug among the present invention and dichloro ethamine kind alkylating agent, antitumor antibiotic or steroids anti-cancer drugs use in conjunction, and be of universal significance.This unexpected formation major technique feature of the present invention of finding.The Anticarcinogenic internal implant agent that contains above effective ingredient can be made into any dosage form or shape, but serves as preferred with the agent for slow releasing of implanting.
The preparation method of Anticarcinogenic internal implant agent 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.
(4) specific embodiment
Embodiment one:
The pharmaceutic adjuvant (molecular weight is 10000 polylactic acid (PLA)) of (80mg) of will weighing is put into container, after adding certain amount of organic solvent dissolving mixing (being as the criterion) with abundant dissolving, add 10 milligrams of carmustines and 10mg melphalan, shake up the dry organic solvent of removing of final vacuum again.Dried solid composite is shaped immediately, and ray sterilizing after the packing obtains Anticarcinogenic internal implant agent and contains 10% carmustine and 10% melphalan.More than be weight percentage.
Embodiment two:
As described in embodiment one, different is that anticancer effective component is:
A) alestramustine of 5-25%, streptozocin, atrimustine, ambamustine, nimustine, bendamustine, ditiomustine, bofumustine, carmustine, elmustine, ecomustine, CNCC, galamustine, fotemustine, estramustine, hemustine heCNU He, pentamustine, mannomustine, lomustine, methyl lomustine, semustine, Ranimustine, Sarmustine SarCNU, prednimustine, uracil mustard, tauromustine, tallimustine or spiromustine and 5-25% Chlorambucil, cyclophosphamide, ifosfamide, melphalan, 4H-peroxide cyclophosphamide, methoxymerphalan, hexamethylmelamine, letrozole, cantharidin, the combination of norcantharidin or azatepa; Or
B) alestramustine of 5-25%, streptozocin, atrimustine, ambamustine, nimustine, bendamustine, ditiomustine, bofumustine, carmustine, elmustine, ecomustine, CNCC, galamustine, fotemustine, estramustine, hemustine heCNU He, pentamustine, mannomustine, lomustine, methyl lomustine, semustine, Ranimustine, Sarmustine SarCNU, prednimustine, uracil mustard, tauromustine, the bleomycin of tallimustine or spiromustine and 5-25%, daunomycin, amycin, epirubicin, pirarubicin, ametycin, actinomycin D, losoxantrone, mitoxantrone, piroxantrone, the combination of teloxantrone or chlorine assistant star; Or
C) alestramustine of 5-25%; streptozocin; atrimustine; ambamustine; nimustine; bendamustine; ditiomustine; bofumustine; carmustine; elmustine; ecomustine; CNCC; galamustine; fotemustine; estramustine; hemustine heCNU He; pentamustine; mannomustine; lomustine; methyl lomustine; semustine; Ranimustine; Sarmustine SarCNU; prednimustine; uracil mustard; tauromustine; the Anastrozole of tallimustine or spiromustine and 5-25%; anticancer steroid alkene phenol; tamoxifen; Drogenil; the combination of bicalutamide or aminoglutethimide.
Below all be weight percentage.
Embodiment three:
With the pharmaceutic adjuvant of the 85mg that weighs, molecular weight is that 15000 polylactic acid (PLGA) is put into container, adds certain amount of organic solvent dissolving mixing, be as the criterion with abundant dissolving, then, add 10mg nimustine and 5mg amycin, shake up the dry organic solvent of removing of final vacuum again.Dried solid composite is shaped immediately, and ray sterilizing after the packing obtains Anticarcinogenic internal implant agent and contains 10% nimustine and 5% amycin.All be weight percentage.
Embodiment four:
As described in embodiment three, different is that different is that contained anticancer effective component is:
A) combination of the nimustine of 5-25%, carmustine, Sarmustine SarCNU, streptozocin or semustine and 5-25% melphalan, Chlorambucil, cyclophosphamide, ifosfamide or 4H-peroxide cyclophosphamide; Or
B) combination of the amycin of the nimustine of 5-25%, carmustine, Sarmustine SarCNU, streptozocin or semustine and 5-25%, epirubicin, pirarubicin, ametycin, losoxantrone, mitoxantrone, piroxantrone or teloxantrone; Or
C) combination of the Anastrozole of the nimustine of 5-25%, carmustine, Sarmustine SarCNU, streptozocin or semustine and 5-25%, anticancer steroid alkene phenol or tamoxifen.
Below all be weight percentage.
Embodiment five:
With the pharmaceutic adjuvant molecular weight of 80mg is that 15000 EVAc puts into container, adds organic dissolution with solvents mixing, is as the criterion with abundant dissolving, adds 10mg carmustine and 10 milligrams of tamoxifens then, shakes up the dry organic solvent of removing of final vacuum again.Dried solid composite is shaped immediately, and ray sterilizing after the packing obtains Anticarcinogenic internal implant agent and contains 10% carmustine and 10% tamoxifen.All be weight percentage.
Embodiment six:
Make Anticarcinogenic internal implant agent by embodiment five described methods, different is that anticancer effective component is:
A) combination of the nimustine of 5-25%, carmustine, Sarmustine SarCNU, streptozocin or semustine and 5-25% melphalan, Chlorambucil, cyclophosphamide, ifosfamide or 4H-peroxide cyclophosphamide; Or
B) combination of the amycin of the nimustine of 5-25%, carmustine, Sarmustine SarCNU, streptozocin or semustine and 5-25%, epirubicin, pirarubicin, ametycin, losoxantrone, mitoxantrone, piroxantrone or teloxantrone; Or
C) combination of the Anastrozole of the nimustine of 5-25%, carmustine, Sarmustine SarCNU, streptozocin or semustine and 5-25%, anticancer steroid alkene phenol or tamoxifen.
Below all be weight percentage.
Embodiment seven:
80mg polifeprosan (to carboxy phenyl propane (p-CPP): certain herbaceous plants with big flowers diacid (SA) is 20: 80) is put into container, after adding 100 milliliters of dichloromethane dissolving mixings, add 15mg carmustine and 5mg mitoxantrone, 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 percentage by weight 15% carmustine and 5% mitoxantrone body is implanted into agent.It is 15-25 days that this body is implanted into the drug release time of agent in external normal saline, is 25-40 days at the subcutaneous drug release time of mice.All be weight percentage.
Embodiment eight:
As described in embodiment seven, but different is that anticancer effective component is:
A) combination of the nimustine of 5-25%, carmustine, Sarmustine SarCNU, streptozocin or semustine and 5-25% melphalan, Chlorambucil, cyclophosphamide, ifosfamide or 4H-peroxide cyclophosphamide; Or
B) combination of the amycin of the nimustine of 5-25%, carmustine, Sarmustine SarCNU, streptozocin or semustine and 5-25%, epirubicin, pirarubicin, ametycin, losoxantrone, mitoxantrone, piroxantrone or teloxantrone; Or
C) combination of the Anastrozole of the nimustine of 5-25%, carmustine, Sarmustine SarCNU, streptozocin or semustine and 5-25%, anticancer steroid alkene phenol or tamoxifen.
Below all be weight percentage.
Embodiment nine:
With the pharmaceutic adjuvant molecular weight of 80mg is that 10000 EVAc puts into container, and the organic solvent dissolution mixing that adds is as the criterion with abundant dissolving, adds 10mg nimustine and 10 milligrams of tamoxifens then, shakes up the dry organic solvent of removing of final vacuum again.Dried solid composite is shaped immediately, and ray sterilizing after the packing obtains Anticarcinogenic internal implant agent and contains 10% nimustine and 10% tamoxifen.All be weight percentage.
Embodiment ten:
As described in embodiment nine, but different is that anticancer effective component is:
A) combination of the nimustine of 5-25%, carmustine, Sarmustine SarCNU, streptozocin or semustine and 5-25% melphalan, Chlorambucil, cyclophosphamide, ifosfamide or 4H-peroxide cyclophosphamide; Or
B) combination of the amycin of the nimustine of 5-25%, carmustine, Sarmustine SarCNU, streptozocin or semustine and 5-25%, epirubicin, pirarubicin, ametycin, losoxantrone, mitoxantrone, piroxantrone or teloxantrone; Or
C) combination of the Anastrozole of the nimustine of 5-25%, carmustine, Sarmustine SarCNU, streptozocin or semustine and 5-25%, anticancer steroid alkene phenol or tamoxifen.
Below all be weight percentage.
Embodiment 11:
With the pharmaceutic adjuvant molecular weight of the 70mg that weighs is that 20000 polylactic acid (PLGA) is put into container, add organic dissolution with solvents mixing, be as the criterion with abundant dissolving, add 15mg carmustine and 15 milligrams of tamoxifens then, shake up the dry organic solvent of removing of final vacuum again.Dried solid composite is shaped immediately, and ray sterilizing after the packing obtains Anticarcinogenic internal implant agent and contains 15% carmustine and 15% tamoxifen.All be weight percentage.
Embodiment 12:
As described in embodiment 11, different is that anticancer effective component is:
(a) 10% carmustine and 10% melphalan; Or
(b) 10% carmustine and 10% amycin; Or
(c) 10% carmustine and 10% epirubicin; Or
(d) 10% carmustine and 10% pirarubicin; Or
(e) 10% carmustine and 10% ametycin; Or
(f) 10% carmustine and 10% mitoxantrone; Or
(g) 10% carmustine and 10% tamoxifen; Or
(h) combination of 10% carmustine and 10% pirarubicin.
Below all be weight percentage.
Embodiment 13:
Make Anticarcinogenic internal implant agent by embodiment one to 13 described method, used pharmaceutic adjuvant is selected from one of following or its combination that different is:
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) polifeprosan is (to carboxy phenyl propane (p-CPP): certain herbaceous plants with big flowers diacid (SA) copolymer), be 10: 90,20: 80,30: 70,40: 60,50: 50 or 60: 40 to the percentage by weight of carboxy phenyl propane (p-CPP) and certain herbaceous plants with big flowers diacid (SA);
E) xylitol, oligosaccharide, chitin, potassium salt, sodium salt, hyaluronic acid, collagen protein, gelatin or albumin.
Embodiment 14: different embodiment medicine extracorporeal releasing characteristics relatively.
Anticarcinogenic internal implant agent among the embodiment 12 is placed in the room temperature normal saline soaks, survey the burst size of different time medicine (nimustine), and calculate accumulative total and discharge percent (%).Be shown in Table 9.
Table 9
| Embodiment 12 | 1 day | 3 days | 5 days | 7 days | ????14 |
| (a) (b) (c) (d) (e) (f) (g) (h) | ????19 ????20 ????21 ????21 ????21 ????23 ????22 ????23 | ????40 ????39 ????41 ????42 ????41 ????39 ????41 ????42 | ????59 ????61 ????61 ????61 ????61 ????60 ????62 ????58 | ????78 ????78 ????72 ????81 ????71 ????79 ????78 ????82 | ????92 ????88 ????89 ????89 ????86 ????92 ????90 ????91 |
Embodiment 15: release characteristics relatively in the different embodiment medicine bodies.
It is subcutaneous that Anticarcinogenic internal implant agent among the embodiment 12 is put in white mice, regularly takes out and measure medicament contg, according to the residual drug amount, and calculates accumulative total and discharge percent (%).Be shown in Table 10.
Table 10
| Embodiment 12 | 1 day | 3 days | 5 days | 7 days | 14 days | 21 days | 28 days |
| ??(a) ??(b) ??(c) ??(d) ??(e) ??(f) ??(g) ??(h) | 9 12 11 14 9 15 11 14 | 27 21 22 20 21 19 20 21 | 33 33 33 29 31 29 33 31 | 50 52 51 48 49 58 56 51 | 78 72 73 72 79 70 75 66 | 92 92 91 89 94 84 88 84 | 97 96 95 94 99 94 97 97 |
As can be seen from Table 9, the different pharmaceutical release in vitro no significant difference that tries discharged the about 20%, the 14th day and discharges 85-90 in first day.
By table on 10 as can be seen, institute try to discharge in the different pharmaceutical body also no significant difference, and release in first day release in the about 10%, 28th day is more than 95%.But the inside and outside discharges notable difference is arranged, release in vitro is fast than being released in the body.Can keep one month in vivo, external then about 15 days.
As mentioned above, Anticarcinogenic internal implant agent 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. Anticarcinogenic internal implant agent, it is characterized in that this implant is made up of anticancer effective component and pharmaceutic adjuvant, wherein anticancer effective component is nitrosourea cancer therapy drug and anticancer synergist, and described anticancer synergist is one or more in dichloro ethamine kind alkylating agent, antitumor antibiotics and the steroids anti-cancer drugs.
2. the Anticarcinogenic internal implant agent according to claim 1 is characterized in that described nitrosourea cancer therapy drug is selected from alestramustine; streptozocin; atrimustine; ambamustine; nimustine; bendamustine; ditiomustine; bofumustine; carmustine; elmustine; ecomustine; CNCC; galamustine; fotemustine; estramustine; hemustine heCNU He; pentamustine; mannomustine; lomustine; methyl lomustine; semustine; Ranimustine; Sarmustine SarCNU; prednimustine; uracil mustard; tauromustine; in tallimustine or the spiromustine one or more.
3. the Anticarcinogenic internal implant agent according to claim 1 is characterized in that the percentage by weight of described nitrosourea cancer therapy drug in Anticarcinogenic internal implant agent is 1-50%.
4. the Anticarcinogenic internal implant agent according to claim 1, it is characterized in that the dichloro ethamine kind alkylating agent is selected from one or more in Chlorambucil, cyclophosphamide, ifosfamide, melphalan, 4H-peroxide cyclophosphamide, methoxymerphalan, hexamethylmelamine, letrozole, cantharidin, norcantharidin or the azatepa, the weight percent content of above dichloro ethamine kind alkylating agent in Anticarcinogenic internal implant agent is 1-30%.
5. the Anticarcinogenic internal implant agent according to claim 1, it is characterized in that antitumor antibiotics is selected from one or more in bleomycin, daunomycin, amycin, epirubicin, pirarubicin, ametycin, actinomycin D, losoxantrone, mitoxantrone, piroxantrone, teloxantrone or the chlorine assistant star, the weight percent content of above antitumor antibiotics in Anticarcinogenic internal implant agent is 1-30%.
6. the Anticarcinogenic internal implant agent according to claim 1, it is characterized in that steroids anti-cancer drugs is selected from one or more in Anastrozole, anticancer steroid alkene phenol, tamoxifen, Drogenil, bicalutamide or the aminoglutethimide, the weight percent content of above steroids anti-cancer drugs in Anticarcinogenic internal implant agent is 1-30%.
7. the Anticarcinogenic internal implant agent according to claim 1 is characterized in that the anticancer effective component of this Anticarcinogenic internal implant agent is:
A) combination of the nimustine of 5-25%, carmustine, Sarmustine SarCNU, streptozocin or semustine and 5-25% melphalan, Chlorambucil, cyclophosphamide, ifosfamide, melphalan or 4H-peroxide cyclophosphamide; Or
B) combination of the amycin of the nimustine of 5-25%, carmustine, Sarmustine SarCNU, streptozocin or semustine and 5-25%, epirubicin, pirarubicin, ametycin, losoxantrone, mitoxantrone, piroxantrone or teloxantrone; Or
C) combination of the Anastrozole of the nimustine of 5-25%, carmustine, Sarmustine SarCNU, streptozocin or semustine and 5-25%, anticancer steroid alkene phenol or tamoxifen;
Below all be weight percentage.
8. the anti-cancer composition according to claim 1 is characterized in that pharmaceutic adjuvant is selected from the mixture of macromolecule polymer, macromolecule polymer or copolymer, water-soluble low-molecular chemical compound.
9. according to the described anti-cancer composition of claim 1, it is characterized in that used pharmaceutic adjuvant is selected from one of following or its combination:
A) molecular weight is the polylactic acid 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;
C) ethylene vinyl acetate copolymer;
D), it is 10: 90,20: 80,30: 70,40: 60,50: 50 or 60: 40 to the weight ratio of carboxy phenyl propane and certain herbaceous plants with big flowers diacid to carboxy phenyl propane and certain herbaceous plants with big flowers diacid copolymer;
E) xylitol, oligosaccharide, chitin, potassium salt, sodium salt, hyaluronic acid, collagen protein, gelatin or albumin.
10. the described Anticarcinogenic internal implant agent of claim 1 is used to prepare the medicine that treatment originates from cancer, sarcoma or the carcinosarcoma of 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, Folium Nicotianae preparatum portion, uterus, ovary, endometrium, cervix uteri, prostate, bladder, colon or rectum former or secondary.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200510042432 CN1679948A (en) | 2005-02-03 | 2005-02-03 | Anticarcinogenic internal implant agent |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200510042432 CN1679948A (en) | 2005-02-03 | 2005-02-03 | Anticarcinogenic internal implant agent |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1679948A true CN1679948A (en) | 2005-10-12 |
Family
ID=35066941
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 200510042432 Pending CN1679948A (en) | 2005-02-03 | 2005-02-03 | Anticarcinogenic internal implant agent |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN1679948A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101390828B (en) * | 2007-02-12 | 2010-06-09 | 济南康泉医药科技有限公司 | Anticancer composition loaded with anti-metabolism medicine and synergist thereof |
-
2005
- 2005-02-03 CN CN 200510042432 patent/CN1679948A/en active Pending
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101390828B (en) * | 2007-02-12 | 2010-06-09 | 济南康泉医药科技有限公司 | Anticancer composition loaded with anti-metabolism medicine and synergist thereof |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN1857208A (en) | Slow released anticancer injection with both antimetabolite and its synergist | |
| CN1857221A (en) | Slow released anticancer medicien containing both platinum compound and its synergist | |
| CN1824319A (en) | Hormone kind anticancer medicine slow release agent | |
| CN1679948A (en) | Anticarcinogenic internal implant agent | |
| CN1279980C (en) | Anti solid tumor medicine composition | |
| CN1686554A (en) | Anti entity tumour medicinal composition containing platinum compound | |
| CN1304054C (en) | Combination of slow released anticancer medication | |
| CN1299774C (en) | Slow released anticancer combination of medication embedded the interior of the body | |
| CN100340296C (en) | Anticarcinogenic internal implant agent | |
| CN100431605C (en) | Anticarcinogen composition | |
| CN100340297C (en) | Anticarcinogenic internal implant agent | |
| CN1286526C (en) | Anti-cancer medicine composition | |
| CN100464783C (en) | Anti-cancer medicine composition containing antineoplastic antibiotics | |
| CN100386115C (en) | Anti-cancer medicine composition | |
| CN101066454A (en) | Solid tumor treating medicine composition | |
| CN100369632C (en) | Anti-cancer medicine composition | |
| CN1299773C (en) | Anti-cancer medicine composition | |
| CN100500220C (en) | Anti entity tumour medicinal composition containing blood vessel inhibitor | |
| CN100350975C (en) | Anticarcinogen composition | |
| CN1311817C (en) | Solid tumor treating medicine composition | |
| CN1857215A (en) | Slow released injection containing antimetabolite | |
| CN1686550A (en) | Anti entity tumour medicinal composition containing dichloro ethamine kind drug | |
| CN1634017A (en) | Pharmaceutical composition for solid tumour | |
| CN1923286A (en) | Anticancer slow release agent of anticancer antibiotics and its progression agent | |
| CN1923172A (en) | Drug slow release agent comprising anticancer antibiotics and booster thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C02 | Deemed withdrawal of patent application after publication (patent law 2001) | ||
| WD01 | Invention patent application deemed withdrawn after publication |