CN101249066A - Sustained-release agent containing hormone anti-cancer medicine - Google Patents
Sustained-release agent containing hormone anti-cancer medicine Download PDFInfo
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Abstract
A sustained-release steroid preparation with antitumor effect is provided, which is characterized in that an antitumor component is coated inside pharmaceutically-acceptable adjuvant to make a sustained-release implant or sustained-release injection. The antitumor component is an antitumor steroid drug or synergists thereof. The antitumor steroid drug is selected from chlormethine drugs and/or antimitotic drugs and/or plant alkaloids. The pharmaceutically-acceptable adjuvant is selected from polylactic acid-polyglycolic acid-hydroxyacetic acid copolymer, ethylene-vinyl acetate copolymer and/or polifeprosan. The sustained-release injection contains sustained-release microspheres and solvents, wherein the solvents include common solvents and special solvents containing a suspending agent, wherein the suspending agent is selected from sodium carboxymethylcellulose, mannitol and the like and used to suspend sustained-release granules or microspheres, thereby facilitating injection. The sustained-release preparation is administered by local delivery in the tumor site or injection, which can not only reduce systemic toxicity but also selectively increase local drug concentration in the tumor site and enhance the therapeutic effect of nonoperative treatment such as drug therapy and radiotherapy.
Description
(1) technical field
The present invention relates to a kind of hormone anti-cancer medicine slow releasing agent and preparation method thereof, belong to technical field of pharmaceuticals.
(2) background technology
The generation development of many cancers is relevant with hormone.Therefore, the action effect of using hormone anti-cancer medicine treatment tumor is comparatively obvious, as pulmonary carcinoma, breast carcinoma, pancreas, ovarian cancer, carcinoma of endometrium, prostate and straight colon cancer etc.
Further discover, 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 phases 2497503 pages of (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, be difficult to tumor by local by the conventional route administration and form effective drug level (referring to " placing cisplatin adding system carmustine treatment rat brain tumor in the tumor " " surgery tumor magazine " 69 phases in 1998 such as Kong Qingzhong 7682 pages of (Kong Q et al., J Surg Oncol.1998 Oct; 69 (2): 76-82)), improve the restriction that dosage is subjected to general reaction again merely.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 " 2004 111 phase 484-93 page or leaf (Liang Y; et al., Int J Cancer.2004; 111 (4): 484-93).
In addition, the DNA repair function in many tumor cells obviously strengthens after hormone anti-cancer medicine, and then causes the enhancing of tumor cell to the toleration of hormone anti-cancer medicine, consequently treatment failure.
Therefore, keep high drug level and increase tumor cell at tumor by local the sensitivity of hormone anti-cancer medicine is just become an important subject.
(3) summary of the invention
The present invention is directed to the deficiencies in the prior art, a kind of hormone anti-cancer medicine slow releasing agent is provided, comprise sustained-release implant and slow releasing injection.
Hormone anti-cancer medicine slow releasing agent of the present invention is made up of anticancer effective component and pharmaceutic adjuvant, wherein, anticancer effective component is the hormone anti-cancer medicine and the hormone anti-cancer medicine synergist of effective anticancer, and synergist is selected from chlormethine series pharmaceuticals and/or anti-mitosis medicine and/or plant alkaloid.
Steroids anti-cancer drugs is mainly steroid hormone and hormone antagonist; comprise; but be not limited to; 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; 5pentafluoropentylsulfinyl) nonyl] estra-1; 3; 5 (10)-triene-3; 17 beta-diol; ICI182780); 4-trans-Hydroxytamoxifen (4-hydroxytamoxifen); γ-linoleic acid (gamma-linolenicacid); 2-methoxyestradiol (2-methoxyestradiol); moxestrol (moxestrol); 4 trans-Hydroxytamoxifens (4-hydroxytamoxifen); benzene hexachloride (benzene hexachloride; Gamma Hexaochlorocyclohexane; beta-hexachlorocyclohexane; beta-HCH); raloxifene (raloxifene); 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; aminoglutethimide (Aminoglutethimide, aminoglutethimidium); betamethasone benzoate; calusterone; triptorelin; goserelin; leuprorelin; megestrol; medroxyprogesterone; datiscoside; epitiostanol; the female sweet smell of bromine vinegar ethane; hisphen; clomifene; toremifene; letrozole; exemestane or testolactone.
Above steroids anti-cancer drugs can singly select or multiselect, with triptorelin, goserelin, leuprorelin, Anastrozole, idoxifene, Miproxifene, tamoxifen, 4 monohydroxy tamoxifens (OH-TAM), not former times sweet smell, raloxifene, ICI-M 164384, anticancer steroid alkene phenol, 4-trans-Hydroxytamoxifen, Drogenil, aminoglutethimide, (.+-.)-Pyridoglutethimide, megestrol, medroxyprogesterone, clomifene, toremifene, letrozole, exemestane or bicalutamide serve as preferred.
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; Triptorelin, goserelin, leuprorelin, tamoxifen, raloxifene, aminoglutethimide, clomifene, toremifene, letrozole, Anastrozole and exemestane are then in order to treatment breast carcinoma, carcinoma of prostate and carcinoma of endometrium.
The content of steroids anti-cancer drugs in slow releasing agent is 0.01%-60%, is good with 1%-40%, is best with 5%-30%, more than all be weight percentage.
Chlormethine series pharmaceuticals as the hormone anti-cancer medicine synergist is selected from mechlorethaminoxide (Mechlorethaminoxide), glyforfin (Glyfosfin), chlornaphazine (Chlornaphazine), chlormethine (Mustine, Mechlorethamine, Chlormethine), nitrocaphane (Nitrocaphane, nitrocaphanum, AT-1258), betamerphalan (Betamerphalan), ocaphane (Ocaphane), the card mustard, methoxymerphalan (Methoxymerphalan), AGN 1414, trichlormethine (Trimustine), desmofosfamide, ocaphane (Ocaphane), Am, Thyminalkylamine, uracil mustard, imidazole mustard, mannomustin, mannomustine, 1-(2-Chloroethyl)-3-neopentyl-1-nitrosourea, nitro can moisten, novoembichin, AT 581., phenesterine, PM, a kind of or combination in tower chlorethyl cyclohexyl nitrosourea or the uraphetinum.
Above chlormethine series pharmaceuticals 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.,
The preferred chlormethine of above-mentioned chlormethine series pharmaceuticals, methoxymerphalan, trichlormethine, nitrocaphanum, mustine hydrochlcride, Thyminalkylamine, uracil mustard, imidazole mustard, mannomustin, mannomustine, novoembichin, AT 581., phenesterine, PM, tower chlorethyl cyclohexyl nitrosourea, uraphetinum or chlormethine uracil.
Anti-mitosis medicine will make tumor cell stop at the different links of cell cycle.Anti-mitosis medicine is selected from cytochalasin (podophyllotoxin), Datelliptium Chloride, ellipticine, 2-Methylellipticine, mitoclomine (Mitoclomine), mitoflaxone (Mitoflaxone), mitoguazone (Mitoguazone), mitonafide (Mitonafide), mitopodozide (Mitopodozide), mitoquidone (Mitoquidone), mitosper (Mitosper), mitotane (Mitotane), mitotenamine (Mitotenamine), mitozolomide (Mitozolomide), Flavone acetic acid, colchisal (colchisal), colchiceinamide (Colchiceinamide), colchicine (Colchicine), 7-acetamido-10-hydroxy-1,2,3-trimethoxy-6,7-dihydrobenzo[a (colchiceine), sulfo--colchicine (thio-colchicine), Demecolcine (Demecolcine), Colchiceinamidum, Colchicine, B cytochalasin B (cytochalasins) is (as A-E, H, J), okadaic acid, carbaryl (sevin, carbaryl), naphthols (naphthol), alpha-Naphthol (1-naphthol), betanaphthol (2-naphthol), alpha-phosphate naphthols (1-naphthylphosphate), malonate, acodazole (Acodazole), procodazole (Procodazole), arsenicum (arsenic trioxide), giracodazole (Giracodazole), nocodazole (nocodazole), a kind of or combination in malonic acid or the malonate.
Above anti-mitosis medicine also comprises its salt, as, but be not limited to sulfate, phosphate, hydrochlorate, Lactobionate, acetate, aspat, nitrate, citrate, purine or pyrimidine salt, succinate and maleate etc.
Above-mentioned anti-mitosis medicine serves as preferred with cytochalasin, mitoclomine, mitoflaxone, mitoguazone, mitonafide, mitopodozide, mitoquidone, mitosper, mitotane, mitotenamine, mitozolomide, Flavone acetic acid, colchisal, colchicine, Demecolcine, B cytochalasin B, naphthols, alpha-Naphthol, betanaphthol, alpha-phosphate naphthols, acodazole, procodazole, arsenicum, giracodazole and nocodazole.
Chlormethine series pharmaceuticals shared ratio in implant is decided because of concrete condition, and generally speaking, percentage by weight can be good with 1%-50% from 0.01%-80%, is best with 5%-30%.
The percentage by weight of above-mentioned anti-mitosis medicine in implant can be 0.01%-80%, is good with 1%-50%, and 5%-30% is best.
Plant alkaloid as the hormone anti-cancer medicine synergist is the anti-tumor botanical that derives from plant, be selected from one of following or combination: vinblastine, leurosidine, the Changchun indole, the Changchun chlormethine, the oxo bridge vinblastine, vincristine (Vincristine, leurocristine), Podophyllinic Acid (mitopodozide), vincristine sulfate, vincaleucoblastine (Vinblastine), the tartaric acid F 81097, the tartaric acid leurosine, leurosine, the tartaric acid catharanthine, Hainanensine, Hainanolide, vinpocetine, vinorelbine (Vinorelbine, Vinorebine), Vinorelbine monotartrate, the two tartrates of vinorelbine, Vinorelbine tartrate, Vinmegallate (Vinmegallate), vinleurosine (Vinleurosine), vinleucinol (Vinleucinol), vinglycinate (Vinglycinate), Deacetylvincaleucoblastine 4-(N,N-dimethylglycinate) sesquisulfate, virosine, vinfosiltine (Vinfosiltine), vinformide (Vinformide), vinflunine (Vinflunine), vinepidine (Vinepidine), vindesine (Vindesine, vindesine), vinzolidine (Vinzolidine), vintriptol (Vintriptol), vinrosidine (Vinrosidine), oxymatrine, cephalotaxin, 3(R)-Deoxyharringtonine, homoharringtonine (Homoharringtonine), aranotin, monocrotaline (Monocrotaline), maitansine, elliptinium acetate, total alkaloid of harmaline, heart chrysanthemum lactone, Mei Dengsu, rubescensine A, pretazettine, thalictrine, thalidasine, 2,3,5,6-tetramethoxyphenanthro[9,10:6',7', tylophorimidine or white cottonrose hibiscus alkali.Above plant alkaloid cancer therapy drug also comprises its salt, as, but be not limited to sulfate, phosphate, hydrochlorate, Lactobionate, acetate, aspat, nitrate, citrate, purine or pyrimidine salt, tartrate, succinate and maleate etc.
Above plant alkaloid serves as preferred with vincristine, vincaleucoblastine, vinorelbine, vindesine, Vinmegallate, vinleurosine, vinleucinol, vinglycinate, vinfosiltine, vinformide, vinflunine, vinepidine, vinzolidine, vintriptol, vinrosidine, monocrotaline or cephalotaxin.
Plant alkaloid shared ratio in compositions is decided because of concrete condition, and generally speaking, percentage by weight can be good with 1%-50% from 0.01%-99.99%, is best with 5%-30%.
The synergist decapacitation suppresses can also increase the sensitivity of tumor cell to hormone anti-cancer medicine outside the tumor growth; Slow-release auxiliary material is used as the carrier holder of medicine, thereby the local concentration of medicine is improved and kept to the rate of release of may command medicine and time.
The content of synergist in slow releasing agent is 0.01%-60%, is good with 1%-40%, is best with 5%-30%, more than all be weight percentage.
Adjuvant is selected from one of copolymer (PLGA), ethylene vinyl acetate copolymer (EVAc), polifeprosan, xylitol, oligosaccharide, chrondroitin, chitin, potassium salt, sodium salt, hyaluronic acid, collagen protein, gelatin and albumin of polylactic acid (PLA), polyglycolic acid and hydroxyacetic acid or its combination.
Polylactic acid in the above-mentioned slow-release auxiliary material (PLA) molecular weight peak value can be, but is not limited to 5,000～100,000, and with 20,000～60,000 is preferred, and with 30,000～50,000 for most preferably; The molecular weight of polyglycolic acid (PGA) can be, but is not limited to 5,000～100,000, and with 20,000～60,000 is preferred, and with 30,000～50,000 for most preferably; The molecular weight of the copolymer of polyglycolic acid and hydroxyacetic acid (PLGA) can be, but is not limited to 5,000～100,000, but with 20,000～60, and 000 is preferred, and with 30,000～50,000 for most preferably; The blend weight ratio of glycolic and hydroxyacetic acid is 10/90-90/10, polifeprosan (poly-(1,3-two (to the carboxyl phenoxy group) propane decanedioic acid) in, to the weight ratio 10/90-90/10 of carboxy phenyl propane (p-CPP) with certain herbaceous plants with big flowers diacid (SA), preferred 20/80-75/25.
One of feature of hormone anti-cancer medicine slow releasing agent of the present invention is that slow releasing agent is an implant.The used pharmaceutic adjuvant of sustained-release implant can be any or multiple material in the above-mentioned pharmaceutic adjuvant, but with the high molecular weight water soluble polymer is main separation, in various high molecular polymers, with polylactic acid, certain herbaceous plants with big flowers diacid, the mixture or the copolymer that contain the macromolecule polymer of polylactic acid or certain herbaceous plants with big flowers diacid is first-selection, mixture and copolymer can be selected from, but be not limited to the mixture or the copolymer of the mixture of PLA, PLGA, PLA and PLGA, certain herbaceous plants with big flowers diacid and fragrant polyanhydride or aliphatic polyanhydride.Polylactic acid (PLA) and polyglycolic acid the blend ratio be 10/90-90/10 (weight), 25/75-75/25 (weight) preferably.The method of blend is arbitrarily.Content when glycolic and lactic acid copolymerization is respectively percentage by weight 10-90% and 90-10%.The representative of fragrance polyanhydride is to carboxy phenyl propane (p-CPP), content during to carboxy phenyl propane (p-CPP) and the copolymerization of certain herbaceous plants with big flowers diacid is respectively percentage by weight 10-60% and 20-90%, the blend weight ratio is 10-40: 50-90, preferably weight ratio 15-30: 65-85.
Pharmaceutic adjuvant has a detailed description in " pharmaceutic adjuvant complete works " (the 123rd page, Sichuan science tech publishing house published in 1993, Luo Mingsheng and Gao Tianhui chief editor).In addition, Chinese patent (application number 96115937.5; 91109723.6; 9710703.3; 01803562.0) and U.S.'s patent of invention (patent No. 5,651,986) also enumerated some pharmaceutic adjuvants.Comprise filler, solubilizing agent, absorption enhancer, film former, gellant, system (or causing) hole agent, excipient or inhibitor.Above pharmaceutic adjuvant has has multiple action, and therefore the material of the same race that has is listed in different classifications.The available holder of 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.
The effective ingredient of anticancer implant 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 and/or the mode of degrading through polymer.
The characteristics of anti-cancer sustained-released implantation agent 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.
The Main Ingredients and Appearance that the present invention resists can be made into multiple dosage form.As, but be not limited to capsule, slow releasing agent, implant, slow releasing agent implant etc.; Be multiple shape, as, but be not limited to granule, pill, tablet, powder, granule, sphere, bulk, needle-like, bar-shaped, column and membranaceous.In various dosage forms, serve as preferred slowly to discharge implant in the body.
The most preferred dosage form of anti-cancer sustained-released implantation agent of the present invention is that the slow releasing agent that biocompatibility, degradable absorb is implanted, and can make different shape and various dosage form 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.
The another technical characterictic of hormone anti-cancer medicine slow releasing agent of the present invention is that slow releasing agent is an injection.The anti-cancer medicine slow release implant also can be made into injection, is made up of sustained-release micro-spheres and solvent:
(A) sustained-release micro-spheres comprises:
Anticancer effective component 0.5-60%
Slow-release auxiliary material 40-99%
More than be weight percentage
With
(B) solvent is for common solvent or contain the special solvent of suspending agent.
Wherein, anticancer effective component is the hormone anti-cancer medicine and/or the hormone anti-cancer medicine synergist of effective anticancer, and synergist is selected from chlormethine series pharmaceuticals and/or anti-mitosis medicine and/or plant alkaloid; Slow-release auxiliary material is selected from one of copolymer (PLGA), ethylene vinyl acetate copolymer (EVAc), polifeprosan, xylitol, oligosaccharide, chrondroitin, chitin, hyaluronic acid, collagen protein, gelatin and albumin of polylactic acid (PLA), polyglycolic acid and hydroxyacetic acid or its combination; Common solvent is selected from distilled water, water for injection, physiology towards liquid, dehydrated alcohol, phosphate or carbonate buffer solution; Suspending agent is selected from one of sodium carboxymethyl cellulose, (iodine) glycerol, simethicone, propylene glycol, carbomer, mannitol, sorbitol, surfactant, soil temperature 20, soil temperature 40 and soil temperature 80 or its combination.Suspending agent helps the suspension of slow releasing pharmaceutical and then makes things convenient for drug administration by injection.The content of suspending agent is 0.1-30% volume weight percentage ratio in the special solvent, is preferably as follows:
A) 0.55% sodium carboxymethyl cellulose and 0.1-0.5% Tween 80; Or
B) 5-20% mannitol and 0.1-0.5% Tween 80; Or.
C) 0.5-5% sodium carboxymethyl cellulose, 5-20% sorbitol and 0.1-0.5% Tween 80.
The above-mentioned volume weight percentage ratio that is contains the weight of suspending agent in the common solvent of unit volume, as g/ml, and kg/l.Down together.
Effective ingredient can be made microsphere for supporting by adjuvant, and its method is arbitrarily, as, but be not limited to (i) fusion method: pharmaceutic adjuvant and medicine are directly pulverized mixed, melt, cool off the preparation slow-releasing granules then; (ii) dissolution method: pharmaceutic adjuvant and medicine dissolution in organic solvent, remove solvent then and prepare sustained-release micro-spheres; (iii) spray drying method for preparation microsphere; (iv) freezing (drying) comminuting method is made micropowder; (v) dissolution method is made micropowder in conjunction with freezing (drying) comminuting method; (vi) liposome bag medicine method and (vii) preparation such as emulsion process sustained-release micro-spheres.The particle size range of made microsphere can be at 5-400um, is preferred with 10-300um, with 20-200um for most preferably.
The percentage by weight of anticancer effective component is 0.5%-60% in sustained-release microparticle, is good with 2%-40%, is best with 5%-30%.
The percentage by weight of slow-release auxiliary material in sustained-release microparticle is 40-99.5%, one of the copolymer (PLGA) of the preferred polylactic acid of slow-release auxiliary material (PLA), polyglycolic acid and hydroxyacetic acid, ethylene vinyl acetate copolymer (EVAc) and polifeprosan or its combination.
Polylactic acid in the above-mentioned slow-release auxiliary material (PLA) molecular weight peak value can be, but is not limited to 5,000～100,000, and with 20,000～60,000 is preferred, and with 30,000～50,000 for most preferably; The molecular weight of polyglycolic acid (PGA) can be, but is not limited to 5,000～100,000, and with 20,000～60,000 is preferred, and with 30,000～50,000 for most preferably; The molecular weight of the copolymer of polyglycolic acid and hydroxyacetic acid (PLGA) can be, but is not limited to 5,000～100,000, but with 20,000～60, and 000 is preferred, and with 30,000～50,000 for most preferably; The blend weight ratio of glycolic and hydroxyacetic acid is 10/90-90/10, polifeprosan (poly-(1,3-two (to the carboxyl phenoxy group) propane-decanedioic acid) in, to the weight ratio 10/90-90/10 of carboxy phenyl propane (p-CPP) with certain herbaceous plants with big flowers diacid (SA), preferred 20/80-75/25.
Sustained-release microparticle can be microgranule, granule, spherical piller, microsphere or micropowder.Be to regulate drug releasing rate, the composition and the proportioning that can change the monomer component of polymer or molecular weight, interpolation or regulate pharmaceutic adjuvant are added any one or multiple other pharmaceutic adjuvant as additive.Additive can be divided into filler, porogen, excipient, dispersant, isotonic agent, preservative agent, blocker, solubilizing agent, absorption enhancer, film former, gellant etc. according to its function, and its content is decided because of concrete condition.Slow release or pharmaceutic adjuvant are in Luo Mingsheng and Gao Tianhui chief editor's " pharmaceutic adjuvant complete works " the 123rd page, had a detailed description in " pharmaceutics " People's Health Publisher in May, 85 version of chief editors such as Sichuan science tech publishing house in March, 1993 version and Tu Xide, 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 enumerate some pharmaceutic adjuvant, comprised filler, solubilizing agent, absorption enhancer, film former, gellant, system (or causing) hole agent, cross-linking agent, the binding agent, excipient or blocker.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 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.
Sustained-release micro-spheres can separate the packing respectively of independent sterilization back, storage, suspendible, injection again during use with the injection solvent; Also sustained-release micro-spheres can be mixed back sterilization, packing with a certain proportion of suspending agent, it is suspended in the common solvent or special solvent of the packing of separately sterilizing during use.Used common solvent refers to clinical injection commonly used, as, but be not limited to, the buffer that distilled water, water for injection, physiology are prepared towards liquid, dehydrated alcohol or various salt is as phosphate or carbonate buffer solution etc.Special solvent is the common solvent that contains a kind of or several suspending agents; Sustained-release micro-spheres is sterilized after also can being suspended in the injection solvent, packing, and the time spent direct injection can add a certain amount of antiseptic in such cases.
Slow releasing injection of the present invention can be further divided into gel-type slow releasing injection, solution-type slow releasing injection, suspension type slow releasing injection, microcapsule-type slow releasing injection, microspheric slow releasing injection, block copolymer micelle injection or liposome slow releasing injection.More than in the multiple slow releasing injection, preferred suspension type slow releasing injection, gel-type slow releasing injection, microspheric slow releasing injection, block copolymer micelle injection.Wherein, the suspension type slow releasing injection is the preparation that the sustained-release microparticle that will contain anticancer component is suspended in gained in the injection.Gel-type slow releasing injection system is dissolved in some amphipathic solvent with biological degradation polyalcohol (as PLA, PLGA or DL-LA and epsilon-caprolactone copolymer), add medicine miscible with it (or suspendible) back again and form flowability gel preferably, can be through tumor week or intratumor injection.In case inject, amphipathic solvent diffuses to body fluid very soon, the moisture in the body fluid then infiltrates gel, makes polymer cure, slowly discharges medicine.The microspheric slow releasing injection comprises microparticulate preparations such as microsphere, sub-micro ball, microemulsion, nanosphere, liposome or gel, and used pharmaceutical carrier is above-mentioned any one or its combination.The block copolymer micelle injection is formed in aqueous solution by hydrophobic-hydrophilic block copolymers, has the spherical inner core shell mechanism, and hydrophobic block forms kernel, and hydrophilic block forms shell.The carrier micelle injection enters the purpose that reaches control drug release or targeted therapy in the body.Used pharmaceutical carrier is above-mentioned any one or its combination.Wherein preferred molecular weight is 1,000-5,000 Polyethylene Glycol (PEG) are as the hydrophilic block of micelle copolymer, and preferred biological degradation polyalcohol is (as PLA, polylactide, polycaprolactone and copolymer thereof (molecular weight 1,500-25,000) as the hydrophobic block of micelle copolymer.The particle size range of block copolymer micelle can be at 10-300um, between the 20-200um serving as preferred.
In above-mentioned all kinds of slow releasing injection with the suspension type slow releasing injection for most preferably, the suspension type slow releasing injection is the preparation that the sustained-release microparticle that will contain anticancer component is suspended in gained in the injection, used adjuvant is a kind of or its combination in the above-mentioned slow-release auxiliary material.The mode that suspends is divided into multiple, but based on following three kinds, the one, the sustained-release microparticle of pastille is packed with suspending agent, before injection, it is suspended in the common solvent, i.e. " sustained-release microparticle and suspending agent+common solvent " scheme; The 2nd, the sustained-release microparticle of pastille is packed separately, before injection, it is suspended in the special solvent, i.e. " sustained-release microparticle+special solvent " scheme; The 3rd, with the packing of behind suspending agent and common solvent suspendible, sterilizing of the sustained-release microparticle of pastille, time spent direct injection.
The used pharmaceutic adjuvant of slow releasing injection is above-mentioned a kind of or several adjuvants, can import in the body cavity, in the tumor or tumor all; The gel-type slow releasing injection is biological degradation polyalcohol PLA, PLGA, hyaluronic acid, chrondroitin, collagen protein, gelatin, albumin etc. to be dissolved with the amphiphilic solvent phase make polymer solution, make after miscible with medicine then, be fruit jelly shape, paste or ointment isogel type; The solution-type slow releasing injection can be selected vegetable oil for use, as, but be not limited to, iodine glycerol, certain herbaceous plants with big flowers acid esters, carnic acid, Oleum sesami, Oleum Ricini, Oleum Glycines, Semen arachidis hypogaeae wet goods are made holder; The suspension type slow releasing injection also can be with medicine separately or be packaged in and make oil suspension after the high molecular polymer, medicine and macromolecular compound be combined into the indissoluble salt suspensoid or with the suspension of medicine and reactant salt formation drug salts crystalline solid.
Hormone anti-cancer medicine can be above-mentioned any one or its combination in the anticancer effective component, but preferred triptorelin, goserelin, leuprorelin, Anastrozole, idoxifene, Miproxifene, tamoxifen, not former times sweet smell, raloxifene, ICI-M 164384, anticancer steroid alkene phenol, 4-trans-Hydroxytamoxifen, Drogenil, aminoglutethimide, (.+-.)-Pyridoglutethimide, megestrol, medroxyprogesterone, clomifene, toremifene, letrozole or exemestane.
The preferred chlormethine of chlormethine series pharmaceuticals, methoxymerphalan, trichlormethine, nitrocaphanum, mustine hydrochlcride, Thyminalkylamine, uracil mustard, imidazole mustard, mannomustin, mannomustine, novoembichin, AT 581., phenesterine, PM, tower chlorethyl cyclohexyl nitrosourea, uraphetinum or chlormethine uracil.
Above-mentioned anti-mitosis medicine serves as preferred with cytochalasin, mitoclomine, mitoflaxone, mitoguazone, mitonafide, mitopodozide, mitoquidone, mitosper, mitotane, mitotenamine, mitozolomide, Flavone acetic acid, colchisal, colchicine, Demecolcine, B cytochalasin B, naphthols, alpha-Naphthol, betanaphthol, alpha-phosphate naphthols, acodazole, procodazole, arsenicum, giracodazole and nocodazole.
Plant alkaloid in the anticancer effective component serves as preferred with vincristine, vincaleucoblastine, vinorelbine, vindesine, Vinmegallate, vinleurosine, vinleucinol, vinglycinate, vinfosiltine, vinformide, vinflunine, vinepidine, vinzolidine, vintriptol, vinrosidine, monocrotaline or cephalotaxin.
The sustained-release micro-spheres anticancer effective component that sustained-release implant of the present invention and being used for prepares slow releasing injection is preferably:
(1) triptorelin of 5-30%, goserelin, leuprorelin, Anastrozole, idoxifene, Miproxifene, tamoxifen, not former times sweet smell, raloxifene, ICI-M 164384, anticancer steroid alkene phenol, the 4-trans-Hydroxytamoxifen, Drogenil, aminoglutethimide, (.+-.)-Pyridoglutethimide, megestrol, medroxyprogesterone, clomifene, toremifene, the chlormethine of letrozole or exemestane and 5-30%, methoxymerphalan, trichlormethine, nitrocaphanum, mustine hydrochlcride, Thyminalkylamine, uracil mustard, imidazole mustard, mannomustin, mannomustine, novoembichin, AT 581., phenesterine, PM, the tower chlorethyl cyclohexyl nitrosourea, the combination of uraphetinum or chlormethine uracil; Or
(2) triptorelin of 5-30%, goserelin, leuprorelin, Anastrozole, idoxifene, Miproxifene, tamoxifen, not former times sweet smell, raloxifene, ICI-M 164384, anticancer steroid alkene phenol, 4 trans-Hydroxytamoxifens, Drogenil, aminoglutethimide, (.+-.)-Pyridoglutethimide, megestrol, medroxyprogesterone, clomifene, toremifene, the cytochalasin of letrozole or exemestane and 5-30%, mitoclomine, mitoflaxone, mitoguazone, mitonafide, mitopodozide, mitoquidone, mitosper, mitotane, mitotenamine, mitozolomide, Flavone acetic acid, colchisal, colchicine, Demecolcine, B cytochalasin B, naphthols, alpha-Naphthol, betanaphthol, the alpha-phosphate naphthols, acodazole, procodazole, arsenicum, the combination of giracodazole or nocodazole; Or
(3) triptorelin of 5-30%, goserelin, leuprorelin, Anastrozole, idoxifene, Miproxifene, tamoxifen, not former times sweet smell, raloxifene, ICI-M 164384, anticancer steroid alkene phenol, the 4-trans-Hydroxytamoxifen, Drogenil, aminoglutethimide, (.+-.)-Pyridoglutethimide, megestrol, medroxyprogesterone, clomifene, toremifene, the vincristine of letrozole or exemestane and 5-30%, vincaleucoblastine, vinorelbine, vindesine, Vinmegallate, vinleurosine, vinleucinol, vinglycinate, vinfosiltine, vinformide, vinflunine, vinepidine, vinzolidine, vintriptol, vinrosidine, the combination of monocrotaline or cephalotaxin.Below all be weight percentage.
The route of administration of hormone anti-cancer medicine slow releasing agent of the present invention depends on multiple factor, wherein depends primarily on its dosage form.For reaching effect concentration at former or position, metastatic tumour place, can give through number of ways, as approach medicine in subcutaneous, intracavity (in abdominal cavity, thoracic cavity and canalis spinalis), the tumor, in all, the selective arterial injection of tumor, lymph node and in the bone marrow, anti-cancer sustained-released implantation agent is placed through puncture or operation, and slow-releasing anticarcinogen injection can reach drug administration by injection, but embedding in all can performing the operation, is coated with and spreads, pour into.With in selective arterial, intracavity, the tumor, tumor week injection or be placed as preferred.
The present invention can be used to prepare the medicine of the various tumors for the treatment of people and animal, be mainly slow releasing injection or implant, the indication tumor comprises former or cancer or sarcoma or the carcinosarcoma that shifts that originates from brain, central nervous system, kidney, liver, gallbladder, incidence, oral cavity, thyroid, skin, mucosa, body of gland, blood vessel, osseous tissue, lymph node, lungs, esophagus, stomach, mammary gland, pancreas, eyes, nasopharynx part, uterus, ovary, endometrium, cervix uteri, prostate, bladder, colon, rectum.
Also can add other medicinal ingredient in the hormone anti-cancer medicine slow releasing agent of the present invention, as, but be not limited to antibiotics, antalgica, anticoagulant medicine, hemorrhage etc.
By following test excellent results of the present invention is further described.
Test 1, plant alkaloid press down the potentiation of tumor to hormone anti-cancer medicine.
Used tumor cell comprises CNS-1, C6,9L, gastric gland epithelial cancer (SA), bone tumor (BC), breast carcinoma (BA), pulmonary carcinoma (LH), papillary adenocarcinoma of thyroid (PAT), hepatocarcinoma etc.Hormone anti-cancer medicine and plant alkaloid are added in 24 hours the various tumor cells of In vitro culture by the 10ug/ml drug level, continue to cultivate counting cells sum after 48 hours.Its growth of tumour cell suppresses effect and is shown in Table 1.
Table 1
| Oncocyte | Vincristine | Vincaleucoblastine | Bright benzene Rayleigh | Vincristine+leuprorelin | Vincaleucoblastine+leuprorelin | Vinorelbine | Tamoxifen | Vinorelbine+tamoxifen |
| CNS | 62％ | 64％ | 66％ | ?86％ | ?92％ | 56％ | 58％ | ?88％ |
| C6 | 62％ | 64％ | 60％ | ?84％ | ?96％ | 60％ | 66％ | ?90％ |
| SA | 58％ | 60％ | 58％ | ?90％ | ?86％ | 54％ | 60％ | ?90％ |
| BC | 54％ | 64％ | 54％ | ?82％ | ?94％ | 64％ | 64％ | ?86％ |
| BA | 54％ | 64％ | 62％ | ?92％ | ?98％ | 62％ | 62％ | ?90％ |
| LH | 60％ | 58％ | 62％ | ?88％ | ?90％ | 62％ | 58％ | ?84％ |
| PAT | 54％ | 56％ | 66％ | ?86％ | ?92％ | 58％ | 56％ | ?86％ |
Above result shows, growth all has the obvious suppression effect to kinds of tumor cells when this concentration is used separately for used various hormone anti-cancer medicine (leuprorelin, tamoxifen) and plant alkaloid (vincristine, vincaleucoblastine, vinorelbine), when use in conjunction, plant alkaloid can significantly strengthen the tumor-inhibiting action of hormone anti-cancer medicine.
Test 2, anti-mitosis medicine press down the potentiation of tumor to hormone anti-cancer medicine.
Used tumor cell comprises carcinoma of prostate, carcinoma of endometrium, breast carcinoma, pulmonary carcinoma, cancer of pancreas, hepatocarcinoma and rectal cancer.Hormone anti-cancer medicine and anti-mitosis medicine are added in 24 hours the various tumor cells of In vitro culture by the 10ug/ml drug level, continue to cultivate counting cells sum after 48 hours.Its growth of tumour cell suppresses effect and is shown in Table 2.
Table 2
| Oncocyte | Acodazole | Letrozole | Bright benzene Rayleigh | Anastrozole | Acodazole+letrozole | Acodazole+leuprorelin | Acodazole+Anastrozole |
| Carcinoma of prostate | 78％ | 64％ | 66％ | 54％ | ?94％ | ?86％ | ?92％ |
| Carcinoma of endometrium | 60％ | 64％ | 60％ | 44％ | ?94％ | ?80％ | ?90％ |
| Breast carcinoma | 68％ | 60％ | 58％ | 50％ | ?86％ | ?84％ | ?90％ |
| Pulmonary carcinoma | 58％ | 64％ | 54％ | 42％ | ?94％ | ?84％ | ?84％ |
| Cancer of pancreas | 54％ | 44％ | 42％ | 52％ | ?96％ | ?92％ | ?90％ |
| Hepatocarcinoma | 60％ | 38％ | 32％ | 58％ | ?90％ | ?92％ | ?84％ |
| Rectal cancer | 62％ | 46％ | 36％ | 46％ | ?92％ | ?88％ | ?90％ |
Above result shows, growth all has the obvious suppression effect to kinds of tumor cells when this concentration is used separately for used anti-mitosis medicine (acodazole) and hormone anti-cancer medicine, when use in conjunction, anti-mitosis medicine can significantly strengthen the tumor-inhibiting action of hormone anti-cancer medicine.
Test 3, chlormethine series pharmaceuticals press down the potentiation of tumor to hormone anti-cancer medicine.
Used tumor cell comprises carcinoma of prostate, carcinoma of endometrium, breast carcinoma, pulmonary carcinoma, cancer of pancreas, hepatocarcinoma and rectal cancer.Hormone anti-cancer medicine and methoxymerphalan are added in 24 hours the various tumor cells of In vitro culture by the 10ug/ml drug level, continue to cultivate counting cells sum after 48 hours.Its growth of tumour cell suppresses effect and is shown in Table 3.
Table 3
| Oncocyte | Methoxymerphalan | Triptorelin | Raloxifene | Goserelin | Methoxymerphalan+triptorelin | Methoxymerphalan+raloxifene | Methoxymerphalan+goserelin |
| Carcinoma of prostate | 68％ | 56％ | 58％ | 56％ | ?90％ | ?88％ | ?90％ |
| Carcinoma of endometrium | 52％ | 60％ | 50％ | 48％ | ?90％ | ?80％ | ?92％ |
| Breast carcinoma | 54％ | 54％ | 48％ | 50％ | ?88％ | ?94％ | ?94％ |
| Pulmonary carcinoma | 46％ | 54％ | 54％ | 46％ | ?92％ | ?89％ | ?84％ |
| Cancer of pancreas | 44％ | 48％ | 44％ | 52％ | ?94％ | ?98％ | ?92％ |
| Hepatocarcinoma | 52％ | 50％ | 36％ | 58％ | ?90％ | ?92％ | ?86％ |
| Rectal cancer | 58％ | 48％ | 42％ | 48％ | ?90％ | ?88％ | ?94％ |
Above result shows, growth all has the obvious suppression effect to kinds of tumor cells when this concentration is used separately for used chlormethine series pharmaceuticals (methoxymerphalan) and hormone anti-cancer medicine, when use in conjunction, chlormethine series pharmaceuticals can significantly strengthen the tumor-inhibiting action of hormone anti-cancer medicine.
Test 4, chlormethine series pharmaceuticals are to pressing down the potentiation of tumor in the hormone anti-cancer medicine slow releasing injection body
With the rat is subjects, with 2 * 10
5Individual breast cancer tumour cell subcutaneous injection is in its hypochondrium, treats that tumor growth after 14 days is divided into it following 10 groups (seeing Table 4).First group is contrast, and the 2nd to 10 group is the treatment group, and slow releasing injection is through intratumor injection.Drug dose is 5mg/kg.The treatment back was measured gross tumor volume size, relatively therapeutic effect (seeing Table 4) on the 10th day.
Table 4
| Test group (n) | Suffered treatment | Gross tumor volume (cm 3) | The P value |
| ?1(6) | Contrast | 78±12 | |
| ?2(6) | Nitrocaphanum | 58±7 | ?＜0.05 |
| ?3(6) | Tamoxifen | 58±6.2 | ?＜0.01 |
| ?4(6) | Nitrocaphanum+tamoxifen | 36±2.4 | ?＜0.001 |
| ?5(6) | Mannomustine | 50±3.2 | ?＜0.01 |
| ?6(6) | Idoxifene | 48±3.0 | ?＜0.01 |
| ?7(6) | Mannomustine+idoxifene | 24±2.4 | ?＜0.001 |
| ?8(6) | PM | 36±3.6 | ?＜0.01 |
| ?9(6) | Exemestane | 36±3.8 | ?＜0.01 |
| ?10(6) | PM+exemestane | 18±2.8 | ?＜0.001 |
Above result shows, growth all has the obvious suppression effect to kinds of tumor cells when this concentration is used separately for used various chlormethine series pharmaceuticals and hormone anti-cancer medicine, when use in conjunction, chlormethine series pharmaceuticals can significantly strengthen the tumor-inhibiting action of hormone anti-cancer medicine.
Test 5, anti-mitosis medicine press down the potentiation of tumor to the hormone anti-cancer medicine slow releasing injection
With the rat is subjects, with 2 * 10
5Individual pancreatic tumor cell subcutaneous injection is in its hypochondrium, treats that tumor growth after 14 days is divided into it following 10 groups (seeing Table 5).First group is contrast, and the 2nd to 10 group is the treatment group, and slow releasing injection is through intratumor injection.Dosage is 5mg/kg.The treatment back was measured gross tumor volume size, relatively therapeutic effect (seeing Table 5) on the 10th day.
Table 5
| Test group (n) | Suffered treatment | Gross tumor volume (cm 3) | The P value |
| ?1(6) | Contrast | 78±128 | |
| ?2(6) | Procodazole | 48±5.4 | ?＜0.05 |
| ?3(6) | Toremifene | 48±4.3 | ?＜0.01 |
| ?4(6) | Toremifene+procodazole | 24±2.6 | ?＜0.001 |
| ?5(6) | Arsenicum | 46±5.0 | ?＜0.01 |
| ?6(6) | Not former times sweet smell | 46±4.0 | ?＜0.01 |
| ?7(6) | Not former times sweet smell+arsenicum | 24±2.4 | ?＜0.001 |
| ?8(6) | Giracodazole | 46±6 | ?＜0.01 |
| ?9(6) | Miproxifene | 46±5.8 | ?＜0.01 |
| ?10(6) | Miproxifene+giracodazole | 18±2.6 | ?＜0.001 |
Above result shows, growth all has the obvious suppression effect to kinds of tumor cells when this concentration is used separately for used anti-mitosis medicine (procodazole, arsenicum, giracodazole) and hormone anti-cancer medicine, when use in conjunction, anti-mitosis medicine can significantly strengthen the tumor-inhibiting action of hormone anti-cancer medicine.
Plant alkaloid is with vincristine, vincaleucoblastine, vinorelbine, vindesine, Vinmegallate, vinleurosine, vinleucinol, vinglycinate, vinfosiltine, vinformide, vinflunine, vinepidine, vinzolidine, vintriptol, vinrosidine or cephalotaxin
Test 6, plant alkaloid slow releasing injection are to pressing down the potentiation of tumor in the hormone anti-cancer medicine sustained-release implant body
With the rat is subjects, with 2 * 10
5Individual prostate tumor cells subcutaneous injection is in its hypochondrium, treats that tumor growth after 14 days is divided into it following 10 groups (seeing Table 6).First group is contrast, and the 2nd to 10 group is the treatment group, and sustained-release implant is placed in tumor.Dosage is 5mg/kg.The treatment back was measured gross tumor volume size, relatively therapeutic effect (seeing Table 6) on the 10th day.
Table 6
| Test group (n) | Suffered treatment | Gross tumor volume (cm 3) | The P value |
| ?1(6) | Contrast | 88±14 | |
| ?2(6) | Vindesine | 52±5.2 | ?＜0.05 |
| ?3(6) | Leuprorelin | 52±4.3 | ?＜0.01 |
| ?4(6) | Vindesine+leuprorelin | 38±2.6 | ?＜0.001 |
| ?5(6) | Vinleurosine | 54±3.2 | ?＜0.01 |
| ?6(6) | Tamoxifen | 44±3.0 | ?＜0.01 |
| ?7(6) | Vinleurosine+tamoxifen | 22±2.2 | ?＜0.001 |
| ?8(6) | Vinrosidine | 50±3.6 | ?＜0.01 |
| ?9(6) | Not former times sweet smell | 34±3.8 | ?＜0.01 |
| ?10(6) | The former times sweet smell of vinrosidine+not | 22±2.2 | ?＜0.001 |
Above result shows, used various plant alkaloid (vindesine, vinleurosine, vinrosidine) and hormone anti-cancer medicine (leuprorelin, tamoxifen, not former times sweet smell) and growth all has the obvious suppression effect to kinds of tumor cells when this concentration is used separately, when use in conjunction, plant alkaloid can significantly strengthen the tumor-inhibiting action of hormone anti-cancer medicine.
In a word, result of the test clearlys show, growth all has the obvious suppression effect to used various medicine to kinds of tumor cells when finite concentration is used separately, and when use in conjunction, chlormethine series pharmaceuticals, anti-mitosis medicine and plant alkaloid all can significantly strengthen the tumor-inhibiting action of steroids anti-cancer drugs.Though its potentiation remains a new step research, used drug regimen has proved absolutely the remarkable potentiation to the steroids anti-cancer drugs tumor-inhibiting action of chlormethine series pharmaceuticals, anti-mitosis medicine or plant alkaloid, and has remarkable representativeness.Therefore, anticancer effective component of the present invention is any one chlormethine series pharmaceuticals, anti-mitosis medicine and or the combination of plant alkaloid and any one strong hormone anti-cancer medicine.The medicine that contains above effective ingredient can be made into sustained-release micro-spheres or the slow releasing injection or the implant of dosage form arbitrarily, wherein with sustained-release implant and with suspendible slow releasing injection that the special solvent that contains suspending agent is combined to form serve as preferred.
(4) specific embodiment
Below each embodiment, anticancer effective component is made sustained-release micro-spheres or the arbitrarily slow releasing injection or the implant of dosage form.When making slow releasing injection, the content of suspending agent is volume weight percentage ratio in the special solvent, promptly contains the weight of suspending agent in the common solvent of unit volume, as g/ml, and kg/l.The content of anticancer effective component all is weight percentage in the sustained-release microparticle (ball).
Embodiment 1.
With 70mg molecular weight peak value is the polyglycolic acid of 20000-40000 and the copolymer (PLGA of hydroxyacetic acid, 65: 35) put into container, add 100 milliliters of dichloromethane, behind the dissolving mixing, add 10mg colchicine and 20mg tamoxifen, shake up the dry organic solvent of removing of final vacuum again.Dried solid composite is shaped immediately, and ray sterilizing after the packing makes the anticancer implant that contains 10% colchicine and 20% tamoxifen.The drug release time of this anticancer implant in external normal saline is 15-20 days, and implanting the subcutaneous drug release time of mice is 25-40 days.
Embodiment 2.
The method step that is processed into anticancer implant is identical with embodiment 1, but different is that the contained anticancer effective component of anticancer implant is:
The triptorelin of 5-30%, goserelin, leuprorelin, Anastrozole, idoxifene, Miproxifene, tamoxifen, not former times sweet smell, raloxifene, ICI-M 164384, anticancer steroid alkene phenol, 4 trans-Hydroxytamoxifens, Drogenil, aminoglutethimide, (.+-.)-Pyridoglutethimide, megestrol, medroxyprogesterone, clomifene, toremifene, the cytochalasin of letrozole or exemestane and 5-30%, mitoclomine, mitoflaxone, mitoguazone, mitonafide, mitopodozide, mitoquidone, mitosper, mitotane, mitotenamine, mitozolomide, Flavone acetic acid, colchisal, colchicine, Demecolcine, B cytochalasin B, naphthols, alpha-Naphthol, betanaphthol, the alpha-phosphate naphthols, acodazole, procodazole, arsenicum, the combination of giracodazole or nocodazole.
Embodiment 3.
With 70mg molecular weight peak value is that the polylactic acid (PLGA, 50: 50) of 15000-25000 is put into container, adds 100 milliliters of dichloromethane, behind the dissolving mixing, adds 20mg Anastrozole and 10mg nitrocaphanum, 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 implant of 20% Anastrozole and 10% nitrocaphanum.The drug release time of this anticancer implant in external normal saline is 15-25 days, and being placed on the subcutaneous drug release time of mice is 25-45 days.
Embodiment 4.
The method step that is processed into anticancer implant is identical with embodiment 3, but different is that the contained anticancer effective component of anticancer implant is:
20% Anastrozole, idoxifene, Miproxifene, tamoxifen, not former times sweet smell, raloxifene, (.+-.)-Pyridoglutethimide, rubitecan, Acapodene, Drogenil, overstate single silicon indigo plant, bicalutamide, aminoglutethimide, calusterone, triptorelin, goserelin, leuprorelin, megestrol, medroxyprogesterone, toremifene, letrozole, exemestane or testolactone and 10% chlormethine, methoxymerphalan, trichlormethine, nitrocaphanum, mustine hydrochlcride, Thyminalkylamine, uracil mustard, imidazole mustard, mannomustin, mannomustine, novoembichin, AT 581., phenesterine, PM, the tower chlorethyl cyclohexyl nitrosourea, the combination of uraphetinum or chlormethine uracil.Below all be weight percentage.
Embodiment 5.
With 70mg molecular weight peak value is that 30000-50000 polifeprosan (to carboxy phenyl propane: certain herbaceous plants with big flowers diacid weight ratio is 20: 80) copolymer is put into container, add 100 milliliters of dichloromethane, behind the dissolving mixing, add 10mg vinorelbine and 20mg exemestane, 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 implant of 10% vinorelbine and 20% exemestane.All be weight percentage.The drug release time of this anticancer implant in external normal saline is 15-20 days, and being placed on the subcutaneous drug release time of mice is 30-40 days.
Embodiment 6.
The method step that is processed into anticancer implant is identical with embodiment 5, but different is that contained anticancer effective component is:
20% triptorelin, goserelin, leuprorelin, Anastrozole, idoxifene, Miproxifene, tamoxifen, not former times sweet smell, raloxifene, ICI-M 164384, anticancer steroid alkene phenol, the 4-trans-Hydroxytamoxifen, Drogenil, aminoglutethimide, (.+-.)-Pyridoglutethimide, megestrol, medroxyprogesterone, clomifene, toremifene, letrozole or exemestane and 10% vincristine, vincaleucoblastine, vinorelbine, vindesine, Vinmegallate, vinleurosine, vinleucinol, vinglycinate, vinfosiltine, vinformide, vinflunine, vinepidine, vinzolidine, vintriptol, vinrosidine, monocrotaline or cephalotaxin
Embodiment 7.
(EVAc) puts into container with the 80mg ethylene vinyl acetate copolymer, add 100 milliliters of dichloromethane dissolving mixings after, adds 10 milligrams of vincaleucoblastines and 10mg letrozole, shake up the dry removal of final vacuum organic solvent again.Dried solid composite is shaped immediately, and ray sterilizing after the packing obtains containing the anticancer implant of 10% vincaleucoblastine and 10% letrozole.All be weight percentage.The drug release time of this anticancer implant 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 implant is identical with embodiment 7, and different is that used adjuvant is polifeprosan (weight ratio to carboxy phenyl propane and certain herbaceous plants with big flowers diacid is 20: 80), must make anticancer implant contain 10% vincristine and 10% leuprorelin.
Embodiment 9.
With 80mg molecular weight peak value is that 25000 polylactic acid (PLGA, 75: 25) is put into container, adds 100 milliliters of dichloromethane, behind the dissolving mixing, adds 10mg vindesine and 10mg leuprorelin, shakes up the dry organic solvent of removing of final vacuum again.Dried pastille solid composite freezing and pulverizing is made the micropowder that contains 10% vindesine and 10% leuprorelin, be suspended in then in the normal saline that contains 1.5% sodium carboxymethyl cellulose, make corresponding suspension type slow releasing injection.The drug release time of this slow releasing injection in external normal saline is 10-15 days, is 20-30 days at the subcutaneous drug release time of mice.
Embodiment 10.
The method step that is processed into slow releasing injection is identical with embodiment 9, but different is that contained anticancer effective component is:
The triptorelin of 5-30%, goserelin, leuprorelin, Anastrozole, idoxifene, Miproxifene, tamoxifen, not former times sweet smell, raloxifene, ICI-M 164384, anticancer steroid alkene phenol, 4 trans-Hydroxytamoxifens, Drogenil, aminoglutethimide, (.+-.)-Pyridoglutethimide, megestrol, medroxyprogesterone, clomifene, toremifene, the vincristine of letrozole or exemestane and 5-30%, vincaleucoblastine, vinorelbine, vindesine, Vinmegallate, vinleurosine, vinleucinol, vinglycinate, vinfosiltine, vinformide, vinflunine, vinepidine, vinzolidine, vintriptol, vinrosidine, the combination of monocrotaline or cephalotaxin.Below all be weight percentage.
Embodiment 11.
80mg polifeprosan (to carboxy phenyl propane: certain herbaceous plants with big flowers diacid weight ratio is 20: 80) copolymer is put into container, add 100 milliliters of dichloromethane, behind the dissolving mixing, add 10mg tamoxifen and 10mg arsenicum, shake up the back contains 10% tamoxifen and 10% arsenicum with spray drying method for preparation injectable microsphere again.Then microsphere is suspended in the normal saline that contains 15% mannitol, makes corresponding suspension type slow releasing injection.The drug release time of this slow releasing injection in external normal saline is 10-15 days, is 20-30 days at the subcutaneous drug release time of mice.
Embodiment 12
The method step that is processed into slow releasing injection is identical with embodiment 11, but different is that contained anticancer effective component is:
10% Anastrozole, idoxifene, Miproxifene, tamoxifen, not former times sweet smell, raloxifene, (.+-.)-Pyridoglutethimide, rubitecan, Acapodene, Drogenil, overstate single silicon indigo plant, bicalutamide, aminoglutethimide, calusterone, triptorelin, goserelin, leuprorelin, megestrol, medroxyprogesterone, toremifene, letrozole, exemestane or testolactone and 10% cytochalasin, mitoclomine, mitoflaxone, mitoguazone, mitonafide, mitopodozide, mitoquidone, mitosper, mitotane, mitotenamine, Flavone acetic acid, colchisal, colchicine, Demecolcine, B cytochalasin B, naphthols, alpha-Naphthol, betanaphthol, the alpha-phosphate naphthols, acodazole, procodazole, arsenicum, the combination of giracodazole or nocodazole.Below all be weight percentage.
Embodiment 13.
With 70mg molecular weight peak value 45000 polylactic acid (PLGA, 75: 25) put into container, add 100 milliliters of dichloromethane, behind the dissolving mixing, add 10mg giracodazole and 20mg Anastrozole, shake up the back contains 10% giracodazole and 20% Anastrozole with spray drying method for preparation injectable microsphere again.Then microsphere is suspended in the normal saline that contains 1.5% sodium carboxymethyl cellulose and 15% sorbitol and 0.2% Tween 80, makes corresponding suspension type slow releasing injection.
Embodiment 14.
The method step that is processed into slow releasing injection is identical with embodiment 13, but different is that contained anticancer effective component is: 20% Anastrozole, idoxifene, Miproxifene, tamoxifen, not former times sweet smell, raloxifene, (.+-.)-Pyridoglutethimide, rubitecan, Acapodene, Drogenil, overstate single silicon indigo plant, bicalutamide, aminoglutethimide, calusterone, triptorelin, goserelin, leuprorelin, megestrol, medroxyprogesterone, toremifene, letrozole, Anastrozole, exemestane or testolactone and 10% cytochalasin, mitoclomine, mitoflaxone, mitoguazone, mitonafide, mitopodozide, mitoquidone, mitosper, mitotane, mitotenamine, Flavone acetic acid, colchisal, colchicine, Demecolcine, B cytochalasin B, naphthols, alpha-Naphthol, betanaphthol, the alpha-phosphate naphthols, acodazole, procodazole, arsenicum, the combination of giracodazole or nocodazole.
Embodiment 15.
The method step that is processed into slow releasing injection is identical with embodiment 1-14, but different is used slow-release auxiliary material is one of following or its combination:
A) molecular weight is polylactic acid (PLA);
B) molecular weight is the copolymer (PLGA) of polyglycolic acid and hydroxyacetic acid, and wherein, the ratio of polyglycolic acid and hydroxyacetic acid is 50-95: 50-5;
C) ethylene vinyl acetate copolymer (EVAc);
D) to carboxy phenyl propane (p-CPP): certain herbaceous plants with big flowers diacid (SA) copolymer (polifeprosan);
E) xylitol, oligosaccharide, chrondroitin, chitin, potassium salt, sodium salt, hyaluronic acid, collagen protein, gelatin or albumin.
Embodiment 16.
The method step that is processed into slow releasing injection is identical with embodiment 1-15, but different is used suspending agent is respectively one of following or its combination:
A) 0.5-3.0% carboxymethyl cellulose or sodium carboxymethyl cellulose;
B) 5-15% mannitol;
C) 5-15% sorbitol;
D) 0.1-1.5% surfactant;
E) 0.1-0.5% polysorbas20.
Claims (9)
1. a hormone anti-cancer medicine slow releasing agent comprises anticancer effective component and pharmaceutic adjuvant, it is characterized in that anticancer effective component is hormone anti-cancer medicine and hormone anti-cancer medicine synergist; Pharmaceutic adjuvant is selected from copolymer, ethylene vinyl acetate copolymer, polifeprosan, xylitol, oligosaccharide, chitin, potassium salt, sodium salt, hyaluronic acid, chondroitin sulfate, collagen protein, gelatin or the albumin of polylactic acid, polylactic acid and hydroxyacetic acid; The hormone anti-cancer medicine synergist is selected from plant alkaloid.
2. the hormone anti-cancer medicine slow releasing agent according to claim 1 is characterized in that described hormone anti-cancer medicine is selected from Anastrozole, idoxifene, Miproxifene, tamoxifen, not former times sweet smell, raloxifene, (.+-.)-Pyridoglutethimide http://china.echinachem.com/category/showChemical_Product.asp? Chemical_ID=64728, triptorelin, goserelin, leuprorelin, megestrol, medroxyprogesterone, toremifene, letrozole, exemestane or testolactone http://china.echinachem.com/category/showChemical_Product.asp? Chemical_ID=64585.
3. the hormone anti-cancer medicine slow releasing agent according to claim 1 is characterized in that described plant alkaloid is selected from vincristine, vincaleucoblastine, vinorelbine, vindesine, Vinmegallate, vinleurosine, vinleucinol, vinglycinate, vinfosiltine, vinformide, vinflunine, vinepidine, vinzolidine, vintriptol, vinrosidine, monocrotaline and cephalotaxin http://china.echinachem.com/category/showChemical_Product.asp? Ch
4. the hormone anti-cancer medicine slow releasing agent according to claim 1 is characterized in that this anticancer medicine slow-release preparation containing is an implant.
5. the anti-cancer sustained-released implantation agent according to claim 4 is characterized in that the anticancer effective component of this implant is:
The triptorelin of 5-30%, goserelin, leuprorelin, Anastrozole, idoxifene, Miproxifene, tamoxifen, not former times sweet smell, raloxifene, ICI-M 164384, anticancer steroid alkene phenol, 4 trans-Hydroxytamoxifens, Drogenil, aminoglutethimide, (.+-.)-Pyridoglutethimide http://china.echinachem.com/category/showChemical_Product.asp? Chemical_ID=64728, new alkali, vincaleucoblastine, vinorelbine, vindesine, Vinmegallate, vinleurosine, vinleucinol, vinglycinate, vinfosiltine, vinformide, vinflunine, vinepidine, vinzolidine, vintriptol, vinrosidine, monocrotaline or cephalotaxin http://china.echinachem.com/category/showChemical_Product.asp? all be weight percentage more than the combination of Chemical_ID=64805.
6. the anticancer anticancer medicine slow-release preparation containing according to claim 1 is characterized in that this anticancer medicine slow-release preparation containing is a slow releasing injection, and it consists of:
(A) sustained-release micro-spheres comprises:
Anticancer effective component 0.5-60%
Slow-release auxiliary material 40-99%
More than be weight percentage
With
(B) solvent is for common solvent or contain the special solvent of suspending agent;
Wherein, anticancer effective component is hormone anti-cancer medicine and hormone anti-cancer medicine synergist; Pharmaceutic adjuvant is selected from copolymer, ethylene vinyl acetate copolymer, polifeprosan, xylitol, oligosaccharide, chitin, potassium salt, sodium salt, hyaluronic acid, chondroitin sulfate, collagen protein, gelatin or the albumin of polylactic acid, polylactic acid and hydroxyacetic acid; Hormone anti-cancer medicine synergist synergist is selected from plant alkaloid; Suspending agent is selected from one of sodium carboxymethyl cellulose, iodine glycerol, simethicone, propylene glycol, carbomer, mannitol, sorbitol, surfactant, polysorbas20, polysorbate40 and Tween 80 or its combination.
7. the slow releasing injection according to claim 6 is characterized in that the hormone anti-cancer medicine synergist is for being selected from vincristine, vincaleucoblastine, vinorelbine, vindesine, Vinmegallate, vinleurosine, vinleucinol, vinglycinate, vinfosiltine, vinformide, vinflunine, vinepidine, vinzolidine, vintriptol, vinrosidine, monocrotaline or cephalotaxin http://china.echinachem.com/category/showChemical_Product.asp? Chemical
8. as the slow releasing injection as described in the claim 6, it is characterized in that used suspending agent is respectively one of following:
A) 0.5-3.0% sodium carboxymethyl cellulose;
B) 5-15% mannitol;
C) 5-15% sorbitol;
D) 0.1-0.5% polysorbas20; Or
E) glycerol, iodine glycerol, simethicone, propylene glycol or carbomer.
9. as the slow releasing injection as described in the claim 6, it is characterized in that used suspending agent is one of following:
A) 0.5-5% sodium carboxymethyl cellulose and 0.1-0.5% Tween 80; Or
B) 5-20% mannitol and 0.1-0.5% Tween 80; Or
C) 0.5-5% sodium carboxymethyl cellulose, 5-20% sorbitol and 0.1-0.5% Tween 80.
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| CNA2008103001138A CN101249066A (en) | 2005-12-20 | 2005-12-20 | Sustained-release agent containing hormone anti-cancer medicine |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107115324A (en) * | 2017-05-08 | 2017-09-01 | 四川双金多肽生物技术有限责任公司 | One kind promotees to secrete sweetfish squama albumen gonad axis controlled release hormone agent and preparation method thereof |
| CN114159415A (en) * | 2021-11-05 | 2022-03-11 | 中国人民解放军海军军医大学第三附属医院 | Application of flutamide in preparation of medicine for treating metastatic liver cancer |
-
2005
- 2005-12-20 CN CNA2008103001138A patent/CN101249066A/en active Pending
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107115324A (en) * | 2017-05-08 | 2017-09-01 | 四川双金多肽生物技术有限责任公司 | One kind promotees to secrete sweetfish squama albumen gonad axis controlled release hormone agent and preparation method thereof |
| CN114159415A (en) * | 2021-11-05 | 2022-03-11 | 中国人民解放军海军军医大学第三附属医院 | Application of flutamide in preparation of medicine for treating metastatic liver cancer |
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