CN1923282B - Anti-cancer slow release injection comprising hormone drug - Google Patents
Anti-cancer slow release injection comprising hormone drug Download PDFInfo
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- CN1923282B CN1923282B CN200510044522A CN200510044522A CN1923282B CN 1923282 B CN1923282 B CN 1923282B CN 200510044522 A CN200510044522 A CN 200510044522A CN 200510044522 A CN200510044522 A CN 200510044522A CN 1923282 B CN1923282 B CN 1923282B
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Abstract
Disclosed is an anticancer slow release injection containing hormone drugs, wherein the constituents include anti-cancer drugs, slow release auxiliary materials, suspending agent and/or dissolvent. The anti-cancer drugs include Anastrozole, Idoxifene, Miproxifene, and Tamoxifen, the slow release auxiliary materials can be selected from polylactic acid, glycolic acid and glycolic acid copolymer, ethylene-vinylacetate copolymer or their combination. The suspending agent is selected from sodium carboxymethylcellulose and mannitol. The dissolvent is selected from distilled water, water for injection, physiological lotion, absolute ethyl alcohol, microcosmic salt or carbonates cushioning liquid. The anticancer slow release injection can be administered through subcutaneous, intracavity, intra-tumor, tumor-surrounding, intra- lymph gland or bone marrow channels, the whole body toxicity reaction of the anti-cancer medicament can be lowered, the tumor local medicinal concentration can also be selectively increased and maintained, and the treatment effect of the non-operative treatment methods such as chemotherapy, medicament and radiation can also be improved.
Description
(1) technical field
The present invention relates to a kind of slow releasing injection that contains hormone anti-cancer medicine, belong to technical field of pharmaceuticals.
(2) background technology
Steroids anti-cancer drugs has been widely used in the treatment of multiple malignant tumor as chemotherapeutics commonly used, and has obtained comparatively significantly action effect.Yet, discover that further unsuitable administration usually causes the generation of toleration, finally cause the failure for the treatment of.Because entity tumor excessive expansion hypertrophy, the viscosity of matter was high than its normal surrounding tissue all between matter pressure, tissue elasticity pressure, fluid pressure reached therebetween, therefore, conventional chemotherapy, be difficult to tumor by local and form effective drug level (referring to " placing cisplatin adding system carmustine treatment rat brain tumor in the tumor " " surgery tumor magazine " 1998 69 phase 76-82 pages or leaves (Kong Q et al., J Surg Oncol.1998Oct such as Kong Qingzhongs; 69 (2): 76-82), improve the restriction that dosage is subjected to general reaction again merely.Medicine is implanted the problem that may solve drug level to a certain extent, yet the caused various complication of operation technique have usually limited its extensive use clinically.
(3) summary of the invention
The present invention is directed to the deficiencies in the prior art, a kind of slow-releasing anticarcinogen injection that contains hormone medicine is provided.
Slow-releasing anticarcinogen injection of the present invention comprises sustained-release microparticle, suspending agent and/or solvent, and sustained-release microparticle is made up of hormone anti-cancer medicine and slow-release auxiliary material.
Hormone medicine is selected from steroid hormone and hormone is robbed anti-agent, is one of following or combination:
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-pentafluoropentylsulfinyl) many or few nonyl] estra-1; 3; 5 (10)-triene-3; 17beta-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.
Above steroids anti-cancer drugs with Anastrozole, idoxifene, Miproxifene, tamoxifen, 4-monohydroxy tamoxifen (OH-TAM), not former times sweet smell, ICI-M 164384, anticancer steroid alkene phenol, 4-trans-Hydroxytamoxifen, Drogenil, aminoglutethimide, (.+-.)-Pyridoglutethimide, megestrol 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; Aminoglutethimide is then in order to treatment breast carcinoma, carcinoma of prostate and carcinoma of endometrium.
The content of steroids anti-cancer drugs in sustained-release microparticle is 1%-99%, is good with 2%-50%, is best with 5%-30%, more than all be weight percentage.
Slow-release auxiliary material is selected from mixture, the ethylene vinyl acetate copolymer (EVAc), [poly-(1 of the copolymer (PLGA), polylactic acid (PLA) of polylactic acid (PLA), polyglycolic acid (PGA), glycolic and hydroxyacetic acid and the copolymer (PLGA) of glycolic and hydroxyacetic acid, 3-two (to the carboxyl phenoxy group) propane-decanedioic acid) one of (p (CPP-SA), polifeprosan), xylitol, oligosaccharide, chrondroitin, chitin, potassium salt, sodium salt, hyaluronic acid, collagen protein, gelatin and white tempera or its combination; Above-mentioned slow-release auxiliary material shared percentage by weight in sustained-release microparticle is 40%-99%.
Polylactic acid in the above-mentioned slow-release auxiliary material (PLA) molecular weight peak value can be, but is not limited to, and 5000～100,000, with 20,000～60,000 is preferred, with 30,000～50,000 for most preferably; The molecular weight of polyglycolic acid (PGA) can be, but is not limited to, and 5000～100,000, with 20,000～60,000 is preferred, with 30,000～50,000 for most preferably; The molecular weight of the copolymer of glycolic and hydroxyacetic acid (PLGA) can be, but is not limited to, and 5000～100,000, but with 20,000～60,000 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.In poly-(1,3-two (to the carboxyl phenoxy group) propane-decanedioic acid) (p (CPP-SA), polifeprosan), to the weight ratio 10/90-90/10 of carboxy phenyl propane (p-CPP) with certain herbaceous plants with big flowers diacid (SA), preferred 25/75-75/25.
Suspending agent is selected from one of carboxymethyl cellulose, sodium carboxymethyl cellulose, glycerol, iodine glycerol, simethicone, propylene glycol, carbomer, mannitol, sorbitol, polysorbas20 or Tween 80 or its combination.
When containing suspending agent and solvent simultaneously, suspending agent and solvent are formed special solvent, also claim the injection system, the content of suspending agent wherein in solvent is 0.1mg/ml-20mg/ml, the kind that depends on used suspending agent, as carboxymethyl cellulose or sodium carboxymethyl cellulose is that the volume weight percentage ratio of solvent can be preferred with 0.5-3% from 0.1-5%, and 1-2% is for most preferably.And the content of tween in solvent is 0.1mg/ml-1mg/ml, and mannitol or the sorbitol content in solvent is 10mg/ml-20mg/ml.
The available some kinds of methods preparation of the sustained-release microparticle of above-mentioned slow releasing injection (also claiming slow-releasing system), as, but be not limited to (i) fusion method: pharmaceutic adjuvant is directly pulverized with medicine 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 between 5-400um, serving as preferred between the 10-300um, with between the 20-200um for most preferably.The weight ratio of anticancer effective component and slow-release auxiliary material can be from 1: 99 to 6: 4 in the slow-releasing system.
Sustained-release microparticle can be different shape, as, but be not limited to, microgranule, granule, spherical piller, microsphere or micropowder. for regulating drug releasing rate, can change the monomer component or the molecular weight of polymer, add or regulate the composition and the proportioning of pharmaceutic adjuvant, adding any one or multiple other pharmaceutic adjuvant as additive. additive can be divided into filler according to its function, porogen, excipient, dispersant, isotonic agent, preservative agent, blocker, solubilizing agent, absorption enhancer, film former, gellant etc., its content is decided because of concrete condition. and 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 enumerated some pharmaceutic adjuvant, comprise 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, therefore the material of the same race that has is listed in different classifications. and 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.
Slow-releasing system can separate the packing respectively of independent sterilization back, storage, suspendible, injection again during use with the injection system; Also slow-releasing system 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; Slow-releasing system is sterilized after also can being suspended in the injection system, 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 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 1,000-15, and 000 Polyethylene Glycol is as the hydrophilic block of micelle copolymer, preferred biological degradation polyalcohol, as PLA, polylactide, polycaprolactone and copolymer thereof (molecular weight 1,500-25,000) hydrophobic block as the micelle copolymer.The particle size range of block copolymer micelle can be preferred with 20-200um between 10-300um.
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 purpose that slow releasing injection of the present invention is used suspending agent is the pastille slow-release microsphere that effectively suspends, thereby is beneficial to 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.
Slow-releasing anticarcinogen injection of the present invention is intracavitary administration agent, intratumor injection agent, all injections of tumor or selective arterial injection, and intracavitary administration comprises in intraperitoneal, the thoracic cavity and injection through vertebral canal.It can also be in the lymph node and the interior injection of bone marrow.
Because the present invention can make the action effect of methods such as conventional chemotherapy, immunization therapy, high thermal therapeutical, photochemical therapy, electrotherapy, Biotherapeutics, hormone therapy, magnetic therapy, ultrasonic therapeutic, radiotherapy and gene therapy strengthen.Therefore when local slow discharges, can share, thereby its anticancer effect is further strengthened with above-mentioned non-operative treatment.When share with above-mentioned non-operative treatment, the present invention can use simultaneously with non-operative treatment, also can use in non-operative treatment is implemented a few days ago, and its purpose is to strengthen as far as possible the sensitivity of tumor.
Route of administration
Route of administration depends on multiple factor, for obtaining valid density in former or position, metastatic tumour place, medicine can give through number of ways, as in the intracavity (in abdominal cavity, thoracic cavity and canalis spinalis), tumor, in all, the selective arterial injection of tumor, lymph node and place in the bone marrow or injection.With in selective arterial, intracavity, the tumor, tumor week injection serves as preferred.
Dosage
Amount of 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.The effective dose of 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.Wherein the content of active ingredient is decided because of different needs.Can be good with 2%-50% from 1%-99%, be best with 5%-30%.
The present invention can be used to prepare the slow releasing injection of the various tumors for the treatment of people and animal, and the indication tumor comprises former of originating from nervous system, digestive system, respiratory system, urinary system, reproductive system and skin etc. or cancer or sarcoma or the carcinosarcoma that shifts.Comprise the cerebral tumor, esophageal carcinoma, hepatocarcinoma, cancer of biliary duct, gastric cancer, pancreas, colon cancer, rectal cancer, pulmonary carcinoma, renal carcinoma, bladder cancer, breast carcinoma, ovarian cancer, carcinoma of endometrium, cervical cancer, carcinoma of prostate, tumor of head and neck, oral cancer, thyroid carcinoma, skin carcinoma, osseous tissue tumor, lymphoma, hemangioma, eyes tumor, retinoblastoma and nasopharyngeal carcinoma.
Also can add other medicinal ingredient in the made slow releasing injection of the present invention, as, but be not limited to antibiotics, antalgica, anticoagulant medicine, hemorrhage etc.
The present invention is a holder with the bio-capacitivity material mainly, so do not cause foreign body reaction.Support to place in the object back degradable and absorb, so no longer operation is taken out.Cause discharges contained drug at tumor by local, thereby optionally improves and prolong local drug concentration, can reduce the general toxic reaction that is caused by the conventional route administration simultaneously.
The characteristics of technology of preparing of the present invention are according to a certain percentage the anticancer effective component taxine kind anti-cancer to be packaged in the slow-release auxiliary material, prepare microsphere (or grain) with methods such as mixing, fusion, dissolving, spray drying, freezing (drying) pulverizing, emulsifying or liposome, microsphere is used to prepare above-mentioned various slow releasing injection, wherein suspension type slow releasing injection most preferably.The slow-releasing system that suspends or be called the injection anticancer medicine slow-release preparation containing with the injection system is as " injection idoxifene slow releasing agent " or " injection Anastrozole slow releasing agent ".
By following test and embodiment technology side of the present invention is further described:
(4) specific embodiment
The present invention is processed into slow-releasing anticarcinogen injection and further is illustrated by following examples, but is not limited thereto.
Embodiment 1.
The PLGA (copolymer of hydroxyacetic acid and glycolic, weight ratio 70: 30) of 80mg pharmaceutic adjuvant 20000 is put into container, add 100 milliliters of dichloromethane dissolving mixings after, add the 20mg idoxifene, shake up the dry organic solvent of removing of final vacuum again.Dried solid composite is made the slow-release pill of the idoxifene that contains percentage by weight 20%, ray sterilizing after the packing with fusion method.Slow-release pill is suspended in the water for injection that contains 1.5% sodium carboxymethyl cellulose, makes corresponding suspension type slow releasing injection.The drug release time of this slow releasing injection in external normal saline is 14-24 days, is 20-35 days at the subcutaneous drug release time of mice.
Embodiment 2.
The method step that is processed into slow-releasing anticarcinogen injection is identical with embodiment 1, but different is that the contained effective antitumor composition of slow releasing injection is: the Anastrozole of percentage by weight 50%, idoxifene, Miproxifene, tamoxifen, 4-monohydroxy tamoxifen, not former times sweet smell, ICI-M 164384, anticancer steroid alkene phenol, the 4-trans-Hydroxytamoxifen, γ-linoleic acid, the 2-methoxyestradiol, moxestrol, the 4-trans-Hydroxytamoxifen, clofenotane, benzene hexachloride, thunder not former times sweet smell, diethylstilbestrol, estradiol, 6-(10-hydroxy-6-oxo-trans-1-undecenyl)-.beta.-resorcylic acid lactone, estrone, 17 alpha-estradiols, estradiol, the 2-hydroxyestrone, 5,7,4 trihydroxy-isoflavones, Progesterone, mepitiostane, androgen, (.+-.)-Pyridoglutethimide, rubitecan, Acapodene, Drogenil, overstate single silicon indigo plant, bicalutamide, aminoglutethimide, betamethasone benzoate, calusterone, megestrol, datiscoside, epitiostanol, the female sweet smell of bromine vinegar ethane, hisphen or testolactone.
Embodiment 3.
80mg pharmaceutic adjuvant ethylene vinyl acetate copolymer (EVAc) is put into container, add 100 milliliters of dichloromethane dissolving mixings after, add the 20mg tamoxifen, shake up the dry organic solvent of removing of final vacuum again.Make to such an extent that contain the slow-release pill of percentage by weight 20% tamoxifen, packing after ray sterilizing with fusion method dried solid composite.Slow-release pill is suspended in the water for injection that contains 1.5% sodium carboxymethyl cellulose and 15% mannitol, makes corresponding suspension type slow releasing injection.The drug release time of this slow releasing injection in external normal saline is 14-24 days, and the drug release time in mouse breast cancer is 20-35 days.
Embodiment 4.
The method step that is processed into slow-releasing anticarcinogen injection is identical with embodiment 3, but different is that the contained effective antitumor composition of slow releasing injection is:
(a) 30% tamoxifen, Anastrozole, idoxifene, Miproxifene, 4-monohydroxy tamoxifen, not former times sweet smell, ICI-M 164384, anticancer steroid alkene phenol, 4-trans-Hydroxytamoxifen, γ-linoleic acid, 2-methoxyestradiol or moxestrol; Perhaps
(b) 20%4-trans-Hydroxytamoxifen, clofenotane, benzene hexachloride, thunder not former times sweet smell, diethylstilbestrol, estradiol, 6-(10-hydroxy-6-oxo-trans-1-undecenyl)-.beta.-resorcylic acid lactone, estrone, 17 alpha-estradiols, estradiol, 2-hydroxyestrone, 5,7,4 trihydroxy-isoflavones, Progesterone, mepitiostane or androgen; Perhaps
(c) 10% not former times sweet smell, (.+-.)-Pyridoglutethimide, rubitecan, Acapodene, Drogenil, overstate single silicon indigo plant, bicalutamide, aminoglutethimide, betamethasone benzoate, calusterone, megestrol, datiscoside, epitiostanol, the female sweet smell of bromine vinegar ethane, hisphen or testolactone.
Below all be weight percentage.
Embodiment 5.
80mg pharmaceutic adjuvant polifeprosan (to carboxy phenyl propane: certain herbaceous plants with big flowers diacid weight ratio is 80: 20) is put into container, add 100 milliliters of dichloromethane dissolving mixings after, add the 20mg Miproxifene and shake up the dry organic solvent of removing of final vacuum again.Dried solid composite is made the slow-release pill that contains percentage by weight 20% Miproxifene with fusion method, ray sterilizing after the packing.Slow-release pill is suspended in the water for injection that contains 1.5% sodium carboxymethyl cellulose and 15% mannitol, makes corresponding suspension type slow releasing injection.The drug release time of this slow releasing injection in external normal saline is 14-24 days, and the drug release time in mice precedent adenocarcinoma is 20-35 days.
Embodiment 6.
The method step that is processed into slow-releasing anticarcinogen injection is identical with embodiment 5, but different is that the contained effective antitumor composition of slow releasing injection is:
(a) 25% Anastrozole, idoxifene, Miproxifene, tamoxifen, 4-monohydroxy tamoxifen, not former times sweet smell, ICI-M 164384, anticancer steroid alkene phenol, 4-trans-Hydroxytamoxifen, γ-linoleic acid, 2-methoxyestradiol or moxestrol; Perhaps
(b) 15%4-trans-Hydroxytamoxifen, clofenotane, benzene hexachloride, thunder not former times sweet smell, diethylstilbestrol, estradiol, 6-(10-hydroxy-6-oxo-trans-1-undecenyl)-.beta.-resorcylic acid lactone, estrone, 17 alpha-estradiols, estradiol, 2-hydroxyestrone, 5,7,4 trihydroxy-isoflavones, Progesterone, mepitiostane or androgen; Perhaps
(c) 5% (.+-.)-Pyridoglutethimide, rubitecan, are overstated single silicon indigo plant, bicalutamide, aminoglutethimide, betamethasone benzoate, calusterone, megestrol, datiscoside, epitiostanol, the female sweet smell of bromine vinegar ethane, hisphen or testolactone at Acapodene, Drogenil.
Below all be weight percentage.
Embodiment 7.
With the 80mg polifeprosan (to carboxy phenyl propane: the certain herbaceous plants with big flowers diacid copolymer, weight ratio 80: 20) puts into container, after adding 100 milliliters of dichloromethane dissolving mixings, add 10mg tamoxifen and 10mg (.+-.)-Pyridoglutethimide, shake up the back becomes to contain percentage by weight 10% tamoxifen and 10% (.+-.)-Pyridoglutethimide with spray drying method for preparation microsphere again.Sustained-release micro-spheres is suspended in the water for injection that contains 1.0% sodium carboxymethyl cellulose and 10% mannitol, makes corresponding suspension type slow releasing injection.The drug release time of this slow releasing injection in external normal saline is 10-20 days, and the drug release time in rat liver cancer is 20-30 days.
Embodiment 8.
With 80mg molecular weight peak value is 35000 the glycolic and the copolymer (PLGA of hydroxyacetic acid, weight ratio 70: 30) puts into container, add 100 milliliters of dichloromethane, behind the dissolving mixing, add the 20mg thunder not former times sweet smell, shake up again the back with spray drying method for preparation become to contain percentage by weight 20% thunder not former times sweet smell microsphere.This is suspended in sustained-release micro-spheres in the dehydrated alcohol that contains 1.0% sodium carboxymethyl cellulose, makes corresponding suspension type slow releasing injection.The drug release time of this slow releasing injection in external normal saline is 10-20 days, is 20-30 days at the subcutaneous drug release time of mice.
Embodiment 9.
With 70mg molecular weight peak value is that 35000 polylactic acid is put into container, adds 100 milliliters of dichloromethane, behind the dissolving mixing, adds the 30mg aminoglutethimide, shakes up the dry organic solvent of removing of final vacuum again.The bead that contains percentage by weight 30% aminoglutethimide is made in dried pastille solids freezing (drying) pulverizing.This is suspended in sustained-release micro-spheres in the dehydrated alcohol that contains 1.0% sodium carboxymethyl cellulose, makes corresponding suspension type slow releasing injection.The drug release time of this slow releasing injection in external normal saline is 15-20 days, and the drug release time in mice lung cancer is 30-40 days.
Embodiment 10.
The method step that is processed into slow-releasing anticarcinogen injection is identical with embodiment 1-9, but different is used slow-release auxiliary material is one of following or its combination:
A) molecular weight is the polylactic acid of 5000-15000,10000-20000,20000-35000 or 30000-50000;
B) molecular weight is the polyglycolic acid of 5000-15000,10000-20000,20000-35000 or 30000-50000 and the copolymer of hydroxyacetic acid (PLGA), and wherein, the ratio of polyglycolic acid and hydroxyacetic acid is 50-95: 50-5;
C) ethylene vinyl acetate copolymer (EVAc);
D) weight ratio 10: 90,20: 80,30: 70,40: 60,50: 50 or 60: 40 to carboxy phenyl propane: certain herbaceous plants with big flowers diacid copolymer (polifeprosan);
E) xylitol, oligosaccharide, chrondroitin, chitin, potassium salt, sodium salt, hyaluronic acid, collagen protein, gelatin or white tempera.
Embodiment 11.
The method step that is processed into slow-releasing anticarcinogen injection is identical with embodiment 1-10, but different is used suspending agent is one of following or its combination:
A) 2.0% carboxymethyl cellulose;
B) 10% mannitol;
C) 15% sorbitol;
D) 1.0% surfactant;
E) 0.3% polysorbas20
F) iodine glycerol, simethicone, propylene glycol or carbomer.
Embodiment 12.
With sustained-release micro-spheres prepared in embodiment 2 or 4 be suspended in contain 0.5-1.5% carboxymethyl cellulose (sodium) and or the water for injection of 5-15% mannitol in, make the be weight percentage Anastrozole of 5-30% of the contained anticancer effective component of corresponding suspension type slow releasing injection, idoxifene, Miproxifene, tamoxifen, 4-monohydroxy tamoxifen, not former times sweet smell, ICI-M 164384, anticancer steroid alkene phenol, the 4-trans-Hydroxytamoxifen, γ-linoleic acid, the 2-methoxyestradiol, moxestrol, the 4-trans-Hydroxytamoxifen, clofenotane, benzene hexachloride, thunder not former times sweet smell, diethylstilbestrol, estradiol, 6-(10-hydroxy-6-oxo-trans-1-undecenyl)-.beta.-resorcylic acid lactone, estrone, 17 alpha-estradiols, estradiol, the 2-hydroxyestrone, 5,7,4 trihydroxy-isoflavones, Progesterone, mepitiostane, androgen, (.+-.)-Pyridoglutethimide, rubitecan, Acapodene, Drogenil, overstate single silicon indigo plant, bicalutamide, aminoglutethimide, betamethasone benzoate, calusterone, megestrol, datiscoside, epitiostanol, the female sweet smell of bromine vinegar ethane, hisphen or testolactone.
As mentioned above, the preparation method of slow-releasing anticarcinogen injection of the present invention can be selected as the case may be.Therefore, above embodiment only is used for explanation and is not limitation application of the present invention.
Embodiment 13.
The method step that is processed into slow-releasing anticarcinogen injection is identical with embodiment 1, and different is that effective ingredient is:
20mg hormone anti-cancer medicine, 80mg slow-release auxiliary material and 1mg suspending agent.
Wherein, hormone anti-cancer medicine be Anastrozole, idoxifene, Miproxifene, tamoxifen, not former times sweet smell, thunder not former times sweet smell, (.+-.)-Pyridoglutethimide, rubitecan, Acapodene, Drogenil, bicalutamide or aminoglutethimide; Slow-release auxiliary material is one of copolymer, ethylene vinyl acetate copolymer and polifeprosan of polylactic acid, glycolic and hydroxyacetic acid or its combination; Suspending agent is selected from one of carboxymethyl cellulose, sodium carboxymethyl cellulose, glycerol, iodine glycerol, simethicone, propylene glycol, carbomer, mannitol, sorbitol, polysorbas20 or Tween 80 or its combination.
Embodiment 14.
The method step that is processed into slow-releasing anticarcinogen injection is identical with embodiment 1, and different is that effective ingredient is:
30mg hormone anti-cancer medicine, 70mg slow-release auxiliary material and 10ml solvent.
Wherein, hormone anti-cancer medicine be Anastrozole, idoxifene, Miproxifene, tamoxifen, not former times sweet smell, thunder not former times sweet smell, (.+-.)-Pyridoglutethimide, rubitecan, Acapodene, Drogenil, bicalutamide or aminoglutethimide; Slow-release auxiliary material is one of copolymer, ethylene vinyl acetate copolymer and polifeprosan of polylactic acid, glycolic and hydroxyacetic acid or its combination; Solvent is selected from distilled water, water for injection, physiology towards liquid, dehydrated alcohol, phosphate or carbonate buffer solution.
Embodiment 15.
The method step that is processed into slow-releasing anticarcinogen injection is identical with embodiment 1, and different is that effective ingredient is:
20mg hormone anti-cancer medicine, 80mg slow-release auxiliary material, 2mg suspending agent and 10ml solvent.
Wherein, hormone anti-cancer medicine be Anastrozole, idoxifene, Miproxifene, tamoxifen, not former times sweet smell, thunder not former times sweet smell, (.+-.)-Pyridoglutethimide, rubitecan, Acapodene, Drogenil, bicalutamide or aminoglutethimide; Slow-release auxiliary material is one of copolymer, ethylene vinyl acetate copolymer and polifeprosan of polylactic acid, glycolic and hydroxyacetic acid or its combination; Solvent is selected from distilled water, water for injection, physiology towards liquid, dehydrated alcohol, phosphate or carbonate buffer solution.
Embodiment 16.
The method step that is processed into slow-releasing anticarcinogen injection is identical with embodiment 1, and different is that effective ingredient is:
(A) 10mg tamoxifen, 90mg polylactic acid (molecular weight peak value 30000), 1mg sodium carboxymethyl cellulose; Or
(B) 20mg tamoxifen, 80mg polylactic acid (molecular weight peak value 30000), 10ml NaCL injection; Or
(C) 30mg tamoxifen, 70mg polylactic acid (molecular weight peak value 30000), 1mg sodium carboxymethyl cellulose, 10mlNaCL injection; Or
(D) 10mg idoxifene, 40mg polylactic acid (molecular weight peak value 30000), the copolymer of 40mg glycolic and hydroxyacetic acid (molecular weight peak value 30000,75: 25), the 1mg carboxymethyl cellulose; Or
(E) 20mg idoxifene, 40mg polylactic acid (molecular weight peak value 30000), 40mg ethylene vinyl acetate copolymer, 10ml dehydrated alcohol; Or
(F) 30mg idoxifene, and the copolymer of 35mg glycolic and hydroxyacetic acid (molecular weight peak value 30000,75: 25), 35mg ethylene vinyl acetate copolymer, 1mg carboxymethyl cellulose, 10ml dehydrated alcohol.
As mentioned above, the preparation method of slow-releasing anticarcinogen injection of the present invention can be selected as the case may be.Slow-releasing anticarcinogen injection 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.This slow-releasing anticarcinogen injection except that independent application, also can with many treatment measure use in conjunction: as with use in conjunction such as radiotherapy, high thermal therapeutical, immunization therapy, phototherapy, electrotherapy.Local injection is used this slow-releasing anticarcinogen injection and is had unique advantage and very high clinical value as synergist.When this slow-releasing anticarcinogen injection and other treatment measure use in conjunction, said composition can be simultaneously or prior to other treatment measure.
In a word, the anticancer slow-releasing anticarcinogen injection that contains above effective ingredient can be made into any dosage form, and the effective ingredient of slow-releasing anticarcinogen injection is any one or multiple steroids anti-cancer drugs, but with the suspension type slow releasing injection.Tumor-inhibiting action can further specify by following examples in its body.
Embodiment 17. contains the interior tumor-inhibiting action of body of the slow releasing injection of steroids anti-cancer drugs
With the white mice is subjects, with 2x10
5Individual tumor cell subcutaneous injection is in its hypochondrium, treat that tumor growth after 7 days is divided into it following 10 groups (seeing Table 1). the injection slow releasing injection is respectively from embodiment 1 in the body, 2, with 3, active constituent content is respectively percentage by weight 10%, 15% and 20%. first groups are contrast, the the 2nd to 10 group is the treatment group, wherein, the the 2nd to 4 group is Anastrozole, the the 5th to 7 group is idoxifene, the the 8th to 10 group is Miproxifene. medicine is respectively through lumbar injection injection (ip), intratumor injection injection (it) and intratumor injection slow releasing agent (itp). dosage is 5mg/kg. treatment back and measured gross tumor volume size, relatively therapeutic effect (seeing Table 1) on the 10th day.
Table 1
| Test group (n) | Suffered treatment | Gross tumor volume (cm 3) | The P value |
| 1(6) | Contrast | 48.5±8.3 | |
| 2(6) | Anastrozole (ip) | 20±5.3 | ＜0.05 |
| 3(6) | Anastrozole (it) | 12±3.5 | ＜0.01 |
| 4(6) | Anastrozole (itp) | 6±1.6 | ＜0.01 |
| 5(6) | Idoxifene (ip) | 26±4 | ＜0.01 |
| 6(6) | Idoxifene (it) | 20±2.6 | ＜0.01 |
| 7(6) | Idoxifene (itp) | 12±1.6 | ＜0.001 |
| 8(6) | Miproxifene (ip) | 24±2.6 | ＜0.001 |
| 9(6) | Miproxifene (it) | 16±1.6 | ＜0.001 |
| 10(6) | Miproxifene (itp) | 8±0.6 | ＜0.001 |
Tumor-inhibiting action in the body of embodiment 18. steroids anti-cancer drugs slow releasing injection
With the rat is subjects, with 2x10
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 2).
The injection slow releasing injection is all from embodiment 4 in the body, and wherein active constituent content is weight percentage 20%.First group for the contrast, the 2nd to 10 group is the treatment group, wherein, the 2nd to 4 group is tamoxifen, the 5th to 7 group is 4-monohydroxy tamoxifen, the 8th to 10 group be not former times sweet smell.Medicine is respectively through lumbar injection injection (ip), intratumor injection injection (it) and intratumor injection slow releasing agent (itp).Dosage is 5mg/kg.The treatment back was measured gross tumor volume size, relatively therapeutic effect (seeing Table 2) on the 10th day.
Table 2
| Test group (n) | Suffered treatment | Gross tumor volume (cm 3) | The P value |
| 1(6) | Contrast | 84±12 | |
| 2(6) | Tamoxifen (ip) | 48±6.3 | ＜0.05 |
| 3(6) | Tamoxifen (it) | 38±4.3 | ＜0.01 |
| 4(6) | Tamoxifen (itp) | 26±3.4 | ＜0.01 |
| 5(6) | 4-monohydroxy tamoxifen (ip) | 46±6.0 | ＜0.01 |
| 6(6) | 4-monohydroxy tamoxifen (it) | 34±3.0 | ＜0.01 |
| 7(6) | 4-monohydroxy tamoxifen (itp) | 18±2.0 | ＜0.001 |
| 8(6) | Former times sweet smell (ip) not | 32±5.6 | ＜0.001 |
| 9(6) | Former times sweet smell (it) not | 24±3.6 | ＜0.001 |
| 10(6) | Former times sweet smell (itp) not | 18±2.6 | ＜0.001 |
Embodiment 17 and 18 result show that used various steroids anti-cancer drugs all have the obvious suppression effect to growth of tumour cell when this concentration, but comparatively obvious with the effect of local application, wherein the local injection slow releasing agent is the most obvious.Selected steroids anti-cancer drugs is of universal significance.The local injection slow releasing injection not only can suppress tumor growth effectively, and can significantly reduce the general toxic reaction of medicine, particularly easy to operate, can be as required frequent repetitively administered, local complication (as hemorrhage, infection etc.) few, damage to patient is little, more can not stimulate tumor diffusion and transfer.
The above unique and significant superiority of slow releasing injection of the present invention has remedied the deficiencies in the prior art, has constituted main feature of the present invention simultaneously.
Claims (1)
1. a slow-releasing anticarcinogen injection is characterized in that, slow-releasing anticarcinogen injection consist of one of following combination:
(1) anticancer effective component is the tamoxifen of 20mg, and slow-release auxiliary material is the ethylene vinyl acetate copolymer of 80mg, and solvent is the water for injection that contains 1.5% sodium carboxymethyl cellulose and 15% mannitol; Be used for the treatment of breast carcinoma;
(2) anticancer effective component is the Miproxifene of 20mg, slow-release auxiliary material be 80mg to carboxy phenyl propane: the decanedioic acid weight ratio is 80: 20 a polifeprosan, and solvent is the water for injection that contains 1.5% sodium carboxymethyl cellulose and 15% mannitol; Be used for the treatment of carcinoma of prostate;
(3) anticancer effective component is the tamoxifen of 10mg and the (.+-.)-Pyridoglutethimide of 10mg, slow-release auxiliary material be 80mg to carboxy phenyl propane: the decanedioic acid weight ratio is 80: 20 a polifeprosan, and solvent is the water for injection that contains 1.0% sodium carboxymethyl cellulose and 10% mannitol; Be used for the treatment of hepatocarcinoma;
Wherein, anticancer effective component and slow-release auxiliary material are formed sustained-release micro-spheres, and described microsphere is suspended in the described solvent.
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| CN1660437A (en) * | 2004-12-29 | 2005-08-31 | 山东蓝金生物工程有限公司 | Combination of slow released anticancer medication |
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