CN1857208A - Slow released anticancer injection with both antimetabolite and its synergist - Google Patents
Slow released anticancer injection with both antimetabolite and its synergist Download PDFInfo
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- CN1857208A CN1857208A CNA2006102002577A CN200610200257A CN1857208A CN 1857208 A CN1857208 A CN 1857208A CN A2006102002577 A CNA2006102002577 A CN A2006102002577A CN 200610200257 A CN200610200257 A CN 200610200257A CN 1857208 A CN1857208 A CN 1857208A
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Abstract
The slow released anticancer injection consists of slow released microsphere and solvent. The slow released microsphere includes effective anticancer component and slow releasing supplementary material, and the solvent is special solvent containing suspending agent. The effective anticancer component is antimetabolite Zalcitabine, Emtricitabine, etc and/or antimetabolite synergist selected from hormone anticarcinogen and/or platinum compound. The slow releasing supplementary material is selected from difatty acid-sebacic acid copolymer, poly (erucic acid dipolymer-sebacic acid), poly(fumaric acid-sebacic acid), etc or their composition. The suspending agent is carboxymethyl cellulose, etc. and has viscosity of 80-3000 cp at 20-30 deg.c. The slow released microsphere may be also prepared into slow released implanting agent for use alone or together with chemotherapeutic medicine, radiotherapeutic medicine, etc.
Description
(1) technical field
The present invention relates to a kind of slow-releasing anticarcinogen injection that contains antimetabolite and synergist thereof, belong to technical field of pharmaceuticals.Particularly, the invention provides the slow releasing injection or the sustained-release implant of a kind of both antimetabolite and/or its synergist.
(2) background technology
Treatment for cancer mainly comprises methods such as operation, radiotherapy and chemotherapy.Therefore wherein operative treatment can not be removed the oncocyte that is dispersed in, and often recurs or causes tumor cell to stimulate diffusion transfer because of operation; Radiotherapy and traditional chemotherapy are not had a selectivity, and be difficult to tumor by local and form effective drug level or therapeutic dose, weak effect, toxicity is big, improves the restriction that medicine or radiological dose are subjected to general toxic reaction again merely.Referring to " placing cisplatin adding system carmustine treatment rat brain tumor in the tumor " " surgery tumor magazine " 69 phase 76-82 pages or leaves (1998) (Kong Q et al., J Surg Oncol.1998 Oct such as Kong Qingzhongs; 69 (2): 76-82).
The local placement of antitumor drug can overcome above defective preferably, not only can obviously improve the drug level of tumor by local, and can significantly reduce general toxic reaction.A large amount of internal and external tests have demonstrated the therapeutic effect to entity tumor, referring to " placing cisplatin adding system carmustine treatment rat brain tumor in the tumor " " surgery tumor magazine " 69 phase 76-82 pages or leaves (1998) (Kong Q et al., J Surg Oncol.1998 Oct such as Kong Qingzhongs; 69 (2): 76-82) and Kong Qingzhong etc. " place cisplatin in the tumor and cure the former carbuncle in the occipital region tumor of rat " " surgery tumor magazine " 64 phase 268-273 pages or leaves (1997) (Kong Q et al., JSurg Oncol.1997 Oct; 64:268-273).Also can be referring to Chinese patent (ZL00111093.4; ZL96115937.5; Application number 001111264,001111272) and U.S.'s patent of invention (patent No. 6,376,525B1; 5,651,986; 5,626,862).
Yet there is great difference in tumor cell to the sensitivity of chemotherapeutics.Many tumor cell medicines are also insensitive, and the tumor cell that has is in the early stage sensitivity of chemotherapy, but very fast tolerance.Particularly work as cancer therapy drug, as antimetabolite, when using separately, the enhancing of toleration usually causes the treatment failure.
In addition, the cancer drug therapy of low dosage not only can increase the Drug tolerance of cancerous cell, but also can promote its infiltrative growth "; referring to beam etc. " increased the Drug tolerance of human lung carcinoma cell and external wetting capacity after the cancer therapy drug pulse screening and with the change of gene expression " " international journal of cancer " 111 phase 484-93 page or leaf (2004) (Liang Y; etal., Int J Cancer.2004; 111 (4): 484-93).
Therefore, the present invention is directed to the deficiencies in the prior art, a kind of anticancer pharmaceutical composition is provided, more specifically, be entity-tumor-resistant medicine composition, this pharmaceutical composition can suppress growth of tumour cell effectively by the generation that reduces toleration, thereby can better treat tumor, reduce recurrence.
(3) summary of the invention
The present invention is directed to the deficiencies in the prior art, a kind of anticancer medicine slow-release preparation containing that contains antimetabolite and synergist thereof is provided, particularly, is a kind of slow releasing injection and sustained-release implant that contains antimetabolite and/or its synergist.
The antimetabolite synergist is the cancer therapy drug that is selected from steroids anti-cancer drugs and/or platinum-like compounds.The cancer therapy drug decapacitation suppresses can also increase the sensitivity of tumor cell to cancer therapy drug outside the tumor growth.
The present invention finds that many medicines and antimetabolite share its antitumaous effect is strengthened mutually, below the antimetabolite antitumaous effect will be increased mutually medicine be referred to as the antimetabolite synergist.The combination of antimetabolite or antimetabolite and its synergist is made drug level that anticancer medicine slow-release preparation containing (being mainly slow releasing injection and sustained-release implant) not only can greatly improve tumor by local, reduces the drug level of medicine in blood circulation, is reduced the toxicity of medicine to normal structure, can also greatly make things convenient for the medicine injection, reduce operation technique complication, reduce patient's expense.But not only potentiation of medication combined application also can reduce the side effect of treatment.The above unexpected main contents of the present invention of finding to constitute.
A kind of form of antimetabolite slow releasing agent of the present invention is a slow releasing injection, is made up of sustained-release micro-spheres and solvent.Particularly, this slow-releasing anticarcinogen injection is grouped into by following one-tenth:
(A) sustained-release microparticle, the one-tenth following by percentage by weight is grouped into:
Biological effective components 0.5-60%
Slow-release auxiliary material 41-99.9%
Suspending agent 0.0-30%
(B) solvent is divided into common solvent and special solvent.
Wherein, common solvent comprises the buffer that distilled water, water for injection, physiology are prepared towards liquid, dehydrated alcohol or various salt; Special solvent is the common solvent that contains suspending agent, and 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.When the suspending agent in the sustained-release microparticle (A) was " 0 ", solvent (B) was special solvent.
Sustained-release microparticle of the present invention is made up of effective medicinal components and slow-release auxiliary material and/or suspending agent, wherein, effective ingredient can be antimetabolite and/or antimetabolite synergist, and the antimetabolite synergist is selected from steroids anti-cancer drugs and/or platinum-like compounds.
The percentage by weight of effective ingredient in medicament slow-release microsphere is 0.5%-60%, is good with 2%-40%, is best with 5%-30%.
Slow-release auxiliary material is selected from one of copolymer (PLGA), xylitol, oligosaccharide, chrondroitin, chitin, hyaluronic acid, collagen protein, gelatin and white tempera of polifeprosan, bis-fatty acid and decanedioic acid copolymer (PFAD-SA), poly-(erucic acid dimer-decanedioic acid) [P (EAD-SA)], poly-(fumaric acid-decanedioic acid) [P (FA-SA)], ethylene vinyl acetate copolymer (EVAc), polylactic acid (PLA), polyglycolic acid and hydroxyacetic acid or its combination; 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.
Antimetabolite is selected from one of following or combination: as pemetrexed, pemetrexed disodium, Rumi Qu Sai, thunder for song account for, his shore of Raltitrexed, 2-Amino-6-methyl-5-(pyridin-4-ylsulfanyl)-3H-quinazolin-4-one, carmofur, dexrazoxane, ftorafur, temozolomide, zalcitabine, emtricitabine, galocitabine, ibacitabine, ancitabine, decitabine, flurocitabine, enocitabine, imidazoles, capecitabine, gemcitabine, fludarabine, cladribine etc.
The percentage by weight of above-mentioned antimetabolitas in compositions is good from 1%-50% with 5%-30%.
Antimetabolite is selected from one of following or combination: above antimetabolite 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.
Platinum-like compounds is selected from cisplatin, carboplatin, ormaplatin, dexormaplatin, heptan platinum, lobaplatin, nedaplatin, ring platinum, oxaliplatin, DNA-2114, cis-Dichlorobis(cyclopentylamine)platinum, platinum blue, cis-Dichlorobis(cyclopropylamine)platinum, Ethylenediammineplatinum(II) malonate, CL 286558., enloplatin, sulfatodiamino cyclohexane platinum, Spiroplatin, iproplatin, rice platinum, pick up platinum, sebriplatin, spiroplatin, zeniplatin.With cisplatin, carboplatin, ormaplatin, dexormaplatin, heptan platinum, lobaplatin, nedaplatin or oxaliplatin serve as preferred.
Above-mentioned platinum-like compounds shared ratio in compositions is decided because of concrete condition, can be 0.1%-50%, is good with 1%-40%, and 5%-30% is best.
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; 5-pentafluoropentylsulfinyl) nonyl] estra-1; 3; 5 (10)-triene-3; 17 beta-diol; ICI 182780); 4-trans-Hydroxytamoxifen (4-hydroxytamoxifen); γ-linoleic acid (gamma-linolenic acid); 2-methoxyestradiol (2-methoxyestradiol); moxestrol (moxestrol); 4-trans-Hydroxytamoxifen (4-hydroxytamoxifen); 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 (Casodex); 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; Anastrozole and exemestane or testolactone.
Above steroids anti-cancer drugs can singly select or multiselect, with triptorelin, goserelin, leuprorelin, Anastrozole, idoxifene, Miproxifene, tamoxifen, 4-monohydroxy tamoxifen (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, Anastrozole, 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, Acapodene 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 compositions is 0.01%-60%, is good with 1%-40%, is best with 5%-30%, more than all be weight percentage.
When the cancer therapy drug in the medicament slow-release microsphere only is antimetabolite or antimetabolite synergist, slow-releasing anticarcinogen injection is mainly used in the antimetabolite of other approach application of increase or the action effect of antimetabolite synergist, or is used for the potentiation to radiotherapy or other therapies.When the cancer therapy drug in the medicament slow-release microsphere only was antimetabolite or its synergist, the application of slow-releasing anticarcinogen injection and potentiation mode were:
(1) contain the slow releasing injection local injection of antimetabolite, and the antimetabolite synergist is used through other approach;
(2) local injection contains the slow releasing injection of antimetabolite synergist, and other approach are used antimetabolite;
(3) local injection contains the slow releasing injection and the slow releasing injection that contains the antimetabolite synergist of antimetabolite; Or
(4) local injection contains the slow releasing injection of antimetabolite and synergist.
Therefore, antimetabolite and antimetabolite synergist can be packed individually or simultaneously, can be successively, simultaneously or alternate application.
The slow-releasing anticarcinogen injection of topical application also is used for the potentiation to radiotherapy, micro-wave therapeutic or other therapies.Other approach refer to, but, be not limited to tremulous pulse, vein, abdominal cavity, subcutaneous, intracavitary administration.
Anticancer effective component antimetabolite and/or the percentage by weight of antimetabolite synergist in medicament slow-release microsphere are 0.5%-60%, are good with 1%-40%, are best with 5%-30%.The weight ratio of antimetabolite and antimetabolite synergist is 1-9: 1 to 1: 1-9, with 1-2: 1 serves as preferred.
Anticancer effective component is a kind of or several antimetabolites and/or combination a kind of or several metabolic drug synergists in the anticancer pharmaceutical composition of the present invention.Anticancer effective component in the slow-releasing anticarcinogen injection microsphere of the present invention is preferably as follows, and all is weight percentage:
(1) pemetrexed of 1-40%, pemetrexed disodium, Rumi Qu Sai, thunder for song account for, his shore of Raltitrexed, 2-Amino-6-methyl-5-(pyridin-4-ylsulfanyl)-3H-quinazolin-4-one, carmofur, dexrazoxane, ftorafur, temozolomide, zalcitabine, emtricitabine, galocitabine, ibacitabine, ancitabine, decitabine, flurocitabine, enocitabine, imidazoles, capecitabine, gemcitabine, fludarabine, cladribine;
(2) cisplatin of 1-40%, carboplatin, ormaplatin, dexormaplatin, heptan platinum, lobaplatin, nedaplatin, ring platinum, oxaliplatin, DNA-2114, cis-Dichlorobis(cyclopentylamine)platinum, platinum blue, cis-Dichlorobis(cyclopropylamine)platinum, Ethylenediammineplatinum(II) malonate, CL 286558., enloplatin, sulfatodiamino cyclohexane platinum, Spiroplatin, iproplatin, rice platinum, pick up platinum, sebriplatin, spiroplatin or zeniplatin;
(3) triptorelin of 1-40%, goserelin, leuprorelin, Anastrozole, idoxifene, Miproxifene, tamoxifen, 4-monohydroxy 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, Anastrozole, exemestane or bicalutamide;
(4) pemetrexed of 1-40%, pemetrexed disodium, Rumi Qu Sai, thunder accounts for for song, Raltitrexed, 2-Amino-6-methyl-5-(pyridin-4-ylsulfanyl)-3H-quinazolin-4-one, carmofur, dexrazoxane, ftorafur, the temozolomide, zalcitabine, emtricitabine, galocitabine, ibacitabine, ancitabine, decitabine, flurocitabine, enocitabine, his shore of imidazoles, capecitabine, gemcitabine, fludarabine, the cisplatin of cladribine and 1-40%, carboplatin, ormaplatin, dexormaplatin, heptan platinum, lobaplatin, nedaplatin, ring platinum, oxaliplatin, DNA-2114, cis-Dichlorobis(cyclopentylamine)platinum, platinum blue, cis-Dichlorobis(cyclopropylamine)platinum, Ethylenediammineplatinum(II) malonate, CL 286558., enloplatin, sulfatodiamino cyclohexane platinum, Spiroplatin, iproplatin, rice platinum, pick up platinum, sebriplatin, the combination of spiroplatin or zeniplatin;
(5) pemetrexed of 1-40%, pemetrexed disodium, Rumi Qu Sai, thunder accounts for for song, Raltitrexed, 2-Amino-6-methyl-5-(pyridin-4-ylsulfanyl)-3H-quinazolin-4-one, carmofur, dexrazoxane, ftorafur, the temozolomide, zalcitabine, emtricitabine, galocitabine, ibacitabine, ancitabine, decitabine, flurocitabine, enocitabine, his shore of imidazoles, capecitabine, gemcitabine, fludarabine, the triptorelin of cladribine and 1-40%, goserelin, leuprorelin, Anastrozole, idoxifene, Miproxifene, tamoxifen, 4-monohydroxy 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, Anastrozole, the combination of exemestane or bicalutamide;
(6) cisplatin of 1-40%, carboplatin, ormaplatin, dexormaplatin, heptan platinum, lobaplatin, nedaplatin, ring platinum, oxaliplatin, DNA-2114, cis-Dichlorobis(cyclopentylamine)platinum, platinum blue, cis-Dichlorobis(cyclopropylamine)platinum, Ethylenediammineplatinum(II) malonate, CL 286558., enloplatin, sulfatodiamino cyclohexane platinum, Spiroplatin, iproplatin, rice platinum, pick up platinum, sebriplatin, the triptorelin of spiroplatin or zeniplatin and 1-40%, goserelin, leuprorelin, Anastrozole, idoxifene, Miproxifene, tamoxifen, 4-monohydroxy 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, Anastrozole, the combination of exemestane or bicalutamide;
(7) pemetrexed of 1-40%, pemetrexed disodium, Rumi Qu Sai, thunder accounts for for song, Raltitrexed, 2-Amino-6-methyl-5-(pyridin-4-ylsulfanyl)-3H-quinazolin-4-one, carmofur, dexrazoxane, ftorafur, the temozolomide, zalcitabine, emtricitabine, galocitabine, ibacitabine, ancitabine, decitabine, flurocitabine, enocitabine, his shore of imidazoles, capecitabine, gemcitabine, the cisplatin of fludarabine or cladribine and 1-40%, carboplatin, ormaplatin, dexormaplatin, heptan platinum, lobaplatin, nedaplatin, ring platinum, oxaliplatin, DNA-2114, cis-Dichlorobis(cyclopentylamine)platinum, platinum blue, cis-Dichlorobis(cyclopropylamine)platinum, Ethylenediammineplatinum(II) malonate, CL 286558., enloplatin, sulfatodiamino cyclohexane platinum, Spiroplatin, iproplatin, rice platinum, pick up platinum, sebriplatin, the triptorelin of spiroplatin or zeniplatin and 1-40%, goserelin, leuprorelin, Anastrozole, idoxifene, Miproxifene, tamoxifen, 4-monohydroxy 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, Anastrozole, the combination of exemestane or bicalutamide.
Slow-release auxiliary material be bio-capacitivity, can (or non-) degraded and absorbed polymer, copolymer (PLGA), ethylene vinyl acetate copolymer (EVAc), polifeprosan, bis-fatty acid and the decanedioic acid copolymer of preferred silicone rubber, polylactic acid (PLA), polyglycolic acid and hydroxyacetic acid, poly-(erucic acid dimer-decanedioic acid) copolymer, gather one of (fumaric acid-decanedioic acid) copolymer or its combination.Its percentage by weight in medicament slow-release microsphere is 41-99.9%.
When slow-release auxiliary material was selected the copolymer (PLGA) of polylactic acid (PLA), polyglycolic acid (PGA), polylactic acid (PLA) and mixture, glycolic and the hydroxy carboxylic acid of polyglycolic acid for use, PLA and PLGA content percentage by weight were respectively 0.1-99.9% and 99.9-0.1%.The molecular weight peak value of polylactic acid can be, but is not limited to, 5000-300, and 000, but with 20,000-100,000 is preferred, with 30,000-50,000 for most preferably; The molecular weight of polyglycolic acid can be, but is not limited to, 5000-300, and 000, but with 20,000-100,000 is preferred, with 30,000-50,000 for most preferably; Above polyhydroxy acid can singly select or multiselect.When singly selecting, serve as preferred with the copolymer (PLGA) of polylactic acid (PLA) or hydroxy carboxylic acid and glycolic, the molecular weight of copolymer can be, but is not limited to, 5000-300,000, but with 20,000-10,000 be preferably, with 30,000-50,000 for most preferably; When multiselect, compound polymer or the copolymer formed with macromolecule polymer or different macromolecule polymer serve as preferred, with the compound polymer that contains different molecular weight polylactic acid or decanedioic acid or copolymer for most preferably, as, but be not limited to, molecular weight is 1000 to 30000 polylactic acid with molecular weight is that 20000 to 50000 polylactic acid mixes, molecular weight is 10000 to 30000 polylactic acid with molecular weight is that 30000 to 80000 PLGA mixes, molecular weight is that 20000 to 30000 polylactic acid mixes with decanedioic acid, molecular weight is that 30000 to 80000 PLGA mixes with decanedioic acid.
In addition, in various high molecular polymers, with polylactic acid, decanedioic acid, the mixture or the copolymer that contain the macromolecule polymer of polylactic acid or decanedioic acid 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, glycolic and hydroxy carboxylic acid, decanedioic acid and fragrant polyanhydride or aliphatic polyanhydride.The blend ratio of glycolic and hydroxy carboxylic acid is 10/90-90/10 (weight), preferably 25/75-75/25 (weight).The method of blend is arbitrarily.Content when glycolic and hydroxy carboxylic acid copolymerization is respectively percentage by weight 10-90% and 90-10%.The representative of fragrance polyanhydride is polifeprosan [poly-(1,3-two (to the carboxyl phenoxy group) propane-decanedioic acid) (p (CPP-SA)), bis-fatty acid-decanedioic acid copolymer (PFAD-SA)], poly-(erucic acid dimer-decanedioic acid) [P (EAD-SA)] and poly-(fumaric acid-decanedioic acid) [P (FA-SA)] etc.Content during to carboxylic phenoxypropane (p-CPP) and decanedioic acid copolymerization is respectively percentage by weight 10-60% and 20-90%, and the blend weight ratio is 10-40: 50-90, preferably weight ratio 15-30: 65-85.
Except that above-mentioned adjuvant, also can select for use other materials to see the United States Patent (USP) (patent No. 4757128; 4857311; 4888176; 4789724) and in " pharmaceutic adjuvant complete works " (the 123rd page, Sichuan science tech publishing house published in 1993, Luo Mingsheng and Gao Tianhui chief editor) have a detailed description.In addition, Chinese patent (application number 96115937.5; 91109723.6; 9710703.3; 01803562.0) and U.S.'s patent of invention (patent No. 5,651,986) also enumerated some pharmaceutic adjuvant, comprise filler, solubilizing agent, absorption enhancer, film former, gellant, system (or causing) hole agent, excipient or blocker etc.
For regulating drug releasing rate or changing other characteristic of the present invention, can change the composition and the proportioning of monomer component or molecular weight, interpolation or the adjusting pharmaceutic adjuvant of polymer, add the water-soluble low-molecular chemical compound, as, but be not limited to various sugar or salt etc.Wherein sugar can be, but is not limited to, xylitol, oligosaccharide, (sulphuric acid) chrondroitin and chitin etc., and wherein salt can be, but is not limited to, potassium salt and sodium salt etc.
Suspending agent be used for preparation and/or effectively suspend, stable and/or protect various medicines or sustained-release micro-spheres (or microcapsule), thereby make prepared injection injectivity good, be not easy obstruction, good stability, be difficult for layering, the viscosity height.
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.
The viscosity of suspending agent is 100cp-3000cp (20 ℃-30 ℃ time), preferred 1000cp-3000cp (20 ℃-30 ℃ time), most preferably 1500cp-3000cp (20 ℃-30 ℃ time).
The application of solvent refers to that mainly the application of special solvent is effective suspension, stablizes and/or protects various medicines or sustained-release micro-spheres (or microcapsule), thereby prepares corresponding injection.The application of special solvent can make prepared injection have better injectivity, stability and higher viscosity.
Common solvent can be, but is not limited to, the buffer that distilled water, water for injection, physiology are prepared towards liquid, dehydrated alcohol or various salt, and pharmacopeia has respective specified; The special solvent of indication of the present invention is the common solvent that contains suspending agent, suspending agent can be, but be not limited to 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.The content of suspending agent is 0.1-30% volume weight percentage ratio in the special solvent, is preferably as follows:
A) 0.5-5% sodium carboxymethyl cellulose; Or
B) 0.5-5% sodium carboxymethyl cellulose and 0.1-0.5% Tween 80; Or
C) 5-20% mannitol; Or
D) 5-20% mannitol and 0.1-0.5% Tween 80; Or
E) 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.
The content of suspending agent is decided because of the medicine that solvent suspended, composition, character and the requirement thereof of sustained-release micro-spheres (or microcapsule), the preparation method of injection and the kind and the composition thereof of suspending agent, as, sodium carboxymethyl cellulose can be 0.5-5%, but with 1-3% is preferred, mannitol and/or sorbitol are 5-30%, but is preferred with 10-20%, and soil temperature 20, soil temperature 40 or soil temperature 80 are 0.05-2%, but are preferred with 0.10-0.5%.In most cases, sustained-release microparticle is made up of effective ingredient and slow-release auxiliary material, and solvent is special solvent.When solvent was common solvent, medicine that is suspended or sustained-release micro-spheres (or microcapsule) then were made up of effective ingredient, slow-release auxiliary material and/or suspending agent.In other words, when the suspending agent in the sustained-release microparticle (A) was " 0 ", solvent (B) was special solvent, and when the suspending agent in the sustained-release microparticle (A) was not " 0 ", solvent (B) can be common solvent or special solvent.The viscosity of suspending agent is 100cp-3000cp (20 ℃-30 ℃ time), preferred 1000cp-3000cp (20 ℃-30 ℃ time), most preferably 1500cp-3000cp (20 ℃-30 ℃ time).
The preparation of injection comprises that the preparation of preparation, solvent of sustained-release micro-spheres or drug microparticles and sustained-release micro-spheres or drug microparticles suspend, and make injection at last in solvent.
Wherein, sustained-release micro-spheres or drug microparticles can prepare with some kinds of methods: as, but be not limited to, mixing method, fusion method, dissolution method, spray drying method for preparation microsphere, dissolution method are in conjunction with freezing (drying) comminuting method, liposome bag medicine method and emulsion process etc.Serve as preferred wherein with dissolution method (being the solvent volatility process), freezing (drying) comminuting method, seasoning, spray drying method and emulsion process.Microsphere then can be used for preparing above-mentioned various slow releasing injection.The particle diameter of suspended drug or sustained-release micro-spheres (or microcapsule) decide because of specifically needing, and can be, but be not limited to, 1-300um, but be that preferably 30-150um most preferably with 20-200um.Medicine or sustained-release micro-spheres can be made into microsphere, sub-micro ball, microemulsion, nanosphere, granule or spherical piller.Slow-release auxiliary material is above-mentioned bio-capacitivity, biodegradable or non-biodegradation polymer.
The kind of solvent is then depended in the preparation of solvent, and common solvent has commercially available, also can make by oneself, and as distilled water, water for injection, physiology buffer towards liquid, dehydrated alcohol or the preparation of various salt, but must be in strict accordance with related standards.Special solvent need be considered the kind of suspending agent and the medicine that composition, solvent suspended, composition, character and the requirement thereof of sustained-release micro-spheres (or microcapsule) and the preparation method of injection, as sodium carboxymethyl cellulose (1.5%)+mannitol and/or sorbitol (15%) and/or soil temperature 80 (0.1%) are dissolved in the normal saline mutually deserved solvent, viscosity is at 10cp-650cp (20 ℃-30 ℃ time).
The present invention finds to influence medicine and/or sustained-release micro-spheres suspends and/or the key factor of injection is the viscosity of solvent, and viscosity is big more, and suspension effect is good more, and syringeability is strong more.This unexpected one of main index characteristic of the present invention of finding to have constituted.The viscosity of solvent depends on the viscosity of suspending agent, and the viscosity of suspending agent is 100cp-3000cp (20 ℃-30 ℃ time), preferred 1000cp-3000cp (20 ℃-30 ℃ time), most preferably 1500cp-3000cp (20 ℃-30 ℃ time).According to the viscosity of the prepared solvent of this condition is 10cp-650cp (20 ℃-30 ℃ time), preferred 20cp-650cp (20 ℃-30 ℃ time), most preferably 60cp-650cp (20 ℃-30 ℃ time).
The preparation of injection has several different methods, and a kind of is that the sustained-release microparticle (A) of suspending agent for " 0 " directly mixed in special solvent, obtains corresponding sustained-release microparticle injection; Another kind is that suspending agent is not mixed in special solvent or common solvent for the sustained-release microparticle (A) of " 0 ", obtains corresponding sustained-release microparticle injection; Another is that sustained-release microparticle (A) is mixed in common solvent, adds the suspending agent mixing then, obtains corresponding sustained-release microparticle injection.Except, also can earlier sustained-release microparticle (A) be mixed and in special solvent, make corresponding suspension, with the moisture in ways such as the vacuum drying removal suspension, special solvent of reuse or common solvent suspendible obtain corresponding sustained-release microparticle injection afterwards then.Above method just is illustrative rather than definitive thereof the present invention.It should be noted that suspended drug or sustained-release micro-spheres (or microcapsule) concentration in injection decide because of specifically needing, can be, but be not limited to, 10-400mg/ml, but be preferably with 30-300mg/ml, with 50-200mg/ml most preferably.The viscosity of injection is 50cp-1000cp (20 ℃-30 ℃ time), preferred 100cp-1000cp (20 ℃-30 ℃ time), most preferably 200cp-650cp (20 ℃-30 ℃ time).This viscosity is applicable to 18-22 injection needle and special bigger (to 3 millimeters) injection needle of internal diameter.
The route of administration of injection depends on multiple factor.Can be in vein, lymphatic vessel, subcutaneous, muscle, intracavity (in as abdominal cavity, thoracic cavity, articular cavity and in the canalis spinalis), tissue, tumor in, reach in the bone marrow in all, the selective arterial injection of tumor, lymph node and inject.For entity tumor, though can be through above-mentioned administration, with in selective arterial, intracavity, the tumor, the injection of tumor week serves as preferred.For obtaining valid density in former or position, metastatic tumour place, also can unite and give through number of ways, in the time of as vein, lymphatic vessel, subcutaneous, muscle, intracavity (as in abdominal cavity, thoracic cavity, the articular cavity and in the canalis spinalis) or selective arterial injection in conjunction with local injection.So administering drug combinations is specially adapted to entity tumor.As in the tumor, tumor week injection time is in conjunction with systemic injection.
The application of injection is to utilize full-bodied special solvent with pastille microgranule (ball), particularly sustained-release microparticle, makes corresponding slow releasing injection, thereby corresponding medicine can be imported in the patient or mammalian body of required medicine in the mode of injection.The medicine that is injected can be, but is not limited to, said medicine micropowder or medicament slow release microgranule.
The application of injection comprises the application of the injection of making after the application of application, solvent of sustained-release micro-spheres or drug microparticles and sustained-release micro-spheres or drug microparticles suspend in solvent.
In the slow releasing injection, drug sustained release system can be made into microsphere, sub-micro ball, microemulsion, nanosphere, granule or spherical piller, makes the injection use then with after the injection solvent mixes.In various slow releasing injection, serve as preferred with the suspension type slow releasing injection, the suspension type slow releasing injection is the preparation that the drug sustained release system 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, and used solvent is common solvent or the special solvent that contains suspending agent.Common solvent is, but is not limited to the buffer that distilled water, water for injection, physiology are prepared towards liquid, dehydrated alcohol or various salt.The purpose of suspending agent is the pastille microsphere that effectively suspends, thereby is beneficial to the usefulness of injection.
Microsphere is used to prepare slow releasing injection, as suspension type slow releasing injection, gel injection, block copolymer micelle injection.In various injections, serve as preferred with the suspension type slow releasing injection.The suspension type slow releasing injection is to contain the medicament slow-release microsphere of effective composition or the preparation that drug microparticles is suspended in gained in the solvent, and used adjuvant is a kind of or its combination in the above-mentioned slow-release auxiliary material, and used solvent is common solvent or the special solvent that contains suspending agent.Common solvent is, but is not limited to the buffer that distilled water, water for injection, physiology are prepared towards liquid, dehydrated alcohol or various salt; Block copolymer micelle 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 the hydrophilic block of the Polyethylene Glycol (PEG) of 1000-15000 as the micelle copolymer, and preferred biological degradation polyalcohol (as PLA, polylactide, polycaprolactone and copolymer thereof (molecular weight 1500-25000)) is as the hydrophobic block of micelle copolymer.The particle size range of block copolymer micelle can be at 1-300um, but is preferred with 20-200um, and 30-150um most preferably; Gel injection system is dissolved in some amphipathic solvent with biological degradation polyalcohol (as PLA, PLGA or DL-LA and epsilon-caprolactone copolymer), adds medicine miscible with it (or suspendible) back again and forms 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.
Sustained-release micro-spheres also can be used for preparing sustained-release implant, used pharmaceutic adjuvant can be any or multiple material in the above-mentioned pharmaceutic adjuvant, in various high molecular polymers, be main separation, as polifeprosan with the high molecular weight water soluble polymer, bis-fatty acid and decanedioic acid copolymer (PFAD-SA), poly-(erucic acid dimer-decanedioic acid) [P (EAD-SA)], poly-(fumaric acid-decanedioic acid) [P (FA-SA)], ethylene vinyl acetate copolymer (EVAc), polylactic acid (PLA), the copolymer of polyglycolic acid and hydroxyacetic acid (PLGA), xylitol, oligosaccharide, chrondroitin, chitin, hyaluronic acid, collagen protein, one of gelatin and white tempera or its combination.
Therefore, another form of anticancer medicine slow-release preparation containing of the present invention is that anticancer medicine slow-release preparation containing is a sustained-release implant, 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 sustained-release implant is the slow releasing agent implant that biocompatibility, degradable absorb, 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, drying, promptly so-called dissolution method; (iv) spray drying method; And (v) freeze-drying etc.
The application of anti-cancer sustained-released implantation agent and the same slow releasing injection of potentiation mode, sustained-release implant anticancer effective component and the same slow releasing injection of percentage by weight thereof, but be preferably:
(1) pemetrexed of 5-30%, pemetrexed disodium, Rumi Qu Sai, thunder for song account for, his shore of Raltitrexed, 2-Amino-6-methyl-5-(pyridin-4-ylsulfanyl)-3H-quinazolin-4-one, carmofur, dexrazoxane, ftorafur, temozolomide, zalcitabine, emtricitabine, galocitabine, ibacitabine, ancitabine, decitabine, flurocitabine, enocitabine, imidazoles, capecitabine, gemcitabine, fludarabine, cladribine;
(2) cisplatin of 5-30%, carboplatin, ormaplatin, dexormaplatin, heptan platinum, lobaplatin, nedaplatin, ring platinum, oxaliplatin, DNA-2114, cis-Dichlorobis(cyclopentylamine)platinum, platinum blue, cis-Dichlorobis(cyclopropylamine)platinum, Ethylenediammineplatinum(II) malonate, CL 286558., enloplatin, sulfatodiamino cyclohexane platinum, Spiroplatin, iproplatin, rice platinum, pick up platinum, sebriplatin, spiroplatin or zeniplatin;
(3) triptorelin of 5-30%, goserelin, leuprorelin, Anastrozole, idoxifene, Miproxifene, tamoxifen, 4-monohydroxy 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, Anastrozole, exemestane or bicalutamide;
(4) pemetrexed of 2-30%, pemetrexed disodium, Rumi Qu Sai, thunder accounts for for song, Raltitrexed, 2-Amino-6-methyl-5-(pyridin-4-ylsulfanyl)-3H-quinazolin-4-one, carmofur, dexrazoxane, ftorafur, the temozolomide, zalcitabine, emtricitabine, galocitabine, ibacitabine, ancitabine, decitabine, flurocitabine, enocitabine, his shore of imidazoles, capecitabine, gemcitabine, fludarabine, the cisplatin of cladribine and 2-30%, carboplatin, ormaplatin, dexormaplatin, heptan platinum, lobaplatin, nedaplatin, ring platinum, oxaliplatin, DNA-2114, cis-Dichlorobis(cyclopentylamine)platinum, platinum blue, cis-Dichlorobis(cyclopropylamine)platinum, Ethylenediammineplatinum(II) malonate, CL 286558., enloplatin, sulfatodiamino cyclohexane platinum, Spiroplatin, iproplatin, rice platinum, pick up platinum, sebriplatin, the combination of spiroplatin or zeniplatin;
(5) pemetrexed of 2-30%, pemetrexed disodium, Rumi Qu Sai, thunder accounts for for song, Raltitrexed, 2-Amino-6-methyl-5-(pyridin-4-ylsulfanyl)-3H-quinazolin-4-one, carmofur, dexrazoxane, ftorafur, the temozolomide, zalcitabine, emtricitabine, galocitabine, ibacitabine, ancitabine, decitabine, flurocitabine, enocitabine, his shore of imidazoles, capecitabine, gemcitabine, fludarabine, the triptorelin of cladribine and 2-30%, goserelin, leuprorelin, Anastrozole, idoxifene, Miproxifene, tamoxifen, 4-monohydroxy 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, Anastrozole, the combination of exemestane or bicalutamide;
(6) cisplatin of 2-30%, carboplatin, ormaplatin, dexormaplatin, heptan platinum, lobaplatin, nedaplatin, ring platinum, oxaliplatin, DNA-2114, cis-Dichlorobis(cyclopentylamine)platinum, platinum blue, cis-Dichlorobis(cyclopropylamine)platinum, Ethylenediammineplatinum(II) malonate, CL 286558., enloplatin, sulfatodiamino cyclohexane platinum, Spiroplatin, iproplatin, rice platinum, pick up platinum, sebriplatin, the triptorelin of spiroplatin or zeniplatin and 2-30%, goserelin, leuprorelin, Anastrozole, idoxifene, Miproxifene, tamoxifen, 4-monohydroxy 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, Anastrozole, the combination of exemestane or bicalutamide;
(7) pemetrexed of 2-30%, pemetrexed disodium, Rumi Qu Sai, thunder accounts for for song, Raltitrexed, 2-Amino-6-methyl-5-(pyridin-4-ylsulfanyl)-3H-quinazolin-4-one, carmofur, dexrazoxane, ftorafur, the temozolomide, zalcitabine, emtricitabine, galocitabine, ibacitabine, ancitabine, decitabine, flurocitabine, enocitabine, his shore of imidazoles, capecitabine, gemcitabine, the cisplatin of fludarabine or cladribine and 2-30%, carboplatin, ormaplatin, dexormaplatin, heptan platinum, lobaplatin, nedaplatin, ring platinum, oxaliplatin, DNA-2114, cis-Dichlorobis(cyclopentylamine)platinum, platinum blue, cis-Dichlorobis(cyclopropylamine)platinum, Ethylenediammineplatinum(II) malonate, CL 286558., enloplatin, sulfatodiamino cyclohexane platinum, Spiroplatin, iproplatin, rice platinum, pick up platinum, sebriplatin, the triptorelin of spiroplatin or zeniplatin and 1-40%, goserelin, leuprorelin, Anastrozole, idoxifene, Miproxifene, tamoxifen, 4-monohydroxy 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, Anastrozole, the combination of exemestane or bicalutamide.
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.In addition, the effective ingredient of anti-cancer sustained-released implantation agent also can be packaged in the liposome equably, or makes microsphere with art methods.
Anticancer implant is multiple shape, as, but be not limited to granule, tablet, powder, granule, sphere, bulk, needle-like, bar-shaped, column and membranaceous.Its volume is decided because of clinical needs, can be 0.5-2.0cm (diameter) * 0.01-0.5cm (thickness) as tablet, serves as preferred with 1-1.5 * 0.1-0.3cm; Stick can be 0.1-2.0cm (length) * 0.05-0.8cm (external diameter), serves as preferred with 0.3-1.0cm * 0.1-0.5cm.Its most preferred dosage form is the implantation slow release agent that biocompatibility, degradable absorb, and can make different shape and various dosage form because of the clinical needs of difference, as, but be not limited to slow releasing agent implant, granule, capsule, ball, ball, diffusing, excellent.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, drying, promptly so-called dissolution method; (iv) spray drying method; And (v) freeze-drying etc.
The anticancer effective component of anti-cancer sustained-released implantation agent of the present invention and percentage by weight are preferably as slow releasing injection.When the cancer therapy drug in the medicament slow-release microsphere only is antimetabolite or its synergist, the application of anti-cancer sustained-released implantation agent and the same slow releasing injection of potentiation mode.
Anti-cancer sustained-released implantation agent of the present invention can give through number of ways, in number of ways, with topical, as with in selective arterial, intracavity, the tumor, tumor week be placed as the master, with in the tumor, the form that slowly discharges of tumor week or tumor chamber serve as preferably, directly to be placed as the best in the tumor body.
The consumption of cancer therapy drug depends on several factors, as, but be not limited to gross tumor volume, patient body weight, administering mode, disease progression situation and therapeutic response.Generally speaking, antimetabolite and synergist thereof can be 0.01-1000 milligram/kg body weight, with 1-800 milligram/kg body weight is ideal, with 5-80 milligram/kg body weight for the most desirable, hormone anti-cancer medicine can be 0.01-500 milligram/kg body weight, with 1-100 milligram/kg body weight is ideal, with 5-50 milligram/kg body weight for the most desirable.
Route of administration depends on multiple factor, for obtain valid density in former or position, metastatic tumour place, medicine can give through number of ways, as in subcutaneous, intracavity (in abdominal cavity, thoracic cavity and canalis spinalis), the tumor, in all injections of tumor or placement, selective arterial injection, the lymph node and injection in the bone marrow.With in selective arterial injection, intracavity, the tumor, tumor week injection or be placed as preferred.When the cancer therapy drug in the medicament slow-release microsphere only is antimetabolite or its synergist, the application of anti-cancer sustained-released implantation agent and the same slow releasing injection of potentiation mode.
The present invention can be used to prepare the pharmaceutical preparation of the various tumors for the treatment of people and animal, be mainly slow releasing injection or sustained-release 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 slow releasing injection that the present invention is made or the sustained-release implant, as, but be not limited to antibiotics, antalgica, anticoagulant medicine, hemorrhage etc.
By following test and embodiment technical method of the present invention is further described:
The local drug concentration that test 1, different modes are used behind the antimetabolite (pemetrexed) compares
With the rat is subjects, with 2 * 10
5Individual prostate tumor cells subcutaneous injection is in its hypochondrium, treats behind tumor growth to 1 cm diameter its grouping.Every group of dosage is the 5mg/kg pemetrexed.Measure medicament contg (%) in the different time tumor, the result shows, the local drug concentration significant difference of pemetrexed after different modes is used, topical can obviously improve and effectively keep the active drug concentration at position, tumor place, and is wherein best with the effect of placing sustained-release implant and intratumor injection slow releasing injection in the tumor.Yet, intratumor injection slow releasing injection operation most convenient, easy.This discovery constitutes key character of the present invention.Following relevant inhibition test has further confirmed this point.
The interior tumor-inhibiting action of body that test 2, different modes are used behind the antimetabolite (Raltitrexed) compares
With the rat is subjects, with 2 * 10
5Individual prostate tumor cells subcutaneous injection is in its hypochondrium, treats behind tumor growth to 0.5 cm diameter its grouping.Every group of dosage is the 5mg/kg Raltitrexed.The treatment back was measured gross tumor volume size, relatively therapeutic effect on the 10th day.The result shows, the tumor-inhibiting action significant difference of Raltitrexed after different modes is used, topical can obviously improve and effectively keep the active drug concentration at position, tumor place, and is wherein best with the effect of placing sustained-release implant and intratumor injection slow releasing injection in the tumor.Yet, intratumor injection slow releasing injection operation most convenient, easy.Good effect not only, toxic and side effects is also little.
Test 3, contain the tumor-inhibiting action of antimetabolite and antimetabolite synergist
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 matched group and treatment group (1-11).The treatment component is antimetabolite group, antimetabolite synergist group, antimetabolite and antimetabolite synergist group.Drug dose is 5mg/kg, and antimetabolite is through intratumor injection, and the antimetabolite synergist is through lumbar injection.The treatment back was measured gross tumor volume size, relatively therapeutic effect (seeing Table 1) on the 10th day.
Table 1
| Group | Antimetabolite | Synergist | Tumor control rate (%) | The P value |
| 1 | + | - | 20 | * |
| 2 | - | Triptorelin | 42 | * |
| 3 | - | Goserelin | 38 | * |
| 4 | - | Leuprorelin | 46 | * |
| 5 | - | Anastrozole | 48 | * |
| 6 | - | Idoxifene | 36 | * |
| 7 | + | Triptorelin | 76 | ** |
| 8 | + | Goserelin | 82 | ** |
| 9 | + | Leuprorelin | 86 | ** |
| 10 | + | Anastrozole | 76 | ** |
| 11 | + | Idoxifene | 68 | ** |
Above result shows, antimetabolite (carmofur) and used antimetabolite synergist (triptorelin, goserelin, leuprorelin, Anastrozole, idoxifene) all have significant inhibitory effect (*: the P value is less than 0.05) to tumor growth when this concentration is used separately, can show the potentiation (* *: the P value is less than 0.001) of highly significant when use in conjunction.
The tumor-inhibiting action of test 4, antimetabolite and antimetabolite synergist (slow releasing injection)
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.Antimetabolite and antimetabolite synergist are added in 24 hours the various tumor cells of In vitro culture by 10ug/ml concentration, 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 | Replace | A | B | C | D | E | For+A | For+B | For+C | For+D | For+E |
| CNS | 38 | 40 | 46 | 38 | 42 | 42 | 80 | 74 | 80 | 86 | 84 |
| C6 | 32 | 52 | 46 | 36 | 44 | 40 | 88 | 84 | 84 | 84 | 92 |
| SA | 36 | 50 | 52 | 40 | 52 | 42 | 82 | 84 | 80 | 82 | 82 |
| BC | 48 | 48 | 40 | 44 | 52 | 54 | 80 | 80 | 78 | 76 | 84 |
| BA | 28 | 48 | 38 | 48 | 42 | 46 | 80 | 80 | 92 | 92 | 82 |
| LH | 28 | 56 | 44 | 54 | 48 | 50 | 90 | 80 | 94 | 76 | 92 |
| PAT | 38 | 44 | 40 | 50 | 40 | 52 | 80 | 78 | 86 | 86 | 88 |
Above result shows, the temozolomide) and antimetabolite synergist (A wherein: Miproxifene used antimetabolite (replaces:, B: tamoxifen, C: not former times sweet smell, D: raloxifene, E: ICI-M 164384) growth all has the obvious suppression effect to kinds of tumor cells when this concentration is used separately, can show significant potentiation when use in conjunction.
The tumor-inhibiting action of test 5, antimetabolite and antimetabolite synergist (slow releasing injection)
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.Antimetabolite and antimetabolite synergist are added in 24 hours the various tumor cells of In vitro culture by 10ug/ml concentration, continue to cultivate counting cells sum after 48 hours.Its growth of tumour cell suppresses effect (%) and is shown in Table 5.The result shows, growth all has obvious suppression effect (P＜0.05) to kinds of tumor cells when using separately for used antimetabolite (emtricitabine) and antimetabolite synergist (anticancer steroid alkene phenol, Drogenil, aminoglutethimide, (.+-.)-Pyridoglutethimide, megestrol), can show significant potentiation (P＜0.01) when use in conjunction.Further test shows, so obvious synergistic effect also sees pemetrexed, pemetrexed disodium, Rumi Qu Sai, thunder accounts for for song, Raltitrexed, 2-Amino-6-methyl-5-(pyridin-4-ylsulfanyl)-3H-quinazolin-4-one, carmofur, dexrazoxane, ftorafur or temozolomide and triptorelin, goserelin, leuprorelin, Anastrozole, idoxifene, Miproxifene, tamoxifen, 4-monohydroxy 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, Anastrozole, the combination of exemestane or bicalutamide.
The tumor-inhibiting action of test 6, antimetabolite and antimetabolite synergist (slow releasing injection)
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 negative control (blank), single therapy group (antimetabolite or antimetabolite synergist) and therapeutic alliance group (antimetabolite and antimetabolite synergist).Medicine is through intratumor injection.Dosage is 5mg/kg.The treatment back was measured the gross tumor volume size on the 10th day, made relatively therapeutic effect of index with inhibition rate of tumor growth.The result shows, growth all has obvious suppression effect (P＜0.05) to kinds of tumor cells when using separately for used antimetabolite (galocitabine) and antimetabolite synergist (medroxyprogesterone, toremifene, Anastrozole, exemestane), can show significant potentiation (P＜0.01) when use in conjunction.Further test shows, so obvious synergistic effect also sees zalcitabine, emtricitabine, galocitabine, ibacitabine, ancitabine, decitabine, flurocitabine, enocitabine, his shore of imidazoles, capecitabine, gemcitabine, fludarabine or cladribine and triptorelin, goserelin, leuprorelin, Anastrozole, idoxifene, Miproxifene, tamoxifen, 4-monohydroxy 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, the combination of exemestane or bicalutamide.
The tumor-inhibiting action of test 7, antimetabolite and antimetabolite synergist (slow releasing injection)
With the rat is subjects, with 2 * 10
5Individual breast tumor cell subcutaneous injection is in its hypochondrium, treats that tumor growth after 14 days is divided into it negative control (blank), single therapy group, therapeutic alliance group.The antimetabolite synergist is through intratumor injection, and antimetabolite is through lumbar injection.Dosage is 5mg/kg.The treatment back was measured the gross tumor volume size on the 10th day, made relatively therapeutic effect (seeing Table 3) of index with inhibition rate of tumor growth.
Table 3
| Test group (n) | Suffered treatment | Tumor control rate (%) | The P value |
| 1(6) | Contrast | - | |
| 2(6) | Ibacitabine | 32 | ＜0.05 |
| 3(6) | Cisplatin | 54 | ＜0.01 |
| 4(6) | Carboplatin | 58 | ＜0.01 |
| 5(6) | Heptan platinum | 54 | ＜0.01 |
| 6(6) | Lobaplatin | 58 | ＜0.01 |
| 7(6) | Ibacitabine+cisplatin | 86 | ＜0.001 |
| 8(6) | Ibacitabine+carboplatin | 80 | ＜0.001 |
| 9(6) | Ibacitabine+heptan platinum | 88 | ＜0.001 |
| 10(6) | Ibacitabine+lobaplatin | 90 | ＜0.001 |
Above result shows, growth all has the obvious suppression effect to kinds of tumor cells when this concentration is used separately, can show significant potentiation when use in conjunction for used antimetabolite and antimetabolite synergist-platinum-like compounds (cisplatin, carboplatin, heptan platinum, lobaplatin).
The tumor-inhibiting action of test 8, antimetabolite and antimetabolite synergist (sustained-release implant)
With the rat is subjects, with 2 * 10
5Individual breast tumor cell subcutaneous injection is in its hypochondrium, treats that tumor growth after 14 days is divided into it negative control (blank), single therapy group, therapeutic alliance group.Sustained-release implant is placed in tumor.Dosage is 5mg/kg.The treatment back was measured the gross tumor volume size on the 10th day, made relatively therapeutic effect (seeing Table 4) of index with inhibition rate of tumor growth.
Table 4
| Test group (n) | Suffered treatment | Tumor control rate (%) | The P value |
| 1(6) | Contrast | - | |
| 2(6) | Ancitabine | 68 | ＜0.05 |
| 3(6) | Nedaplatin | 52 | ＜0.05 |
| 4(6) | Ring platinum | 46 | ＜0.05 |
| 5(6) | Oxaliplatin | 66 | ＜0.05 |
| 6(6) | Heptan platinum | 46 | ＜0.01 |
| 7(6) | Ancitabine+nedaplatin | 88 | ＜0.01 |
| 8(6) | Ancitabine+ring platinum | 86 | ＜0.01 |
| 9(6) | Ancitabine+oxaliplatin | 90 | ＜0.01 |
| 10(6) | Ancitabine+heptan platinum | 94 | ＜0.001 |
Above result shows, growth all has the obvious suppression effect to kinds of tumor cells when this concentration is used separately, can show significant potentiation when use in conjunction for used antimetabolite (ancitabine) and antimetabolite synergist-platinum-like compounds (nedaplatin, ring platinum, oxaliplatin, heptan platinum).
The tumor-inhibiting action of test 9, antimetabolite synergist (sustained-release implant)
By the tumor-inhibiting action of test 8 described methods mensuration antimetabolite synergists (sustained-release implant), its inhibition rate of tumor growth sees Table 5.
Table 5
| Test group (n) | Suffered treatment | Tumor control rate (%) | The P value |
| 1(6) | Contrast | - | |
| 2(6) | Oxaliplatin | 68 | ＜0.05 |
| 3(6) | Triptorelin | 52 | ＜0.01 |
| 4(6) | Goserelin | 54 | ＜0.01 |
| 5(6) | Leuprorelin | 60 | ＜0.01 |
| 6(6) | Anastrozole | 52 | ＜0.01 |
| 7(6) | Oxaliplatin+triptorelin | 86 | ＜0.001 |
| 8(6) | Oxaliplatin+goserelin | 88 | ＜0.001 |
| 9(6) | Oxaliplatin+leuprorelin | 82 | ＜0.001 |
| 10(6) | Oxaliplatin+Anastrozole | 90 | ＜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 antimetabolite synergist (oxaliplatin) and other antimetabolite synergist (triptorelin, goserelin, leuprorelin, Anastrozole), can show significant potentiation when use in conjunction.
The tumor-inhibiting action of test 10, antimetabolite synergist (sustained-release implant)
By the tumor-inhibiting action of test 8 described methods mensuration antimetabolite synergists (sustained-release implant), its inhibition rate of tumor growth sees Table 6.
Table 6
| Test group (n) | Suffered treatment | Tumor control rate (%) | The P value |
| 1(6) | Contrast | - | |
| 2(6) | Nedaplatin | 58 | ＜0.05 |
| 3(6) | Idoxifene | 48 | ＜0.01 |
| 4(6) | Miproxifene | 38 | ＜0.01 |
| 5(6) | Tamoxifen | 42 | ＜0.01 |
| 6(6) | Sutent | 52 | ＜0.01 |
| 7(6) | Nedaplatin+idoxifene | 72 | ＜0.01 |
| 8(6) | Nedaplatin+Miproxifene | 76 | ＜0.001 |
| 9(6) | Nedaplatin+tamoxifen | 92 | ＜0.001 |
| 10(6) | The former times sweet smell of nedaplatin+not | 88 | ＜0.001 |
Above result shows, growth all has the obvious suppression effect to used other antimetabolite synergist (nedaplatin, idoxifene, Miproxifene, tamoxifen, not former times sweet smell) to kinds of tumor cells when this concentration is used separately, can show significant potentiation when use in conjunction.
The tumor-inhibiting action of test 11, antimetabolite synergist (slow releasing injection)
Measure the tumor-inhibiting action of antimetabolite synergist (slow releasing injection) by test 7 described methods, the result shows and is selected from platinum in heptan, lobaplatin, nedaplatin, DNA-2114, iproplatin, rice platinum, pick up platinum, sebriplatin, the antimetabolite synergist of spiroplatin or zeniplatin can significantly strengthen triptorelin, goserelin, leuprorelin, Anastrozole, idoxifene, Miproxifene, tamoxifen, raloxifene, ICI-M 164384, anticancer steroid alkene phenol, the 4-trans-Hydroxytamoxifen, Drogenil, aminoglutethimide, (.+-.)-Pyridoglutethimide, megestrol, medroxyprogesterone, clomifene, toremifene, letrozole, the tumor killing effect of exemestane or bicalutamide, potentiation is in 50-88% (P＜0.01).
The tumor-inhibiting action of test 12, antimetabolite and antimetabolite synergist (sustained-release implant)
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.Antimetabolite and antimetabolite synergist are added in 24 hours the various tumor cells of In vitro culture by 5ug/ml concentration, continue to cultivate counting cells sum after 48 hours.Its growth of tumour cell suppresses effect (%) and is shown in Table 7.
Table 7
| Oncocyte | Lobaplatin | Carmofur | Goserelin | Lobaplatin+carmofur | Lobaplatin+goserelin | Carmofur+goserelin | Lobaplatin+carmofur+goserelin |
| CNS | 28 | 20 | 36 | 48 | 40 | 52 | 80 |
| C6 | 30 | 42 | 48 | 66 | 64 | 60 | 86 |
| SA | 36 | 40 | 52 | 60 | 62 | 72 | 88 |
| BC | 48 | 40 | 42 | 54 | 62 | 64 | 90 |
| BA | 28 | 28 | 30 | 48 | 46 | 48 | 82 |
| LH | 28 | 36 | 44 | 54 | 68 | 60 | 94 |
| PAT | 30 | 46 | 40 | 58 | 60 | 62 | 88 |
Above result shows, growth all has certain inhibitory action to kinds of tumor cells when this concentration is used separately for used antimetabolite (carmofur) and antimetabolite synergist (lobaplatin and goserelin), but the community of the two obviously strengthens its inhibitory action.And three's use in conjunction shows the most significant potentiation.
Further test shows that so potentiation also sees 5% pemetrexed, Raltitrexed, 2-Amino-6-methyl-5-(pyridin-4-ylsulfanyl)-3H-quinazolin-4-one, carmofur, dexrazoxane, ftorafur, the temozolomide, zalcitabine, emtricitabine, galocitabine, ibacitabine, ancitabine, decitabine, flurocitabine, enocitabine, his shore of imidazoles, capecitabine, gemcitabine, fludarabine or cladribine and 5% cisplatin, carboplatin, heptan platinum, lobaplatin, nedaplatin or oxaliplatin and 5% 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, Anastrozole, the combination of exemestane or bicalutamide.
In a word, growth all had the obvious suppression effect to kinds of tumor cells when used antimetabolite and various antimetabolite synergist were used separately, can show significant potentiation when use in conjunction.Therefore, effective ingredient of the present invention is the combination of antimetabolite and/or any one antimetabolite synergist.The medicine that contains above effective ingredient can be made into sustained-release micro-spheres, and then make slow releasing injection and implant, serve as preferred wherein with the suspensoid injectio that is combined to form with the special solvent that contains suspending agent, the viscosity of the solvent of suspensoid injectio is 10cp-650cp (20 ℃-30 ℃ time), preferred 20cp-650cp (20 ℃-30 ℃ time), most preferably 60cp-650cp (20 ℃-30 ℃ time).
Slow releasing injection or sustained-release implant also can be further specified by following embodiment.Just the invention will be further described for the foregoing description and following examples, is not its content and use are imposed any restrictions.
(4) specific embodiment
Embodiment 1.
80mg polifeprosan (to carboxy phenyl propane (p-CPP): decanedioic acid (SA) is 20: 80) copolymer is put into container, add the 100ml dichloromethane, behind the dissolving mixing, add 10mg platinum in heptan and leuprorelin, shake up again the back with spray drying method for preparation contain 10% heptan platinum and the injectable microsphere of 10% leuprorelin.Then microsphere is suspended in the normal saline that contains 15% mannitol, makes corresponding suspension type slow releasing injection, viscosity is 20cp-300cp (20 ℃-30 ℃ time).The drug release time of this slow releasing injection in external normal saline is 10-15 days, is about 20-30 days at the subcutaneous drug release time of mice.
Embodiment 2.
The method step that is processed into slow releasing injection is identical with embodiment 1, but different is that contained anticancer effective component and percentage by weight thereof are:
(a) cisplatin of 5-20%, carboplatin, ormaplatin, dexormaplatin, heptan platinum, lobaplatin, nedaplatin or oxaliplatin;
(b) triptorelin of 5-30%, goserelin, leuprorelin, Anastrozole, idoxifene, Miproxifene, tamoxifen, 4-monohydroxy 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, Anastrozole, exemestane or bicalutamide; Or
(c) cisplatin of 5-20%, carboplatin, ormaplatin, dexormaplatin, heptan platinum, lobaplatin, the triptorelin of nedaplatin or oxaliplatin and 5-30%, goserelin, leuprorelin, Anastrozole, idoxifene, Miproxifene, tamoxifen, 4-monohydroxy 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, Anastrozole, the combination of exemestane or bicalutamide.
The viscosity of slow releasing injection is 10cp-650cp (20 ℃-30 ℃ time).
Embodiment 3.
With 70mg 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 15mg lobaplatin and 15mg pemetrexed, 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% lobaplatin and 10% pemetrexed, be suspended in then in the normal saline that contains 1.5% sodium carboxymethyl cellulose, make corresponding suspension type slow releasing injection, viscosity is 220cp-340cp (20 ℃-30 ℃ time).The drug release time of this slow releasing injection in external normal saline is 10-15 days, is about 20-30 days at the subcutaneous drug release time of mice.
Embodiment 4
The method step that is processed into slow releasing injection is identical with embodiment 3, but different is that contained anticancer effective component and percentage by weight thereof are:
(1) pemetrexed of 5-30%, pemetrexed disodium, Rumi Qu Sai, thunder for song account for, his shore of Raltitrexed, 2-Amino-6-methyl-5-(pyridin-4-ylsulfanyl)-3H-quinazolin-4-one, carmofur, dexrazoxane, ftorafur, temozolomide, zalcitabine, emtricitabine, galocitabine, ibacitabine, ancitabine, decitabine, flurocitabine, enocitabine, imidazoles, capecitabine, gemcitabine, fludarabine, cladribine;
(2) cisplatin of 5-30%, carboplatin, ormaplatin, dexormaplatin, heptan platinum, lobaplatin, nedaplatin, ring platinum, oxaliplatin, DNA-2114, cis-Dichlorobis(cyclopentylamine)platinum, platinum blue, cis-Dichlorobis(cyclopropylamine)platinum, Ethylenediammineplatinum(II) malonate, CL 286558., enloplatin, sulfatodiamino cyclohexane platinum, Spiroplatin, iproplatin, rice platinum, pick up platinum, sebriplatin, spiroplatin or zeniplatin; Or
(3) pemetrexed of 2-30%, pemetrexed disodium, Rumi Qu Sai, thunder accounts for for song, Raltitrexed, 2-Amino-6-methyl-5-(pyridin-4-ylsulfanyl)-3H-quinazolin-4-one, carmofur, dexrazoxane, ftorafur, the temozolomide, zalcitabine, emtricitabine, galocitabine, ibacitabine, ancitabine, decitabine, flurocitabine, enocitabine, his shore of imidazoles, capecitabine, gemcitabine, fludarabine, the cisplatin of cladribine and 2-30%, carboplatin, ormaplatin, dexormaplatin, heptan platinum, lobaplatin, nedaplatin, ring platinum, oxaliplatin, DNA-2114, cis-Dichlorobis(cyclopentylamine)platinum, platinum blue, cis-Dichlorobis(cyclopropylamine)platinum, Ethylenediammineplatinum(II) malonate, CL 286558., enloplatin, sulfatodiamino cyclohexane platinum, Spiroplatin, iproplatin, rice platinum, pick up platinum, sebriplatin, the combination of spiroplatin or zeniplatin.
The viscosity of injection is 10cp-650cp (20 ℃-30 ℃ time).
Embodiment 5.
(EVAc) puts into container with the 70mg ethylene vinyl acetate copolymer, after adding 100 milliliters of dichloromethane dissolving mixings, add 20 milligrams of nedaplatins and 10 milligrams of tamoxifens, shake up the back contains 20% nedaplatin and 10% tamoxifen with spray drying method for preparation injectable microsphere again.Then microsphere is suspended in the injection that contains the 5-15% sorbitol, makes corresponding suspension type slow releasing injection, viscosity is 100cp-160cp (25 ℃-30 ℃ time).The drug release time of this slow releasing injection in external normal saline is 10-15 days, is about 20-30 days at the subcutaneous drug release time of mice.
Embodiment 6.
The method step that is processed into slow releasing injection is identical with embodiment 5, but different is that contained anticancer effective component is:
The cisplatin of 10-20%, carboplatin, ormaplatin, dexormaplatin, heptan platinum, lobaplatin, the triptorelin of nedaplatin or oxaliplatin and 10-20%, 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, Anastrozole, the combination of exemestane or bicalutamide.The slow releasing injection viscosity is 500cp-600cp (25 ℃-30 ℃ time).
Embodiment 7.
70mg polifeprosan (to carboxy phenyl propane (p-CPP): decanedioic acid (SA) is 20: 80) copolymer is put into container, add 100 milliliters of dichloromethane, behind the dissolving mixing, add 20mg Ao Lisha platinum and 10mg letrozole, shake up the back contains 20% Ao Lisha platinum and 10% letrozole with spray drying method for preparation injectable microsphere again.Microsphere is suspended in the normal saline that contains 1.5% sodium carboxymethyl cellulose and 0.5% Tween 80 then, makes corresponding suspension type slow releasing injection, viscosity is 180cp-260cp (25 ℃-30 ℃ time).The drug release time of this slow releasing injection in external normal saline is 10-15 days, is about 20-30 days at the subcutaneous drug release time of mice.
Embodiment 8.
The method step that is processed into slow releasing injection is identical with embodiment 7, but different is that contained anticancer effective component is: the cisplatin of 5-30%, carboplatin, ormaplatin, dexormaplatin, heptan platinum, lobaplatin, the triptorelin of nedaplatin or oxaliplatin and 10-20%, 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, Anastrozole, the combination of exemestane or bicalutamide; Viscosity is 400cp-560cp (25 ℃-30 ℃ time).
Embodiment 9
70mg polifeprosan (to carboxy phenyl propane (p-CPP): decanedioic acid (SA) is 20: 80) copolymer is put into container, add 100 milliliters of dichloromethane, behind the dissolving mixing, add 20mg goserelin and 10mg decitabine, shake up the back contains 20% goserelin and 10% decitabine 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, viscosity is 100cp-160cp (25 ℃-30 ℃ time).The drug release time of this slow releasing injection in external normal saline is 10-15 days, is about 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:
(1) triptorelin of 1-40%, goserelin, leuprorelin, Anastrozole, idoxifene, Miproxifene, tamoxifen, 4-monohydroxy 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, Anastrozole, exemestane or bicalutamide; Or
(2) pemetrexed of 1-40%, pemetrexed disodium, Rumi Qu Sai, thunder accounts for for song, Raltitrexed, 2-Amino-6-methyl-5-(pyridin-4-ylsulfanyl)-3H-quinazolin-4-one, carmofur, dexrazoxane, ftorafur, the temozolomide, zalcitabine, emtricitabine, galocitabine, ibacitabine, ancitabine, decitabine, flurocitabine, enocitabine, his shore of imidazoles, capecitabine, gemcitabine, the triptorelin of fludarabine or cladribine and 1-40%, goserelin, leuprorelin, Anastrozole, idoxifene, Miproxifene, tamoxifen, 4-monohydroxy 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, Anastrozole, the combination of exemestane or bicalutamide.
Viscosity is 560cp-640cp (25 ℃-30 ℃ time).
Embodiment 11
70mg polifeprosan (to carboxy phenyl propane (p-CPP): decanedioic acid (SA) is 20: 80) copolymer is put into container, add 100 milliliters of dichloromethane, behind the dissolving mixing, add 10mg Anastrozole and 20mg flurocitabine, shake up the back contains 10% Anastrozole and 20% flurocitabine with spray drying method for preparation injectable microsphere again.Then microsphere is made corresponding sustained-release implant through pressed disc method.The drug release time of this sustained-release implant in external normal saline is 10-15 days, is about 30-40 days at the subcutaneous drug release time of mice.
Embodiment 12
The method step that is processed into sustained-release implant is identical with embodiment 11, but different is that used slow-release auxiliary material is: the bis-fatty acid of 60-95% and decanedioic acid copolymer (PFAD-SA), poly-(erucic acid dimer-decanedioic acid) [P (EAD-SA)] or poly-(fumaric acid-decanedioic acid) [P (FA-SA)].
Embodiment 13
With 70mg molecular weight peak value 35000 polylactic acid (PLGA, 50: 50) put into container, add 100 milliliters of dichloromethane, behind the dissolving mixing, add 10mg cisplatin and 20mg exemestane, shake up the back contains 10% cisplatin and 20% exemestane with spray drying method for preparation injectable microsphere again.Then microsphere is made corresponding sustained-release implant through pressed disc method.The drug release time of this sustained-release implant in external normal saline is 10-15 days, is about 35-50 days at the subcutaneous drug release time of mice.
Embodiment 14
The method step that is processed into sustained-release implant is identical with embodiment 11-13, but different is that contained anticancer effective component and percentage by weight are:
(a) platinum in heptan, lobaplatin, nedaplatin or the oxaliplatin of 5-30%;
(b) 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-Hydroxytamoxifen, Drogenil, aminoglutethimide, (.+-.)-Pyridoglutethimide, megestrol, medroxyprogesterone, clomifene, toremifene, letrozole, Anastrozole, exemestane or bicalutamide;
(c) pemetrexed of 5-30%, pemetrexed disodium, Rumi Qu Sai, thunder for song account for, his shore of Raltitrexed, 2-Amino-6-methyl-5-(pyridin-4-ylsulfanyl)-3H-quinazolin-4-one, carmofur, dexrazoxane, ftorafur, temozolomide, zalcitabine, emtricitabine, galocitabine, ibacitabine, ancitabine, decitabine, flurocitabine, enocitabine, imidazoles, capecitabine, gemcitabine, fludarabine or cladribine;
(d) pemetrexed of 5-30%, pemetrexed disodium, Rumi Qu Sai, thunder accounts for for song, Raltitrexed, 2-Amino-6-methyl-5-(pyridin-4-ylsulfanyl)-3H-quinazolin-4-one, carmofur, dexrazoxane, ftorafur, the temozolomide, zalcitabine, emtricitabine, galocitabine, ibacitabine, ancitabine, decitabine, flurocitabine, enocitabine, his shore of imidazoles, capecitabine, gemcitabine, the cisplatin of fludarabine or cladribine and 5-30%, carboplatin, ormaplatin, dexormaplatin, heptan platinum, lobaplatin, the combination of nedaplatin or oxaliplatin; Or
(e) pemetrexed of 5-30%, pemetrexed disodium, Rumi Qu Sai, thunder accounts for for song, Raltitrexed, 2-Amino-6-methyl-5-(pyridin-4-ylsulfanyl)-3H-quinazolin-4-one, carmofur, dexrazoxane, ftorafur, the temozolomide, zalcitabine, emtricitabine, galocitabine, ibacitabine, ancitabine, decitabine, flurocitabine, enocitabine, his shore of imidazoles, capecitabine, gemcitabine, the triptorelin of fludarabine or cladribine and 5-30%, goserelin, leuprorelin, Anastrozole, idoxifene, Miproxifene, tamoxifen, 4-monohydroxy 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, Anastrozole, the combination of exemestane or bicalutamide;
(f) ormaplatin of 5-30%, dexormaplatin, heptan platinum, lobaplatin, the triptorelin of nedaplatin or oxaliplatin and 5-30%, goserelin, leuprorelin, Anastrozole, idoxifene, Miproxifene, tamoxifen, 4-monohydroxy 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, Anastrozole, the combination of exemestane or bicalutamide.
Embodiment 15
The method step that is processed into slow releasing agent is identical with embodiment 1-14, but different is used slow-release auxiliary material is one of following or its combination:
A) polylactic acid (PLA), the molecular weight peak value is 10000-30000,300000-60000,60000-100000 or 100000-150000;
B) copolymer of polyglycolic acid and hydroxyacetic acid (PLGA), wherein, the ratio of polyglycolic acid and hydroxyacetic acid is 50-95: 50-50, the molecular weight peak value is 10000-30000,300000-60000,60000-100000 or 100000-150000;
C) ethylene vinyl acetate copolymer (EVAc);
D) polifeprosan, to carboxy phenyl propane (p-CPP): decanedioic acid (SA) is 10: 90,20: 80,30: 70,40: 60,50: 50 or 60: 40;
D) bis-fatty acid and decanedioic acid copolymer (PFAD-SA);
E) poly-(erucic acid dimer-decanedioic acid) [P (EAD-SA)];
F) poly-(fumaric acid-decanedioic acid) [P (FA-SA)];
G) xylitol, oligosaccharide, chrondroitin, chitin, hyaluronic acid, collagen protein, gelatin or white tempera.
Embodiment 16
The method step that is processed into slow releasing injection is identical with embodiment 1-10, but different is used suspending agent is respectively one of following or its combination:
A) 0.5-3.0% carboxymethyl cellulose (sodium);
B) 5-15% mannitol;
C) 5-15% sorbitol;
D) 0.1-1.5% surfactant;
E) 0.1-0.5% polysorbas20.
Above embodiment only is used for explanation, and is not limitation application of the present invention.
The present invention disclosed and the protection the content see claim.
Claims (10)
1. the anticancer medicine slow-release preparation containing of both antimetabolite and synergist thereof is a slow releasing injection, is grouped into by following one-tenth:
(A) sustained-release micro-spheres comprises:
Biological effective components 0.5-60%
Slow-release auxiliary material 41-99.9%
Suspending agent 0.0-30%
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 antimetabolite and/or antimetabolite synergist, and the antimetabolite synergist is steroids anti-cancer drugs and/or platinum-like compounds;
Slow-release auxiliary material is selected from one of following or its combination:
A) polylactic acid;
B) copolymer of polyglycolic acid and hydroxyacetic acid;
C) polifeprosan;
D) ethylene vinyl acetate copolymer;
E) bis-fatty acid and decanedioic acid copolymer;
F) poly-(erucic acid dimer-decanedioic acid) copolymer;
G) poly-(fumaric acid-decanedioic acid) copolymer;
H) xylitol, oligosaccharide, chrondroitin, chitin, hyaluronic acid, collagen protein, gelatin or white tempera.
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, and the viscosity of suspending agent is 100cp-3000cp (20 ℃-30 ℃ time).
2. the slow-releasing anticarcinogen injection according to claim 1, it is characterized in that antimetabolite be selected from pemetrexed, pemetrexed disodium, Rumi Qu Sai, thunder for song account for, one of his shore of Raltitrexed, 2-Amino-6-methyl-5-(pyridin-4-ylsulfanyl)-3H-quinazolin-4-one, carmofur, dexrazoxane, ftorafur, temozolomide, zalcitabine, emtricitabine, galocitabine, ibacitabine, ancitabine, decitabine, flurocitabine, enocitabine, imidazoles, capecitabine, gemcitabine, fludarabine, cladribine or its combination.
3. the slow-releasing anticarcinogen injection according to claim 1 is characterized in that platinum-like compounds is selected from cisplatin, carboplatin, ormaplatin, dexormaplatin, heptan platinum, lobaplatin, nedaplatin, ring platinum, oxaliplatin, DNA-2114, cis-Dichlorobis(cyclopentylamine)platinum, platinum blue, cis-Dichlorobis(cyclopropylamine)platinum, Ethylenediammineplatinum(II) malonate, CL 286558., enloplatin, sulfatodiamino cyclohexane platinum, Spiroplatin, iproplatin, rice platinum, pick up platinum, sebriplatin, spiroplatin, zeniplatin.With cisplatin, carboplatin, ormaplatin, dexormaplatin, heptan one of platinum, lobaplatin, nedaplatin, oxaliplatin or its combination.
4. the slow-releasing anticarcinogen injection according to claim 1; it is characterized in that steroids anti-cancer drugs is an Anastrozole; idoxifene; Miproxifene; tamoxifen; 4-monohydroxy tamoxifen; not former times sweet smell; ICI-M 164384; 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; the 4-trans-Hydroxytamoxifen; γ-linoleic acid; the 2-methoxyestradiol; moxestrol; the 4-trans-Hydroxytamoxifen; benzene hexachloride; raloxifene; diethylstilbestrol; estradiol; estrone; 17 alpha-estradiols; 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; triptorelin; goserelin; leuprorelin; megestrol; medroxyprogesterone; datiscoside; epitiostanol; the female sweet smell of bromine vinegar ethane; hisphen; clomifene; toremifene; letrozole; Anastrozole and exemestane or testolactone.
5. the slow-releasing anticarcinogen injection according to claim 1 is characterized in that the anticancer effective component of slow-releasing anticarcinogen injection is:
(1) pemetrexed of 1-40%, pemetrexed disodium, Rumi Qu Sai, thunder for song account for, his shore of Raltitrexed, 2-Amino-6-methyl-5-(pyridin-4-ylsulfanyl)-3H-quinazolin-4-one, carmofur, dexrazoxane, ftorafur, temozolomide, zalcitabine, emtricitabine, galocitabine, ibacitabine, ancitabine, decitabine, flurocitabine, enocitabine, imidazoles, capecitabine, gemcitabine, fludarabine or cladribine;
(2) cisplatin of 1-40%, carboplatin, ormaplatin, dexormaplatin, heptan platinum, lobaplatin, nedaplatin, ring platinum, oxaliplatin, DNA-2114, cis-Dichlorobis(cyclopentylamine)platinum, platinum blue, cis-Dichlorobis(cyclopropylamine)platinum, Ethylenediammineplatinum(II) malonate, CL 286558., enloplatin, sulfatodiamino cyclohexane platinum, Spiroplatin, iproplatin, rice platinum, pick up platinum, sebriplatin, spiroplatin or zeniplatin;
(3) triptorelin of 1-40%, goserelin, leuprorelin, Anastrozole, idoxifene, Miproxifene, tamoxifen, 4-monohydroxy 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, Anastrozole, exemestane or bicalutamide;
(4) pemetrexed of 1-40%, pemetrexed disodium, Rumi Qu Sai, thunder accounts for for song, Raltitrexed, 2-Amino-6-methyl-5-(pyridin-4-ylsulfanyl)-3H-quinazolin-4-one, carmofur, dexrazoxane, ftorafur, the temozolomide, zalcitabine, emtricitabine, galocitabine, ibacitabine, ancitabine, decitabine, flurocitabine, enocitabine, his shore of imidazoles, capecitabine, gemcitabine, the cisplatin of fludarabine or cladribine and 1-40%, carboplatin, ormaplatin, dexormaplatin, heptan platinum, lobaplatin, nedaplatin, ring platinum, oxaliplatin, DNA-2114, cis-Dichlorobis(cyclopentylamine)platinum, platinum blue, cis-Dichlorobis(cyclopropylamine)platinum, Ethylenediammineplatinum(II) malonate, CL 286558., enloplatin, sulfatodiamino cyclohexane platinum, Spiroplatin, iproplatin, rice platinum, pick up platinum, sebriplatin, the combination of spiroplatin or zeniplatin;
(5) pemetrexed of 1-40%, pemetrexed disodium, Rumi Qu Sai, thunder accounts for for song, Raltitrexed, 2-Amino-6-methyl-5-(pyridin-4-ylsulfanyl)-3H-quinazolin-4-one, carmofur, dexrazoxane, ftorafur, the temozolomide, zalcitabine, emtricitabine, galocitabine, ibacitabine, ancitabine, decitabine, flurocitabine, enocitabine, his shore of imidazoles, capecitabine, gemcitabine, the triptorelin of fludarabine or cladribine and 1-40%, goserelin, leuprorelin, Anastrozole, idoxifene, Miproxifene, tamoxifen, 4-monohydroxy 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, Anastrozole, the combination of exemestane or bicalutamide;
(6) cisplatin of 1-40%, carboplatin, ormaplatin, dexormaplatin, heptan platinum, lobaplatin, nedaplatin, ring platinum, oxaliplatin, DNA-2114, cis-Dichlorobis(cyclopentylamine)platinum, platinum blue, cis-Dichlorobis(cyclopropylamine)platinum, Ethylenediammineplatinum(II) malonate, CL 286558., enloplatin, sulfatodiamino cyclohexane platinum, Spiroplatin, iproplatin, rice platinum, pick up platinum, sebriplatin, the triptorelin of spiroplatin or zeniplatin and 1-40%, goserelin, leuprorelin, Anastrozole, idoxifene, Miproxifene, tamoxifen, 4-monohydroxy 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, Anastrozole, the combination of exemestane or bicalutamide; Or
(7) pemetrexed of 1-40%, pemetrexed disodium, Rumi Qu Sai, thunder accounts for for song, Raltitrexed, 2-Amino-6-methyl-5-(pyridin-4-ylsulfanyl)-3H-quinazolin-4-one, carmofur, dexrazoxane, ftorafur, the temozolomide, zalcitabine, emtricitabine, galocitabine, ibacitabine, ancitabine, decitabine, flurocitabine, enocitabine, his shore of imidazoles, capecitabine, gemcitabine, the cisplatin of fludarabine or cladribine and 1-40%, carboplatin, ormaplatin, dexormaplatin, heptan platinum, lobaplatin, nedaplatin, ring platinum, oxaliplatin, DNA-2114, cis-Dichlorobis(cyclopentylamine)platinum, platinum blue, cis-Dichlorobis(cyclopropylamine)platinum, Ethylenediammineplatinum(II) malonate, CL 286558., enloplatin, sulfatodiamino cyclohexane platinum, Spiroplatin, iproplatin, rice platinum, pick up platinum, sebriplatin, the triptorelin of spiroplatin or zeniplatin and 1-40%, goserelin, leuprorelin, Anastrozole, idoxifene, Miproxifene, tamoxifen, 4-monohydroxy 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, Anastrozole, the combination of exemestane or bicalutamide.
6. the slow-releasing anticarcinogen injection according to claim 1 is characterized in that:
A) the molecular weight peak value of polylactic acid is 10000-30000,300000-60000,60000-100000 or 100000-150000;
B) in the copolymer of polyglycolic acid and hydroxyacetic acid, the ratio of polyglycolic acid and hydroxyacetic acid is 50-95: 50-50, and the molecular weight peak value is 10000-30000,300000-60000,60000-100000 or 100000-150000;
C) in the polifeprosan, to carboxy phenyl propane: decanedioic acid is 10: 90,20: 80,30: 70,40: 60,50: 50 or 60: 40.
7. the slow-releasing anticarcinogen injection according to claim 1 is characterized in that used suspending agent is respectively one of following:
A) 0.5-3.0% carboxymethyl cellulose (sodium);
B) 5-15% mannitol;
C) 5-15% sorbitol;
D) 0.1-1.5% surfactant;
E) 0.1-0.5% polysorbas20;
F) (iodine) glycerol, simethicone, propylene glycol or carbomer;
G) 0.5-5% sodium carboxymethyl cellulose+0.1-0.5% soil temperature 80;
H) 5-20% mannitol+0.1-0.5% soil temperature 80;
I) 0.5-5% sodium carboxymethyl cellulose+5-20% sorbitol+0.1-0.5% soil temperature 80.
8. the slow-releasing anticarcinogen injection according to claim 1 is characterized in that described pharmaceutical preparation is the sustained-release implant that sustained-release micro-spheres is made, in tumor or tumor week injection or place administration.
9. described according to Claim 8 anti-cancer sustained-released implantation agent is characterized in that the used slow-release auxiliary material of described sustained-release implant is selected from one of following or its combination:
A) polylactic acid;
B) copolymer of polyglycolic acid and hydroxyacetic acid;
C) polifeprosan;
D) ethylene vinyl acetate copolymer;
E) bis-fatty acid and decanedioic acid copolymer;
F) poly-(erucic acid dimer-decanedioic acid) copolymer;
G) poly-(fumaric acid-decanedioic acid) copolymer;
H) xylitol, oligosaccharide, chrondroitin, chitin, hyaluronic acid, collagen protein, gelatin or white tempera.
Anticancer effective component and percentage by weight thereof are:
(1) pemetrexed of 5-30%, pemetrexed disodium, Rumi Qu Sai, thunder for song account for, his shore of Raltitrexed, 2-Amino-6-methyl-5-(pyridin-4-ylsulfanyl)-3H-quinazolin-4-one, carmofur, dexrazoxane, ftorafur, temozolomide, zalcitabine, emtricitabine, galocitabine, ibacitabine, ancitabine, decitabine, flurocitabine, enocitabine, imidazoles, capecitabine, gemcitabine, fludarabine, cladribine;
(2) cisplatin of 5-30%, carboplatin, ormaplatin, dexormaplatin, heptan platinum, lobaplatin, nedaplatin, ring platinum, oxaliplatin, DNA-2114, cis-Dichlorobis(cyclopentylamine)platinum, platinum blue, cis-Dichlorobis(cyclopropylamine)platinum, Ethylenediammineplatinum(II) malonate, CL 286558., enloplatin, sulfatodiamino cyclohexane platinum, Spiroplatin, iproplatin, rice platinum, pick up platinum, sebriplatin, spiroplatin or zeniplatin;
(3) triptorelin of 5-30%, goserelin, leuprorelin, Anastrozole, idoxifene, Miproxifene, tamoxifen, 4-monohydroxy 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, Anastrozole, exemestane or bicalutamide;
(4) pemetrexed of 2-30%, pemetrexed disodium, Rumi Qu Sai, thunder accounts for for song, Raltitrexed, 2-Amino-6-methyl-5-(pyridin-4-ylsulfanyl)-3H-quinazolin-4-one, carmofur, dexrazoxane, ftorafur, the temozolomide, zalcitabine, emtricitabine, galocitabine, ibacitabine, ancitabine, decitabine, flurocitabine, enocitabine, his shore of imidazoles, capecitabine, gemcitabine, fludarabine, the cisplatin of cladribine and 2-30%, carboplatin, ormaplatin, dexormaplatin, heptan platinum, lobaplatin, nedaplatin, ring platinum, oxaliplatin, DNA-2114, cis-Dichlorobis(cyclopentylamine)platinum, platinum blue, cis-Dichlorobis(cyclopropylamine)platinum, Ethylenediammineplatinum(II) malonate, CL 286558., enloplatin, sulfatodiamino cyclohexane platinum, Spiroplatin, iproplatin, rice platinum, pick up platinum, sebriplatin, the combination of spiroplatin or zeniplatin;
(5) pemetrexed of 2-30%, pemetrexed disodium, Rumi Qu Sai, thunder accounts for for song, Raltitrexed, 2-Amino-6-methyl-5-(pyridin-4-ylsulfanyl)-3H-quinazolin-4-one, carmofur, dexrazoxane, ftorafur, the temozolomide, zalcitabine, emtricitabine, galocitabine, ibacitabine, ancitabine, decitabine, flurocitabine, enocitabine, his shore of imidazoles, capecitabine, gemcitabine, fludarabine, the triptorelin of cladribine and 2-30%, goserelin, leuprorelin, Anastrozole, idoxifene, Miproxifene, tamoxifen, 4-monohydroxy 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, Anastrozole, the combination of exemestane or bicalutamide;
(6) cisplatin of 2-30%, carboplatin, ormaplatin, dexormaplatin, heptan platinum, lobaplatin, nedaplatin, ring platinum, oxaliplatin, DNA-2114, cis-Dichlorobis(cyclopentylamine)platinum, platinum blue, cis-Dichlorobis(cyclopropylamine)platinum, Ethylenediammineplatinum(II) malonate, CL 286558., enloplatin, sulfatodiamino cyclohexane platinum, Spiroplatin, iproplatin, rice platinum, pick up platinum, sebriplatin, the triptorelin of spiroplatin or zeniplatin and 2-30%, goserelin, leuprorelin, Anastrozole, idoxifene, Miproxifene, tamoxifen, 4-monohydroxy 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, Anastrozole, the combination of exemestane or bicalutamide; Or
(7) pemetrexed of 2-30%, pemetrexed disodium, Rumi Qu Sai, thunder accounts for for song, Raltitrexed, 2-Amino-6-methyl-5-(pyridin-4-ylsulfanyl)-3H-quinazolin-4-one, carmofur, dexrazoxane, ftorafur, the temozolomide, zalcitabine, emtricitabine, galocitabine, ibacitabine, ancitabine, decitabine, flurocitabine, enocitabine, his shore of imidazoles, capecitabine, gemcitabine, the cisplatin of fludarabine or cladribine and 2-30%, carboplatin, ormaplatin, dexormaplatin, heptan platinum, lobaplatin, nedaplatin, ring platinum, oxaliplatin, DNA-2114, cis-Dichlorobis(cyclopentylamine)platinum, platinum blue, cis-Dichlorobis(cyclopropylamine)platinum, Ethylenediammineplatinum(II) malonate, CL 286558., enloplatin, sulfatodiamino cyclohexane platinum, Spiroplatin, iproplatin, rice platinum, pick up platinum, sebriplatin, the triptorelin of spiroplatin or zeniplatin and 1-40%, goserelin, leuprorelin, Anastrozole, idoxifene, Miproxifene, tamoxifen, 4-monohydroxy 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, Anastrozole, the combination of exemestane or bicalutamide.
10. described according to Claim 8 anti-cancer sustained-released implantation agent is characterized in that:
A) the molecular weight peak value of polylactic acid is 10000-30000,300000-60000,60000-100000 or 100000-150000;
B) in the copolymer of polyglycolic acid and hydroxyacetic acid, the ratio of polyglycolic acid and hydroxyacetic acid is 50-95: 50-50, and the molecular weight peak value is 10000-30000,300000-60000,60000-100000 or 100000-150000;
C) in the polifeprosan, to carboxy phenyl propane: decanedioic acid is 10: 90,20: 80,30: 70,40: 60,50: 50 or 60: 40.
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| US8168661B2 (en) | 2006-11-06 | 2012-05-01 | Poniard Pharmaceuticals, Inc. | Use of picoplatin to treat colorectal cancer |
| US8168662B1 (en) | 2006-11-06 | 2012-05-01 | Poniard Pharmaceuticals, Inc. | Use of picoplatin to treat colorectal cancer |
| US8173686B2 (en) | 2006-11-06 | 2012-05-08 | Poniard Pharmaceuticals, Inc. | Use of picoplatin to treat colorectal cancer |
| US8178564B2 (en) | 2006-11-06 | 2012-05-15 | Poniard Pharmaceuticals, Inc. | Use of picoplatin to treat colorectal cancer |
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| CN114081885A (en) * | 2022-01-10 | 2022-02-25 | 广东工业大学 | Application of dexrazoxane in preparation of medicine for preventing or treating adverse reaction caused by platinum chemotherapy drugs in chemotherapy |
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| DK0797988T3 (en) * | 1993-07-19 | 2009-05-11 | Univ British Columbia | Anti-angiogenic compositions and methods for their use |
| FR2793684B1 (en) * | 1999-05-17 | 2001-08-10 | Ethypharm Lab Prod Ethiques | USE OF BIODEGRADABLE MICROSPHERES RELEASING ANTI-CANCER AGENT FOR THE TREATMENT OF GLIOBLASTOMA, PROCESS FOR PREPARING SUCH MICROSPHERES AND SUSPENSION CONTAINING THEM |
| CN100374160C (en) * | 2004-11-22 | 2008-03-12 | 山东蓝金生物工程有限公司 | Anti-cancer medicine composition containing antimetabolite |
| CN100500219C (en) * | 2005-04-06 | 2009-06-17 | 山东蓝金生物工程有限公司 | Anti tumour medicinal composition containing platinum compound |
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| US8168661B2 (en) | 2006-11-06 | 2012-05-01 | Poniard Pharmaceuticals, Inc. | Use of picoplatin to treat colorectal cancer |
| US8168662B1 (en) | 2006-11-06 | 2012-05-01 | Poniard Pharmaceuticals, Inc. | Use of picoplatin to treat colorectal cancer |
| US8173686B2 (en) | 2006-11-06 | 2012-05-08 | Poniard Pharmaceuticals, Inc. | Use of picoplatin to treat colorectal cancer |
| US8178564B2 (en) | 2006-11-06 | 2012-05-15 | Poniard Pharmaceuticals, Inc. | Use of picoplatin to treat colorectal cancer |
| CN105078996A (en) * | 2014-05-05 | 2015-11-25 | 中国人民解放军南京军区南京总医院 | Pharmaceutical composition and application thereof on suppression of osteosarcoma proliferation |
| CN114081885A (en) * | 2022-01-10 | 2022-02-25 | 广东工业大学 | Application of dexrazoxane in preparation of medicine for preventing or treating adverse reaction caused by platinum chemotherapy drugs in chemotherapy |
| CN114209807A (en) * | 2022-01-13 | 2022-03-22 | 南京昂谷医药科技有限公司 | Goserelin implant preparation and preparation method thereof |
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Effective date of registration: 20110421 Address after: High tech Zone Tianchen road Ji'nan City, Shandong province 250101 No. 1750 201 Patentee after: Shandong many biological pharmaceutical Co., Ltd. Address before: High tech Zone Tianchen road Ji'nan City, Shandong province 250101 No. 1750 Co-patentee before: Kong Qingzhong Patentee before: Shandong Lanjin Pharmaceuticals Co., Ltd. |
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| C17 | Cessation of patent right | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20090304 Termination date: 20120317 |