CN1846688A - Slow-released anticancer prepn containing taxane and its synergist - Google Patents
Slow-released anticancer prepn containing taxane and its synergist Download PDFInfo
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Abstract
The slow released anticancer preparation with taxane and its synergist is slow released injection comprising slow released microballoon and solvent. The slow released microballoon includes effective anticancer component and slow releasing supplementary material, and the solvent is common solvent or special solvent containing suspending agent. The effective anticancer component is anticarcinogen of taxane or polyene taxane and/or taxane synergist of hormone anticarcinogen and/or blood vessel inhibitor; the slow releasing supplementary material is PLA, PLGA, EVAc, etc or their composition; and the suspending agent is sodium carboxymethyl cellulose, etc of viscosity of 100-3000 cp(at 20-30 deg.c). The slow released microballoon may be also prepared into slow released implantation preparation. The present invention is set or injected inside or around the tumor alone or in combination with chemotherapy or radiotherapy.
Description
(1) technical field
The present invention relates to a kind of anticancer medicine slow-release preparation containing that contains taxane and synergist thereof, belong to technical field of pharmaceuticals.Particularly, the invention provides a kind of slow releasing injection or sustained-release implant with loaded taxane and synergist thereof.
(2) background technology
Treatment for cancer still mainly comprises methods such as operation, radiotherapy and chemotherapy at present.Therefore wherein operative treatment not only 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.1998Oct such as Kong Qingzhongs; 69 (2): 76-82).
Chemotherapeutics topical application (placing as the part) 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) (KongQ et al., J Surg 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, entity tumor is made up of tumor cell and mesenchyma stroma of tumors, wherein the blood vessel in the mesenchyma stroma of tumors not only provides support and requisite nutrient substance for the growth of tumor cell, also influenced chemotherapeutics around tumor and the infiltration in the tumor tissues and diffusion (carry and to wait " situation of extracellular matrix to entity tumor in the medicine influence of turning round " " cancer research " 60 phase 2497-503 page or leaf (2000) (Netti PA referring to the Buddhist nun, Cancer Res.2000,60 (9): 2497-503).Moreover, the blood vessel in the mesenchyma stroma of tumors often causes the enhancing of tumor cell to the toleration of cancer therapy drug to conventional chemotherapy medicine and insensitive, consequently 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, develop a kind of effective cancer therapy drug or Therapeutic Method and just become a current important topic.The present invention provides a kind of new anticancer pharmaceutical composition just at the deficiencies in the prior art, not only can suppress growth of tumour cell effectively, and can strengthen the treatment tumor effect of other medicines, reduces 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 taxane and synergist thereof is provided, particularly, is a kind of slow releasing injection and sustained-release implant that contains taxane and synergist thereof.
Taxane has been crossed both at home and abroad and has been widely used in the multiple entity tumor of treatment as the new cancer therapy drug of a class.Yet in application process, its tangible general toxicity has greatly limited the application of this medicine.
Be effectively to improve tumor by local drug level, reduce the drug level of medicine in blood circulation, people have studied the drug sustained release system that contains taxane, comprise that magnetic microsphere (sees: China Patent No. CN200410044113.8; CN200410009233.4), sustained-release micro-spheres (capsule) (see: China Patent No. CN200410023746.0) and nanoparticle (see: China Patent No. CN200410099292.5; CN200510002387.5) etc.Yet, solid sustained-release implant (China Patent No. ZL96115937.5; ZL97107076.8; CN200410084621.9), miniature implantation device (China Patent No. CN200510011250.6), sustained-release micro-spheres (the China Patent No. ZL00809160.9 of band radioactive source; U.S. Pat 5,651,986) all there are the problems such as operation, weak curative effect, complication be many that are not easy.In addition, the sensitivity that many entity tumors are drawn together taxane to anticancer medicated bag is relatively poor, and is easy to generate drug resistance in therapeutic process.
The present invention finds that many medicines and taxane share its antitumaous effect is strengthened mutually, below the taxane antitumaous effect will be increased mutually medicine be referred to as the taxane synergist; In addition, the combination of taxane or taxane 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.The above unexpected main contents of the present invention of finding to constitute.
A kind of form of taxane 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 micro-spheres comprises:
Anticancer effective component 0.5-60%
Slow-release auxiliary material 40-99%
More than be weight percentage
With
(B) solvent is for common solvent or contain the special solvent of suspending agent.
Wherein,
Anticancer effective component is taxane and/or taxane synergist, and the taxane synergist is selected from steroids anti-cancer drugs and/or vasoinhibitor; Slow-release auxiliary material is selected from copolymer (PLGA), ethylene vinyl acetate copolymer (EVAc), polifeprosan, bis-fatty acid and the decanedioic acid copolymer (PFAD-SA) of polylactic acid (PLA), polyglycolic acid and hydroxyacetic acid], one of poly-(erucic acid dimer-decanedioic acid) [P (EAD-SA)], poly-(fumaric acid-decanedioic acid) [P (FA-SA)], xylitol, oligosaccharide, chrondroitin, chitin, hyaluronic acid, collagen protein, gelatin and white tempera 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.
Taxane in the anticancer effective component (Taxanes) kind anti-cancer drugs owner to be selected from paclitaxel, Docetaxel (Docetaxel, taxotere, docetaxel), 2 '-hydroxyl paclitaxel (paclitaxel-2 '-hydroxy), 10-removes acetyl paclitaxel (10-deacetyl taxol), 7-table-paclitaxel (7-epi-taxol).
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; 7 alpha-[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 2%-30%, more than all be weight percentage.
Vasoinhibitor can suppress or destroy the blood vessel of tumor effectively and can suppress the new vessels formation of tumor, and then not only make tumor cell lose the required support of growth and the source of nutrient substance, also promoted chemotherapeutics around tumor, to reach infiltration and the diffusion in the tumor tissues.
Vasoinhibitor is selected from one of following or combination: and gefitinib (Gefitinib claims 4-quinazoline oxazolone amine again, N-(3-chloro-4-fluoro phenyl)-7-methoxyl group-6-[3-4-morpholine] propoxyl group) [4-Quinazolinamine; N-(3-chloro-4-fluorophenyl)-7-methoxy-6-[3-4-morpholin] propoxy]; Erlotinib (4-quinazoline oxazolone amine, N-(3-acetenyl)-6, two (the 2-methoxy ethyl)-monohydrochloride [4-Quinazolinamine of 7-; N-(3-ethynylphenyl)-6,7-bis (2-methoxyethoxy)-monohydrochlo ride, Tarceva; OSI-774, erlotinib, CP-358774; OSI-774, R-1415]; (phenol, 4-(4-(((1R)-1-phenethyl) amino)-1H-pyrrolo-(2; 3-d) pyrimidine-6-yl) (Phenol, 4-(4-(((1R)-1-phenylethyl) amino)-1H-pyrrolo (2,3-d) pyrimidine-6-yl)-; PKI-166; CGP-59326; CGP-59326B; CGP-62706; CGP-74321; CGP-75166; CGP-76627); Lapatinib (4-quinazoline oxazolone amine, N-[3-chloro-4-[(3-fluoro) methoxy ethyl]-the 6-[5-[[2-[sulfidomethyl] ethyl] the furan food in one's mouth-2-yl]] two (4-tolyl sulfate) single hydrate] [4-Quinazolinamine, N-[3-chloro-4-[(3-fluorobenzyl) methoxyphenyl]-6-[5-[[[2-[methylsulfonyl] ethyl] amino] methyl] furan-2-yl]] bis (4-methylbenzenesulfonate) monohydrate; lapatinib ditosylate; GW-2016; GW-572016; GW-572016F]; (N-(4-chlorphenyl)-4-(pyridine-4-methyl) faces phenylenedimethylidyne-1-amine (N-(4-chlorophenyl)-4-(pyridin-4-ylmethyl) phtalazin-l-amine to votaranib; vatalanib; PTK-787; PTK/ZK; Schering VEGF-TKl; Schering AG; ZK-222584)); WAY-EKB 569 ((2E)-N-[4-[(3-chloro-4-fluoro phenyl) amine]-3-cyanogen-7-ethoxyquin-6-yl]-4-(dimethylamino) also-the 2-amide ((2E)-N-[4-[(3-chloro-4-fluorophenyl) amino]-3-cyano-7-ethoxyquinolin-6-yl]-4-(dimethy lamino) but-2-enamide; EKB-569; pelitinib); NSC 609974 (carboxyamidotriazole; CAT); thalidomide (thalidomide, Thalidomide); LS-2616 (linomide, inhibitors of integrin); angiostatin (angiostatin); Endostatin (endostatin); VEGF (VEGF) acceptor inhibitor; imatinib mesylate (Imatinib mesylate; have another name called imatinib mesylate, Glivec); 4-[(4-methyl isophthalic acid-piperazine) methyl]-N-[4-methyl-3-[[4-(3-pyridine)-2-pyrimidine] amino] phenyl]-the aniline mesylate (4-((Methyl-1-piperazinyl) methyl)-N-[4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl] amino]-phenyl] benzamide methanesulfonate, STI 571; CGP-57148B, STI-571A, CGP57148); 5-[5-fluoro-2-oxygen-1; the 2-indoline-(3Z)-methylene]-2,4-dimethyl-1H-pyrroles-3-carboxylic acid (2-diethylaminoethyl) amide (5-[5-Fluoro-2-oxo-1,2-dihydroindol-(3Z)-ylidenemethyl]-2; 4-dimethyl-1H-pyrrole-3 carboxylic Acid (2-Diethylaminoethyl) amide, Sutent, SU11248; SU011248); 3, and 3-two chloro-5-(4-sulfonyloxy methyl yl pyridines)-2-dihydroindole ketone (3,3-Dichloro-5-(4-methyl piperidinosulfonyl)-2-indolinone; DCM); 3-[1-(the 3H-imidazoles-4-yl)-first-(Z)-Ya Neiweng-5-methoxy-1,3-dihydro-indole-2-dihydroindole ketone (3-[1-(3H-imidazol-4-yl)-meth-(Z)-ylidene]-5-methoxy-1,3-dihydro-indol-2-one; SU9516, SU 95 18); 1H-pyrroles-3-propanoic acid, 2-[(1; 2-dihydro-2-oxygen-3H-indole-3-subunit) methyl]-4-methyl (SU6663, SU-5402,1H-Pyrrole-3-propanoic acid; 2-[(1,2-dihydro-2-oxo-3H-indol-3-ylidene) methyl]-4-methyl); 2H-indole-2-dihydroindole ketone (2H-Indol-2-one); Sugen 5416 (3-((4,5-dimethyl-1H-pyrroles-2-yl) methylene)-1; (3-((4 for 3-dihydro-[CAS]; 5-dimethyl-1H-pyrrol-2-yl) methylene)-1,3-dihydro-[CAS], SU5614; semaxanib; SU-011271, SU-011606, SU-11612)); pyrroles's lactone dihydroindole ketone (pyrrolyllactone indolinones; SU6577); lactams dihydroindole ketone (pyrrolyllactam indolinones; SU6597); 3-(4-dimethylamino-naphthal-1-methylene)-1,3-dihydro-indole-2-dihydroindole ketone (3-(4-Dimethylamino-naphthalen-1-ylmethylene)-1,3-dihydro-indol-2-one; MAZ51); 1; 3-dihydro-5,6-dimethoxy-3-[(4-hydroxyphenyl) methylene]-2H-indole-2-dihydroindole ketone (1,3-dihydro-5; 6-dimethoxy-3-[(4-hydroxyphenyl) methylene]-2H-indol-2-indolinone; RPI-1); 3-[5-methyl-2-(2-oxygen-1,2-dihydro-indol-3-yl)-1H-pyrroles-3-methyl]-propanoic acid (3-[5-methyl-2-(2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-1H-pyrrol-3-yl]-proprionic acid; SU10944); 5-[(Z)-(5-chloro-2-oxygen-1; 2-dihydro-3H-indole-3-methylene) methyl]-N-(2-(diethylin) ethyl-1H-pyrroles-3-carboxylic acid amides (5-[(Z)-(5-chloro-2-oxo-1,2-dihydro-3H-indol-3-ylidene) methyl]-N-[2-(diethylamino) ethyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide; SU11652); 5-[(Z)-(5-fluoro-2-oxygen-1; 2-dihydro-3H-indole-3-subunit) methyl]-2,4-dimethyl-N-(2-pyrrolidinyl-1-ethyl)-1H-pyrroles-3-carboxylic acid amides (5-[(Z)-(5-fluoro-2-oxo-1,2-dihydro-3H-indol-3-ylidene) methyl]-2; 4-dimethyl-N-(2-pyrrolidin-1-ylethyl)-1H-pyrrole-3-carboxamide); SU11654); 5-[(Z)-(5-chloro-2-oxygen-1,2-dihydro-3H-indole-3-subunit) methyl]-2,4-dimethyl-N-(2-pyrrolidinyl-1-ethyl)-1H-pyrroles-3-carboxylic acid amides ((5-[(Z)-(5-chloro-2-oxo-1; 2-dihydro-3H-indol-3-ylidene) methyl]-2; 4-dimethyl-N-(2-pyrrolidin-1-ylethyl)-1H-pyrrole-3-carboxamide), SU11655); 3-[[3-phenyl-4 (3H)-quinazolinone-2-methyl] TGA] hydrazono-]-the 1H-2-dihydroindole ketone (3-[[(3-phenyl-4 (3H)-quinazolinone-2-yl) mercaptoacetyl] hydrazono]-1H-2-indolinones, SU1165); 3-two (4-anisyl) methylene-2-dihydroindole ketone (3-bis (4-methoxyphenyl) methylene-2-indolinone; TAS-301); 3-[4-formyl piperazine-4yl]-benzal]-the 2-dihydroindole ketone (3-[4-(1-formylpiperazin-4yl)-benzylidenyl]-2-indolinone; SU4984); 3-([5-imidazoles] 2,1-methylene thiazole)-2-dihydroindole ketone (3-(5-imidazo) 2,1-blthiazolylmethylene)-2-indolinone; IBMI); 3-1 (2; 6-methylimidazole [2,1-Bj-thiazole-5-yl] methylene-5-methoxyl group-2-dihydroindole ketone (3-1 (2,6-dimethylimidazo[2; 1-bJ-thiazol-5-yl] methylenel-5-methoxy-2-indolinone; DMMI, SU9518]; imidazoles [2,1-b] methylene thiazole-2-dihydroindole ketone (Imidazo[2; 1-b] thiazolylmethylene-2-indolinones; ITI); methylene indole-2-dihydroindole ketone (indolylmethylene-2-indolinones, IMI); (2-chloro-indole) methylene-2-dihydroindole ketone (2-chloroindolyl) methylene-2-indolinone, CMI); arlydene 2-dihydroindole ketone (arylidene2-indolinone; AI); 1; 3-dihydro-5,6-dimethoxy-3-[(4-hydroxyphenyl) methylene]-2H-indole-2-dihydroindole ketone (1,3-dihydro-5; 6-dimethoxy-3-[(4-hydroxyphenyl) methylene]-2H-indol-2-one); cpd1); 3-(4-dimethylamino-benzal)-2-dihydroindole ketone (3-(4-dimethylamino-benzylidenyl)-2-indolinone, DMBI); 5-chloro-3-methylene pyridine-2-dihydroindole ketone (5-chloro-3-pyridylmethylene-2-indolinone, cpMI); 3; 3-lutidines-1-phenyl-2-dihydroindole ketone (3; 3-dipyridylmethyl-1-phenyl-2-indolinone, DPMPI) and E-3-(2-chloro-3-methylene indole) 1,3-indoline-2-dihydroindole ketone (E-3-(2-chloro-3-indolyl methylene) 1; 3-dihydroindol-2-indolinone, CIDI); BMS 354825 (dasatinib); Avastin (avastin); Cl 1033 (canertinib); Sorafenib (sorafenib); Sutent (sunitinib; sutent; SU11248); TLK286 (Telcyta); ABX-EGF (panitumumab).
Other vasoinhibitor is referring to relevant international monopoly, application number: WO 97/22596, and WO 97/30035, WO97/32856 and WO 98/13354.
Above vasoinhibitor 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.
Preferred one of the following or combination of above-mentioned vasoinhibitor:
Gefitinib; Erlotinib; Lapatinib; votaranib; WAY-EKB 569; NSC 609974; thalidomide; LS-2616; angiostatin; Endostatin; blood vessel endothelium chalone (grace degree; endostar); imatinib mesylate; 4-[(4-methyl isophthalic acid-piperazine) methyl]-N-[4-methyl-3-[[4-(3-pyridine)-2-pyrimidine] amino] phenyl]-the aniline mesylate; 5-[5-fluoro-2-oxygen-1; the 2-indoline-(3Z)-methylene]-2; 4-dimethyl-1H-pyrroles-3-carboxylic acid (2-diethylaminoethyl) amide; 3; 3-two chloro-5-(4-sulfonyloxy methyl yl pyridines)-2-dihydroindole ketone; 3-[1-(the 3H-imidazoles-4-yl)-first-(Z)-Ya Neiweng-5-methoxy-1; 3-dihydro-indole-2-dihydroindole ketone; 1H-pyrroles-3-propanoic acid; 2-[(1; 2-dihydro-2-oxygen-3H-indole-3-subunit) methyl]-the 4-methyl; 2H-indole-2-dihydroindole ketone; Sugen 5416; pyrroles's lactone dihydroindole ketone; the lactams dihydroindole ketone; 3-(4-dimethylamino-naphthal-1-methylene)-1; 3-dihydro-indole-2-dihydroindole ketone; 1; 3-dihydro-5; 6-dimethoxy-3-[(4-hydroxyphenyl) methylene]-2H-indole-2-dihydroindole ketone; 3-[5-methyl-2-(2-oxygen-1; 2-dihydro-indol-3-yl)-1H-pyrroles-3-methyl]-propanoic acid; 5-[(Z)-(5-chloro-2-oxygen-1; 2-dihydro-3H-indole-3-methylene) methyl]-N-(2-(diethylin) ethyl-1H-pyrroles-3-carboxylic acid amides; 5-[(Z)-(5-fluoro-2-oxygen-1; 2-dihydro-3H-indole-3-subunit) methyl]-2; 4-dimethyl-N-(2-pyrrolidinyl-1-ethyl)-1H-pyrroles-3-carboxylic acid amides; 5-[(Z)-(5-chloro-2-oxygen-1; 2-dihydro-3H-indole-3-subunit) methyl]-2; 4-dimethyl-N-(2-pyrrolidinyl-1-ethyl)-1H-pyrroles-3-carboxylic acid amides; 3-[[3-phenyl-4 (3H)-quinazolinone-2-methyl] TGA] hydrazono-]-the 1H-2-dihydroindole ketone; 3-two (4-anisyl) methylene-2-dihydroindole ketone; 3-[4-formyl piperazine-4yl]-benzal]-the 2-dihydroindole ketone; 3-([5-imidazoles] 2; 1-methylene thiazole)-the 2-dihydroindole ketone; 3-1 (2; 6-methylimidazole [2; 1-Bj-thiazole-5-yl] methylene-5-methoxyl group-2-dihydroindole ketone; imidazoles [2; 1-b] methylene thiazole-2-dihydroindole ketone; methylene indole-2-dihydroindole ketone; (2-chloro-indole) methylene-2-dihydroindole ketone; arlydene 2-dihydroindole ketone; 1; 3-dihydro-5; 6-dimethoxy-3-[(4-hydroxyphenyl) methylene]-2H-indole-2-dihydroindole ketone; 3-(4-dimethylamino-benzal)-2-dihydroindole ketone; 5-chloro-3-methylene pyridine-2-dihydroindole ketone; 3; 3-lutidines-1-phenyl-2-dihydroindole ketone or E-3-(2-chloro-3-methylene indole) 1,3-indoline-2-dihydroindole ketone; BMS 354825; Avastin; Cl 1033; Sorafenib; Sutent; TLK286; ABX-EGF.
Above-mentioned vasoinhibitor can singly select or multiselect, with gefitinib, Erlotinib, Lapatinib, votaranib, WAY-EKB 569, NSC 609974, thalidomide, LS-2616, angiostatin, Endostatin, imatinib mesylate, Sugen 5416, BMS 354825, Avastin, Cl 1033, Sorafenib, Sutent, TLK286, ABX-EGF for most preferably.
The percentage by weight of cancer therapy drug in sustained-release micro-spheres is 0.5%-60%, is good with 2%-40%, is best with 5%-30%.During taxane and its synergist (steroids anti-cancer drugs and/or vasoinhibitor) use in conjunction, the weight ratio of taxane and steroids anti-cancer drugs and/or vasoinhibitor is that the weight ratio of taxane and taxane synergist is 1-9: 1 to 1: 1-9, with 1-2: 1 serves as preferred.
Anticancer effective component in the slow-releasing anticarcinogen injection microsphere of the present invention is preferably as follows, and all is weight percentage:
(a) paclitaxel of 2-40%, Docetaxel, 2 '-hydroxyl paclitaxel, 10-remove acetyl paclitaxel, 7-table-paclitaxel;
(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;
(c) triptorelin of the paclitaxel of 2-40% or Docetaxel and 5-30%, goserelin, leuprorelin, Anastrozole, idoxifene, Miproxifene, tamoxifen, 4-monohydroxy tamoxifen (OH-TAM), 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;
(d) gefitinib of 5-30%, Erlotinib, Lapatinib, votaranib, WAY-EKB 569, NSC 609974, thalidomide, LS-2616, angiostatin, Endostatin, blood vessel endothelium chalone, imatinib mesylate, Sugen 5416, BMS 354825, Avastin, Cl 1033, Sorafenib, Sutent, TLK286 or ABX-EGF;
(e) combination of the gefitinib of the paclitaxel of 2-40% or Docetaxel and 5-30%, Erlotinib, Lapatinib, votaranib, WAY-EKB 569, NSC 609974, thalidomide, LS-2616, angiostatin, Endostatin, blood vessel endothelium chalone, imatinib mesylate, Sugen 5416, BMS 354825, Avastin, Cl 1033, Sorafenib, Sutent, TLK286 or ABX-EGF;
(f) gefitinib of 5-30%, Erlotinib, Lapatinib, votaranib, WAY-EKB 569, NSC 609974, thalidomide, LS-2616, angiostatin, Endostatin, the blood vessel endothelium chalone, imatinib mesylate, Sugen 5416, BMS 354825, Avastin, Cl 1033, Sorafenib, Sutent, the triptorelin of TLK286 or ABX-EGF and 5-30%, goserelin, leuprorelin, Anastrozole, idoxifene, Miproxifene, tamoxifen, 4-monohydroxy tamoxifen (OH-TAM), 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.
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).
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 copolymer (PLGA) of the preferred polylactic acid of slow-release auxiliary material (PLA), polyglycolic acid and hydroxyacetic acid, ethylene vinyl acetate copolymer (EVAc), FAD: SA copolymer, polifeprosan, bis-fatty acid and decanedioic acid copolymer (PFAD-SA)], one of poly-(erucic acid dimer-decanedioic acid) [P (EAD-SA)], poly-(fumaric acid-decanedioic acid) [P (FA-SA)] or its combination.
When selecting 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 are 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, 5000-150, and 000, but with 20,000-60,000 is preferred, with 30,000-50,000 for most preferably; The molecular weight of polyglycolic acid can be, but is not limited to, 5000-100, and 000, but with 20,000-60,000 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, 5000-150,000, but with 20,000-60,000 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 various high molecular polymers, with polylactic acid, decanedioic acid, the mixture or the copolymer that contain the macromolecule polymer of polylactic acid or certain herbaceous plants with big flowers diacid is first-selection, mixture and copolymer can be selected from, but be not limited to the mixture or the copolymer of the mixture of PLA, PLGA, glycolic and hydroxy carboxylic acid, certain herbaceous plants with big flowers diacid and fragrant polyanhydride or aliphatic polyanhydride.The blend ratio of glycolic and hydroxy carboxylic acid is 10/90-90/10 (weight), preferably 25/75-75/25 (weight).The method of blend is arbitrarily.Content when glycolic and hydroxy carboxylic acid copolymerization is respectively percentage by weight 10-90% and 90-10%.The representative of fragrance polyanhydride is 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.
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.
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 sustained-release microparticle is directly mixed in special solvent, obtains corresponding sustained-release microparticle injection; Another kind is that sustained-release microparticle is mixed in special solvent or common solvent, obtains corresponding sustained-release microparticle injection; Another is that sustained-release microparticle is mixed in common solvent, adds the suspending agent mixing then, obtains corresponding sustained-release microparticle injection.Except, also can earlier sustained-release microparticle 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 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 is (as PLA, polylactide, polycaprolactone and copolymer thereof (molecular weight 1500-25000) hydrophobic block as the 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.
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.
The application of injection be with full-bodied special solvent with pastille microgranule, particularly sustained-release microparticle, make corresponding slow releasing injection, thus make corresponding medicine can with the injection mode import in the patient or mammalian body of required medicine.The medicine that is injected can be, but is not limited to, said medicine micropowder or medicament slow release microgranule.
The route of administration of injection depends on multiple factor.Though can be through the number of ways 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.
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, but with the high molecular weight water soluble polymer is main separation, in various high molecular polymers, with polylactic acid, certain herbaceous plants with big flowers diacid, the mixture or the copolymer that contain the macromolecule polymer of polylactic acid or certain herbaceous plants with big flowers diacid is first-selection, mixture and copolymer can be selected from, but be not limited to the mixture or the copolymer of the mixture of PLA, PLGA, PLA and PLGA, FAD:SA copolymer, certain herbaceous plants with big flowers diacid and fragrant polyanhydride or aliphatic polyanhydride.Polylactic acid (PLA) and polyglycolic acid the blend ratio be 10/90-90/10 (weight), 25/75-75/25 (weight) preferably.The method of blend is arbitrarily.Content when glycolic and lactic acid copolymerization is respectively percentage by weight 10-90% and 90-10%.The representative of fragrance polyanhydride is to carboxy phenyl propane (p-CPP), content during to carboxy phenyl propane (p-CPP) and the copolymerization of certain herbaceous plants with big flowers diacid is respectively percentage by weight 10-60% and 20-90%, the blend weight ratio is 10-40: 50-90, preferably weight ratio 15-30: 65-85.
Except that above-mentioned adjuvant, also can select for use other materials to see United States Patent (USP) (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.
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 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.
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, taxane and synergist thereof can be 0.1-1000 milligram/kg body weight, with 1-600 milligram/kg body weight is ideal, with 5-80 milligram/kg body weight for the most desirable, hormone anti-cancer medicine can be 0.1-500 milligram/kg body weight, with 1-120 milligram/kg body weight is ideal, with 5-50 milligram/kg body weight for the most desirable.
The present invention can be used for preparation treatment people, the pharmaceutical preparation of the various entity tumors of house pet and animal, be mainly sustained-release implant and slow releasing injection, entity tumor comprises the tumor that originates from brain and central nervous system, also comprises originating from kidney, liver, gallbladder, incidence, the oral cavity, thyroid, skin, mucosa, body of gland, blood vessel, osseous tissue, lymph node, lungs, esophagus, stomach, mammary gland, pancreas, eyes, nasopharynx part, the uterus, ovary, endometrium, cervix uteri, prostate, bladder, colon, former or cancer or sarcoma or the carcinosarcoma that shifts of rectum.
Also can add other medicinal ingredient in anti-cancer sustained-released implantation agent of the present invention and the slow releasing injection, as, but be not limited to antibiotics, antalgica, anticoagulant medicine, hemorrhage etc.Above medicinal ingredient can singly select or multiselect, can join the compositions that contains or do not contain additive, and its content is because of specifically deciding.
Above-mentioned effective ingredient is packaged in the pharmaceutic adjuvant, then topical application optionally.Good as injecting or be placed as in selective arterial injection and the direct tumor body, be the best with part placement or injection again wherein.When used the part, anti-cancer sustained-released implantation agent of the present invention can directly place around former or the entity tumor that shifts or in the tumor body, also can directly place or be injected in former or all or part of excision of entity tumor shifted formed intracavity afterwards.
Main Ingredients and Appearance of the present invention is holder with the biocompatible substance, so do not cause foreign body reaction.Support to place in the object back degradable and absorb, so no longer operation is taken out, because of at tumor by local release contained drug, thereby optionally improve and prolong local drug concentration, the while can be reduced the general toxic reaction that is caused by the conventional route administration.
Above cancer therapy drug local injection or placement not only can overcome the toxic reaction that the whole body administration brings, and solved the tumor by local drug level and cross the low and cell sensitive question to medicine.Effective killing tumor cell, and can suppress tumor vessel simultaneously, therefore, have unique advantages.
Clinical needs are depended in the packing of taxane and/or taxane synergist and application.Taxane and taxane synergist can be packed alone or in combination.Assembly packaging is mainly used in local potentiation, and separately packing then is mainly used in to the potentiation of different approaches administration or to the potentiation of other therapies.As, local separately placement (or injection) taxane and taxane synergist then can be united with the taxane synergist and the taxane of intravenous applications respectively; The taxane and/or the taxane synergist of local placement the (or injection) also can be used for radiocurable potentiation.
By following test and embodiment technology of the present invention is further described:
The local drug concentration that test 1, different modes are used behind the taxane (paclitaxel) 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 5mg/kg.Measure medicament contg (%) in the different time tumor, the result shows, the local drug concentration significant difference of paclitaxel 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 taxane (paclitaxel) 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 5mg/kg.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 paclitaxel 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 paclitaxel and paclitaxel 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 paclitaxel group, paclitaxel synergist group, paclitaxel and paclitaxel synergist group.Drug dose is 5mg/kg, through intratumor injection.The treatment back was measured gross tumor volume size, relatively therapeutic effect (seeing Table 1) on the 10th day.
Table 1
| Group | Paclitaxel | Synergist | Tumor control rate (%) | The P value |
| 1 | + | - | 64 | * |
| 2 | - | Triptorelin | 46 | * |
| 3 | - | Goserelin | 42 | * |
| 4 | - | Leuprorelin | 38 | * |
| 5 | - | Anastrozole | 48 | * |
| 6 | - | Idoxifene | 36 | * |
| 7 | + | Triptorelin | 86 | ** |
| 8 | + | Goserelin | 82 | ** |
| 9 | + | Leuprorelin | 88 | ** |
| 10 | + | Anastrozole | 86 | ** |
| 11 | + | Idoxifene | 82 | ** |
Above result shows, taxane (paclitaxel) and used paclitaxel 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, paclitaxel and paclitaxel 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.Paclitaxel and paclitaxel 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 | Purple | A | B | C | D | E | Purple+A | Purple+B | Purple+C | Purple+D | Purple+E |
| CNS | 52 | 50 | 48 | 38 | 58 | 42 | 88 | 88 | 82 | 78 | 88 |
| C6 | 54 | 52 | 46 | 36 | 64 | 40 | 90 | 80 | 84 | 84 | 90 |
| SA | 52 | 58 | 36 | 42 | 62 | 48 | 88 | 84 | 86 | 82 | 82 |
| BC | 58 | 54 | 40 | 42 | 64 | 54 | 88 | 80 | 74 | 74 | 80 |
| BA | 68 | 46 | 38 | 48 | 60 | 56 | 80 | 80 | 92 | 92 | 80 |
| LH | 66 | 56 | 40 | 52 | 58 | 60 | 90 | 82 | 94 | 78 | 94 |
| PAT | 60 | 48 | 46 | 50 | 54 | 68 | 82 | 76 | 82 | 80 | 80 |
Above result shows, used purple (paclitaxel) and paclitaxel synergist (A wherein: Miproxifene, 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, paclitaxel and paclitaxel 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.Paclitaxel and paclitaxel 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 paclitaxel and paclitaxel synergist (anticancer steroid alkene phenol, Drogenil, aminoglutethimide, (.+-.)-Pyridoglutethimide, megestrol), can show significant potentiation (P＜0.01) when use in conjunction.
The tumor-inhibiting action of test 6, paclitaxel and paclitaxel 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 (paclitaxel or paclitaxel synergist) and therapeutic alliance group (paclitaxel and paclitaxel 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 paclitaxel and paclitaxel synergist (medroxyprogesterone, toremifene, Anastrozole, exemestane), can show significant potentiation (P＜0.01) when use in conjunction.
The tumor-inhibiting action of test 7, paclitaxel and paclitaxel 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.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 (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) | Paclitaxel | 58 | ＜0.05 |
| 3(6) | Gefitinib | 50 | ＜0.01 |
| 4(6) | Erlotinib | 40 | ＜0.01 |
| 5(6) | Lapatinib | 36 | ＜0.01 |
| 6(6) | Votaranib | 36 | ＜0.01 |
| 7(6) | Paclitaxel+gefitinib | 86 | ＜0.001 |
| 8(6) | Paclitaxel+Erlotinib | 88 | ＜0.001 |
| 9(6) | Paclitaxel+Lapatinib | 94 | ＜0.001 |
| 10(6) | Paclitaxel+votaranib | 96 | ＜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 paclitaxel and paclitaxel synergist-vasoinhibitor (gefitinib, Erlotinib, Lapatinib, votaranib), can show significant potentiation when use in conjunction.
The tumor-inhibiting action of test 8, paclitaxel and paclitaxel 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) | Docetaxel | 58 | ＜0.05 |
| 3(6) | WAY-EKB 569 | 58 | ＜0.05 |
| 4(6) | Thalidomide | 36 | ＜0.05 |
| 5(6) | LS-2616 | 46 | ＜0.05 |
| 6(6) | Angiostatin | 36 | ＜0.01 |
| 7(6) | Docetaxel+WAY-EKB 569 | 84 | ＜0.01 |
| 8(6) | Docetaxel+thalidomide | 86 | ＜0.01 |
| 9(6) | Docetaxel+LS-2616 | 92 | ＜0.01 |
| 10(6) | Docetaxel+angiostatin | 92 | ＜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 Docetaxel and Docetaxel synergist-vasoinhibitor (WAY-EKB 569, NSC 609974, thalidomide, LS-2616, angiostatin), can show significant potentiation when use in conjunction.
The tumor-inhibiting action of test 9, paclitaxel and paclitaxel synergist (sustained-release implant)
By the tumor-inhibiting action of test 8 described methods mensuration paclitaxels and paclitaxel synergist (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) | Paclitaxel | 58 | ＜0.05 |
| 3(6) | Endostatin | 40 | ＜0.01 |
| 4(6) | The methanesulfonic acid methanesulfonic acid | 50 | ＜0.01 |
| 5(6) | Sugen 5416 | 40 | ＜0.01 |
| 6(6) | BMS 354825 | 42 | ＜0.01 |
| 7(6) | Paclitaxel+Endostatin | 88 | ＜0.001 |
| 8(6) | Paclitaxel+methanesulfonic acid methanesulfonic acid | 84 | ＜0.001 |
| 9(6) | Paclitaxel+Sugen 5416 | 82 | ＜0.001 |
| 10(6) | Paclitaxel+BMS 354825 | 44 | ＜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 paclitaxel and paclitaxel synergist-vasoinhibitor (Endostatin, imatinib mesylate, Sugen 5416, BMS 354825), can show significant potentiation when use in conjunction.
The tumor-inhibiting action of test 10, paclitaxel and paclitaxel synergist (slow releasing injection)
By the tumor-inhibiting action of test 8 described methods mensuration paclitaxels and paclitaxel synergist (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) | Paclitaxel | 58 | ＜0.05 |
| 3(6) | Avastin | 48 | ＜0.01 |
| 4(6) | Cl 1033 | 38 | ＜0.01 |
| 5(6) | Sorafenib | 40 | ＜0.01 |
| 6(6) | Sutent | 50 | ＜0.01 |
| 7(6) | Paclitaxel+Avastin | 84 | ＜0.001 |
| 8(6) | Paclitaxel+Cl 1033 | 88 | ＜0.001 |
| 9(6) | Paclitaxel+Sorafenib | 80 | ＜0.001 |
| 10(6) | Paclitaxel+Sutent | 92 | ＜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 paclitaxel and paclitaxel synergist-vasoinhibitor (Avastin, Cl 1033, Sorafenib, Sutent), can show significant potentiation when use in conjunction.
The tumor-inhibiting action of test 11, taxane synergist (slow releasing injection)
Measure the tumor-inhibiting action of taxane synergist (slow releasing injection) by test 5 described methods.The result shows, used taxane synergist (anticancer steroid alkene phenol, Drogenil, aminoglutethimide, (.+-.)-Pyridoglutethimide, megestrol) all has obvious suppression effect (P＜0.05) to kinds of tumor cells growth when using separately, can show significant potentiation (P＜0.01) when with vasoinhibitor use in conjunction such as gefitinib, Erlotinib, Lapatinib, votaranib.
The tumor-inhibiting action of test 12, taxane synergist (slow releasing injection)
Measure the tumor-inhibiting action of taxane synergist (slow releasing injection) by test 5 described methods.The result shows, used taxane synergist (medroxyprogesterone, toremifene, Anastrozole, exemestane) all has obvious suppression effect (P＜0.05) to kinds of tumor cells growth when using separately, can show significant potentiation (P＜0.01) when with vasoinhibitor use in conjunction such as WAY-EKB 569, NSC 609974, thalidomide, LS-2616, angiostatin.
The tumor-inhibiting action of test 13, taxane synergist (slow releasing injection)
Measure the tumor-inhibiting action of taxane synergist (slow releasing injection) by test 5 described methods.The result shows, used taxane synergist (medroxyprogesterone, toremifene, Anastrozole, exemestane) all has obvious suppression effect (P＜0.05) to kinds of tumor cells growth when using separately, can show significant potentiation (P＜0.01) when with vasoinhibitor use in conjunction such as Endostatin, blood vessel endothelium chalone, imatinib mesylate, Sugen 5416, BMS 354825, Avastin, Cl 1033, Sorafenib, Sutent.
In a word, growth all had the obvious suppression effect to kinds of tumor cells when used taxane and various taxane synergist were used separately, when use in conjunction, can show significant potentiation, growth all had the obvious suppression effect to kinds of tumor cells when various taxane synergists were used separately, also can show significant potentiation when use in conjunction.Therefore, effective ingredient of the present invention is the combination of taxane and/or any one or several taxane synergist or the combination of several taxane synergists.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): certain herbaceous plants with big flowers diacid (SA) is 20: 80) copolymer is put into container, add the 100ml dichloromethane, behind the dissolving mixing, add 10mg paclitaxel and leuprorelin, shake up the back contains 10% paclitaxel and 10% leuprorelin with spray drying method for preparation injectable microsphere again.Then microsphere is suspended in the normal saline that contains 15% mannitol, makes corresponding suspension type slow releasing injection, 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:
(1) paclitaxel of 2-40%, Docetaxel, 2 '-hydroxyl paclitaxel, 10-remove acetyl paclitaxel or 7-table-paclitaxel;
(2) triptorelin of 5-30%, 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; Or
(3) triptorelin of the paclitaxel of 2-40% and 5-30%, 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 the combination of bicalutamide.
The viscosity of above 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 paclitaxel and 15mg gefitinib, 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% paclitaxel and 10% gefitinib, 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) gefitinib of 5-30%, Erlotinib, Lapatinib, votaranib, WAY-EKB 569, NSC 609974, thalidomide, LS-2616, angiostatin, Endostatin, imatinib mesylate, Sugen 5416, BMS 354825, Avastin, Cl 1033, Sorafenib, Sutent, TLK286 or ABX-EGF; Or
(2) paclitaxel of 2-40%, Docetaxel, 2 '-hydroxyl paclitaxel, 10-go the combination of gefitinib, Erlotinib, Lapatinib, votaranib, WAY-EKB 569, NSC 609974, thalidomide, LS-2616, angiostatin, Endostatin, imatinib mesylate, Sugen 5416, BMS 354825, Avastin, Cl 1033, Sorafenib, Sutent, TLK286 or the ABX-EGF of acetyl paclitaxel or 7-table-paclitaxel and 5-30%.
The viscosity of above 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 Docetaxels and 10 milligrams of tamoxifens, shake up the back contains 20% Docetaxel 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 triptorelin of the paclitaxel of 10-20% or Docetaxel and 10-20%, 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 the combination of bicalutamide, the slow releasing injection viscosity is 500cp-600cp (25 ℃-30 ℃ time).
Embodiment 7.
70mg polifeprosan (to carboxy phenyl propane (p-CPP): certain herbaceous plants with big flowers diacid (SA) is 20: 80) copolymer is put into container, add 100 milliliters of dichloromethane, behind the dissolving mixing, add 20mg paclitaxel and 10mg gefitinib, shake up the back contains 20% paclitaxel and 10% gefitinib 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 combination of the gefitinib of the paclitaxel of 5-20% or Docetaxel and 10-20%, Erlotinib, Lapatinib, votaranib, WAY-EKB 569, NSC 609974, thalidomide, LS-2616, angiostatin, Endostatin, imatinib mesylate, Sugen 5416, BMS 354825, Avastin, Cl 1033, Sorafenib, Sutent, TLK286 or ABX-EGF.The viscosity of above injection is 400cp-560cp (25 ℃-30 ℃ time).
Embodiment 9
70mg polifeprosan (to carboxy phenyl propane (p-CPP): certain herbaceous plants with big flowers diacid (SA) is 20: 80) copolymer is put into container, add 100 milliliters of dichloromethane, behind the dissolving mixing, add 20mg paclitaxel and 10mg Erlotinib, shake up the back contains 20% paclitaxel and 10% Erlotinib 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: the combination of 20% the paclitaxel polyenoid or gefitinib, Erlotinib, Lapatinib, votaranib, WAY-EKB 569, NSC 609974, thalidomide, LS-2616, angiostatin, Endostatin, imatinib mesylate, Sugen 5416, BMS 354825, Avastin, Cl 1033, Sorafenib, Sutent, TLK286 or the ABX-EGF of paclitaxel and 10%; Viscosity is 560cp-640cp (25 ℃-30 ℃ time).
Embodiment 11
70mg polifeprosan (to carboxy phenyl propane (p-CPP): certain herbaceous plants with big flowers diacid (SA) is 20: 80) copolymer is put into container, add 100 milliliters of dichloromethane, behind the dissolving mixing, add 10mg Anastrozole and 20mg paclitaxel, shake up the back contains 10% Anastrozole and 20% paclitaxel 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 contained anticancer effective component is: 20% paclitaxel or Docetaxel and 10% 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, the 4-trans-Hydroxytamoxifen, Drogenil, aminoglutethimide, (.+-.)-Pyridoglutethimide, megestrol, medroxyprogesterone, clomifene, toremifene, letrozole, Anastrozole, the combination of exemestane or bicalutamide.
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 tamoxifen and 20mg imatinib, shake up the back contains 10% tamoxifen and 20% imatinib 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, and different is that contained anticancer effective component is:
(1) triptorelin of the paclitaxel of 2-40% or Docetaxel and 5-30%, goserelin, leuprorelin, Anastrozole, idoxifene, Miproxifene, tamoxifen, 4-monohydroxy tamoxifen (OH-TAM), 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;
(2) 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, the 4-trans-Hydroxytamoxifen, Drogenil, aminoglutethimide, (.+-.)-Pyridoglutethimide, megestrol, medroxyprogesterone, clomifene, toremifene, letrozole, Anastrozole, the gefitinib of exemestane or bicalutamide and 5-30%, Erlotinib, Lapatinib, votaranib, WAY-EKB 569, NSC 609974, thalidomide, LS-2616, angiostatin, Endostatin, imatinib mesylate, Sugen 5416, BMS 354825, Avastin, Cl 1033, Sorafenib, Sutent, the combination of TLK286 or ABX-EGF; Or
(3) combination of the gefitinib of the paclitaxel of 2-40% or Docetaxel and 5-30%, Erlotinib, Lapatinib, votaranib, WAY-EKB 569, NSC 609974, thalidomide, LS-2616, angiostatin, Endostatin, imatinib mesylate, Sugen 5416, BMS 354825, Avastin, Cl 1033, Sorafenib, Sutent, TLK286 or ABX-EGF.
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): certain herbaceous plants with big flowers diacid (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 1-15, 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 with loaded taxane and synergist thereof is a slow releasing injection, is grouped into by following one-tenth:
(A) sustained-release micro-spheres comprises:
Anticancer effective component 0.5-60%
Slow-release auxiliary material 40-99%
More than be weight percentage
With
(B) solvent is for common solvent or contain the special solvent of suspending agent.
Wherein,
Anticancer effective component is the combination of taxane and/or taxane synergist, and taxane is selected from paclitaxel, Docetaxel (docetaxel), 2 '-hydroxyl taxol, 10-and removes acetyl taxol or 7-table-taxol; The taxane synergist is steroids anti-cancer drugs and/or vasoinhibitor;
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.
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 is characterized in that steroids anti-cancer drugs is selected from 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 paclitaxel of the combination 2-40% of exemestane or bicalutamide and the wortmannin of 2-40%, .alpha.-5:6-benzopyran, 2-(morphol-4-yl)-.alpha.-5:6-benzopyran-4-base, 2-(4-Lin Ji)-8-phenylchromone, 1-(2-hydroxyl-4-morphol-4-base-phenyl)-ethano-), inhibitors of kinases, vanillin, 2-aminopurine, 7-ethyl-10-hydroxycamptothecine, phenylbutyric acid salt, methylamine, methoxamine, hydroxylamine, minocycline, the O-hydroxylamine, one of O-methyl hydroxylamine or O-6-ammonia oxygen-butyl hydroxylamine or its combination.
3. the slow-releasing anticarcinogen injection according to claim 1 is characterized in that vasoinhibitor is selected from one of gefitinib, Erlotinib, Lapatinib, votaranib, WAY-EKB 569, NSC 609974, thalidomide, LS-2616, angiostatin, Endostatin, imatinib mesylate, Sugen 5416, BMS 354825, Avastin, Cl 1033, Sorafenib, Sutent, TLK286, ABX-EGF or its combination.
4. the slow-releasing anticarcinogen injection according to claim 1 is characterized in that the anticancer effective component of slow-releasing anticarcinogen injection is:
(1) paclitaxel of 2-40% or Docetaxel;
(2) 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;
(3) gefitinib of 5-30%, Erlotinib, Lapatinib, votaranib, WAY-EKB 569, NSC 609974, thalidomide, LS-2616, angiostatin, Endostatin, imatinib mesylate, Sugen 5416, BMS 354825, Avastin, Cl 1033, Sorafenib, Sutent, TLK286 or ABX-EGF;
(4) triptorelin of the paclitaxel of 2-40% or Docetaxel 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, 4-trans-Hydroxytamoxifen, Drogenil, aminoglutethimide, (.+-.)-Pyridoglutethimide, megestrol, medroxyprogesterone, clomifene, toremifene, letrozole, Anastrozole, exemestane or the combination of bicalutamide;
(5) combination of the gefitinib of the paclitaxel of 2-40% or Docetaxel and 5-30%, Erlotinib, Lapatinib, votaranib, WAY-EKB 569, NSC 609974, thalidomide, LS-2616, angiostatin, Endostatin, imatinib mesylate, Sugen 5416, BMS 354825, Avastin, Cl 1033, Sorafenib, Sutent, TLK286 or ABX-EGF; Or
(6) 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, the 4-trans-Hydroxytamoxifen, Drogenil, aminoglutethimide, (.+-.)-Pyridoglutethimide, megestrol, medroxyprogesterone, clomifene, toremifene, letrozole, Anastrozole, the gefitinib of exemestane or bicalutamide and 5-30%, Erlotinib, Lapatinib, votaranib, WAY-EKB 569, NSC 609974, thalidomide, LS-2616, angiostatin, Endostatin, imatinib mesylate, Sugen 5416, BMS 354825, Avastin, Cl 1033, Sorafenib, Sutent, the combination of TLK286 or ABX-EGF.
5. the slow-releasing anticarcinogen injection according to claim 1 is characterized in that slow-release auxiliary material is selected from one of following or its combination:
A) polylactic acid, molecular weight peak value are 10000-30000,300000-60000,60000-100000 or 100000-150000;
B) copolymer of polyglycolic acid and hydroxyacetic acid, 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;
D) polifeprosan, to carboxy phenyl propane: the certain herbaceous plants with big flowers diacid is 10: 90,20: 80,30: 70,40: 60,50: 50 or 60: 40;
D) bis-fatty acid and decanedioic acid copolymer;
E) poly-(erucic acid dimer-decanedioic acid);
F) poly-(fumaric acid-decanedioic acid);
G) xylitol, oligosaccharide, chrondroitin, chitin, hyaluronic acid, collagen protein, gelatin or white tempera.
6. 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.
7. the slow-releasing anticarcinogen injection according to claim 1, it is characterized in that slow-releasing anticarcinogen injection is used for the preparation treatment and originates from people and animal brain, the central nervous system, kidney, liver, gallbladder, incidence, the oral cavity, thyroid, skin, mucosa, body of gland, blood vessel, osseous tissue, lymph node, lungs, esophagus, stomach, mammary gland, pancreas, eyes, nasopharynx part, the uterus, ovary, endometrium, cervix uteri, prostate, bladder, former or the cancer of secondary of colon or rectum, the sustained-release implant of sarcoma or carcinosarcoma is in tumor or tumor week injection or place administration.
8. the anti-cancer sustained-released implantation agent according to claim 7 is characterized in that the contained anticancer effective component of described sustained-release implant is:
(a) paclitaxel of 2-40%, Docetaxel, 2 '-hydroxyl paclitaxel, 10-remove acetyl paclitaxel, 7-table-paclitaxel;
(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;
(c) triptorelin of the paclitaxel of 2-40% or Docetaxel and 5-30%, goserelin, leuprorelin, Anastrozole, idoxifene, Miproxifene, tamoxifen, 4-monohydroxy tamoxifen (OH-TAM), 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;
(d) gefitinib of 5-30%, Erlotinib, Lapatinib, votaranib, WAY-EKB 569, NSC 609974, thalidomide, LS-2616, angiostatin, Endostatin, blood vessel endothelium chalone, imatinib mesylate, Sugen 5416, BMS 354825, Avastin, Cl 1033, Sorafenib, Sutent, TLK286 or ABX-EGF;
(e) combination of the gefitinib of the paclitaxel of 2-40% or Docetaxel and 5-30%, Erlotinib, Lapatinib, votaranib, WAY-EKB 569, NSC 609974, thalidomide, LS-2616, angiostatin, Endostatin, blood vessel endothelium chalone, imatinib mesylate, Sugen 5416, BMS 354825, Avastin, Cl 1033, Sorafenib, Sutent, TLK286 or ABX-EGF; Or
(f) gefitinib of 5-30%, Erlotinib, Lapatinib, votaranib, WAY-EKB 569, NSC 609974, thalidomide, LS-2616, angiostatin, Endostatin, the blood vessel endothelium chalone, imatinib mesylate, Sugen 5416, BMS 354825, Avastin, Cl 1033, Sorafenib, Sutent, the triptorelin of TLK286 or ABX-EGF and 5-30%, goserelin, leuprorelin, Anastrozole, idoxifene, Miproxifene, tamoxifen, 4-monohydroxy tamoxifen (OH-TAM), 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.
Below all be weight percentage.
9. the anti-cancer sustained-released implantation agent according to claim 7 is characterized in that 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.
10. the anti-cancer sustained-released implantation agent according to claim 7, it is one of following to it is characterized in that slow-release auxiliary material is selected from:
A) polylactic acid, molecular weight peak value are 5000-15000,10000-20000,20000-35000,30000-50000,50000-100000 or 100000-150000;
B) copolymer of polyglycolic acid and hydroxyacetic acid, the molecular weight peak value is 5000-15000,10000-20000,20000-35000,30000-50000,50000-100000 or 100000-150000, wherein, the ratio of polyglycolic acid and hydroxyacetic acid is 50-95: 50-50;
C) polifeprosan, to carboxy phenyl propane: the certain herbaceous plants with big flowers diacid is 10: 90,20: 80,30: 70,40: 60,50: 50 or 60: 40;
D) xylitol, oligosaccharide, chrondroitin, chitin, hyaluronic acid, collagen protein, gelatin or white tempera.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
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| CNA2006102001131A CN1846688A (en) | 2006-02-10 | 2006-02-10 | Slow-released anticancer prepn containing taxane and its synergist |
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| CNA2006102001131A CN1846688A (en) | 2006-02-10 | 2006-02-10 | Slow-released anticancer prepn containing taxane and its synergist |
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| Application Number | Title | Priority Date | Filing Date |
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| CNA2008103029646A Division CN101380296A (en) | 2006-02-10 | 2006-02-10 | Anticancer sustained-release formulation loaded with platinum compound and synergist thereof |
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| CN1846688A true CN1846688A (en) | 2006-10-18 |
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| CNA2006102001131A Pending CN1846688A (en) | 2006-02-10 | 2006-02-10 | Slow-released anticancer prepn containing taxane and its synergist |
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