CN1883451A - A sustained-release anticancer injection containing angiogenesis inhibitor and synergist thereof - Google Patents
A sustained-release anticancer injection containing angiogenesis inhibitor and synergist thereof Download PDFInfo
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- CN1883451A CN1883451A CNA2006102005202A CN200610200520A CN1883451A CN 1883451 A CN1883451 A CN 1883451A CN A2006102005202 A CNA2006102005202 A CN A2006102005202A CN 200610200520 A CN200610200520 A CN 200610200520A CN 1883451 A CN1883451 A CN 1883451A
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Abstract
Disclosed is an anti-cancer medicament containing blood vessel inhibitor and synergistic agent, wherein the slow release injection comprises slow release microspheres and dissolvent, wherein the slow release microballoons comprise anti-cancer active constituents and slow release auxiliary materials, the dissolvent being specific dissolvent containing suspension adjuvant. the anticancer active constituents include blood vessel inhibiting agent and / or blood vessel depressant synergistic agent selected from hormone anti-cancer drugs and / or platinum-group compounds, the slow release auxiliary materials include one selected from poly-D,L-lactic acid and its copolymer, polyethylene glycol mono methyl and polylactic acid copolymer, polyethylene glycol and polylactic acid copolymer, PLA-COOH and glycollic acid copolymer, di-aliphatic acid and sebacylic acid copolymer, poly(erucic aciddipolymer-sebacylic acid), poly(fumaric acid-sebacylic acid), Polifeprosan, ethylene-vinylacetate copolymer or their combination.
Description
(1) technical field
The present invention relates to a kind of slow-releasing anticarcinogen injection that contains vasoinhibitor 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 carried with blood-vessel inhibiting and/or its synergist.
(2) background technology
Treatment for cancer still mainly comprises methods such as operation, radiotherapy and chemotherapy at present.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 chemotherapeutics 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.1998Oct 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, 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, 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 vasoinhibitor and synergist thereof is provided, particularly, is a kind of slow releasing injection and sustained-release implant that contains vasoinhibitor and/or its synergist.
The vasoinhibitor 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.Vasoinhibitor can suppress or destroy the blood vessel of tumor effectively and can suppress the formation of the new vessels 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 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.
The present invention finds that many medicines and vasoinhibitor share its antitumaous effect is strengthened mutually, below the vasoinhibitor antitumaous effect will be increased mutually medicine be referred to as the vasoinhibitor synergist; In addition, the combination of vasoinhibitor or vasoinhibitor 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 vasoinhibitor 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 vasoinhibitor and/or vasoinhibitor synergist, and the vasoinhibitor 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 range of viscosities IV (dl/g) is 0.1～0.8, be selected from poly-dl-lactide (D, L-PLA), poly-dl-lactide/ethanol copolymer (D, L-PLGA), monomethyl polyethylene glycol (MPEG-PLA), monomethyl polyethylene glycol copolymer (MPEG-PLGA), polyethylene glycol (PLA-PEG-PLA), polyethylene glycol copolymer (PLGA-PEG-PLGA), end carboxyl polylactic acid (PLA-COOH), end carboxyl polylactic acid/ethanol copolymer (PLGA-COOH), 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), the copolymer of polyglycolic acid and hydroxyacetic acid (PLGA), PPDO (PDO), PTMC (PTMC), xylitol, oligosaccharide, chrondroitin, chitin, hyaluronic acid, collagen protein, gelatin, one of albumin glue 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.
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] furan-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-1-amine to votaranib; vatalanib; PTK-787; PTK/ZK; Schering VEGF-TK1; 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; blood vessel endothelium chalone (endostar; the grace degree); (Imatinib mesylate has another name called imatinib mesylate, Glivec) to imatinib mesylate; 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] benzamidemethanesulfonate; STI 571, CGP-57148B, STI-571A; CGP 57148); 5-[5-fluoro-2-oxygen-1, the 2-indoline-(3Z)-and 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); 3,3-two chloro-5-(4-sulfonyloxy methyl yl pyridines)-2-dihydroindole ketone (3; 3-Dichloro-5-(4-methylpiperidinosulfonyl)-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); (3-((4 for Sugen 5416; 5-dimethyl-1H-pyrroles-2-yl) methylene)-1,3-dihydro-[CAS] (3-((4,5-dimethyl-1H-pyrrol-2-yl) methylene)-1; 3-dihydro-[CAS]; SU5614, semaxanib, SU-011271; SU-011606; SU-11612)); pyrroles's lactone dihydroindole ketone (pyrrolyllactoneindolinones, SU6577); the 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)-(and 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-(3-1 (2 for 5-methoxyl group-2-dihydroindole ketone; 6-dimethylimidazo[2,1-bJ-thiazol-5-yl] methylenel-5-methoxy-2-indolinone, DMMI; SU9518]; imidazoles [2; 1-b] and 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), cpd 1); 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, and 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).
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.
Above-mentioned vasoinhibitor is with gefitinib; Erlotinib; Lapatinib; votaranib; WAY-EKB 569; NSC 609974; thalidomide; LS-2616; angiostatin; Endostatin; the blood vessel endothelium chalone; 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 is preferred.
Above-mentioned vasoinhibitor can singly select or multiselect, with gefitinib, Erlotinib, Lapatinib, votaranib, WAY-EKB 569, NSC 609974, thalidomide, LS-2616, angiostatin, Endostatin, blood vessel endothelium chalone, imatinib mesylate, LS-2616, Sugen 5416, BMS 354825, Avastin, Cl 1033, Sorafenib, Sutent, TLK286, ABX-EGF for most preferably.
Above-mentioned vasoinhibitor shared percentage by weight in slow releasing agent is decided because of concrete condition, can be 0.1%-50%, is good with 1%-40%, and 5%-30% is best.
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; 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 (diethyl stilbestrol); 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.
Anticancer effective component in the slow-releasing anticarcinogen injection microsphere of the present invention is preferably as follows, and all is weight percentage:
(1) gefitinib of 1-40%, Erlotinib, Lapatinib, votaranib, WAY-EKB 569, NSC 609974, thalidomide, LS-2616, angiostatin, Endostatin, blood vessel endothelium chalone, imatinib mesylate, LS-2616, Sugen 5416, BMS 354825, Avastin, Cl 1033, Sorafenib, Sutent, TLK286 or ABX-EGF;
(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) gefitinib of 1-40%, Erlotinib, Lapatinib, votaranib, WAY-EKB 569, NSC 609974, thalidomide, LS-2616, angiostatin, Endostatin, the blood vessel endothelium chalone, imatinib mesylate, LS-2616, Sugen 5416, BMS 354825, Avastin, Cl 1033, Sorafenib, Sutent, the cisplatin of TLK286 or ABX-EGF 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) gefitinib of 1-40%, Erlotinib, Lapatinib, votaranib, WAY-EKB 569, NSC 609974, thalidomide, LS-2616, angiostatin, Endostatin, the blood vessel endothelium chalone, imatinib mesylate, LS-2616, Sugen 5416, BMS 354825, Avastin, Cl 1033, Sorafenib, Sutent, the triptorelin of TLK286 or ABX-EGF 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.
Slow-release auxiliary material is selected from poly-dl-lactide, poly-dl-lactide/ethanol copolymer, the monomethyl polyethylene glycol, monomethyl polyethylene glycol copolymer, polyethylene glycol, the polyethylene glycol copolymer, end carboxyl polylactic acid, end carboxyl polylactic acid/ethanol copolymer, polifeprosan, bis-fatty acid and decanedioic acid copolymer, poly-(erucic acid dimer-decanedioic acid), poly-(fumaric acid-decanedioic acid), ethylene vinyl acetate copolymer, polylactic acid, the copolymer of polyglycolic acid and hydroxyacetic acid, xylitol, oligosaccharide, chrondroitin, chitin, hyaluronic acid, collagen protein, one of gelatin and albumin glue or its combination.
Slow-release auxiliary material and percentage by weight thereof are most preferably as follows in the sustained-release micro-spheres of the present invention:
(1) PLA of 55-90%;
(2) PLGA of 50-90%;
(3) polifeprosan of 50-85%;
(4) bis-fatty acid of 55-90% and decanedioic acid copolymer;
(5) EVAc of 55-90%;
(6) xylitol of 40-95%, oligosaccharide, chrondroitin, chitin, hyaluronic acid, collagen protein, gelatin or white tempera; Or
(7) poly-dl-lactide of 40-95%, poly-dl-lactide/ethanol copolymer, monomethyl polyethylene glycol, monomethyl polyethylene glycol copolymer, polyethylene glycol, polyethylene glycol copolymer, end carboxyl polylactic acid or end carboxyl polylactic acid/ethanol copolymer.
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.
The molecular weight peak value of polylactic acid can be, but is not limited to, 5000-100, and 000, but with 20,000-60,000 is preferred, with 5,000-30,000 for most preferably; The molecular weight of polyglycolic acid can be, but is not limited to, 5000-100, and 000, but with 5,000-50,000 is preferred, with 10,000-30,000 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, 5000-100,000, 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.Used polylactic acid serves as preferred with Poly-L-lactic acid (L-PLA).Poly-L-lactic acid (L-PLA) range of viscosities IV (dl/g) is 0.2～0.8, and glass transition temperature range is 55～65 ℃, 175～185 ℃ of fusing points.
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 1500ep-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 corresponding 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).So 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.
Anticancer effective component is mainly vasoinhibitor and/or its synergist.When the cancer therapy drug in the medicament slow-release microsphere only is vasoinhibitor or vasoinhibitor synergist, slow-releasing anticarcinogen injection is mainly used in the vasoinhibitor of other approach application of increase or the action effect of vasoinhibitor 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 vasoinhibitor or its synergist, the application of slow-releasing anticarcinogen injection and potentiation mode were:
(1) local injection contains the slow releasing injection of vasoinhibitor and the vasoinhibitor synergist associating that other approach are used;
(2) local injection contains the slow releasing injection of vasoinhibitor synergist and the vasoinhibitor associating that other approach are used; Or
(3) local injection contains the associating of the slow releasing injection that contains the vasoinhibitor synergist of the slow releasing injection of vasoinhibitor synergist and topical application.
The slow-releasing anticarcinogen injection of topical application also is used for the potentiation to radiotherapy or other therapies.Other approach refer to, but, be not limited to tremulous pulse, vein, abdominal cavity, subcutaneous, intracavitary administration.
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 vasoinhibitor and its synergist (steroids anti-cancer drugs and/or platinum-like compounds) use in conjunction, the weight ratio of vasoinhibitor and steroids anti-cancer drugs and/or platinum-like compounds is 1-9: 1 to 1: 1-9, with 1-2: 1 serves as preferred.
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, and used slow-release auxiliary material can be any or multiple material in the above-mentioned pharmaceutic adjuvant, is main separation with the high molecular weight water soluble polymer in various high molecular polymers.
Slow-release auxiliary material and percentage by weight thereof are most preferably as follows in the sustained-release implant of the present invention:
(1) PLA of 55-90%;
(2) PLGA of 50-90%;
(3) polifeprosan of 50-85%;
(4) bis-fatty acid of 55-90% and decanedioic acid copolymer;
(5) EVAc of 55-90%;
(6) xylitol of 40-95%, oligosaccharide, chrondroitin, chitin, hyaluronic acid, collagen protein, gelatin or albumin glue; Or
(7) poly-dl-lactide of 40-95%, poly-dl-lactide/ethanol copolymer, monomethyl polyethylene glycol, monomethyl polyethylene glycol copolymer, polyethylene glycol, polyethylene glycol copolymer, end carboxyl polylactic acid or end carboxyl polylactic acid/ethanol copolymer.
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, sphere, bulk, needle-like, bar-shaped, column and membranaceous.In various dosage forms, serve as preferred slowly to discharge implant in the body.Can be the bar-shaped of 0.1-5mm (slightly) * 1-10mm (length), also can be other shapes such as lamellar.
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) gefitinib of 1-40%, Erlotinib, Lapatinib, votaranib, WAY-EKB 569, NSC 609974, thalidomide, LS-2616, angiostatin, Endostatin, blood vessel endothelium chalone, imatinib mesylate, LS-2616, Sugen 5416, BMS 354825, Avastin, Cl 1033, Sorafenib, Sutent, TLK286 or ABX-EGF;
(2) ormaplatin of 1-40%, dexormaplatin, heptan platinum, lobaplatin, nedaplatin, ring platinum, oxaliplatin, DNA-2114, cis-Dichlorobis(cyclopentylamine)platinum, platinum blue, cis-Dichlorobis(cyclopropylamine)platinum, CL 286558., enloplatin, sulfatodiamino cyclohexane platinum, Spiroplatin, iproplatin, rice platinum, pick up platinum, sebriplatin, spiroplatin, zeniplatin;
(3) triptorelin of 1-40%, goserelin, leuprorelin, Anastrozole, idoxifene, Miproxifene, tamoxifen, not former times sweet smell, raloxifene, ICI-M 164384, anticancer steroid alkene phenol, Drogenil, aminoglutethimide, (.+-.)-Pyridoglutethimide, megestrol, medroxyprogesterone, clomifene, toremifene, letrozole, Anastrozole, exemestane or bicalutamide;
(4) gefitinib of 1-40%, Erlotinib, Lapatinib, votaranib, WAY-EKB 569, NSC 609974, thalidomide, LS-2616, angiostatin, Endostatin, the blood vessel endothelium chalone, imatinib mesylate, LS-2616, Sugen 5416, BMS 354825, Avastin, Cl 1033, Sorafenib, Sutent, the ormaplatin of TLK286 or ABX-EGF and 1-40%, dexormaplatin, heptan platinum, lobaplatin, nedaplatin, ring platinum, oxaliplatin, DNA-2114, cis-Dichlorobis(cyclopentylamine)platinum, platinum blue, cis-Dichlorobis(cyclopropylamine)platinum, CL 286558., enloplatin, sulfatodiamino cyclohexane platinum, Spiroplatin, iproplatin, rice platinum, pick up platinum, sebriplatin, the combination of spiroplatin or zeniplatin;
(5) gefitinib of 1-40%, Erlotinib, Lapatinib, votaranib, WAY-EKB 569, NSC 609974, thalidomide, LS-2616, angiostatin, Endostatin, the blood vessel endothelium chalone, imatinib mesylate, LS-2616, Sugen 5416, BMS 354825, Avastin, Cl 1033, Sorafenib, Sutent, the triptorelin of TLK286 or ABX-EGF and 1-40%, goserelin, leuprorelin, Anastrozole, idoxifene, Miproxifene, tamoxifen, not former times sweet smell, raloxifene, ICI-M 164384, anticancer steroid alkene phenol, Drogenil, aminoglutethimide, (.+-.)-Pyridoglutethimide, megestrol, medroxyprogesterone, clomifene, toremifene, letrozole, Anastrozole, the combination of exemestane or bicalutamide; Or
(6) cisplatin of 1-40%, carboplatin, heptan platinum, lobaplatin, nedaplatin or oxaliplatin and 1-40% triptorelin, goserelin, leuprorelin, Anastrozole, idoxifene, Miproxifene, tamoxifen, not former times sweet smell, raloxifene, Drogenil, aminoglutethimide, (.+-.)-Pyridoglutethimide, megestrol, medroxyprogesterone, clomifene, toremifene, letrozole, Anastrozole, exemestane or the combination of 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 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 vasoinhibitor 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, vasoinhibitor 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 vasoinhibitor 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 technology of the present invention is further described:
The local drug concentration that test 1, different modes are used after the vasoinhibitor (gefitinib) 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 gefitinib.Measure medicament contg (%) in the different time tumor, the result shows, the local drug concentration significant difference of gefitinib 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 after the vasoinhibitor (Erlotinib) 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 Erlotinib.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 Erlotinib 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 vasoinhibitor and vasoinhibitor 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 vasoinhibitor group, vasoinhibitor synergist group, vasoinhibitor and vasoinhibitor synergist group.Drug dose is 5mg/kg, and vasoinhibitor is through intratumor injection, and the vasoinhibitor 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 | Vasoinhibitor | Synergist | Tumor control rate (%) | The P value |
| 1 | + | - | 28 | * |
| 2 | - | Triptorelin | 42 | * |
| 3 | - | Goserelin | 38 | * |
| 4 | - | Leuprorelin | 46 | * |
| 5 | - | Anastrozole | 48 | * |
| 6 | - | Idoxifene | 36 | * |
| 7 | + | Triptorelin | 78 | ** |
| 8 | + | Goserelin | 80 | ** |
| 9 | + | Leuprorelin | 82 | ** |
| 10 | + | Anastrozole | 74 | ** |
| 11 | + | Idoxifene | 64 | ** |
Above result shows, vasoinhibitor (Lapatinib) and used vasoinhibitor 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, vasoinhibitor and vasoinhibitor 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.Vasoinhibitor and vasoinhibitor 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 | Votaranib | A | B | C | D | E | Votaranib+A | Votaranib+B | Votaranib+C | Votaranib+D | Votaranib+E |
| CNS | 34 | 50 | 56 | 38 | 52 | 42 | 82 | 70 | 86 | 88 | 88 |
| C6 | 22 | 52 | 46 | 36 | 64 | 40 | 90 | 84 | 84 | 84 | 92 |
| SA | 26 | 50 | 58 | 40 | 62 | 42 | 84 | 84 | 80 | 82 | 82 |
| BC | 38 | 58 | 40 | 44 | 502 | 54 | 88 | 80 | 78 | 76 | 84 |
| BA | 18 | 48 | 38 | 48 | 62 | 56 | 82 | 80 | 90 | 92 | 82 |
| LH | 26 | 56 | 44 | 54 | 58 | 60 | 92 | 80 | 94 | 76 | 90 |
| PAT | 34 | 54 | 50 | 50 | 50 | 62 | 80 | 76 | 82 | 88 | 82 |
Above result shows, used vasoinhibitor (votaranib) and vasoinhibitor 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, vasoinhibitor and vasoinhibitor 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.Vasoinhibitor and vasoinhibitor 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 3.The result shows, growth all has obvious suppression effect (P＜0.05) to kinds of tumor cells when using separately for used vasoinhibitor (WAY-EKB 569) and vasoinhibitor 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 NSC 609974, thalidomide, LS-2616, angiostatin, Endostatin, blood vessel endothelium chalone or imatinib mesylate 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, vasoinhibitor and vasoinhibitor 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 (vasoinhibitor or vasoinhibitor synergist) and therapeutic alliance group (vasoinhibitor and vasoinhibitor 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 vasoinhibitor (NSC 609974) and vasoinhibitor 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 thalidomide, LS-2616, Sugen 5416, BMS 354825, Avastin, Cl 1033, Sorafenib, Sutent, TLK286 or ABX-EGF 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, vasoinhibitor and vasoinhibitor 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 vasoinhibitor synergist is through intratumor injection, and vasoinhibitor 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) | Thalidomide | 38 | ＜0.05 |
| 3(6) | Cisplatin | 52 | ＜0.01 |
| 4(6) | Carboplatin | 48 | ＜0.01 |
| 5(6) | Heptan platinum | 56 | ＜0.01 |
| 6(6) | Lobaplatin | 56 | ＜0.01 |
| 7(6) | Thalidomide+cisplatin | 84 | ＜0.001 |
| 8(6) | Thalidomide+carboplatin | 82 | ＜0.001 |
| 9(6) | Thalidomide+heptan platinum | 84 | ＜0.001 |
| 10(6) | Thalidomide+lobaplatin | 92 | ＜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 vasoinhibitor and vasoinhibitor synergist-platinum-like compounds (cisplatin, carboplatin, heptan platinum, lobaplatin).
The tumor-inhibiting action of test 8, vasoinhibitor and vasoinhibitor 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) | BMS 354825 | 58 | ＜0.05 |
| 3(6) | Nedaplatin | 58 | ＜0.05 |
| 4(6) | Ring platinum | 36 | ＜0.05 |
| 5(6) | Oxaliplatin | 46 | ＜0.05 |
| 6(6) | Heptan platinum | 36 | ＜0.01 |
| 7(6) | BMS 354825+nedaplatin | 88 | ＜0.01 |
| 8(6) | BMS 354825+ring platinum | 76 | ＜0.01 |
| 9(6) | BMS 354825+oxaliplatin | 94 | ＜0.01 |
| 10(6) | BMS 354825+heptan platinum | 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 vasoinhibitor (BMS 354825) and vasoinhibitor synergist-platinum-like compounds (nedaplatin, ring platinum, oxaliplatin, heptan platinum).
The tumor-inhibiting action of test 9, vasoinhibitor synergist (sustained-release implant)
By the tumor-inhibiting action of test 8 described methods mensuration vasoinhibitor 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 vasoinhibitor synergist (oxaliplatin) and other vasoinhibitor synergist (triptorelin, goserelin, leuprorelin, Anastrozole), can show significant potentiation when use in conjunction.
The tumor-inhibiting action of test 10, vasoinhibitor synergist (sustained-release implant)
By the tumor-inhibiting action of test 8 described methods mensuration vasoinhibitor 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) | Not former times sweet smell | 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 vasoinhibitor 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, vasoinhibitor synergist (slow releasing injection)
Measure the tumor-inhibiting action of vasoinhibitor synergist (slow releasing injection) by test 7 described methods, the result shows and 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, the vasoinhibitor synergist of spiroplatin or zeniplatin can significantly strengthen 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 tumor killing effect of exemestane or bicalutamide, potentiation is in 50-88% (P＜0.01).
Release ratio in the body of the gefitinib sustained-release implantation agent that test 12, different molecular weight polylactic acid are made
With the rat is subjects, grouping (3/group) and the equivalent gefitinib sustained-release implantation agent that carries in the subcutaneous polylactic acid (PLA) that contains different molecular weight (MW).Then respectively at 1,3,7,14,21,28
With the surplus of 35 days survey medicines in implant, and then draw rate of release (%) in its body.The result shows, molecular weight is 20000 is released to: 1 day (8%), 3 (28%), 7 (56%), 14 (82%), 21 (90), 28 (94) and 35 (98%).Discharge in the body of the gefitinib sustained-release implantation agent that comparison different molecular weight polylactic acid is made and find, slack-off with the molecular weight increase, with the 7th day was example, compare with whole body administration group, the bacteriostatic rate increases with the polylactic acid molecule amount and improves, and is followed successively by 68% (MW:5000), 66% (MW:15000), 54% (MW:25000), 50% (MW:40000) and 48 (MW:60000).
It is 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 the ABX-EGF slow releasing agent that adjuvant is made that same result also sees with polylactic acid.
That pays special attention to is simple to operation, the good reproducibility of slow releasing agent of the present invention, particularly slow releasing injection.Good effect not only, toxic and side effects is also little.
Different drug packages is to want characteristic different with different Biodegradable high moleculars.Discover that further the slow-release auxiliary material that is most appropriate to medicament slow release of the present invention is a poly-dl-lactide, poly-dl-lactide/ethanol copolymer, the monomethyl polyethylene glycol, monomethyl polyethylene glycol copolymer, polyethylene glycol, the polyethylene glycol copolymer, end carboxyl polylactic acid, end carboxyl polylactic acid/ethanol copolymer, polifeprosan, bis-fatty acid and decanedioic acid copolymer, poly-(erucic acid dimer-decanedioic acid), poly-(fumaric acid-decanedioic acid), ethylene vinyl acetate copolymer, polylactic acid, the copolymer of polyglycolic acid and hydroxyacetic acid, xylitol, oligosaccharide, chrondroitin, chitin, hyaluronic acid, collagen protein, gelatin, one of albumin glue or its combination; Optimum suspending agent is one of methylcellulose, hydroxy methocel, sodium carboxymethyl cellulose, (iodine) glycerol, simethicone, propylene glycol, carbomer, mannitol, sorbitol, surfactant, soil temperature 20, soil temperature 40, soil temperature 80 or its combination.
In a word, growth all had the obvious suppression effect to kinds of tumor cells when used vasoinhibitor and various vasoinhibitor synergist were used separately, can show significant potentiation when use in conjunction.Therefore, effective ingredient of the present invention is the combination of vasoinhibitor and/or any one vasoinhibitor 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.
Used adjuvant is: poly-dl-lactide, poly-dl-lactide/ethanol copolymer, monomethyl polyethylene glycol, monomethyl polyethylene glycol copolymer, polyethylene glycol, polyethylene glycol copolymer, end carboxyl polylactic acid or end carboxyl polylactic acid/ethanol copolymer; 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 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 15% lobaplatin and 15% 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 1-40%, Erlotinib, Lapatinib, votaranib, WAY-EKB 569, NSC 609974, thalidomide, LS-2616, angiostatin, Endostatin, blood vessel endothelium chalone, imatinib mesylate, LS-2616, Sugen 5416, BMS 354825, Avastin, Cl 1033, Sorafenib, Sutent, TLK286 or ABX-EGF; Or
(2) gefitinib of 1-40%, Erlotinib, Lapatinib, votaranib, WAY-EKB 569, NSC 609974, thalidomide, LS-2616, angiostatin, Endostatin, the blood vessel endothelium chalone, imatinib mesylate, LS-2616, Sugen 5416, BMS 354825, Avastin, Cl 1033, Sorafenib, Sutent, the cisplatin of TLK286 or ABX-EGF 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, 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 gefitinib, shake up the back contains 20% goserelin and 10% gefitinib 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: 15% 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, exemestane or bicalutamide and 15% gefitinib, Erlotinib, Lapatinib, votaranib, WAY-EKB 569, NSC 609974, thalidomide, LS-2616, angiostatin, Endostatin, the blood vessel endothelium chalone, imatinib mesylate, LS-2616, Sugen 5416, BMS 354825, Avastin, Cl 1033, Sorafenib, Sutent, the combination of TLK286 or ABX-EGF; 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 imatinib mesylate, shake up the back contains 10% Anastrozole and 20% imatinib mesylate 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) gefitinib of 5-30%, Erlotinib, Lapatinib, votaranib, WAY-EKB 569, NSC 609974, thalidomide, LS-2616, angiostatin, Endostatin, blood vessel endothelium chalone, imatinib mesylate, LS-2616, Sugen 5416, BMS 354825, Avastin, Cl 1033, Sorafenib, Sutent, TLK286 or ABX-EGF;
(d) gefitinib of 5-30%, Erlotinib, Lapatinib, votaranib, WAY-EKB 569, NSC 609974, thalidomide, LS-2616, angiostatin, Endostatin, the blood vessel endothelium chalone, imatinib mesylate, LS-2616, Sugen 5416, BMS 354825, Avastin, Cl 1033, Sorafenib, Sutent, the cisplatin of TLK286 or ABX-EGF and 5-30%, carboplatin, ormaplatin, dexormaplatin, heptan platinum, lobaplatin, the combination of nedaplatin or oxaliplatin; Or
(e) gefitinib of 5-30%, Erlotinib, Lapatinib, votaranib, WAY-EKB 569, NSC 609974, thalidomide, LS-2616, angiostatin, Endostatin, the blood vessel endothelium chalone, imatinib mesylate, LS-2616, 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, 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;
H) poly-dl-lactide, poly-dl-lactide/ethanol copolymer, monomethyl polyethylene glycol, monomethyl polyethylene glycol copolymer, polyethylene glycol, polyethylene glycol copolymer, end carboxyl polylactic acid or end carboxyl polylactic acid/ethanol copolymer.
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. an anticancer medicine slow-release preparation containing that contains vasoinhibitor 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 vasoinhibitor and/or vasoinhibitor synergist, and the vasoinhibitor 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;
I) poly-dl-lactide, poly-dl-lactide/ethanol copolymer, monomethyl polyethylene glycol, monomethyl polyethylene glycol copolymer, polyethylene glycol, polyethylene glycol copolymer, end carboxyl polylactic acid or end carboxyl polylactic acid/ethanol 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; it is characterized in that vasoinhibitor is selected from gefitinib; Erlotinib; Lapatinib; votaranib; WAY-EKB 569; NSC 609974; thalidomide; LS-2616; angiostatin; Endostatin; the blood vessel endothelium chalone; 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; one of ABX-EGF 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; estradiol; the 2-hydroxyestrone; 5; 7,4 trihydroxy-isoflavones; Progesterone; mepitiostane; androgen; (.+-.)-Pyridoglutethimide; rubitecan; Acapodene; Drogenil; overstate single silicon indigo plant; bicalutamide; aminoglutethimide; betamethasone benzoate; calusterone; 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) gefitinib of 1-40%, Erlotinib, Lapatinib, votaranib, WAY-EKB 569, NSC 609974, thalidomide, LS-2616, angiostatin, Endostatin, blood vessel endothelium chalone, imatinib mesylate, LS-2616, Sugen 5416, BMS 354825, Avastin, Cl 1033, Sorafenib, Sutent, TLK286 or ABX-EGF;
(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) gefitinib of 1-40%, Erlotinib, Lapatinib, votaranib, WAY-EKB 569, NSC 609974, thalidomide, LS-2616, angiostatin, Endostatin, the blood vessel endothelium chalone, imatinib mesylate, LS-2616, Sugen 5416, BMS 354825, Avastin, Cl 1033, Sorafenib, Sutent, the cisplatin of TLK286 or ABX-EGF 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) gefitinib of 1-40%, Erlotinib, Lapatinib, votaranib, WAY-EKB 569, NSC 609974, thalidomide, LS-2616, angiostatin, Endostatin, the blood vessel endothelium chalone, imatinib mesylate, LS-2616, Sugen 5416, BMS 354825, Avastin, Cl 1033, Sorafenib, Sutent, the triptorelin of TLK286 or ABX-EGF 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.
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;
I) poly-dl-lactide, poly-dl-lactide/ethanol copolymer, monomethyl polyethylene glycol, monomethyl polyethylene glycol copolymer, polyethylene glycol, polyethylene glycol copolymer, end carboxyl polylactic acid or end carboxyl polylactic acid/ethanol copolymer.
Anticancer effective component and percentage by weight thereof are:
(1) gefitinib of 1-40%, Erlotinib, Lapatinib, votaranib, WAY-EKB 569, NSC 609974, thalidomide, LS-2616, angiostatin, Endostatin, blood vessel endothelium chalone, imatinib mesylate, LS-2616, Sugen 5416, BMS 354825, Avastin, Cl 1033, Sorafenib, Sutent, TLK286 or ABX-EGF;
(2) ormaplatin of 1-40%, dexormaplatin, heptan platinum, lobaplatin, nedaplatin, ring platinum, oxaliplatin, DNA-2114, cis-Dichlorobis(cyclopentylamine)platinum, platinum blue, cis-Dichlorobis(cyclopropylamine)platinum, CL 286558., enloplatin, sulfatodiamino cyclohexane platinum, Spiroplatin, iproplatin, rice platinum, pick up platinum, sebriplatin, spiroplatin, zeniplatin;
(3) triptorelin of 1-40%, goserelin, leuprorelin, Anastrozole, idoxifene, Miproxifene, tamoxifen, not former times sweet smell, raloxifene, ICI-M 164384, anticancer steroid alkene phenol, Drogenil, aminoglutethimide, (.+-.)-Pyridoglutethimide, megestrol, medroxyprogesterone, clomifene, toremifene, letrozole, Anastrozole, exemestane or bicalutamide;
(4) gefitinib of 1-40%, Erlotinib, Lapatinib, votaranib, WAY-EKB 569, NSC 609974, thalidomide, LS-2616, angiostatin, Endostatin, the blood vessel endothelium chalone, imatinib mesylate, LS-2616, Sugen 5416, BMS 354825, Avastin, Cl 1033, Sorafenib, Sutent, the ormaplatin of TLK286 or ABX-EGF and 1-40%, dexormaplatin, heptan platinum, lobaplatin, nedaplatin, ring platinum, oxaliplatin, DNA-2114, cis-Dichlorobis(cyclopentylamine)platinum, platinum blue, cis-Dichlorobis(cyclopropylamine)platinum, CL 286558., enloplatin, sulfatodiamino cyclohexane platinum, Spiroplatin, iproplatin, rice platinum, pick up platinum, sebriplatin, the combination of spiroplatin or zeniplatin;
(5) gefitinib of 1-40%, Erlotinib, Lapatinib, votaranib, WAY-EKB 569, NSC 609974, thalidomide, LS-2616, angiostatin, Endostatin, the blood vessel endothelium chalone, imatinib mesylate, LS-2616, Sugen 5416, BMS 354825, Avastin, Cl 1033, Sorafenib, Sutent, the triptorelin of TLK286 or ABX-EGF and 1-40%, goserelin, leuprorelin, Anastrozole, idoxifene, Miproxifene, tamoxifen, not former times sweet smell, raloxifene, ICI-M 164384, anticancer steroid alkene phenol, Drogenil, aminoglutethimide, (.+-.)-Pyridoglutethimide, megestrol, medroxyprogesterone, clomifene, toremifene, letrozole, Anastrozole, the combination of exemestane or bicalutamide; Or
(6) cisplatin of 1-40%, carboplatin, heptan platinum, lobaplatin, nedaplatin or oxaliplatin and 1-40% triptorelin, goserelin, leuprorelin, Anastrozole, idoxifene, Miproxifene, tamoxifen, not former times sweet smell, raloxifene, Drogenil, aminoglutethimide, (.+-.)-Pyridoglutethimide, megestrol, medroxyprogesterone, clomifene, toremifene, letrozole, Anastrozole, exemestane or the combination of 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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| CNA2008103002304A Division CN101234082A (en) | 2006-06-06 | 2006-06-06 | Sustained-release injection containing angiogenic inhibitor votaranib |
| CNA2008103002291A Division CN101234081A (en) | 2006-06-06 | 2006-06-06 | Sustained-release injection containing angiogenic inhibitor |
| CNA2008103002272A Division CN101234080A (en) | 2006-06-06 | 2006-06-06 | Sustained-release injection containing angiogenic inhibitor and synergistic agent thereof |
| CNA2008103002323A Division CN101234083A (en) | 2006-06-06 | 2006-06-06 | Sustained-release injection containing angiogenic inhibitor thalidomide |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA2006102005202A Withdrawn CN1883451A (en) | 2006-06-06 | 2006-06-06 | A sustained-release anticancer injection containing angiogenesis inhibitor and synergist thereof |
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| Country | Link |
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| CN (1) | CN1883451A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101292951B (en) * | 2007-04-23 | 2012-03-28 | 江苏先声药物研究有限公司 | Recombined human vascellum esoderma inhibin durative action preparation, preparation method and application thereof |
-
2006
- 2006-06-06 CN CNA2006102005202A patent/CN1883451A/en not_active Withdrawn
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101292951B (en) * | 2007-04-23 | 2012-03-28 | 江苏先声药物研究有限公司 | Recombined human vascellum esoderma inhibin durative action preparation, preparation method and application thereof |
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