CN101380296A - Anticancer sustained-release formulation loaded with platinum compound and synergist thereof - Google Patents

Anticancer sustained-release formulation loaded with platinum compound and synergist thereof Download PDF

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CN101380296A
CN101380296A CNA2008103029646A CN200810302964A CN101380296A CN 101380296 A CN101380296 A CN 101380296A CN A2008103029646 A CNA2008103029646 A CN A2008103029646A CN 200810302964 A CN200810302964 A CN 200810302964A CN 101380296 A CN101380296 A CN 101380296A
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acid
sustained
release
anticancer
injection
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刘玉燕
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Jinan Kangquan Medicine Science and Technology Co Ltd
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Jinan Kangquan Medicine Science and Technology Co Ltd
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Abstract

A slow release anticarcinogenic preparation carrying taxane and a synergist thereof is composed of slow release microspheres and a dissolvant, wherein, the slow release microspheres comprise anticancer active components and slow release adjuvants, and the dissolvant is a common dissolvant or a special dissolvant containing a suspending agent. The anticancer active components are selected from taxane anticancer drugs such as taxol or docetaxel, and/or a taxol synergist selected from hormones anticancer drugs and/or an angiogenesis inhibitor; the slow release adjuvants are selected from one or a combination of copolymer of polylactic acid, polyglycolic acid and hydroxyacetic acid, copolymer of ethylene vinyl acetate, polifeprosan, copolymer of dienoic fatty acid and sebacic acid, poly (erucic acid dimer-sebacic acid), poly (fumaric acid-sebacic acid), and the like; the suspending agent is selected from sodium carboxymethyl cellulose, and the like, and the viscosity of the suspending agent is 100cp-3,000cp (at the temperature of 20-30 DEG C). The slow release microspheres can also be made into a slow release implant. The preparation can be injected or placed in tumors or around the tumors, and is used independently or used together with non-operative therapies such as radio-therapeutic and chemotherapeutic drugs, and the like.

Description

Anticancer drug sustained release agent loaded with taxane and synergist thereof
(I) technical field
The invention relates to an anticancer drug sustained release agent containing taxane and a synergist thereof, belonging to the technical field of drugs. Specifically, the invention provides a slow-release injection or a slow-release implant loaded with taxane and a synergist thereof.
(II) background of the invention
The current cancer treatment mainly comprises methods such as surgery, radiotherapy, chemotherapy and the like. The surgical treatment can not only not remove scattered tumor cells, so that the tumor cells are frequently relapsed or diffused and metastasized due to surgical stimulation; radiotherapy and traditional chemotherapy have no selectivity, are difficult to form effective drug concentration or therapeutic dose locally on tumors, have poor effect and high toxicity, and are limited by systemic toxicity reaction when the drug or radiation dose is simply increased. See Kongqingzhong et al, "cisplatin placement in tumor plus systemic carmustine treatment of rat brain tumors" [ J. Otsugaku "J. Oncsu 69, pp 76-82 (1998) (Kong Q et al, J Surg Oncol.1998Oct; 69(2): 76-82).
The above defects can be better overcome by the local application (such as local placement) of the chemotherapy drugs, so that the drug concentration of local tumor can be obviously improved, and the systemic toxic reaction can be obviously reduced. A number of in vitro and in vivo experiments have shown therapeutic efficacy against solid tumors, see Kongqing et al, "J.Surg Oncol.1998 (Kong Q et al, J.Surg Oncol.1998 Oct.; 69 (2); 76-82) in intratumoral cisplatin treatment of rat brain tumors and Kongqing et al," J.Surg Oncol.64, 268-273 (1997) in intratumoral cisplatin treatment of rat primary brain tumors "(KongQ et al, J.Surg Oncol.1997 Oct; 64: 268-273). See also Chinese patent (ZL 00111093.4; ZL 96115937.5; application Nos. 001111264, 001111272) and U.S. patent Nos. 6,376,525B 1; 5,651,986; 5,626,862).
However, solid tumors are composed of tumor cells and tumor stroma, wherein blood vessels in the tumor stroma not only provide a scaffold and essential nutrients for the growth of tumor cells, but also influence the penetration and diffusion of chemotherapeutic drugs around tumors and in tumor tissues (see ninti et al, "influence of extracellular stroma conditions on drug transport in solid tumors" ("Cancer research 60: 2497-) -503 (2000) (Netti PA, Cancer res.2000, 60(9): 2497-) -503).
In addition, low dose anti-cancer drug therapy not only increases drug resistance of cancer cells, but also promotes invasive growth thereof, see beam et al, "increasing drug resistance and in vitro infiltration capacity of human lung cancer cells with alteration of gene expression after anti-cancer drug pulse screening" [ J.ImationMegaku (Liang Y, et al, Int J cancer. 2004; 111(4):484-93, 2004) ].
Therefore, the development of an effective anticancer drug or therapeutic method is currently an important issue. Aiming at the defects of the prior art, the invention provides a novel anticancer pharmaceutical composition, which can effectively inhibit the growth of tumor cells, enhance the tumor treatment effect of other medicines and reduce the recurrence.
Disclosure of the invention
The invention provides an anticancer drug sustained-release preparation containing taxane and a synergist thereof, and particularly relates to a sustained-release injection and a sustained-release implant containing taxane and a synergist thereof.
Taxane is used as a new anticancer drug and has been widely used for treating various solid tumors at home and abroad. However, during the application process, the obvious systemic toxicity greatly limits the application of the medicine.
In order to effectively increase the local drug concentration of tumor and reduce the drug concentration of the drug in the circulatory system, a drug sustained-release system containing taxane is researched, which comprises magnetic microspheres (see Chinese patent No. CN 200410044113.8; CN200410009233.4), sustained-release microspheres (capsules) (see Chinese patent No. CN200410023746.0) and nanoparticles (see Chinese patent No. CN 200410099292.5; CN200510002387.5) and the like. However, solid sustained-release implants (Chinese patent No. ZL 96115937.5; ZL 97107076.8; CN200410084621.9), mini implants with radioactive sources (Chinese patent No. CN200510011250.6) and sustained-release microspheres (Chinese patent No. ZL 00809160.9; U.S. Pat. No. 5,651,986) have the problems of difficult operation, poor curative effect, more complications and the like. In addition, many solid tumors are poorly sensitive to anticancer drugs, including taxanes, and are susceptible to development of resistance during treatment.
The invention finds that the anticancer effect of a plurality of medicaments can be mutually enhanced by combining the medicaments with the taxane, and the medicaments which can mutually enhance the anticancer effect of the taxane are called taxane synergist in the following; besides, the taxane or the combination of the taxane and the synergist thereof is prepared into the anticancer drug sustained release preparation (mainly a sustained release injection and a sustained release implant), which not only can greatly improve the drug concentration of local tumor, reduce the drug concentration of the drug in a circulatory system and reduce the toxicity of the drug to normal tissues, but also can greatly facilitate the drug injection, reduce the complications of surgical operation and reduce the cost of patients. The above unexpected findings constitute the subject of the present invention.
One form of the taxane slow release preparation is slow release injection, which consists of slow release microspheres and a solvent. Specifically, the anticancer sustained-release injection consists of the following components:
(A) a sustained release microsphere comprising:
0.5-60% of anticancer active ingredient
Sustained release auxiliary materials 40-99%
The above are weight percentages
And
(B) the solvent is common solvent or special solvent containing suspending agent.
Wherein,
the anticancer active component is taxane and/or taxane synergist, and the taxane synergist is selected from hormone anticancer drugs and/or blood vessel inhibitor; the sustained-release auxiliary material is selected from one or the combination of polylactic acid (PLA), polyglycolic acid and glycolic acid copolymer (PLGA), ethylene vinyl acetate copolymer (EVAc), polifeprosan, di-fatty acid and sebacic acid copolymer (PFAD-SA) ], poly (erucic aciddipolymer-sebacic acid) [ P (EAD-SA) ], poly (fumaric acid-sebacic acid) [ P (FA-SA) ], xylitol, oligosaccharide, chondroitin, chitin, hyaluronic acid, collagen, gelatin and albumin glue; the suspending agent is selected from one or more of sodium carboxymethylcellulose, (iodine) glycerol, dimethicone, propylene glycol, carbomer, mannitol, sorbitol, surfactant, Tween 20, Tween 40 and Tween 80.
The taxane (Taxanes) anticancer drugs in the anticancer active ingredients are mainly selected from paclitaxel, docetaxel (D-docetaxel, docetaxel), 2 '-hydroxypaclitaxel (paclitaxel-2' -hydroxy), 10-deacetyl paclitaxel (10-deacetyltaxol) and 7-epi-taxol.
Hormonal anticancer drugs are mainly steroid hormones and hormone antagonists including, but not limited to, anastrozole (anastrozole), idoxifene (idoxifene), milbexifene (Miproxifene), tamoxifen (tamoxifen ), 4-monohydroxytamoxifen (trans-4-monohydroxytamoxifen, OH-TAM), moxifene (keoxifene, LY156758), steroidal anti-estra (ICI164384, 7- α -alkylamide analogue of estradiol), 7- α - [9- (4, 4, 5, 5-pentafluoropentylsulfinyl) nonyl ] estra-1, 3, 5(10) -triene-3, 17 β -diol (anticancer sterenol, fulvestrant, 7- [9- (4, 4, 5, 5, 5-pentafluoropentylsulene) finyl ] beta-1, 3, 5, 17-alpha-diol (anticancer sterenol, fulvestrant, 7- [9- (4, 4, 5, 5, 5-pentafluoropentylsulene) triene ] 1, 3, 17-alpha-1, 3, 17-alpha-diol, ICI 182780), 4-hydroxytamoxifen (4-hydroxytetramoxifen), gamma-linoleic acid (gamma-linolenic acid), 2-methoxyestradiol (2-methoxyestradiol), methoxynorgestrienediol (moxystrol), 4-hydroxytamoxifen (4-hydroxytetramoxifen), hexachlorocyclohexane (hexachlorobenzene, hexachlorocyclohexane, beta-hexachlorocyclohexocyclohexane, beta-HCH), raloxifene (raloxifene), stilbestrol (diethylstilbestrol), estradiol (estradiol), zearalenone (zearalenone), estrone (estrone), 17alpha-estradiol (17-estradiol), estradiol (riol), 2-hydroxyestrone (2-hydroxydihydrotestosterone), 5, 7, 4-trihydroxyisoestrogen (trihydroxyisoflavone), alpha-ketorolene (fludroxyquinone), Flutamide (Flutamide ), Flutamide (Flutamide), Flutamide (4-hydroxyestriol), Flutamide (Flutamide, 4-droxytrexaglitazone (fludroxide), fludroxytrexaben-ne (fludroxyfuroxanide), fludroxide, Flutamide (fludroxynil), Flutamide (Flutamide, flu, Bicalutamide (Casodex), Aminoglutethimide (aminomeptylimide), betamethasone benzoate, carroterone, triptorelin, goserelin, leuprorelin, megestrol, medroxyprogesterone, dartikoside, epithioandrostanol, estrene with ethyl bromide, hesfen, clomiphene, toremifene, letrozole, anastrozole and exemestane or testolactone.
The hormone anticancer drug can be selected singly or in multiple, preferably triptorelin, goserelin, leuprorelin, anastrozole, idoxifene, mirtaxifene, tamoxifen, 4-monohydroxytamoxifen (OH-TAM), comoxifene, raloxifene, sterculia, anticancer sterenol, 4-hydroxyttamoxifen, flutamide, aminoglutethimide, pirimimide, megestrol, medroxyprogesterone, clomiphene, toremifene, letrozole, anastrozole, exemestane or bicalutamide.
The hormone anticancer drugs can be used for various hormone-dependent tumors, but different drugs have relative tumor selectivity, such as tamoxifen, pirimid, rubitecan, and toremifene, which are mainly used for treating estrogen-dependent tumors, such as breast cancer and endometrial cancer; flutamide, quart monosilicon blue, and bicalutamide are used primarily to treat androgen dependent tumors, such as prostate cancer; triptorelin, goserelin, leuprorelin, tamoxifen, raloxifene, aminoglutethimide, clomiphene, toremifene, letrozole, anastrozole and exemestane are used to treat breast cancer, prostate cancer and endometrial cancer.
The content of the hormone anticancer drug in the composition is 0.01-60%, preferably 1-40%, more preferably 2-30%, all of which are weight percentages.
The blood vessel inhibitor can effectively inhibit or destroy blood vessels of tumors and inhibit the formation of new blood vessels of the tumors, thereby not only leading tumor cells to lose the sources of stents and nutrient substances required by the growth, but also promoting the penetration and the diffusion of chemotherapeutic drugs around the tumors and in tumor tissues.
The vascular inhibitor is selected from one or a combination of the following: gefitinib (Gefitinib, also known as 4-quinazolinone amine, N- (3-chloro-4-fluorophenyl) -7-methoxy-6- [3-4-morpholin ] propoxy) [ 4-Quinazolinine, N- (3-chloro-4-fluorophenyl) -7-methoxy-6- [ 3-4-morpholino ] propoxy ], erlotinib (4-quinazolinone amine, N- (3-ethynyl) -6, 7-bis (2-methoxyethyl) -monohydrochloride [ 4-Quinazolinine, N- (3-ethylphenyl) -6, 7-bis (2-methoxyethyl) -monohydrochloride, Tarceva, OSI-774, erlotinib, CP-358774, OSI-774, R-5 ] (Phenol, 4- (4- (((1R) -1-phenylethyl) amino) -1H-pyrrolo (2, 3-d) pyrimidin-6-yl) (Phenol, 4- (4- (((1R) -1-phenylethyl) amino) -1H-pyrrolo (2, 3-d) pyrimidin-6-yl) -, PKI-166, CGP-59326, CGP-59326B, CGP-62706, CGP-74321, CGP-75166, CGP-76627), lapatinib (4-quinazolinolone, N- [3-chloro-4- [ (3-fluoro) methoxyethyl ] -6- [5- [ [2- [ thiomethyl ] furan-2-yl ] ] bis (4-tolyl sulfate) monohydrate ] [ 4-Quinazoline, n- [3-chloro-4- [ (3-fluorobenzyl) methoxyphenyl ] -6- [5- [ [ [2- [ methylsulfonyl ] ethyl ] amino ] methyl ] furan-2-yl ] bis (4-methylsulbene-zenesulfonate) monohydrate, lapatinib ditosylate, GW-2016, GW-572016F ], Votalanib (N- (4-chlorophenyl) -4- (pyridine-4-methyl) benzodimethylene-1-amine (N- (4-chlorophenyl) -4- (pyridine-4-ylmethyl) phthalazin-1-amine, vatalanib, PTK-787, PTK/ZK, Schering-TK-78, VEGF 898989 1, ZK-222584)), pezib-4- [ (E-3-fluoro-quinoline) -4-yl ] -7-cyano-3-4-fluoro-quinoline-3-4-yl ] amide 6-yl ] -4- (dimethylamino) and-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), carboxyamidotriazole (carboxyamidrazole, CAT), thalidomide (thalidomide), ranolamide (linominide, inhibitors of integrin), angiostatin (angiostatin), endostatin (endostatin), Vascular Endothelial Growth Factor (VEGF) receptor inhibitor, Imatinib mesylate (Imatinib mesylate), also known as Glivec, Glivec), 4- [ (4-methyl-1-piperazine) methyl ] -N- [4-methyl-3- (pyrimidine) -2-amino ] pyridine ] phenyl -aniline methanesulfonate (4- ((Methyl-1-piperazinyl) Methyl) -N- [4-Methyl-3- [ [4- (3-pyridinyl) -2-pyridinyl ] amino ] -phenyl ] benzamido Methyl fonato, STI 571, CGP-57148B, STI-571A, CGP57148), 5- [5-Fluoro-2-oxo-1, 2-indoline- (3Z) -methylene ] -2, 4-dimethyl-1H-pyrrole-3-carboxylic Acid (2-Diethylaminoethyl) amide (5- [5-Fluoro-2-oxo-1, 2-dihydroindol- (3Z) -ylidenemethyl ]2, 4-dimethyl-1H-pylolic-3-carbonylacrylic Acid (2-diazethylamido) amide, sutent, SU11248, SU011248), 3-Dichloro-5- (4-methylsulfonylpyridinyl) -2-indolinone (3, 3-dichoro-5- (4-methyl piperidinosylfonyl) -2-indolinone, DCM), 3- [1- (3H-imidazol-4-yl) -methyl- (Z) -yliden-5-methoxy-1, 3-dihydro-indol-2-indolinone (3- [1- (3H-imidozol-4-yl) -meth- (Z) -yliden ] -5-methoxy-1, 3-dihydro-indol-2-one, SU9516, SU 9518), 1H-pyrrole-3-propionic acid, 2- [ (1, 2-dihydro-2-oxo-3H-Indol-3-ylidene) methyl ] -4-methyl (SU6663, SU-5402, 1H-Pyrrole-3-propanoic acid, 2- [ (1, 2-dihydro-2-oxo-3H-indole-3-ylidene) methyl ] -4-methyl), 2H-Indol-2-indolinone (2H-Indol-2-one), simatinib (3- ((4, 5-dimethyl-1H-pyrrol-2-yl) methylene) -1, 3-dihydro- [ CAS ] (3- ((4, 5-dimethyl-1H-pyrrolol-2-yl) methyl) -1, 3-dihydro- [ CAS ], SU5614, semaxanib, SU-011271, SU-011606, SU-11612)), pyrrololide indolinone (pyrrolidinone indolinones, SU6577), lactam indolinone (pyrrolidinone indolinones, SU6597), 3- (4-Dimethylamino-naphthylmethylene-1-methylene) -1, 3-dihydro-indol-2-indolinone (3- (4-Dimethylamino-naphtalene-1-ylmethylene) -1, 3-dihydro-indol-2-indolinone, MAZ51), 1, 3-dihydro-5, 6-dimethoxy-3- [ (4-hydroxyphenyl) methylene ] -2H-indol-2-indolinone (1, 3-dihydro-5, 6-dimethoxy-3- [ (4-hydroxyphenyl) H ] -2H-indol-2-indolinone indolinone, RPI-1), 3- [5-methyl-2- (2-oxo-1, 2-dihydro-indol-3-yl) -1H-pyrrol-3-methyl ] -propionic acid (3- [5-methyl-2- (2-oxo-1, 2-dihydro-indole-3-ylidenemethyl) -1H-pyrro-3-yl ] -proprionic acid, SU10944), 5- [ (Z) - (5-chloro-2-oxo-1, 2-dihydro-3H-indol-3-methylene) methyl ] -N- (2- (diethylamino) ethyl-1H-pyrrole-3-carboxamide (5- [ (Z) - (5-chloro-2-oxo-1, 2-dihydro-3H-indole-3-ylidine) methyl ] -N- [2- (dimethylamino) ethyl ] -2, 4-dimethyl-1H-pyrolole-3-carboxamide, SU11652), 5- [ (Z) - (5-fluoro-2-oxo-1, 2-dihydro-3H-indol-3-ylidene) methyl ] -2, 4-dimethyl-N- (2-pyrrolidinyl-1-ethyl) -1H-pyrrole-3-carboxamide (5- [ (Z) - (5-fluoro-2-oxo-1, 2-dihydro-3H-indol-3-ylidine) methyl ] -2, 4-dimethyl-N- (2-pyrolidin-1-ylidine) -1H-pyrolole- 3-carboxamide), SU11654), 5- [ (Z) - (5-chloro-2-oxo-1, 2-dihydro-3H-indol-3-ylidene) methyl ] -2, 4-dimethyl-N- (2-pyrrolidinyl-1-ethyl) -1H-pyrrole-3-carboxamide ((5- [ (Z) - (5-chloro-2-oxo-1, 2-dihydro-3H-indole-3-ylidene) methyl ] -2, 4-dimethyl-N- (2-pyrrolidino-1-ylethyl) -1H-pyrrolidone-3-carboxamide), SU 55), 3- [ [ 3-phenyl-4(3H) -quinazolinone-2 methyl ] mercaptoacetic acid ] hydrazono ] -1H-2-indolinone (3- [ [ (3-phenyl-4(3H) -quinazolinone-2-yl) merptoacetyl ] hydrazono ] -1H-2-indolines, SU1165), 3-bis (4-methoxyphenyl) methylene-2-indolinone (3-bis (4-methoxyphenylyl) methyl-2-indolinone, TAS-301), 3- [ 4-formylpiperazin-4 yl ] -benzylidene ] -2-indolinone (3- [4- (1-formalpiperazin-4 yl) -benzidinyl ] -2-indolinone, SU 84), 3- ([ 5-imidazole ]2, 1-methylthiazolo) -2-indolinone (3- (5-imidazoyl) 2, 1-tolylindolinone) -2-indolinone, IBMI), 3-1(2, 6-dimethylimidazo [2, 1-Bj-thiazol-5-yl ] methylene-5-methoxy-2-indolinone (3-1(2, 6-dimethyllimidazo [2, 1-Bj-thiazol-5-yl ] methylene-5-methoxy-2-indolinone, DMMI, SU9518], Imidazo [2, 1-b ] methylenethiazol-2-indolinone (Imidazo [2, 1-b ] methylenethiazol-2-indolinone, ITI), methyleneindole-2-indolinone (IMI), (2-chloroindole) methylene-2-indolinone, CMI), AI), 1, 3-dihydro-5, 6-dimethoxy-3- [ (4-hydroxyphenyl) methylene ] -2H-indol-2-indolinone (1, 3-dihydro-5, 6-dimethoxy-3- [ (4-hydroxyphenyl) methyl ] -2H-indoline-2-one), cpd1), 3- (4-dimethylamino-benzylidene) -2-indolinone (3- (4-dimethylamino-benzylidene) -2-indolinone, DMBI), 5-chloro-3-methylenepyridine-2-indolinone (5-chloro-3-pyridone-2-indolinone, cPMI), 3-dimethylpyridine-1-phenyl-2-indolinone (3, 3-dipyridylmethyl-1-phenyl-2-indolinone, DPMPI) and E-3- (2-chloro-3-methylindole) 1, 3-indoline-2-indolinone (E-3- (2-chloro-3-indolinyl methyl) 1, 3-dihydroindol-2-indolinone, CIDI), dasatinib (dasatinib), avastin (avastin), canatinib (canertinib), sorafenib (sorafenib), sunitinib (sunitinib, sutent, SU11248), Teolyta (Telkyyta), Panitoma (panitumumab).
Other vasoinhibitors are described in related international patents, application numbers: WO 97/22596, WO 97/30035, WO97/32856 and WO 98/13354.
The above vascular inhibitors also include their salts, such as, but not limited to, sulfate, phosphate, hydrochloride, lactobionate, acetate, aspartate, nitrate, citrate, purine or pyrimidine salts, succinate, maleate, and the like.
The vascular inhibitor is preferably one or a combination of the following:
gefitinib, erlotinib, lapatinib, vatalanib, pelitinib, carboxyaminotriazole, thalidomide, ranolamine, angiostatin, endostatin (endostatin), imatinib mesylate, 4- [ (4-methyl-1-piperazine) methyl ] -N- [4-methyl-3- [ [4- (3-pyridine) -2-pyrimidine ] amino ] phenyl ] -aniline methanesulfonate, 5- [5-fluoro-2-oxo-1, 2-dihydroindole- (3Z) -methylene ] -2, 4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylaminoethyl) amide, 3-dichloro-5- (4-methylsulfonylpyridine) -2-indolinone, 3- [1- (3H-imidazol-4-yl) -methyl- (Z) -yliden-5-methoxy-1, 3-dihydro-indol-2-indolinone, 1H-pyrrole-3-propionic acid, 2- [ (1, 2-dihydro-2-oxo-3H-indol-3-ylidene) methyl ] -4-methyl, 2H-indol-2-indolinone, semasnib, pyrrololide indolinone, lactam indolinone, 3- (4-dimethylamino-naphthylmethylene-1-methylene) -1, 3-dihydro-indol-2-indolinone, 1, 3-dihydro-5, 6-dimethoxy-3- [ (4-hydroxyphenyl) methylene ] -2H-indol-2-indolinone, 3- [5-methyl-2- (2-oxo-1, 2-dihydro-indol-3-yl) -1H-pyrrol-3-methyl ] -propionic acid, 5- [ (Z) - (5-chloro-2-oxo-1, 2-dihydro-3H-indol-3-methylene) methyl ] -N- (2- (diethylamino) ethyl-1H-pyrrole-3-carboxamide, 5- [ (Z) - (5-fluoro-2-oxo-1, 2-dihydro-3H-indol-3-ylidene) methyl ] -2, 4-dimethyl-N- (2-pyrrolidinyl-1-ethyl) -1H-pyrrole-3-carboxamide, 5- [ (Z) - (5-chloro-2-oxo-1, 2-dihydro-3H-indol-3-ylidene) methyl ] -2, 4-dimethyl-N- (2-pyrrolidinyl-1-ethyl) -1H-pyrrole-3-carboxamide, 3- [ [ 3-phenyl-4(3H) -quinazolinone-2-methyl ] mercaptoacetic acid ] hydrazono ] -1H-2-indolinone, pharmaceutically acceptable salts thereof, and pharmaceutically acceptable salts thereof, 3-bis (4-methoxyphenyl) methylene-2-indolinone, 3- [ 4-formylpiperazin-4 yl ] -benzylidene ] -2-indolinone, 3- ([ 5-imidazole ]2, 1-methylenethiazole) -2-indolinone, 3-1(2, 6-dimethylimidazo [2, 1-Bj-thiazol-5-yl ] methylene-5-methoxy-2-indolinone, imidazo [2, 1-b ] methylenethiazole-2-indolinone, methyleneindole-2-indolinone, (2-chloroindole) methylene-2-indolinone, arylene 2-indolinone, 1, 3-dihydro-5, 6-dimethoxy-3- [ (4-hydroxyphenyl) methylene ] -2H-indol-2-indolinone, 3- (4-dimethylamino-benzylidene) -2-indolinone, 5-chloro-3-methylenepyridine-2-indolinone, 3-dimethylpyridine-1-phenyl-2-indolinone or E-3- (2-chloro-3-methyleneindole) 1, 3-indoline-2-indolinone, dasatinib, avastin, canatinib, sorafenib, sunitinib, Teoseta, panitoma.
The above-mentioned vascular inhibitor may be singly or multiply selected, and gefitinib, erlotinib, lapatinib, vatalanib, pelitinib, carboxyamidotriazole, thalidomide, ranolamine, angiostatin, endostatin, imatinib mesylate, sematinib, dasatinib, avastin, canatinib, sorafenib, sunitinib, telosta, panitoma are most preferred.
The weight percentage of the anticancer drug in the sustained release microspheres is 0.5-60%, preferably 2-40%, and most preferably 5-30%. When the taxane and the synergist thereof (the hormone anticancer drug and/or the blood vessel inhibitor) are used in combination, the weight ratio of the taxane to the hormone anticancer drug and/or the blood vessel inhibitor is 1-9:1 to 1:1-9, preferably 1-2: 1.
The anticancer active ingredients in the anticancer sustained-release injection microsphere are preferably as follows, and the weight percentages are as follows:
(a) 2-40% of paclitaxel, docetaxel, 2' -hydroxypaclitaxel, 10-deacetyl paclitaxel, and 7-epi-paclitaxel;
(b) 5-30% triptorelin, goserelin, leuprorelin, anastrozole, idoxifene, milbexifene, tamoxifen, 4-monohydroxytamoxifen, comoxifene, raloxifene, sterculia, antiestrol, anticancer sterenol, 4-hydroxyttamoxifen, flutamide, aminoglutethimide, pirglutethimide, megestrol, medroxyprogesterone, clomiphene, toremifene, letrozole, anastrozole, exemestane, or bicalutamide;
(c) a combination of 2-40% paclitaxel or docetaxel with 5-30% triptorelin, goserelin, leuprorelin, anastrozole, idoxifene, mirtaxifene, tamoxifen, 4-monohydroxytamoxifen (OH-TAM), comoxifene, raloxifene, sterculia estra, anticancer sterenol, 4-hydroxyttamoxifen, flutamide, aminoglutethimide, pirglutethimide, megestrol, medroxyprogesterone, clomiphene, toremifene, letrozole, anastrozole, exemestane, or bicalutamide;
(d) 5-30% of gefitinib, erlotinib, lapatinib, vatalanib, pelitinib, carboxyamidotriazole, thalidomide, ranolamine, angiostatin, endostatin, imatinib mesylate, semasnib, dasatinib, avastin, canatinib, sorafenib, sunitinib, teosinte or panitoma;
(e) 2-40% paclitaxel or docetaxel in combination with 5-30% gefitinib, erlotinib, lapatinib, vatalanib, pelitinib, carboxyamidotriazole, thalidomide, ranolamine, angiostatin, endostatin, imatinib mesylate, semasnib, dasatinib, avastin, canatinib, sorafenib, sunitinib, telosta, or panitoma;
(f) 5-30% of gefitinib, erlotinib, lapatinib, vatalanib, pelitinib, carboxyamidotriazole, thalidomide, ranolamine, angiostatin, endostatin, imatinib mesylate, sematinib, dasatinib, avastin, canatinib, sorafenib, sunitinib, Teotat or panitoma with 5-30% of triptorelin, goserelin, leuprorelin, combinations of anastrozole, idoxifene, mirtaoxifene, tamoxifen, 4-monohydroxytamoxifen (OH-TAM), comoxifene, raloxifene, sterculia, anti-cancer sterenol, 4-hydroxyttamoxifen, flutamide, aminoglutethimide, pirglutethimide, megestrol, medroxyprogesterone, clomiphene, toremifene, letrozole, anastrozole, exemestane, or bicalutamide.
The suspending agent is used for preparing and/or effectively suspending, stabilizing and/or protecting various medicaments or sustained-release microspheres (or microcapsules), so that the prepared injection has good injectability, difficult blockage, good stability, difficult layering and high viscosity.
The suspending agent is selected from one or more of sodium carboxymethylcellulose, (iodine) glycerol, dimethicone, propylene glycol, carbomer, mannitol, sorbitol, surfactant, Tween 20, Tween 40 and Tween 80.
The viscosity of the suspending agent is 100cp-3000cp (at 20-30 ℃), preferably 1000cp-3000cp (at 20-30 ℃), and most preferably 1500cp-3000cp (at 20-30 ℃).
The common solvent can be, but is not limited to, distilled water, water for injection, physiological saline, absolute ethyl alcohol or buffer solution prepared from various salts, and the pharmacopoeia has corresponding regulations; the special solvent in the invention is a common solvent containing a suspending agent, and the suspending agent can be, but is not limited to, sodium carboxymethylcellulose, (iodine) glycerol, simethicone, propylene glycol, carbomer, mannitol, sorbitol, a surface active substance, Tween 20, Tween 40 and Tween 80 or a combination thereof. The content of the suspending agent in the special solvent is 0.1-30% by volume weight, preferably as follows:
a) 0.5-5% sodium carboxymethylcellulose; or
b) 0.5-5% sodium carboxymethylcellulose 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% of sodium carboxymethylcellulose, 5-20% of sorbitol and 0.1-0.5% of tween 80.
The above-mentioned all are volume weight percentages, and the weight of suspending agent in the common solvent of unit volume, for example, g/ml, kg/l. The same applies below.
The sustained release excipient is preferably one of polylactic acid (PLA), polyglycolic acid and glycolic acid copolymer (PLGA), ethylene vinyl acetate copolymer (EVAc), FAD SA copolymer, polifeprosan, di-fatty acid and sebacic acid copolymer (PFAD-SA) ], poly (erucic acid dimmer-sebacic acid) [ P (EAD-SA) ], poly (fumaric acid-sebacic acid) [ P (FA-SA) ], or a combination thereof.
When polylactic acid (PLA), polyglycolic acid (PGA), a mixture of the PLA and the polyglycolic acid, and a copolymer (PLGA) of glycolic acid and hydroxycarboxylic acid are selected, the contents and weight percentages of the PLA and the PLGA are respectively 0.1-99.9% and 99.9-0.1%. The molecular weight peak of polylactic acid may be, but is not limited to, 5000-; the molecular weight of polyglycolic acid may be, but is not limited to, 5000-; the polyhydroxy acids can be selected singly or in multiple ways. When selected alone, polylactic acid (PLA) or a copolymer of hydroxycarboxylic acid and glycolic acid (PLGA) is preferred, and the molecular weight of the copolymer may be, but is not limited to, 5000-150,000, but is preferably 20,000-60,000, and is most preferably 30,000-50,000; when more than one choice is selected, the polymer or the composite polymer or copolymer of different polymers is preferred, and the composite polymer or copolymer of polylactic acid or sebacic acid with different molecular weight is most preferred, such as, but not limited to, polylactic acid with molecular weight of 1000 to 30000 mixed with polylactic acid with molecular weight of 20000 to 50000, polylactic acid with molecular weight of 10000 to 30000 mixed with PLGA with molecular weight of 30000 to 80000, polylactic acid with molecular weight of 20000 to 30000 mixed with sebacic acid, PLGA with molecular weight of 30000 to 80000 mixed with sebacic acid.
Among the various polymers, preferred are polylactic acid, sebacic acid, and a mixture or copolymer of polylactic acid and sebacic acid, and the mixture or copolymer can be selected from, but not limited to, PLA, PLGA, a mixture of glycolic acid and hydroxycarboxylic acid, and a mixture or copolymer of sebacic acid and an aromatic polyanhydride or an aliphatic polyanhydride. The blending ratio of glycolic acid and hydroxycarboxylic acid is 10/90-90/10 (by weight), preferably 25/75-75/25 (by weight). The method of blending is arbitrary. The contents of glycolic acid and hydroxycarboxylic acid in copolymerization are 10-90 wt% and 90-10 wt%, respectively. Representative of the aromatic polyanhydrides are polifeprosan [ poly (1, 3-di (P-carboxyphenoxy) propane-sebacic acid) (P (CPP-SA)), difatty acid-sebacic acid copolymer (PFAD: SA) ], poly (erucic acid dimer-sebacic acid) [ P (EAD: SA) ], and poly (fumaric acid-sebacic acid) [ P (FA: SA) ], and the like. The contents of p-carboxyphenoxy propane (p-CPP) and sebacic acid in copolymerization are respectively 10-60 percent and 20-90 percent by weight, and the blending weight ratio is 10-40: 50-90, preferably 15-30: 65-85.
In order to adjust the drug release rate or change other characteristics of the present invention, the monomer component or molecular weight of the polymer can be changed, and the composition and ratio of the pharmaceutical excipients can be added or adjusted, and water-soluble low molecular compounds such as, but not limited to, various sugars or salts can be added. The sugar can be, but is not limited to, xylitol, oligosaccharide, (chondroitin sulfate), chitin, etc., and the salt can be, but is not limited to, potassium salt, sodium salt, etc.
The preparation of the injection comprises the preparation of sustained release microspheres or drug particles, the preparation of a solvent, the suspension of the sustained release microspheres or drug particles in the solvent and the final preparation of the injection.
Wherein, the sustained release microspheres or drug microparticles can be prepared by several methods: such as, but not limited to, mixing, melting, dissolving, spray-drying to prepare microspheres, dissolving in combination with freeze (dry) milling, liposome encapsulation, and emulsification. Among them, the dissolution method (i.e., solvent evaporation method), the freeze (dry) pulverization method, the drying method, the spray drying method and the emulsification method are preferable. The microspheres can be used for preparing the various sustained-release injections. The particle size of the suspension drug or sustained release microspheres (or microcapsules) is determined by specific needs and can be, but is not limited to, 1-300um, but is preferably 20-200um, and most preferably 30-150 um. The drug or the sustained-release microspheres can be prepared into microspheres, submicron spheres, micro-emulsion, nanospheres, granules or spherical pellets. The slow release auxiliary material is the above-mentioned biocompatible, biodegradable or non-biodegradable polymer.
The preparation of the solvent depends on the kind of the solvent, and common solvents are commercially available or self-made, such as distilled water, water for injection, physiological saline, absolute ethanol or buffers prepared from various salts, but the preparation must strictly follow the relevant standards. The special solvent should be selected from the type and composition of suspending agent, the composition, properties and required amount of the medicine suspended in the solvent, sustained release microsphere (or microcapsule), and the preparation method of injection, for example, sodium carboxymethylcellulose (1.5%) + mannitol and/or sorbitol (15%) and/or Tween-80 (0.1%) are dissolved in physiological saline to obtain corresponding solvent with viscosity of 10-650 cp (at 20-30 deg.C).
The invention discovers that the key factor influencing the suspension and/or injection of the medicament and/or the sustained-release microspheres is the viscosity of the solvent, and the higher the viscosity is, the better the suspension effect is and the stronger the injectability is. This unexpected finding constitutes one of the main exponential features of the present invention. The viscosity of the solvent depends on the viscosity of the suspending agent, and the viscosity of the suspending agent is 100cp-3000cp (at 20-30 ℃), preferably 1000cp-3000cp (at 20-30 ℃), and most preferably 1500cp-3000cp (at 20-30 ℃). The viscosity of the solvent prepared according to the condition is 10cp-650cp (at 20-30 ℃), preferably 20cp-650cp (at 20-30 ℃), and most preferably 60cp-650cp (at 20-30 ℃).
The preparation of the injection has a plurality of methods, one is that the sustained-release particles are directly mixed in a special solvent to obtain the corresponding sustained-release particle injection; the other is to mix the sustained-release particles in a special solvent or a common solvent to obtain a corresponding sustained-release particle injection; and the other one is to mix the slow release particles in common dissolvent, then add suspending agent and mix evenly to obtain the corresponding slow release particle injection. Besides, the slow release particles can be mixed in a special solvent to prepare a corresponding suspension, then the water in the suspension is removed by methods such as vacuum drying, and the like, and then the suspension is suspended by the special solvent or a common solvent to obtain a corresponding slow release particle injection. The above methods are merely illustrative and not restrictive of the invention. It is noted that the concentration of the suspended drug or the sustained release microspheres (or microcapsules) in the injection may be, but is not limited to, 10-400mg/ml, but is preferably 30-300mg/ml, and most preferably 50-200mg/ml, depending on the particular need. The viscosity of the injection is 50-1000 cp (at 20-30 deg C), preferably 100-1000 cp (at 20-30 deg C), and most preferably 200-650 cp (at 20-30 deg C). This viscosity is suitable for 18-22 gauge needles and specially made needles with larger (to 3 mm) inside diameters.
The application of the injection comprises the application of sustained-release microspheres or drug particles, the application of a solvent and the application of the injection prepared by suspending the sustained-release microspheres or the drug particles in the solvent.
In the slow release injection, the drug slow release system can be prepared into microspheres, submicron spheres, micro emulsion, nanospheres, granules or spherical pellets, and then the injection is prepared after the drug slow release system is mixed with an injection solvent. The suspension type sustained-release injection is preferably selected from various sustained-release injections, the suspension type sustained-release injection is a preparation obtained by suspending a drug sustained-release system containing an anticancer component in injection, the used auxiliary materials are one or the combination of the sustained-release auxiliary materials, and the used solvent is a common solvent or a special solvent containing a suspending agent. Common solvents are, but not limited to, distilled water, water for injection, physiological saline, absolute ethanol or buffers formulated with various salts. The suspending agent is intended to effectively suspend the microspheres containing the drug, thereby facilitating injection.
The microsphere is used for preparing sustained release injection, such as suspension sustained release injection, gel injection, and block copolymer micelle injection. Among various injections, a suspension type sustained-release injection is preferable. The suspension type sustained-release injection is a preparation obtained by suspending medicament sustained-release microspheres or medicament particles containing active ingredients in a solvent, the used auxiliary material is one or the combination of the sustained-release auxiliary materials, and the used solvent is a common solvent or a special solvent containing a suspending agent. Common solvent is, but not limited to, distilled water, water for injection, physiological saline, absolute ethyl alcohol or buffer solution prepared by various salts; the block copolymer micelle is formed by a hydrophobic-hydrophilic block copolymer in an aqueous solution and has a spherical core-shell structure, wherein the hydrophobic block forms a core, and the hydrophilic block forms a shell. The drug-loaded micelle is injected into the body to achieve the purpose of controlling the release of the drug or targeting therapy. The drug carrier is any one of the above or the combination thereof. The polyethylene glycol (PEG) with the molecular weight of 1000-15000 is preferably used as a hydrophilic block of a micelle copolymer, a biodegradable polymer (such as PLA, polylactide, polycaprolactone and a copolymer thereof (with the molecular weight of 1500-25000) is preferably used as a hydrophobic block of the micelle copolymer, the particle size of the block copolymer micelle can be 1-300um, but 20-200um is preferred, and 30-150um is most preferred, and the gel injection is prepared by dissolving the biodegradable polymer (such as PLA, PLGA or DL-LA and epsilon-caprolactone copolymer) in certain amphiphilic solvent, adding the drug to be miscible (or suspended) to form gel with better fluidity, and injecting the gel around or in tumor.
The application of the solvent mainly refers to the application of the special solvent in effectively suspending, stabilizing and/or protecting various medicines or sustained-release microspheres (or microcapsules) so as to prepare corresponding injections. The application of the special solvent can lead the prepared injection to have better injection property, stability and higher viscosity.
The injection is prepared by using special solvent with high viscosity to make drug-containing microparticles, especially slow-release microparticles, into corresponding slow-release injection, so that the corresponding drug can be injected into the body of patient or mammal. The injected drug may be, but is not limited to, the above drug fine powder or drug sustained-release fine particles.
The route of administration of the injection depends on various factors. While administration can be by a variety of routes, selective arterial, intracavitary, intratumoral, peritumoral injection is preferred.
In order to obtain effective concentration at the site of primary or metastatic tumor, it can also be administered by combination of multiple routes, such as intravenous, lymphatic, subcutaneous, intramuscular, intracavity (such as intraperitoneal, thoracic, intraarticular and intraspinal) or selective arterial injection in combination with local injection. Such combination administration is particularly useful for solid tumors. For example, the injection is combined with the systemic injection at the same time of intratumoral injection and peritumoral injection.
The sustained-release microspheres can also be used for preparing sustained-release implants, the used pharmaceutic adjuvant can be any one or more of the above pharmaceutic adjuvants, but the water-soluble high-molecular polymer is taken as the main choice, and the mixture or the copolymer of polylactic acid, sebacic acid, and high-molecular polymer containing polylactic acid or sebacic acid is taken as the first choice among various high-molecular polymers, and the mixture or the copolymer can be selected from, but is not limited to, PLA, PLGA, the mixture of PLA and PLGA, FAD, SA copolymer, and the mixture or the copolymer of sebacic acid and aromatic polyanhydride or aliphatic polyanhydride. The blending ratio of polylactic acid (PLA) to polyglycolic acid is 10/90 to 90/10 (by weight), preferably 25/75 to 75/25 (by weight). The method of blending is arbitrary. The contents of glycolic acid and lactic acid in copolymerization are respectively 10-90% and 90-10% by weight. The aromatic polyanhydride is represented by p-carboxyphenylpropane (p-CPP), the content of the p-carboxyphenylpropane (p-CPP) and sebacic acid in copolymerization is respectively 10-60% and 20-90% by weight, and the blending weight ratio is 10-40: 50-90, preferably 15-30: 65-85.
In addition to the above-mentioned adjuvants, other substances may be used as described in detail in U.S. Pat. No. 4757128 (4857311) (4888176 (4789724)) and "pharmaceutical adjuvants" in general (p. 123, published by Sichuan scientific and technical Press 1993, compiled by Luomingsheng and high-tech). In addition, Chinese patent (application No. 96115937.5; 91109723.6; 9710703.3; 01803562.0) and U.S. patent No. 5,651,986) also list some pharmaceutical excipients, including fillers, solubilizers, absorption promoters, film-forming agents, gelling agents, pore-forming agents, excipients or retarders.
The effective components of the anticancer implant can be uniformly packaged in the whole pharmaceutic adjuvant, and also can be packaged in the center of a carrier support or on the surface of the carrier support; the active principle can be released by direct diffusion and/or by degradation via polymers. In addition, the active ingredients of the anticancer sustained-release implant can also be uniformly packaged in liposome or made into microspheres by the prior art method.
The anticancer implant is in various shapes such as, but not limited to, granules, tablets, powders, granules, spheres, blocks, needles, rods, columns and films. The optimal preparation form is a biocompatible and degradable and absorbable implant sustained-release agent, and can be prepared into various shapes and various preparation forms according to different clinical requirements, such as, but not limited to, sustained-release implant tablets, granules, capsules, balls, pills, powders and rods. The packaging method and procedure for its main ingredients are described in detail in US patent (US5651986) and include several methods for preparing sustained release formulations: such as, but not limited to, (i) mixing a carrier support powder with a drug and then compressing into an implant, a so-called mixing process; (ii) melting the carrier support, mixing with the drug to be packaged, and then cooling the solid, the so-called melt process; (iii) dissolving the carrier support in a solvent, dissolving or dispersing the drug to be packaged in a polymer solution, and then evaporating the solvent and drying, the so-called dissolution method; (iv) spray drying; and (v) freeze-drying method.
The anticancer sustained-release implant can be administered by various routes, and in various routes, local administration is mainly performed, such as selective arterial, intracavity, intratumoral and peritumoral placement, and a slow release form in intratumoral, peritumoral or tumor cavity is preferred, and direct placement in tumor body is optimal.
The amount of the anti-cancer agent to be administered depends on many factors, such as, but not limited to, tumor volume, patient weight, mode of administration, disease progression, and response to treatment. In general, the taxane and the synergist thereof may be 0.1-1000 mg/kg body weight, preferably 1-600 mg/kg body weight, most preferably 5-80 mg/kg body weight, and the hormone anticancer drug may be 0.1-500 mg/kg body weight, preferably 1-120 mg/kg body weight, most preferably 5-50 mg/kg body weight.
The invention can be used for preparing pharmaceutical preparations for treating various solid tumors of human beings, pets and animals, mainly sustained-release implants and sustained-release injections, wherein the solid tumors comprise tumors originating in the brain and central nervous system, and also comprise primary or metastatic cancers or sarcomas or carcinosarcomas originating in the kidney, liver, gall bladder, head and neck, oral cavity, thyroid gland, skin, mucous membrane, gland, blood vessel, bone tissue, lymph node, lung, esophagus, stomach, breast, pancreas, eye, nasopharynx part, uterus, ovary, endometrium, cervix, prostate, bladder, colon and rectum.
The anticancer sustained-release implant and the sustained-release injection of the invention can also be added with other medicinal components, such as, but not limited to, antibiotics, analgesic, anticoagulant, hemostatic, etc. The above medicinal components can be selected individually or in multiple ways, and can be added into the composition with or without additives, and the content is determined according to specific needs.
Packaging the above effective components in medicinal adjuvants, and selectively topically applying. Such as selective arterial injection and direct intratumoral injection or placement, with local placement or injection being preferred. When being applied locally, the anticancer sustained-release implant can be directly placed around or in a tumor body of a primary or metastatic solid tumor, and also can be directly placed or injected into a cavity formed after the primary or metastatic solid tumor is completely or partially cut off.
The main component of the invention takes biocompatible substance as a support, thus not causing foreign body reaction. The support can be degraded and absorbed after being placed in vivo, so that the support can be taken out without operation, and the drug contained in the support can be locally released in the tumor, so that the local drug concentration can be selectively increased and prolonged, and the systemic toxicity reaction caused by the conventional route of administration can be reduced.
The anticancer drug is locally injected or placed, so that not only can the toxic reaction caused by systemic administration be overcome, but also the problems of too low local tumor drug concentration and sensitivity of cells to the drug are solved. Not only can effectively kill tumor cells, but also can inhibit tumor blood vessels, thereby having unique superiority.
The packaging and use of the taxane and/or taxane synergist is dependent on the clinical need. The taxane and taxane synergist can be packaged separately or in combination. Combination packs are mainly used for local potentiation, while individual packs are mainly used for potentiation of different routes of administration or for potentiation of other therapies. For example, a taxane and taxane synergist when placed (or injected) topically alone may be combined with an intravenously applied taxane synergist and taxane synergist, respectively; topically placed (or injected) taxanes and/or taxane synergists may also be used to potentiate radiation therapy.
The technique of the present invention is further described by the following tests and examples:
test 1 comparison of local drug concentrations after different modes of taxane (paclitaxel) application
Using white rat as test object, 2X 105Individual prostate tumor cells were injected subcutaneously into their quaternary costal regions and grouped after tumors grew to 1 cm in diameter. The dose of each group was 5 mg/kg. The results of the determination of the content (%) of the medicament in the tumor at different times show that the concentration difference of the local medicament of the paclitaxel applied in different modes is obvious, the effective medicament concentration of the part where the tumor is positioned can be obviously improved and effectively maintained by local administration, and the effect of placing the sustained-release implant in the tumor and injecting the sustained-release injection in the tumor is the best. However, the intratumoral injection of the sustained-release injection is most convenient and easy to operate. This finding constitutes an important feature of the present invention. This is further confirmed by the following relevant tumor inhibition test.
Experiment 2 comparison of in vivo tumor inhibition Using taxane (paclitaxel) in different modes
Using white rat as test object, 2X 105Individual prostate tumor cells were injected subcutaneously into their quaternary costal regions and grouped after tumors grew to 0.5 cm diameter. The dose of each group was 5 mg/kg. The volume of the tumor was measured on the 10 th day after the treatment, and the treatment effect was compared. The results show that the difference of the tumor inhibition effect of the paclitaxel after being applied in different modes is obvious, the effective drug concentration of the tumor part can be obviously improved and effectively maintained by local administration, wherein the effect of placing the sustained-release implant in the tumor and injecting the sustained-release injection in the tumorThe best result is obtained. However, the intratumoral injection of the sustained-release injection is most convenient and easy to operate. Not only has good curative effect, but also has little toxic and side effect.
Experiment 3 tumor inhibition effect of synergist containing paclitaxel and paclitaxel
Using white rat as test object, 2X 105Individual pancreatic tumor cells were subcutaneously injected into the quaternary costal region, and were divided into control and treatment groups (1-11) after the tumors had grown for 14 days. The treatment components comprise paclitaxel group, paclitaxel synergist group, paclitaxel and paclitaxel synergist group. The drug dose is 5mg/kg, and the injection is performed in tumor. Tumor volume was measured on day 10 after treatment and the treatment effect was compared (see table 1).
TABLE 1
Group of Paclitaxel Synergist Tumor inhibition ratio (%) P value
1 + - 64 *
2 - Triptorelin 46 *
3 - Goserelin 42 *
4 - Leuprorelin 38 *
5 - Anastrozole 48 *
6 - Idoxifene 36 *
7 + Triptorelin 86 **
8 + Goserelin 82 **
9 + Leuprorelin 88 **
10 + Anastrozole 86 **
11 + Idoxifene 82 **
The above results show that both the taxane (paclitaxel) and the paclitaxel potentiators used (triptorelin, goserelin, leuprolide, anastrozole, idoxifene) exhibit significant inhibition of tumor growth at these concentrations alone (P value less than 0.05) and when used in combination exhibit very significant potentiation (P value less than 0.001).
Test 4 antitumor Effect of paclitaxel and paclitaxel synergist (sustained Release injection)
The tumor cells include CNS-1, C6, 9L, gastric gland epithelial cancer (SA), bone tumor (BC), breast cancer (BA), lung cancer (LH), papillary thyroid adenocarcinoma (PAT), and liver cancer. Paclitaxel and paclitaxel synergist were added to each tumor cell cultured in vitro for 24 hours at a concentration of 10ug/ml, and the total number of cells was counted after culturing for another 48 hours. The tumor cell growth inhibitory effect (%) is shown in Table 2.
TABLE 2
Tumor cell Purple pigment A B C D E Purple + A Purple + B Purple + C Purple + D Purple + E
CNS 52 50 48 38 58 42 88 88 82 78 88
C6 54 52 46 36 64 40 90 80 84 84 90
SA 52 58 36 42 62 48 88 84 86 82 82
BC 58 54 40 42 64 54 88 80 74 74 80
BA 68 46 38 48 60 56 80 80 92 92 80
LH 66 56 40 52 58 60 90 82 94 78 94
PAT 60 48 46 50 54 68 82 76 82 80 80
The results show that the used purple (paclitaxel) and paclitaxel synergist (wherein A: milbexifene, B: tamoxifen, C: tamoxifen, D: raloxifene, and E: steroidal antiestrogen) have obvious inhibition effect on the growth of various tumor cells when being singly used at the concentration, and can show obvious synergistic effect when being used in combination.
Test 5 antitumor Effect of paclitaxel and paclitaxel synergist (sustained Release injection)
The tumor cells include CNS-1, C6, 9L, gastric gland epithelial cancer (SA), bone tumor (BC), breast cancer (BA), lung cancer (LH), papillary thyroid adenocarcinoma (PAT), and liver cancer. Paclitaxel and paclitaxel synergist were added to each tumor cell cultured in vitro for 24 hours at a concentration of 10ug/ml, and the total number of cells was counted after culturing for another 48 hours. The tumor cell growth inhibitory effect (%) is shown in Table 5. The results show that the paclitaxel and the paclitaxel synergist (anticancer sterenol, flutamide, aminoglutethimide, pirglutethimide and megestrol) have obvious inhibition effect on the growth of various tumor cells when being used independently (P <0.05), and can show obvious synergistic effect (P <0.01) when being used in combination.
Test 6 antitumor Effect of paclitaxel and paclitaxel synergist (sustained Release injection)
Using white rat as test object, 2X 105Each prostate tumor cell was injected subcutaneously into the costal region of the prostate, and after the tumor had grown for 14 days, it was divided into a negative control (blank), a single-drug treatment group (paclitaxel or paclitaxel potentiator), and a combination treatment group (paclitaxel and paclitaxel potentiator). The medicine is injected intratumorally. The dosage is 5 mg/kg. The volume of the tumor was measured on the 10 th day after the treatment, and the therapeutic effect was compared using the tumor growth inhibition rate as an index. The results show that the paclitaxel and paclitaxel synergist (medroxyprogesterone, toremifene, anastrozole, exemestane) have obvious inhibition effect on the growth of various tumor cells when being independently applied (P)<0.05), when used in combination, can exhibit a significant synergistic effect (P)<0.01)。
Test 7 antitumor Effect of paclitaxel and paclitaxel synergist (sustained Release injection)
Using white rat as test object, 2X 105Each breast tumor cell was injected subcutaneously into the costal region of the patient, and the tumor was divided into a negative control (blank), a single drug treatment group, and a combination treatment group 14 days after the tumor had grown. The medicine is injected intratumorally. The dosage is 5 mg/kg. Measuring tumor volume on day 10 after treatment, and using tumor growth inhibition rate as indexThe standard compares the therapeutic effect (see table 3).
TABLE 3
Test set (n) Is treated by Tumor inhibition ratio (%) P value
1(6) Control -
2(6) Paclitaxel 58 <0.05
3(6) Gefitinib 50 <0.01
4(6) Erlotinib 40 <0.01
5(6) Lapatinib 36 <0.01
6(6) Votalanib 36 <0.01
7(6) Paclitaxel + gefitinib 86 <0.001
8(6) Paclitaxel + erlotinib 88 <0.001
9(6) Paclitaxel + lapatinib 94 <0.001
10(6) Paclitaxel + Votalanib 96 <0.001
The results show that the used paclitaxel and paclitaxel synergist vascular inhibitors (gefitinib, erlotinib, lapatinib and vatalanib) have obvious inhibition effect on the growth of various tumor cells when being singly applied at the concentration, and can show obvious synergistic effect when being jointly applied.
Test 8 antitumor Effect of paclitaxel and paclitaxel synergist (sustained Release implant)
Using white rat as test object, 2X 105Each breast tumor cell was injected subcutaneously into the costal region of the patient, and the tumor was divided into a negative control (blank), a single drug treatment group, and a combination treatment group 14 days after the tumor had grown. The sustained release implant is placed intratumorally. The dosage is 5 mg/kg. The volume of the tumor was measured on the 10 th day after the treatment, and the therapeutic effect was compared using the tumor growth inhibition rate as an index (see Table 4).
TABLE 4
Test set (n) Is treated by Tumor inhibition ratio (%) P value
1(6) Control -
2(6) Docetaxel 58 <0.05
3(6) Pelitinib 58 <0.05
4(6) Reaction stop 36 <0.05
5(6) Reynolds amine 46 <0.05
6(6) Angiostatin 36 <0.01
7(6) Docetaxel + pelitinib 84 <0.01
8(6) Docetaxel + reactionstop 86 <0.01
9(6) Docetaxel + Reynolds amine 92 <0.01
10(6) Docetaxel + angiostatin 92 <0.001
The results show that the docetaxel and the docetaxel synergist-the vascular inhibitor (pelitinib, carboxyamidotriazole, thalidomide, ranolamine and angiostatin) have obvious inhibition effect on the growth of various tumor cells when being singly applied at the concentration, and can show obvious synergistic effect when being jointly applied.
Test 9 antitumor Effect of paclitaxel and paclitaxel synergist (sustained Release implant)
The tumor-inhibiting effect of paclitaxel and paclitaxel synergist (sustained release implant) was determined as described in test 8, and the tumor growth inhibition rate is shown in table 5.
TABLE 5
Test set (n) Is treated by Tumor inhibition ratio (%) P value
1(6) Control -
2(6) Paclitaxel 58 <0.05
3(6) Endostatin 40 <0.01
4(6) Methanesulfonic acid 50 <0.01
5(6) Simassini 40 <0.01
6(6) Dasatinib 42 <0.01
7(6) Paclitaxel + endostatin 88 <0.001
8(6) Paclitaxel + methanesulfonic acid 84 <0.001
9(6) Paclitaxel + simassnib 82 <0.001
10(6) Paclitaxel + dasatinib 44 <0.001
The results show that the paclitaxel and the paclitaxel synergist-blood vessel inhibitor (endostatin, imatinib mesylate, semastinib and dasatinib) have obvious inhibition effect on the growth of various tumor cells when being used at the concentration alone, and can show obvious synergistic effect when being used in combination.
Test 10 tumor inhibition of paclitaxel and paclitaxel synergist (sustained release injection)
The tumor-inhibiting effect of paclitaxel and paclitaxel synergist (sustained release implant) was determined as described in test 8, and the tumor growth inhibition rate is shown in table 6.
TABLE 6
Test set (n) Is treated by Tumor inhibition ratio (%) P value
1(6) Control -
2(6) Paclitaxel 58 <0.05
3(6) Avastin 48 <0.01
4(6) Caratinib 38 <0.01
5(6) Sorafenib 40 <0.01
6(6) Sunitinib 50 <0.01
7(6) Paclitaxel + avastin 84 <0.001
8(6) Paclitaxel + Caratinib 88 <0.001
9(6) Paclitaxel + SoraxNon-damping 80 <0.001
10(6) Paclitaxel + sunitinib 92 <0.001
The results show that the paclitaxel and the paclitaxel synergist-angiogenesis inhibitor (avastin, canatinib, sorafenib and sunitinib) have obvious inhibition effect on the growth of various tumor cells when being applied at the concentration alone, and can show obvious synergistic effect when being applied in combination.
Experiment 11. antitumor Effect of taxane synergist (sustained-release injection)
The tumor suppressive effect of the taxane synergist (sustained release injection) was determined as described in test 5. The results show that the taxane synergist (anticancer sterenol, flutamide, aminoglutethimide, pirglutethimide and megestrol) has obvious inhibition effect on the growth of various tumor cells when being singly used (P <0.05), and can show obvious synergistic effect (P <0.01) when being used together with vascular inhibitors such as gefitinib, erlotinib, lapatinib and Votalanib.
Experiment 12. the antitumor effect of taxane synergist (slow release injection)
The tumor suppressive effect of the taxane synergist (sustained release injection) was determined as described in test 5. The result shows that the used taxane synergist (medroxyprogesterone, toremifene, anastrozole and exemestane) has obvious inhibition effect (P <0.05) on the growth of various tumor cells when being singly applied, and can show obvious synergistic effect (P <0.01) when being combined with blood vessel inhibitors such as pelitinib, carboxyamidotriazole, thalidomide, ranolamine, angiostatin and the like.
Experiment 13, antitumor Effect of taxane synergist (sustained Release injection)
The tumor suppressive effect of the taxane synergist (sustained release injection) was determined as described in test 5. The results show that the used taxane synergist (medroxyprogesterone, toremifene, anastrozole and exemestane) has obvious inhibition effect (P <0.05) on the growth of various tumor cells when being singly used, and can show obvious synergistic effect (P <0.01) when being used together with vascular inhibitors such as endostatin, vascular endostatin, imatinib mesylate, semasnib, dasatinib, avastin, kanatinib, sorafenib, sunitinib and the like.
In conclusion, the taxane and the various taxane synergists have obvious inhibition effect on the growth of various tumor cells when being applied independently, can show obvious synergistic effect when being applied jointly, have obvious inhibition effect on the growth of various tumor cells when being applied independently, and can also show obvious synergistic effect when being applied jointly. Thus, the active ingredient of the present invention is a taxane and/or any one or combination of several taxane synergists. The medicine containing the effective components can be prepared into sustained-release microspheres and further prepared into sustained-release injection and implant, wherein the suspension injection formed by combining the suspension injection with a special solvent containing a suspending agent is preferred, and the viscosity of the solvent of the suspension injection is 10cp-650cp (at 20-30 ℃), preferably 20cp-650cp (at 20-30 ℃), and most preferably 60cp-650cp (at 20-30 ℃).
The sustained-release injection or sustained-release implant can be further explained by the following embodiments. The above examples and the following examples are only for further illustration of the present invention and are not intended to limit the contents and uses thereof in any way.
(IV) detailed description of the preferred embodiments
Example 1.
80mg of polifeprosan (p-carboxyphenylpropane (p-CPP): Sebacic Acid (SA) is 20: 80) copolymer is put into a container, 100ml of dichloromethane is added, after dissolving and mixing uniformly, 10mg of paclitaxel and leuprorelin are added, after shaking uniformly again, the microspheres for injection containing 10% of paclitaxel and 10% of leuprorelin are prepared by a spray drying method. Then suspending the microspheres in physiological saline containing 15 percent mannitol to prepare the corresponding suspension type sustained-release injection with the viscosity of 20-300 cp (at 20-30 ℃). The slow release injection has the release time of 10-15 days in-vitro physiological saline and the release time of about 20-30 days under the skin of a mouse.
Example 2.
The steps of the method for processing the sustained-release injection are the same as the example 1, but the difference is that the anticancer active ingredients and the weight percentage thereof are as follows:
(1) 2-40% of paclitaxel, docetaxel, 2' -hydroxypaclitaxel, 10-deacetyl paclitaxel or 7-epi-paclitaxel;
(2) 5-30% triptorelin, goserelin, leuprorelin, anastrozole, idoxifene, mirtaxifene, tamoxifen, 4-monohydroxytamoxifen (OH-TAM), comoxifene, raloxifene, sterculia, anticancer sterenol, 4-hydroxyttamoxifen, flutamide, aminoglutethimide, pirglutethimide, megestrol, medroxyprogesterone, clomiphene, toremifene, letrozole, anastrozole, exemestane, or bicalutamide; or
(3) 2-40% paclitaxel in combination with 5-30% triptorelin, goserelin, leuprorelin, anastrozole, idoxifene, mirtaxifene, tamoxifen, 4-monohydroxytamoxifen (OH-TAM), comoxifene, raloxifene, sterculia, anticancer sterenol, 4-hydroxyttamoxifen, flutamide, aminoglutethimide, pirimimide, megestrol, medroxyprogesterone, clomiphene, toremifene, letrozole, anastrozole, exemestane, or bicalutamide.
The viscosity of the sustained-release injection is 10-650 cp (at 20-30 ℃).
Example 3.
Putting 70mg of polylactic acid (PLGA, 75: 25) with a molecular weight peak of 25000 into a container, adding 100ml of dichloromethane, dissolving and uniformly mixing, adding 15mg of paclitaxel and 15mg of gefitinib, shaking up again, and drying in vacuum to remove the organic solvent. Freeze-pulverizing the dried solid composition containing drug to obtain micropowder containing 10% paclitaxel and 10% gefitinib, and suspending in physiological saline containing 1.5% sodium carboxymethylcellulose to obtain suspension type sustained-release injection with viscosity of 220-340 cp (at 20-30 deg.C). The slow release injection has the release time of 10-15 days in-vitro physiological saline and the release time of about 20-30 days under the skin of a mouse.
Example 4
The steps of the method for processing the sustained-release injection are the same as the example 3, but the difference is that the anticancer active ingredients and the weight percentage thereof are as follows:
(1) 5-30% of gefitinib, erlotinib, lapatinib, vatalanib, pelitinib, carboxyamidotriazole, thalidomide, ranolamine, angiostatin, endostatin, imatinib mesylate, semasnib, dasatinib, avastin, canatinib, sorafenib, sunitinib, telosta, or panitoma; or
(2) 2-40% paclitaxel, docetaxel, 2' -hydroxypaclitaxel, 10-deacetylpaclitaxel or 7-epi-paclitaxel in combination with 5-30% gefitinib, erlotinib, lapatinib, vatalanib, pelitinib, carboxyamidotriazole, thalidomide, angiostatin, endostatin, imatinib mesylate, semasnib, dasatinib, avastin, canatinib, sorafenib, sunitinib, telosta or panitoma.
The viscosity of the injection is 10-650 cp (at 20-30 deg.C).
Example 5.
70mg of ethylene vinyl acetate copolymer (EVAc) is put into a container, 100ml of dichloromethane is added to dissolve and mix evenly, 20mg of docetaxel and 10mg of tamoxifen are added, and spray drying is carried out after shaking up again to prepare microspheres for injection containing 20% of docetaxel and 10% of tamoxifen. Then suspending the microspheres in injection containing 5-15% sorbitol to obtain corresponding suspension type sustained release injection with viscosity of 100-160 cp (at 25-30 deg.C). The slow release injection has the release time of 10-15 days in-vitro physiological saline and the release time of about 20-30 days under the skin of a mouse.
Example 6.
The procedure of the process for preparing the sustained-release injection is the same as that of example 5, except that the anticancer active ingredients are:
10-20% of paclitaxel or docetaxel in combination with 10-20% of triptorelin, goserelin, leuprorelin, anastrozole, idoxifene, mirtaoxifene, tamoxifen, 4-monohydroxytamoxifen, comoxifene, raloxifene, sterculia, anticancer sterenol, 4-hydroxyttamoxifen, flutamide, aminoglutethimide, pirglutethimide, megestrol, medroxyprogesterone, clomiphene, toremifene, letrozole, anastrozole, exemestane or bicalutamide, the viscosity of the sustained release injection being 500-600 cp (at 25-30 ℃).
Example 7.
70mg of polifeprosan (p-carboxyphenylpropane (p-CPP): Sebacic Acid (SA) is 20: 80) copolymer is placed into a container, 100ml of dichloromethane is added, after dissolving and mixing uniformly, 20mg of paclitaxel and 10mg of gefitinib are added, after shaking uniformly again, the microspheres for injection containing 20% of paclitaxel and 10% of gefitinib are prepared by a spray drying method. Then suspending the microspheres in physiological saline containing 1.5 percent of sodium carboxymethylcellulose and 0.5 percent of Tween 80 to prepare the corresponding suspension type sustained-release injection with the viscosity of 180cp-260cp (at the temperature of 25 ℃ -30 ℃). The slow release injection has the release time of 10-15 days in-vitro physiological saline and the release time of about 20-30 days under the skin of a mouse.
Example 8.
The procedure of the process for preparing the sustained-release injection is the same as that of example 7, except that the anticancer active ingredients are: a combination of 5-20% paclitaxel or docetaxel and 10-20% gefitinib, erlotinib, lapatinib, vatalanib, pelitinib, carboxyamidotriazole, thalidomide, ranolamine, angiostatin, endostatin, imatinib mesylate, semasnib, dasatinib, avastin, canatinib, sorafenib, sunitinib, telosta, or panitoma. The viscosity of the injection is 400-560 cp (at 25-30 ℃).
Example 9
70mg of polifeprosan (p-carboxyphenylpropane (p-CPP): Sebacic Acid (SA) 20: 80) copolymer is put into a container, 100ml of dichloromethane is added, after dissolving and mixing uniformly, 20mg of paclitaxel and 10mg of erlotinib are added, after shaking uniformly again, the microspheres for injection containing 20% of paclitaxel and 10% of erlotinib are prepared by a spray drying method. Then suspending the microspheres in physiological saline containing 1.5 percent of sodium carboxymethylcellulose, 15 percent of sorbitol and 0.2 percent of Tween 80 to prepare the corresponding suspension type sustained-release injection with the viscosity of 100cp-160cp (at 25 ℃ -30 ℃). The slow release injection has the release time of 10-15 days in-vitro physiological saline and the release time of about 20-30 days under the skin of a mouse.
Example 10
The procedure of the process for preparing the sustained-release injection is the same as that of example 9, except that the anticancer active ingredients are: 20% of a paclitaxel polyene or paclitaxel in combination with 10% of gefitinib, erlotinib, lapatinib, vatalanib, pelitinib, carboxyamidotriazole, thalidomide, ranolamine, angiostatin, endostatin, imatinib mesylate, sematinib, dasatinib, avastin, canatinib, sorafenib, sunitinib, telosta, or panitoma; the viscosity is 560cp-640cp (at 25 ℃ -30 ℃).
Example 11
70mg of polifeprosan (p-carboxyphenylpropane (p-CPP): Sebacic Acid (SA) 20: 80) copolymer is put into a container, 100ml of dichloromethane is added, after dissolving and mixing uniformly, 10mg of anastrozole and 20mg of paclitaxel are added, after shaking uniformly again, the injection microspheres containing 10% of anastrozole and 20% of paclitaxel are prepared by a spray drying method. Then the microspheres are prepared into the corresponding sustained-release implant by a tabletting method. The slow release implant has the release time of 10-15 days in-vitro physiological saline and the release time of about 30-40 days under the skin of a mouse.
Example 12
The procedure of processing into a sustained-release implant was the same as in example 11, except that the anticancer active ingredient contained therein was: a combination of 20% paclitaxel or docetaxel and 10% triptorelin, goserelin, leuprorelin, anastrozole, idoxifene, mirtaxifene, tamoxifen, 4-monohydroxytamoxifen (OH-TAM), comoxifene, raloxifene, sterculia, anticancer sterenol, 4-hydroxyttamoxifen, flutamide, aminoglutethimide, pirimimide, megestrol, medroxyprogesterone, clomiphene, toremifene, letrozole, anastrozole, exemestane, or bicalutamide.
Example 13
70mg of polylactic acid (PLGA, 50: 50) with the molecular weight peak value of 35000 is put into a container, 100ml of dichloromethane is added, after being dissolved and mixed evenly, 10mg of tamoxifen and 20mg of imatinib are added, after being shaken up again, injection microspheres containing 10% of tamoxifen and 20% of imatinib are prepared by a spray drying method. Then the microspheres are prepared into the corresponding sustained-release implant by a tabletting method. The slow release implant has the release time of 10-15 days in vitro physiological saline and the release time of about 35-50 days under the skin of a mouse.
Example 14
The procedure of processing into sustained release implant was the same as in examples 11 and 13, except that the anticancer active ingredient contained was:
(1) a combination of 2-40% paclitaxel or docetaxel with 5-30% triptorelin, goserelin, leuprorelin, anastrozole, idoxifene, mirtaxifene, tamoxifen, 4-monohydroxytamoxifen (OH-TAM), comoxifene, raloxifene, sterculia estra, anticancer sterenol, 4-hydroxyttamoxifen, flutamide, aminoglutethimide, pirglutethimide, megestrol, medroxyprogesterone, clomiphene, toremifene, letrozole, anastrozole, exemestane, or bicalutamide;
(2) 5-30% of triptorelin, goserelin, leuprorelin, anastrozole, idoxifene, mircopoxifene, tamoxifen, 4-monohydroxytamoxifen, comoxifene, raloxifene, sterculia, anti-cancer sterenol, 4-hydroxyttamoxifen, flutamide, aminoglutethimide, pirglutethimide, megestrol, medroxyprogesterone, clomiphene, toremifene, letrozole, anastrozole, exemestane or bicalutamide in combination with 5-30% of gefitinib, erlotinib, lapatinib, volatinib, pelitinib, carboxyamidotriazole, thalidomide, angiostatin, endostatin, imatinib mesylate, semasinib, dasatinib, avastin, canatinib, sorafenib, sunitinib, octreotide or panitumomab; or
(3) 2-40% paclitaxel or docetaxel in combination with 5-30% gefitinib, erlotinib, lapatinib, vatalanib, pelitinib, carboxyamidotriazole, thalidomide, ranolamine, angiostatin, endostatin, imatinib mesylate, semasinib, dasatinib, avastin, canatinib, sorafenib, sunitinib, telosta, or panitoma.
Example 15
The procedure of processing into sustained release preparation is the same as that of examples 1-14, except that the sustained release excipient is one or a combination of the following:
a) polylactic acid (PLA) with a molecular weight peak of 10000-;
b) a copolymer of polyglycolic acid and glycolic acid (PLGA), wherein the ratio of polyglycolic acid to glycolic acid is 50-95: 50-50, the peak value of molecular weight is 10000-30000, 300000-60000, 60000-100000 or 100000-150000;
c) ethylene vinyl acetate copolymer (EVAc);
d) polifeprosan, p-carboxyphenylpropane (p-CPP): sebacic Acid (SA) 10:90, 20:80, 30:70, 40:60, 50:50 or 60: 40;
d) di-fatty acid and sebacic acid copolymer (PFAD-SA) ];
e) poly (erucic acid dimer-sebacic acid) [ P (EAD-SA) ];
f) poly (fumaric-sebacic acid) [ P (FA-SA) ];
g) xylitol, oligosaccharide, chondroitin, chitin, hyaluronic acid, collagen, gelatin or albumin glue.
Example 16
The procedure for preparing a sustained release injection is the same as in examples 1 to 15, except that the suspending agent used is one or a combination of the following:
a) 0.5-3.0% carboxymethylcellulose (sodium):
b) 5-15% mannitol;
c) 5-15% sorbitol;
d) 0.1-1.5% of surface active substances;
e) 0.10.5% Tween 20.
The above examples are intended to illustrate, but not limit, the application of the invention.
The invention is disclosed and claimed.

Claims (8)

  1. The claim 1 discloses an anticancer drug loaded with taxane and the synergist thereof, which is a sustained-release injection, and consists of the following components:
    (A) a sustained release microsphere comprising:
    0.5-60% of anticancer active ingredient
    Sustained release auxiliary materials 40-99%
    The above are weight percentages
    And
    (B) the menstruum is common menstruum or special menstruum containing a suspending agent;
    wherein,
    the anticancer effective component is a combination of taxane and taxane synergist, wherein the taxane is selected from paclitaxel, docetaxel, 2' -hydroxy taxol, 10-deacetyltaxol or 7-epi-taxol; the taxane synergist is a blood vessel inhibitor;
    the vascular inhibitor is selected from one of gefitinib, erlotinib, lapatinib, vatalanib, pelitinib, carboxyamidotriazole, thalidomide, ranolamine, angiostatin, endostatin, imatinib mesylate, semasnib, dasatinib, avastin, canatinib, sorafenib, sunitinib, teosinte, panitoma or a combination thereof;
    the slow release auxiliary material is selected from one or the combination of the following materials:
    a) polylactic acid;
    b) copolymers of polyglycolic acid and glycolic acid;
    c) polifeprosan;
    d) ethylene vinyl acetate copolymers;
    e) a di-fatty acid and sebacic acid copolymer;
    f) poly (erucic acid dimer-sebacic acid) copolymer;
    g) poly (fumaric acid-sebacic acid) copolymer;
    the suspending agent is selected from sodium carboxymethylcellulose, iodoglycerol, dimethicone, propylene glycol, carbomer, mannitol, sorbitol, surfactant, Tween-20, Tween-40 and Tween-80 or their combination, and has viscosity of 100-3000 cp (at 20-30 deg.C).
  2. The sustained-release anticancer injection according to claim 1, wherein the anticancer active ingredients of the sustained-release anticancer injection are:
    combination of 2-40% paclitaxel or docetaxel with 5-30% gefitinib, erlotinib, lapatinib, vatalanib, pelitinib, carboxyamidotriazole, thalidomide, ranolamine, angiostatin, endostatin, imatinib mesylate, sematinib, dasatinib, avastin, canatinib, sorafenib, sunitinib, telosta or panitoma
  3. The sustained-release anticancer injection according to claim 1, wherein the sustained-release excipients are selected from one or a combination of the following:
    a) polylactic acid with the molecular weight peak value of 10000-;
    b) a copolymer of polyglycolic acid and glycolic acid, wherein the ratio of polyglycolic acid to glycolic acid is 50-95: 50-50, the peak value of molecular weight is 10000-30000, 300000-60000, 60000-100000 or 100000-150000;
    c) ethylene vinyl acetate copolymers;
    d) polifeprosan, p-carboxyphenylpropane: sebacic acid is 10:90, 20:80, 30:70, 40:60, 50:50 or 60: 40;
    e) a di-fatty acid and sebacic acid copolymer;
    f) poly (erucic acid dimer-sebacic acid);
    g) poly (fumaric-sebacic acid);
    h) xylitol, oligosaccharide, chondroitin, chitin, hyaluronic acid, collagen, gelatin or albumin glue.
  4. The sustained-release anticancer injection according to claim 1, wherein the suspending agents are selected from the following:
    a) 0.5-3.0% carboxymethylcellulose (sodium);
    b) 5-15% mannitol;
    c) 5-15% sorbitol;
    d) 0.1-1.5% of surface active substances;
    e) 0.1-0.5% tween 20;
    f) (iodine) glycerol, dimethicone, propylene glycol or carbomer;
    g) 0.5-5% of sodium carboxymethylcellulose and 0.1-0.5% of Tween 80;
    h) 5-20% of mannitol and 0.1-0.5% of Tween 80;
    i)0.5 to 5 percent of sodium carboxymethylcellulose, 5 to 20 percent of sorbitol and 0.1 to 0.5 percent of Tween 80.
  5. The sustained-release anticancer injection according to claim 1, wherein the sustained-release anticancer injection is used for preparing a sustained-release implant for treating primary or secondary cancer, sarcoma or carcinosarcoma originated from brain, central nervous system, kidney, liver, gallbladder, head and neck, oral cavity, thyroid gland, skin, mucosa, gland, blood vessel, bone tissue, lymph node, lung, esophagus, stomach, breast, pancreas, eye, nasopharynx, uterus, ovary, endometrium, cervix, prostate, bladder, colon or rectum of human and animal, and is administered by intratumoral or peritumoral injection or placement.
  6. The sustained-release anticancer implant according to claim 5, wherein the sustained-release implant contains the following anticancer active ingredients:
    2-40% paclitaxel or docetaxel in combination with 5-30% gefitinib, erlotinib, lapatinib, vatalanib, pelitinib, carboxyamidotriazole, thalidomide, ranolamine, angiostatin, endostatin, imatinib mesylate, semasnib, dasatinib, avastin, canatinib, sorafenib, sunitinib, telosta, or panitoma;
    the above are all weight percentages.
  7. The sustained-release anticancer implant according to claim 5, characterized in that the sustained-release excipients are selected from one or a combination of the following:
    a) polylactic acid;
    b) copolymers of polyglycolic acid and glycolic acid;
    c) polifeprosan;
    d) ethylene vinyl acetate copolymers;
    e) a di-fatty acid and sebacic acid copolymer;
    f) poly (erucic acid dimer-sebacic acid) copolymer;
    g) poly (fumaric acid-sebacic acid) copolymer.
  8. The sustained-release anticancer implant according to claim 5, characterized in that the sustained-release excipients are selected from one of the following:
    a) polylactic acid with the molecular weight peak value of 5000-;
    b) the molecular weight peak value of the copolymer of polyglycolic acid and glycolic acid is 5000-15000, 10000-20000, 20000-35000, 30000-50000, 50000-100000 or 100000-150000, wherein the ratio of polyglycolic acid to glycolic acid is 50-95: 50-50;
    c) polifeprosan, p-carboxyphenylpropane: sebacic acid 10: 90. 20: 80. 30: 70. 40: 60. 50:50 or 60: 40;
    d) xylitol, oligosaccharide, chondroitin, chitin, hyaluronic acid, collagen, gelatin or albumin glue.
CNA2008103029646A 2006-02-10 2006-02-10 Anticancer sustained-release formulation loaded with platinum compound and synergist thereof Pending CN101380296A (en)

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