CN1961861A - An anticancer sustained releasing agent - Google Patents

An anticancer sustained releasing agent Download PDF

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CN1961861A
CN1961861A CNA2006102011843A CN200610201184A CN1961861A CN 1961861 A CN1961861 A CN 1961861A CN A2006102011843 A CNA2006102011843 A CN A2006102011843A CN 200610201184 A CN200610201184 A CN 200610201184A CN 1961861 A CN1961861 A CN 1961861A
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sustained
release
acid
tumor
copolymer
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孔庆忠
贺润平
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Shandong Lanjin Pharmaceuticals Co Ltd
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Shandong Lanjin Pharmaceuticals Co Ltd
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Abstract

Disclosed is an anti-cancer slow release agent comprising slow release microspheres and dissolvent, wherein the slow release microspheres include slow release auxiliary materials, anti-angiogenesis agent and/or proteolytic enzyme, the dissolvent comprises suspension adjuvant. The anti-angiogenesis agent is selected from gefinitib, erlotinib, lapatinib, pelitinib, endostatin, imatinib, smasnib, avastin, sorafenib, sunitinib, oersted or panitoma, the proteolytic enzyme is selected from collagenase, hyaluronidase, relaxin and thrombase or the combination of them, the slow release auxiliary materials are selected from Polifeprosan, sebacylic acid copolymer, EVAc, polylactic acid and their mixture of copolymer, the viscosity of the suspension adjuvant is 100-3000cp (at 25-30 deg C), and is selected from sodium carboxymethylcellulose. The agent can also be prepared into implanting agent for injection or placement in or around tumor with the effects of selectively increasing local concentration, lowering general reaction of the drugs, suppressing growth of tumor cells and blood vessel, and improving the treatment effect of the non-operative treatment methods such as chemotherapy.

Description

Anticancer sustained-release preparation
(I) technical field
The invention relates to an anticancer sustained release agent, belonging to the technical field of medicaments. More particularly, the sustained-release preparation for resisting solid tumors mainly comprises sustained-release implant and injection. The anti-solid tumor sustained release agent can effectively inhibit or destroy tumor blood vessels and inhibit tumor neovascularization; the sustained-release implant for resisting the solid tumor also relates to the effects of effectively reducing tension, interstitial pressure and interstitial viscosity in the tumor, further improving the interstitial fluid conductivity of the sustained-release implant, and being beneficial to the effective diffusion of the drug into the solid tumor and in the tumor.
(II) background of the invention
The treatment of cancer mainly comprises methods such as surgery, radiotherapy, chemotherapy and the like. Wherein the surgical treatment can not eliminate scattered tumor cells, so that the tumor cells are frequently relapsed or caused to spread and metastasize 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, e.g., "Intratumoral Placement of cisplatin plus systemic Carmustine in rat brain tumors" J.Takema.69, pp 76-82, 1998 (Kong Q et al, J Surg Oncol.1998 Oct; 69 (2): 76-82).
Low dose anti-cancer drug therapy can not only increase drug tolerance of cancer cells, but also promote invasive growth thereof, see Beam et al, "anti-cancer drug pulsed screening increases drug tolerance and in vitro infiltration capacity of human lung cancer cells with concomitant changes in gene expression" [ International journal of cancer (Liang Y, et al, Int Jcancer. 2004; 111 (4): 484-93) ].
The local placement of the antitumor drug can better overcome the defects, not only can obviously improve the local drug concentration of the tumor, but also can obviously reduce the systemic toxic reaction. A number of in vitro and in vivo experiments have shown therapeutic efficacy against solid tumors, see Kongqing et al, "cisplatin placement in tumors plus systemic carmustine for treatment of rat brain tumors", J.Surg Oncol.1998 Oct (Kong Q et al, J.Surg.Oncol.1998 Oct; 69 (2): 76-82) and Kongqing et al, "cisplatin placement in tumors for cure of rat primary brain tumors", 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. 6,376,525B1, 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 Niti et al, "influence of extracellular stroma conditions on drug transport in solid tumors" [ Cancer research ] No. 60, No. 2497, No. 503, 2000 (Netti PA, Cancer Res.2000, No. 60 (9): 2497, No. 503).
The components of fibrin and collagen in blood vessels and connective tissues in tumor stroma and hyperproliferative tumor cells cause high interstitial pressure (interstitial pressure), high interstitial viscosity (interstitial viscosity), high tissue tension coefficient (tissue tension module) and low interstitial fluid conductivity (hydralic con) of solid tumors. These factors greatly limit the effective diffusion of drugs into solid tumors and within tumors, and thus constitute a major obstacle to tumor chemotherapy.
Moreover, blood vessels in the tumor stroma are insensitive to conventional chemotherapeutic drugs, often resulting in increased resistance of tumor cells to anticancer drugs, with consequent failure of the treatment.
Disclosure of the invention
Aiming at the defects of the prior art, the invention provides a novel pharmaceutical composition, in particular to a sustained-release agent for resisting solid tumors. The anti-solid tumor sustained release preparation mainly comprises a sustained release implant and a sustained release injection, and can effectively inhibit or destroy tumor blood vessels and inhibit tumor neovascularization by local application; can inhibit tumor growth and increase the sensitivity of tumor cells to anticancer drugs; the sustained release agent for resisting solid tumor can effectively reduce tension, interstitial pressure and interstitial viscosity in tumor, thereby improving interstitial fluid conductivity, and facilitating the drug to enter solid tumor and effectively diffuse in tumor.
The anti-solid tumor slow release agent comprises anti-cancer active ingredients and pharmaceutic adjuvant, wherein the anti-cancer active ingredients are a vascular inhibitor and/or proteolytic enzyme, the vascular inhibitor has the function of inhibiting the growth of tumor cells, can effectively inhibit or destroy tumor blood vessels and inhibit the formation of new blood vessels of the tumor, so that the tumor cells lose the sources of a stent and nutrient substances required by the growth, and the sustained release agent can be used together with or independently applied from the proteolytic enzyme and also can obviously promote chemotherapeutic drugs to enter the tumor and permeate and spread around the tumor and in tumor tissues. The proteolytic enzyme can effectively remove fibrin, collagen and other components in blood vessels and connective tissues in tumor interstitium, and can obviously promote the penetration and diffusion of chemotherapeutic drugs into tumors, the periphery of tumors and 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-zene sulfonate) monohydrate, lapatinib ditosylate, GW-2016, GW-572016F ], Votalanib (N- (4-chlorophenyl) -4- (pyridine-4-methyl) benzodimethylene-1-amine (N- (4-chlorophenyl)4- (pyridine-4-ylmeth-yl) phtalzin-1-amine, vatalanb, PTK-787, PTK/ZK, ScheringVEGF-TK1, AG, ZK-222584)), pezib-4-ethoxyquinoline-4- [ (3-fluoro-quinoline) -4-yl ] -7- [ (4-fluoro-3-quinoline) -4-yl ] cyanogen-3-4-methyl) benzethonium-1-amine Group ] -4- (dimethylamino) and-2-amide ((2E) -N- [4- [ (3-chloro-4-fluorophenyl) amino ] -3-cyano-7-ethoxyquinolin-6-yl ] -4- (dimethyllamino) but-2-enamide, EKB-569, pelitinib), carboxyamidotriazole (carboxyamidinate, CAT), thalidomide (thalidomide), ranolamide (linoids, inhitols of integrins), angiostatin (angiostatin), endostatin (endostatin), Vascular Endothelial Growth Factor (VEGF) receptor inhibitor, vascular endostatin (Endostar, degree), imatinib mesylate (Imatinib mesylate, also known as Glc), 4-methyl-1- [ (4-methyl) piperazine-4- (3-methylpiperazine) -2-pyridine-4- (3-methylpyrimidino) -2-enamide Pyrimidine ] amino ] phenyl ] -aniline methanesulfonate (4- ((Methyl-1-piperazinyl) Methyl) -N- [4-Methyl-3- [ [4- (3-pyridinyl) -2-pyridinyl ] amino ] -phenyl ] benzamidomethane fonato, STI 571, CGP-57148B, STI-571A, CGP 57148), 5- [5-Fluoro-2-oxo-1, 2-indolin- (3Z) -methylene ] -2, 4-dimethyl-1H-pyrrole-3-carboxylic Acid (2-Diethylaminoethyl) amide (5- [5-Fluoro-2-oxo-1, 2-dihydroindole- (3Z) -ylidenemethyl ] -2, 4-dimethylindole-1H-pynolic-3 carboxylic Acid (2-diazylamine), sutent, SU11248, SU011248), 3-Dichloro-5- (4-methylsulfonylpyridinyl) -2-indolinone (3, 3-dichoro-5- (4-methylperidinonyl) -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 indolinones (pyrrolidinone indolines, SU6577), lactam indolinones (pyrrolidinone indolines, SU6597), 3- (4-Dimethylamino-naphthylmethylene-1-methylene) -1, 3-dihydro-indol-2-indolinone (3- (4-Dimethylamino-naphtalene-1-yl) -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) methylene ] -2H-indol-2-indolinone, RPI-1), 3- [5-methyl-2- (2-oxo-1, 2-dihydro-indol-3-yl) -1H-pyrrole-3-methyl ] -propionic acid (3- [5-methyl-2- (2-oxo-1, 2-dihydro-indol-3-ylidenemethyl) -1H-pyrro-l-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-pyrolole-3-carboxamide), SU 55), 3- [ [ 3-phenyl-4(3H) -quinazolinone-2-methyl ] mercaptoacetic acid ] hydrazono ] -1H-carbazolyl ] -1H-2-indolinone (3- [ [ (3-phenyl-4(3H) -quinazolin-2-yl) mercaptoacetyl ] hydrazono ] -1H-2-indolinone, SU1165), 3-bis (4-methoxyphenyl) methylene-2-indolinone (3-bis (4-methoxyphenylphenyl) methyl-2-indolinone, TAS-301), 3- [ 4-formylpiperazin-4 yl ] -benzylidene ] -2-indolinone (3- [4- (1-formylpiperazin-4yl) -benzylidene ] -2-indolinone, SU 84), 3- ([ 5-imidazole ]2, 1-methylenethiazole) -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), cpd 1), 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-indolinone) 1, 3-dihydroindo ] -2-indolinone, CIDI), dasatinib (dasatinib), avastin (avastin), canatinib (canertinib), sorafenib (sorafenib), sunitinib (sunitinib, sutent, SU11248), Teolyta (Telkyyta), panitumoma (panitumumab).
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 above-mentioned angiogenesis inhibitor is selected from gefitinib, erlotinib, lapatinib, vatalanib, pelitinib, carboxyamidotriazole, thalidomide, ranolamine, angiostatin, 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-indoline- (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, semasinib, 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 are preferred.
The above-mentioned vascular inhibitor may be singly or multiply selected, and gefitinib, erlotinib, lapatinib, vatalanib, pelitinib, carboxyamidotriazole, thalidomide, ranolamine, angiostatin, endostatin, engdu, imatinib mesylate, semasinib, dasatinib, avastin, canatinib, sorafenib, sunitinib, telosta, panitoma are most preferred.
In addition, the latest preclinical tests show that dozens of TA inhibitors have certain inhibition effect on tumor angiogenesis. Such as Matrix Metalloproteinase (MMP) inhibitors (inhibitors), inhibitors of angiogenic factor activation, endothelial cell inhibitors, and the like.
Matrix metalloproteinase inhibitors (MMPi) exert their effects of inhibiting tumor growth and metastasis by inhibiting degradation of basement membrane. The representative drug is marimastat (marimastat, MP-4), which can selectively inhibit matrix metalloproteases such as MMP-1, MMP-2, MMP-3, MMP-7 and MMP-9. Has obvious inhibiting effect on the growth and metastasis of ovarian cancer, breast cancer, pancreatic cancer, prostatic cancer, non-small cell lung cancer, small cell lung cancer and colon cancer.
The inhibitor can inhibit the activation of the angiogenic growth factor, thereby inactivating the angiogenic growth factor. The representative drugs are indolone small molecular compounds such as SU5416 and SU 6668. SU5416 is a small molecule inhibitor that specifically inhibits VEGF receptor 2. The function of inhibiting the growth of the tumor is related to the reduction of the angiogenesis of the tumor, thereby inhibiting the proliferation of the tumor cells and promoting the apoptosis of the tumor cells. Clinical tests show that SU5416 can be used for treating solid tumors such as malignant melanoma and metastatic colon cancer. SU6668[ (Z) -3- [2, 4-dimethyl-5- (2-oxo-1, 2-dihydro-indol-3-ylidenemethyl) -1H-pyrro-3-yl ] propionic acid ] is a multi-target neovascularization inhibitor, is a small molecule inhibitor of VEGF, FGF and PDGF receptors, and can achieve an antitumor effect by inducing apoptosis of endothelial cells and tumor cells. Has better treatment effect on a plurality of advanced solid tumors.
Endothelial cell inhibitors can directly inhibit the growth of endothelial cells. The representative drug is fumagillin (fumagillin) and its derivatives such as TNP-470. As a vascular endothelial chalone, TNP-470 can block the DNA replication of neovascular endothelial cells and inhibit the proliferation of microvasculature. It has growth inhibiting effect on human breast cancer, prostate cancer and nerve sheath tumor cells. Clinical tests show that the Chinese medicinal composition has a certain therapeutic effect on senile late-stage solid tumors, lymphomas, acute leukemia and the like.
Thus, the neovascular inhibitor of the present invention is further selected from one or a combination of the following:
(1) a matrix metalloproteinase inhibitor (MMP inhibitor, MMPi) selected from marimastat;
(2) an angiogenesis factor activation inhibitor selected from small molecule compounds such as SU5416 and SU 6668;
(3) an endothelial cell inhibitor selected from fumagillin (fumagillin) and its derivatives such as TNP-470.
The above neovascularization 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 proportion of the angiogenesis inhibitor in the sustained release preparation is determined by specific conditions, and can be 0.1-50%, preferably 1-40%, and most preferably 5-30%.
When the anticancer active ingredient in the medicament is only proteolytic enzyme, the anticancer sustained-release implant is mainly used for increasing the effect of the angiogenesis inhibitor applied by other ways or for the synergy of radiotherapy or other therapies. When the effective anticancer component is a neovascular inhibitor, the application and the synergistic mode of the anticancer sustained-release agent are as follows:
(1) the slow release preparation containing the angiogenesis inhibitor is locally injected, and the proteolytic enzyme is applied by other ways;
(2) the sustained release preparation containing proteolytic enzyme is applied locally, and the angiogenesis inhibitor is applied by other ways;
(3) the slow release agent containing the angiogenesis inhibitor and the slow release injection containing the proteolytic enzyme are locally applied; or
(4) A sustained release formulation comprising a neovascular inhibitor and a proteolytic enzyme is applied topically.
Sustained release formulations for topical application of anticancer agents are also useful for potentiation of radiation or other therapies. Other routes refer, but are not limited to, arterial, venous, intraperitoneal, subcutaneous, intraluminal administration.
The weight percentage of the anti-cancer active ingredient neoangiogenesis inhibitor and/or proteolytic enzyme in the drug sustained release agent is 0.5 to 60 percent, preferably 2 to 40 percent, and most preferably 5 to 30 percent. The weight ratio of the angiogenesis inhibitor to the proteolytic enzyme is 1-9: 1 to 1: 1-9, preferably 1-2: 1.
The proteolytic enzyme is selected from one or a combination of elastase, pancreatic elastase, metalloprotease, trypsin, chymotrypsin, pepsin, pronase, dispase, bromelain, chymotrypsin, clostripain, thermolysin, subtilisin, papain, chymopapain, plasmin, serenethiopeptidase, pancreatin, cathepsin-G, cysteine protease, thioesterase, amidotransferase, transesterase activity, plasminogen activator, collagenase, polymorphonuclear leukocyte serine protease, nuclease, lipase, esterase, streptokinase, glycosidase, hyaluronidase, neuraminidase, amylase, lysozyme, relaxin, interferon (gamma-interferon), and fibrin.
Wherein the collagenase degrades collagen or connective tissue, tumor blood vessels and/or tumor cell basement membrane. As a result, blood supply to the tumor is reduced or stopped, and the pressure in the tumor is reduced, facilitating the entry and effective diffusion of the drug. Experiments show that intravenous injection of collagenase has a very low degree of harm to the test animals. For mice, LD50 of the crude product of intravenous collagenase is 300mg/Kg of body weight, and the oral water solution of the crude product of intravenous collagenase is nontoxic when the dosage is up to 8,000mg/Kg of body weight, and the LD50 of acute intravenous injection of rats can reach 1272 units/Kg.
Proteases include any enzyme capable of catalyzing the hydrolysis of one or more peptide bonds in a protein or peptide, such as carboxypeptidases, aminopeptidases and endopeptidases. Preferably elastase, pancreatic elastase, (neutral) metalloprotease, trypsin, chymotrypsin, pepsin, pronase, dispase, bromelain, chymotrypsin, clostripain, thermolysin, subtilisin, papain, chymopapain, plasmin (also known as plasmin), serrathiopeptidase (serrathoplastase), pancreatin, cathepsin-G, cysteine protease, thioesterases, amidotransferase, transesterase activity, plasminogen activator and Polymorphonuclear (PMN) leukocyte serine protease.
Glycosidases include any enzyme that catalyzes the hydrolysis of a glycosidic bond. Suitable examples include hyaluronidase, neuraminidase, amylase (e.g., alpha-amylase or beta-amylase), and lysozyme. Preferred glycoxinases include hyaluronidase. Experiments have shown that 75,000 international units of hyaluronidase injected into animals has no significant change in blood pressure, respiration, body temperature or kidney function.
Nucleases include any enzyme that catalyzes the hydrolysis of an ester bond within a nucleic acid, such as ribonucleases and deoxyribonucleases. Suitable examples include DNaseI (deoxyribonuclease I) and RNase. Among them, DNaseI is an enzyme that catalyzes the cleavage of DNA into 5 '-phosphodinucleotide and 5' -phosphooligonucleotide end products. RNases are a class of nucleases that cleave phosphodiester bonds and RNA strands.
Esterases include any enzyme that catalyzes the hydrolysis of an ester. Suitable examples include cholesterol esterase.
Lipases include any enzyme capable of catalyzing the acetolysis of acylglycerol carboxylic acids. Suitable examples include phosphatases.
Streptokinase includes proteins that form complexes with plasminogen, thereby catalyzing the activation of plasminogen to plasmin.
The composition may also contain, or be administered in combination with, calcium ions, surfactants and/or antibiotics. The collagenase, other protease, protein, or enzyme, calcium ion, surfactant, and antibiotic, components of the composition can be administered separately, sequentially.
Compositions suitable for the present invention contain collagenase, hyaluronidase and/or trypsin. Preferably the composition comprises collagenase and at least one glycosidase, preferably hyaluronidase, protease, preferably trypsin, chymotrypsin, pronase, elastase, dispase or plasmin, or nuclease, preferably DNaseI. More preferably, the composition comprises collagenase and a glycosidase, preferably hyaluronidase. The crude collagenase preparations contain low amounts of contaminating enzymes such as trypsin and clostripain and are often more potent than collagenase preparations of high purity.
Application of the invention
The compositions of the invention may be prepared in a manner known per se, for example, by means of conventional mixing, dissolving, dragee-making, levigating, emulsifying, encapsulating, entrapping or lyophilizing processes. The carrier includes various excipients and adjuvants. Suitable formulations may be prepared according to the chosen route of administration. Such as injection, oral administration, inhalation, suppository, patch, implant, etc. For transmucosal and transdermal administration, the use of penetrants appropriate to the permeation barrier in the formulation is generally known in the art.
Can be made into oral preparation in the form of tablet, pill, disintegrating agent, dragee, capsule, push-fit capsule, soft capsule, liquid, gel, syrup, slurry, suspension, etc.
Among the various formulations, long acting formulations are preferred, with topical application of long acting formulations being most preferred. The latter can be applied locally to the tumor by implantation (rectal, transmucosal, transdermal, enteral, intramuscular, subcutaneous, intramedullary injections, as well as intrathecal, direct intraventricular, intravenous, intraperitoneal, intranasal, or intraocular injections), with significantly reduced systemic toxicity while effectively achieving and maintaining local drug concentrations.
Administration is by topical means, e.g., by direct injection into a particular tissue, usually in the form of a depot or sustained release formulation.
Thus, the main form of the present invention is a sustained release agent including a sustained release implant and a sustained release injection.
One main form of the present invention is a sustained-release injection comprising:
(A) a sustained release microsphere comprising:
0.5-60% of anticancer active ingredient
Sustained release auxiliary materials 40-99%
0.0 to 30 percent of suspending agent
The above are weight percentages
And
(B) the solvent is common solvent or special solvent containing suspending agent.
Wherein,
the anticancer active component is a neovascular inhibitor and/or proteolytic enzyme;
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 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 ℃).
The anticancer active ingredients in the sustained-release injection microsphere are preferably as follows, and the weight percentages are as follows:
(a) 2-40% Marimastat, SU5416, SU6668, fumagillin, TNP-470, gefitinib, erlotinib, lapatinib, Votalanib, pelitinib, carboxyamidotriazole, thalidomide, Renax, angiostatin, endostatin, Endol, imatinib mesylate, semasinib, dasatinib, avastin, Caratinib, Sorafenib, sunitinib, Teotestat or Panitoma;
(b) 2-40% of elastase, pancreatic elastase, metalloproteinase, trypsin, chymotrypsin, pepsin, pronase, dispase, bromelain, chymotrypsin, clostripain, thermolysin, subtilisin, papain, chymopapain, plasmin, serenethiopeptidase, pancreatin, cathepsin-G, cysteine protease, thioesterase, amidotransferase, transesterase activity, plasminogen activator, collagenase, polymorphonuclear leukocyte serine protease, nuclease, lipase, esterase, streptokinase, glycosidase, hyaluronidase, neuraminidase, amylase, lysozyme, relaxin, interferon, or cellulase;
(c) 2-40% Marimastat, SU5416, SU6668, fumagillin, TNP-470, gefitinib, erlotinib, lapatinib, Votalanib, pelitinib, carboxyamidotriazole, thalidomide, Renamine, angiostatin, endostatin, Endostatin, imatinib mesylate, semasinib, dasatinib, avastin, Caratinib, Sorafenib, sunitinib, Teotestan or Panitoma with 2-40% elastase, trypsin, metalloprotease, chymotrypsin, pepsin, pronase, dispase, bromelain, chymotrypsin, thermolysin, subtilisin, papain, chymopapain, plasmin, serriethiopeptidase, pancreatin, cathepsin-G, trypsin, and the like, A combination of a cysteine protease, thioesterase, amidotransferase, transesterase activity, plasminogen activator, collagenase, polymorphonuclear leukocyte serine protease, nuclease, lipase, esterase, streptokinase, glycosidase, hyaluronidase, neuraminidase, amylase, lysozyme, relaxin, interferon, or a protease.
The sustained-release excipients used for preparing the sustained-release agent can be various water-soluble or water-insoluble polymer polymers, and one or the combination of polylactic acid (PLA), polyglycolic acid-glycolic acid copolymer (PLGA), ethylene vinyl acetate copolymer (EVAc), polifeprosan, fatty acid dimer and sebacic acid copolymer (PFAD-SA), poly (erucic acid dimer-sebacic acid) [ P (EAD-SA) ], poly (fumaric acid-sebacic acid) [ P (FA-SA) ] is preferred in various sustained-release excipients.
When polylactic acid (PLA), polyglycolic acid (PGA), a mixture of polylactic acid (PLA) and polyglycolic acid, and a copolymer of glycolic acid and hydroxycarboxylic acid (PLGA) are selected, the PLA and PLGA content is arbitrary, but is preferably 1 to 99% and 99 to 1% by weight. 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-; when more than one choice is selected, a polymer or a composite polymer or copolymer of different polymers is preferred, and a composite polymer or copolymer of polylactic acid or sebacic acid with different molecular weights is most preferred, such as, but not limited to, polylactic acid with a molecular weight of 10000 to 100000 mixed with polylactic acid with a molecular weight of 20000 to 150000, polylactic acid with a molecular weight of 10000 to 100000 mixed with PLGA with a molecular weight of 30000 to 80000, polylactic acid with a molecular weight of 20000 to 30000 mixed with sebacic acid, PLGA with a 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 aromatic polyanhydrides are polifeprosan [ poly (1, 3-di (P-carboxyphenoxy) propane-sebacic acid) (P (CPP-SA)), di-fatty 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 content of p-carboxyphenoxy propane (p-CPP) and sebacic acid in copolymerization is 10-60 wt% and 20-90 wt%, respectively, and the blending weight ratio is 10-40: 50-90, preferably 15-30: 65-85.
In addition to the above sustained-release excipients, other substances can be selected and used as described in detail in U.S. Pat. Nos. 4757128 (4857311; 4888176; 4789724) and "pharmaceutical excipients" in general (p. 123, published by Sichuan scientific and technical Press 1993, compiled by Luoming 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.
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. Wherein the sugar can be, but is not limited to, xylitol, oligosaccharide, (chondroitin sulfate), chitin, etc.; wherein the salt can be, but is not limited to, potassium salt, sodium salt, and the like; other pharmaceutical adjuvants such as, but not limited to, fillers, solubilizers, absorption enhancers, film-forming agents, gelling agents, pore-forming agents, excipients, or retarders may also be added.
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 anti-cancer component in injection, the used sustained-release 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 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. For convenient injection, the suspending agent has viscosity of 100-3000 cp (at 20-30 deg C), preferably 1000-3000 cp (at 20-30 deg C), and most preferably 1500-3000 cp (at 20-30 deg C). 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 content of the suspending agent in the common solvent depends on the characteristics of the suspending agent, and can be 0.1-30% according to the specific situation. Preferably, the suspending agent consists of:
A) 0.5-5% of sodium carboxymethylcellulose and 0.1-0.5% of Tween 80; or
B) 5-20% of mannitol and 0.1-0.5% of Tween 80; or
C)0.5 to 5 percent of sodium carboxymethylcellulose, 5 to 20 percent of sorbitol and 0.1 to 0.5 percent of Tween 80.
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 and properties of the drug suspended in the solvent, the sustained release microsphere (or microcapsule), and the required amount thereof, and the preparation method of the 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 the 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 injection has several methods, one is that the slow release particles (A) whose suspending agent is '0' are directly mixed in special solvent to obtain correspondent slow release particle injection; the other is that the slow release particles (A) of which the suspending agent is not 0 are mixed in a special solvent or a common solvent to obtain the corresponding slow release particle injection; and the other one is that the slow release particles (A) are mixed in common dissolvent, then suspending agent is added and mixed evenly, and the corresponding slow release particle injection is obtained. Besides, the sustained-release particles (A) can be mixed in special solvent to prepare corresponding suspension, then the water in the suspension is removed by methods such as vacuum drying, and then the suspension is suspended by special solvent or common solvent to obtain the corresponding sustained-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 method of preparation of the sustained release injection is arbitrary and can be prepared by several methods: such as, but not limited to, mixing, melting, dissolving, spray drying to prepare microspheres, dissolving in combination with freezing (drying) and pulverizing to form fine powders, liposome-encapsulating, and emulsifying. Among them, a dissolving method (i.e., solvent evaporation method), a drying method, a spray drying method and an emulsification method are preferable. The microspheres can be used for preparing the various sustained-release injections, and the method is arbitrary. The microspheres used may have a particle size in the range of 5-400um, preferably 10-300um, most preferably 20-200 um.
The microspheres can also be used for preparing other sustained-release injections, such as gel injections and block copolymer micelle injections. 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. Of these, polyethylene glycol (PEG) having a molecular weight of 1000-15000 is preferable as the hydrophilic block of the micelle copolymer, and biodegradable polymers such as PLA, polylactide, polycaprolactone and copolymers thereof (molecular weight 1500-25000) are preferable as the hydrophobic block of the micelle copolymer. The block copolymer micelles may have a particle size in the range of 10 to 300um, preferably 20 to 200 um. The gel injection is prepared by dissolving biodegradable polymer (such as PLA, PLGA or DL-LA and epsilon-caprolactone copolymer) in certain amphiphilic solvent, adding the medicine, mixing (or suspending) with the solvent to form gel with good fluidity, and can be injected around tumor or in tumor. Once injected, the amphiphilic solvent diffuses into the body fluid quickly, and the water in the body fluid permeates into the gel, so that the polymer is solidified and the drug is released slowly.
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 polymer is selected as the main choice, and the mixture or copolymer of polylactic acid, sebacic acid, and high polymer containing polylactic acid or sebacic acid is selected as the first choice among various high polymers, and the mixture and copolymer can be selected from, but are not limited to, PLA, PLGA, mixture of PLA and PLGA, mixture or copolymer of sebacic acid and aromatic polyanhydride or aliphatic polyanhydride, fatty acid dimer-sebacic acid [ P (EAD-SA) ], poly (fumaric acid-sebacic acid) [ P (FA-SA) ]. 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.
Still another form of the anticancer drug sustained-release preparation of the present invention is that the anticancer drug sustained-release preparation is a sustained-release implant. 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.
The slow release implant is characterized in that the slow release auxiliary material contains any one or more of the other auxiliary materials besides the high molecular polymer. The added pharmaceutic adjuvants are collectively called as additives. The additives can be classified into fillers, pore-forming agents, excipients, dispersants, isotonic agents, preservatives, retarding agents, solubilizers, absorption enhancers, film-forming agents, gelling agents, etc. according to their functions.
The main components of the sustained-release implant can be prepared into various dosage forms. Such as, but not limited to, capsules, sustained release formulations, implants, sustained release implants, and the like; in various shapes such as, but not limited to, granules, pills, tablets, powders, spheres, cubes, needles, rods, columns, and films. Among various dosage forms, slow release implants in vivo are preferred.
The optimal dosage form of the sustained-release implant is biocompatible, degradable and absorbable sustained-release implant, and can be prepared into various shapes and various dosage forms according to different clinical requirements. 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 active ingredients of the sustained-release implant are preferably as follows, and the weight percentages are as follows:
(a) 2-40% Marimastat, SU5416, SU6668, fumagillin, TNP-470, gefitinib, erlotinib, lapatinib, Votalanib, pelitinib, carboxyamidotriazole, thalidomide, Renax, angiostatin, endostatin, Endol, imatinib mesylate, semasinib, dasatinib, avastin, Caratinib, Sorafenib, sunitinib, Teotestat or Panitoma;
(b) 2-40% of elastase, pancreatic elastase, metalloproteinase, trypsin, chymotrypsin, pepsin, pronase, dispase, bromelain, chymotrypsin, clostripain, thermolysin, subtilisin, papain, chymopapain, plasmin, serenethiopeptidase, pancreatin, cathepsin-G, cysteine protease, thioesterase, amidotransferase, transesterase activity, plasminogen activator, collagenase, polymorphonuclear leukocyte serine protease, nuclease, lipase, esterase, streptokinase, glycosidase, hyaluronidase, neuraminidase, amylase, lysozyme, relaxin, interferon, or cellulase;
(c) 2-40% Marimastat, SU5416, SU6668, fumagillin, TNP-470, gefitinib, erlotinib, lapatinib, Votalanib, pelitinib, carboxyamidotriazole, thalidomide, Renamine, angiostatin, endostatin, Endostatin, imatinib mesylate, semasinib, dasatinib, avastin, Caratinib, Sorafenib, sunitinib, Teotestan or Panitoma with 2-40% elastase, trypsin, metalloprotease, chymotrypsin, pepsin, pronase, dispase, bromelain, chymotrypsin, thermolysin, subtilisin, papain, chymopapain, plasmin, serriethiopeptidase, pancreatin, cathepsin-G, trypsin, and the like, A combination of a cysteine protease, thioesterase, amidotransferase, transesterase activity, plasminogen activator, collagenase, polymorphonuclear leukocyte serine protease, nuclease, lipase, esterase, streptokinase, glycosidase, hyaluronidase, neuraminidase, amylase, lysozyme, relaxin, interferon, or a protease.
The sustained-release excipients can be various water-soluble or water-insoluble polymer polymers, and one or a combination of polylactic acid (PLA), polyglycolic acid-glycolic acid copolymer (PLGA), ethylene vinyl acetate copolymer (EVAc), polifeprosan, fatty acid dimer-sebacic acid copolymer (PFAD-SA), poly (erucic acid dimer-sebacic acid) [ P (EAD-SA) ], poly (fumaric acid-sebacic acid) [ P (FA-SA) ] is preferred among various sustained-release excipients.
The route of administration depends on a variety of factors, and in order to achieve effective concentrations at the site of the primary or metastatic tumor, the drug may be administered by a variety of routes, such as subcutaneous, intraluminal (e.g., intraperitoneal, thoracic, and intravertebral), intratumoral, peritumoral injection or placement, selective arterial injection, intralymph node, and intramedulary injection. Selective arterial injection, intracavitary, intratumoral, peritumoral injection or placement is preferred. When the anticancer drug in the drug sustained-release microspheres is only a neovascular inhibitor or a synergist thereof (cytotoxic drug), the application and the synergy mode of the anticancer sustained-release implant are the same as those of a sustained-release injection.
The invention can be used for preparing pharmaceutical preparations for treating various tumors of human and animals, mainly sustained-release injections or sustained-release implants, wherein the tumors comprise primary or metastatic cancers or sarcomas or carcinosarcomas originated from brain, central nervous system, kidney, liver, gall bladder, head and neck, oral cavity, thyroid, skin, mucous membrane, gland, blood vessel, bone tissue, lymph node, lung, esophagus, stomach, mammary gland, pancreas, eye, nasopharynx, uterus, ovary, endometrium, cervix, prostate, bladder, colon and rectum. The tumors of the viscera can be of different pathological types, the tumors of the lymph nodes are Hodgkin lymphoma and non-Hodgkin lymphoma, the lung cancer comprises small cell lung cancer, non-small cell lung cancer and the like, and the brain tumor comprises glioma and the like. However, common tumors include solid tumors such as brain tumor, kidney cancer, liver cancer, gallbladder cancer, head and neck tumor, oral cancer, thyroid cancer, skin cancer, hemangioma, osteosarcoma, lymphoma, lung cancer, thymus cancer, esophageal cancer, stomach cancer, breast cancer, pancreatic cancer, retinoblastoma of eye, nasopharyngeal cancer, ovarian cancer, endometrial cancer, cervical cancer, prostate cancer, bladder cancer, colon cancer, rectal cancer, testicular cancer, and the like.
The clinically applicable dose will depend on the particular patient and may range from 0.1 to 3000mg/kg body weight, with 0.5 to 2000mg/kg being preferred and 0.8 to 1000mg/kg being most preferred.
The sustained-release injection or the sustained-release implant prepared by the invention can also be added with other medicinal components, such as, but not limited to, antibiotics, analgesic drugs, anticoagulant drugs, hemostatic drugs and the like.
The technical process of the present invention is further described by the following examples. The following examples are intended to illustrate but not limit the scope of the invention. The present invention is not to be limited in scope by the illustrated embodiments, which are intended as individual illustrations of the invention. Indeed, various modifications of the invention in addition to those shown and described herein will become apparent to those skilled in the art from the foregoing description and accompanying drawings. Such modifications are, of course, intended to be within the scope of the appended claims.
It should be understood, therefore, that the foregoing description focuses on certain specific embodiments of the invention and that equivalent alterations and substitutions made thereto are within the spirit and scope of the appended claims.
Example 1 comparison of local drug concentrations following different modes of administration of a neovascular inhibitor (marimastat)
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. Each group dose was 5mg/kg marimastat. The results of measuring the content (%) of the drug in the tumor at different times show that the local drug concentration difference of marimastat applied in different modes is obvious, the effective drug concentration of the part where the tumor is located 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.
Example 2 comparison of the in vivo tumor-inhibiting action of a neovascular inhibitor (fumagillin) applied in different ways
Using white rat as test object, 2X 105Individual brain 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 10mg/kg fumagillin. 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 fumagillin has obvious difference in tumor inhibition effect after being applied in different modes, the local administration can obviously improve and effectively maintain the effective drug concentration of the tumor part, 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. Not only has good curative effect, but also has little toxic and side effect.
Example 3 in vivo tumor-inhibiting action of neovascular inhibitor and proteolytic enzyme (sustained-Release injection)
Using white rat as test object, 2X 105Individual pancreatic cancer tumor cells were injected subcutaneously into the quaternary costal region and divided into the following 10 groups 14 days after tumor growth (see table 1). The first group was control, and the groups 2 to 10 were treatmentIn the treatment group, the medicine is injected in tumor. The dosage of the angiogenesis inhibitor is 7.5mg/kg, and the dosage of the proteolytic enzyme is 2.5 mg/kg. Tumor volume was measured on day 20 after treatment and the effect was compared (see table 1).
TABLE 1
Test set (n) Is treated by Tumor volume (cm)3) P value
1(6) Control 62±10
2(6) Proteolytic enzymes 40±5.0 ＜0.05
3(6) Marimastat 40±2.2 ＜0.01
4(6) Fumagillin 48±4.4 ＜0.01
5(6) SU5416 46±4.2 ＜0.01
6(6) SU6668 48±3.6 ＜0.01
7(6) Proteolytic enzyme + marimastat 14±2.0 ＜0.001
8(6) Proteolytic enzyme plus fumagillin 22±3.0 ＜0.001
9(6) Proteolytic enzyme + SU5416 18±2.2 ＜0.001
10(6) Proteolytic enzyme + SU6668 20±2.0 ＜0.001
The results show that the angiogenesis inhibitors (marimastat, fumagillin, SU5416 and SU6668) and the proteolytic enzyme (collagenase) have obvious inhibition effects on the growth of various tumor cells when used alone at the concentration, and can show obvious synergistic effects when used together. This finding constitutes a further important feature of the present invention.
Example 4 tumor inhibition by neovascular inhibitor and proteolytic enzyme (sustained Release injection)
Using white rat as test object, 2X 105Individual tumor cell (including pancreatic cancer-PC, brain tumor-C6, gastric cancer (SA), bone tumor (BC), breast cancer (BA), liver cancer (LH), thyroid cancer (PAT)) were subcutaneously injected into the quaternary costal region, and the tumors were divided into the following 7 groups (see table 2) after 14 days of tumor growth. The medicine is injected intratumorally. Therapeutic efficacy (see table 2). The dosage of the angiogenesis inhibitor is 2.5mg/kg, and the dosage of the proteolytic enzyme is 7.5 mg/kg. The size of tumor volume was measured on day 20 after the treatment, and the treatment effect was compared using the tumor growth inhibition (%) as an index (see table 2).
TABLE 2
Tumor cell Proteolytic enzymes Marimastat Fumagillin TNP-470 Proteolytic enzyme + marimastat Proteolytic enzyme plus fumagillin Proteolytic enzyme + TNP-470
PC 52％ 40％ 38％ 36％ 78％ 76％ 86％
C6 60％ 50％ 38％ 24％ 84％ 86％ 82％
SA 60％ 40％ 22％ 22％ 88％ 86％ 80％
BC 58％ 44％ 26％ 28％ 80％ 86％ 72％
BA 54％ 42％ 22％ 26％ 88％ 76％ 76％
LH 58％ 50％ 22％ 28％ 80％ 86％ 80％
PAT 52％ 46％ 48％ 38％ 82％ 84％ 82％
The results show that the used proteolytic enzyme (hyaluronidase) and angiogenesis inhibitor (marimastat, fumagillin, TNP-470) have obvious inhibition effect on the growth of a plurality of tumor cells when being used independently at the concentration, and can show obvious synergistic effect when being used jointly.
Example 5 tumor inhibition by neovascular inhibitor and proteolytic enzyme (sustained Release injection)
Using white rat as test object, 2X 105Injecting lung cancer cells into the quaternary costal region, and allowing the tumor to grow for 14 daysThey were divided into the following 10 groups (see table 3). The first group was the control, and groups 2 to 10 were the treatment groups, with the sustained release implant placed intratumorally. The dosage of the angiogenesis inhibitor is 2.5mg/kg, and the dosage of the proteolytic enzyme is 10 mg/kg. Tumor volume was measured on day 20 after treatment and the treatment effect was compared (see table 3).
TABLE 3
Test set (n) Is treated by Tumor volume (cm)3) P value
1(6) Control 62±10
2(6) Proteolytic enzymes 40±4.0 ＜0.05
3(6) Gefitinib 44±2.0 ＜0.01
4(6) Proteolytic enzyme + gefitinib 20±2.2 ＜0.001
5(6) Erlotinib 36±3.2 ＜0.01
6(6) Proteolytic enzyme + erlotinib 18±1.8 ＜0.001
7(6) Lapatinib 30±2.8 ＜0.01
8(6) Proteolytic enzyme + lapatinib 18±2.4 ＜0.001
9(6) Votalanib 42±4.0 ＜0.01
10(6) Proteolytic enzyme + Votalanib 24±2.0 ＜0.001
The results show that the used neovascular inhibitors (gefitinib, erlotinib, lapatinib and voltalanib) and proteolytic enzymes (clostripain) have obvious inhibition effect on the growth of a plurality of tumor cells when being singly used at the concentration, and can show obvious synergistic effect when being used in combination. This finding constitutes a further important feature of the present invention.
Example 6 tumor inhibition by neovascular inhibitor and proteolytic enzyme (sustained Release injection)
Using white rat as test object, 2X 105Individual prostate tumor cells were injected subcutaneously into the quaternary costal region and were classified into negative controls (blank), monotherapy (neovascular inhibitor or proteolytic enzyme) and combination therapy (neovascular inhibitor and proteolytic enzyme) after 14 days of tumor growth. The medicine is injected intratumorally. The dosage of the angiogenesis inhibitor is 12.5mg/kg, and the dosage of the proteolytic enzyme is 2.5 mg/kg. Tumor volume was measured on day 20 after treatment, and the therapeutic effect was compared using tumor growth inhibition as an index (see table 4).
TABLE 4
Test set (n) Is treated by Tumor inhibition ratio (%) P value
1(6) Control -
2(6) ProteinHydrolytic enzyme 46 ＜0.05
3(6) Pelitinib 36 ＜0.01
4(6) Reaction stop 46 ＜0.01
5(6) Reynolds amine 52 ＜0.01
6(6) Angiostatin 42 ＜0.01
7(6) Proteolytic enzyme + pelitinib 80 ＜0.001
8(6) Proteolytic enzyme + reaction stop 76 ＜0.001
9(6) Proteolytic enzyme + Reynolds amine 82 ＜0.001
10(6) Proteolytic enzyme + angiostatin 86 ＜0.001
The results show that the used neovascular inhibitors (pelitinib, thalidomide, ranolamine and angiostatin) and proteolytic enzymes (chymotrypsin) have obvious inhibition effects on the growth of various tumor cells when being singly used at the concentration, and can show obvious synergistic effects when being jointly used.
Example 7 tumor inhibition by neovascular inhibitor and proteolytic enzyme (sustained Release injection)
Using white rat as test object, 2X 105The ovarian cancer tumor cells are injected subcutaneously into the costal region of the patient, and the tumor cells are divided into a negative control (blank), a single-drug treatment group and a combined treatment group after the tumor grows for 14 days. The medicine is injected intratumorally. The dosage of the angiogenesis inhibitor is 5mg/kg, and the dosage of the proteolytic enzyme is 15 mg/kg. Tumor volume was measured on day 20 after treatment, and the therapeutic effect was compared using tumor growth inhibition as an index (see table 5).
TABLE 5
Test set (n) Is treated by Tumor inhibition ratio (%) P value
1(6) Control -
2(6) Proteolytic enzymes 44 ＜0.05
3(6) Endostatin 36 ＜0.01
4(6) Endostatin for blood vessel 36 ＜0.01
5(6) Imatinib mesylate 38 ＜0.01
6(6) Simassini 44 ＜0.01
7(6) Proteolytic enzyme + endostatin 80 ＜0.001
8(6) Proteolytic enzyme + vascular endothelial chalone 72 ＜0.001
9(6) Proteolytic enzyme + imatinib mesylate 82 ＜0.001
10(6) Proteolytic enzyme + simasini 84 ＜0.001
The results show that the used neovascularization inhibitors (endostatin, vascular endostatin, imatinib mesylate and semasnil) and proteolytic enzymes (dispase) have obvious inhibition effect on the growth of a plurality of tumor cells when being used independently at the concentration, and can show obvious synergistic effect when being used jointly. This finding constitutes a further important feature of the present invention.
Example 8 tumor inhibition by neovascular inhibitors and proteolytic enzymes (sustained Release implants)
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 of the angiogenesis inhibitor is 15mg/kg, and the dosage of the proteolytic enzyme is 2.5 mg/kg. Tumor volume was measured on day 20 after treatment, and the therapeutic effect was compared using tumor growth inhibition as an index (see table 6).
TABLE 6
Test set (n) Is treated by Tumor inhibition ratio (%) P value
1(6) Control -
2(6) Proteolytic enzymes 48 ＜0.05
3(6) Dasatinib 40 ＜0.01
4(6) Avastin 36 ＜0.01
5(6) Caratinib 32 ＜0.01
6(6) Sorafenib 36 ＜0.01
7(6) Proteolytic enzyme + dasatinib 80 ＜0.001
8(6) Proteolytic enzyme + avastin 84 ＜0.001
9(6) Proteolytic enzyme + Caratinib 78 ＜0.001
10(6) Proteolytic enzyme + sorafenib 78 ＜0.001
The results show that the used angiogenesis inhibitors (dasatinib, avastin, canatinib and sorafenib) and proteolytic enzymes (relaxin) have obvious inhibition effects on the growth of various tumor cells when being applied at the concentration alone, and can show obvious synergistic effects when being applied in combination. This finding constitutes a further important feature of the present invention.
Example 9 tumor inhibition by neovascular inhibitor and proteolytic enzyme (sustained Release injection)
The tumor inhibition effect of the proteolytic enzyme (sustained release injection) is determined by the method described in example 7, and the result shows that the proteolytic enzyme can obviously enhance the tumor inhibition effect of marimastat, SU5416, SU6668, fumagillin, TNP-470, sorafenib, sunitinib, Teotesta and Panitoma, and the synergistic effect is 50-60% (P < 0.01).
In conclusion, the neovascular inhibitor and/or the proteolytic enzyme have obvious inhibition effects on the growth of various tumor cells when being used independently, and can show obvious synergistic effects when being used in combination. Therefore, the active ingredient of the invention is any one of the neovascularization inhibitors or proteolytic enzymes or the combination of any one of the neovascularization inhibitors and proteolytic enzymes. The medicine containing the above effective components can be made into sustained release microsphere, and further made into sustained release injection and implant, wherein suspension injection formed by combining with special solvent containing suspending agent is preferred.
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.
Example 10.
80mg of polifeprosan (p-carboxyphenylpropane (p-CPP): Sebacic Acid (SA) 20: 80) copolymer is put into a container, 100 ml of dichloromethane is added, after dissolving and mixing uniformly, 10mg of collagenase and 10mg of marimastat are added, after shaking uniformly again, injection microspheres containing 10% of collagenase and 10% of marimastat are prepared by a spray drying method. Then suspending the microspheres in physiological saline containing 15 percent of mannitol to prepare the corresponding suspension type sustained-release injection with the viscosity of 220-460 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 11.
The steps of the method for processing the sustained-release injection are the same as the example 10, but the difference is that the polifeprosan is 50: 50, and the anticancer active ingredients and the weight percentage thereof are as follows:
(a) 20% marimastat, SU5416, SU6668, fumagillin or TNP-470 in combination with 10% collagenase, relaxin or hyaluronidase;
(b) 20% gefitinib, erlotinib, lapatinib, vatalanib, pelitinib, carboxyamidotriazole, thalidomide, ranolamine, angiostatin, endostatin, onddegree, imatinib mesylate, semasnib, dasatinib, avastin, canatinib, sorafenib, sunitinib, teosinte or panitoma in combination with 10% collagenase, relaxin or hyaluronidase.
Example 12.
70mg of polylactic acid (PLGA, 75: 25) with a molecular weight peak of 65000 was placed in a container, 100 ml of dichloromethane was added, after dissolving and mixing, 15mg of fumagillin and 15mg of hyaluronidase were added, shaking again and vacuum drying was carried out to remove the organic solvent. Freeze-pulverizing dried solid composition containing drug to obtain micropowder containing 15% fumagillin and 15% hyaluronidase, and suspending in physiological saline containing 1.5% sodium carboxymethylcellulose to obtain suspension type sustained-release injection with viscosity of 300-400 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 13
The procedure of the method for preparing the sustained-release injection is the same as that of example 12, except that the polylactic acid (PLGA, 50: 50) with the molecular weight peak of 45000 contains the following effective anticancer components in percentage by weight:
(1) 10% marimastat, SU5416, SU6668, fumagillin or TNP-470 in combination with 20% collagenase, relaxin or hyaluronidase; or
(2) 10% gefitinib, erlotinib, lapatinib, vatalanib, pelitinib, carboxyamidotriazole, thalidomide, ranolamine, angiostatin, endostatin, onddegree, imatinib mesylate, semasnib, dasatinib, avastin, canatinib, sorafenib, sunitinib, teosinte or panitoma in combination with 20% collagenase, relaxin or hyaluronidase.
Example 14.
70mg of ethylene vinyl acetate copolymer (EVAc) is put into a container, 100 ml of dichloromethane is added to dissolve and mix evenly, 5mg of relaxin and 25 mg of marimastat are added, the mixture is shaken up again, and then the spray drying method is used for preparing the microspheres for injection containing 5% of relaxin and 25% of marimastat. Then suspending the microspheres in injection containing 5-15% sorbitol to obtain corresponding suspension type sustained release injection with viscosity of 100-200 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 15.
The procedure of processing into sustained release injection is the same as that of example 14, except that the anticancer active ingredient is:
20% gefitinib, erlotinib, lapatinib, vatalanib, pelitinib, carboxyamidotriazole, thalidomide, ranolamine, angiostatin, endostatin, onddegree, imatinib mesylate, semasnib, dasatinib, avastin, canatinib, sorafenib, sunitinib, teosinte or panitoma in combination with 10% relaxin peptide.
Example 16.
70mg of polifeprosan (p-carboxyphenylpropane (p-CPP): Sebacic Acid (SA) is 20: 80) copolymer is put into a container, 100 ml of dichloromethane is added, after dissolving and mixing uniformly, 10mg of gefitinib and 20mg of chymotrypsin are added, after shaking uniformly again, the microspheres for injection containing 10% of gefitinib and 20% of chymotrypsin 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 80-150 cp (at the temperature of 20-25 ℃). 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 17.
The steps of the method for processing the sustained-release injection are the same as the example 16, but the difference is that the polifeprosan is 50: 50, and the anticancer active ingredients are: 10% gefitinib, erlotinib, lapatinib, vatalanib, pelitinib, carboxyamidotriazole, thalidomide, ranolamine, angiostatin, endostatin, ondoid, imatinib mesylate, sematinib, dasatinib, avastin, canatinib, sorafenib, sunitinib, telosta or panitoma in combination with 20% trypsin, pepsin, pronase, dispase, bromelain, chymotrypsin, clostripase, papain, plasmin, cathepsin-G, cysteine protease, plasminogen activator, nuclease, lipase, esterase, streptokinase, glycosidase, neuraminidase, amylase, lysozyme, gamma interferon, collagenase, relaxin, fibrin or hyaluronidase.
Example 18
70mg of polifeprosan (p-carboxyphenylpropane (p-CPP): Sebacic Acid (SA) 20: 80) copolymer is put into a container, 100 ml of dichloromethane is added, after dissolving and mixing evenly, 15mg of erlotinib and 15mg of trypsin are added, after shaking evenly again, the microspheres for injection containing 15% of erlotinib and 15% of trypsin 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 560cp to 640cp (at the temperature of 20 ℃ to 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 19
The procedure of the process for preparing the sustained-release injection is the same as that of example 18, except that the anticancer active ingredients are: 15% gefitinib, erlotinib, lapatinib, vatalanib, pelitinib, carboxyamidotriazole, thalidomide, ranolamine, angiostatin, endostatin, onddegree, imatinib mesylate, semasnib, dasatinib, avastin, canatinib, sorafenib, sunitinib, telosta, or panitoma in combination with 15% collagenase, relaxin, a fibrin enzyme, or a hyaluronidase.
Example 20
70mg of polifeprosan (p-carboxyphenylpropane (p-CPP): Sebacic Acid (SA) 20: 80) copolymer is put into a container, 100 ml of dichloromethane is added, after dissolving and mixing uniformly, 10mg of gefitinib, 10mg of collagenase and 10mg of hyaluronidase are added, after shaking uniformly again, microspheres for injection containing 10% of gefitinib, 10% of collagenase and 10% of hyaluronidase 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 21
The procedure of processing into a sustained-release implant was the same as in example 20, except that the anticancer active ingredient contained therein was:
(1) 10% of emnity, imatinib mesylate, semasnib, dasatinib, avastin, canatinib, sorafenib, sunitinib, teosinte or panitoma and a combination of% 10% collagenase and 10% hyaluronidase; or
(2) 10% erlotinib, lapatinib, vatalanib, pelitinib, carboxyamidotriazole, thalidomide, ranolamine, angiostatin, endostatin or a combination of vascular endostatin and 10% collagenase and 10% hyaluronidase.
Example 22
60mg of polylactic acid (PLGA, 50: 50) with a molecular weight peak of 35000 is put into a container, 100 ml of dichloromethane is added, after dissolving and mixing uniformly, 20mg of erlotinib, 10mg of hyaluronidase and 10mg of relaxin are added, after shaking uniformly again, injection microspheres containing 20% of erlotinib, 10% of hyaluronidase and 10% of relaxin 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 23
The procedure for preparing a sustained-release implant was the same as in example 22, except that the anticancer active ingredient contained therein was:
(1) 20% marimastat, SU5416, SU6668, fumagillin or a combination of TNP-470 and 10% hyaluronidase and 10% relaxin; or
(2) 20% gefitinib, erlotinib, lapatinib, vatalanib, pelitinib, carboxyamidotriazole, thalidomide, ranolamine, angiostatin, endostatin, imatinib mesylate, semasnib, dasatinib, avastin, canatinib, sorafenib, sunitinib, teosinte or panitoma in combination with 10% hyaluronidase and 10% relaxin peptide.
Example 24.
Putting 60mg of polylactic acid (PLA) with the molecular weight peak value of 35000 into a container, adding 100 ml of dichloromethane, dissolving and uniformly mixing, adding 10mg of plasminogen activator, 10mg of relaxin and 20mg of fumagillin, shaking uniformly again, and drying in vacuum to remove the organic solvent. The dried drug-containing solid composition is frozen and crushed into micro powder containing 10 percent of plasminogen activator, 10 percent of relaxin and 20 percent of fumagillin, and then the micro powder is suspended in physiological saline containing 1.5 percent of sodium carboxymethylcellulose to prepare the corresponding suspension type sustained-release injection with the viscosity of 220cp-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 25
The steps of the method for processing the sustained-release injection are the same as the example 24, but the difference is that the anticancer active ingredients and the weight percentage thereof are as follows:
(1) a combination of 10% plasminogen activator and 10% relaxin and 10% marimastat, SU5416, SU6668, fumagillin or TNP-470;
(2) a combination of 10% plasminogen activator and 10% relaxin and 10% gefitinib, erlotinib, lapatinib, vatalanib, pelitinib, carboxyamidotriazole, thalidomide, ranolamine, angiostatin, endostatin, imatinib mesylate, semasnib, dasatinib, avastin, canatinib, sorafenib, sunitinib, telosta, or panitoma.
Example 26.
70mg of a copolymer of difatty acid and Sebacic Acid (SA) with a molecular weight peak of 30000 (difatty acid: sebacic acid: 20: 80) was placed in a container, 100 ml of dichloromethane was added, after dissolving and mixing, 15mg of imatinib mesylate and 15mg of clostripain were added, shaking again and vacuum drying was carried out to remove the organic solvent. Freeze-pulverizing the dried solid composition containing drug to obtain micropowder containing 15% imatinib mesylate and 15% clostripain, and suspending in physiological saline containing 1.5% sodium carboxymethylcellulose to obtain suspension type sustained-release injection with viscosity of 380-460 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 27.
The steps of the method for processing the sustained-release injection are the same as the example 26, but the difference is that the anticancer active ingredients and the weight percentage thereof are as follows:
(1) a combination of 15% clostripain with 15% marimastat, SU5416, SU6668, fumagillin or TNP-470;
(2) 15% of gefitinib, erlotinib, lapatinib, vatalanib, pelitinib, carboxyamidotriazole, thalidomide, ranolamine, angiostatin, endostatin, imatinib mesylate, semasnib, dasatinib, avastin, canatinib, sorafenib, sunitinib, teosinte or panitoma in combination with 15% clostripain.
Example 28
The procedure of processing into sustained release preparation is the same as that of examples 1-27, 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 (PLGA) of polyglycolic acid and glycolic acid, wherein the ratio of the polyglycolic acid to the glycolic acid is 50-95: 50-50, and the peak value of the molecular weight is 10000-30000, 300000-60000, 60000-100000 or 100000-150000;
c) ethylene vinyl acetate copolymer (EVAc);
d) polifeprosan, p-carboxyphenylpropane (p-CPP) to Sebacic Acid (SA) at a ratio of 10: 90, 20: 80, 30: 70, 40: 60, 50: 50 or 60: 40;
e) di-fatty acid and sebacic acid copolymer (PFAD-SA);
f) poly (erucic acid dimer-sebacic acid) [ P (EAD-SA) ];
g) poly (fumaric-sebacic acid) [ P (FA-SA) ];
h) xylitol, oligosaccharide, chondroitin, chitin, hyaluronic acid, collagen, gelatin or albumin glue.
Example 29
The procedure for preparing a sustained release injection is the same as in examples 1 to 28, 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) 0.1-0.5% tween 20.
Example 30
The procedure of processing into sustained release injection is the same as in examples 1 to 29, except that the anticancer active ingredient is:
(1) a combination of 5-30% marimastat, SU5416, SU6668, fumagillin or TNP-470 and 5-30% plasmin, cathepsin-G, cysteine proteinase, plasminogen activator, nuclease, lipase, esterase, streptokinase or glycosidase; or
(2) 5-30% gefitinib, erlotinib, lapatinib, vatalanib, pelitinib, carboxyamidotriazole, thalidomide, ranolamine, angiostatin, endostatin, imatinib mesylate, sematinib, dasatinib, avastin, canatinib, sorafenib, sunitinib, teosinte or panitoma in combination with 5-30% plasmin, cathepsin-G, cysteine protease, plasminogen activator, nuclease, lipase, esterase, streptokinase or glycosidase.
The above examples are intended to illustrate, but not limit, the application of the invention.
The invention is disclosed and claimed.

Claims (10)

1. The sustained release preparation for resisting solid tumors is characterized by containing the sustained release preparation for resisting solid tumors
(A) A sustained release microsphere comprising:
0.5-60% of anticancer active ingredient
Sustained release auxiliary materials 40-99%
0.0 to 30 percent of suspending agent
The above are weight percentages
And
(B) the solvent is common solvent or special solvent containing suspending agent.
Wherein,
the anticancer active component is a neovascular inhibitor and/or proteolytic enzyme, wherein the weight percentage of the proteolytic enzyme and the neovascular inhibitor in the sustained release agent is 1-9: 1 to 1: 1-9;
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 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 ℃).
2. The sustained-release solid tumor-resistant formulation according to claim 1, wherein the angiogenesis inhibitor is selected from marimastat, SU5416, SU6668, fumagillin, TNP-470, gefitinib, erlotinib, lapatinib, vatalanib, pelitinib, carboxyamidotriazole, thalidomide, ranolamine, angiostatin, endostatin, englerian, imatinib mesylate, sematinib, dasatinib, avastin, canatinib, sorafenib, sunitinib, testa, panitoma or a combination thereof.
3. The sustained-release preparation according to claim 1, wherein the proteolytic enzyme is selected from the group consisting of:
one or a combination of elastase, pancreatic elastase, metalloprotease, trypsin, chymotrypsin, pepsin, pronase, dispase, bromelain, chymotrypsin, clostripain, thermolysin, subtilisin, papain, chymopapain, plasmin, serenethiopeptidase, pancreatin, cathepsin-G, cysteine protease, thioesterase, amidotransferase, transesterase activity, plasminogen activator, collagenase, polymorphonuclear leukocyte serine protease, nuclease, lipase, esterase, streptokinase, glycosidase, hyaluronidase, neuraminidase, amylase, lysozyme, relaxin, interferon, and fibrin.
4. The sustained-release anticancer injection according to claim 1, wherein the sustained-release anticancer injection comprises the following active anticancer components in percentage by weight:
(a) 2-40% Marimastat, SU5416, SU6668, fumagillin, TNP-470, gefitinib, erlotinib, lapatinib, Votalanib, pelitinib, carboxyamidotriazole, thalidomide, Renax, angiostatin, endostatin, Endol, imatinib mesylate, semasinib, dasatinib, avastin, Caratinib, Sorafenib, sunitinib, Teotestat or Panitoma;
(b) 2-40% of elastase, pancreatic elastase, metalloproteinase, trypsin, chymotrypsin, pepsin, pronase, dispase, bromelain, chymotrypsin, clostripain, thermolysin, subtilisin, papain, chymopapain, plasmin, serenethiopeptidase, pancreatin, cathepsin-G, cysteine protease, thioesterase, amidotransferase, transesterase activity, plasminogen activator, collagenase, polymorphonuclear leukocyte serine protease, nuclease, lipase, esterase, streptokinase, glycosidase, hyaluronidase, neuraminidase, amylase, lysozyme, relaxin, interferon, or cellulase;
(c) 2-40% Marimastat, SU5416, SU6668, fumagillin, TNP-470, gefitinib, erlotinib, lapatinib, Votalanib, pelitinib, carboxyamidotriazole, thalidomide, Renamine, angiostatin, endostatin, Endostatin, imatinib mesylate, semasinib, dasatinib, avastin, Caratinib, Sorafenib, sunitinib, Teotestan or Panitoma with 2-40% elastase, trypsin, metalloprotease, chymotrypsin, pepsin, pronase, dispase, bromelain, chymotrypsin, thermolysin, subtilisin, papain, chymopapain, plasmin, serriethiopeptidase, pancreatin, cathepsin-G, trypsin, and the like, A combination of a cysteine protease, thioesterase, amidotransferase, transesterase activity, plasminogen activator, collagenase, polymorphonuclear leukocyte serine protease, nuclease, lipase, esterase, streptokinase, glycosidase, hyaluronidase, neuraminidase, amylase, lysozyme, relaxin, interferon, or a protease.
5. The sustained-release anticancer injection according to claims 1 and 6, characterized in that in the sustained-release excipients,
a) the peak value of the molecular weight of the polylactic acid is 10000-, 30000-, 300000-60000-, 60000-100000-or 100000-150000;
b) in the copolymer of polyglycolic acid and glycolic acid, the ratio of polyglycolic acid to glycolic acid is 50-95: 50-50, and the peak value of molecular weight is 10000-30000, 300000-60000, 60000-100000 or 100000-150000;
c) in polifeprosan, the ratio of p-carboxyphenylpropane to sebacic acid is 10: 90, 20: 80, 30: 70, 40: 60, 50: 50 or 60: 40.
6. The slow released anticancer injection as claimed in claims 1 and 6, characterized in that the suspending agent is one or the 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) 0.1-0.5% 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; or
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.
7. The sustained-release anticancer injection according to claims 1 and 6, characterized in that the sustained-release microspheres in the sustained-release anticancer injection are further used for preparing 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 are injected or placed intratumorally or peritumorally.
8. The sustained-release anticancer implant according to claim 7, wherein the sustained-release implant comprises the following components:
(a) 2-40% Marimastat, SU5416, SU6668, fumagillin, TNP-470, gefitinib, erlotinib, lapatinib, Votalanib, pelitinib, carboxyamidotriazole, thalidomide, Renax, angiostatin, endostatin, Endol, imatinib mesylate, semasinib, dasatinib, avastin, Caratinib, Sorafenib, sunitinib, Teotestat or Panitoma;
(b) 2-40% of elastase, pancreatic elastase, metalloproteinase, trypsin, chymotrypsin, pepsin, pronase, dispase, bromelain, chymotrypsin, clostripain, thermolysin, subtilisin, papain, chymopapain, plasmin, serenethiopeptidase, pancreatin, cathepsin-G, cysteine protease, thioesterase, amidotransferase, transesterase activity, plasminogen activator, collagenase, polymorphonuclear leukocyte serine protease, nuclease, lipase, esterase, streptokinase, glycosidase, hyaluronidase, neuraminidase, amylase, lysozyme, relaxin, interferon, or cellulase;
(c) 2-40% Marimastat, SU5416, SU6668, fumagillin, TNP-470, gefitinib, erlotinib, lapatinib, Votalanib, pelitinib, carboxyamidotriazole, thalidomide, Renamine, angiostatin, endostatin, Endostatin, imatinib mesylate, semasinib, dasatinib, avastin, Caratinib, Sorafenib, sunitinib, Teotestan or Panitoma with 2-40% elastase, trypsin, metalloprotease, chymotrypsin, pepsin, pronase, dispase, bromelain, chymotrypsin, thermolysin, subtilisin, papain, chymopapain, plasmin, serriethiopeptidase, pancreatin, cathepsin-G, trypsin, and the like, A combination of a cysteine protease, thioesterase, amidotransferase, transesterase activity, plasminogen activator, collagenase, polymorphonuclear leukocyte serine protease, nuclease, lipase, esterase, streptokinase, glycosidase, hyaluronidase, neuraminidase, amylase, lysozyme, relaxin, interferon, or a protease.
9. The sustained-release anticancer implant according to claim 7, characterized in that the sustained-release excipients are selected from:
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; or
g) Poly (fumaric acid-sebacic acid) copolymer.
10. The sustained-release anticancer implant according to claim 7, wherein the suspending agent is selected from the group consisting of suspending agents
a) 0.0-3.0% carboxymethylcellulose (sodium);
b) 0.0-15% mannitol;
c) 0.0-15% sorbitol;
d) 0.0-1.5% of surface active substance; and/or
e) 0.0-0.5% tween 20.
CNA2006102011843A 2006-12-01 2006-12-01 An anticancer sustained releasing agent Pending CN1961861A (en)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013156835A1 (en) * 2012-04-16 2013-10-24 Laurus Labs Private Limited An improved process for the preparation of erlotinib hydrochloride form a

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013156835A1 (en) * 2012-04-16 2013-10-24 Laurus Labs Private Limited An improved process for the preparation of erlotinib hydrochloride form a

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