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CN101380304A - Anticancer sustained-released formulation loaded with blood vessel inhibitor and synergist thereof - Google Patents

Anticancer sustained-released formulation loaded with blood vessel inhibitor and synergist thereof Download PDF

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Publication number
CN101380304A
CN101380304A CNA2008103008512A CN200810300851A CN101380304A CN 101380304 A CN101380304 A CN 101380304A CN A2008103008512 A CNA2008103008512 A CN A2008103008512A CN 200810300851 A CN200810300851 A CN 200810300851A CN 101380304 A CN101380304 A CN 101380304A
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Prior art keywords
inhibitor
release
sustained
acid
slow release
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孔庆忠
张红军
邹会凤
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Shandong Lanjin Pharmaceuticals Co Ltd
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Shandong Lanjin Pharmaceuticals Co Ltd
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Abstract

An anticarcinogenic slow release injection carrying an angiogenesis inhibitor and a synergist thereof is made from slow release microspheres and a dissolvant. The slow release microspheres comprise anticancer active components and a slow release adjuvant, and the dissolvant is a special dissolvant containing a suspending agent. The anticancer active components are angiogenesis inhibitors such as gefitinib, erlotinib, lapatinib, vatalanib, pelitinib, thalidomide, ranolamine, angiostatin, endostatin, imatinib, thalidomide, ranolamine, simatinib, dasatinib, avastin, kanatini, sorafenib, sunitinib, telstar or panitoma, and the like, and/or cytotoxic drugs selected from a phosphoinositide-3-kinase inhibitor, pyrimidine analogue and/or a DNA repair enzyme inhibitor; the slow release adjuvant is biocompatible macromolecule; the viscosity of the suspending agent is 100cp-3,000cp (at the temperature of 20-30 DEG C), and the suspending agent is selected from sodium carboxymethyl cellulose, and the like. The slow release microspheres can be also made into a slow release implant, and the curative effects of non-operative therapies such as radiotherapy, chemotherapy, and the like, can be improved when the slow release injection is injected or placed in tumors or around the tumors.

Description

Slow released anticancer injection containing blood vessel inhibitor and its synergist
(I) technical field
The invention relates to a compound anticancer sustained-release injection, belonging to the technical field of medicines. Specifically, the invention provides a compound anticancer drug sustained release preparation containing a vascular inhibitor and/or a synergist thereof, which is mainly a sustained release injection and a sustained release implant.
(II) background of the invention
The current cancer treatment 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 Kongqingzhong et al, "treatment of rat brain tumors by intratumoral Placement of cisplatin plus systemic Carmustine" [ J.Oncology ] 76-82, 69 (1998) (Kong Q et al, J Surg Oncol.1998 Oct; 69(2): 76-82).
The local placement of the chemotherapy drugs can better overcome the defects, not only can obviously improve the drug concentration of local tumor, but also can obviously reduce the systemic toxicity reaction. A number of in vitro and in vivo experiments have shown therapeutic efficacy against solid tumors, see Kongqing et al, "J.Sci. tumor J.Oncol. (1998) 76-82, p.kong Q et al, J.Surg Oncol.1998 Oct. (69 (2):76-82) and Kongqing et al," J.Sci. tumor J.64, 268. Oncol. (1997) 273, in vivo experiments (Kong Q et al, JSURg Oncol.1997 Oct.; 64: 268. gall 273). See also Chinese patents (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 Niti et al, "influence of extracellular stromal status on drug transport in solid tumors" ("Cancer research 60: 2497-) (2000) (Netti PA, Cancer Res.2000, 60(9): 2497-)). 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.
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
Aiming at the defects of the prior art, the invention provides a compound vascular inhibitor sustained-release preparation. Specifically, the invention provides an anticancer drug sustained release preparation containing a vascular inhibitor and/or a synergist thereof, which is mainly a sustained release injection and a sustained release implant.
The blood vessel inhibitor is used as a new anticancer drug and is mainly used for treating solid tumors such as ovarian cancer, lung cancer and the like abroad. However, the application process still shows obvious systemic toxicity, thereby greatly limiting the application of the medicaments.
The invention discovers that the anticancer effect of some anticancer drugs and the blood vessel inhibitor can be mutually enhanced by combining the anticancer drugs and the blood vessel inhibitor, the drugs which can mutually enhance the anticancer effect of the blood vessel inhibitor are called blood vessel inhibitor synergist hereinafter, and mainly are cytotoxic drugs; in addition, the anti-cancer drug sustained release preparation (mainly sustained release injection and sustained release implant) prepared from the vascular inhibitor or the vascular inhibitor synergist not only can greatly improve the local drug concentration of the tumor, reduce the drug concentration of the drug in the circulatory system and reduce the toxicity of the drug to normal tissues, but also can greatly facilitate the drug injection, reduce the complications of the operation and reduce the cost of patients. The anticancer medicine can inhibit tumor growth and raise the sensitivity of tumor cell to anticancer medicine. 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 growth, but also promoting the penetration and diffusion of chemotherapeutic drugs around the tumors and in tumor tissues. The above unexpected findings constitute the subject of the present invention.
One form of the slow release agent of the vascular inhibitor is a 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%
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 ingredient is a vascular inhibitor and/or a synergist thereof, and the vascular inhibitor synergist is selected from phosphoinositide 3-kinase (PI3K) inhibitor, pyrimidine analogue and/or DNA repair enzyme inhibitor; the viscosity range IV (dl/g) of the sustained-release auxiliary material is 0.1-0.8, and the sustained-release auxiliary material is selected from racemic polylactic acid (D, L-PLA), racemic polylactic acid/glycollic acid copolymer (D, L-PLGA), monomethyl polyethylene glycol/polylactic acid (MPEG-PLA), monomethyl polyethylene glycol/polylactic acid copolymer (MPEG-PLGA), polyethylene glycol/polylactic acid (PLA-PEG-PLA), polyethylene glycol/polylactic acid copolymer (PLGA-PEG-PLGA), carboxyl-terminated polylactic acid (PLA-COOH), carboxyl-terminated polylactic acid/glycollic acid copolymer (PLGA-COOH), polifeprosan, difatty fatty acid and sebacic acid copolymer (PFAD-SA), poly (erucic acid dimer-sebacic acid) [ P (EAD-SA) ], poly (fumaric acid-sebacic acid) [ P (FA-SA) ], poly (FA-sebacic acid) ], and the like, Ethylene vinyl acetate copolymer (EVAc), polylactic acid (PLA), polyglycolic acid and glycolic acid copolymer (PLGA), poly-dioxanone (PDO), polytrimethylene carbonate (PTMC), xylitol, oligosaccharide, chondroitin, chitin, hyaluronic acid, collagen, gelatin, albumin glue or one of the combination thereof; 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 blood vessel inhibitor is selected from blood vessel inhibitors such as 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-dihydroindole- (3Z) -methylene ] -2, 4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylaminoethyl) amide, 3, 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, semastoni, 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-pyrrole-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, salts thereof, solvates thereof, and solvates thereof, 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, 3-bis (4-methoxyphenyl) methylene-2-indolinone, 3- [ 4-formylpiperazin-4 yl ] -benzylidene ] -2-indolinone, 3- ([ 5-imidazole ]2, 1-methylthiazol) -2-indolinone, 3-1(2, 6-dimethylimidazo [2, 1-Bj-thiazol-5-yl ] methylene-5-methoxy-2-indolinone, imidazo [2, 1-b ] methylenethiazol-2-indolinone, methylindole-2-indolinone, (2-chloroindole) methylene-2-indolinone, arylene 2-indolinone, indolone, indomethacylin-2-indolinone, indomethacylin-one, indomethacylin-2-indolinone, indomethan-one, indomethan-2-indolinone, indo, 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-lutidine-1-phenyl-2-indolinone or E-3- (2-chloro-3-methyleneindole) 1, 3-indoline-2-indolinone, dasatinib, avastin, canatinib, sorafenib, sunitinib, telosta, 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, imatinib mesylate, sematinib, dasatinib, avastin, canatinib, sorafenib, sunitinib, telosta, panitoma are most preferred.
The ratio of the above-mentioned blood vessel inhibitor in the sustained-release agent is determined by specific conditions, and can be 0.1% -50%, preferably 1% -40%, and most preferably 2% -30%.
Phosphoinositide 3-kinase (abbreviated PI3K) inhibitors are selected from one or a combination of the following: 7- (hydroxy-staurosporine (UCN-01), 7-O-alkyl-staurosporine (UCN-02), beta-methoxystaurosporine, alkylphosphocholines (alkylphosphocholines), hexadecylphosphocholine (hexadecylphosphocholine, MIL, HPC, Miltefosine), Octadecyl- (1, 1-dimethyl-4-piperidine) phosphate (octadecoyl- (1, 1-dimethyl-4-piperidyl) phosphate, perifosine, D-21266), 1-O-hexadecyl-2-O-methyl-rac-propanetriyl-3-phosphocholine (AMG-PC, 1-O-heptadecyl-2-O-meta-glycero-3-phosphocholine, ET-16-OCH3), 1-O-Octadecyl-2-O-methyl-rac-propanetriol-3-phosphocholine (1-O-Octadecyl-2-O-methyl-rac-glycerophosphocholine, ET-18-OCH3, edelfosine), 1-O-Octadecyl-2-O-methyl-sn-propanetriol-3-phosphocholine (1-O-Octadecyl-2-O-methyl-sn-glycerylphosphocholine-3-phosphocholine, ilmofosine, L-ET-18-OCH (3)), inositol polyphosphates (inositols), Tetradecyl Phosphocholine (TPC), hexakis (N-N-trimethyl) hexanolamine (hexakis (N-N-trimethyl) phosphate, HPC6), Octadecyl Phosphorylcholine (OPC), octadecyl- [2- (N-methylpiperidine) ethyl ] -phosphate (octadecyl- [2- (N-methylpiperidino) ethyl ] -phosphate, D-20133, or OMPEP).
Among the above phosphoinositide 3-kinase inhibitors, 7-hydroxide radical-astrosporin, 7-O-alkyl-astrosporin, beta-methoxyastrosporin, alkylphosphocholine, hexadecylphosphocholine, octadecyl- (1, 1-dimethyl-4-piperidine) phosphate, 1-O-hexadecyl-2-O-methyl-rac-propanetriyl-3-phosphocholine, 1-O-octadecyl-2-O-methyl-sn-propanetriyl-3-phosphocholine, inositol polyphosphate, tetradecyl phosphocholine, etc., are used, Hexakis (N-N-trimethyl) hexanolamine phosphate, octadecyl phosphorylcholine or octadecyl- [2- (N-methylpiperidine) ethyl ] -phosphate. Among them, 7-hydroxy-astrosporin, 7-O-alkyl-astrosporin, beta-methoxyastrosporin, alkylphosphocholine, and hexadecylphosphocholine are preferable.
The pyrimidine analogue is selected from one or more of O4-benzyl folic acid, 2, 4, 5-triamino-6-benzyloxy pyrimidine, 2, 4-diamino-6-benzyloxy-5-nitrosopyrimidine, 2, 4-diamino-6-benzyloxy-5-bromopyrimidine, 2-amino-4-benzyloxy-5-nitropyrimidine, 2-amino-4-benzyloxy-6-methyl-5-nitropyrimidine, 2, 4-diamino-6-benzyloxy-s-triazine and 2-amino-O4-benzyl pteridine.
The DNA repair enzyme inhibitor can be any one of DNA-dependent protein kinase inhibitor and/or poly (ADP-ribose) polymerase inhibitor, but is selected from imidazopiperazine, imidazopyridine, wortmannin, benzopyran, 6-aryl-2-morphinan-4-yl-pyran-4-yl, 2- (4-morpholino) -8-phenylchromone, 7-ethyl-10-hydroxycamptothecin, 3-cyano-6-hydrazonomethyl-5- (4-pyridyl) pyridine- [1H ] -2-1, phenylbutyric acid, methoxyamine, hydroxylamine, inositol polyphosphate, tetradecyl phosphorylcholine, hexakis (N-N-trimethyl) hexanolamine phosphate, poly (ADP-ribose) polymerase inhibitor, and pharmaceutically acceptable salts thereof, Octadecylphosphocholine, octadecyl- [2- (N-methylpiperidine) ethyl ] -phosphate, Aminotriazole (AT) and butylthionine sulfoximine are preferred.
When the anticancer drug in the drug sustained-release microspheres is only a vascular inhibitor or a synergist thereof, the application and the synergy mode of the anticancer sustained-release injection are as follows:
(1) the slow release injection containing the blood vessel inhibitor is locally injected, and the blood vessel inhibitor synergist is applied by other ways;
(2) the slow release injection containing the vascular inhibitor synergist is locally injected, and the vascular inhibitor is applied in other ways;
(3) locally injecting a slow-release injection containing a vascular inhibitor and a slow-release injection containing a vascular inhibitor synergist; or
(4) The slow release injection containing the blood vessel inhibitor and the synergist is locally injected.
The slow released anticancer injection for local application may be also used in raising the effect of radiotherapy and other treatment. Other routes refer, but are not limited to, arterial, intravenous, intraperitoneal, subcutaneous, intraluminal administration.
The weight percentage of the synergist of the blood vessel inhibitor in the drug sustained-release microspheres is 0.5-60%, preferably 1-40%, and most preferably 5-30%. The weight ratio of the vascular inhibitor to the vascular inhibitor synergist is 1-9: 1 to 1: 1-9. Mixing the following raw materials in a ratio of 1-2: 1 is preferred.
The anticancer active ingredients in the anticancer sustained-release injection microsphere are preferably as follows, and the weight percentages are as follows:
(a) 1-40% of gefitinib, erlotinib, lapatinib, vatalanib, pelitinib, carboxyamidotriazole, thalidomide, ranolamine, angiostatin, endostatin, imatinib mesylate, semasnib, dasatinib, avastin, canatinib, sorafenib, sunitinib, teosinte or panitoma;
(b) 1-40% of 7-hydroxy-astrosporin, 7-O-alkyl-astrosporin, beta-methoxyastrosporin, alkylphosphocholine or hexadecylphosphocholine;
(c) 1-40% O4-benzylfolic acid, 2, 4, 5-triamino-6-benzyloxypyrimidine, 2, 4-diamino-6-benzyloxy-5-nitrosopyrimidine, 2, 4-diamino-6-benzyloxy-5-bromopyrimidine, 2-amino-4-benzyloxy-5-nitropyrimidine, 2-amino-4-benzyloxy-6-methyl-5-nitropyrimidine, 2, 4-diamino-6-benzyloxy-s-triazine, or 2-amino-O4-benzylpteridine;
(d) 1-40% of imidazopiperazine, imidazopyridine, wortmannin, benzopyran, 6-aryl-2-morphinan-4-yl-pyran-4-yl, 2- (4-morpholino) -8-phenylchromone, 7-ethyl-10-hydroxycamptothecin, 3-cyano-6-hydrazonomethyl-5- (4-pyridyl) pyridine- [1H ] -2-1, phenylbutyric acid, methoxyamine, hydroxylamine, inositol polyphosphate, tetradecyl phosphorylcholine, hexakis (N-N-N-trimethyl) hexanolamine, octadecyl choline phosphate, octadecyl- [2- (N-methylpiperidine) ethyl ] -phosphate, wortmannin, benzopyran, and the like, Aminotriazoles or butylthioiolixime;
(e) 1-40% gefitinib, erlotinib, lapatinib, vatalanib, pelitinib, carboxyamidotriazole, thalidomide, ranolamine, angiostatin, endostatin, imatinib mesylate, sematinib, dasatinib, avastin, canatinib, sorafenib, sunitinib, teosinte or panitoma in combination with 1-40% 7-hydroxy-staurosporine, 7-O-alkyl-staurosporine, β -methoxystaurosporine, alkylphosphocholine or hexadecylphosphocholine;
(f) 1-40% of gefitinib, erlotinib, lapatinib, vatalanib, pelitinib, carboxyamidotriazole, thalidomide, ranolamine, angiostatin, endostatin, imatinib mesylate, semasnib, dasatinib, avastin, canatinib, sorafenib, sunitinib, teosta or panitoma with 1-40% of O4-benzylfolic acid, 2, 4, 5-triamino-6-benzyloxypyrimidine, 2, 4-diamino-6-benzyloxy-5-nitrosopyrimidine, 2, 4-diamino-6-benzyloxy-5-bromopyrimidine, 2-amino-4-benzyloxy-5-nitropyrimidine, 2-amino-4-benzyloxy-6-methyl-5-nitropyrimidine, A combination of 2, 4-diamino-6-benzyloxy-s-triazine or 2-amino-O4-benzylpteridine;
(g) 1-40% of gefitinib, erlotinib, lapatinib, vatalanib, pelitinib, carboxyamidotriazole, thalidomide, ranolamine, angiostatin, endostatin, imatinib mesylate, simatinib, dasatinib, avastin, canatinib, sorafenib, sunitinib, teosta or panitoma with 1-40% of imidazopiperazine, imidazopyridine, wortmannin, benzopyran, 6-aryl-2-morphinan-4-yl-pyran-4-yl, 2- (4-morpholino) -8-phenylchromone, 7-ethyl-10-hydroxycamptothecin, 3-cyano-6-hydrazinomethyl-5- (4-pyridyl) pyridine- [1H ] -2-1H ] -2-1, Combinations of phenylbutyric acid, methoxyamine, hydroxylamine, inositol polyphosphate, tetradecyl phosphocholine, hexakisdecyl (N-N-trimethyl) hexanolamine phosphate, octadecyl phosphocholine, octadecyl- [2- (N-methylpiperidine) ethyl ] -phosphate, aminotriazole, or butylthionine sulfoximine.
The slow release auxiliary material is selected from one or the combination of racemic polylactic acid, racemic polylactic acid/glycollic acid copolymer, monomethyl polyethylene glycol/polylactic acid copolymer, polyethylene glycol/polylactic acid copolymer, carboxyl-terminated polylactic acid/glycollic acid copolymer, polifeprosan, difatty acid and sebacic acid copolymer, poly (erucic acid dimmer-sebacic acid), poly (fumaric acid-sebacic acid), ethylene-vinyl acetate copolymer, polylactic acid, polyglycolic acid and glycolic acid copolymer, xylitol, oligosaccharide, chondroitin, chitin, hyaluronic acid, collagen, gelatin and albumin glue.
The most preferable sustained-release auxiliary materials in the sustained-release microspheres and the weight percentage thereof are as follows:
(1) 55-90% PLA;
(2) 50-90% PLGA;
(3) 50-85% of polifeprosan;
(4) 55-90% of a copolymer of di-fatty acid and sebacic acid;
(5) 55-90% EVAc;
(6) 40-95% of xylitol, oligosaccharide, chondroitin, chitin, hyaluronic acid, collagen, gelatin or albumin glue; or
(7) 40-95% of racemic polylactic acid, racemic polylactic acid/glycollic acid copolymer, monomethyl polyethylene glycol/polylactic acid copolymer, polyethylene glycol/polylactic acid copolymer, carboxyl-terminated polylactic acid or carboxyl-terminated polylactic acid/glycollic acid copolymer.
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)), 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 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.
The molecular weight peak of polylactic acid may be, but is not limited to, 5000-100,000, but is preferably 20,000-60,000, and most preferably 5,000-30,000; 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, 5000-100,000, 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. The polylactic acid used is preferably L-polylactic acid (L-PLA). The viscosity range IV (dl/g) of the L-polylactic acid (L-PLA) is 0.2-0.8, the glass transition temperature range is 55-65 ℃, and the melting point is 175-185 ℃.
In addition to the above-mentioned adjuvants, other substances can be selected and used as described in detail in U.S. Pat. Nos. 4757128, 4857311, 4888176 and 4789724 and "pharmaceutical adjuvants" 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. 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.
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 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 (b).
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, 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 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). Such a viscosity is suitable for 18-22 gauge needles and for 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 pharmaceutical excipients can be any one or more of the above pharmaceutical excipients, but water-soluble high molecular polymers are taken as the main choice, and in various high molecular polymers, polylactic acid, sebacic acid, a mixture or copolymer of high molecular polymers containing polylactic acid or sebacic acid are taken as the first choice, and the mixture and copolymer can be selected from, but are not limited to, PLA, PLGA, a mixture of PLA and PLGA, and a mixture or 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.
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, chunks, needles, rods, columns, and films. Among various dosage forms, slow release implants in vivo are preferred. The size of the volume depends on the location and size of the lesion. It can be in the form of rod of 0.1-5mm (thick) × 1-10mm (long), or in the form of sheet.
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 in the sustained-release implant and the weight percentage are preferably as follows:
(a) 1-40% of gefitinib, erlotinib, lapatinib, vatalanib, pelitinib, carboxyamidotriazole, thalidomide, ranolamine, angiostatin, endostatin, imatinib mesylate, semasnib, dasatinib, avastin, canatinib, sorafenib, sunitinib, teosinte or panitoma;
(b) 1-40% of 7-hydroxy-astrosporin, 7-O-alkyl-astrosporin, beta-methoxyastrosporin, alkylphosphocholine or hexadecylphosphocholine;
(c) 1-40% O4-benzylfolic acid, 2, 4, 4-triamino-6-benzyloxypyrimidine, 2, 4-diamino-6-benzyloxy-5-nitrosopyrimidine, 2, 4-diamino-6-benzyloxy-5-bromopyrimidine, 2-amino-4-benzyloxy-5-nitropyrimidine, 2-amino-4-benzyloxy-6-methyl-5-nitropyrimidine, 2, 4-diamino-6-benzyloxy-s-triazine, or 2-amino-O4-benzylpteridine;
(d) 1-40% of imidazopiperazine, imidazopyridine, wortmannin, benzopyran, 6-aryl-2-morphinan-4-yl-pyran-4-yl, 2- (4-morpholino) -8-phenylchromone, 7-ethyl-10-hydroxycamptothecin, 3-cyano-6-hydrazonomethyl-5- (4-pyridyl) pyridine- [1H ] -2-1, phenylbutyric acid, methoxyamine, hydroxylamine, inositol polyphosphate, tetradecyl phosphorylcholine, hexakis (N-N-N-trimethyl) hexanolamine, octadecyl choline phosphate, octadecyl- [2- (N-methylpiperidine) ethyl ] -phosphate, wortmannin, benzopyran, and the like, Aminotriazoles or butylthioiolixime;
(e) 1-40% gefitinib, erlotinib, lapatinib, vatalanib, pelitinib, carboxyamidotriazole, thalidomide, ranolamine, angiostatin, endostatin, imatinib mesylate, sematinib, dasatinib, avastin, canatinib, sorafenib, sunitinib, teosinte or panitoma in combination with 1-40% 7-hydroxy-staurosporine, 7-O-alkyl-staurosporine, β -methoxystaurosporine, alkylphosphocholine or hexadecylphosphocholine;
(f) 1-40% of gefitinib, erlotinib, lapatinib, vatalanib, pelitinib, carboxyamidotriazole, thalidomide, ranolamine, angiostatin, endostatin, imatinib mesylate, semasnib, dasatinib, avastin, canatinib, sorafenib, sunitinib, teosta or panitoma with 1-40% of O4-benzylfolic acid, 2, 4, 5-triamino-6-benzyloxypyrimidine, 2, 4-diamino-6-benzyloxy-5-nitrosopyrimidine, 2, 4-diamino-6-benzyloxy-5-bromopyrimidine, 2-amino-4-benzyloxy-5-nitropyrimidine, 2-amino-4-benzyloxy-6-methyl-5-nitropyrimidine, A combination of 2, 4-diamino-6-benzyloxy-s-triazine or 2-amino-O4-benzylpteridine;
(g) 1-40% of gefitinib, erlotinib, lapatinib, vatalanib, pelitinib, carboxyamidotriazole, thalidomide, ranolamine, angiostatin, endostatin, imatinib mesylate, simatinib, dasatinib, avastin, canatinib, sorafenib, sunitinib, teosta or panitoma with 1-40% of imidazopiperazine, imidazopyridine, wortmannin, benzopyran, 6-aryl-2-morphinol 4-yl-pyran-4-yl, 2- (4-morpholino) -8-phenylchromone, 7-ethyl-10-hydroxycamptothecin, 3-cyano-6-hydrazinomethyl-5- (4-pyridyl) pyridine- [1H ] -2-1, Combinations of phenylbutyric acid, methoxyamine, hydroxylamine, inositol polyphosphate, tetradecyl phosphocholine, hexakisdecyl (N-N-trimethyl) hexanolamine phosphate, octadecyl phosphocholine, octadecyl- [2- (N-methylpiperidine) ethyl ] -phosphate, aminotriazole, or butylthionine sulfoximine.
The sustained-release auxiliary materials in the sustained-release implant and the weight percentage thereof are most preferably as follows:
(1) 55-90% PLA;
(2) 50-90% PLGA;
(3) 50-85% of polifeprosan;
(4) 55-90% of a copolymer of di-fatty acid and sebacic acid;
(5) 55-90% EVAc;
(6) 40-95% of xylitol, oligosaccharide, chondroitin, chitin, hyaluronic acid, collagen, gelatin or albumin glue; or
(7) 40-95% of racemic polylactic acid, racemic polylactic acid/glycollic acid copolymer, monomethyl polyethylene glycol/polylactic acid copolymer, polyethylene glycol/polylactic acid copolymer, carboxyl-terminated polylactic acid or carboxyl-terminated polylactic acid/glycollic acid copolymer.
When the anticancer drug in the drug sustained-release microspheres is only a vascular inhibitor or a synergist thereof, the application and the synergy mode of the anticancer sustained-release implant are the same as those of a sustained-release injection.
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.
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 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 invention is further described by the following tests and examples:
test 1 comparison of local drug concentrations after different modes of application of vascular inhibitor (gefitinib)
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 5mg/kg gefitinib. The results of the determination of the content (%) of the medicament in the tumor at different times show that the local medicament concentration difference of the gefitinib applied in different modes is obvious, the local administration can obviously improve and effectively maintain the effective medicament concentration of the part where the tumor is located, 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.
Test 2 comparison of the in vivo tumor-inhibiting action of vascular inhibitor (erlotinib) after different modes of 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 0.5 cm diameter. Each group was dosed with 5mg/kg erlotinib. 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 tumor inhibition effect difference of erlotinib applied by different modes is obvious, the effective drug concentration of the tumor part 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. Not only has good curative effect, but also has little toxic and side effect.
Experiment 3 in vivo tumor inhibition effect of synergist containing angiogenesis inhibitor and angiogenesis inhibitor (sustained release injection)
Using white rat as test object, 2X 105Individual pancreatic tumor cells were injected subcutaneously into the quaternary costal region and were divided into the following 10 groups 14 days after tumor growth (see table 1). The first group was the control, and groups 2 to 10 were the treatment groups, all of which were intratumorally injected. The dosage is 5 mg/kg. Tumor volume was measured on day 10 after treatment and the treatment effect was compared (see table 1).
TABLE 1
Test set (n) Is treated by Tumor volume (cm)3) P value
1(6) Control 68±10
2(6) Blood vessel inhibitor 50±5.0 <0.05
3(6) UCN-01 52±2.0 <0.01
4(6) UCN-02 48±2.2 <0.01
5(6) MIL 58±5.2 <0.01
6(6) D-21266 40±3.0 <0.01
7(6) Angiostatic agent + UCN-01 20±2.0 <0.001
8(6) Angiostatic agent + UCN-02 32±3.6 <0.001
9(6) Angiostatic + MIL 30±3.2 <0.001
10(6) Angiostatic agent + D-21266 18±2.2 <0.001
The results show that the angiogenesis inhibitor (gefitinib) and the angiogenesis inhibitor synergist-phosphoinositide 3-kinase (PI3K) inhibitor (UCN-01: 7-hydroxyl-astrosporin; UCN-02: 7-O-alkyl-astrosporin; MIL: Miltefosine; D-21266: octadecyl- (1, 1-dimethyl-4-piperidine) phosphate or perifosine) 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 4 antitumor Effect of angiostatic agent and angiostatic 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. The angiogenesis inhibitor and the angiogenesis inhibitor synergist are added into various tumor cells cultured in vitro for 24 hours at a concentration of 10ug/ml, and the total number of the cells is counted after culturing for 48 hours. The tumor cell growth inhibitory effect is shown in Table 2.
TABLE 2
Tumor cell Erlotinib O4-BA UCN-01 UCN-02 Erlotinib + O4-BA Erlotinib + UCN-1 Erlotinib + UCN-2
CNS 30％ 50％ 62％ 62％ 88％ 86％ 80％
C6 34％ 64％ 60％ 64％ 94％ 80％ 94％
SA 38％ 60％ 50％ 62％ 86％ 92％ 92％
BC 36％ 62％ 54％ 64％ 94％ 82％ 82％
BA 38％ 60％ 62％ 60％ 92％ 92％ 92％
LH 42％ 56％ 62％ 58％ 90％ 86％ 84％
PAT 44％ 50％ 66％ 52％ 90％ 82％ 82％
The results show that the blood vessel inhibitor (erlotinib) and the blood vessel inhibitor synergist (O4-BA: O4-benzyluric acid, UCN-01: 7-hydroxyl-astrosporin and UCN-02: 7-O-alkyl-astrosporin) 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 5 antitumor Effect of angiostatic agent and angiostatic synergist (sustained Release injection)
Using white rat as test object, 2X 105Individual liver tumor cells were injected subcutaneously into the quaternary costal region and were divided into the following 10 groups 14 days after tumor growth (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 is 5 mg/kg. Tumor volume was measured on day 10 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 72±10
2(6) ilmofosine 46±5.0 <0.05
3(6) Blood vessel inhibitor 50±2.2 <0.01
4(6) ilmofosine + vascular inhibitor 32±2.6 <0.001
5(6) AMG-PC 48±3.2 <0.01
6(6) AMG-PC + angiostatic agent 22±3.0 <0.001
7(6) edelfosine 32±2.6 <0.01
8(6) Edelfosine + vascular inhibitors 22±2.4 <0.001
9(6) IDOU 32±3.4 <0.01
10(6) IDOU + vascular inhibitors 18±2.2 <0.001
The results show that the used vascular inhibitor (lapatinib) and the vascular inhibitor synergist-PI 3K inhibitor (wherein AMG-PC: 1-O-hexadecyl-2-O-methyl-rac-propanetriyl-3-phosphorylcholine; edelfosine: 1-O-octadecyl-2-O-methyl-rac-propanetriyl-3-phosphorylcholine; ilmofosine: 1-O-octadecyl-2-O-methyl-sn-propanetriyl-3-phosphorylcholine; IDOU: 5-iodo-2' -deoxyguanosine) have obvious inhibition effects on the growth of various tumor cells when being used alone at the concentration, and can show obvious synergistic effects when being used in combination.
Test 6 antitumor Effect of angiostatic agent and angiostatic synergist (sustained Release injection)
Using white rat as test object, 2X 105The prostate tumor cells were injected subcutaneously into the quaternary costal region, and were divided into negative control (blank), monotherapy (angiostatin or angiostatin potentiator) and combination therapy (angiostatin and angiostatin) 14 days after tumor growthA vasculostatic synergist). The blood vessel inhibitor is injected intratumorally, and the blood vessel inhibitor synergist is injected intraperitoneally. 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) Blood vessel inhibitor 60 <0.05
3(6) Imidazopiperazines 28 <0.01
4(6) Imidazopyridines as inhibitors of HIV 38 <0.01
5(6) Wortmannin 34 <0.01
6(6) Benzopyrans 30 <0.01
7(6) Angiostatic agent + imidazopiperazine 88 <0.001
8(6) Vasculostatic agents + imidazopyridines 80 <0.001
9(6) Angiostatin + wortmanninMycin 82 <0.001
10(6) Angiostatic agent + benzopyran 84 <0.001
The results show that the used vascular inhibitor (Votalanib) and the vascular inhibitor synergist-DNA-dependent protein kinase inhibitor (wherein, the imidazopyrazine, the imidazopyridine, the wortmannin and the benzopyran) have obvious inhibition effect on the growth of various tumor cells when being used independently at the concentration, and can show obvious synergistic effect when being used together.
Test 7 antitumor Effect of angiostatic agent and angiostatic 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 blood vessel inhibitor is injected into abdominal cavity, and the blood vessel inhibitor synergist is injected around tumor. 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 5).
TABLE 5
Test set (n) Is treated by Tumor inhibition ratio (%) P value
1(6) Control -
2(6) Blood vessel inhibitor 48 <0.05
3(6) LY294002 70 <0.01
4(6) SU11752 66 <0.01
5(6) SN-38 74 <0.01
6(6) OK-1035 66 <0.01
7(6) Angiostatic agent + LY294002 88 <0.001
8(6) Angiostatic agent + SU11752 96 <0.001
9(6) Angiostatic agent + SN-38 92 <0.001
10(6) Angiostatic agent + OK-1035 92 <0.001
The results show that the used vascular inhibitor (pelitinib) and the vascular inhibitor synergist-DNA-dependent protein kinase inhibitor (wherein, LY 294002: 2- (4-morpholino) -8-phenylchromone; SU 11752: the kinase inhibitor; SN-38: 7-ethyl-10-hydroxycamptothecin; OK-1035: 3-cyano-6-hydrazonomethyl-5- (4-pyridyl) pyridine- [1H ] -2-1) 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 8 antitumor Effect of angiostatic agent and angiostatic 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 slow release implant is placed in the tumor. 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 6).
TABLE 6
Test set (n) Is treated by Tumor inhibition ratio (%) P value
1(6) Control -
2(6) Blood vessel inhibitor 48 <0.05
3(6) Methoxyamine 30 <0.05
4(6) Minocycline 38 <0.05
5(6) Hydroxy amines 32 <0.05
6(6) O-methylhydroxylamine 30 <0.01
7(6) Vascular inhibitor + methoxyamine 82 <0.01
8(6) Angiostatic agent + minocycline 74 <0.01
9(6) Angiostatic agent + hydroxylamine 84 <0.01
10(6) Angiostatic agent + O-methylhydroxylamine 88 <0.001
The results show that the used vascular inhibitor (imatinib mesylate) and the vascular inhibitor synergist-DNA-dependent protein kinase inhibitor 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 together.
Test 9 antitumor Effect of angiostatic agent and angiostatic agent potentiator (sustained Release implant)
The tumor-inhibiting effect of the angiostatic agent and the angiostatic agent potentiator (sustained release implant) was measured as described in test 8, and the tumor growth inhibition rate thereof is shown in Table 7.
TABLE 7
Test set (n) Is treated by Tumor inhibition ratio (%) P value
1(6) Control -
2(6) Blood vessel inhibitor 50 <0.05
3(6) 3-AB 46 <0.01
4(6) Benzamide derivatives 46 <0.01
5(6) PD128763 42 <0.01
6(6) AG14361 38 <0.01
7(6) Angiostatic agent +3-AB 78 <0.001
8(6) Angiostatic agent + benzamide 76 <0.001
9(6) Angiostatic + PD128763 84 <0.001
10(6) Angiostatic + AG14361 80 <0.001
The results show that the used vascular inhibitor (Reation-induced abortion) and the vascular inhibitor synergist-poly (ADP-ribose) polymerase inhibitor (wherein, 3-AB: 3-aminobenzamide; benzamide; PD 128763: 3, 4-dihydromethoxyisoquinoline-1 (2H) -benzamide; AG 14361: polymerase inhibitor) have obvious inhibition effect on the growth of a plurality of tumor cells when being singly applied at the concentration, and can show obvious synergistic effect when being combined.
Test 10 antitumor Effect of angiostatic agent and angiostatic synergist (sustained Release injection)
The tumor-inhibiting effects of the angiostatic agent and the angiostatic agent potentiator (sustained release implant) were measured as described in test 8, and the tumor growth inhibition rates are shown in Table 8.
TABLE 8
Test set (n) Is treated by Tumor inhibition ratio (%) P value
1(6) Control -
2(6) Blood vessel inhibitor 58 <0.05
3(6) BZ1-6 52 <0.01
4(6) TI1-5 38 <0.01
5(6) TBC 44 <0.01
6(6) Benzimidazole compounds 48 <0.01
7(6) Angiostatic + BZ1-6 78 <0.001
8(6) Angiostatic agent + TI1-5 80 <0.001
9(6) Vasculostatic + TBC 76 <0.001
10(6) Vasculostatic agents + benzimidazoles 90 <0.001
The results show that the used angiostatic agent (semasoni) and the angiostatic agent synergist-poly (ADP-ribose) polymerase inhibitor (wherein, BZ 1-6: benzimidazole-4-carboxamide; TI 1-5: tricyclic lactam hydrogen sulfide; TBC: tricyclic benzimidazole carboxamide, benzimidazole) have obvious inhibition effect on the growth of a plurality of tumor cells when being used alone at the concentration, and can show obvious synergistic effect when being used in combination.
Test 11 antitumor Effect of angiostatic agent and/or angiostatic synergist (sustained Release implant)
The tumor-inhibiting effect of the angiostatic agent and/or the angiostatic synergist (sustained release implant) was measured as described in test 8, and the tumor growth inhibition rate thereof is shown in Table 9.
TABLE 9
Test set (n) Is treated by Tumor inhibition ratio (%) P value
1(6) Control -
2(6) Blood vessel inhibitor 40 <0.05
3(6) NU1025 56 <0.01
4(6) PBC 42 <0.01
5(6) MPBC 40 <0.01
6(6) NU1085 46 <0.01
7(6) Angiostatic + NU1025 88 <0.001
8(6) Angiostatic agent + PBC 82 <0.001
9(6) Vascular inhibitor + MPBC 78 <0.001
10(6) Angiostatic agent + NU1085 90 <0.001
The above results show that the angiostatic agent (dasatinib) and the angiostatic synergist poly (ADP-ribose) polymerase inhibitor (PBC: 2-phenyl-1H-benzimidazole-4-carboxamide; MPBC: 2- (3-methoxyphenyl) -1H-benzimidazole-4-carboxamide (2- (3-methoxyphenyl) -1H-benzimidazole-4-carboxamide), NU 1025: 8-hydroxy-2-methylquinazolinone; NU 1085: 2- (4-hydroxyphenyl) benzimidazole-4-carboxamide) used have significant inhibitory effects on the growth of various tumor cells when used alone at these concentrations and show significant synergistic effects when used in combination.
Test 12 antitumor Effect of angiostatic agent and/or angiostatic synergist (sustained Release implant)
The tumor-inhibiting effect of the angiostatic agent and/or the angiostatic synergist (sustained release implant) was measured as described in test 6, and the tumor growth inhibition rate thereof is shown in Table 10.
Watch 10
Test set (n) Is treated by Tumor inhibition ratio (%) P value
1(6) Control -
2(6) Blood vessel inhibitor 62 <0.05
3(6) BSO 56 <0.01
4(6) Amino triazoles 34 <0.01
5(6) Lasiosphaeric acid 42 <0.01
6(6) Podophyllotoxin 40 <0.01
7(6) Vasculostatic + BSO 84 <0.001
8(6) Angiostatic agent plus aminotriazole 84 <0.001
9(6) Vasculostatic agent + puffball acid 78 <0.001
10(6) Vascular inhibitor + neopodophyllotoxin 88 <0.001
The results show that the used vascular inhibitor (canatinib) and the vascular inhibitor synergist-poly (ADP-ribose) polymerase inhibitor (wherein BSO is butylthioninoxime) 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.
Further experiments have shown that gefitinib, erlotinib, lapatinib, vatalanib, pelitinib, carboxyamidotriazole, thalidomide, ranolamine, angiostatin, endostatin, imatinib mesylate, semasnib, dasatinib, avastin, canatinib, sorafenib, sunitinib, telosta, or panitoma enhance the effect of poly (ADP-ribose) polymerase inhibitors and other vasoinhibitor synergists to varying degrees.
Experiment 13, comparison of in vivo release of gefitinib sustained release implants prepared from polylactic acid with different molecular weights
Rats were used as subjects, and divided into groups (3/group) and subcutaneously administered equivalent amounts of gefitinib sustained release implants loaded with polylactic acid (PLA) of different Molecular Weights (MW). Then 1, 3, 7, 14, 21, 28 respectively
And measuring the residual quantity of the medicine in the implant for 35 days, and further obtaining the in vivo release rate (%). The results show that the release with molecular weight 20000 is: 1 day (8%), 3 (28%), 7 (56%), 14 (82%), 21 (90%), 28(94) and 35 (98%). Comparing the in vivo release of gefitinib sustained release implants made of different polylactic acid molecular weights, it was found that the release was slowed down with the increase of the molecular weight, and the bacterial inhibition rate was increased with the increase of the molecular weight of polylactic acid, as compared to the systemic administration group, in the order of 68% (MW: 5000), 66% (MW: 15000), 54% (MW: 25000), 50% (MW: 40000) and 48 (MW: 60000), taking day 7 as an example.
The same results are seen with erlotinib, lapatinib, vatalanib, pelitinib, carboxyamidotriazole, thalidomide, ranolamine, angiostatin, endostatin, imatinib mesylate, sematinib, dasatinib, avastin, canatinib, sorafenib, sunitinib, telosta or panitoma sustained release formulations prepared with polylactic acid as adjuvant.
Particularly, the sustained-release preparation, particularly the sustained-release injection, has simple and convenient operation and good repeatability. Not only has good curative effect, but also has little toxic and side effect.
Different drug packages differ from different biodegradable polymers in their essential characteristics. Further research finds that the slow-release auxiliary materials most suitable for the slow release of the medicament are one or a combination of racemic polylactic acid, racemic polylactic acid/glycolic acid copolymer, monomethyl polyethylene glycol/polylactic acid copolymer, polyethylene glycol/polylactic acid copolymer, terminal carboxyl polylactic acid/glycolic acid copolymer, polifeprosan, di-fatty acid and sebacic acid copolymer, poly (erucic aciddipolymer-sebacic acid), poly (fumaric acid-sebacic acid), ethylene vinyl acetate copolymer, polylactic acid, polyglycolic acid and glycolic acid copolymer, xylitol, oligosaccharide, chondroitin, chitin, hyaluronic acid, collagen, gelatin and albumin glue; the most suitable suspending agent is one or more of methylcellulose, hydroxymethyl cellulose, sodium carboxymethylcellulose, (iodine) glycerol, dimethicone, propylene glycol, carbomer, mannitol, sorbitol, surfactant, Tween 20, Tween 40, Tween 80, or their combination.
In conclusion, the vascular inhibitor and various vascular inhibitor synergists have obvious inhibition effect on the growth of various tumor cells when being used independently, and can show obvious synergistic effect when being used together. Therefore, the active ingredient of the invention is any one (or more than one) vascular inhibitor and/or any one (or more than one) vascular inhibitor synergist. 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.
(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, 100 ml of dichloromethane is added, after dissolving and mixing uniformly, 10mg of gefitinib and 7-hydroxyl-astrosporin are added, after shaking uniformly again, microspheres for injection containing 10% of gefitinib and 10% of 7-hydroxyl-astrosporin 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. 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) 1-40% of gefitinib, erlotinib, lapatinib, vatalanib, pelitinib, carboxyamidotriazole, thalidomide, ranolamine, angiostatin, endostatin, imatinib mesylate, semasnib, dasatinib, avastin, canatinib, sorafenib, sunitinib, teosinte or panitoma;
(2) 1-40% of 7-hydroxide-starchysporine, 7-O-alkyl-starchysporine, beta-methoxystaurosporine, alkylphosphocholine, hexadecylphosphocholine, octadecyl- (1, 1-dimethyl-4-piperidine) phosphate, 1-O-hexadecyl-2-O-methyl-rac-propanetriyl-3-phosphocholine, 1-O-octadecyl-2-O-methyl-sn-propanetriyl-3-phosphocholine, inositol polyphosphate, cyclosporin A, tetradecyl phosphocholine, beta-methoxystaurosporine, alkylphosphocholine, 1-O-methyl-rac-propanetriyl-3-phosphocholine, Hexakis (N-trimethyl) hexanolamine phosphate, octadecyl choline phosphate or octadecyl- [2- (N-methylpiperidine) ethyl ] -phosphate; or
(3) 1-40% gefitinib, erlotinib, lapatinib, vatalanib, pelitinib, carboxyamidotriazole, thalidomide, ranolamine, angiostatin, endostatin, imatinib mesylate, sematinib, dasatinib, avastin, canatinib, sorafenib, sunitinib, teosinte or panitoma with 1-40% 7-hydroxy-staurosporine, 7-O-alkyl-staurosporine, beta-methoxystaurosporine, alkylphosphocholine, hexadecylphosphocholine, octadecyl- (1, 1-dimethyl-4-piperidine) phosphate, 1-O-hexadecyl-2-O-methyl-rac-propanetriyl-3-phosphocholine, 1-O-octadecyl-2-O-methyl-rac-propanetriyl-3-phosphocholine, 1-O-octadecyl-2-O-methyl-sn-propanetriyl-3-phosphocholine, inositol polyphosphate, cyclosporin a, tetradecyl phosphocholine, hexakisdecyl (N-trimethyl) propanolamine phosphate, octadecyl phosphocholine or octadecyl- [2- (N-methylpiperidine) ethyl ] -phosphate.
The used auxiliary materials are: racemic polylactic acid, racemic polylactic acid/glycolic acid copolymer, monomethyl polyethylene glycol/polylactic acid copolymer, polyethylene glycol/polylactic acid copolymer, carboxyl-terminated polylactic acid or carboxyl-terminated polylactic acid/glycolic acid copolymer.
Example 3.
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 well, 15mg of erlotinib and 15mg of 7-ethyl-10-hydroxycamptothecin 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% erlotinib and 15% 7-ethyl-10-hydroxycamptothecin, and suspending in physiological saline containing 1.5% sodium carboxymethylcellulose to obtain suspension type sustained-release injection. The slow release injection has the release time of 20-35 days in-vitro physiological saline and the release time of about 35-50 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) 1-40% of imidazopiperazine, imidazopyridine, wortmannin, benzopyran, 2- (morphin-4-yl) -chromen-4-yl, 2- (4-morpholino) -8-phenylchromone, 1- (2-hydroxy-4-morphin-4-ylphenyl) -ethanone, a kinase inhibitor, vanillin, 2-aminopurine, 7-ethyl-10-hydroxycamptothecin, phenylbutyrate, methylamine, methoxyamine, hydroxylamine, minotetracycline, O-hydroxylamine, O-methylhydroxylamine or O-delta-aminobutylhydroxylamine; or
(2) 1-40% of gefitinib, erlotinib, lapatinib, vatalanib, pelitinib, carboxyamidotriazole, thalidomide, ranolamine, angiostatin, endostatin, imatinib mesylate, simatinib, dasatinib, avastin, canatinib, sorafenib, sunitinib, telosta or panitoma with 1-40% of imidazopiperazine, imidazopyridine, wortmannin, benzopyran, 2- (morphinan-4-yl) -chromen-4-yl, 2- (4-morpholino) -8-phenylchromone, 1- (2-hydroxy-4-morphol-4-ylphenyl) -ethanone, a kinase inhibitor, vanillin, 2-aminopurine, 2-amino acid, and a pharmaceutically acceptable salt thereof, A combination of 7-ethyl-10-hydroxycamptothecin, phenylbutyrate, methylamine, methoxyamine, hydroxylamine, minocycline, O-hydroxylamine, O-methylhydroxylamine, or O-delta-aminooxybutylhydroxylamine.
Example 5.
Putting 70mg of ethylene vinyl acetate copolymer (EVAc) into a container, adding 100 ml of dichloromethane, dissolving and uniformly mixing, adding 20mg of lapatinib and 10mg of benzimidazole, shaking up again, and preparing microspheres for injection containing 20% of lapatinib and 10% of benzimidazole by using a spray drying method. Then suspending the microspheres in injection containing 5-15% of sorbitol to prepare the corresponding suspension type sustained-release injection. 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:
(1) 1-40% of 3-aminobenzamide, benzamide, 3, 4-dihydromethoxyisoquinoline-1 (2H) -benzamide, polymerase inhibitor, amino-substituted 2-arylbenzimidazole-4-carboxamide, benzimidazole-4-carboxamide, tricyclo-lactam hydrogen sulfide, tricyclic benzimidazole carboxamide, benzimidazole, 1H-tricyclic benzimidazole carboxamide, 2-aryl-1H-benzimidazole-4-carboxamide, 2-phenyl-1H-benzimidazole-4-carboxamide, 2- (4-hydroxymethylphenyl) -1H-benzimidazole-4-carboxamide, 2- (3-methoxyphenyl) -1H-benzimidazole-4-carboxamide, bis (hydroxymethyl) sulfonamide, bis (hydroxymethyl) amide, 8-hydroxy-2-methylquinazolinone or 2- (4-hydroxyphenyl) benzimidazole-4-carboxamide; or
(2) 1-40% gefitinib, erlotinib, lapatinib, vatalanib, pelitinib, carboxyamidotriazole, thalidomide, ranolamine, angiostatin, endostatin, imatinib mesylate, semasnib, dasatinib, avastin, canatinib, sorafenib, sunitinib, teosinte or panitoma with 1-40% of 3-aminobenzamide, benzamide, 3, 4-dihydromethoxyisoquinoline-1 (2H) -benzamide, polymerase inhibitor, amino-substituted 2-arylbenzimidazole-4-carboxamide, benzimidazole-4-carboxamide, tricyclic lactam hydrogen sulfide, tricyclic benzimidazole carboxamide, 1H-tricyclic benzimidazole-amide, carboxyamide, a combination of 2-aryl-1H-benzimidazole-4-carboxamide, 2-phenyl-1H-benzimidazole-4-carboxamide, 2- (4-hydroxymethylphenyl) -1H-benzimidazole-4-carboxamide, 2- (3-methoxyphenyl) -1H-benzimidazole-4-carboxamide, 8-hydroxy-2-methylquinazolinone, or 2- (4-hydroxyphenyl) benzimidazole-4-carboxamide.
Example 7.
70mg of polifeprosan (p-carboxyphenylpropane (p-CPP): Sebacic Acid (SA) is 20: 80) copolymer is placed into a container, 100 ml of dichloromethane is added, after dissolving and mixing uniformly, 20mg of vorexanib and 10mg of butylthionine sulfoximine are added, after shaking uniformly again, the injection microspheres containing 20% of vorexanib and 10% of butylthionine sulfoximine 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. 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:
(1) 1-40% of glutathione disulfide, tetramethylthiuram disulfide, aminotriazole, butylthioneoxime, puffball acid, S-hexyl glutathione and neopropodophyllycin; or
(2) 1-40% gefitinib, erlotinib, lapatinib, vatalanib, pelitinib, carboxyamidotriazole, thalidomide, ranolamine, angiostatin, endostatin, imatinib mesylate, semasnib, dasatinib, avastin, canatinib, sorafenib, sunitinib, teosinte or panitoma in combination with 2-40% glutathione disulfide, tetramethylthiuram disulfide, aminotriazole, butylthioneoxime, marbomycolic acid, S-hexylglutathione, neopropodophyllycin, hexacyclic camptothecin or tetrazobenzamide.
Example 9
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, 20mg of peritinib and 10mg of O4-benzyl folic acid are added, after shaking uniformly again, microspheres for injection containing 20% of peritinib and 10% of O4-benzyl folic acid 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. 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:
(1) 10-40% O4-benzylfolic acid, 2, 4, 5-triamino-6-benzyloxypyrimidine, 2, 4-diamino-6-benzyloxy-5-nitrosopyrimidine, 2, 4-diamino-6-benzyloxy-5-bromopyrimidine, 2-amino-4-benzyloxy-5-nitropyrimidine, 2-amino-4-benzyloxy-6-methyl-5-nitropyrimidine, 2, 4-diamino-6-benzyloxy-s-triazine, or 2-amino-O4-benzylpteridine; or
(2) 10-30% of gefitinib, erlotinib, lapatinib, vatalanib, pelitinib, carboxyamidotriazole, thalidomide, ranolamine, angiostatin, endostatin, imatinib mesylate, semasnib, dasatinib, avastin, canatinib, sorafenib, sunitinib, teosta or panitoma with 10-40% of O4-benzylfolic acid, 2, 4, 5-triamino-6-benzyloxypyrimidine, 2, 4-diamino-6-benzyloxy-5-nitrosopyrimidine, 2, 4-diamino-6-benzyloxy-5-bromopyrimidine, 2-amino-4-benzyloxy-5-nitropyrimidine, 2-amino-4-benzyloxy-6-methyl-5-nitropyrimidine, A combination of 2, 4-diamino-6-benzyloxy-s-triazine or 2-amino-O4-benzylpteridine.
Example 11
70mg of a polifeprosan (p-carboxyphenylpropane (p-CPP): Sebacic Acid (SA) 20: 80) copolymer was placed in a container, 100 ml of dichloromethane was added, after dissolving and mixing uniformly, 10mg of 7-hydroxy-astrosporin and 20mg of dasatinib were added, after shaking uniformly again, microspheres for injection containing 10% of 7-hydroxy-astrosporin and 20% of dasatinib were 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:
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% 7-hydroxy-staurosporine, 7-O-alkyl-staurosporine, β -methoxystaurosporine, alkylphosphocholine or hexadecylphosphocholine.
Example 13
70mg of polylactic acid (PLGA, 50: 50) with a molecular weight peak of 80000 is put into a container, 100 ml of dichloromethane is added, after dissolving and mixing uniformly, 10mg of avastin and 20mg of neopodophyllotoxin are added, after shaking uniformly again, injection microspheres containing 10% of avastin and 20% of neopodophyllotoxin 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 in vitro physiological saline of 25-30 days and the release time under the skin of a mouse of about 35-50 days.
Example 14
The procedure of processing into sustained release implant is the same as in examples 11 and 13, except that the anticancer active ingredient is: 10% gefitinib, erlotinib, lapatinib, vatalanib, pelitinib, carboxyamidotriazole, thalidomide, ranolamine, angiostatin, endostatin, imatinib mesylate, semasnib, dasatinib, avastin, canatinib, sorafenib, sunitinib, teosinte or panitoma in combination with 20% aminotriazole, butylthioxoxime, mability, S-hexyl glutathione, neopropodophyllycin, hexacyclic camptothecin or tetrarylobenzamide.
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 the molecular weight peak value of 5000-10000, 10000-30000, 30000-60000, 60000-100000 or 100000-150000;
b) copolymer (PLGA) of polyglycolic acid and glycolic acid with peak molecular weight of 5000-10000, 10000-30000, 30000-60000, 60000-100000 or 100000-150000, wherein the ratio of polyglycolic acid to glycolic acid is 50-95: 50-50;
c) ethylene vinyl acetate copolymer (EVAc);
d)10:90, 20:80, 30:70, 40:60, 50:50 or 60:40 para-carboxyphenylpropane (p-CPP): sebacic Acid (SA) copolymer (polifeprosan);
e) a di-fatty acid and sebacic acid copolymer;
f) poly (erucic acid dimer-sebacic acid) copolymer;
g) poly (fumaric acid-sebacic acid) copolymer;
h) xylitol, oligosaccharide, chondroitin, chitin, potassium salt, sodium salt, hyaluronic acid, collagen, gelatin or albumin glue;
i) racemic polylactic acid, racemic polylactic acid/glycolic acid copolymer, monomethyl polyethylene glycol/polylactic acid copolymer, polyethylene glycol/polylactic acid copolymer, carboxyl-terminated polylactic acid or carboxyl-terminated polylactic acid/glycolic acid copolymer.
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.
Example 17
The procedure of processing into sustained release injection is the same as in examples 11-15, except that the anticancer active ingredient is:
(a) 1-40% of gefitinib, erlotinib, lapatinib, vatalanib, pelitinib, carboxyamidotriazole, thalidomide, ranolamine, angiostatin, endostatin, imatinib mesylate, semasnib, dasatinib, avastin, canatinib, sorafenib, sunitinib, teosinte or panitoma;
(b) 1-40% of 7-hydroxy-astrosporin, 7-O-alkyl-astrosporin, beta-methoxyastrosporin, alkylphosphocholine or hexadecylphosphocholine;
(c) 1-40% O4-benzylfolic acid;
(d) 1-40% of methoxyamine, hydroxylamine, inositol polyphosphate, aminotriazole or butylthionine sulfoximine;
(e) 1-40% gefitinib, erlotinib, lapatinib, vatalanib, pelitinib, carboxyamidotriazole, thalidomide, ranolamine, angiostatin, endostatin, imatinib mesylate, sematinib, dasatinib, avastin, canatinib, sorafenib, sunitinib, teosinte or panitoma in combination with 1-40% 7-hydroxy-staurosporine, 7-O-alkyl-staurosporine, β -methoxystaurosporine, alkylphosphocholine or hexadecylphosphocholine;
(f) 1-40% gefitinib, erlotinib, lapatinib, vatalanib, pelitinib, carboxyamidotriazole, thalidomide, ranolamine, angiostatin, endostatin, imatinib mesylate, semasnib, dasatinib, avastin, canatinib, sorafenib, sunitinib, teosinte or panitoma in combination with 1-40% O4-benzylfolate;
(g) 1-40% gefitinib, erlotinib, lapatinib, vatalanib, pelitinib, carboxyamidotriazole, thalidomide, ranolamine, angiostatin, endostatin, imatinib mesylate, semasnib, dasatinib, avastin, canatinib, sorafenib, sunitinib, teosinte or panitoma in combination with 1-40% methoxyamine, hydroxylamine, aminotriazole or butylthioninoxime.
The above examples are intended to illustrate, but not limit, the application of the invention.
The invention is disclosed and claimed.

Claims (1)

  1. [ claim 1 ] an anticancer sustained release injection, which consists of the following components:
    (A) a sustained release microsphere comprising:
    anticancer active ingredient
    Sustained release excipients
    And
    (B) the menstruum is common menstruum or special menstruum containing a suspending agent;
    wherein,
    the anticancer active ingredient is a vascular inhibitor and a synergist thereof, and the vascular inhibitor synergist is selected from pyrimidine analogues;
    the components of the slow release injection are as follows:
    the anticancer active components are 20% of pelitinib and 10% of O4-benzyl folic acid, and the slow release auxiliary materials are p-carboxyphenylpropane: sebacic acid is 20: polifeprosan 80, wherein the solvent is normal saline containing 1.5 percent of sodium carboxymethylcellulose, 15 percent of sorbitol and 0.2 percent of Tween 80;
    the above are all weight percentages.
CNA2008103008512A 2006-06-06 2006-06-06 Anticancer sustained-released formulation loaded with blood vessel inhibitor and synergist thereof Pending CN101380304A (en)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114533871A (en) * 2020-11-19 2022-05-27 中国科学院上海营养与健康研究所 Application of targeted PLK3 in preventing and treating skin proliferative diseases

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114533871A (en) * 2020-11-19 2022-05-27 中国科学院上海营养与健康研究所 Application of targeted PLK3 in preventing and treating skin proliferative diseases

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