CN101380303A - Anti-cancer medicine sustained-released injection loaded with platinum compound and synergist thereof - Google Patents

Anti-cancer medicine sustained-released injection loaded with platinum compound and synergist thereof Download PDF

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CN101380303A
CN101380303A CNA2008103008480A CN200810300848A CN101380303A CN 101380303 A CN101380303 A CN 101380303A CN A2008103008480 A CNA2008103008480 A CN A2008103008480A CN 200810300848 A CN200810300848 A CN 200810300848A CN 101380303 A CN101380303 A CN 101380303A
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release
platinum compound
acid
sustained
slow release
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孔庆忠
张红军
俞建江
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Shandong Lanjin Pharmaceuticals Co Ltd
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Shandong Lanjin Pharmaceuticals Co Ltd
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Abstract

A anticarcinogenic slow release injection carrying platinum compounds and a synergist thereof is composed of slow release microspheres and a dissolvant, wherein, 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 component comprises platinum compounds such as sunpla, dicycloplatin, eptaplatin, (cis-amminedichloro(2-methylpyridine) platinum, camphoramine chloroacetic platinum or picoplatin, and the like, and a cytotoxic drug selected from a phosphoinositide 3-kinase inhibitor, pyrimidine analogue and/or a DNA repair enzyme inhibitor; the slow release adjuvant is biocompatible macromolecules such as polylactic acid and copolymer thereof, polyethylene glycol, carboxyl end polylactic acid copolymer, copolymer of dienoic fatty acid and sebacic acid, poly (erucic acid dimer-sebacic acid), poly (fumaric acid-sebacic acid), polifeprosan, polylactic acid, EVAc, and the like, and the suspending agent has the viscosity of 100cp-3,000cp (at the temperature of 20-30 DEG C) and is selected from sodium carboxymethyl cellulose, and the like. The slow release microspheres can also be made into a slow release implant. The slow release injection is injected or placed in tumors or around the tumors, which can improve the curative effects of non-operative therapies such as radiotherapy, chemotherapy, and the like.

Description

Anticancer drug sustained-release injection loaded with platinum compound and synergist thereof
(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 platinum compounds and synergists thereof, which mainly comprises 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 platinum compound sustained-release agent. Specifically, the invention provides an anticancer drug sustained release agent containing platinum compounds and synergists thereof, which mainly comprises a sustained release injection and a sustained release implant.
The platinum compound is used as a new anti-cancer 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 can be mutually enhanced by combining with the platinum compound, and the drugs which can mutually enhance the anticancer effect of the platinum compound are called platinum compound synergist hereinafter, mainly cytotoxic drugs; in addition, the platinum compound or the platinum compound synergist is prepared into the anti-cancer drug sustained-release preparation (mainly a sustained-release injection and a sustained-release implant), so that the drug concentration of local tumor can be greatly improved, the drug concentration of the drug in a circulatory system can be reduced, the toxicity of the drug to normal tissues can be reduced, the drug injection can be greatly facilitated, the complications of surgical operation can be reduced, and the cost of patients can be reduced. The anticancer medicine can inhibit tumor growth and raise the sensitivity of tumor cell to anticancer medicine. The above unexpected findings constitute the subject of the present invention.
One form of the platinum compound sustained release preparation is sustained release injection, which consists of sustained 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 ingredients are platinum compounds and synergists thereof, and the platinum compound synergists are selected from phosphoinositide 3-kinase (PI3K) inhibitors, pyrimidine analogues and/or DNA repair enzyme inhibitors; 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 platinum group anticancer drugs are mainly administered by oral administration or intravenous injection and other conventional routes, the administration mode of the invention is local slow release administration, and the systemic toxicity effect of the drugs is obviously reduced while the treatment effect of the drugs is obviously enhanced. The reported platinum compounds applied by a slow release way comprise cisplatin, carboplatin and the like, however, after thousands of existing platinum compounds are screened, only 28 compounds enter clinical research, 4 compounds are approved to enter the market, and 2-3 compounds can obtain production documents. Therefore, in the platinum compounds with anticancer activity, not all of them can achieve the slow release effect of effective release in the slow release auxiliary materials of the invention. The medicinal auxiliary materials are more than hundreds of medicinal auxiliary materials with slow release effect, particularly, the platinum compounds selected in the invention can be slowly released in human bodies or animal bodies within a certain time period, which is not obvious, and the selection of the specific slow release auxiliary materials and the slow release medicines can be determined only by a great deal of creative labor. The related data, particularly the data of the release characteristics in animals, can be obtained through a large number of creative experiments in vivo and in vitro, can not be determined through limited experiments, and is non-obvious.
The platinum compound selected in the invention is mainly selected from sulplatin (sunpla), dicycloplatin (bicycloplatin), eptaplatin (eptalatin), picoplatin, cerriplatin (citricplatin) and picoplatin (picoplatin).
The proportion of the platinum compound in the composition may be, depending on the particular case, from 0.1% to 50%, preferably from 1% to 30%, most preferably from 5% to 20%.
The proportion of the platinum compound 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-hexadecyl-2-omega-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 platinum compound 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 platinum compound is locally injected, and the platinum compound synergist is applied in other ways;
(2) the slow release injection containing the synergist of the platinum compound is locally injected, and the platinum compound is applied in other ways;
(3) locally injecting a slow-release injection containing a platinum compound and a slow-release injection containing a synergist of the platinum compound; or
(4) A sustained release injection comprising a platinum compound and a potentiating agent is topically 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 platinum compound synergist in the drug sustained-release microspheres is 0.5-60%, preferably 1-40%, and most preferably 5-30%. The weight ratio of the platinum compound to the platinum compound 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:
(1) 1-40% of sulplatin, dicycloplatin, eptaplatin, picoplatin, rubiplatin or picoplatin;
(2) 1-40% of a combination of sulplatin, dicycloplatin, eptaplatin, picoplatin, rubiplatin or picoplatin with 1-40% of 7-hydroxy-astrosporin, 7-O-alkyl-astrosporin, β -methoxyastrosporin, alkylphosphocholine or hexadecylphosphocholine;
(3) 1-40% of a combination of sulplatin, dicycloplatin, eptaplatin, picoplatin, cerivaplatin or picoplatin with 1-40% of O4-benzylfolate, 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
(4) 1-40% of sulplatin, dicycloplatin, eptaplatin, picoplatin, cerivaplatin or picoplatin and 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 choline phosphate, hexakis (N-N-N-trimethyl) hexanolamine, octadecyl choline phosphate, Combinations of octadecyl- [2- (N-methylpiperidine) ethyl ] -phosphate, aminotriazole, or butylthioiolithromycin.
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:
(1) 1-40% of sulplatin, dicycloplatin, eptaplatin, picoplatin, rubiplatin or picoplatin;
(2) 1-40% of a combination of sulplatin, dicycloplatin, eptaplatin, picoplatin, rubiplatin or picoplatin with 1-40% of 7-hydroxy-astrosporin, 7-O-alkyl-astrosporin, β -methoxyastrosporin, alkylphosphocholine or hexadecylphosphocholine;
(3) 1-40% of a combination of sulplatin, dicycloplatin, eptaplatin, picoplatin, cerivaplatin or picoplatin with 1-40% of O4-benzylfolate, 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
(4) 1-40% of sulplatin, dicycloplatin, eptaplatin, picoplatin, cerivaplatin or picoplatin and 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 choline phosphate, hexakisdecyl (N-N-N-trimethyl) hexanolamine, octadecyl choline phosphate, Combinations of octadecyl- [2- (N-methylpiperidine) ethyl ] -phosphate, aminotriazole, or butylthioiolithromycin.
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 platinum compound 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 platinum-based Compounds (eptaplatin)
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 is 5mg/kg of eptaplatin. 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 eptaplatin 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.
Experiment 2, comparison of in vivo tumor-inhibiting action of platinum compounds (dicycloplatin) applied in different ways
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 dose was 5mg/kg dicycloplatin. 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 dicycloplatin after different modes of application is obvious, the local administration can be obviously improved, and the effective vitaminThe effective drug concentration of the tumor part is kept, wherein 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.
Test 3 in vivo antitumor Effect of platinum-containing Compound and platinum-Compound synergist (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) Platinum compound 52±5.0 <0.05
3(6) UCN-01 54±2.0 <0.01
4(6) UCN-02 48±2.4 <0.01
5(6) MIL 56±5.2 <0.01
6(6) D-21266 42±3.0 <0.01
7(6) Platinum compound + UCN-01 22±2.2 <0.001
8(6) Platinum compound + UCN-02 34±3.6 <0.001
9(6) Platinum compound + MIL 32±3.2 <0.001
10(6) Platinum compound + D-21266 20±2.2 <0.001
The results show that the platinum compound (Shu platinum) and the platinum compound synergist-phosphoinositide 3-kinase (PI3K) inhibitor (wherein UCN-01: 7-hydroxide radical-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 jointly used.
Test 4. antitumor Effect of platinum Compound and platinum Compound 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. Adding platinum compound and platinum compound synergist into various tumor cells cultured in vitro for 24 hr at a concentration of 10ug/ml, and counting the total number of cells after culturing for 48 hr. The tumor cell growth inhibitory effect is shown in Table 2.
TABLE 2
Tumor cell Xializatinu (platinum) O4-BA UCN-01 UCN-02 Xializatin + O4-BA Xializatin + UCN-1 Xializatin + 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 platinum compound (Xializatin) and the platinum compound synergist (O4-BA: O4-benzyluric acid; UCN-01: 7-hydroxyl-astrosporin; 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 platinum Compound and platinum Compound 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) Platinum compound 50±2.2 <0.01
4(6) ilmofosine + platinum compound 32±2.6 <0.001
5(6) AMG-PC 48±3.2 <0.01
6(6) AMG-PC + platinum compound 22±3.0 <0.001
7(6) edelfosine 32±2.6 <0.01
8(6) Edelfosine + platinum compound 22±2.4 <0.001
9(6) IDOU 32±3.4 <0.01
10(6) IDOU + platinum compound 18±2.2 <0.001
The results show that the used platinum compound (picoplatin) and the platinum compound 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 have obvious synergistic effects when being used in combination.
Test 6. antitumor Effect of platinum Compound and platinum Compound synergist (sustained Release injection)
Using white rat as test object, 2X 105Each prostate tumor cell was injected subcutaneously into the quaternary costal region and was classified into a negative control (blank), a monotherapy group (platinum compound or platinum compound synergist) and a combination therapy group (platinum compound and platinum compound synergist) after the tumor had grown for 14 days. The platinum compound is injected intratumorally, and the platinum compound 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) Platinum compound 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) Platinum compound + imidazopiperazine 88 <0.001
8(6) Platinum compound + imidazopyridine 80 <0.001
9(6) Platinum compound + wortmannin 82 <0.001
10(6) Platinum compound + benzopyran 84 <0.001
The results show that the platinum compound (sulplatin) and the platinum compound synergist-DNA-dependent protein kinase inhibitor (wherein, the imidazopiperazine, 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 jointly.
Test 7. antitumor Effect of platinum Compound and platinum Compound 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 platinum compound is injected into the abdominal cavity, and the platinum compound synergist is injected around 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 5).
TABLE 5
Test set (n) Is treated by Tumor inhibition ratio (%) P value
1(6) Control -
2(6) Platinum compound 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) Platinum compound + LY294002 88 <0.001
8(6) Platinum compound + SU11752 96 <0.001
9(6) Platinum compound + SN-38 92 <0.001
10(6) Platinum compound + OK-1035 92 <0.001
The results show that the platinum compound (dicycloplatin) and the platinum compound synergist-DNA-dependent protein kinase inhibitor (LY 294002: 2- (4-morpholino) -8-phenylchromone; SU 11752: 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 applied independently at the concentration, and can show obvious synergistic effect when being applied jointly.
Test 8 antitumor Effect of platinum Compound and platinum Compound 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) Platinum compound 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) Platinum compound + methoxyamine 82 <0.01
8(6) Platinum compound + minocycline 74 <0.01
9(6) Platinum compound + hydroxylamine 84 <0.01
10(6) Platinum compound + O-methylhydroxylamine 88 <0.001
The results show that the platinum compound (picoplatin) and the platinum compound synergist-DNA-dependent protein kinase 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 jointly applied.
Test 9 tumor inhibition Effect of platinum Compound and platinum Compound synergist (sustained Release implant)
The tumor-inhibiting effect of the platinum compound and the synergist (sustained release implant) of the platinum compound was determined 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) Platinum compound 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) Platinum compound +3-AB 78 <0.001
8(6) Platinum compound + benzamide 76 <0.001
9(6) Platinum compound + PD128763 84 <0.001
10(6) Platinum compound + AG14361 80 <0.001
The results show that the platinum compound (sulplatin) and the platinum compound 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 platinum Compound and platinum Compound synergist (sustained Release injection)
The tumor-inhibiting action of the platinum compound and the synergist (sustained release implant) of the platinum compound was measured as described in test 8, and the tumor growth inhibition rate thereof is shown in table 8.
TABLE 8
Test set (n) Is treated by Tumor inhibition ratio (%) P value
1(6) Control -
2(6) Platinum compound 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) Platinum compound + BZ1-6 78 <0.001
8(6) Platinum compound + TI1-5 80 <0.001
9(6) Platinum compound + TBC 76 <0.001
10(6) Platinum compound + benzimidazole 90 <0.001
The results show that the platinum compound (eptaplatin) and the platinum compound 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 platinum-based Compound and/or platinum-based Compound potentiator (sustained Release implant)
The tumor-inhibiting effect of the platinum compound and/or the platinum compound 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) Platinum compound 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) Platinum compound + NU1025 88 <0.001
8(6) Platinum compound + PBC 82 <0.001
9(6) Platinum compound + MPBC 78 <0.001
10(6) Platinum compound + NU1085 90 <0.001
The above results show that the platinum compound (picoplatin) and the platinum compound 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) have significant inhibitory effects on the growth of various tumor cells when used alone, and have significant synergistic effects when used in combination.
Test 12 antitumor Effect of platinum-based Compound and/or platinum-based Compound potentiator (sustained Release implant)
The tumor-inhibiting effect of the platinum compound and/or the platinum compound 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) Platinum compound 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) Platinum compound + BSO 84 <0.001
8(6) Platinum compound + aminotriazole 84 <0.001
9(6) Platinum compound + puffball acid 78 <0.001
10(6) Platinum compound + neopodophyllotoxin 88 <0.001
The results show that the platinum compound (sulplatin) and the platinum compound synergist-poly (ADP-ribose) polymerase inhibitor (wherein BSO is butylthioninoxime) 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.
Experiment 13, comparison of in vivo Release of eptaplatin sustained Release implants made of polylactic acid of different molecular weights
Rats were used as subjects, and divided into groups (3/group) and subcutaneously administered equal amounts of sustained release implants containing polylactic acid (PLA) carriers of different Molecular Weights (MW). Then, the remaining amount of the drug in the implant was measured on days 1, 3, 7, 14, 21, 28 and 35, respectively, to obtain 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 in vivo release of eptaplatin implants made of polylactic acid of different molecular weights, it was found that the release was slowed down with increasing molecular weight, and the bacterial inhibition was increased with increasing molecular weight of polylactic acid, as compared to the systemic administration group, at day 7, in the order of 68% (MW: 5000), 66% (MW: 15000), 54% (MW: 25000), 50% (MW: 40000) and 48 (MW: 60000).
The same result is also seen in the sustained release agent of the rubiadin, the picoplatin, the sulplatin and the dicycloplatin which are prepared by taking the polylactic acid as the auxiliary material.
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 platinum compound and various platinum compound 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 jointly. Therefore, the effective component of the invention is any one (or more than one) platinum compound and/or any one (or more than one) platinum compound 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) 20: 80) copolymer is put into a container, 100 ml of dichloromethane is added, after dissolving and mixing uniformly, 10mg of eptaplatin and 7-hydroxide radical-astrosporin are added, after shaking uniformly again, microspheres for injection containing 10% of eptaplatin and 10% of 7-hydroxide radical-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 sulplatin, dicycloplatin, eptaplatin, picoplatin, rubiplatin or picoplatin;
(2) 1-40% of a combination of sulplatin, dicycloplatin, eptaplatin, picoplatin, rubiplatin or picoplatin with 1-40% of 7-hydroxy-astrosporin, 7-O-alkyl-astrosporin, β -methoxyastrosporin, alkylphosphocholine or hexadecylphosphocholine;
(3) 1-40% of a combination of sulplatin, dicycloplatin, eptaplatin, picoplatin, cerivaplatin or picoplatin with 1-40% of O4-benzylfolate, 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
(4) 1-40% of sulplatin, dicycloplatin, eptaplatin, picoplatin, cerivaplatin or picoplatin and 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 choline phosphate, hexakis (N-N-N-trimethyl) hexanolamine, octadecyl choline phosphate, Combinations of octadecyl- [2- (N-methylpiperidine) ethyl ] -phosphate, aminotriazole, or butylthioiolithromycin.
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 is put into a container, 100 ml of dichloromethane is added, after dissolving and mixing evenly, 15mg of cerivalate and 15mg of 7-ethyl-10-hydroxycamptothecin are added, shaking is carried out again evenly, and vacuum drying is carried out to remove the organic solvent. Freeze-pulverizing the dried solid composition containing the medicine to obtain micropowder containing 15% of rubiplatinum and 15% of 7-ethyl-10-hydroxycamptothecin, and suspending in physiological saline containing 1.5% of sodium carboxymethylcellulose to obtain the corresponding 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: 1-40% of sulplatin, dicycloplatin, eptaplatin, picoplatin, cerivaplatin or picoplatin and 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 choline phosphate, hexakisdecyl (N-N-N-trimethyl) hexanolamine, octadecyl choline phosphate, Combinations of octadecyl- [2- (N-methylpiperidine) ethyl ] -phosphate, aminotriazole, or butylthioiolithromycin.
Example 5.
70mg of ethylene vinyl acetate copolymer (EVAc) is put into a container, 100 ml of dichloromethane is added to dissolve and mix evenly, 20mg of picoplatin and 10mg of benzimidazole are added, the mixture is shaken up again, and then the spray drying method is used to prepare the microspheres for injection containing 20% picoplatin and 10% benzimidazole. 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: 1-40% of sulplatin, dicycloplatin, eptaplatin, picoplatin, rubiplatin or picoplatin in combination with 1-40% of 7-hydroxy-astrosporin, 7-O-alkyl-astrosporin, beta-methoxyastrosporin, alkylphosphocholine or hexadecylphosphocholine.
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 the mixture is dissolved and mixed uniformly, 20mg of sulplatin and 10mg of butylthionine sulfoximine are added, the mixture is shaken uniformly again, and then the spray drying method is used for preparing the microspheres for injection containing 20% of sulplatin and 10% of butylthionine sulfoximine. 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: 1-40% of eptaplatin, cerivalate, picoplatin, sulplatin or dicycloplatin in combination with 2-40% of glutathione disulfide, tetramethylthiuram disulfide, aminotriazole, butylthioneoxime, puffball acid, S-hexyl glutathione, neopropodophyllin, hexacyclic camptothecin or tetrarylbenzamide.
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, 20mg of dicycloplatin and 10mg of O4-benzyl folic acid are added after being dissolved and mixed evenly, and the microspheres for injection containing 20% of dicycloplatin and 10% of O4-benzyl folic acid are prepared by a spray drying method after being shaken evenly again. 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:
10-30% of eptaplatin, cerivalate, picoplatin, sulplatin or dicycloplatin in combination 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, 2, 4-diamino-6-benzyloxy-s-triazine or-2-amino-O4-benzylpteridine.
Example 11
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 7-hydroxyl-astrosporin and 20mg of Shuplatinum are added, after shaking uniformly again, microspheres for injection containing 10% of 7-hydroxyl-astrosporin and 20% of Shuplatinum are prepared by a spray drying method. Then the microspheres are prepared into the corresponding sustained-release implant by a tabletting method. The slow release implant has the release time of 10-15 days in-vitro physiological saline and the release time of about 30-40 days under the skin of a mouse.
Example 12
The procedure of processing into a sustained-release implant was the same as in example 11, except that the anticancer active ingredient contained therein was: a combination of 20% eptaplatin, rubiplatin, picoplatin, sulplatin or dicycloplatin 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 eptaplatin and 20mg of neopodophyllotoxin are added, after shaking uniformly again, injection microspheres containing 10% of eptaplatin 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: a combination of 10% eptaplatin, cerivalate, picoplatin, sulplatin or dicycloplatin with 20% aminotriazole, butylthionine oxime, puffball acid, S-hexyl glutathione, neopodophyllomycin, hexacyclic camptothecin or tetrarylbenzamide.
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:
(1) 1-40% of sulplatin, dicycloplatin, eptaplatin, picoplatin, rubiplatin or picoplatin;
(2) 1-40% of a combination of sulplatin, dicycloplatin, eptaplatin, picoplatin, rubiplatin or picoplatin with 1-40% of 7-hydroxy-astrosporin, 7-O-alkyl-astrosporin, β -methoxyastrosporin, alkylphosphocholine or hexadecylphosphocholine;
(3) 1-40% of a combination of sulplatin, dicycloplatin, eptaplatin, picoplatin, cerivaplatin or picoplatin with 1-40% of O4-benzylfolate, 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
(4) 1-40% of sulplatin, dicycloplatin, eptaplatin, picoplatin, cerivaplatin or picoplatin and 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 choline phosphate, hexakis (N-N-N-trimethyl) hexanolamine, octadecyl choline phosphate, Combinations of octadecyl- [2- (N-methylpiperidine) ethyl ] -phosphate, aminotriazole, or butylthioiolithromycin.
The above examples are intended to illustrate, but not limit, the application of the invention.
The invention is disclosed and claimed.

Claims (1)

  1. The claim 1 discloses an anticancer sustained-release injection loaded with platinum compounds and synergists thereof, 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 ingredients are platinum compounds and synergists thereof, and the synergists of the platinum compounds are selected from phosphoinositide 3-kinase inhibitors;
    the components of the slow release injection are as follows:
    the effective anticancer components are 10mg of eptaplatin and 7-hydroxide radical-stellacyclosporine, and the slow release auxiliary materials are p-carboxyphenylpropane: sebacic acid is 20:80 polifeprosan, wherein the solvent is physiological saline containing 15 percent of mannitol;
    the above are all weight percentages.
CNA2008103008480A 2006-06-21 2006-06-21 Anti-cancer medicine sustained-released injection loaded with platinum compound and synergist thereof Pending CN101380303A (en)

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8168661B2 (en) 2006-11-06 2012-05-01 Poniard Pharmaceuticals, Inc. Use of picoplatin to treat colorectal cancer
US8168662B1 (en) 2006-11-06 2012-05-01 Poniard Pharmaceuticals, Inc. Use of picoplatin to treat colorectal cancer
US8173686B2 (en) 2006-11-06 2012-05-08 Poniard Pharmaceuticals, Inc. Use of picoplatin to treat colorectal cancer
US8178564B2 (en) 2006-11-06 2012-05-15 Poniard Pharmaceuticals, Inc. Use of picoplatin to treat colorectal cancer

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8168661B2 (en) 2006-11-06 2012-05-01 Poniard Pharmaceuticals, Inc. Use of picoplatin to treat colorectal cancer
US8168662B1 (en) 2006-11-06 2012-05-01 Poniard Pharmaceuticals, Inc. Use of picoplatin to treat colorectal cancer
US8173686B2 (en) 2006-11-06 2012-05-08 Poniard Pharmaceuticals, Inc. Use of picoplatin to treat colorectal cancer
US8178564B2 (en) 2006-11-06 2012-05-15 Poniard Pharmaceuticals, Inc. Use of picoplatin to treat colorectal cancer

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