CN101380299A - Sustained-release injection containing methotrexate and synergist thereof - Google Patents

Sustained-release injection containing methotrexate and synergist thereof Download PDF

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CN101380299A
CN101380299A CNA2008103029684A CN200810302968A CN101380299A CN 101380299 A CN101380299 A CN 101380299A CN A2008103029684 A CNA2008103029684 A CN A2008103029684A CN 200810302968 A CN200810302968 A CN 200810302968A CN 101380299 A CN101380299 A CN 101380299A
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methotrexate
sustained
injection
release
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孙中先
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Jinan Shuaihua Pharmaceutical Technology Co Ltd
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Jinan Shuaihua Pharmaceutical Technology Co Ltd
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Abstract

A slow release injection containing amethopterin 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 common dissolvant or a special dissolvant containing a suspending agent. The anticancer active component is a combination of amethopterin and amethopterin synergist which is selected from platinum compounds, a topoisomerase inhibitor and/or tetrazine compounds; the slow release adjuvant is selected from one or a combination of: polylactic acid, copolymer of polyglycolic acid and hydroxyacetic acid, copolymer of ethylene vinyl acetate, polifeprosan, and copolymer of FAD and sebacic acid; the suspending agent is selected from sodium carboxymethyl cellulose, and the like, and is used for suspending the anticancer active component or the slow release particles or microspheres containing the anticancer active component so as to make the slow release injection. The slow release injection is injected into tumors, which can reduce general toxic reaction of the injection, selectively improve the local drug concentration in the tumors, and enhance the curative effects of non-operative therapies such as radiotherapy, chemotherapy, and the like.

Description

Sustained-release injection containing methotrexate and synergist thereof
(I) technical field
The invention relates to a sustained-release injection containing methotrexate and a synergist thereof and a preparation method thereof, belonging to the technical field of medicaments. Specifically, the invention provides an anticancer drug sustained release preparation containing methotrexate and a synergist thereof.
(II) background of the invention
As a commonly used chemotherapeutic drug, Methotrexate (MTX) has been widely used for the treatment of various malignant tumors, and the effect is more obvious. However, its unexpected neurotoxicity greatly limits the use of this drug. The blood vessels, connective tissues, matrix proteins, fibrin and collagen 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 and in the tumor tissue (see Niti et al, "the influence of extracellular stroma conditions on the drug operation in solid tumors" [ Cancer research, stage 60 2497 and 503 (2000)) (Netti PA, Cancer Res.2000, 60(9):2497 and 503) ], since solid tumors excessively swell and proliferate, the interstitial pressure, tissue elastic pressure, fluid pressure and interstitial viscosity are all higher than those of the surrounding normal tissues, so that conventional chemotherapy is difficult to form effective drug concentration locally, see Kongqing et al, "the treatment of rat brain tumors by placing and adding systemic carmustine in tumors" [ J.S. J.69, 76-82 (1998, Kong Q et al, J., j Surg Oncol.1998 Oct; 69(2) and 76-82), and the simple increase of the administration dosage is limited by the systemic reaction. The problem of drug concentration may be solved to some extent by the local application of drugs, however, the surgical operations such as drug implantation and the like are complicated, the wound is large, and besides various complications such as bleeding, infection, immunity reduction and the like are easily caused, the diffusion and metastasis of tumors can be caused or accelerated. In addition, the preparation itself before and after the operation and the high cost often affect the effective implementation.
In addition, DNA repair function in many tumor cells is significantly increased following chemotherapy. The latter often leads to an increased tolerance of the tumor cells to anticancer drugs, with consequent therapeutic failure.
In addition, low dose anti-cancer drug therapy not only increases drug tolerance but also promotes invasive growth of cancer cells (see beam et al, "increasing drug tolerance and in vitro infiltration capacity of human lung cancer cells with altered gene expression after anti-cancer drug pulse screening" [ J.Immunol.Cancer, 111, et al, pp.484-93 (2004) ] (Liang Y, et al, Int J cancer.2004; 111(4): 484-93)).
Methotrexate is a commonly used anticancer drug and has been widely used for treating various tumors, such as digestive system tumors including gastrointestinal tumors. However, during the application process, the obvious systemic toxicity greatly limits the application of the medicine.
In order to effectively increase the local drug concentration of tumor and reduce the drug concentration in the circulatory system, the slow release system of drug containing methotrexate has been studied, including slow release implants (see: chinese patent nos. ZL96115937.5 and ZL97107077.6 and U.S. Pat. No. 5,651,986). However, the solid sustained-release implant (Chinese patent No. ZL 96115937.5; ZL97107077.6) and the existing sustained-release microspheres for treating brain tumor (ZL00809160.9) or the U.S. Pat. No. 5,651,986 have the problems of difficult operation, poor curative effect, more complications and the like. In addition, many solid tumors are poorly sensitive to anticancer drugs, including methotrexate, and are susceptible to drug resistance during treatment.
Therefore, preparations and methods that facilitate the maintenance of high drug concentrations locally in tumors and increase the sensitivity of tumor cells to drugs have become an important subject of research.
Disclosure of the invention
Aiming at the defects of the prior art, the invention provides a novel sustained-release injection containing methotrexate and/or a methotrexate synergist.
The invention finds that the combination of the drug and the methotrexate can enhance the anticancer effect (hereinafter, the drug which can increase the anticancer effect of the methotrexate is called methotrexate synergist). Besides, the methotrexate or the combination of the methotrexate and the synergist thereof is packaged in a specific sustained-release adjuvant and matched with a special solvent to prepare the anticancer drug sustained-release injection, so that the local drug concentration of tumors can be greatly improved, the drug concentration of the drugs in a circulatory system can be reduced, the toxicity of the drugs 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 above unexpected findings constitute the subject of the present invention.
The slow released anticancer injection consists of slow released microsphere and solvent. Specifically, the anticancer sustained-release injection consists of the following components:
(A) a sustained release microsphere comprising:
0.5-50% of anticancer active ingredient
Sustained release auxiliary materials 50-99%
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 methotrexate and a methotrexate synergist, and the methotrexate synergist is selected from platinum compounds, topoisomerase inhibitors and/or tetrazine compounds; the suspending agent is favorable for suspending the slow-release medicine so as to facilitate injection administration, and is selected from one or the combination of sodium carboxymethylcellulose, (iodine) glycerol, dimeticone, propylene glycol, carbomer, mannitol, sorbitol, Tween 20, Tween 40 and Tween 80.
The proportion of methotrexate in the composition is determined by the particular circumstances, and in general, can be from 0.01% to 55%, preferably from 1% to 50%, and most preferably from 2% to 40%. All are weight percent.
The platinum compound is selected from one or a combination of the following: cisplatin (cisplatin, DDP), Carboplatin (Carboplatin), Cycloplatin (Cycloplatin), heptaplatin (sunoplatin), denaplatin (dacarbazine; dacarbazine), cyclopentamine platinum, platinum blue, cycloproplatin, ethylenediamine-malonic acid platinum, senoplatin, Enloplatin (Enloplatin), sulfoplatine (sulfoplatine-sulfoplatine), sulfoplatine (sulfopodine-sulfoplatine, SHP), cis-spiroplatine (spirosulfoplatine), Dexormaplatin (Dexooplatin), Iproplatin (Iproplatin), Lobaplatin (lotatin, Lobaplatin), miboplatine (miboplatine), picoplatin (picoplatine), Nedaplatin (Nedaplatin), ormoplatin (Ormaplatin), Oxaliplatin (Oxaliplatin ), Spiroplatin (spiplatin), Spiroplatin (spipitaplatin), or spipitaplatin (spipitaplatin).
The platinum compound is preferably cisplatin, carboplatin, ormaplatin, dexormaplatin, heptaplatin, lobaplatin, nedaplatin or oxaliplatin.
The weight percentage of the platinum compound in the composition can be 0.1-50%, preferably 1-30%, and most preferably 5-20%.
The topoisomerase inhibitor is selected from one or a combination of the following: camptothecin (CPT), derivatives of camptothecin, Lurtotecan (Lurtocan), topotecan (10-hydroxy-9-methylenethomethyl (S) -camptothecin, topotecan), irinotecan (IRINOTECT, IRT), 9-nitrocamptothecin (9-nitrocamptothecin, 9NC), 7-ethyl-10-hydroxy-camptothecin (7-ethyl-10-Hydroxycamptothecin, SN-38), 7-ethyl-10- [4- (1-piperidino) -1-piperidino ] carbonylcamptothecin (7-ethyl-10- [4- (1-piperidino) -1-piperidino ] carbonylcamptothecin, CPT-11), 10-hydroxy-camptothecin (10-Hydroxycamptothecin, PT), homocamptothecin (HCdioxy), camptothecin (HCMOTEOXY, HCT-11), MD-CPT), (RS) -methylenedioxycamptothecin (10, 11-MD-20(RS) -CPT), (S) -methylenedioxycamptothecin glycinate (10, 11-MD-20(S) -cpT-glycinate ester (Gly). HCl), 9-amino- (S) -methylenedioxycamptothecin glycinate (9-amino-10, 11-MD-20(S) -CPT-Gly), N- [2- (dimethylamino) ethyl ] piperidine-4-carboxamide (N- [2- (dimethylamino) ethyl ] acridine-4-carboxamide, DACA) and its 5-or 7-substituted derivatives, podophyllotoxin, Etoposide, epipodophyllotoxins, Etoposide, VP-16), and pharmaceutically acceptable salts thereof, Teniposide (Teniposide, etoposide, VM-26), podophyllic acid, podophyllotoxin, trihydroxyisoflavone (Genistein), 14-hydroxydaunorubicin, Amrubicin (Amrubicin), doxorubicin (4 ' - (acridinylamino) methylsufon-m-aniside (amsacrine, m-AMSA)), 4-demethoxydaunorubicin (4-demethoxydaunorubicin), ditobicin, 7-O-methylnocar-4 ' -epirubicin (7-O-methylnocalol-4 ' -epirubicin), Esorubicin (Esorubicin), carrubicin, idarubicin (idarubicin, IDA), Roubicin, Florirubicin (Leurirubicin), medubicin, nemulin (Nemorubicin), Nemourubicin (Nemourubicin), Doxilin (N-trifloxystrobin, N-14-norubicin, 14-trifloxystrobactrubicin, 14-32-D-Adriarubicin, valrubicin), 2- [4- (7-chloro-2-quinoxalinyloxyphenoxy ] -propionic acid ((2- [4- (7-chloro-2-quinoxalinyloxyphenoxy ] -propionic acid, XK469), Zorubicin (Zorubicin), N- (2-chloroethane) -N-nitrosoureidodaunorubicin (N- (2-Chloroethyl) -N-nitrosoneurodaunorubicin, AD312), pyrazolo [1, 5-a ] indole derivatives, such as, but not limited to, GS-2, -3, -4, GS-5, dioxopiperazine derivatives, such as, but not limited to, (+) -1, 2-bis (3, 5-dioxopiperazinyl) propane ((+) -1, 2-bis (3, 5-dioxopiperazinyl-1-yl) propane, ICRF-187), m-2, 3-bis (3, 5-dioxopiperazin-1-yl) butane (meso-2, 3-bis (3, 5-dioxopiperazine-1-yl) butane, ICRF-193), bis-dioxopiperazine (bisdioxopiperazine); suramin (Suramin), Deoxyguanosine (Deoxyguanosine), lithocholic acid (LCA) or sodium azide (sodium azide).
Among the above-mentioned topoisomerase inhibitors, camptothecin, hydroxycamptothecin, lurtotecan, topotecan, irinotecan, etoposide, teniposide, amrubicin, doxorubicin, roxobicin, epirubicin, zorubicin, valrubicin, or idarubicin are preferable.
The proportion of the topoisomerase inhibitor in the composition is determined by the particular circumstances, and in general, it may be from 0.01% to 50%, preferably from 1% to 40%, and most preferably from 5% to 30%. All are weight percent.
The tetrazine compound is selected from one or a combination of the following: imidazotetrazine (imidazotetrazine), imidazopyridine (imidazopyrazine), 1H-imidazopyridine [ b ] piperazine (1H-imidazopyridine [ b ] pyrazine), imidazopyridine (imidazopyridine), 1H-imidazo [1, 2-a ] pyridine (1H-imidazoie [1, 2-a ] pyridine), Procarbazine (PCB), Mitozolamide (MTZ), Dacarbazide (DCB), Temozolomide (Temozolomide or 8-Carbamoyl-3-methylimidazo [5, 1-d ] -1, 2, 3, 5-temozin-4 (3H) -one or NSC 362856)), 4-carboxytemozolomide [4 ] tetrazol ] methyl-3-tetrazolamide ], 4-tetrazolamide [1, 2, 3, 5-methyl-3H ] -2, 3-oxazolylamine (pyrrazine [1, 2-methyl-3, 3-methyl ] pyrrole [1, 2-azolo ] 2, 3-methyl-3-azolidine [3, 5-methyl ] pyrrole [1, 2-3H ] -3-one or (pyrromazine [1, 2-methyl ] pyrrole [3, 3H ] -2-methyl-3-methyl ] pyrrole [1, 2, 3-methyl ] pyrrole (4-3, 3-methyl ] pyrrole [3, 3, 1-d ] [1, 2, 3, 5] tetrazine-4(3H) -ones), pyrrole [2, 1-d ] [1, 2, 3, 5] tetrazine 10a-o (Pyrrolo [2, 1-d ] [1, 2, 3, 5] tetrazinones10a-o), 5- (3-N-methyltriazin-1-yl) -imidazo-4-carboxamide (MTIC, 5- (3-N-methyltriazen-1-yl) -imidazole-4-carboxamide), 8-nitro-3-methylbenzo-1, 2, 3, 5-tetraazepine-4-temozolomide (8-nitro-3-methyl-benzole-1, 2, 3, 5-tetraazepine-4 (3H) -zeone, NIME), 3, 5-dimethyl-pyrido-1, 2, 3, 5-tetraazepin-4-temozolomide (3, 5-dimethyl-pyrido-1, 2, 3, 5-tetrazepin-4-one, PYRZ) or 3- (2-chloroethane) -N, N-dimethyl-4-oxo-3, 4-dihydroimidazo [5, 1-d ] -1, 2, 3, 5-tetrazine-8-carboxamide (3- (2-chloroethyl) -N, N-dimethyl-4-oxo-3, 4-dihydroimido [5, 1-d ] -1, 2, 3, 5-tetrazine-8-carboxamide, CDODTC).
The tetrazine compound is preferably imidazotetrazine, imidazopiperazine, 1H-imidazo [ b ] piperazine, imidazopyridine, 1H-imidazo [1, 2-a ] pyridine, procarbazine, mitozolamide, dacarbazine or temozolomide.
The proportion of the tetrazine compound in the sustained release agent is determined by specific conditions, generally speaking, can be from 0.01% to 55%, preferably from 1% to 40%, and most preferably from 5% to 30%. All are weight percent.
The anticancer active ingredient is methotrexate synergist or the composition of methotrexate and synergist thereof. When the anticancer drug in the drug sustained-release microspheres is only a methotrexate synergist, the anticancer sustained-release injection is mainly used for increasing the effect of methotrexate applied by other ways or enhancing the effect of radiotherapy or other therapies. When used to increase the effect of methotrexate applied by other routes, methotrexate may be administered by arterial, intravenous or local injection, or by placement.
The weight percentage of the anti-tumor drug in the drug sustained-release microspheres is 0.5-60%, preferably 2-40%, and most preferably 5-30%. When used in combination, the weight ratio of the methotrexate to the methotrexate synergist is 1-9: 1 to 1: 1-9, with a molar ratio of 1-2: 1 and 2-1: 1 is preferred, 1: 1 is most preferred.
The anticancer active ingredients in the anticancer sustained-release injection microsphere are preferably as follows, and the weight percentages are as follows:
1-40% methotrexate in combination with 1-40% cisplatin, carboplatin, heptaplatin, dexormaplatin, lobaplatin, nedaplatin, ormaplatin, oxaliplatin or zeniplatin; or
1-40% methotrexate in combination with 1-40% camptothecin, hydroxycamptothecin, lurtotecan, topotecan, irinotecan, etoposide, teniposide, amrubicin, doxorubicin, roxydicin, doxorubicin, zorubicin, valrubicin, or idarubicin; or
1-40% of methotrexate and 1-40% of procarbazine, mitozolomide, nitazoxanide or temozolomide.
Sustained release excipients the sustained release excipients are selected from polylactic acid (PLA), copolymer of polyglycolic acid and glycolic acid (PLGA), ethylene vinyl acetate copolymer (EVAc), polifeprosan, copolymer of FAD and sebacic acid, xylitol, oligosaccharide, chondroitin, chitin, hyaluronic acid, collagen, gelatin and albumin or a combination thereof, wherein preferably polylactic acid (PLA), copolymer of polyglycolic acid and glycolic acid (PLGA), ethylene vinyl acetate copolymer (EVAc), copolymer of FAD and sebacic acid, polifeprosan or a combination thereof.
When polylactic acid (PLA), polyglycolic acid (PGA), a mixture of polylactic acid (PLA) and polyglycolic acid, and a copolymer of glycolic acid and hydroxycarboxylic acid (PLGA) are selected, the contents of PLA and PLGA are 0.1-99.9% and 99.9-0.1% by weight, respectively. The molecular weight peak of polylactic acid may be, but is not limited to, 5000-; the molecular weight of polyglycolic acid may be, but is not limited to, 5000-; the polyhydroxy acids can be selected singly or in multiple ways. When selected alone, polylactic acid (PLA) or a copolymer of hydroxycarboxylic acid and glycolic acid (PLGA) is preferred, and the molecular weight of the copolymer may be, but is not limited to, 5000-; the blending ratio of glycolic acid and hydroxycarboxylic acid is 10/90-90/10 (by weight), preferably 25/75-75/25 (by weight), most preferably 75: 25. 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. When more than one choice is selected, the polymer or the composite polymer or copolymer of different polymers is preferred, and the composite polymer or copolymer of polylactic acid or sebacic acid with different molecular weight is most preferred, such as, but not limited to, polylactic acid with molecular weight of 1000 to 30000 mixed with polylactic acid with molecular weight of 20000 to 50000, polylactic acid with molecular weight of 10000 to 30000 mixed with PLGA with molecular weight of 30000 to 80000, polylactic acid with molecular weight of 20000 to 30000 mixed with sebacic acid, PLGA with molecular weight of 30000 to 80000 mixed with sebacic acid. Among the various polymers, preferred are polylactic acid, sebacic acid, and a mixture or copolymer of polylactic acid and sebacic acid, and the mixture or copolymer can be selected from, but not limited to, PLA, PLGA, a mixture of glycolic acid and hydroxycarboxylic acid, and a mixture or copolymer of sebacic acid and an aromatic polyanhydride or an aliphatic polyanhydride. Representative of aromatic polyanhydrides are polifeprosan [ poly (1, 3-di (P-carboxyphenoxy) propane-sebacic acid) (P (CPP-SA)), difatty acid-sebacic acid copolymer (PFAD-SA) ], poly (erucic acid dimer-sebacic acid) [ P (EAD-SA) ], and poly (fumaric acid-sebacic acid) [ P (FA-SA) ], and the like. The contents of p-carboxyphenoxy propane (p-CPP) and sebacic acid in copolymerization are respectively 10-60 percent and 20-90 percent by weight, and the blending weight ratio is 10-40: 50-90, preferably 15-30: 65-85.
In order to adjust the drug release rate or change other characteristics of the present invention, the monomer component or molecular weight of the polymer can be changed, and the composition and ratio of the pharmaceutical excipients can be added or adjusted, and water-soluble low molecular compounds such as, but not limited to, various sugars or salts can be added. The sugar can be, but is not limited to, xylitol, oligosaccharide, (chondroitin sulfate), chitin, etc., and the salt can be, but is not limited to, potassium salt, sodium salt, etc.
In addition to the above-mentioned adjuvants, other substances may be used as described in detail in U.S. Pat. No. 4757128 (4857311) (4888176 (4789724)) and "pharmaceutical adjuvants" in general (p. 123, published by Sichuan scientific and technical Press 1993, compiled by Luomingsheng and high-tech). In addition, Chinese patent (application No. 96115937.5; 91109723.6; 9710703.3; 01803562.0) and U.S. patent No. 5,651,986) also list some pharmaceutical excipients, including fillers, solubilizers, absorption promoters, film-forming agents, gelling agents, pore-forming agents, excipients or retarders.
The content of the suspending agent depends on the composition, nature and required amount of the medicine suspended in the solvent, the sustained-release microsphere (or microcapsule), the preparation method of the injection, the kind and composition of the suspending agent, for example, the content of sodium carboxymethylcellulose can be 0.5-5%, but is preferably 1-3%, the content of mannitol and/or sorbitol is 5-30%, but is preferably 10-20%, and the content of tween 20, tween 40 or tween 80 is 0.05-2%, but is preferably 0.10-0.5%. In most cases, the sustained-release particles are composed of active ingredients and sustained-release excipients, and the solvent is a special solvent. When the solvent is common solvent, the suspended drug or sustained release microsphere (or microcapsule) is composed of effective components, sustained release adjuvant and/or suspending agent. In other words, when the suspending agent in sustained release particle (A) is "0", solvent (B) is a special solvent, and when the suspending agent in sustained release particle (A) is not "0", solvent (B) can be a common solvent or a special solvent. The viscosity of the suspending agent is 100cp-3000cp (at 20-30 ℃), preferably 1000cp-3000cp (at 20-30 ℃), and most preferably 1500cp-3000cp (at 20-30 ℃).
The common solvent can be, but is not limited to, distilled water, water for injection, physiological saline, absolute ethyl alcohol or buffer solution prepared from various salts, and the pharmacopoeia has corresponding regulations; the special solvent in the invention is a common solvent containing a suspending agent, and the suspending agent can be, but is not limited to, sodium carboxymethylcellulose, (iodine) glycerol, simethicone, propylene glycol, carbomer, mannitol, sorbitol, a surfactant, tween 20, tween 40 and tween 80 or a combination thereof. The content of the suspending agent in the special solvent is 0.1-30% by volume weight, preferably as follows:
(a) 0.5-5% sodium carboxymethylcellulose; or
(b) 0.5-5% sodium carboxymethylcellulose and 0.1-0.5% tween 80; or
(c) 5-20% mannitol; or
(d) 5-20% mannitol and 0.1-0.5% tween 80; or (b).
(e) 0.5-5% of sodium carboxymethylcellulose, 5-20% of sorbitol and 0.1-0.5% of tween 80.
The above-mentioned all are volume weight percentages, and the weight of suspending agent contained in the common solvent of unit volume, such as g/ml, kg/l, the same is used hereinafter.
The preparation of the injection comprises the preparation of sustained release microspheres or drug particles, the preparation of a solvent, the suspension of the sustained release microspheres or drug particles in the solvent and the final preparation of the injection.
Wherein, the sustained release microspheres or drug microparticles can be prepared by several methods: such as, but not limited to, mixing, melting, dissolving, spray-drying to prepare microspheres, dissolving in combination with freeze (dry) milling, liposome encapsulation, and emulsification. Among them, the dissolution method (i.e., solvent evaporation method), the freeze (dry) pulverization method, the drying method, the spray drying method and the emulsification method are preferable. The microspheres can be used for preparing the various sustained-release injections. The particle size of the suspension drug or sustained release microspheres (or microcapsules) is determined by specific needs and can be, but is not limited to, 1-300um, but is preferably 20-200um, and most preferably 30-150 um. The drug or the sustained-release microspheres can be prepared into microspheres, submicron spheres, micro-emulsion, nanospheres, granules or spherical pellets. The slow release auxiliary material is the above-mentioned biocompatible, biodegradable or non-biodegradable polymer.
The preparation of the solvent depends on the kind of the solvent, and common solvents are commercially available or self-made, such as distilled water, water for injection, physiological saline, absolute ethanol or buffers prepared from various salts, but the preparation must strictly follow the relevant standards. The special solvent should be selected from the type and composition of suspending agent, the composition, properties and required amount of the medicine suspended in the solvent, sustained release microsphere (or microcapsule), and the preparation method of injection, for example, sodium carboxymethylcellulose (1.5%) + mannitol andor sorbitol (15%) and/or tween 80 (0.1%) is dissolved in physiological saline to obtain the corresponding solvent with viscosity of 10-650 cp (20-30 deg.C).
The invention discovers that the key factor influencing the suspension and/or injection of the medicament and/or the sustained-release microspheres is the viscosity of the solvent, and the higher the viscosity is, the better the suspension effect is and the stronger the injectability is. This unexpected finding constitutes one of the main exponential features of the present invention. The viscosity of the solvent depends on the viscosity of the suspending agent, and the viscosity of the suspending agent is 100cp-3000cp (at 20-30 ℃), preferably 1000cp-3000cp (at 20-30 ℃), and most preferably 1500cp-3000cp (at 20-30 ℃). The viscosity of the solvent prepared according to the condition is 10cp-650cp (at 20-30 ℃), preferably 20cp-650cp (at 20-30 ℃), and most preferably 60cp-650cp (at 20-30 ℃).
The preparation of injection has several methods, one is that the slow release particles (A) whose suspending agent is '0' are directly mixed in special solvent to obtain correspondent slow release particle injection; the other is that the slow release particles (A) of which the suspending agent is not 0 are mixed in a special solvent or a common solvent to obtain the corresponding slow release particle injection; and the other one is that the slow release particles (A) are mixed in common dissolvent, then suspending agent is added and mixed evenly, and the corresponding slow release particle injection is obtained. Besides, the sustained-release particles (A) can be mixed in special solvent to prepare corresponding suspension, then the water in the suspension is removed by methods such as vacuum drying, and then the suspension is suspended by special solvent or common solvent to obtain the corresponding sustained-release particle injection. The above methods are merely illustrative and not restrictive of the invention. It is noted that the concentration of the suspended drug or the sustained release microspheres (or microcapsules) in the injection may be, but is not limited to, 10-400mg/ml, but is preferably 30-300mg/ml, and most preferably 50-200mg/ml, depending on the particular need. The viscosity of the injection is 50-1000 cp (at 20-30 deg C), preferably 100-1000 cp (at 20-30 deg C), and most preferably 200-650 cp (at 20-30 deg C). This viscosity is suitable for 18-22 gauge needles and specially made needles with larger (to 3 mm) inside diameters.
The application of the injection comprises the application of sustained-release microspheres or drug particles, the application of a solvent and the application of the injection prepared by suspending the sustained-release microspheres or the drug particles in the solvent.
The microsphere is used for preparing sustained release injection, such as suspension sustained release injection, gel injection, and block copolymer micelle injection. Among various injections, a suspension type sustained-release injection is preferable. The suspension type sustained-release injection is a preparation obtained by suspending medicament sustained-release microspheres or medicament particles containing active ingredients in a solvent, the used auxiliary material is one or the combination of the sustained-release auxiliary materials, and the used solvent is a common solvent or a special solvent containing a suspending agent. Common solvent is, but not limited to, distilled water, water for injection, physiological saline, absolute ethyl alcohol or buffer solution prepared by various salts; the block copolymer micelle is formed by a hydrophobic hydrophilic block copolymer in an aqueous solution and has a spherical core-shell structure, wherein the hydrophobic block forms a core, and the hydrophilic block forms a shell. The drug-loaded micelle is injected into the body to achieve the purpose of controlling the release of the drug or targeting therapy. The drug carrier is any one of the above or the combination thereof. The polyethylene glycol (PEG) with the molecular weight of 1000-15000 is preferably used as a hydrophilic block of a micelle copolymer, a biodegradable polymer (such as PLA, polylactide, polycaprolactone and a copolymer thereof (with the molecular weight of 1500-25000) is preferably used as a hydrophobic block of the micelle copolymer, the particle size of the block copolymer micelle can be 1-300um, but 20-200um is preferred, and 30-150um is most preferred, and the gel injection is prepared by dissolving the biodegradable polymer (such as PLA, PLGA or DL-LA and epsilon-caprolactone copolymer) in certain amphiphilic solvent, adding the drug to be miscible (or suspended) to form gel with better fluidity, and injecting the gel around or in tumor.
The application of the solvent mainly refers to the application of the special solvent in effectively suspending, stabilizing and/or protecting various medicines or sustained-release microspheres (or microcapsules) so as to prepare corresponding injections. The application of the special solvent can lead the prepared injection to have better injection property, good stability and higher viscosity.
The injection is prepared by using special solvent with high viscosity to make drug-containing microparticles, especially slow-release microparticles, into corresponding slow-release injection, so that the corresponding drug can be injected into the body of patient or mammal. The injected drug may be, but is not limited to, the above drug fine powder or drug sustained-release fine particles.
The route of administration of the injection depends on various factors. For non-proliferative lesions, intravenous, lymphatic, subcutaneous, intramuscular, intraluminal (e.g., intraperitoneal, thoracic, intraarticular, and intraspinal), intrahistological, intratumoral, peritumoral, elective arterial, intralymph node, and intramedullary injections may be used. For proliferative lesions, such as solid tumors, selective arterial, intraluminal, intratumoral, or peritumoral injection is preferred, although administration can be by the routes described above.
In order to obtain effective concentration at the site of primary or metastatic tumor, it can also be administered by combination of multiple routes, such as intravenous, lymphatic, subcutaneous, intramuscular, intracavity (such as intraperitoneal, thoracic, intraarticular and intraspinal) or selective arterial injection in combination with local injection. Such combination administration is particularly useful for solid tumors. For example, the injection is combined with the systemic injection at the same time of intratumoral injection and peritumoral injection.
The invention can be used for preparing medicaments for treating various tumors of human and animals, and is mainly a sustained-release injection.
The technical scheme of the invention is further described by taking the anti-tumor drug as an example through the following tests and examples:
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, selective arterial, intralymphatic, and intramedullary. Selective arterial, intracavitary, intratumoral, peritumoral injection is preferred.
The invention can be used for preparing medicaments for treating various tumors of human and animals, mainly sustained-release injection, wherein the tumors comprise primary or metastatic carcinoma or sarcoma or carcinosarcoma originated from brain, central nervous system, kidney, liver, gall bladder, head and neck, oral cavity, thyroid gland, 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 microspheres can be used for preparing sustained-release implants for treating various tumors of human and animals.
The sustained-release injection prepared by the invention can also be added with other medicinal components, such as, but not limited to, antibiotics, analgesic, anticoagulant, hemostatic, etc.
The technique of the present invention is further described by the following tests and examples:
test 1 comparison of local drug concentrations of methotrexate after different modes of administration
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 methotrexate in each group was 5 mg/kg. The content (%) of methotrexate in tumors was determined at different times. The results show that the difference of local drug concentration of the methotrexate applied in different modes is obvious, the local administration can obviously improve and effectively maintain the effective drug concentration of the tumor part, and the effect of placing the sustained-release implant in the tumor and injecting the sustained-release injection in the tumor is the best. However, the intratumoral injection of the sustained-release injection is most convenient and easy to operate. The invention not only can greatly improve the drug concentration of local 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 and reduce the complications of the operation. This is further confirmed by the following relevant tumor inhibition test.
Test 2 comparison of in vivo antitumor Effect after administration in different modes
Using white rat as test object, 2X 105Individual prostate tumor cells were injected subcutaneously into the quaternary costal region and divided into the following 9 groups after the tumors had grown to a diameter of 0.5 cm (see table 2). The dose of methotrexate per group was 5mg/kg and 2mg/kgO 6-BG. The volume of the tumor was measured on the 10 th day after the treatment, and the treatment effect was compared.
TABLE 2
Test set (n) Mode of administration Tumor volume (cm)3) P value
1(6) - 70
2(6) Tail vein injection common injection 64 0.06
3(6) Common injection for intraperitoneal injection 63 0.06
4(6) General injection for injection around tumor 55 0.03
5(6) Tumor injection slow-release injection 27 <0.01
6(6) Slow release implant placed around tumor 19 <0.01
7(6) General injection for intratumoral injection 51 0.04
8(6) Sustained-release injection for intratumoral injection 17 <0.001
9(6) Sustained-release implant placed in tumor 15 <0.001
The results show that the difference of the tumor inhibition effect of the methotrexate and the cisplatin applied in different modes is obvious, the tumor inhibition effect can be obviously improved 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. the antitumor effect of methotrexate and methotrexate synergist (sustained release injection)
Using white rat as test object, 2X 105Each breast tumor cell was injected subcutaneously into the costal region of the patient, and the tumor was divided into a negative control (blank), a single drug treatment group, and a combination treatment group 14 days after the tumor had grown. The medicine is injected intratumorally. The dosage is 5 mg/kg. 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 3).
TABLE 3
Test set (n) Is treated by Tumor inhibition ratio (%) P value
1(6) Control -
2(6) Methotrexate (MTX) 58 <0.05
3(6) Cis-platinum 50 <0.01
4(6) Carboplatin 52 <0.01
5(6) Oma platinum 48 <0.01
6(6) Dermatoplatin 52 <0.01
7(6) Methotrexate + cisplatin 82 <0.001
8(6) Methotrexate + carboplatin 86 <0.001
9(6) Methotrexate + ormaplatin 92 <0.001
10(6) Methotrexate + dexomaplatin 90 <0.001
The results show that the used methotrexate and the methotrexate synergist-platinum compounds (cisplatin, carboplatin, ormaplatin and dexormaplatin) 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 methotrexate and methotrexate potentiator
Using white rat as test object, 2X 105Each breast tumor cell was injected subcutaneously into the costal region of the patient, and the tumor was divided into a negative control (blank), a single drug treatment group, and a combination treatment group 14 days after the tumor had grown. The sustained release implant is placed intratumorally. The dosage is 5 mg/kg. The volume of the tumor was measured on the 10 th day after the treatment, and the therapeutic effect was compared using the tumor growth inhibition rate as an index (see Table 4).
TABLE 4
Test set (n) Is treated by Tumor inhibition ratio (%) P value
1(6) Control -
2(6) Methotrexate (MTX) 58 <0.05
3(6) Heptaplatin 50 <0.05
4(6) Lobaplatin 48 <0.05
5(6) Nedaplatin 56 <0.05
6(6) Oxaliplatin 52 <0.01
7(6) Methotrexate + heptaplatin 84 <0.01
8(6) Methotrexate + lobaplatin 80 <0.01
9(6) Methotrexate + nedaplatin 92 <0.01
10(6) Methotrexate + oxaliplatin 94 <0.001
The results show that the used methotrexate and methotrexate synergist-platinum compounds (heptaplatin, lobaplatin, nedaplatin and oxaliplatin) have obvious inhibition effect on the growth of various tumor cells when being singly used at the concentration, and can show obvious synergistic effect when being used in combination
Test 5 antitumor Effect in vivo of methotrexate-containing and methotrexate-potentiating Agents (sustained-release injections)
Using white rat as test object, 2X 105Fine tumor of pancreasCells were injected subcutaneously into the costal region of the tumor and were divided into the following 10 groups 14 days after the tumor growth (see Table 3). The first group was the control, and groups 2 to 10 were the treatment groups, and the drug was injected intratumorally. The dosage is 5 mg/kg. Tumor volume was measured on day 10 after treatment and the treatment effect was compared (see table 5).
TABLE 5
Test set (n) Is treated by Tumor volume (cm)3) P value
1(6) Control 72±10
2(6) Methotrexate (MTX) 48±5.4 <0.05
3(6) Camptothecin 48±2.0 <0.01
4(6) Hydroxycamptothecin 46±2.2 <0.01
5(6) Topotecan 42±3.2 <0.01
6(6) Irinotecan 44±3.0 <0.01
7(6) Methotrexate + camptothecin 22±2.0 <0.001
8(6) Methotrexate + hydroxycamptothecin 30±3.6 <0.001
9(6) Methotrexate + topotecan 32±3.6 <0.001
10(6) Methotrexate + irinotecan 18±2.2 <0.001
The results show that the methotrexate and the methotrexate synergist-topoisomerase inhibitor (camptothecin, hydroxycamptothecin, topotecan and irinotecan) have obvious inhibition effect on the growth of various tumor cells when being used alone at the concentration, and can show obvious synergistic effect when being used together.
Test 6. the antitumor Effect of methotrexate and methotrexate potentiator (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. Methotrexate and methotrexate potentiator were added at a concentration of 10ug/ml to each tumor cell cultured in vitro for 24 hours, and the total number of cells was counted after 48 hours of further culture. The tumor cell growth inhibitory effect is shown in Table 6.
TABLE 6
Tumor cell Methotrexate (MTX) Lurtotecan Etoposide Teniposide Methotrexate + lurtotecan Methotrexate + etoposide Methotrexate + teniposide
CNS 62％ 58％ 64％ 68％ 92％ 88％ 98％
C6 64％ 64％ 60％ 64％ 94％ 84％ 96％
SA 58％ 62％ 56％ 62％ 88％ 92％ 92％
BC 54％ 64％ 54％ 64％ 94％ 84％ 82％
BA 58％ 60％ 62％ 60％ 98％ 92％ 92％
LH 60％ 58％ 62％ 58％ 90％ 88％ 88％
PAT 64％ 54％ 62％ 58％ 92％ 88％ 92％
The results show that the used methotrexate and the methotrexate synergist-topoisomerase inhibitor (lurtotecan, etoposide and teniposide) phosphate 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 show that the methotrexate can also obviously enhance the tumor inhibition effect of other topoisomerase inhibitors, such as amrubicin, evericin, roxydicin, epirubicin, zorubicin, valrubicin, idarubicin and the like.
Test 7. antitumor Effect of methotrexate and methotrexate potentiator
Using white rat as test object, 2X 105Each prostate tumor cell was injected subcutaneously into the quaternary rib area and 14 days after tumor growth was assigned to negative control (blank), single drug treatment (methotrexate or methotrexate potentiating agent) and combination treatment (methotrexate and methotrexate potentiating agent). The medicine is injected intratumorally. The dosage is 5 mg/kg. The volume of the tumor was measured on the 10 th day after the treatment, and the therapeutic effect was compared using the tumor growth inhibition rate as an index (see Table 7).
TABLE 7
Test set (n) Is treated by Tumor inhibition ratio (%) P value
1(6) Control -
2(6) Methotrexate (MTX) 42 <0.05
3(6) Methyl benzyl hydrazine 40 <0.01
4(6) Mitozolomide 36 <0.01
5(6) Azolides 34 <0.01
6(6) Temozolomide 32 <0.01
7(6) Methotrexate + procarbazine 86 <0.001
8(6) Methotrexate + mitozolomide 84 <0.001
9(6) Methotrexate + Azole 86 <0.001
10(6) Methotrexate + temozolomide 92 <0.001
The results show that the used methotrexate and the methotrexate synergist-tetrazine compounds (procarbazine, mitozolomide, dacarbazine and temozolomide) 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 influence of injection viscosity on injectability of sustained-release preparation
Methotrexate is dissolved in a solvent containing suspending agents with different viscosities, and sustained-release injections with different viscosities are prepared according to the method described in the examples 1 to 16. The injectability was then represented by the success (%) of 20 subcutaneous injections in mice. See table 8. The viscosity of the solvent is in the range of 10cp-650 (at 20 ℃ -30 ℃). An equivalent amount of sustained release microspheres (about 25 mg) was suspended in 5 ml of vehicle and injected subcutaneously into mice using a 5 ml syringe with an 18 gauge needle. The time of each injection is 1-2 minutes, and the injection failure is caused when the residual quantity of the medicine in the injector is more than 5 percent after the injection.
TABLE 8
Menstruum viscosity (cp) Number of successful injections Injection success rate (%)
10 1 5
50 2 10
100 4 20
200 7 35
300 9 45
400 12 60
500 14 70
550 14 70
600 16 80
650 18 90
The results show that the main factor influencing the injectability of the injection is the viscosity of the solvent, wherein the success rate of the solvent with the viscosity of 400 to 650cp is more than 50 percent. This finding constitutes a further main feature of the present invention. Trial 8 was repeated with a 22 gauge needle to give the same results.
In conclusion, the used methotrexate and various methotrexate 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 in combination. Therefore, the active ingredient of the invention is the combination of methotrexate and any methotrexate 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.
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 the mixture is dissolved and mixed evenly, 20mg of methotrexate and 10mg of cisplatin are added, the mixture is shaken again evenly, and then the spray drying method is used for preparing the microspheres for injection containing 20% of methotrexate and 10% of cisplatin. 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 2.
The procedure of the process for preparing the sustained-release injection is the same as that of example 1, except that the anticancer active ingredients are:
(1) 5-30% methotrexate; or
(2) A combination of 2-40% methotrexate with 1-30% cisplatin, carboplatin, ormaplatin, dexormaplatin, heptaplatin, lobaplatin, nedaplatin or oxaliplatin.
Example 3.
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 the mixture is dissolved and mixed evenly, 10mg of methotrexate and 10mg of camptothecin are added, the mixture is shaken again and evenly, and then the spray drying method is used for preparing the microspheres for injection containing 10% of methotrexate and 10% of camptothecin. 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 in vitro physiological saline of 15-25 days and the release time under the skin of a mouse of about 30-40 days.
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) 2-40% methotrexate; or
(2) 2-40% methotrexate in combination with 5-30% camptothecin, hydroxycamptothecin, lurtotecan, topotecan, irinotecan, etoposide, teniposide, amrubicin, doxorubicin, roxydicin, doxorubicin, zorubicin, valrubicin, or idarubicin.
Example 5.
70mg of polylactic acid (PLGA, 75: 25) with a molecular weight peak of 25000 is put into a container, 100 ml of dichloromethane is added, after dissolving and mixing evenly, 15mg of methotrexate and 15mg of nedaplatin are added, shaking up again and vacuum drying is carried out to remove the organic solvent. Freeze-pulverizing the dried solid composition containing drug to obtain fine powder containing 10% methotrexate and 10% nedaplatin, and suspending in physiological saline containing 1.5% sodium carboxymethylcellulose to obtain corresponding suspension type sustained-release injection. The slow release injection has the release time in vitro physiological saline of 10-15 days and the release time under the skin of a mouse of about 30-35 days.
Example 6
The steps of the method for processing the sustained-release injection are the same as the example 5, but the difference is that the anticancer active ingredients and the weight percentage thereof are as follows: a combination of 2-40% methotrexate with 2-40% cisplatin, carboplatin, ormaplatin, dexormaplatin, heptaplatin, lobaplatin, nedaplatin or oxaliplatin.
Example 7.
Putting 70mg of ethylene-vinyl acetate copolymer (EVAc) into a container, adding 100 ml of dichloromethane, dissolving and uniformly mixing, adding 20mg of methotrexate and 10mg of temozolomide, shaking uniformly again, and preparing microspheres for injection containing 20% of methotrexate and 10% of temozolomide 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 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) 2-40% methotrexate; or
(2) 2-40% methotrexate in combination with 2-40% imidazotetrazine, imidazopiperazine, 1H-imidazo [ b ] piperazine, imidazopyridine, 1H-imidazo [1, 2-a ] pyridine, procarbazine, mitozolomide, dacarbazine or temozolomide.
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 the mixture is dissolved and mixed evenly, 20mg of methotrexate and 10mg of etoposide are added, after the mixture is shaken again evenly, the microspheres for injection containing 20% of methotrexate and 10% of etoposide 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) 2-40% methotrexate; or
(2) 2-40% methotrexate in combination with 5-30% camptothecin, hydroxycamptothecin, lurtotecan, topotecan, irinotecan, etoposide, teniposide, amrubicin, doxorubicin, roxydicin, doxorubicin, zorubicin, valrubicin, or idarubicin.
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 the mixture is dissolved and mixed evenly, 10mg of camptothecin and 20mg of methotrexate are added, the mixture is shaken again evenly, and then the spray drying method is used for preparing the microspheres for injection containing 10% of camptothecin and 20% of methotrexate. 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 2-40% methotrexate with 2-40% camptothecin, hydroxycamptothecin, lurtotecan, topotecan, irinotecan, etoposide, teniposide, amrubicin, doxorubicin, roxydicin, doxorubicin, zorubicin, valrubicin, or idarubicin.
Example 13
70mg of polylactic acid (PLA) with the molecular weight peak value of 35000 is put into a container, 100 ml of dichloromethane is added, after the mixture is dissolved and uniformly mixed, 10mg of methotrexate and 20mg of mitozolomide are added, and after the mixture is uniformly shaken again, the microspheres for injection containing 10% of methotrexate and 20% of mitozolomide are prepared by a spray drying method. Then the microspheres are prepared into the corresponding sustained-release implant by a tabletting method. The slow release implant has the release time of 10-15 days in vitro physiological saline and the release time of about 35-50 days under the skin of a mouse.
Example 14
The procedure of processing into sustained release implant is the same as in examples 11 and 13, except that the anticancer active ingredient is: a combination of 10% methotrexate with 20% imidazotetrazine, imidazopiperazine, 1H-imidazo [ b ] piperazine, imidazopyridine, 1H-imidazo [1, 2-a ] pyridine, procarbazine, mitozolomide, dacarbazine or temozolomide.
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 5000-30000, 30000-60000, 60000-100000 or 100000-150000;
b) copolymer (PLGA) of polyglycolic acid and glycolic acid with peak molecular weight of 5000-30000, 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);
d) FAD and Sebacic Acid (SA) copolymer;
e) xylitol, oligosaccharide, chondroitin, chitin, potassium salt, sodium salt, hyaluronic acid, collagen, gelatin or albumin glue.
Example 16
The procedure for preparing a sustained release injection is the same as in examples 1 to 15, except that the suspending agent used is one or a combination of the following:
a) 0.5-3.0% carboxymethylcellulose (sodium);
b) 5-15% mannitol;
c) 5-15% sorbitol;
d) 0.1-1.5% of surface active substances;
e) 0.1-0.5% tween 20.
Example 17
80mg of polylactic acid (PLGA, 75: 25) with a molecular weight peak of 25000 is put into a container, 100 ml of dichloromethane is added, after dissolving and mixing evenly, 10mg of oxaliplatin and 10mg of methotrexate are added, shaking up again and vacuum drying is carried out to remove the organic solvent. Freeze-pulverizing the dried drug-containing solid composition to obtain methotrexate micropowder containing 10% oxaliplatin and 10%, 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 10-15 days in-vitro physiological saline and the release time of about 20-30 days under the skin of a mouse.
Example 18.
The procedure of processing into sustained release injection is the same as in examples 1 to 17, except that the anticancer active ingredient is:
(a) 15% methotrexate; or
(b) A combination of 15% methotrexate with 10% cisplatin, carboplatin, ormaplatin, dexormaplatin, heptaplatin, lobaplatin, nedaplatin, or oxaliplatin; or
(c) A combination of 15% methotrexate with 15% camptothecin, hydroxycamptothecin, lurtotecan, topotecan, irinotecan, etoposide, teniposide, amrubicin, doxorubicin, roxydicin, doxorubicin, zorubicin, valrubicin, or idarubicin; or
(d) A combination of 15% methotrexate with 15% procarbazine, mitozolomide, dacarbazine or temozolomide.
Example 19.
The procedure for processing into sustained-release injections was the same as in examples 1 to 18, except that:
the slow release auxiliary material is selected from one or the combination of the following materials:
a) polylactic acid with the molecular weight peak value of 10000-;
b) the molecular weight peak value of the copolymer of polyglycolic acid and glycolic acid is 10000-30000, 30000-60000, 60000-100000 or 100000-150000, wherein the proportion of the polyglycolic acid and the glycolic acid is 75: 25;
c) FAD and sebacic acid copolymer;
d) para-carboxyphenylpropane (p-CPP) in polifeprosan: sebacic Acid (SA) 10: 90. 20: 80. 30: 70. 40: 60. 50: 50 or 60: 40;
the viscosity of the suspending agent is 100cp-2000cp (at 20-30 ℃), and the suspending agent is selected from one or the combination of the following components:
a) 1% sodium carboxymethylcellulose;
b) 10% mannitol;
c) 5% sorbitol;
d) 0.3% tween 20;
e) 1% sodium carboxymethylcellulose + 0.5% Tween 80;
f) 12% mannitol + 0.5% Tween 80;
g) 1.5% sodium carboxymethylcellulose, 10% sorbitol and 0.5% Tween 80;
h) 1% sodium carboxymethylcellulose, 15% mannitol and 0.5% Tween 20.
The above examples are intended to illustrate, but not limit, the application of the invention.
The invention is disclosed and claimed.

Claims (4)

  1. The sustained-release injection containing methotrexate for anticancer drugs, according to claim 1, is characterized in that the sustained-release injection comprises 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 menstruum is common menstruum or special menstruum containing a suspending agent;
    wherein,
    the anticancer active ingredient is the combination of methotrexate and methotrexate synergist selected from topoisomerase inhibitor;
    the topoisomerase inhibitor is selected from one or a combination of camptothecin, hydroxycamptothecin, lurtotecan, topotecan, irinotecan, etoposide, teniposide, amrubicin, doxorubicin, roxobicin, epirubicin, zorubicin, valrubicin, and idarubicin;
    the slow release auxiliary material is one or the combination of the following materials:
    a) polylactic acid with the molecular weight peak value of 5000-30000, 30000-60000, 60000-100000 or 100000-150000;
    b) the copolymer of polyglycolic acid and glycolic acid with the peak value of 5000-30000, 30000-60000, 60000-100000 or 100000-150000, wherein the proportion of polyglycolic acid and glycolic acid is 50-95: 50-5;
    c) ethylene vinyl acetate copolymers;
    d) 10: 90. 20: 80. 30: 70. 40: 60. 50: 50 or 60: 40 p-carboxyphenylpropane: sebacic acid copolymer (polifeprosan);
    e) FAD and sebacic acid copolymer;
    f) xylitol, oligosaccharide, chondroitin, chitin, potassium salt, sodium salt, hyaluronic acid, collagen, gelatin or albumin;
    the viscosity of the suspending agent is 100cp-3000cp (at 20-30 ℃), and the suspending agent is selected from one or the combination of the following components:
    a) 0.5-3.0% carboxymethylcellulose (sodium);
    b) 5-15% mannitol;
    c) 5-15% sorbitol;
    d) 0.1-1.5% of surface active substances;
    e) 0.1-0.5% tween 20;
    f) (iodine) glycerol, dimethicone, propylene glycol or carbomer;
    g) 0.5-5% of sodium carboxymethylcellulose and 0.1-0.5% of Tween 80;
    h) 5-20% of mannitol and 0.1-0.5% of Tween 80; or
    i)0.5 to 5 percent of sodium carboxymethylcellulose, 5 to 20 percent of sorbitol and 0.1 to 0.5 percent of Tween 80.
  2. The sustained-release injection of anticancer drug according to claim 1, characterized in that the anticancer active ingredients of the sustained-release injection of anticancer drug are:
    1-40% methotrexate in combination with 1-40% camptothecin, hydroxycamptothecin, lurtotecan, topotecan, irinotecan, etoposide, teniposide, amrubicin, doxorubicin, roxydicin, doxorubicin, zorubicin, valrubicin, or idarubicin;
    the above are all weight percentages.
  3. The sustained-release anticancer injection according to claim 1, wherein:
    the anticancer active ingredients in the anticancer sustained-release injection are as follows:
    a combination of 15% methotrexate with 15% camptothecin, hydroxycamptothecin, lurtotecan, topotecan, irinotecan, etoposide, teniposide, amrubicin, doxorubicin, roxydicin, doxorubicin, zorubicin, valrubicin, or idarubicin; or
    The slow release auxiliary material is selected from one or the combination of the following materials:
    a) polylactic acid with the peak value of molecular weight of 30000-60000;
    b) the peak value of molecular weight of the copolymer of polyglycolic acid and glycolic acid is 30000-60000, wherein the ratio of polyglycolic acid to glycolic acid is 75: 25;
    c) FAD and sebacic acid copolymer;
    d) p-carboxyphenylpropane in polifeprosan: sebacic acid is 20: 80;
    the viscosity of the suspending agent is 100cp-2000cp (at 20-30 ℃), and the suspending agent is selected from one or the combination of the following components:
    a) 1% sodium carboxymethylcellulose;
    b) 10% mannitol;
    c) 5% sorbitol;
    d) 0.3% tween 20;
    e) 1% sodium carboxymethylcellulose + 0.5% Tween 80;
    f) 12% mannitol + 0.5% Tween 80;
    g) 1.5% sodium carboxymethylcellulose, 10% sorbitol and 0.5% Tween 80;
    h) 1% sodium carboxymethylcellulose, 15% mannitol and 0.5% Tween 20.
  4. The sustained-release anticancer injection according to claim 1, wherein:
    the anticancer active ingredients in the anticancer sustained-release injection are as follows:
    a combination of 15% methotrexate with 15% camptothecin, hydroxycamptothecin, lurtotecan, topotecan, irinotecan, etoposide, teniposide, amrubicin, doxorubicin, roxydicin, doxorubicin, zorubicin, valrubicin, or idarubicin; or
    The slow release auxiliary material is selected from one or the combination of the following materials:
    a) polylactic acid with a molecular weight peak of 60000-100000;
    b) a copolymer of polyglycolic acid and glycolic acid having a molecular weight peak of 60000-100000, wherein the ratio of polyglycolic acid to glycolic acid is 75: 25;
    c) FAD and sebacic acid copolymer;
    d) p-carboxyphenylpropane in polifeprosan: sebacic acid is 20: 80.
    the suspending agent has the viscosity of 100cp-2000cp (at the temperature of 20-30 ℃), and is selected from one of the following components:
    a) 1% sodium carboxymethylcellulose;
    b) 10% mannitol;
    c) 5% sorbitol;
    d) 0.3% tween 20;
    e) 1% sodium carboxymethylcellulose + 0.5% Tween 80;
    f) 12% mannitol + 0.5% Tween 80;
    g) 1.5% sodium carboxymethylcellulose, 10% sorbitol and 0.5% Tween 80;
    h) 1% sodium carboxymethylcellulose, 15% mannitol and 0.5% Tween 20.
CNA2008103029684A 2006-01-23 2006-01-23 Sustained-release injection containing methotrexate and synergist thereof Pending CN101380299A (en)

Priority Applications (1)

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Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CNA2008103029684A CN101380299A (en) 2006-01-23 2006-01-23 Sustained-release injection containing methotrexate and synergist thereof

Related Parent Applications (1)

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Publications (1)

Publication Number Publication Date
CN101380299A true CN101380299A (en) 2009-03-11

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Family Applications (1)

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Country Status (1)

Country Link
CN (1) CN101380299A (en)

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