CN101380298A - Methotrexate sustained-release injection - Google Patents

Methotrexate sustained-release injection Download PDF

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CN101380298A
CN101380298A CNA200810302967XA CN200810302967A CN101380298A CN 101380298 A CN101380298 A CN 101380298A CN A200810302967X A CNA200810302967X A CN A200810302967XA CN 200810302967 A CN200810302967 A CN 200810302967A CN 101380298 A CN101380298 A CN 101380298A
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methotrexate
release
sustained
injection
combination
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高化兰
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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 amethopterin injection 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 suspending agent is selected from one or a combination of sodium carboxymethyl cellulose, mannitol, sorbierite and Tween 80. The anticancer active components include amethopterin or a combination of the amethopterin and amethopterin synergist which is selected from antimitotic drugs and/or an alkylating agent; the slow release adjuvant is selected from one or a combination of polylactic acid, copolymer of ethylene vinyl acetate, polifeprosan, FAD, sebacic acid copolymer, and copolymer of polyglycolic acid and glycolic acid; 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 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

Methotrexate sustained-release injection
(I) technical field
The invention relates to a sustained-release injection containing methotrexate and a preparation method thereof, belonging to the technical field of medicaments.
(II) background of the invention
Methotrexate is a commonly used anticancer drug and has been widely used for treating various tumors, such as nervous system tumors including brain 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.
As a common chemotherapeutic drug, methotrexate is widely applied to the treatment of various malignant tumors, and the effect is obvious. However, its unexpected neurotoxicity greatly limits the use of this drug. Blood vessels, connective tissues, matrix proteins, fibrin, collagen and the like 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 the condition of extracellular stroma on drug transport in solid tumors" [ Cancer research ] No. 60, No. 2497, No. 503 (2000)) (NettiPA, Cancer Res.2000, No. 60(9): No. 2497, No. 503)). Due to the fact that solid tumors are over-swollen and hyperplastic, the interstitial pressure, the tissue elastic pressure, the fluid pressure and the interstitial viscosity are higher than those of the surrounding normal tissues, therefore, the effective drug concentration is difficult to form locally in the tumor in conventional chemotherapy, see Kongqingzhong et al, "cisplatin and systemic carmustine can be placed in the tumor to treat the brain tumor of rats" [ J. Ou. Oncao. (1998) J. Surg. Oncol.19980ct (Kong Q et al; 69(2):76-82), and the simple increase of the administration dose 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, repair function in many tumor cells is significantly increased after 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)).
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.
One form of the methotrexate sustained release preparation of the invention is sustained release injection, which consists of sustained release microspheres and dissolvent. Specifically, the anticancer sustained-release injection consists of the following components:
(A) a sustained release microsphere comprising:
0.5-60% of anticancer active ingredient
Sustained release auxiliary materials 40-99%
0.0 to 30 percent of suspending agent
The above are weight percentages
And
(B) the solvent is common solvent or special solvent containing suspending agent.
Wherein,
the anticancer active ingredient is methotrexate or the combination of methotrexate and methotrexate synergist selected from antimitotic drugs andor alkylating agents; the sustained release adjuvant is selected from polylactic acid (PLA), polyglycolic acid and glycolic acid copolymer (PLGA), ethylene vinyl acetate copolymer (EVAc), polifeprosan, FAD: one or a combination of Sebacic Acid (SA) copolymer, xylitol, oligosaccharide, chondroitin, chitin, potassium salt, sodium salt, hyaluronic acid, collagen, gelatin and egg gelatin; 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.
Anti-mitotic drugs will stop tumor cells at different stages of the cell cycle. The antimitotic drug is selected from the group consisting of cytochalasin (podophyllotoxin), ethacrylatine chloride, ellipticine, methylellipticine, mitochloramine (Mitoclomine), mitolapone (mitoflumoxone), Mitoguazone (Mitoguazone), mitonaphthylamine (Mitonafide), mitohydrazine (mitopozide), mitoquinolones (mitoquinolones), mitosapropsie (Mitosper), Mitotane (Mitotane), mitonaramine (Mitotenamine), Mitozolomide (Mitozolomide), mitopyrone, Colchicine salicylate (colchical), Colchicine (Colchicine), thiocolchicine (thiocolchicine), Colchicine (demeclochicine), Colchicine (Colchicine), narcissus (1-carbachol), narcisone (beta-naphthoic acid), beta-naphthoic acid (E), betanaphthoic acid (E), meclol, mecloline (E), mecloline (methamphetamine, meclol), mecloline (E-1, mecloline (mecloline, meclo, Alpha-naphthol phosphate (1-naphthylphosphate), malonate, ecodazole (Acodazole), propiconazole (Procodazol), arsenicum (arsenic trioxide), Giracodazole (Giracodazole), nocodazole (nocodazole), malonic acid or malonate.
The above antimitotic drugs also include salts such as, but not limited to, sulfate, phosphate, hydrochloride, lactobionate, acetate, aspartate, nitrate, citrate, purine or pyrimidine salts, succinate, maleate, and the like.
The antimitotic drug is preferably cytochalasin, mitochloramine, mitoxantone, mitoguazone, mitonaphthylamine, mitohydrazine, mitoquinolone, mitospertine, mitotane, mitonamine, mitozolomide, mitopyrone, colchicine salicylate, colchicine, cytochalasin, naphthol, alpha-naphthol, beta-naphthol, alpha-naphthol phosphate, aconazole, propiconazole, arsenicum, giradazole, and nocodazole.
The weight percentage of the antimitotic drug in the sustained release agent can be 0.01-80%, preferably 1-50%, and most preferably 5-30%.
The alkylating agent is selected from one or a combination of the following: cyclophosphamide (CTX), Melphalan (Melphalan), meclizine (chlorembucil), 4H-peroxycyclophosphamide (4H-CTX), Ifosfamide (Ifosfamide, apine), tris-mustard cyclophosphamide, sultamide (sulfofamide), desphosphoramide (defufamide), macsfamide (Mafosfamide), Perfosfamide (perffamide), triamcinolone (Trofosfamide), carbazone sulfamide, metafamam (metamlfalan), methylmethane (formmelphalan), hexamethylmelamine (hexamethymellamine), amantanone, thymopentin, clomiphene, letrozole, sodium cantharidine, cantharidine (cantharidine), sodium methamphetamine, hydroxycarbaridine (Norcantharidin), thiocolchicine, Melphalan, tresulosin, tresultam (Treosulfan), thimod, thifluzine, trimethopamide (sulfamethamine), trimethopamide (sulfamethamine, trimethoprim, thidine, thidin, mechlorethamine, thidin (trimethoprim), mechlorethamine, thidin, thimidine, thiiramine, thimide, thiiramide, thiira, Triazinimidazolamine, enrofloxacin, epipipidine, butenol imine, ethodimorph, glycoluril, ethylenimine, Etoglucid, benomyl ammonium, diproponimine, pipobromazine, Pipobroman, Piposulfan, pirlimacin, bipaturon, reotroxerutine, sodium cyclamate, rofecoxib, larninone, tris (hydroxymethyl) triazine, uratan, nordiphenylhydrazide hydrochloride, nordiphenylhydrazide, canonine (triethyleneterelamine), piperazine epoxide (epoxypiperine), benzotepa (Benzodepa), puripeline (pumitepapa), Meturedepa (Meturedepa), azatepa (azatepa), retere (Uredepa) or salts thereof.
The alkylating agent is preferably cyclophosphamide, melphalan, oncoclonine, ifosfamide, 4H-peroxycyclophosphamide, cyclophosphamide, macsfamide, cyclophosphamide, hexamethyl-pyriminone, cantharidin, norcantharidin, mannosylfan, trooshusuo, ritrosufen, improsulfan, etogrel, pipobroman, piposulfan, canonin, epoxy piperazine, benzotepa, purepipipa, meltutepa, uretepa or azatepa.
Salts of the above alkylating agents include: sulphate, phosphate, hydrochloride, lactobionate, acetate, aspartate, nitrate, citrate, purine or pyrimidine salt, succinate or maleate.
The weight percentage of the alkylating agent in the sustained-release agent is 0.01-99.99%, preferably 1-50%, and most preferably 5-30%.
The weight percentage of the anticancer drug in the drug sustained-release microspheres is 0.5-60%, preferably 2-40%, and most preferably 5-30%. The weight ratio of the methotrexate to the methotrexate synergist is 1-9: 1 to 1: 1-9.
The anticancer active ingredients in the anticancer sustained-release microspheres of the invention preferably have the following weight percentages:
(a) 5-30% methotrexate; or
(b) 5-30% of methotrexate 5-30% of a combination of cytochalasin, mitochloramine, mitolaranone, mitoguanhydrazone, mitonaphthylamine, mitohydrazine, mitoquinolone, mitosappan, mitotane, mitonaramin, mitozolomide, mitopyrone, colchicine salicylate, colchicine, cytochalasin, naphthol, alpha-naphthol, beta-naphthol, alpha-naphthol phosphate, ecodazole, propidazole, arsenicum, giradazole or nocodazole; or
(c) 5-30% methotrexate in combination with 5-30% cyclophosphamide, melphalan, tumorigenin, ifosfamide, 4H peroxycyclophosphamide, cyclophosphamide, macsfamide, perfosfamide, hexamethyl pyrimethanil, cantharidin, norcantharidin, mannosuman, troosulfan, ritrosufan, improsulfan, etoglut, pipobroman, piposulfan, canonin, oxidopiperazine, zotepa, purothipine, meltupipa, uretepa or azatepa.
The weight percentage of the anticancer active ingredients in the anticancer sustained-release microspheres is most preferably as follows:
(a) 10-20% methotrexate; or
(b) 10-20% of methotrexate 10-20% of a combination of cytochalasin, mitochloramine, mitolaranone, mitoguanhydrazone, mitonaphthylamine, mitohydrazine, mitoquinolone, mitosappan, mitotane, mitonaramin, mitozolomide, mitopyrone, colchicine salicylate, colchicine, cytochalasin, naphthol, alpha-naphthol, beta-naphthol, alpha-naphthol phosphate, ecodazole, propidazole, arsenicum, giradazole or nocodazole; or
(c) 10-20% methotrexate in combination with 10-20% cyclophosphamide, melphalan, tumorigenin, ifosfamide, 4H peroxycyclophosphamide, cyclophosphamide, macsfamide, phosphoramide, hexamethyl pyrimethanil, cantharidin, norcantharidin, mannosuman, troosulfan, ritrosufan, improsulfan, etoglut, pipobroman, piposulfan, canonin, epoxy piperazine, zotepa, purothipine, meltupipa, uretepa or azatepa.
The sustained release excipients are various high molecular polymers, wherein a mixture or copolymer of polylactic acid, sebacic acid, and high molecular polymers containing polylactic acid or sebacic acid is preferred, 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 aromatic polyanhydride or aliphatic polyanhydride. The blending ratio of glycolic acid and hydroxycarboxylic acid is 10/90-90/10 (by weight), preferably 25/75-75/25 (by weight). The method of blending is arbitrary. The contents of glycolic acid and hydroxycarboxylic acid in copolymerization are 10-90 wt% and 90-10 wt%, respectively. Representative of aromatic polyanhydrides are polifeprosan [ poly (1, 3-di (P-carboxyphenoxy) propane-sebacic acid) (P (CPP-SA)), di-fatty acid-sebacic acid copolymer (PFAD-SA) ], poly (erucic acid dimer-sebacic acid) [ P (EAD-SA) ], and poly (fumaric acid-sebacic acid) [ P (FA-SA) ], and the like. The 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 sustained release excipient is preferably one or a combination of polylactic acid (PLA), polyglycolic acid and glycolic acid copolymer (PLGA), ethylene vinyl acetate copolymer (EVAc), FAD: SA copolymer and polifeprosan.
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-; 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.
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.
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 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 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, 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, granules, spheres, chunks, needles, rods, columns, and films. Among various dosage forms, slow release implants in vivo are preferred.
The optimal dosage form of the sustained-release implant is biocompatible, degradable and absorbable sustained-release implant, and can be prepared into various shapes and various dosage forms according to different clinical requirements. The packaging method and procedure for its main ingredients are described in detail in US patent (US5651986) and include several methods for preparing sustained release formulations: such as, but not limited to, (i) mixing a carrier support powder with a drug and then compressing into an implant, a so-called mixing process; (ii) melting the carrier support, mixing with the drug to be packaged, and then cooling the solid, the so-called melt process; (iii) dissolving the carrier support in a solvent, dissolving or dispersing the drug to be packaged in a polymer solution, followed by evaporation of the solvent and drying, a so-called dissolution method; (iv) spray drying; and (v) freeze-drying method.
The invention can be used for preparing pharmaceutical preparations for treating various tumors of human and animals, and is mainly a sustained-release injection or a sustained-release implant. The prepared tumors comprise various solid tumors. Including primary or metastatic, originating in the brain and central nervous system; and various solid tumors of extracranial origin, such as primary or metastatic cancers of kidney, liver, gall bladder, head and neck, oral cavity, thyroid, skin, mucosa, glands, blood vessels, bone tissue, lymph nodes, lung, esophagus, stomach, breast, pancreas, eye, nasopharynx, uterus, ovary, endometrium, cervix, prostate, bladder, colon, rectum, or sarcomas or carcinosarcomas, with brain tumors, kidney cancers, head and neck tumors, thyroid cancers, lung cancers, esophageal cancers, stomach cancers, breast cancers, pancreatic cancers, cervical cancers, ovarian cancers, prostate cancers, bladder cancers, colorectal primary or metastatic cancers being preferred.
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. Can be injected or placed in or around tumor during or before operation; can be applied simultaneously with or separately before and after radiation and systemic chemotherapy, but the slow release implant is preferably injected or placed in or around tumor.
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 aspects of the present invention are further described by the following tests and examples:
test 1 comparison of local drug concentrations after different modes of methotrexate application
Using white rat as test object, 2X 105Individual prostate tumor cells were injected subcutaneously into the quaternary costal region and divided into groups after tumors had grown to 1 cm diameter. The dose of each group was 5 mg/kg. The content (%) of the drug in the tumor was measured 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. 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 improve the drug concentration of local tumorThe discovery that drug injection can be greatly facilitated and complications of surgical procedures are reduced 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 antitumor Effect of methotrexate
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 each group was 5 mg/kg. The volume of the tumor was measured on the 10 th day after the treatment, and the treatment effect was compared.
TABLE 2
Test set (n) Mode of administration Tumor volume (cm)3) P value
1(6) - 70
2(6) Tail vein injection common injection 68 0.05
3(6) Common injection for intraperitoneal injection 64 0.05
4(6) General injection for injection around tumor 56 0.04
5(6) Tumor injection slow-release injection 34 <0.01
6(6) Slow release implant placed around tumor 22 <0.01
7(6) General injection for intratumoral injection 52 0.03
8(6) Sustained-release injection for intratumoral injection 20 <0.001
9(6) Sustained-release implant placed in tumor 18 <0.001
The results show that the difference of the tumor inhibition effect 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. Not only has good curative effect, but also has little toxic and side effect.
Experiment 3, antitumor effect in vivo of methotrexate and methotrexate 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 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 3).
TABLE 3
Test set (n) Is treated by Tumor volume (cm)3) P value
1(6) Control 60±10
2(6) Methotrexate (MTX) 42±5.4 <0.05
3(6) Colchicine 46±2.0 <0.01
4(6) Beta-naphthols 40±2.2 <0.01
5(6) Acodazole 44±3.2 <0.01
6(6) Cytochalasin 40±3.0 <0.01
7(6) Methotrexate + colchicine 32±2.0 <0.001
8(6) Methotrexate + beta-naphthol 30±1.8 <0.001
9(6) Methotrexate + ecodazole 34±3.0 <0.001
10(6) Methotrexate + cytochalasin 18±2.2 <0.001
The results show that the methotrexate and the methotrexate synergist antimitotic drugs (colchicine, cytochalasin, beta-naphthol and ecodazole) 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 4. antitumor Effect of methotrexate and methotrexate potentiator
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 4.
TABLE 4
Tumor cell Methotrexate (MTX) Propiodazole Arsenic white Nocodazole Methotrexate + propiodazole Methotrexate + arsenic trioxide Methotrexate + nocodazole
CNS 46％ 46％ 60％ 56％ 92％ 88％ 94％
C6 44％ 54％ 60％ 60％ 94％ 89％ 90％
SA 38％ 52％ 52％ 62％ 86％ 90％ 92％
BC 34％ 54％ 50％ 60％ 92％ 84％ 88％
BA 38％ 50％ 58％ 62％ 92％ 90％ 90％
LH 40％ 48％ 58％ 56％ 90％ 84％ 88％
PAT 50％ 48％ 54％ 50％ 92％ 88％ 90％
The results show that the used methotrexate and methotrexate synergist-antimitotic drugs (propiconazole, arsenicum and nocodazole) 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 in combination.
Test 5. antitumor Effect of methotrexate and methotrexate potentiator
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 5). 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 5).
TABLE 5
Test set (n) Is treated by Tumor volume (cm)3) P value
1(6) Control 60±10
2(6) Cyclophosphamide 42±5.0 <0.05
3(6) Methotrexate (MTX) 36±2.0 <0.01
4(6) Cyclophosphamide and methotrexate 24±1.4 <0.001
5(6) Melphalan 38±2.0 <0.01
6(6) Melphalan + methotrexate 24±2.0 <0.001
7(6) Medicine for curing tumor 36±3.0 <0.01
8(6) Tuokening plus methotrexate 18±2.0 <0.001
9(6) Isocyclophosphamide (ACS) 40±4.6 <0.01
10(6) Ifosfamide + methotrexate 18±1.8 <0.001
The results show that the used methotrexate and the methotrexate synergist-alkylating agent (cyclophosphamide, melphalan, oncoclonine and ifosfamide) have obvious inhibition effect on the growth of various tumor cells when being used at the concentration alone, and can show obvious synergistic effect when being used in combination.
Test 6. the antitumor Effect of methotrexate and methotrexate potentiator (sustained-release injection)
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 6).
TABLE 6
Test set (n) Is treated by Tumor inhibition ratio (%) P value
1(6) Control -
2(6) Methotrexate (MTX) 48 <0.05
3(6) 4H-peroxycyclophosphamide 46 <0.01
4(6) Diphosphamide 36 <0.01
5(6) Malachite 42 <0.01
6(6) Pesphamide 46 <0.01
7(6) Methotrexate + 4H-peroxycyclophosphamide 92 <0.001
8(6) Methotrexate + desphosphamide 80 <0.001
9(6) Methotrexate + macosphamide 86 <0.001
10(6) Methotrexate + pexanide 90 <0.001
The results show that the used methotrexate and the methotrexate synergist alkylating agent (4H-cyclophosphamide peroxide, cyclophosphamide, and phosphoramide) have obvious inhibition effect on the growth of various tumor cells when being used at the concentration alone, and can show obvious synergistic effect when being used in combination.
Test 7. 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 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) 56 <0.05
3(6) Hexamethyl pyrimidine 52 <0.01
4(6) Cantharidin 46 <0.01
5(6) Norcantharidin 42 <0.01
6(6) Ganloushufan 46 <0.01
7(6) Methotrexate + hexametholamine 86 <0.001
8(6) Methotrexate + cantharidin 80 <0.001
9(6) Methotrexate + norcantharidin 92 <0.001
10(6) Methotrexate and manna soothing fan 82 <0.001
The results show that the used methotrexate and the methotrexate synergist-alkylating agent (hexamethyl-pyrimethanil, cantharidin, norcantharidin and mannosulfan) 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.
Experiment 8, the antitumor action of methotrexate and methotrexate synergist (sustained release implant)
Using white rat as test object, 2X 105Each breast tumor cell was injected subcutaneously into the costal region of the patient, and the tumor was divided into a negative control (blank), a single drug treatment group, and a combination treatment group 14 days after the tumor had grown. The sustained release implant is placed intratumorally. The dosage is 5 mg/kg. The volume of the tumor was measured on the 10 th day after the treatment, and the therapeutic effect was compared using the tumor growth inhibition rate as an index (see Table 8).
TABLE 8
Test set (n) Is treated by Tumor inhibition ratio (%) P value
1(6) Control -
2(6) Methotrexate (MTX) 52 <0.05
3(6) Quaoshufan 40 <0.05
4(6) Litreshufan 42 <0.05
5(6) Yingpropylshufan 52 <0.05
6(6) Etogelu 60 <0.01
7(6) Methotrexate + trooshusufen 78 <0.01
8(6) Methotrexate + littreufan 82 <0.01
9(6) Methotrexate + Yingpropylshufan 88 <0.01
10(6) Methotrexate + etoglut 82 <0.001
The results show that the used methotrexate and the methotrexate synergist-alkylating agent (trooshusan, ritrosufan, improsulfan and etoglut) 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 in combination.
Test 9. antitumor Effect of methotrexate and methotrexate potentiator
Methotrexate and methotrexate synergist sustained release implant) were tested as described in test 8, and the tumor growth inhibition rates are shown in table 9.
TABLE 9
Test set (n) Is treated by Tumor inhibition ratio (%) P value
1(6) Control -
2(6) Methotrexate (MTX) 58 <0.05
3(6) Aining medicine for treating cancer 42 <0.01
4(6) Epoxy piperazine 32 <0.01
5(6) Uretipipa 32 <0.01
6(6) Azatipipa 44 <0.01
7(6) Methotrexate + cancinonin 80 <0.001
8(6) Methotrexate + epoxy piperazine 70 <0.001
9(6) Methotrexate + uredepa 92 <0.001
10(6) Methotrexate + azatepa 90 <0.001
The results show that the used methotrexate and the methotrexate synergist-alkylating agent (canning, epoxy piperazine, uretepa and azatepa) 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 in combination.
Test 10 Effect of injection viscosity on injectability of sustained Release formulations
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 10. The viscosity of the solvent is in the range of 10cp-650cp (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.
Watch 10
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 10 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. The viscosity of the solvent influences the injectability of the injection, and the success rate of the solvent with the viscosity of 300 to 650cp is higher. 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 or 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.
90, 90 and 80mg of polifeprosan (p-carboxyphenylpropane (p-CPP): Sebacic Acid (SA) is 20: 80) copolymer is respectively put into three containers of A, B and C, then 100 ml of dichloromethane is added into each copolymer, after dissolving and mixing evenly, 10mg of methotrexate, 10mg of colchicine, 10mg of methotrexate and 10mg of colchicine are respectively added, after shaking up again, the injection microspheres containing 10% of methotrexate, 10% of colchicine, 10% of methotrexate and 10% of colchicine 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) 5-30% methotrexate; or
(2) 5-30% methotrexate in combination with 5-30% of cytochalasin, mitochloramine, mitoralenone, mitoguanzone, mitonaphthylamine, mitohydrazine, mitoquinolone, mitosappan, mitotane, mitonaramin, mitozolomide, mitopyrone, colchicine salicylate, colchicine, cytochalasin, naphthol, alpha-naphthol, beta-naphthol, alpha-naphthol phosphate, ecodazole, propidazole, arsenicum, giradazole, or nocodazole.
Example 3.
70mg of polylactic acid (PLGA, 75: 25) with a molecular weight peak of 25000 is respectively put into three containers, namely, a container (A), a container (B) and a container (C), then 100 ml of dichloromethane is added into each container, after the materials are dissolved and uniformly mixed, 30mg of methotrexate, 30mg of cyclophosphamide, 15mg of methotrexate and 15mg of cyclophosphamide are respectively added into the three containers, after shaking up again, the injection microspheres containing 30% of methotrexate, 30% of cyclophosphamide, 15% of methotrexate and 15% of cyclophosphamide are prepared by a spray drying method. Suspending the dried microspheres in physiological saline containing 1.5 percent of sodium carboxymethylcellulose 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 4
The steps of the method for processing the sustained-release injection are the same as the example 3, but the difference is that the anticancer active ingredients and the weight percentage thereof are as follows:
(1) 5-30% cyclophosphamide, melphalan, meclizine, ifosfamide, 4H-peroxycyclophosphamide, cyclophosphamide, macsfamide, phosphoramide, hexamethyl-pyriminone, cantharidin, norcantharidin, mannosuman, trooshusuo, ritrosufan, improsulfan, etoglut, pipobroman, piposulfan, canonin, epoxy piperazine, benzotepa, purepipipa, metotepipa, uretepa, or azatepa; or
(2) 5-30% methotrexate in combination with 5-30% cyclophosphamide, melphalan, tumorigenin, ifosfamide, 4H peroxycyclophosphamide, cyclophosphamide, macsfamide, perfosfamide, hexamethyl pyrimethanil, cantharidin, norcantharidin, mannosuman, troosulfan, ritrosufan, improsulfan, etoglut, pipobroman, piposulfan, canonin, oxidopiperazine, zotepa, purothipine, meltupipa, uretepa or azatepa.
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 methotrexate and 10mg of aristodazole are added, after shaking up again, the injection microspheres containing 20% of methotrexate and 10% of aristodazole are prepared by a spray drying method. Then suspending the microspheres in injection containing 5-15% of sorbitol to prepare the corresponding suspension type sustained-release injection. The slow release injection has the release time of 10-15 days in-vitro physiological saline and the release time of about 20-30 days under the skin of a mouse.
Example 6.
The procedure of the process for preparing the sustained-release injection is the same as that of example 5, except that the anticancer active ingredients are:
(1) 10-20% methotrexate; or
(2) 10-20% methotrexate in combination with 10-20% of cytochalasin, mitochloramine, mitoralenone, mitoguanzone, mitonaphthylamine, mitohydrazine, mitoquinolone, mitosappan, mitotane, mitonaramin, mitozolomide, mitopyrone, colchicine salicylate, colchicine, cytochalasin, naphthol, alpha-naphthol, beta-naphthol, alpha-naphthol phosphate, ecodazole, propidazole, arsenicum, giradazole, or nocodazole.
Example 7.
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 melphalan are added, the mixture is shaken up again, and then the spray drying method is used for preparing the microspheres for injection containing 20% of methotrexate and 10% of melphalan. 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:
10-20% methotrexate in combination with 10-20% cyclophosphamide, melphalan, tumorigenin, ifosfamide, 4H peroxycyclophosphamide, cyclophosphamide, macsfamide, phosphoramide, hexamethyl pyrimethanil, cantharidin, norcantharidin, mannosuman, troosulfan, ritrosufan, improsulfan, etoglut, pipobroman, piposulfan, canonin, epoxy piperazine, zotepa, purothipine, meltupipa, uretepa or azatepa.
Example 9
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, 15mg of methotrexate and 15mg of nocodazole are added, the mixture is shaken again evenly, and then the injection microspheres containing 15% of methotrexate and 15% of nocodazole 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:
15% methotrexate in combination with 15% of a cytochalasin, mitochloramine, mitoralenone, mitoguazone, mitonaphthylamine, mitohydrazine, mitoquinolone, mitospedene, mitotane, mitonamine, mitozolomide, mitopyrone, colchicine salicylate, colchicine, cytochalasin, naphthol, alpha-naphthol, beta-naphthol, alpha-naphthol phosphate, ecodazole, propiconazole, arsenic trioxide, giraldazole, or nocodazole.
Example 11
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, 10mg of tumorigenin and 20mg of methotrexate are added after the mixture is dissolved and mixed evenly, and the mixture is shaken again and evenly to prepare the microspheres for injection containing 10% of tumorigenin and 20% of methotrexate 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:
10-20% methotrexate; or
10-20% methotrexate in combination with 10-20% cyclophosphamide, melphalan, tumorigenin, ifosfamide, 4H peroxycyclophosphamide, cyclophosphamide, macsfamide, phosphoramide, hexamethyl pyrimethanil, cantharidin, norcantharidin, mannosuman, troosulfan, ritrosufan, improsulfan, etoglut, pipobroman, piposulfan, canonin, epoxy piperazine, zotepa, purothipine, meltupipa, uretepa or azatepa.
Example 13
70mg of polylactic acid (PLGA, 50: 50) with the molecular weight peak of 35000 is put into a container, 100 ml of dichloromethane is added, after being dissolved and mixed evenly, 10mg of methotrexate and 20mg of 4H-peroxycyclophosphamide are added, after shaking up again, injection microspheres containing 10% of methotrexate and 20% of 4H-peroxycyclophosphamide 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:
(1) 10-20% methotrexate in combination with 10-20% cyclophosphamide, melphalan, tumorigenin, ifosfamide, 4H peroxycyclophosphamide, cyclophosphamide, macsfamide, phosphoramide, hexamethyl pyrimethanil, cantharidin, norcantharidin, mannosuman, troosulfan, ritrosufan, improsulfan, etoglut, pipobroman, piposulfan, canonin, epoxy piperazine, zotepa, purothipine, meltupipa, uretepa or azatepa; or
(2) 10-25% methotrexate in combination with 10-25% of cytochalasin, mitochloramine, mitoralenone, mitoguanylhydrazone, mitonaphthylamine, mitohydrazine, mitoquinolone, mitosappan, mitotane, mitonamine, mitozolomide, mitopyrone, colchicine salicylate, colchicine, cytochalasin, naphthol, alpha-naphthol, beta-naphthol, alpha-naphthol phosphate, ecodazole, propidazole, arsenicum, giradazole, or nocodazole; or
(5) 5-30% of methotrexate.
Example 15
The procedure of processing into sustained release preparation is the same as that of examples 1-14, except that the sustained release excipient is one or a combination of the following:
a) polylactic acid (PLA) with a molecular weight peak of 10000-30000, 30000-60000, 60000-100000 or 100000-150000;
b) copolymer (PLGA) of polyglycolic acid and glycolic acid with a molecular weight peak of 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);
d) FAD and Sebacic Acid (SA) copolymer;
e) xylitol, oligosaccharide, chondroitin, chitin, hyaluronic acid, collagen, gelatin or albumin glue.
Example 16
The procedure for preparing a sustained release injection is the same as in examples 1 to 15, except that the suspending agent used is one or a combination of the following:
a) 0.5-3.0% carboxymethylcellulose (sodium);
b) 5-15% mannitol;
c) 5-15% sorbitol;
d) 0.1-1.5% of surface active substances;
e) 0.1-0.5% tween 20.
The above examples are intended to illustrate, but not limit, the application of the invention.
The invention is disclosed and claimed.

Claims (5)

  1. The claim 1, an anticancer sustained release injection containing methotrexate 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 alkylating agent;
    the alkylating agent is selected from one or the combination of cyclophosphamide, melphalan, oncoclonine, ifosfamide, 4H-peroxy-cyclophosphamide, macsfamide, cyclophosphamide, hexamethyl-pyriminone, cantharidin, norcantharidin, mannosuman, trooshusuo, ritrosufan, improsulfan, etoglut, pipobroman, piposulfan, canonin, epoxy piperazine, benzotepa, purepipipa, meltutepa, uretepa and azatepa;
    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 10000-30000, 30000-60000, 60000-100000 or 100000-150000;
    b) copolymer of polyglycolic acid and glycolic acid with a molecular weight peak of 10000-30000, 30000-60000, 60000-100000 or 100000-150000, wherein the ratio of polyglycolic acid to 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);
    d) FAD and sebacic acid copolymer;
    e) xylitol, oligosaccharide, chondroitin, chitin, 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 anticancer injection according to claim 1, wherein the anticancer active ingredients of the sustained-release anticancer injection are:
    a combination of 5-30% methotrexate with 5-30% cyclophosphamide, melphalan, tumorigenin, ifosfamide, 4H-peroxycyclophosphamide, cyclophosphamide, macsfamide, phosphoramide, hexamethyl pyrimethanil, cantharidin, norcantharidin, mannosuman, troosulfan, ritrosufan, improsulfan, etoglut, pipobroman, piposulfan, canonin, epidopiperazine, zotepa, purothipine, meltupipa, uretepa or azatepa;
    the above are all weight percentages.
  3. The anticancer sustained release microspheres according to claim 1, for preparing sustained release implant for treating extracranial solid tumor or brain tumor originated from human and animal.
  4. The sustained-release anticancer implant according to claim 3, characterized in that the anticancer active ingredients are: 10-20% methotrexate in combination with 10-20% cyclophosphamide, melphalan, tumorigenin, ifosfamide, 4H-peroxycyclophosphamide, cyclophosphamide, macsfamide, phosphoramide, hexamethylpyrimidineamine, cantharidin, norcantharidin, mannosuman, troosulfan, ritrosufan, improsulfan, etoglut, pipobroman, piposulfan, canonin, oxipiperazine, zotepa, purepitepa, meltupipa, uretepa or azatepa.
  5. The sustained-release anticancer implant according to claim 3, wherein the extracranial solid tumor is primary or secondary cancer, sarcoma or carcinosarcoma derived from human or animal origin, such as kidney, liver, gallbladder, head and neck, oral cavity, thyroid gland, skin, mucosa, gland, blood vessel, bone tissue, lymph node, lung, esophagus, stomach, breast, pancreas, eye, nasopharynx, uterus, ovary, endometrium, cervix, prostate, bladder, colon or rectum.
CNA200810302967XA 2006-01-23 2006-01-23 Methotrexate sustained-release injection Pending CN101380298A (en)

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CN101380298A true CN101380298A (en) 2009-03-11

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