CN101023930A - Anti-cancer composition carried with new-born blood-vessel inhibiting agent and alkalating agent - Google Patents

Anti-cancer composition carried with new-born blood-vessel inhibiting agent and alkalating agent Download PDF

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CN101023930A
CN101023930A CNA2007102004399A CN200710200439A CN101023930A CN 101023930 A CN101023930 A CN 101023930A CN A2007102004399 A CNA2007102004399 A CN A2007102004399A CN 200710200439 A CN200710200439 A CN 200710200439A CN 101023930 A CN101023930 A CN 101023930A
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poly
release
terephthalate
ethyl phosphate
sustained
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孙娟
张红军
俞建江
邹会风
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Jinan Kangquan Medicine Science and Technology Co Ltd
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Jinan Kangquan Medicine Science and Technology Co Ltd
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Abstract

The present invention relates to an anti-cancer medicine composition containing angiogenesis inhibitor and alkylation agent. Said anti-cancer medicine composition is a slow-release injection formed from microsphere and solvent, in which the slow-release microsphere includes anti-cancer effective component and slow-release auxiliary material, and the solvent is general one or special one containing suspension adjuvant. The suspension adjuvant is selected from carboxymethylcellulose sodium, etc. and its viscosity is 100 cp-3000 cp (at 20 deg.C-30 deg.C). The anti-cancer effective component is combination of angiogenesis inhibitor and/or alkylation agent selected from melphalan, cyclophosphamide and cyclophosphamide 4-hydroperoxide. The slow-release auxiliary material is selected from polyphosphate copolymer of p(LAEG-EOP) and p(DAPG-EOP) or polyphosphate and polylactic acid, difatty acid and sebacic acid copolymer, poly (erucidic acid dimmer-sebacic acid) or poly (fumaric acid-sebacic acid) copolymer or mixture. Said anti-cancer medicine composition also can be made into slow-release implantation preparation.

Description

Anti-cancer composition loaded with angiogenesis inhibitor and alkylating agent
(I) technical field
The invention relates to an anti-cancer composition containing a neovascular inhibitor and/or an alkylating agent, belonging to the technical field of medicaments. Specifically, the invention relates to a sustained-release preparation capable of stably releasing a neovascular inhibitor and/or an alkylating agent to a solid tumor part, which is mainly a sustained-release implant and a sustained-release injection, can prolong the release time of a medicament and can increase the sensitivity of the medicament.
(II) background of the invention
The local application of chemotherapy drugs, especially local slow release, has become the research direction and hot spot of the current solid tumor chemotherapy. See (Chinese patent application No. 200510042234.3, 03148624.X, 200510042236.2, 96116041.1, 97107078.4, 200510042260.6, 200510042261.0, 200510042262.5, 200510042263. X; U.S. Pat. No. 5,5651986,RE 37410).
However, the sustained release excipients used in the prior art and other pharmaceutical preparations cause more or less abrupt or uneven release of the drug when it is delivered. Some drugs are released too slowly, which is not enough to obtain effective drug concentration locally, so that tumor cells cannot be killed effectively; some of them are released too fast, often causing burst release, and easily causing systemic toxicity like conventional injection.
Therefore, research and development of a drug delivery system capable of releasing different drugs in stable or constant amounts and rates at a specific time has become a problem to be solved.
Disclosure of the invention
Aiming at the defects of the prior art, the invention provides an anti-cancer drug sustained-release preparation containing a neovascularization inhibitor and/or an alkylating agent, in particular to a sustained-release injection or a sustained-release implant containing a neovascularization inhibitor and/or an alkylating agent. Can stably release the angiogenesis inhibitor and/or the alkylating agent to the local sustained release preparation of the solid tumor, can prolong the release time of the medicine, can maintain higher medicine concentration and can increase the sensitivity of the medicine.
The invention discovers that not all sustained-release auxiliary materials can achieve the sustained-release effect of effective release for the components with anticancer activity. The medicinal auxiliary materials are more than hundreds of medicinal auxiliary materials with slow release function, in particular the medicinal auxiliary materials which can slowly release different medicines in human bodies or animal bodies within a certain time can be obtained through a large number of creative experiments, and the selection of the combination of the specific slow release auxiliary materials and the medicines which can be slowly released can be determined through a large number of creative labor. Too slow release to achieve effective drug concentration and thus ineffective killing of tumor cells; if too rapid a Release causes a burst, systemic toxic reactions are easily induced, such as polifeprosan (A.J. Domb et al, Biomaterials (1995), 16 (14): 1069-. The related data, particularly the data of the release characteristics in animals, can be obtained through a large number of creative experiments in vivo and in vitro, can not be determined through limited experiments, and is non-obvious.
The invention discovers that phosphate ester high molecular polymers such as polyphosphoester (polyphosphates), polyphosphoester (polyphosphate), polyphosphite (polyphosphate), polyphosphonate (polyphosphonate), poly (cyclophosphate), ethyl phosphate (EOP) and the like can stably and slowly release the active ingredients of the invention, and the release period is more than 40 to 100 days. And has no burst release, especially mixing or copolymerizing with anhydrosugar polymers such as polylactic acid. The discovery solves the defects of burst release and over-quick release of the existing sustained-release preparation, and can release the medicine slowly for more than 40-100 days. The above findings constitute the main features of the present invention.
One form of the slow release preparation of the angiogenesis inhibitor is a slow release injection, which consists of slow release microspheres and a solvent. Specifically, the anticancer sustained-release injection consists of the following components:
(A) a sustained release microsphere comprising:
0.5-70% of anticancer active ingredient
Sustained release auxiliary materials 30-99%
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 effective anticancer component is a neovascular inhibitor and/or an alkylating agent;
the viscosity range IV (dl/g) of the slow release auxiliary material is 0.05-1.8, preferably 0.1-1.4, and most preferably 0.1-1.4. The sustained-release excipients used in the present invention are selected from the group consisting of polyphosphates, polyphosphonates, polycycloalkylphosphates, ethyl phosphate (EOP), poly (1, 4-bis (hydroxyethyl) terephthalate-co-ethyl phosphate/terephthalate ester, 80/20) (p (BHET-EOP/TC, 80/20)), p (BHET-EOP/TC, 50/50), poly (L-lactide-co-ethyl phosphate (p (LAEG-EOP)), poly (L-lactide-co-propyl phosphate) (p (DAPG-EOP)), trans (trans) -1, 4-dimethylcyclohexane, CHDM, hexyldichlorophosphate (hexylchlorophosphorate), HOP), 4-dimethylaminopyridine (4-dimethylaminopyridine, DMAP), poly (1, 4-bis (hydroxyethyl) terephthalate-co-4-dimethylaminopyridine-co-ethyl phosphate/terephthalate hydrochloride, 80/20) (p (BHDPT-EOP/TC, 80/20)), p (BHDPT-EOP/TC, 50/50), poly (trans- (formula) -ethyl 1, 4-dimethylcyclohexane phosphate) (p (CHDM-HOP)), poly (trans- (formula) -1, 4-dimethylcyclohexylphosphorodichloridate (p (CHDM-EOP)), or a combination thereof.
Among the above phosphates, p (BHET-EOP/TC), p (LAEG-EOP), p (DAPG-EOP), p (BHDPT-EOP/TC), p (CHDM-HOP) and p (CHDM-EOP) are preferable.
The sustained-release auxiliary material used by the invention is also selected from racemic polylactic acid (D, L-PLA), racemic polylactic acid/glycollic acid copolymer (D, L-PLGA), monomethyl polyethylene glycol/polylactic acid (MPEG-PLA), monomethyl polyethylene glycol/polylactic acid copolymer (MPEG-PLGA), polyethylene glycol/polylactic acid (PLA-PEG-PLA), polyethylene glycol/polylactic acid copolymer (PLGA-PEG-PLGA), carboxyl-terminated polylactic acid (PLA-COOH), carboxyl-terminated polylactic acid/glycollic acid copolymer (PLGA-COOH), polifeprosan, difatty acid and sebacic acid copolymer (PFAD-SA), poly (erucic acid dipolymer sebacic acid) [ P (EAD-SA) ], poly (fumaric acid sebacic acid) [ P (FA-SA) ], ethylene vinyl acetate copolymer (EVAc), Polylactic acid (PLA), copolymers of polyglycolic acid and glycolic acid (PLGA), Polydioxanone (PDO), polytrimethylene carbonate (PTMC), xylitol, oligosaccharides, chondroitin, chitin, chitosan, poloxamer 188, poloxamer 407, hyaluronic acid, collagen, gelatin, or a blend or copolymer of protein gels, or in combination with the above phosphates.
The sustained release excipient used in the present invention is also selected from polifeprosan and polylactic acid (PLA) or a copolymer of polyglycolic acid and glycolic acid (PLGA).
The slow release auxiliary material used in the invention is also selected from organic silicon or the combination of the organic silicon and the auxiliary material, and the organic silicon can be used as the sphere center of the microsphere or as the carrier of the microsphere.
The suspending agent is selected from one or more of sodium carboxymethylcellulose, (iodine) glycerol, dimethicone, propylene glycol, carbomer, mannitol, sorbitol, surfactant, Tween 20, Tween 40 and Tween 80.
The blood vessel inhibitor in the anticancer active ingredients is selected from one or the combination of the following components: vandetanib, tipifarnib, sirolimus, rapamycin, lenalidomide, isatecan, gefitinib, erlotinib, lapatinib, vatalanib, pelitinib, carboxyaminotriazole, thalidomide, ranolamine, angiostatin, endostatin, englodine, imatinib mesylate, semasinib, dasatinib, avastin, canatinib, sorafenib, sunitinib, teosinte, panitoma, marimastat, SU5416, SU6668, fumagillin, TNP-470.
The above vascular inhibitors also include their salts, such as, but not limited to, sulfate, phosphate, hydrochloride, lactobionate, acetate, aspartate, nitrate, citrate, purine or pyrimidine salts, succinate, maleate, and the like.
The content of the angiogenesis inhibitor in the composition is 0.01-60%, preferably 1-40%, and most preferably 2-30%, by weight.
The alkylating agent is selected from cyclophosphamide, melphalan, meclizine, ifosfamide, 4H peroxycyclophosphamide, cyclophosphamide, macsfamide, perfosfamide, hexamethyl pyrimethanil, cantharidin, norcantharidin, mannosylfan, troosulfan, ritrosufen, improsulfan, etogreu, pipobroman, piposulfan, canonin, epoxy piperazine, benzotepa, puropyrimidin, meltutepa, uretepa or azatepa and salts thereof, such as, but not limited to, sulfate, phosphate, hydrochloride, lactobionate, acetate, aspartate, nitrate, citrate, purine or pyrimidine salts, succinate or maleate.
The weight percentage of the alkylating agent in the sustained-release agent is 0.01-70%, preferably 1-50%, and most preferably 5-30%.
The weight percentage of the drug in the sustained release microspheres is 0.5-60%, preferably 2-40%, and most preferably 5-30%. The weight ratio of the angiogenesis inhibitor to the alkylating agent is 1-9: 1 to 1: 1-9. Preferably 1-2: 1.
The packaging and use of the neovascular inhibitor and/or alkylating agent depends on the clinical need. The neovascular inhibitor and alkylating agent may be packaged separately or in combination. Combination packs are mainly used for local potentiation, while individual packs are mainly used for potentiation of different routes of administration or for potentiation of other therapies. For example, topical placement (or injection) of a neovascular inhibitor and an alkylating agent alone may be combined with an intravenously applied alkylating agent and a neovascular inhibitor, respectively; locally placed (or injected) neovascular inhibitors and/or alkylating agents may also be used to potentiate radiation therapy.
Therefore, the anticancer active ingredients in the anticancer sustained-release microspheres of the invention preferably have the following weight percentages:
(a) 5-30% of vandetanib, tipifarnib, sirolimus, rapamycin, lenalidomide, ixatecan, gefitinib, erlotinib, lapatinib, vatalanib, pelitinib, carboxyamidotriazole, thalidomide, ranolamide, angiostatin, endostatin, angiostatin, englestatin, imatinib mesylate, semasinib, dasatinib, avastin, canatinib, sorafenib, sunitinib, telosta, panitoma, marimastat, SU5416, SU6668, fumagillin or TNP-470; or
(b) 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
(c) 5-30% of vandetanib, tipifarnib, sirolimus, rapamycin, lenalidomide, ixotecan, gefitinib, erlotinib, lapatinib, vatalanib, pelitinib, carboxyamidotriazole, thalidomide, ranolamide, angiostatin, endostatin, englestatin, imatinib mesylate, semasinib, dasatinib, avastin, canatinib, sorafenib, sunitinib, teosarta, panitoma, marimastat, SU5416, SU6668, fumagillin or TNP-470 in combination with 5-30% of cyclophosphamide, melphalan, meconin, ifosfamide, 4H peroxycyclophosphamide, norepinephrine, meltutepa, uretepa or azatepa.
The most preferable anticancer active components and weight percentages in the anticancer sustained-release microspheres are as follows:
10-30% of vandetanib, tipifarnib, sirolimus, rapamycin, lenalidomide, ixotecan, gefitinib, erlotinib, lapatinib, vatalanib, pelitinib, carboxyamidotriazole, thalidomide, ranolamide, angiostatin, endostatin, englestatin, imatinib mesylate, semasinib, dasatinib, avastin, canatinib, sorafenib, sunitinib, telosta, panitoma, marimastat, SU5416, SU6668, fumagillin or TNP-470 in combination with 10-30% of cyclophosphamide, melphalan, ifosfamide, 4H peroxycyclophosphamide or norcantharidin.
In the slow release injection, the drug slow release system can be prepared into microspheres, submicron spheres, micro emulsion, nanospheres, granules or spherical pellets, and then the injection is prepared after the drug slow release system is mixed with an injection solvent. The suspension type sustained-release injection is preferably selected from various sustained-release injections, the suspension type sustained-release injection is a preparation obtained by suspending a drug sustained-release system containing an anti-cancer component in injection, the used sustained-release auxiliary material is one or the combination of the sustained-release auxiliary materials, and the used solvent is a common solvent or a special solvent containing a suspending agent. Common solvents are, but not limited to, distilled water, water for injection, physiological saline, absolute ethanol or buffers formulated with various salts. The suspending agent is intended to effectively suspend the microspheres containing the drug, thereby facilitating injection. For convenient injection, the suspending agent has viscosity of 100-3000 cp (at 20-30 deg C), preferably 1000-3000 cp (at 20-30 deg C), and most preferably 1500-3000 cp (at 20-30 deg C). The suspending agent is selected from one or more of sodium carboxymethylcellulose, (iodine) glycerol, dimethicone, propylene glycol, carbomer, mannitol, sorbitol, surfactant, Tween 20, Tween 40 and Tween 80.
The content of the suspending agent in the common solvent depends on the characteristics of the suspending agent, and can be 0.1-30% according to the specific situation. Preferably, the suspending agent consists of:
A) 0.5-5% of sodium carboxymethylcellulose and 0.1-0.5% of Tween 80; or
B) 5-20% of mannitol and 0.1-0.5% of Tween 80; or
C)0.5 to 5 percent of sodium carboxymethylcellulose, 5 to 20 percent of sorbitol and 0.1 to 0.5 percent of Tween 80.
The preparation of the solvent depends on the kind of the solvent, and common solvents are commercially available or self-made, such as distilled water, water for injection, physiological saline, absolute ethanol or buffers prepared from various salts, but the preparation must strictly follow the relevant standards. The special solvent should be selected from the type and composition of suspending agent, the composition and properties of the drug suspended in the solvent, the sustained release microsphere (or microcapsule), and the required amount thereof, and the preparation method of the injection, for example, sodium carboxymethylcellulose (1.5%) + mannitol and/or sorbitol (15%) and/or tween 80 (0.1%) are dissolved in physiological saline to obtain the corresponding solvent with viscosity of 10-650 cp (at 20-30 deg.C).
The invention discovers that the key factor influencing the suspension and/or injection of the medicament and/or the sustained-release microspheres is the viscosity of the solvent, and the higher the viscosity is, the better the suspension effect is and the stronger the injectability is. This unexpected finding constitutes one of the main exponential features of the present invention. The viscosity of the solvent depends on the viscosity of the suspending agent, and the viscosity of the suspending agent is 100cp-3000cp (at 20-30 ℃), preferably 1000cp-3000cp (at 20-30 ℃), and most preferably 1500cp-3000cp (at 20-30 ℃). The viscosity of the solvent prepared according to the condition is 10cp-650cp (at 20-30 ℃), preferably 20cp-650cp (at 20-30 ℃), and most preferably 60cp-650cp (at 20-30 ℃).
The preparation of injection has several methods, one is that the slow release particles (A) whose suspending agent is '0' are directly mixed in special solvent to obtain correspondent slow release particle injection; the other is that the slow release particles (A) of which the suspending agent is not 0 are mixed in a special solvent or a common solvent to obtain the corresponding slow release particle injection; and the other one is that the slow release particles (A) are mixed in common dissolvent, then suspending agent is added and mixed evenly, and the corresponding slow release particle injection is obtained. Besides, the sustained-release particles (A) can be mixed in special solvent to prepare corresponding suspension, then the water in the suspension is removed by methods such as vacuum drying, and then the suspension is suspended by special solvent or common solvent to obtain the corresponding sustained-release particle injection. The above methods are merely illustrative and not restrictive of the invention. It is noted that the concentration of the suspended drug or the sustained release microspheres (or microcapsules) in the injection may be, but is not limited to, 10-400mg/ml, but is preferably 30-300mg/ml, and most preferably 50-200mg/ml, depending on the particular need. The viscosity of the injection is 50-1000 cp (at 20-30 deg C), preferably 100-1000 cp (at 20-30 deg C), and most preferably 200-650 cp (at 20-30 deg C). This viscosity is suitable for 18-22 gauge needles and specially made needles with larger (to 3 mm) inside diameters.
The method of preparation of the sustained release injection is arbitrary and can be prepared by several methods: such as, but not limited to, mixing, melting, dissolving, spray drying and emulsifying to prepare microspheres, dissolving in combination with freezing (drying) and pulverizing to obtain 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. Among them, 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 are preferable as the hydrophobic block of the micelle copolymer. The block copolymer micelles may have a particle size in the range of 10 to 300um, preferably 20 to 200 um. The gel injection is prepared by dissolving biodegradable polymer (such as PLA, PLGA or DL-LA and epsilon-caprolactone copolymer) in certain amphiphilic solvent, adding the medicine, mixing (or suspending) with the solvent to form gel with good fluidity, and can be injected around tumor or in tumor. Once injected, the amphiphilic solvent diffuses into the body fluid quickly, and the water in the body fluid permeates into the gel, so that the polymer is solidified and the drug is released slowly.
The sustained-release microspheres can also be used for preparing sustained-release implants, the used pharmaceutic adjuvant can be any one or more of the above pharmaceutic adjuvants, but the water-soluble high polymer is selected as the main choice, and the mixture or copolymer of polylactic acid, sebacic acid, and high polymer containing polylactic acid or sebacic acid is selected as the first choice among various high polymers, and the mixture and copolymer can be selected from, but are not limited to, PLA, PLGA, mixture of PLA and PLGA, mixture or copolymer of sebacic acid and aromatic polyanhydride or aliphatic polyanhydride, fatty acid dimer and sebacic acid copolymer (PFAD-SA) ], poly (erucic acid dimer-sebacic acid) [ P (EAD-SA) ], and poly (fumaric acid sebacic acid) [ P (FA-SA) ]. The blending ratio of polylactic acid (PLA) to polyglycolic acid is 10/90 to 90/10 (by weight), preferably 25/75 to 75/25 (by weight). The method of blending is arbitrary. The contents of glycolic acid and lactic acid in copolymerization are respectively 10-90% and 90-10% by weight. The aromatic polyanhydride is represented by p-carboxyphenylpropane (p-CPP), the content of the p-carboxyphenylpropane (p-CPP) and sebacic acid in copolymerization is respectively 10-60% and 20-90% by weight, and the blending weight ratio is 10-40: 50-90, preferably 15-30: 65-85.
Wherein, the molecular weight peak of polylactic acid can be, but is not limited to, 5000-; the molecular weight of the copolymer of hydroxycarboxylic acid and glycolic acid (PLGA) may be, but is not limited to, 5000-200,000, but is preferably 20,000-60,000, most preferably 30,000-50,000, and the blending ratio of glycolic acid and hydroxycarboxylic acid is 10/90-90/10 (by weight), most preferably 25/75-75/25 (by weight). The method of blending is arbitrary. The contents of glycolic acid and hydroxycarboxylic acid in copolymerization are 10-90 wt% and 90-10 wt%, respectively. Representative of the aromatic polyanhydrides are polifeprosan [ poly (1, 3-di (P-carboxyphenoxy) propane-sebacic acid) (P (CPP-SA)), di-fatty acid sebacic acid copolymer (PFAD-SA) ], poly (erucic acid dimer-sebacic acid) [ P (EAD-SA) ], and poly (fumaric acid sebacic acid) [ P (FA-SA) ], and the like. The content of p-carboxyphenoxy propane (p-CPP) and sebacic acid in copolymerization is 10-60 wt% and 20-90 wt%, respectively, and the blending weight ratio is 10-40: 50-90, preferably 15-30: 65-85.
In addition to the above-mentioned original adjuvants, other substances can be selected and used as described in detail in U.S. Pat. Nos. 4757128 (4857311; 4888176; 4789724) and "pharmaceutical adjuvants" in general (p. 123, published by Sichuan scientific and technical Press 1993, compiled by Luoming and high-tech). In addition, Chinese patent (application No. 96115937.5; 91109723.6; 9710703.3; 01803562.0) and U.S. patent No. 5,651,986) also list some pharmaceutical excipients, including fillers, solubilizers, absorption promoters, film-forming agents, gelling agents, pore-forming agents, excipients or retarders.
In order to adjust the drug release rate or change other characteristics of the present invention, the monomer component or molecular weight of the polymer can be changed, and the composition and ratio of the pharmaceutical excipients can be added or adjusted, and water-soluble low molecular compounds such as, but not limited to, various sugars or salts can be added. Wherein the sugar can be, but is not limited to, xylitol, oligosaccharide, (chondroitin sulfate), chitin, chitosan, poloxamer, etc., and the salt can be, but is not limited to, potassium salt, sodium salt, etc.; other pharmaceutical adjuvants such as, but not limited to, filler, solubilizer, absorption enhancer, film-forming agent, gelling agent, pore-forming agent, excipient or retarder can also be added
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, and then evaporating the solvent and drying, the so-called dissolution method; (iv) spray drying; and (v) freeze-drying method.
The route of administration of the sustained release agent depends on various factors, and in order to obtain an effective concentration at the site of primary or metastatic tumor, the drug may be administered by various routes, such as subcutaneous, intraluminal (e.g., intraperitoneal, thoracic, and intraspinal), intratumoral, peritumoral injection or placement, selective arterial injection, intralymphatic, and intramedullary injections. Selective arterial injection, intracavitary, intratumoral, peritumoral injection or placement is preferred.
The invention can be used for preparing pharmaceutical preparations for treating various tumors of human and animals, mainly sustained-release injections or sustained-release implants, wherein the tumors comprise primary or metastatic cancers or sarcomas or carcinosarcomas originated from brain, central nervous system, kidney, liver, gall bladder, head and neck, oral cavity, thyroid, skin, mucous membrane, gland, blood vessel, bone tissue, lymph node, lung, esophagus, stomach, mammary gland, pancreas, eye, nasopharynx, uterus, ovary, endometrium, cervix, prostate, bladder, colon and rectum.
The tumors of the viscera can be of different pathological types, the tumors of the lymph nodes are Hodgkin lymphoma and non-Hodgkin lymphoma, the lung cancer comprises small cell lung cancer, non-small cell lung cancer and the like, and the brain tumor comprises glioma and the like. However, common tumors include solid tumors such as brain tumor, brain glioma, kidney cancer, liver cancer, gallbladder cancer, head and neck tumor, oral cancer, thyroid cancer, skin cancer, hemangioma, osteosarcoma, lymphoma, lung cancer, thymus cancer, esophageal cancer, stomach cancer, breast cancer, pancreatic cancer, retinoblastoma of eyes, nasopharyngeal cancer, ovarian cancer, endometrial cancer, cervical cancer, prostate cancer, bladder cancer, colon cancer, rectal cancer, and testicular cancer.
The application and the synergy mode of the sustained-release implant are the same as those of an anticancer sustained-release injection, namely the combination of a locally-placed chemotherapy synergist and an anticancer medicament administrated by other routes, the combination of a locally-placed anticancer medicament and a chemotherapy synergist administrated by other routes, and the combination of a locally-placed anticancer medicament and a locally-placed chemotherapy synergist. Wherein the locally applied anticancer drug and the chemotherapeutic synergist can be produced, packaged, sold and used separately or jointly. The package refers to the loading process of the drug for the auxiliary materials and the internal and external package of the drug-containing sustained release agent for transportation and/or storage. Drug loading processes include, but are not limited to, weighing, dissolving, mixing, drying, shaping, coating, spraying, granulating, and the like. If the medicine is mixed with different auxiliary materials to prepare the sustained-release microspheres containing different medicines, the sustained-release microspheres can be independently packaged and stored, and can be injected into the body simultaneously or sequentially when in use; the sustained release microspheres can also be further formed by various methods to prepare sustained release implants with various shapes.
The medicine in the sustained-release implant and the weight ratio thereof are the same as those of the anticancer sustained-release injection, but the sustained-release implant is preferably as follows:
(a) 5-30% of vandetanib, tipifarnib, sirolimus, rapamycin, lenalidomide, ixatecan, gefitinib, erlotinib, lapatinib, vatalanib, pelitinib, carboxyamidotriazole, thalidomide, ranolamide, angiostatin, endostatin, angiostatin, englestatin, imatinib mesylate, semasinib, dasatinib, avastin, canatinib, sorafenib, sunitinib, telosta, panitoma, marimastat, SU5416, SU6668, fumagillin or TNP-470; or
(b) 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
(c) 5-30% of vandetanib, tipifarnib, sirolimus, rapamycin, lenalidomide, ixotecan, gefitinib, erlotinib, lapatinib, vatalanib, pelitinib, carboxyamidotriazole, thalidomide, ranolamide, angiostatin, endostatin, englestatin, imatinib mesylate, semasinib, dasatinib, avastin, canatinib, sorafenib, sunitinib, teosarta, panitoma, marimastat, SU5416, SU6668, fumagillin or TNP-470 in combination with 5-30% of cyclophosphamide, melphalan, meconin, ifosfamide, 4H peroxycyclophosphamide, norepinephrine, meltutepa, uretepa or azatepa.
The anticancer active ingredients and the weight percentage in the anticancer sustained-release implant are most preferably as follows:
10-30% of vandetanib, tipifarnib, sirolimus, rapamycin, lenalidomide, ixotecan, gefitinib, erlotinib, lapatinib, vatalanib, pelitinib, carboxyamidotriazole, thalidomide, ranolamide, angiostatin, endostatin, englestatin, imatinib mesylate, semasinib, dasatinib, avastin, canatinib, sorafenib, sunitinib, telosta, panitoma, marimastat, SU5416, SU6668, fumagillin or TNP-470 in combination with 10-30% of cyclophosphamide, melphalan, ifosfamide, 4H peroxycyclophosphamide or norcantharidin.
The clinically applicable dose of the active ingredient may vary depending on the patient's condition and may range from 0.01 to 1000mg/kg body weight, with 0.1 to 800mg/kg being preferred and 1 to 500mg/kg being most preferred.
The sustained-release injection or the sustained-release implant prepared by the invention can also be added with other medicinal components, such as, but not limited to, antibiotics, analgesic drugs, anticoagulant drugs, hemostatic drugs and the like.
The technical process of the invention is further described by the following tests and examples:
test 1 comparison of local drug concentrations after different modes of erlotinib application
Using white rat as test object, 2X 105Individual prostate tumor cells were injected subcutaneously into their quaternary costal regions and grouped after tumors grew to 1 cm in diameter. The dose of each group was 5 mg/kg. Measuring different timesThe results of the intratumoral drug content (%) show that the local drug concentration difference of erlotinib 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. This finding constitutes an important feature of the present invention. This is further confirmed by the following relevant tumor inhibition test.
Experiment 2 comparison of in vivo tumor inhibition effects of gefitinib applied in different modes
Using white rat as test object, 2X 105Individual thyroid gland tumor cells were injected subcutaneously into the quaternary costal region and grouped after tumors grew to 0.5 cm diameter. The dose of each group was 5 mg/kg. The volume of the tumor was measured on the 20 th day after treatment, and the therapeutic effect was compared. The results show that the tumor inhibition effect difference of the gefitinib applied in different modes is obvious, the local administration can obviously improve and effectively maintain the effective drug concentration of the tumor part, wherein the effect of placing the sustained-release implant in the tumor and injecting the sustained-release injection in the tumor is the best. However, the intratumoral injection of the sustained-release injection is most convenient and easy to operate. Not only has good curative effect, but also has little toxic and side effect.
Experiment 3 in vivo tumor inhibition containing neovascular inhibitor and alkylating agent (sustained release injection)
Using white rat as test object, 2X 105Individual pancreatic tumor cells were injected subcutaneously into the quaternary costal region and were divided into the following 10 groups 14 days after tumor growth (see table 1). The first group was the control, and groups 2 to 10 were the treatment groups, and the drug was injected intratumorally. The dosage is 5 mg/kg. Tumor volume was measured on day 30 after treatment and the treatment effect was compared (see table 1).
TABLE 1
Test set (n) Is treated by Tumor volume (cm)3) P value
1(6) Control 60±12
2(6) Angiogenesis inhibitor 50±6.4 ＜0.05
3(6) Cyclophosphamide 50±6.0 ＜0.01
4(6) Melphalan 48±6.2 ＜0.01
5(6) Medicine for curing tumor 50±7.2 ＜0.01
6(6) Isocyclophosphamide (ACS) 46±6.0 ＜0.01
7(6) Angiogenesis inhibitor + cyclophosphamide 34±6.2 ＜0.001
8(6) Angiogenesis inhibitor + melphalan 30±6.8 ＜0.001
9(6) Angiogenesis inhibitor + tumorigenin 20±4.4 ＜0.001
10(6) Angiogenesis inhibitor + ifosfamide 22±4.0 ＜0.001
The results show that the angiogenesis inhibitor (lapatinib) and the used alkylating agent (cyclophosphamide, melphalan, oncoclonine and ifosfamide) have obvious inhibition effect on the growth of a plurality of tumor cells when being used independently at the concentration, and can show obvious synergistic effect when being used jointly.
Test 4 antitumor Effect of neovascular inhibitor and alkylating agent (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. Angiogenesis inhibitor (gefitinib) and alkylating agent were added to each tumor cell cultured in vitro for 24 hours at a concentration of 10. mu.g/ml, and the total number of cells was counted after further culturing for 48 hours. The tumor cell growth inhibitory effect is shown in Table 2.
TABLE 2
Tumor cell Gefitinib Melphalan Medicine for curing tumor Aining medicine for treating cancer Gefitinib + melphalan Gefitinib + tumorigenin Gefitinib and cancinonin
CNS 56％ 52％ 64％ 60％ 90％ 84％ 84％
C6 52％ 64％ 64％ 60％ 90％ 88％ 92％
SA 46％ 62％ 56％ 62％ 86％ 90％ 90％
BC 44％ 64％ 54％ 64％ 88％ 86％ 80％
BA 48％ 60％ 62％ 66％ 82％ 84％ 90％
LH 54％ 58％ 62％ 52％ 90％ 88％ 86％
PAT 58％ 50％ 60％ 52％ 90％ 88％ 86％
The results show that the used angiogenesis inhibitor (gefitinib) and alkylating agent (melphalan, oncoclonine and cancinonin) have obvious inhibition effect on the growth of a plurality of tumor cells when being used alone at the concentration, and can show obvious synergistic effect when being used in combination.
Test 5 antitumor Effect of neovascular inhibitor and alkylating agent (sustained Release injection)
Using white rat as test object, 2X 105Individual liver tumor cells were injected subcutaneously into the quaternary costal region and were divided into the following 10 groups 14 days after tumor growth (see table 3). The first group was the control, and groups 2 to 10 were the treatment groups, with the sustained release implant placed intratumorally. The dosages of alkylating agent and neovascular inhibitor are respectively 5mg/kg and 15 mg/kg. Tumor volume was measured on day 30 post-treatmentSize, compare the therapeutic effect (see table 3).
TABLE 3
Test set (n) Is treated by Tumor volume (cm)3) P value
1(6) Control 80±10
2(6) Cyclophosphamide 52±5.3 ＜0.05
3(6) NewAngiogenesis inhibitor 48±2.0 ＜0.01
4(6) Cyclophosphamide and neovascular inhibitor 32±2.4 ＜0.001
5(6) Melphalan 46±3.0 ＜0.01
6(6) Melphalan + angiogenesis inhibitor 22±2.0 ＜0.001
7(6) Medicine for curing tumor 36±3.8 ＜0.01
8(6) Oncoining and angiogenesis inhibitor 20±2.6 ＜0.001
9(6) Isocyclophosphamide (ACS) 44±4.6 ＜0.01
10(6) Ifosfamide + angiogenesis inhibitors 16±2.0 ＜0.001
The results show that the used neovascular inhibitor (rapamycin) and alkylating agent (cyclophosphamide, melphalan, cinchonine and ifosfamide) have obvious inhibition effect on the growth of a plurality of tumor cells when being used independently at the concentration, and can show obvious synergistic effect when being used jointly.
Test 6 antitumor Effect of neovascular inhibitor and alkylating agent (sustained Release injection)
Using white rat as test object, 2X 105Swelling of the brainTumor cells were injected subcutaneously into the costal region of the patient, and were classified into a negative control (blank), a single-drug treatment group (neovascular inhibitor or alkylating agent), and a combination treatment group (neovascular inhibitor and alkylating agent) 14 days after the tumor had grown. The medicine is injected intratumorally. The dosages of alkylating agent and neovascular inhibitor are respectively 5mg/kg and 25 mg/kg. The volume of the tumor was measured on day 30 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) Angiogenesis inhibitor 40 ＜0.05
3(6) 4H-peroxycyclophosphamide 32 ＜0.01
4(6) Diphosphamide 48 ＜0.01
5(6) Malachite 46 ＜0.01
6(6) Pesphamide 44 ＜0.01
7(6) Angiogenesis inhibitor + 4H-peroxycyclophosphamide 92 ＜0.001
8(6) Neovascularization inhibitor + cyclophosphamide 88 ＜0.001
9(6) Angiogenesis inhibitor + phosphoramide 82 ＜0.001
10(6) Angiogenesis inhibitor + pefamide 90 ＜0.001
The results show that the used neovascularization inhibitors (pelitinib) and alkylating agents (4H peroxycyclophosphamide, cyclophosphamide, and phosphoramide) have obvious inhibition effects on the growth of various tumor cells when being used independently at the concentration, and can show obvious synergistic effects when being used in combination.
Test 7 tumor-inhibiting action of neovascular inhibitor and alkylating agent (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 dosages of alkylating agents are 2.5mg/kg and the dosage of angiogenesis inhibitor is 20 mg/kg. Tumor volume was measured on day 20 after treatment, and the therapeutic effect was compared using tumor growth inhibition as an index (see table 5).
TABLE 5
Test set (n) Is treated by Tumor inhibition ratio (%) P value
1(6) Control -
2(6) Angiogenesis inhibitor 50 ＜0.05
3(6) Hexamethyl pyrimidine 48 ＜0.01
4(6) Cantharidin 42 ＜0.01
5(6) Norcantharidin 44 ＜0.01
6(6) Ganloushufan 48 ＜0.01
7(6) Angiogenesis inhibitor + hexamethopyrimethanil 86 ＜0.001
8(6) Angiogenesis inhibitor + cantharidin 80 ＜0.001
9(6) Angiogenesis inhibitor + norcantharidin 82 ＜0.001
10(6) Angiogenesis inhibitor and ganlushufan 86 ＜0.001
The results show that the used angiogenesis inhibitor (dasatinib) and alkylating agent (hexamethyl-pyrimethanil, cantharidin, norcantharidin and mannosuman) have obvious inhibition effect on the growth of a plurality of tumor cells when being used independently at the concentration, and can show obvious synergistic effect when being used jointly.
Test 8 tumor-inhibiting action of neovascular inhibitor and alkylating agent (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 of alkylating agent is 25mg/kg, and the dosage of angiogenesis inhibitor is 5 mg/kg. Tumor volume was measured on day 20 after treatment, and the therapeutic effect was compared using tumor growth inhibition as an index (see table 6).
TABLE 6
Test set (n) Is treated by Tumor inhibition ratio (%) P value
1(6) Control -
2(6) Angiogenesis inhibitor 40 ＜0.05
3(6) Quaoshufan 42 ＜0.05
4(6) Litreshufan 40 ＜0.05
5(6) Yingpropylshufan 54 ＜0.05
6(6) Etogelu 60 ＜0.01
7(6) Angiogenesis inhibitor and trooshusufen 82 ＜0.01
8(6) Angiogenesis inhibitor and ritrosufen 84 ＜0.01
9(6) Angiogenesis inhibitor and Yingpropylshufan 80 ＜0.01
10(6) Angiogenesis inhibitor + etoglut 84 ＜0.001
The results show that the used neovascularization inhibitors (tipifarnib) and alkylating agents (trooshusuo, ritrosufen, imperial and etoglut) have obvious inhibition effect on the growth of various tumor cells when being singly applied at the concentration, and can show obvious synergistic effect when being jointly applied.
Test 9 tumor-inhibiting action of neovascular inhibitor and alkylating agent (sustained-release implant)
The tumor suppression of the neovascular inhibitor and the alkylating agent (slow release implant) was determined as described in test 8.
The results show that the used neovascular inhibitor (Endotey) and alkylating agent (canonin, epoxy piperazine, uretepa and azatepa) have obvious inhibition effect on the growth of rectal tumor cells when being used alone at the concentration, and can show obvious synergistic effect when being used in combination.
Test 10 tumor-inhibiting action of neovascular inhibitor and alkylating agent (sustained-release implant)
The tumor-inhibiting effects of the neovascular inhibitor and the alkylating agent (sustained release implant) were determined as described in test 4. As a result, the effect of 30% of cyclophosphamide, melphalan, oncoclonine, ifosfamide, 4H-peroxy-cyclophosphamide or azatepa on the growth of brain tumor cells is remarkably enhanced by 25% of imatinib (P is less than 0.05).
In conclusion, the used neovascular inhibitor and various alkylating agents have obvious inhibition effect on the growth of various tumor cells when being used independently, can show obvious synergistic effect when being used jointly, have obvious inhibition effect on the growth of various tumor cells when being used independently, and can also show obvious synergistic effect when being used jointly. Therefore, the active ingredient of the invention is a combination of a neovascular inhibitor and/or any one or more alkylating agents. 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.
90, 90 and 80mg of p (BHET-EOP/TC), the BHET-EOP: TC is 80: 20) copolymer is respectively put into a container A, a container B and a container C, then 100 ml of dichloromethane is added into each of the copolymer A, the copolymer B and the container C, after the mixture is dissolved and mixed evenly, 10mg of erlotinib, 10mg of cyclophosphamide, 10mg of erlotinib and 10mg of cyclophosphamide are respectively added, after the mixture is shaken again, injection microspheres containing 10% of erlotinib, 10% of cyclophosphamide, 10% of erlotinib and 10% of cyclophosphamide 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 40-50 days in vitro physiological saline and the release time of more than 50 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 used auxiliary material is p (BHET-EOP/TC) with the ratio of 50: 50, the anticancer active ingredients and the weight percentage thereof are as follows:
(1) 5-30% erlotinib or gefitinib;
(2) 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
(3) A combination of 5-30% erlotinib or gefitinib with 5-30% cyclophosphamide, melphalan, onconine, ifosfamide, 4H peroxycyclophosphamide, cyclophosphamide, macsfamide, phosphoramide, hexamethyl pyrimethanil or norcantharidin.
Example 3.
70mg of p (LAEG-EOP) with the molecular weight peak value of 10000-25000 is respectively placed into a container A, a container B and a container C, then 100 ml of dichloromethane is added into each container, after the p (LAEG-EOP) is dissolved and uniformly mixed, 30mg of polyene erlotinib, 30mg of ifosfamide, 15mg of gefitinib and 15mg of ifosfamide are respectively added into the three containers, after the p (LAEG-EOP) is uniformly dissolved, the microspheres for injection containing 30% of polyene gefitinib, 30% of ifosfamide, 15% of polyene gefitinib and 15% of ifosfamide are prepared by a spray drying method after the p is uniformly shaken again. 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 55-65 days in vitro physiological saline and the release time of about 60 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 molecular weight peak value of p (LAEG-EOP) is 25000-45000, and the anticancer active ingredients and the weight percentage thereof are as follows:
(1) 5-30% cyclophosphamide, melphalan, busonin, ifosfamide, 4H peroxycyclophosphamide or norcantharidin; or
(2) 5-30% gefitinib; or
(3) A combination of 5-30% gefitinib with 5-30% cyclophosphamide, melphalan, busonin, ifosfamide, 4H-peroxycyclophosphamide or norcantharidin.
Example 5.
70mg of p (DAPG-EOP) with the molecular weight peak value of 10000-25000 is put into a container, 100 ml of dichloromethane is added to dissolve and mix evenly, 20mg of dasatinib and 10mg of norcantharidin are added, after shaking evenly, microspheres containing 20% of dasatinib and 10% of norcantharidin are prepared by a spray drying method. Then suspending the microspheres in injection containing 15 percent of sorbitol to prepare the corresponding suspension type sustained-release injection. The slow release injection has the release time of 45-55 days in-vitro physiological saline and the release time of about 55 days under the skin of a mouse.
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 molecular weight peak value of the used auxiliary materials is 25000-:
(1) 5-30% of dasatinib; or
(2) 5-30% of dasatinib in combination with 5-30% of cyclophosphamide, melphalan, tumorigenin, ifosfamide, 4H-peroxycyclophosphamide or norcantharidin.
Example 7.
70mg of p (BHDPT-EOP/TC, 80/20) with the molecular weight peak of 10000-25000 is put into a container, 100 ml of dichloromethane is added, after the p is dissolved and mixed evenly, 20mg of erlotinib and 10mg of melphalan are added, after the p is shaken again evenly, the microspheres for injection containing 20 percent of erlotinib and 10 percent of melphalan are prepared by a spray drying method. Then suspending the microspheres in physiological saline containing 1.5 percent of sodium carboxymethylcellulose and 0.5 percent of Tween 80 to prepare the corresponding suspension type sustained-release injection. The slow release injection has the release time of 40-45 days in vitro physiological saline and the release time of about 50 days under the skin of a mouse.
Example 8.
The steps of the method for processing the sustained-release injection are the same as the example 7, but the difference is that the peak value of the molecular weight of p (BHDPT-EOP/TC) is 40000-65000, the BHDPT-EOP: TC position is 50: 50, and the anticancer active ingredients are:
10-20% cyclophosphamide, melphalan, tumorigenin, ifosfamide, 4H-peroxycyclophosphamide, norcantharidin or azatepa in combination with 10-25% erlotinib or gefitinib.
Example 9.
30mg of polifeprosan (p-carboxyphenylpropane (p-CPP): Sebacic Acid (SA) is 20: 80) and 40mg of p (DAPG-EOP) copolymer with the molecular weight peak value of 30000-45000 are put into a container, 100 ml of dichloromethane is added, after dissolving and mixing uniformly, 30mg of erlotinib, 30mg of melphalan, 15mg of erlotinib and 15mg of melphalan are respectively added, after shaking uniformly again, injection microspheres containing 30% of erlotinib, 30% of melphalan, 15% of erlotinib and 15% of melphalan 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 40-45 days in vitro physiological saline and the release time of about 45 days under the skin of a mouse.
Example 10.
The steps of the method for processing the sustained-release injection are the same as the example 9, but the difference is that the ratio of the p-carboxyphenylpropane to the sebacic acid in the polifeprosan is 50: 50, the molecular weight peak value of p (DAPG-EOP) is 40000-65000, and the anticancer active ingredients are:
(1) 20-40% erlotinib or gefitinib;
(2) 20-40% melphalan;
(3) 20% erlotinib or gefitinib in combination with 20-40% melphalan.
Example 11
40mg of (LAEG-EOP) copolymer with the molecular weight peak value of 20000-45000p and 30mg of PLA copolymer with the molecular weight peak value of 10000-25000 p are placed into a container, 100 ml of dichloromethane is added, after the mixture is dissolved and mixed evenly, 10mg of tumorigenin and 20mg of erlotinib 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 tumorigenin and 20% of erlotinib. Then the microspheres are prepared into the corresponding sustained-release implant by a tabletting method. The slow release implant has the release time of 40-45 days in vitro physiological saline and the release time of about 45 days under the skin of a mouse.
Example 12
The steps of the method for processing the sustained-release implant are the same as the example 11, but the difference is that the used auxiliary materials are (LAEG-EOP) with the molecular weight peak value of 40000-65000p and PLA with the molecular weight peak value of 25000-45000, and the anti-cancer active ingredients are as follows:
(1) 10-20% cyclophosphamide, melphalan, tumorigenin, ifosfamide or 4H peroxycyclophosphamide; or
(2) 10-20% erlotinib or polyene erlotinib in combination with 10-20% cyclophosphamide, melphalan, meconin, ifosfamide, 4H-peroxycyclophosphamide, norcantharidin, meltupipa, uretepa or azatepa.
Example 13
40mg of polylactic acid (PLGA, 50: 50) with a molecular weight peak of 15000-35000 and 30 (LAEG-EOP) with a molecular weight peak of 20000-45000p are put into a container, 100 ml of dichloromethane is added, after being dissolved and mixed uniformly, 10mg of rapamycin and 20mg of 4H-peroxycyclophosphamide are added, after being shaken again, the microspheres for injection containing 10% of rapamycin 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 50-60 days in vitro physiological saline and the release time of about 60 days under the skin of a mouse.
Example 14
The procedure for manufacturing the sustained-release implant was the same as in examples 11 and 13, except that the anticancer active ingredient contained:
(1) 10-20% cyclophosphamide, melphalan, tumorigenin, ifosfamide, 4H peroxycyclophosphamide, uretepa or azatepa; or
(2) 10-20% erlotinib or rapamycin; or
(3) 10-20% erlotinib or rapamycin in combination with 10-20% cyclophosphamide, melphalan, tumorigenin, ifosfamide, 4H-peroxycyclophosphamide, uretepa or azatepa.
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) p (BHET-EOP/TC), p (LAEG-EOP), p (DAPG-EOP), p (BHDPT-EOP/TC), p (CHDM-HOP) or p (CHDM-EOP);
b) a combination of p (BHET-EOP/TC), p (LAEG-EOP), p (DAPG-EOP), p (BHDPT-EOP/TC), p (CHDM-HOP) or p (CHDM-EOP) and a copolymer (PLGA) of polyglycolic acid and glycolic acid having 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) a combination of p (BHET-EOP/TC), p (LAEG-EOP), p (DAPG-EOP), p (BHDPT-EOP/TC), p (CHDM-HOP) or p (CHDM-EOP) with polylactic acid (PLA) having a molecular weight peak of 10000-;
d) p (BHET-EOP/TC), p (LAEG-EOP), p (DAPG-EOP), p (BHDPT-EOP/TC), p (CHDM-HOP) or a combination of p (CHDM-EOP) and polifeprosan, wherein the ratio of p-carboxyphenylpropane (p-CPP) to Sebacic Acid (SA) in the polifeprosan is 10: 90, 20: 80, 30: 70, 40: 60, 50: 50 or 60: 40;
e) combinations of P (BHET-EOP/TC), P (LAEG-EOP), P (DAPG-EOP), P (BHDPT-EOP/TC), P (CHDM-HOP) or P (CHDM-EOP) with a di-fatty acid and sebacic acid copolymer (PFAD-SA) ], poly (erucic acid dimer sebacic acid) [ P (EAD-SA) ], poly (fumaric acid sebacic acid) [ P (FA-SA) ], xylitol, oligosaccharides, chondroitin, chitin, chitosan, poloxamer, hyaluronic acid, collagen, gelatin or gelatin; or
f) PLA or PLGA in combination with polifeprosan or silicone.
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
The procedure for manufacturing the sustained-release implant was the same as in examples 11 and 13, except that the anticancer active ingredient contained:
(a) 5-30% of vandetanib, tipifarnib, sirolimus, rapamycin, lenalidomide, ixatecan, gefitinib, erlotinib, lapatinib, vatalanib, pelitinib, carboxyamidotriazole, thalidomide, ranolamide, angiostatin, endostatin, angiostatin, englestatin, imatinib mesylate, semasinib, dasatinib, avastin, canatinib, sorafenib, sunitinib, telosta, panitoma, marimastat, SU5416, SU6668, fumagillin or TNP-470; or
(b) 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
(c) 5-30% of vandetanib, tipifarnib, sirolimus, rapamycin, lenalidomide, ixotecan, gefitinib, erlotinib, lapatinib, vatalanib, pelitinib, carboxyamidotriazole, thalidomide, ranolamide, angiostatin, endostatin, englestatin, imatinib mesylate, semasinib, dasatinib, avastin, canatinib, sorafenib, sunitinib, teosarta, panitoma, marimastat, SU5416, SU6668, fumagillin or TNP-470 in combination with 5-30% of cyclophosphamide, melphalan, onconine, ifosfamide, 4H-peroxycyclophosphamide, desmosine, meltutepa, uretipipepa or azatepa.
Example 18 comparison of drug Release characteristics of different Release excipients and their combination (Table 7)
The procedure of the method for manufacturing the sustained-release implant is the same as that of example 11, and the release characteristics of different sustained-release excipients and the combined sustained-release excipients are compared. The first day of drug release (in vitro) exceeds 20% of the total is burst release.
TABLE 7
Sustained release excipients Molecular weight Medicine and content Time of release (Tian) Whether there is a burst release
(1) PLA (2) PLGA (50/50) (3) polifeprosan (20/80) (4) p (LAEG-EOP) (1): (4): 1 (2): 4): 1 (3): 4): 1 (5)) PLA (6) PLGA (75/25) (7) polifeprosan (50/50) (8) p (DAPG-EOP) (5): 8): 6: 4 (6): 8): 7: 3 (7): 8): 5 10000-2500020000-4000020000-4000015000-3500025000-4500010000-2000010000-2000035000-55000 Erlotinib (20%) melphalan (5%) 222810484244402424854505246 Whether or not it is present or not is not present or not
The data in the table show that when the anhydroglucose high-molecular polymers such as PLA, PLGA (50/50), polifeprosan (20/80) and the like are independently applied, the drug release is fast, wherein the drug release time of the polifeprosan is 8-10 days and the polifeprosan has obvious burst release. The polyphosphate ester high molecular polymers such as p (LAEG-EOP) and p (DAPG-EOP) are slow and stable in drug release, and when the polyphosphate ester high molecular polymers are combined with the sugar anhydride high molecular polymers such as PLA, PLGA and polifeprosan, the burst release caused by the sugar anhydride high molecular polymers can be reduced, but the stable and slow drug release characteristics are not greatly influenced.
Example 19 comparison of drug Release characteristics of different Release excipients and their combinations (Table 8)
The procedure of the method for manufacturing the sustained-release implant is the same as that of example 11, and the release characteristics of different sustained-release excipients and the combined sustained-release excipients are compared. The first day of drug release (in vitro) exceeds 20% of the total is burst release.
TABLE 8
Sustained release excipients Molecular weight Medicine and content Time of release (Tian) Whether there is a burst release
(1) PLA (2) PLGA (50/50) (3) polifeprosan (20/80) (4) p (LAEG-EOP) (1): (4): 1 (2): 4): 1 (3): 4): 1 (5)) PLA (6) PLGA (75/25) (7) polifeprosan (50/50) (8) p (DAPG-EOP) (5): 8): 6: 4 (6): 8): 7: 3 (7): 8): 5 20000-3500030000-4500020000-4000025000-4500025000-4500020000-4000020000-4000035000-55000 Tipifarnib (20%) cyclophosphamide (10%)) 2532114843454227251357555250 Whether or not it is present or not is not present or not
The data in the table show that when the anhydroglucose high-molecular polymers such as PLA, PLGA (50/50), polifeprosan (20/80) and the like are independently applied, the drug release is fast, wherein the drug release time of the polifeprosan is 10-13 days and the polifeprosan has obvious burst release. The polyphosphate ester high molecular polymers such as p (LAEG-EOP) and p (DAPG-EOP) are slow and stable in drug release, and when the polyphosphate ester high molecular polymers are combined with the sugar anhydride high molecular polymers such as PLA, PLGA and polifeprosan, the burst release caused by the sugar anhydride high molecular polymers can be reduced, but the stable and slow drug release characteristics are not greatly influenced. This unexpected finding constitutes a further main technical feature of the present invention. Because the polyphosphate ester high molecular polymer is expensive, the cost of the sustained-release preparation can be reduced, and the drug release characteristic of the sustained-release preparation can be improved.
The above examples are intended to illustrate, but not limit, the application of the invention.
The invention is disclosed and claimed.

Claims (10)

1. An anticancer composition carrying both a neovascular inhibitor and an alkylating agent is characterized in that the anticancer composition is a sustained-release injection and comprises the following components:
(A) a sustained release microsphere comprising:
0.5-70% of anticancer active ingredient
Sustained release auxiliary materials 30-99%
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 effective anticancer component is a neovascular inhibitor and/or an alkylating agent;
the suspending agent has viscosity of 100-3000 cp (at 20-30 deg C), and is selected from one or more of sodium carboxymethylcellulose, iodoglycerol, dimethicone, propylene glycol, carbomer, mannitol, sorbitol, surfactant, Tween-20, Tween-40 and Tween-80.
2. The sustained-release anticancer injection according to claim 1, wherein the angiogenesis inhibitor is selected from vandetanib, tipifarnib, sirolimus, rapamycin, lenalidomide, ixatecan, gefitinib, erlotinib, lapatinib, volatinib, pelitinib, carboxyamidotriazole, thalidomide, ranolamide, angiostatin, endostatin, englerin, imatinib mesylate, sematinib, dasatinib, avastin, canatinib, sorafenib, sunitinib, teoseta, panitumumab, marimastat, SU5416, SU6668, fumagillin, TNP-470 or their combination.
3. The sustained-release anticancer injection as claimed in claim 1, wherein the alkylating agent is selected from one of cyclophosphamide, melphalan, tumorigenin, ifosfamide, 4H-peroxycyclophosphamide, cyclophosphamide, macsfamide, perfosfamide, hexamethylpyrimidineamine, cantharidin, norcantharidin, mannosuman, troosulfan, ritrosufan, improsulfan, etoglut, pipobroman, piposulfan, canonin, epoxy piperazine, zotepa, purepitepa, meltutepa, uretepa, and azatepa, or a combination thereof.
4. The sustained-release anticancer injection according to claim 1, wherein the weight ratio of the neovascularization inhibitor and the alkylating agent is 1-9: 1 to 1: 1-9.
5. The sustained-release anticancer injection according to claim 1, wherein the sustained-release anticancer injection comprises the following anticancer active ingredients:
(a) 5-30% of vandetanib, tipifarnib, sirolimus, rapamycin, lenalidomide, ixatecan, gefitinib, erlotinib, lapatinib, vatalanib, pelitinib, carboxyamidotriazole, thalidomide, ranolamide, angiostatin, endostatin, angiostatin, englestatin, imatinib mesylate, semasinib, dasatinib, avastin, canatinib, sorafenib, sunitinib, telosta, panitoma, marimastat, SU5416, SU6668, fumagillin or TNP-470; or
(b) 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
(c) 5-30% of vandetanib, tipifarnib, sirolimus, rapamycin, lenalidomide, ixotecan, gefitinib, erlotinib, lapatinib, vatalanib, pelitinib, carboxyamidotriazole, thalidomide, ranolamide, angiostatin, endostatin, englestatin, imatinib mesylate, semasinib, dasatinib, avastin, canatinib, sorafenib, sunitinib, teosarta, panitoma, marimastat, SU5416, SU6668, fumagillin or TNP-470 in combination with 5-30% of cyclophosphamide, melphalan, onconine, ifosfamide, 4H-peroxycyclophosphamide, desmosine, meltutepa, uretipipepa or azatepa.
The above are all weight percentages.
The slow release auxiliary material is one or the combination of the following materials:
a) poly (1, 4-bis (hydroxyethyl) terephthalate-co-ethyl phosphate/terephthalate ester hydrochloride), poly (L-lactide-co-ethyl phosphate, poly (L-lactide-co-propyl phosphate), poly (1, 4-bis (hydroxyethyl) terephthalate-co-4-dimethylaminopyridine-co-ethyl phosphate/terephthalate ester hydrochloride), poly (trans- (formula) -1, 4-dimethylcyclohexane-ethyl phosphate), or poly (trans- (formula) -1, 4-dimethylcyclohexane-hexylphosphorodichloridate (p (CHDM-EOP));
b) poly (1, 4-bis (hydroxyethyl) terephthalate-co-ethyl phosphate/terephthalate ester hydrochloride), poly (L-lactide-co-ethyl phosphate, poly (L-lactide-co-propyl phosphate), poly (1, 4-bis (hydroxyethyl) terephthalate-co-4-dimethylaminopyridine-co-ethyl phosphate/terephthalate ester hydrochloride), poly (trans- (formula) -1, 4-dimethylcyclohexane-ethyl phosphate) or poly (trans- (formula) -1, 4-dimethylcyclohexane-hexylphosphorodichloridate (p (CHDM-EOP)) with a copolymer of polyglycolic acid and glycolic acid, wherein the ratio of polyglycolic acid to glycolic acid is 50-95: 50-50;
c) a combination of poly (1, 4-bis (hydroxyethyl) terephthalate-co-ethyl phosphate/terephthalate ester hydrochloride), poly (L-lactide-co-ethyl phosphate, poly (L-lactide-co-propyl phosphate), poly (1, 4-bis (hydroxyethyl) terephthalate-co-4-dimethylaminopyridine-co-ethyl phosphate/terephthalate ester hydrochloride), poly (trans- (formula) -1, 4-dimethylcyclohexane-ethyl phosphate), or poly (trans- (formula) -1, 4-dimethylcyclohexane-hexylphosphorodichloridate (p (CHDM-EOP)) with polylactic acid;
d) poly (1, 4-bis (hydroxyethyl) terephthalate-co-ethyl phosphate/terephthalate ester hydrochloride), poly (L-lactide-co-ethyl phosphate, poly (L-lactide-co-propyl phosphate), poly (1, 4-bis (hydroxyethyl) terephthalate-co-4-dimethylaminopyridine-co-ethyl phosphate/terephthalate ester hydrochloride), poly (trans) -1, 4-dimethylcyclohexane-ethyl phosphate) or poly (trans) -1, 4-dimethylcyclohexane-hexylphosphorodiamidate (p (CHDM-EOP)) with polifeprosan, wherein the ratio of p-carboxyphenylpropane to sebacic acid in polifeprosan is 10: 90, 20: 80, 30: 70, p-xylylene-p-hexylphosphorate (p (CHDM-EOP)) and polifeprosan, 40: 60, 50: 50 or 60: 40; or
e) Poly (1, 4-bis (hydroxyethyl) terephthalate-co-ethyl phosphate/terephthalate ester hydrochloride), poly (L-lactide-co-ethyl phosphate, poly (L-lactide-co-propyl phosphate), poly (1, 4-bis (hydroxyethyl) terephthalate-co-4-dimethylaminopyridine-co-ethyl phosphate/terephthalate ester hydrochloride), poly (trans) -1, 4-dimethylcyclohexane-ethyl phosphate) or poly (trans) -1, 4-dimethylcyclohexane-hexyldichlorophosphate (p (CHDM-EOP)) with a copolymer of di-fatty acid and sebacic acid, poly (erucic acid dimer-sebacic acid), poly (fumaric acid-sebacic acid), Xylitol, oligosaccharide, chondroitin, chitin, chitosan, poloxamer, hyaluronic acid, collagen, gelatin or egg gelatin; or
f) PLA or PLGA in combination with polifeprosan or silicone.
6. The slow released anticancer injection as claimed in claims 1 and 5, characterized in that the suspending agent is one or the combination of the following:
a) 0.5-3.0% carboxymethylcellulose (sodium);
b) 5-15% mannitol;
c) 5-15% sorbitol;
d) 0.1-1.5% of surface active substances;
e) 0.1-0.5% tween 20; or
f) Glycerin, dimethicone, propylene glycol, or carbomer.
7. The sustained-release anticancer injection according to claim 1, wherein the suspending agent is one of the following:
A) 0.5-5% of sodium carboxymethylcellulose and 0.1-0.5% of Tween 80;
B) 5-20% of mannitol and 0.1-0.5% of Tween 80; or
C)0.5 to 5 percent of sodium carboxymethylcellulose, 5 to 20 percent of sorbitol and 0.1 to 0.5 percent of Tween 80.
8. The anticancer sustained release microspheres of claim 1, used for preparing sustained release implant.
9. The sustained-release anticancer implant according to claim 8, characterized in that the anticancer active ingredients are:
(1) 5-25% cyclophosphamide, melphalan, ifosfamide or 4H-peroxycyclophosphamide; or
(2) 1-40% of vandetanib, tipifarnib, sirolimus, rapamycin, lenalidomide, ixatecan, gefitinib, erlotinib, lapatinib, vatalanib, pelitinib, carboxyamidotriazole, thalidomide, ranolamide, angiostatin, endostatin, angiostatin, endstatin, englerin, imatinib mesylate, semasinib, dasatinib, avastin, canatinib, sorafenib, sunitinib, telosta, panitoma, marimastat, SU5416, SU6668, fumagillin or TNP-470; or
(3) 5-30% of vandetanib, tipifarnib, sirolimus, rapamycin, lenalidomide, ixotecan, gefitinib, erlotinib, lapatinib, voltalanib, pelitinib, carboxyamidotriazole, thalidomide, ranolamide, angiostatin, endostatin, englestatin, imatinib mesylate, semasinib, dasatinib, avastin, canatinib, sorafenib, sunitinib, telosta, panitoma, marimastat, SU5416, SU6668, fumagillin or TNP-470 in combination with 1-30% of cyclophosphamide, melphalan, ifosfamide, 4H-peroxycyclophosphamide or norcantharidin.
The slow release auxiliary material is selected from phosphate ester high molecular polymer or the mixture or copolymer of phosphate ester high molecular polymer and polysaccharide anhydride high molecular polymer.
10. The sustained-release anticancer implant according to claim 8, characterized in that the sustained-release excipients are selected from one of the following:
a) poly (1, 4-bis (hydroxyethyl) terephthalate-co-ethyl phosphate/terephthalate ester hydrochloride), poly (L-lactide-co-ethyl phosphate, poly (L-lactide-co-propyl phosphate), poly (1, 4-bis (hydroxyethyl) terephthalate-co-4-dimethylaminopyridine-co-ethyl phosphate/terephthalate ester hydrochloride), poly (trans- (formula) -1, 4-dimethylcyclohexane-ethyl phosphate), or poly (trans- (formula) -1, 4-dimethylcyclohexane-hexylphosphorodichloridate (p (CHDM-EOP));
b) poly (1, 4-bis (hydroxyethyl) terephthalate-co-ethyl phosphate/terephthalate ester hydrochloride), poly (L-lactide-co-ethyl phosphate, poly (L-lactide-co-propyl phosphate), poly (1, 4-bis (hydroxyethyl) terephthalate-co-4-dimethylaminopyridine-co-ethyl phosphate/terephthalate ester hydrochloride), poly (trans- (formula) -1, 4-dimethylcyclohexane-ethyl phosphate) or poly (trans- (formula) -1, 4-dimethylcyclohexane-hexylphosphorodichloridate (p (CHDM-EOP)) with a copolymer of polyglycolic acid and glycolic acid, wherein the ratio of polyglycolic acid to glycolic acid is 50-95: 50-50;
c) a combination of poly (1, 4-bis (hydroxyethyl) terephthalate-co-ethyl phosphate/terephthalate ester hydrochloride), poly (L-lactide-co-ethyl phosphate, poly (L-lactide-co-propyl phosphate), poly (1, 4-bis (hydroxyethyl) terephthalate-co-4-dimethylaminopyridine-co-ethyl phosphate/terephthalate ester hydrochloride), poly (trans- (formula) -1, 4-dimethylcyclohexane-ethyl phosphate), or poly (trans- (formula) -1, 4-dimethylcyclohexane-hexylphosphorodichloridate (p (CHDM-EOP)) with polylactic acid;
d) poly (1, 4-bis (hydroxyethyl) terephthalate-co-ethyl phosphate/terephthalate ester hydrochloride), poly (L-lactide-co-ethyl phosphate, poly (L-lactide-co-propyl phosphate), poly (1, 4-bis (hydroxyethyl) terephthalate-co-4-dimethylaminopyridine-co-ethyl phosphate/terephthalate ester hydrochloride), poly (trans) -1, 4-dimethylcyclohexane-ethyl phosphate) or poly (trans) -1, 4-dimethylcyclohexane-hexylphosphorodiamidate (p (CHDM-EOP)) with polifeprosan, wherein the ratio of p-carboxyphenylpropane to sebacic acid in polifeprosan is 10: 90, 20: 80, 30: 70, p-xylylene-p-hexylphosphorate (p (CHDM-EOP)) and polifeprosan, 40: 60, 50: 50 or 60: 40; or
e) Poly (1, 4-bis (hydroxyethyl) terephthalate-co-ethyl phosphate/terephthalate ester hydrochloride), poly (L-lactide-co-ethyl phosphate, poly (L-lactide-co-propyl phosphate), poly (1, 4-bis (hydroxyethyl) terephthalate-co-4-dimethylaminopyridine-co-ethyl phosphate/terephthalate ester hydrochloride), poly (trans) -1, 4-dimethylcyclohexane-ethyl phosphate) or poly (trans) -1, 4-dimethylcyclohexane-hexylphosphorodiamidate (p (CHDM-EOP)) with a copolymer of di-fatty acid and sebacic acid, poly (erucic acid dimer sebacic acid), poly (fumaric acid sebacic acid), xylitol, and mixtures thereof, A combination of oligosaccharide, chondroitin, chitin, chitosan, poloxamer, hyaluronic acid, collagen, gelatin or egg gelatin; or
f) PLA or PLGA in combination with polifeprosan or silicone.
CNA2007102004399A 2007-04-12 2007-04-12 Anti-cancer composition carried with new-born blood-vessel inhibiting agent and alkalating agent Pending CN101023930A (en)

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