CN1969823A

CN1969823A - Sustained release agent containing fluorouracil and synergist thereof

Info

Publication number: CN1969823A
Application number: CNA2006102009415A
Authority: CN
Inventors: 孔庆忠; 栾永祖
Original assignee: Shandong Lanjin Pharmaceuticals Co Ltd
Current assignee: Shandong Lanjin Pharmaceuticals Co Ltd
Priority date: 2006-09-28
Filing date: 2006-09-28
Publication date: 2007-05-30

Abstract

Disclosed is an anticancer slow release injection containing fluorouracil and synergistic agents, which comprises slow release micro-balloons and dissolvent, wherein the slow release microballoons comprise anti-cancer active constituents and slow release auxiliary materials, the dissolvent being specific dissolvent containing suspension adjuvant. The suspending agent is selected from sodium carboxymethylcellulose, mannitol, sorbitol, Tween-80 or their combination. The anticancer active constituents are the combination of 5-FU and Paclitaxel, camptothecine and Vinorelbine. The slow release auxiliary materials are selected from polylactic acid, ethylene-vinylacetate copolymer, Polifeprosan, FAD, sebacic acid copolymer, polyglycolic acid and glycolic acid copolymer or their combination. The viscosity of the injection 50-1000cp (at 20-30 deg C). The slow release microspheres can also be prepared into slow release implanting agent. When in-tumor or around-tumor injected or placed, the slow release agent can not only lower down the whole body toxicity reaction of the anti-cancer medicament, but also can selectively increase the tumor local medicinal concentration, and improve the treatment effect of the non-operative treatment methods such as chemotherapy, medicament and radiation.

Description

Sustained-release agent containing fluorouracil and synergist thereof

(I) technical field

The invention relates to a sustained release preparation containing fluorouracil (5-FU) and a synergist thereof and a preparation method thereof, belonging to the technical field of medicines. The sustained release agent is mainly sustained release injection and sustained release implant.

(II) background of the invention

As a common chemotherapeutic drug, 5-fluorouracil (5-FU) is widely applied to the treatment of various malignant tumors and has obvious effect. However, its unexpected neurotoxicity greatly limits the use of this drug. Blood vessels, connective tissues, matrix proteins, fibrin and collagen in tumor stroma not only provide a scaffold and essential nutrients for the growth of tumor cells, but also influence the penetration and diffusion of chemotherapeutic drugs around tumors and in tumor tissues (see Niti et al, "influence of extracellular stroma conditions on drug transport in solid tumors" ("Cancer research 60: 2497 and 503 (2000)) (Netti PA, Cancer Res.2000, 60 (9): 2497503)). Due to the fact that solid tumors are over-swollen and hyperplastic, and the interstitial pressure, the tissue elastic pressure, the fluid pressure and the interstitial viscosity are higher than those of the surrounding normal tissues, the effective drug concentration is difficult to form locally in the tumor in conventional chemotherapy, see Kongqing et al, "cisplatin and systemic carmustine can be placed in the tumor to treat the brain tumor of rats" [ J. Otsugaku et al, J. Surginocol.1998 Oct. (69 (2): 7682) ], and the simple increase of the administration dose is limited by the systemic reaction. The local application of the medicine may solve the problem of the concentration of the medicine to some extent (Chinese patent), however, the operation operations such as medicine implantation and the like are complex and traumatic, and can cause or accelerate the diffusion and metastasis of tumors besides easily causing various complications such as bleeding, infection, immunity reduction and the like. In addition, the preparation itself before and after the operation and the high cost often affect the effective implementation.

In addition, DNA repair function in many tumor cells is significantly increased following chemotherapy. The latter often leads to an increased tolerance of the tumor cells to anticancer drugs, with consequent therapeutic failure.

In addition, low dose anti-cancer drug therapy not only increases drug tolerance but also promotes invasive growth of cancer cells (see beam et al, "increasing drug tolerance and in vitro infiltration capacity of human lung cancer cells with altered gene expression after anti-cancer drug pulse screening" [ J.Immunol.Cancer, 111, et al, pp.484-93 (2004) ] (Liang Y, et al, Int J cancer.2004; 111 (4): 484-93)).

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

5-fluorouracil is a commonly used anticancer drug and has been widely used for treating various tumors, such as colorectal cancer and the like. 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 of drug in the circulatory system, a drug sustained-release system containing 5-fluorouracil has been studied, which comprises sustained-release microspheres (capsules) (see (Chinese patent No. ZL 00809160.9; application No. 91109723.6), Ciftci K, etc. 'research on treating solid tumor and drug release using fluorouracil-containing polylactic acid microspheres' drug development technology (Pharm Dev Technol.)2 (2): 151-60, 1997), sustained-release implant (see (Chinese patent No. ZL 96115937.5; ZL97107076.8), etc. However, the solid sustained-release implant (Chinese patent No. ZL 96115937.5; ZL97107076.8) 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 5-fluorouracil, and are susceptible to development of resistance during treatment. The present invention has found that the combination of 5-FU with the drug mentioned in the present invention enhances the anticancer effect (hereinafter, the drug capable of enhancing the anticancer effect of 5-FU is referred to as 5-FU potentiator).

In addition, the anti-cancer drug sustained-release injection prepared by packaging the combination of 5-FU and the synergist thereof in a specific sustained-release auxiliary material and matching with a special solvent can greatly improve the local drug concentration of tumors, reduce the drug concentration of the drugs in the circulatory system, reduce the toxicity of the drugs to normal tissues, greatly facilitate the drug injection, reduce the complications of surgical operation and reduce the cost of patients. The 5-FU synergist can inhibit tumor growth and increase the sensitivity of tumor cells to anticancer drugs.

The present invention has found that not all excipients are effective in releasing 5-FU. 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 the 5-FU selected by the invention 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 medicine which can be slowly released can be determined through a large number of creative labor. The related data, particularly the data of the release characteristics in animals, can be obtained through a large number of creative experiments in vivo and in vitro, can not be determined through limited experiments, and is non-obvious.

The sustained release of the local drug can ensure the lasting and stable drug concentration in the local application range, obviously reduce the drug concentration of the whole body and reduce the toxic and side effects.

Aiming at the defects of the prior art, the invention provides a sustained release preparation containing 5-FU and a synergist thereof. The sustained release preparation comprises an anticancer active ingredient and a medicinal sustained release adjuvant. Mainly comprises a slow release injection and a slow release implant

Aiming at the defects of the prior art, the invention provides a novel sustained-release injection containing fluorouracil and 5-fluorouracil synergist.

One form of the invention is a sustained-release injection, which consists of sustained-release microspheres and a solvent. Specifically, the anticancer sustained-release injection consists of the following components:

(A) a sustained release microsphere comprising:

0.5-60% of anticancer active ingredient

Sustained release auxiliary materials 40-99%

0.0 to 30 percent of suspending agent

The above are weight percentages

And

(B) the solvent is common solvent or special solvent containing suspending agent.

Wherein,

the anticancer effective component is 5-FU and 5-FU synergist, and the 5-FU synergist is selected from taxol, camptothecin, and vinorelbine; the slow release auxiliary material comprises one or the combination of the following components: the polylactic acid-based coating comprises one or a combination of racemic polylactic acid, racemic polylactic acid/glycolic acid copolymer, monomethyl polyethylene glycol/polylactic acid copolymer, polyethylene glycol/polylactic acid copolymer, carboxyl-terminated polylactic acid/glycolic acid copolymer, polifeprosan, di-fatty acid and sebacic acid copolymer, poly (erucic acid dimer-sebacic acid), poly (fumaric acid-sebacic acid), ethylene vinyl acetate copolymer, polylactic acid, polyglycolic acid and glycolic acid copolymer, xylitol, oligosaccharide, chondroitin, chitin, hyaluronic acid, collagen, gelatin and albumin glue.

Among the various polymers, preferred are polylactic acid, sebacic acid, and a mixture or copolymer of polylactic acid and sebacic acid, and the mixture or copolymer can be selected from, but not limited to, PLA, PLGA, a mixture of glycolic acid and hydroxycarboxylic acid, and a mixture or copolymer of sebacic acid and an aromatic polyanhydride or an aliphatic polyanhydride. The blending ratio of glycolic acid and hydroxycarboxylic acid is 10/90-90/10 (by weight), preferably 25/75-75/25 (by weight). The method of blending is arbitrary. The contents of glycolic acid and hydroxycarboxylic acid in copolymerization are 10-90 wt% and 90-10 wt%, respectively. Representative of the aromatic polyanhydrides are polifeprosan [ poly (1, 3 di (P-carboxyphenoxy) propane-sebacic acid) (P (CPP-SA)), di-fatty acid sebacic acid copolymer (PFAD-SA) ], poly (erucic acid dimer sebacic acid) [ P (EAD-SA) ], and poly (fumaric acid sebacic acid) [ P (FA-SA) ], and the like. The 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.

The molecular weight peak of polylactic acid may be, but is not limited to, 5000-100,000, but is preferably 20,000-60,000, and most preferably 5,000-30,000; the molecular weight of polyglycolic acid may be, but is not limited to, 5000-; the polyhydroxy acids can be selected singly or in multiple ways. When selected alone, polylactic acid (PLA) or a copolymer of hydroxycarboxylic acid and glycolic acid (PLGA) is preferred, and the molecular weight of the copolymer may be, but is not limited to, 5000-100,000, but is preferably 20,000-60,000, and is most preferably 30,000-50,000; when more than one choice is selected, the polymer or the composite polymer or copolymer of different polymers is preferred, and the composite polymer or copolymer of polylactic acid or sebacic acid with different molecular weight is most preferred, such as, but not limited to, polylactic acid with molecular weight of 1000 to 30000 mixed with polylactic acid with molecular weight of 20000 to 50000, polylactic acid with molecular weight of 10000 to 30000 mixed with PLGA with molecular weight of 30000 to 80000, polylactic acid with molecular weight of 20000 to 30000 mixed with sebacic acid, PLGA with molecular weight of 30000 to 80000 mixed with sebacic acid. The polylactic acid used is preferably L-polylactic acid (L-PLA). The viscosity range IV (dl/g) of the L-polylactic acid (L-PLA) is 0.2-0.8, the glass transition temperature range is 55-65 ℃, and the melting point is 175-185 ℃.

In addition to the above sustained-release excipients, other substances can be selected and used as described in detail in U.S. Pat. Nos. 4757128, 4857311, 4888176 and 4789724 and "pharmaceutical excipients" in general (p. 123, published by Sichuan scientific and technical Press 1993, compiled by Roming and Gaoyun). 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, 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, fillers, solubilizers, absorption enhancers, film-forming agents, gelling agents, pore-forming agents, excipients, or retarders may also be added.

The weight percentage of the synergist (paclitaxel, camptothecin and vinorelbine) in the sustained release agent is 0.1-60%, preferably 1-50%, and most preferably 5-30%.

The anticancer active ingredient is the combination of 5-FU and a synergist thereof. When the anticancer drug in the drug sustained-release microspheres is only 5-FU synergist, the anticancer sustained-release injection is mainly used for increasing the effect of 5-FU applied by other ways or the synergism of radiotherapy or other therapies. When used for increasing the action effect of 5-FU applied by other routes, the 5-FU can be administered by artery, vein or local injection and placement.

The weight percentage of the anticancer active ingredients in the sustained-release microspheres is 0.5-60%, preferably 2-40%, and most preferably 5-30%. The weight ratio of the 5-FU to the 5-FU synergist is 1-9: 1 to 1: 1-9. Preferably 1-2: 1.

The anticancer active ingredients in the anticancer sustained-release microspheres of the invention preferably have the following weight percentages:

5-30% of 5-FU in combination with 5-30% of paclitaxel, camptothecin or vinorelbine.

The weight percentage of the anticancer active ingredients in the anticancer sustained-release microspheres is most preferably as follows:

(a) 5-30% of 5-FU and 5-30% of paclitaxel;

(b) 5-30% of 5-FU and 5-30% of camptothecin;

(c) 5-30% of 5-FU and 5-30% of vinorelbine.

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 can 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 individually, 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.

Among the various polymers, preferred are polylactic acid, sebacic acid, and a mixture or copolymer of polylactic acid and sebacic acid, and the mixture or copolymer can be selected from, but not limited to, PLA, PLGA, a mixture of glycolic acid and hydroxycarboxylic acid, and a mixture or copolymer of sebacic acid and an aromatic polyanhydride or an aliphatic polyanhydride. The blending ratio of glycolic acid and hydroxycarboxylic acid is 10/90-90/10 (by weight), preferably 25/75-75/25 (by weight). The method of blending is arbitrary. The contents of glycolic acid and hydroxycarboxylic acid in copolymerization are 10-90 wt% and 90-10 wt%, respectively. Representative of the aromatic polyanhydrides are polifeprosan [ poly (1, 3-di (P-carboxyphenoxy) propane sebacic acid) (P (CPP-SA)), di-fatty acid sebacic acid copolymer (PFAD-SA) ], poly (erucic acid dimer-sebacic acid) [ P (EAD-SA) ], and poly (fumaric acid-sebacic acid) [ P (FA-SA) ], and the like. The 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 adjuvants, other substances may be selected and used as described in detail in U.S. Pat. Nos. 4757128, 4857311, 4888176, 4789724 and the "pharmaceutical adjuvants Pan" (published by Sichuan scientific and technical Press 1993, published by Luoming and high-tech Master), and further, some pharmaceutical adjuvants including fillers, solubilizers, absorption promoters, film-forming agents, gelling agents, pore-forming agents, excipients or retarders are listed in the Chinese patent No. 96115937.5, 91109723.6, 9710703.3, 01803562.0 and the U.S. patent No. 5,651,986).

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 purpose of the suspending agent is 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 is determined by 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 consider 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, the viscosity is 10-650 cp (at 20-30 ℃).

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 a special solvent to prepare a corresponding suspension, then the water in the suspension is removed by methods such as vacuum drying, and the like, and then the suspension is suspended by the special solvent or a common solvent to obtain a 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, preferably 30-300mg/ml, and most preferably 50-200mg/ml, depending on the particular needs. 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, wherein the hydrophobic block forms a core, and the hydrophilic block forms a shell. The drug-loaded micelle is injected into the body to achieve the purpose of controlling the release of the drug or targeting therapy. The drug carrier is any one of the above or the combination thereof. Of these, polyethylene glycol (PEG) having a molecular weight of 1000-15000 is preferable as the hydrophilic block of the micelle copolymer, and biodegradable polymers such as PLA, polylactide, polycaprolactone and copolymers thereof (molecular weight 1500-25000) are preferable as the hydrophobic block of the micelle copolymer. The block copolymer micelles may have a particle size in the range of 10 to 300um, preferably 20 to 200 um. The gel injection is prepared by dissolving biodegradable polymer (such as PLA, PLGA or DL-LA and epsilon-caprolactone copolymer) in certain amphiphilic solvent, adding the medicine, mixing (or suspending) with the solvent to form gel with good fluidity, and can be injected around tumor or in tumor. Once injected, the amphiphilic solvent diffuses into the body fluid quickly, and the water in the body fluid permeates into the gel, so that the polymer is solidified and the drug is released slowly.

The sustained-release microspheres can also be used for preparing sustained-release implants, the used pharmaceutical excipients can be any one or more of the above pharmaceutical excipients, but water-soluble high molecular polymers are taken as the main choice, and in various high molecular polymers, polylactic acid, sebacic acid, a mixture or copolymer of high molecular polymers containing polylactic acid or sebacic acid are taken as the first choice, and the mixture and copolymer can be selected from, but are not limited to, PLA, PLGA, a mixture of PLA and PLGA, and a mixture or copolymer of sebacic acid and aromatic polyanhydride or aliphatic polyanhydride. The blending ratio of polylactic acid (PLA) to polyglycolic acid is 10/90 to 90/10 (by weight), preferably 25/75 to 75/25 (by weight). The method of blending is arbitrary. The contents of glycolic acid and lactic acid in copolymerization are respectively 10-90% and 90-10% by weight. The aromatic polyanhydride is represented by p-carboxyphenylpropane (p-CPP), the content of the p-carboxyphenylpropane (p-CPP) and sebacic acid in copolymerization is respectively 10-60% and 20-90% by weight, and the blending weight ratio is 10-40: 50-90, preferably 15-30: 65-85.

The other form of the anticancer drug sustained release preparation of the 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 a 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 weight percentage of the anticancer active ingredients in the sustained-release implant is as follows, 5-30% of 5-FU and 5-30% of the combination of taxol, camptothecin and vinorelbine.

The weight percentage of the anticancer active ingredients in the sustained-release implant is most preferably as follows:

(a) 5-30% of 5-FU and 5-30% of paclitaxel;

(b) 5-30% of 5-FU and 5-30% of camptothecin;

(c) 5-30% of 5-FU and 5-30% of vinorelbine.

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 cancers originating in the brain and central nervous system, and various solid tumors originating extracranially, such as primary or metastatic cancers of the kidney, liver, gallbladder, 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 sarcoma or carcinosarcoma, with brain, kidney, head and neck, thyroid, lung, esophagus, stomach, breast, pancreas, cervix, ovary, prostate, bladder, colorectal, 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 process of the invention is further described by the following tests and examples:

test 1 comparison of local drug concentrations after different modes of application of 5-FU

The white rat is used as a testObject, 2X 10⁵Individual prostate tumor cells were injected subcutaneously into the quaternary costal region and divided into the following 8 groups after the tumors had grown to 1 cm diameter (see table 1). The dose of each group was 5 mg/kg. The content (%) of the drug in the tumor was measured at different times.

TABLE 1

Test set (n)	Mode of administration	The amount of drug in the tumor on day one	The content of the drug in the tumor on the third day	The drug content in the tumor on day 7
Test set (n)	Mode of administration	The amount of drug in the tumor on day one	The content of the drug in the tumor on the third day	The drug content in the tumor on day 7	1(3)	Tail vein injection common injection	0.60	0.32	0.12
2(3)	Common injection for intraperitoneal injection	0.56	0.3	0.08	1(3)	Tail vein injection common injection	0.60	0.32	0.12
2(3)	Common injection for intraperitoneal injection	0.56	0.3	0.08	3(3)	General injection for injection around tumor	2.6	1.2	0.3
4(3)	Tumor injection slow-release injection	10	18	20	3(3)	General injection for injection around tumor	2.6	1.2	0.3
4(3)	Tumor injection slow-release injection	10	18	20	5(3)	Slow release implant placed around tumor	18	30	32
6(3)	General injection for intratumoral injection	4	2	1	5(3)	Slow release implant placed around tumor	18	30	32
6(3)	General injection for intratumoral injection	4	2	1	7(3)	Sustained-release injection for intratumoral injection	92	80	60
8(3)	Sustained-release implant placed in tumor	94	92	86	7(3)	Sustained-release injection for intratumoral injection	92	80	60

The results show that the local drug concentration difference of the 5-FU 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 after application of 5-FU in different ways

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 20 th day after treatment, and the therapeutic effect was compared.

TABLE 2

Test set (n)	Mode of administration	Tumor volume (cm)³)	P value
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	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	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	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	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 tumor inhibition effect difference of the 5-FU applied in different modes is obvious, the effective drug concentration of the tumor part can be obviously improved and effectively maintained by local administration, and the effect of placing the sustained-release implant in the tumor and injecting the sustained-release injection in the tumor is the best. However, the intratumoral injection of the sustained-release injection is most convenient and easy to operate. Not only has good curative effect, but also has little toxic and side effect.

Experiment 3, in vivo tumor inhibiting effect of synergist containing 5-FU and 5-FU (sustained release injection)

Using rat (Fisher344) as test object, 2 × 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 shown in the table. Tumor volume was measured on day 20 after treatment and the treatment effect was compared (see table 3).

TABLE 3

Test set (n)	Is receiving treatment (mg/kg)	Tumor volume (cm)³)	P value
Test set (n)	Is receiving treatment (mg/kg)	Tumor volume (cm)³)	P value	1(6)	Control	52±12
2(6)	5-FU(1)	44±10.4	＜0.05	1(6)	Control	52±12
2(6)	5-FU(1)	44±10.4	＜0.05	3(6)	5-FU(2)	34±8.0	＜0.01
4(6)	5-FU(4)	32±6.2	＜0.01	3(6)	5-FU(2)	34±8.0	＜0.01
4(6)	5-FU(4)	32±6.2	＜0.01	5(6)	5-FU(8)	24±6.0	＜0.01
6(6)	Paclitaxel (4)	36±6.0	＜0.01	5(6)	5-FU(8)	24±6.0	＜0.01
6(6)	Paclitaxel (4)	36±6.0	＜0.01	7(6)	5-FU (1) + taxol	32±6.2	＜0.001
8(6)	5-FU (2) + taxol	28±4.8	＜0.001	7(6)	5-FU (1) + taxol	32±6.2	＜0.001
8(6)	5-FU (2) + taxol	28±4.8	＜0.001	9(6)	5-FU (4) + taxol	20±3.6	＜0.001
10(6)	5-FU (8) + taxol	16±2.0	＜0.001	9(6)	5-FU (4) + taxol	20±3.6	＜0.001

The results show that 5-FU and the used 5-FU synergist (taxol) have obvious inhibition effect on tumor growth when being used alone at the concentration, and can show obvious synergistic effect when being used together. Among them, the inhibitory effect of 5-FU on tumor growth is dose-dependent.

Tests on the antitumor Effect of 4, 5-FU and 5-FU potentiators (sustained-release injections)

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. 5-FU and 5-FU potentiator 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 4.

TABLE 4

Tumor cell	5-FU	Camptothecin	Vinorelbine	Paclitaxel	5-FU + camptothecin	5-FU + vinorelbine	5-FU + paclitaxel
Tumor cell	5-FU	Camptothecin	Vinorelbine	Paclitaxel	5-FU + camptothecin	5-FU + vinorelbine	5-FU + paclitaxel	CNS	58％	52％	64％	42％	90％	84％	90％
C6	54％	64％	64％	44％	94％	84％	90％	CNS	58％	52％	64％	42％	90％	84％	90％
C6	54％	64％	64％	44％	94％	84％	90％	SA	48％	62％	56％	42％	88％	90％	92％
BC	44％	64％	54％	34％	94％	84％	82％	SA	48％	62％	56％	42％	88％	90％	92％
BC	44％	64％	54％	34％	94％	84％	82％	BA	48％	60％	62％	50％	90％	90％	90％
LH	50％	58％	62％	48％	90％	88％	84％	BA	48％	60％	62％	50％	90％	90％	90％
LH	50％	58％	62％	48％	90％	88％	84％	PAT	58％	52％	52％	34％	94％	86％	92％

The results show that the 5-FU and the 5-FU synergist (camptothecin, vinorelbine and taxol) 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.

Tests on the tumor-inhibiting action of 5, 5-FU and 5-FU synergist (sustained-release injection)

Using white rat as test object, 2X 10⁵Individual liver tumor cells were injected subcutaneously into the quaternary costal region and divided into the following 8 groups 14 days after tumor growth (see table 5). The first group was the control, and groups 2 to 8 were the treatment groups, with the sustained release implant placed intratumorally. The dosages of 5-FU and synergist are respectively 5mg/kg and 2.5 mg/kg. Tumor volume was measured on day 20 after treatment and the effect was compared (see table 5).

TABLE 5

Test set (n)	Is treated by	Tumor volume (cm)³)	P value
Test set (n)	Is treated by	Tumor volume (cm)³)	P value	1(6)	Control	50±10
2(6)	Paclitaxel	42±8.4	＜0.05	1(6)	Control	50±10
2(6)	Paclitaxel	42±8.4	＜0.05	3(6)	5-FU	36±6.8	＜0.01
4(6)	Paclitaxel +5-FU	30±6.4	＜0.001	3(6)	5-FU	36±6.8	＜0.01
4(6)	Paclitaxel +5-FU	30±6.4	＜0.001	5(6)	Camptothecin	46±6.0	＜0.01
6(6)	Camptothecin +5-FU	30±6.0	＜0.001	5(6)	Camptothecin	46±6.0	＜0.01
6(6)	Camptothecin +5-FU	30±6.0	＜0.001	7(6)	Vinorelbine	36±6.8	＜0.01
8(6)	Vinorelbine +5-FU	22±4.6	＜0.001	7(6)	Vinorelbine	36±6.8	＜0.01

The results show that the 5-FU and the 5-FU synergist (taxol, camptothecin and vinorelbine) 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.

Tests on the antitumor Effect of 6, 5-FU and 5-FU potentiators (sustained-release injections)

Using white rat as test object, 2X 10⁵Individual prostate tumor cells were injected subcutaneously into the limbus, and after 14 days of tumor growth they were divided into negative controls (blank), single drug treatment groups (5-FU or 5-FU potentiator), and combination treatment groups (5-FU and 5-FU potentiator). The medicine is injected intratumorally. The dosages of 5-FU and synergist are shown in Table 6. 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 6).

TABLE 6

Test set (n)	Is receiving treatment (mg/kg)	Tumor inhibition ratio (%)	P value
Test set (n)	Is receiving treatment (mg/kg)	Tumor inhibition ratio (%)	P value	1(6)	Control	-
2(6)	5-FU(4)	50	＜0.05	1(6)	Control	-
2(6)	5-FU(4)	50	＜0.05	3(6)	Paclitaxel (1)	44	＜0.01
4(6)	Paclitaxel (2)	48	＜0.01	3(6)	Paclitaxel (1)	44	＜0.01
4(6)	Paclitaxel (2)	48	＜0.01	5(6)	Paclitaxel (4)	58	＜0.01
6(6)	Paclitaxel (8)	62	＜0.01	5(6)	Paclitaxel (4)	58	＜0.01
6(6)	Paclitaxel (8)	62	＜0.01	7(6)	5-FU + paclitaxel (1)	72	＜0.001
8(6)	5-FU + paclitaxel (2)	80	＜0.001	7(6)	5-FU + paclitaxel (1)	72	＜0.001
8(6)	5-FU + paclitaxel (2)	80	＜0.001	9(6)	5-FU + paclitaxel (4)	88	＜0.001
10(6)	5-FU + paclitaxel (8)	92	＜0.001	9(6)	5-FU + paclitaxel (4)	88	＜0.001

The results show that the 5-FU and the 5-FU synergist (taxol) have obvious inhibition effect on the growth of tumor cells when being independently used at the concentration, and can show obvious synergistic effect when being used in combination.

Tests on the antitumor Effect of 7, 5-FU and 5-FU potentiators (sustained-release injections)

Using rat (Fisher344) as test object, 2 × 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 5-FU and synergist are shown in Table 7. 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 7).

TABLE 7

Test set (n)	Is receiving treatment (mg/kg)	Tumor inhibition ratio (%)	P value
Test set (n)	Is receiving treatment (mg/kg)	Tumor inhibition ratio (%)	P value	1(6)	Control	-
2(6)	5-FU(5)	54	＜0.05	1(6)	Control	-
2(6)	5-FU(5)	54	＜0.05	3(6)	Camptothecin (1)	40	＜0.01
4(6)	Camptothecin (2)	48	＜0.01	3(6)	Camptothecin (1)	40	＜0.01
4(6)	Camptothecin (2)	48	＜0.01	5(6)	Camptothecin (4)	52	＜0.01
6(6)	Camptothecin (8)	56	＜0.01	5(6)	Camptothecin (4)	52	＜0.01
6(6)	Camptothecin (8)	56	＜0.01	7(6)	5-FU + camptothecin (1)	68	＜0.001
8(6)	5-FU + camptothecin (2)	78	＜0.001	7(6)	5-FU + camptothecin (1)	68	＜0.001
8(6)	5-FU + camptothecin (2)	78	＜0.001	9(6)	5-FU + camptothecin (4)	84	＜0.001
10(6)	5-FU + camptothecin (8)	90	＜0.001	9(6)	5-FU + camptothecin (4)	84	＜0.001

The results show that the 5-FU and the 5-FU synergist (camptothecin) have obvious inhibition effect on the growth of tumor cells when being used independently at the concentration, and can show obvious synergistic effect when being used together.

Tests on the antitumor Effect of 8, 5-FU and 5-FU synergists (sustained-release implants)

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. Tumor volume was measured on day 20 after treatment, and the therapeutic effect was compared using tumor growth inhibition as an index (see table 8).

TABLE 8

Test set (n)	Is receiving treatment (mg/kg)	Tumor inhibition ratio (%)	P value
Test set (n)	Is receiving treatment (mg/kg)	Tumor inhibition ratio (%)	P value	1(6)	Control	-
2(6)	5-FU(10)	66	＜0.05	1(6)	Control	-
2(6)	5-FU(10)	66	＜0.05	3(6)	Paclitaxel (2)	38	＜0.05
4(6)	Paclitaxel (4)	46	＜0.05	3(6)	Paclitaxel (2)	38	＜0.05
4(6)	Paclitaxel (4)	46	＜0.05	5(6)	Paclitaxel (8)	54	＜0.05
6(6)	Paclitaxel (16)	60	＜0.01	5(6)	Paclitaxel (8)	54	＜0.05
6(6)	Paclitaxel (16)	60	＜0.01	7(6)	5-FU + paclitaxel (2)	78	＜0.01
8(6)	5-FU + paclitaxel (4)	84	＜0.01	7(6)	5-FU + paclitaxel (2)	78	＜0.01
8(6)	5-FU + paclitaxel (4)	84	＜0.01	9(6)	5-FU + paclitaxel (8)	86	＜0.01
10(6)	5-FU + paclitaxel (16)	96	＜0.001	9(6)	5-FU + paclitaxel (8)	86	＜0.01

The results show that the 5-FU and the 5-FU synergist (taxol) have obvious inhibition effect on the growth of tumor cells when being independently used at the concentration, and can show obvious synergistic effect when being jointly used, and the synergistic effect is in a dose-effect relationship.

Tests 9, 5-FU and 5-FU potentiators (sustained-release implants) for tumor inhibition

The tumor-inhibiting effect of 5-FU and 5-FU potentiators (sustained-release implants) was measured as described in test 8, and the tumor growth inhibition rate thereof is shown in Table 9.

TABLE 9

Test set (n)	Is receiving treatment (mg/kg)	Tumor inhibition ratio (%)	P value
Test set (n)	Is receiving treatment (mg/kg)	Tumor inhibition ratio (%)	P value	1(6)	Control	-
2(6)	5-FU(8)	56	＜0.05	1(6)	Control	-
2(6)	5-FU(8)	56	＜0.05	3(6)	Vinorelbine (2)	32	＜0.05
4(6)	Vinorelbine (4)	40	＜0.05	3(6)	Vinorelbine (2)	32	＜0.05
4(6)	Vinorelbine (4)	40	＜0.05	5(6)	Vinorelbine (8)	52	＜0.05
6(6)	Vinorelbine (16)	62	＜0.01	5(6)	Vinorelbine (8)	52	＜0.05
6(6)	Vinorelbine (16)	62	＜0.01	7(6)	5-FU + vinorelbine (2)	76	＜0.01
8(6)	5-FU + vinorelbine (4)	82	＜0.01	7(6)	5-FU + vinorelbine (2)	76	＜0.01
8(6)	5-FU + vinorelbine (4)	82	＜0.01	9(6)	5-FU + vinorelbine (8)	88	＜0.01
10(6)	5-FU + vinorelbine (16)	94	＜0.001	9(6)	5-FU + vinorelbine (8)	88	＜0.01

The results show that the 5-FU and the 5-FU synergist (vinorelbine) 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.

In conclusion, the 5-FU and various 5-FU synergists have obvious inhibition effect on the growth of various tumor cells when being used independently, and can show obvious synergistic effect when being used in combination. Therefore, the effective component of the invention is the combination of 5-FU and any 5-FU synergist. The medicine containing the above effective components can be made into sustained release microsphere, and further made into sustained release injection and implant, wherein suspension injection formed by combining with special solvent containing suspending agent is preferred.

The sustained-release injection or sustained-release implant can be further explained by the following embodiments. The above examples and the following examples are only for further illustration of the present invention and are not intended to limit the contents and uses thereof in any way.

(IV) detailed description of the preferred embodiments

Example 1.

80mg of polifeprosan (p-carboxyphenylpropane (p-CPP): Sebacic Acid (SA) is 20: 80) copolymer is respectively put into a container, then 100 ml of dichloromethane is added, 10mg of 5-FU and 10mg of paclitaxel are added after the mixture is dissolved and mixed evenly, and the microspheres for injection containing 10 percent of 5-FU and 10 percent of paclitaxel are prepared by a spray drying method after the mixture is shaken again evenly. Then suspending the microspheres in physiological saline containing 15 percent mannitol to prepare the corresponding suspension type sustained-release injection with the viscosity of 360-480 cp (at 25-30 ℃). 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.

80mg of polifeprosan (p-carboxyphenylpropane (p-CPP): Sebacic Acid (SA) 50: 50) copolymer is respectively put into a container, then 100 ml of dichloromethane is added, 5mg of 5-FU and 15mg of paclitaxel are added after the mixture is dissolved and mixed evenly, and the microspheres for injection containing 5 percent of 5-FU and 15 percent of paclitaxel are prepared by a spray drying method after the mixture is shaken again evenly. Then suspending the microspheres in physiological saline containing 1.5 percent of sodium carboxymethylcellulose to prepare the corresponding suspension type sustained-release injection with the viscosity of 380-460 cp (at the temperature of 25-30 ℃). The slow release injection has the release time in vitro physiological saline of 14-20 days and the release time under the skin of a mouse of about 25-35 days.

Example 3

The steps of the method for processing the sustained-release injection are the same as the example 2, but the difference is that the anticancer active ingredients and the weight percentage thereof are as follows: 15 percent of 5-FU and 5 percent of paclitaxel, and the viscosity of the suspension type sustained-release injection is 420cp-520cp (at 25 ℃ and 30 ℃). The slow release injection has the release time in vitro physiological saline of 15-22 days and the release time under the skin of a mouse of about 25-35 days.

Example 4.

80mg of PLGA (50: 50) copolymer with the molecular weight peak of 25000-50000 is respectively put into a container, then 100 ml of dichloromethane is added, 10mg of 5-FU and 10mg of paclitaxel are added after the mixture is dissolved and mixed evenly, and the microspheres for injection containing 10% of 5-FU and 10% of paclitaxel are prepared by a spray drying method after the mixture is shaken again evenly. Then suspending the microspheres in physiological saline containing 1.5 percent of sodium carboxymethylcellulose to prepare the corresponding suspension type sustained-release injection with the viscosity of 340-420 cp (at 25-30 ℃). The slow release injection has the release time of 14-20 days in-vitro physiological saline and the release time of about 20-25 days under the skin of a mouse.

Example 5.

70mg of PLGA (75: 25) with the molecular weight peak of 40000-60000 is respectively put into a container, then 100 ml of dichloromethane is added, 10mg of 5-FU and 20mg of paclitaxel are added after the mixture is dissolved and mixed evenly, and the microspheres for injection containing 10% of 5-FU and 20% of paclitaxel are prepared by a spray drying method after the mixture is shaken again evenly. 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 6

80mg of PLGA (50: 50) with the molecular weight peak of 20000-40000 is respectively put into a container, then 100 ml of dichloromethane is added, after being dissolved and mixed evenly, 15mg of 5-FU and 5mg of oxypetaxel are added, after shaking up again, the microspheres for injection containing 15% of 5-FU and 5% of oxypetaxel 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 14-20 days in-vitro physiological saline and the release time of about 20-25 days under the skin of a mouse.

Example 7

The steps of the method for processing the sustained-release injection are the same as the example 6, but the difference is that the anticancer active ingredients and the weight percentage thereof are as follows: 5-30% of 5-FU in combination with 5-30% of paclitaxel, camptothecin or vinorelbine.

Example 8.

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 5-FU and 10mg of camptothecin are added, the mixture is shaken up again, and then the spray drying method is used to prepare the microspheres for injection containing 20% of 5-FU and 10% of camptothecin. 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 9.

The procedure of the process for preparing the sustained-release injection is the same as that of example 8, except that the anticancer active ingredients are: 10-20% of 5-FU and 10-20% of taxol, camptothecin and vinorelbine.

Example 10.

70mg of polifeprosan (p-carboxyphenylpropane (p-CPP): Sebacic Acid (SA) 50: 50) copolymer is put into a container, 100 ml of dichloromethane is added, after being dissolved and mixed evenly, 10mg of 5-FU and 20mg of camptothecin are added, after shaking up again, the microspheres for injection containing 10% of 5-FU and 20% of camptothecin are prepared by a spray drying method. Then suspending the microspheres in physiological saline containing 1.5 percent of sodium carboxymethylcellulose and 0.5 percent of Tween 80 to prepare the corresponding suspension type sustained-release injection. The slow release injection has the release time of 10-15 days in-vitro physiological saline and the release time of about 20-30 days under the skin of a mouse.

Example 11.

The procedure of the process for preparing the sustained-release injection is the same as that of example 10, except that the anticancer active ingredients are: a combination of 10% 5-FU with 20% paclitaxel, camptothecin or vinorelbine.

Example 12.

70mg of polifeprosan (p-carboxyphenylpropane (p-CPP): Sebacic Acid (SA) is 20: 80) copolymer is put into a container, 100 ml of dichloromethane is added, after being dissolved and mixed evenly, 15mg of 5-FU and 15mg of paclitaxel are added, after shaking up again, the microspheres for injection containing 15% of 5-FU and 15% of paclitaxel 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 13.

The procedure of the process for preparing the sustained-release injection is the same as that of example 12, except that the anticancer active ingredients are: a combination of 15% 5-FU with 15% paclitaxel, camptothecin or vinorelbine.

Example 14

80mg of polifeprosan (p-carboxyphenylpropane (p-CPP): Sebacic Acid (SA) is 20: 80) copolymer is put into a container, 100 ml of dichloromethane is added, after being dissolved and mixed evenly, 7.5mg of vinorelbine and 12.5mg of 5-FU are added, after being shaken again evenly, the injection microsphere containing 7.5 percent of vinorelbine and 12.5 percent of 5-FU is prepared by a spray drying method. Then the microspheres are prepared into the corresponding sustained-release implant by a tabletting method. The slow release implant has the release time of 10-15 days in-vitro physiological saline and the release time of about 30-40 days under the skin of a mouse.

Example 15

The procedure of processing into a sustained-release implant was the same as in example 14, except that the anticancer active ingredient contained therein was: 12.5% of 5-FU in combination with 7.5% of paclitaxel, camptothecin or vinorelbine.

Example 16

70mg of PLGA (50: 50) with the molecular weight peak of 20000-40000 is put into a container, 100 ml of dichloromethane is added, after being dissolved and mixed evenly, 10mg of 5-FU and 20mg of paclitaxel are added, after being shaken again, the microspheres for injection containing 10% of 5-FU and 20% of paclitaxel 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 15-25 days in vitro physiological saline and the release time of about 35-50 days under the skin of a mouse.

Example 17

70mg of PLA with the molecular weight peak of 20000-40000 is put into a container, 100 ml of dichloromethane is added, 10mg of 5-FU and 20mg of vinorelbine are added after the mixture is dissolved and mixed evenly, and the mixture is shaken up again and then spray-dried to prepare microspheres for injection containing 10% of 5-FU and 20% of vinorelbine. Then the microspheres are prepared into the corresponding sustained-release implant by a tabletting method. The sustained-release implant has the drug release time of 20-25 days in-vitro physiological saline and the drug release time of about 30-40 days under the skin of a mouse.

Example 18

70mg of PLGA (50: 50) with the molecular weight peak of 40000-60000 is put into a container, 100 ml of dichloromethane is added, after the mixture is dissolved and mixed evenly, 20mg of 5-FU and 10mg of vinorelbine are added, and after the mixture is shaken again, the microspheres for injection containing 20% of 5-FU and 10% of vinorelbine are prepared by a spray drying method. Then the microspheres are prepared into the corresponding sustained-release implant by a tabletting method. The sustained-release implant has the drug release time of 20-25 days in-vitro physiological saline and the drug release time of about 35-40 days under the skin of a mouse.

Example 19

The procedure for manufacturing the sustained-release implant was the same as in examples 17 and 18, except that the anticancer active ingredient contained:

(1) a combination of 15% 5-FU with 5% paclitaxel, camptothecin or vinorelbine; or

(2) A combination of 10% 5-FU with 10% paclitaxel, camptothecin or vinorelbine; or

(3) A combination of 5% 5-FU with 15% paclitaxel, camptothecin or vinorelbine.

Example 20

70mg of PLGA (50: 50) with a molecular weight peak of 25000-40000 is put into a container, 100 ml of dichloromethane is added, after being dissolved and mixed evenly, 20mg of 5-FU and 10mg of camptothecin are added, after being shaken again, the microspheres for injection containing 20% of 5-FU and 10% of camptothecin are prepared by a spray drying method. Then the microspheres are prepared into the corresponding sustained-release implant by a tabletting method. The sustained-release implant has the drug release time of 20-25 days in-vitro physiological saline and the drug release time of about 35-40 days under the skin of a mouse.

Example 21

70mg of PLA with the molecular weight peak of 25000-40000 is put into a container, 100 ml of dichloromethane is added, after the mixture is dissolved and mixed evenly, 10mg of 5-FU and 20mg of camptothecin are added, the mixture is shaken up again and then the spray drying method is used for preparing the microspheres for injection containing 10% of 5-FU and 20% of camptothecin. Then the microspheres are prepared into the corresponding sustained-release implant by a tabletting method. The sustained-release implant has the drug release time of 20-25 days in-vitro physiological saline and the drug release time of about 30-35 days under the skin of a mouse.

Example 22

The procedure of the process for preparing the sustained release formulation is the same as in examples 1-21, except that the sustained release excipient used 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) a 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) p-carboxyphenylpropane (p-CPP) to Sebacic Acid (SA) copolymer (polifeprosan) 10: 90, 20: 80, 30: 70, 40: 60, 50: 50 or 60: 40;

e) FAD and Sebacic Acid (SA) copolymer;

f) xylitol, oligosaccharide, chondroitin, chitin, hyaluronic acid, collagen, gelatin or albumin glue.

Example 23.

The procedure for preparing a sustained release injection is the same as in examples 1 to 21, 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

1. A sustained-release injection carrying fluorouracil and a synergist thereof 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

Wherein,

the anticancer active ingredients are 5-FU and 5-FU synergist;

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 viscosity of the injection is 50-1000 cp (at 20-30 deg C)

2. The sustained-release anticancer injection according to claim 1, wherein the synergist is selected from one of paclitaxel, camptothecin, vinorelbine or their combination.

3. The sustained-release anticancer injection according to claim 1, wherein the sustained-release anticancer injection comprises the following anticancer active ingredients: 5-30% of 5-FU in combination with 5-30% of paclitaxel, camptothecin or vinorelbine.

The above are all weight percentages.

4. The sustained-release anticancer injection according to claim 1, wherein the sustained-release anticancer injection comprises the following anticancer active ingredients:

(3) A combination of 5% 5-FU with 15% paclitaxel, camptothecin or vinorelbine; or

(4) A combination of 25% 5-FU with 5% paclitaxel, camptothecin or vinorelbine.

5. The sustained-release anticancer injection according to claim 1, wherein the sustained-release excipient is selected from one or a combination of the following:

a) polylactic acid;

b) copolymers of polyglycolic acid and glycolic acid;

c) polifeprosan;

d) ethylene vinyl acetate copolymers;

e) FAD and sebacic acid copolymer.

6. The sustained-release anticancer injection according to claim 1, wherein the suspending agent 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, or

f) (iodine) glycerol, 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 sustained-release anticancer microspheres according to claim 1, which are used for preparing sustained-release implants for treating extracranial solid tumors or brain tumors originated from human and animals.

9. The sustained-release anticancer implant according to claim 8, characterized in that: the anticancer active ingredients are:

(4) A combination of 25% 5-FU with 5% paclitaxel, camptothecin or vinorelbine.

The slow release auxiliary material is selected from one or the combination of the following materials:

a) polylactic acid;

b) copolymers of polyglycolic acid and glycolic acid;

c) polifeprosan;

d) ethylene vinyl acetate copolymers;

e) FAD and sebacic acid copolymer.

10. The sustained-release anticancer implant according to claim 8, wherein the extracranial solid tumor is primary or secondary cancer, sarcoma or carcinosarcoma originated from human or animal 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.