CN101040843A

CN101040843A - Solid tumor resisting release agent including nimustine and the intensifier

Info

Publication number: CN101040843A
Application number: CNA2007102003837A
Authority: CN
Inventors: 孔庆忠; 刘玉燕; 邹会凤; 张红军; 张婕
Original assignee: Jinan Kangquan Medicine Science and Technology Co Ltd
Current assignee: Jinan Kangquan Medicine Science and Technology Co Ltd
Priority date: 2006-09-22
Filing date: 2007-04-03
Publication date: 2007-09-26

Abstract

A nimustine slow release injection for treating solid cancer comprises slow release finding and nimustine, or the combination of nimustine and relative booster (pidorubicin, osaliplatinum, adriablastina, amethopterin or the like). The viscidity of slow-release injection is 10-650cp (20-30Deg. C). The anti-cancer effective component can be made into slow release plant agent. The slow release finding substantially comprises macromolecule polymer with biological soluble degradable and absorb property, which can slow release the anti-cancer effective component to cancer part in the degradation process, significantly reduce general reaction and hold effective drug density on cancer. The anti-cancer compound can be arranged part of cancer to reduce the general toxicity reaction, selectively improve the drug density locally, and strengthen the effect of non-surgery treatments as chemotherapy, and radiation therapy or the like. The solid cancer comprises glioma, lung carcinoma, intestinal cancer, breast cancer or the like.

Description

Anti-solid tumor sustained release agent containing nimustine and its synergist

(I) technical field

The invention relates to an anti-solid tumor sustained release agent containing nimustine and its synergist, belonging to the technical field of medicines. Mainly comprises a slow release injection and a slow release implant.

(II) background of the invention

The study of cancer has progressed greatly, but its mortality rate still remains the front of various common causes of death. In China, about 160 million people suffer from cancer every year, and nearly 130 million people die of cancer, accounting for one fifth of the total death number. The incidence of cancer is rising year by year and is in a trend of youthful, and data show that the incidence of cancer is rising 69% and the death rate is rising 29.4% in less than 20 years. According to the latest statistics of the world health organization, the global cancer incidence rate will increase by fifty percent and the incidence number increases to fifteen million by 2020. Therefore, it has become a hot spot of current research to explore an effective method or drug for treating cancer.

Nimustine (ACNU) is used as one of the first-choice drugs for treating brain tumor, and the experience of using ACNU to treat brain tumor through local slow release shows that the local slow release of the drug ensures the lasting and stable drug concentration in the local application range, reduces the drug concentration of the whole body, relieves the toxic and side effects, and brings hope for glioma chemotherapy. The theory of using ACNU, especially local slow-release ACNU to treat brain tumor lies in: (1) due to the limitation of the blood brain barrier, many chemotherapy drugs can not enter the brain during conventional intravenous chemotherapy or the drug concentration is difficult to achieve or maintain for a long time effective concentration, compared with ACNU which is less limited by the blood brain barrier; (2) 90% of patients relapse locally (within 2 cm) within 1 year after surgery; (3) ACNU, as the most commonly used drug for treating brain tumors, has a relatively high selectivity for brain tumors.

However, the effect of ACNU on other tumors is not clear.

Disclosure of the invention

Based on the examination of the prior art, the invention compares brain tumors with certain extracranial tumors, and finds that nimustine has obvious effect on solid tumors such as bone tumors, thymus cancer, lymphoma, liver cancer, lung cancer, esophageal cancer, gastric cancer, breast cancer, pancreatic cancer, bladder cancer, testicular cancer, colon cancer, rectal cancer and the like. Further research shows that the ACNU local sustained-release preparation has good therapeutic effect on thyroid cancer, nasopharyngeal carcinoma, ovarian cancer, endometrial cancer, cervical cancer, renal cancer, prostate cancer and other solid tumors.

Many solid tumors are not as sensitive as nimustine, but are susceptible to drug resistance during treatment. The main reason for this is the difficulty in obtaining and maintaining effective drug concentrations locally at the tumor. Simply increasing systemic dose is limited by systemic toxicity. In order to effectively increase the local drug concentration of tumor and reduce the drug concentration of the drug in the circulatory system, a sustained-release system containing anticancer drug 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): 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.

The invention discovers that the anticancer effect of the drug mentioned in the invention can be mutually enhanced by combining the drug with the nimustine (the drug which can increase the anticancer effect of the nimustine is called as a nimustine synergist in the following). Besides, the nimustine or the combination of nimustine and its synergist is packaged in the special slow release auxiliary materials and matched with the special solvent to prepare the anticancer drug slow release injection, which not only can greatly improve the local drug concentration of the tumor, reduce the drug concentration of the drug in the circulatory system and reduce the toxicity of the drug to the normal tissues, but also can greatly facilitate the drug injection, reduce the complications of the operation and reduce the cost of the patients. The nimustine synergist can inhibit the growth of tumor and increase the sensitivity of tumor cells to anticancer drugs.

The present invention has found that not all adjuvants are able to release ACNU effectively. 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 nimustine 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 slow-release medicines 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 discloses an anti-solid tumor sustained release agent containing nimustine and a synergist thereof. The sustained release preparation for treating solid tumors comprises an anticancer active ingredient and a medicinal sustained release adjuvant.

The anticancer active ingredient is Nimustine (ACNU, Nimustine) or the combination of Nimustine and Nimustine synergist, and the Nimustine synergist comprises platinum compound selected from oxaliplatin or carboplatin, antimetabolite selected from gemcitabine or methotrexate, and/or antitumor antibiotic selected from adriamycin or epirubicin.

The medicinal slow release auxiliary materials comprise one or the combination of the following materials: 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 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.

One form of sustained release formulation is a sustained release injection, which consists of:

the sustained-release particles comprise the following components in percentage by weight:

0.5-60% of anticancer active ingredient

Sustained release auxiliary materials 40-99.5%

0.0 to 30 percent of suspending agent

The menstruum is divided into common menstruum and special menstruum.

Wherein the common solvent comprises distilled water, water for injection, physiological solution, absolute ethyl alcohol or buffer solution prepared from various salts; the special solvent is common solvent containing suspending agent selected from sodium carboxymethylcellulose, (iodine) glycerol, dimethicone, propylene glycol, carbomer, mannitol, sorbitol, surfactant, Tween 20, Tween 40 and Tween 80 or their combination. When the suspending agent in the sustained-release particles (A) is '0', the solvent (B) is a special solvent.

The most preferable sustained-release auxiliary materials in the sustained-release microspheres and the weight percentage thereof are as follows:

(1) 55-90% PLA;

(2) 50-90% PLGA;

(3) 50-85% of polifeprosan;

(4) 55-90% of a copolymer of di-fatty acid and sebacic acid;

(5) 55-90% EVAc;

(6) 40-95% of xylitol, oligosaccharide, chondroitin, chitin, hyaluronic acid, collagen, gelatin or albumin glue; or

(7) 40-95% of racemic polylactic acid, racemic polylactic acid/glycollic acid copolymer, monomethyl polyethylene glycol/polylactic acid copolymer, polyethylene glycol/polylactic acid copolymer, carboxyl-terminated polylactic acid or carboxyl-terminated polylactic acid/glycollic acid copolymer.

The weight percentage of the anticancer active ingredients in the sustained release preparation is 1-50%, 5-30% is preferable, and 10-25% is most preferable. The weight ratio of the nimustine to the nimustine synergist is 1-9: 1-5.

The anticancer active ingredients of the sustained-release injection are preferably one of the following components in percentage by weight:

(A) 5-15% nimustine and 85-95% polyglycolic acid and glycolic acid copolymer;

(B) 15-35% nimustine and 65-85% polyglycolic acid and glycolic acid copolymer;

(C) 5-15% of nimustine and 85-95% of polylactic acid;

(D) 15-35% of nimustine and 65-85% of polylactic acid;

(E) 5-15% nimustine and 85-95% polifeprosan;

(F) 15-35% nimustine and 65-85% polifeprosan;

(G) 5-35% of nimustine, 1-95% of polyglycolic acid and glycolic acid copolymer and 1-95% of polifeprosan;

(H) 5-35% of nimustine, 1-95% of polylactic acid and 1-95% of polifeprosan;

(I) 5-35% of nimustine, 1-95% of polylactic acid and 1-95% of polyglycolic acid and glycolic acid copolymer;

(J) 5-35% of nimustine, 1-95% of polylactic acid, 1-95% of polyglycolic acid-glycolic acid copolymer and 1-95% of polifeprosan.

(A) 5-30% nimustine and 5-20% oxaliplatin or carboplatin;

(B) 5-25% nimustine and 5-35% gemcitabine or methotrexate;

(C) 5-25% of nimustine and 5-25% of epirubicin or adriamycin.

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 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 special solvent to prepare corresponding suspension, then the water in the suspension is removed by methods such as vacuum drying, and then the suspension is suspended by special solvent or common solvent to obtain the corresponding sustained-release particle injection. The above methods are merely illustrative and not restrictive of the invention. It is noted that the concentration of the suspended drug or the sustained release microspheres (or microcapsules) in the injection may be, but is not limited to, 10-400mg/ml, but is preferably 30-300mg/ml, and most preferably 50-200mg/ml, depending on the particular need. The viscosity of the injection is 50-1000 cp (at 20-30 deg C), preferably 100-1000 cp (at 20-30 deg C), and most preferably 200-650 cp (at 20-30 deg C). This viscosity is suitable for 18-22 gauge needles and specially made needles with larger (to 3 mm) inside diameters.

The method of preparation of the sustained release injection is arbitrary and can be prepared by several methods: such as, but not limited to, mixing, melting, dissolving, spray drying to prepare microspheres, dissolving in combination with freezing (drying) and pulverizing to form fine powders, liposome-encapsulating, and emulsifying. Among them, a dissolving method (i.e., solvent evaporation method), a drying method, a spray drying method and an emulsification method are preferable. The microspheres can be used for preparing the various sustained-release injections, and the method is arbitrary. The microspheres used may have a particle size in the range of 5-400um, preferably 10-300um, most preferably 20-200 um.

The microspheres can also be used for preparing other sustained-release injections, such as gel injections and block copolymer micelle injections. The block copolymer micelle is formed by a hydrophobic hydrophilic block copolymer in an aqueous solution and has a spherical core-shell structure, the hydrophobic block forms a core, and the hydrophilic block forms a shell. The drug-loaded micelle is injected into the body to achieve the purpose of controlling the release of the drug or targeting therapy. The drug carrier is any one of the above or the combination thereof. Of these, polyethylene glycol (PEG) having a molecular weight of 1000-15000 is preferable as the hydrophilic block of the micelle copolymer, and biodegradable polymers such as PLA, polylactide, polycaprolactone and copolymers thereof (molecular weight 1500-25000) are preferable as the hydrophobic block of the micelle copolymer. The block copolymer micelles may have a particle size in the range of 10 to 300um, preferably 20 to 200 um. The gel injection is prepared by dissolving biodegradable polymer (such as PLA, PLGA or DL-LA and epsilon-caprolactone copolymer) in certain amphiphilic solvent, adding the medicine, mixing (or suspending) with the solvent to form gel with good fluidity, and can be injected around tumor or in tumor. Once injected, the amphiphilic solvent diffuses into the body fluid quickly, and the water in the body fluid permeates into the gel, so that the polymer is solidified and the drug is released slowly.

The sustained-release microspheres can also be used for preparing sustained-release implants, the used 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-sebacic acid [ P (EAD-SA) ], 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.

Still another form of the anticancer drug sustained-release preparation of the present invention is that the anticancer drug sustained-release preparation is a sustained-release implant. The effective components of the anticancer implant can be uniformly packaged in the whole pharmaceutic adjuvant, and also can be packaged in the center of a carrier support or on the surface of the carrier support; the active principle can be released by direct diffusion and/or by degradation via polymers.

The slow release implant is characterized in that the slow release auxiliary material contains any one or more of the other auxiliary materials besides the high molecular polymer. The added pharmaceutic adjuvants are collectively called as additives. The additives can be classified into fillers, pore-forming agents, excipients, dispersants, isotonic agents, preservatives, retarding agents, solubilizers, absorption enhancers, film-forming agents, gelling agents, etc. according to their functions.

The main components of the sustained-release implant can be prepared into various dosage forms. Such as, but not limited to, capsules, sustained release formulations, implants, sustained release implants, and the like; in various shapes such as, but not limited to, granules, pills, tablets, powders, spheres, chunks, needles, rods, columns, and films. Among various dosage forms, slow release implants in vivo are preferred. It can be in the form of rod of 0.1-5mm (thick) × 1-10mm (long), or in the form of sheet.

The optimal dosage form of the sustained-release implant is biocompatible, degradable and absorbable sustained-release implant, and can be prepared into various shapes and various dosage forms according to different clinical requirements. The packaging method and procedure for its main ingredients are described in detail in US patent (US5651986) and include several methods for preparing sustained release formulations: such as, but not limited to, (i) mixing a carrier support powder with a drug and then compressing into an implant, a so-called mixing process; (ii) melting the carrier support, mixing with the drug to be packaged, and then cooling the solid, the so-called melt process; (iii) dissolving the carrier support in a solvent, dissolving or dispersing the drug to be packaged in a polymer solution, and then evaporating the solvent and drying, the so-called dissolution method; (iv) spray drying; and (v) freeze-drying method.

The anticancer active ingredients of the sustained-release implant are preferably as follows, and the weight percentages are as follows:

the sustained release agent for treating solid tumors is preferably one of the following components in percentage by weight:

(A) 5-15% nimustine and 85-95% polyglycolic acid and glycolic acid copolymer;

(B) 15-35% nimustine and 65-85% polyglycolic acid and glycolic acid copolymer;

(C) 5-15% of nimustine and 85-95% of polylactic acid;

(D) 15-35% of nimustine and 65-85% of polylactic acid;

(E) 5-15% nimustine and 85-95% polifeprosan;

(F) 15-35% nimustine and 65-85% polifeprosan;

(H) 5-35% of nimustine, 1-95% of polylactic acid and 1-95% of polifeprosan;

The anticancer active ingredients of the sustained-release implant are preferably one of the following components in percentage by weight:

(A) 2-20% nimustine and 2-20% oxaliplatin or carboplatin;

(B) 2-25% nimustine and 5-35% gemcitabine or methotrexate;

(C) 5-25% of nimustine and 5-25% of adriamycin or epiadriamycin.

The pharmaceutical composition is used for treating solid tumors, wherein the solid tumors comprise brain tumors, gliomas, osteosarcomas, lymphomas, primary or secondary carcinomas of the digestive system, respiratory system, urogenital system, sarcomas or carcinosarcomas. Such as: liver cancer, lung cancer, esophageal cancer, stomach cancer, breast cancer, pancreatic cancer, thyroid cancer, nasopharyngeal cancer, ovarian cancer, endometrial cancer, cervical cancer, kidney cancer, prostate cancer, bladder cancer, colon cancer, rectal cancer, testicular cancer, skin cancer, head and neck cancer, and primary or secondary cancer, sarcoma or carcinosarcoma derived from gall bladder, oral cavity, peripheral nervous system, mucosa, gland, blood vessel, bone tissue, lymph node, eye. Therefore, the application of the present invention is for manufacturing the above-mentioned various pharmaceutical preparations for treating the above-mentioned tumors, wherein injections, suspensions, ointments, capsules, implants, sustained release agents and sustained release implants are preferred, and sustained release injections, sustained release implants, controlled release implants or delayed release implants are most preferred.

The pharmaceutical composition for treating solid tumors of the present invention may further comprise other medicinal ingredients, such as, but not limited to, antibiotics, analgesic drugs, anticoagulant drugs, hemostatic drugs, etc. The anticancer medicine composition of the present invention can strengthen the effect of conventional chemotherapy, immunotherapy, high fever therapy, photochemistry therapy, electrotherapy, biotherapy, hormone therapy, magnetotherapy, ultrasonic therapy, radiotherapy, gene therapy, etc. Therefore, the slow release of the traditional Chinese medicine composition can be combined with the non-operative treatment at the same time of local slow release, so that the anti-cancer effect of the traditional Chinese medicine composition is further enhanced. When the anticancer medicinal composition is used together with the non-operative therapy, the anticancer medicinal composition can be applied simultaneously with the non-operative therapy and can also be applied within a few days before the non-operative therapy is implemented, and the purpose is to enhance the sensitivity of tumors as much as possible, so that a more effective and new method is provided for radically treating various primary and metastatic solid tumors of human bodies and animals, and the anticancer medicinal composition has very high clinical application value and remarkable economic and social benefits.

When applied topically, the composition can be placed directly around or within the body of a primary or metastatic solid tumor, or directly into a cavity formed by excision of all or part of a primary or metastatic solid tumor.

The main component of the pharmaceutical composition for treating solid tumors takes the biocompatible substance as a support, so foreign body reaction is not caused. The support can be degraded after being placed in the body, so that the support can not be taken out again after operation. The local drug concentration is selectively increased and prolonged due to the local release of the contained drug in the tumor, and the systemic toxicity reaction caused by the conventional route of administration can be reduced. Has obvious therapeutic effect on solid tumors.

The pharmaceutical compositions for treating solid tumors of the present invention can be implemented in a number of embodiments for the purpose of further illustration only, and are not intended to limit the practice of the present invention in any way.

The technical process of the invention is further described by the following tests and examples:

test I, the inhibition effect of nimustine on the growth of tumor cells.

To verify the inhibition of nimustine on tumor cell growth, nimustine (10ug/ml) was added to various tumor cells cultured in vitro for 24 hours (table 1), and the total number of cells was counted and the inhibition (%) of tumor cell growth was calculated after 48 hours of culture.

The inhibition rate (%) of tumor cell growth was [ ((number of cells in test group for control group)/number of cells in control group) × 100% ]

TABLE 1

Tumor cells	Inhibition ratio (%)
Tumor cells	Inhibition ratio (%)	Liver cancer, esophageal cancer, breast cancer, pancreatic cancer, thyroid cancer, nasopharyngeal cancer, endometrial cancer, cervical cancer, renal cancer, prostate cancer, bladder cancer, colorectal cancer, skin cancer, testicular cancer	908080868692908866808468708288808688

The result of the first test shows that nimustine has obvious inhibition effect (P is less than 0.05) on the growth of the tested tumor, and the unexpected discovery forms the main technical characteristic of the invention and provides a new choice for treating solid tumor.

The pharmaceutical composition for treating solid tumors of the present invention may be prepared in any dosage form or shape, but preferably is an implanted slow-release agent.

Experiment two, comparison of local drug concentration after applying nimustine in different modes

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 5mg/kg nimustine. The results of measuring the content (%) of the drug in the tumor at different times show that the local drug concentration difference of the nimustine applied in different ways 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 (PLA with molecular weight of 15000-25000 as an auxiliary material) 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 III, comparison of in vivo tumor inhibition effects after applying nimustine in different modes

Using white rat as test object, 2X 10⁵Individual prostate tumor cells were injected subcutaneously into their quaternary costal regions and grouped after tumors grew to 0.8 cm diameter. The dose of each group was 5mg/kg nimustine. 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 nimustine applied by different modes is obvious, the effective drug concentration of the tumor part can be obviously improved and effectively maintained by local administration, wherein the slow release is placed in the tumorThe implant and the slow release injection (PLGA (75: 25) with the molecular weight of 30000-50000 is taken as an auxiliary material) injected in the tumor have the best effect. 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 on in vivo tumor inhibition effect of nimustine (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 7 groups 14 days after tumor growth (see table 2). The first group is control group, the groups 2 to 7 are treatment groups, and sustained-release injection (containing 1-32% ACNU and PLA with molecular weight of 20000-40000 as adjuvant) is injected intratumorally. Tumor volume was measured on day 20 after treatment and the effect was compared (see table 2).

TABLE 2

Test set (n)	ACNU therapeutic amount (mg/kg)	Tumor volume (cm)³)	P value
Test set (n)	ACNU therapeutic amount (mg/kg)	Tumor volume (cm)³)	P value	1(6)	Control	62±10
2(6)	0.5	58±8.2	＞0.05	1(6)	Control	62±10
2(6)	0.5	58±8.2	＞0.05	3(6)	1.0	52±6.6	＜0.01
4(6)	2.0	44±6.0	＜0.01	3(6)	1.0	52±6.6	＜0.01
4(6)	2.0	44±6.0	＜0.01	5(6)	4.0	32±4.8	＜0.01
6(6)	8.0	18±2.8	＜0.01	5(6)	4.0	32±4.8	＜0.01
6(6)	8.0	18±2.8	＜0.01	7(6)	16.0	12±2.0	＜0.001

The results show that the nimustine sustained release injection has obvious inhibition effect on solid tumors, and the effect is related to the dosage of the drug.

Experiment five, the tumor inhibition effect of nimustine and nimustine synergist (slow release injection)

The tumor cells include pancreatic cancer, esophageal cancer, gastric gland epithelial cancer (SA), bone tumor (BC), breast cancer (BA), lung cancer (LH), papillary thyroid adenocarcinoma (PAT), and liver cancer. The nimustine and the nimustine synergist are added into various tumor cells cultured in vitro for 24 hours according to the concentration ratio of 1: 1, and the total number of the cells is counted after the tumor cells are continuously cultured for 48 hours. The tumor cell growth inhibitory effect is shown in Table 3.

TABLE 3

Tumor cell	Nimustine	Methotrexate (MTX)	Carboplatin	Adriamycin	Nimustine and methotrexate	Nimustine + carboplatin	Nimustine and adriamycin
Tumor cell	Nimustine	Methotrexate (MTX)	Carboplatin	Adriamycin	Nimustine and methotrexate	Nimustine + carboplatin	Nimustine and adriamycin	Pancreatic cancer	48％	40％	58％	44％	72％	88％	86％
Esophageal cancer	60％	50％	60％	54％	74％	82％	78％	Pancreatic cancer	48％	40％	58％	44％	72％	88％	86％
Esophageal cancer	60％	50％	60％	54％	74％	82％	78％	SA	48％	52％	66％	42％	68％	84％	82％
BC	52％	42％	54％	64％	66％	86％	80％	SA	48％	52％	66％	42％	68％	84％	82％
BC	52％	42％	54％	64％	66％	86％	80％	BA	54％	50％	52％	42％	68％	92％	88％
LH	52％	52％	62％	48％	60％	84％	82％	BA	54％	50％	52％	42％	68％	92％	88％
LH	52％	52％	62％	48％	60％	84％	82％	PAT	46％	42％	62％	58％	78％	86％	80％

The results show that the used nimustine synergist (methotrexate, carboplatin and adriamycin) and nimustine have obvious inhibition effect on the growth of various tumor cells when the nimustine synergist and the nimustine are used at the concentration singly, and can show obvious synergistic effect when the nimustine synergist and the nimustine are used in combination. The same effect can be seen in other types of tumors, such as brain glioma, osteosarcoma, esophageal cancer, ovarian cancer, pancreatic cancer, intestinal cancer, etc.

Experiment shows that the antitumor effect of nimustine and its synergist

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 4). The first group is the control group, the groups 2 to 10 are the treatment groups, and the sustained-release implant is placed in the tumor (containing 5-30% ACNU, PLGA (50: 50) with molecular weight of 30000-50000 as adjuvant). Tumor volume was measured on day 20 post treatmentSize, compare the therapeutic effect (see table 4).

TABLE 4

Test set (n)	Therapeutic amounts	Tumor volume (cm)³)	P value
Test set (n)	Therapeutic amounts	Tumor volume (cm)³)	P value	1(6)	Control	54±12
2(6)	Nimustine (5%)	46±8.0	＜0.05	1(6)	Control	54±12
2(6)	Nimustine (5%)	46±8.0	＜0.05	3(6)	Nimustine (10%)	38±6.0	＜0.01
4(6)	Nimustine (15%)	28±4.4	＜0.001	3(6)	Nimustine (10%)	38±6.0	＜0.01
4(6)	Nimustine (15%)	28±4.4	＜0.001	5(6)	Nimustine (30)	18±3.2	＜0.01
6(6)	Adriamycin (10%)	48±8.2	＜0.001	5(6)	Nimustine (30)	18±3.2	＜0.01
6(6)	Adriamycin (10%)	48±8.2	＜0.001	7(6)	Nimustine (5%) + doxorubicin	36±6.6	＜0.01
8(6)	Nimustine (10%) + doxorubicin	26±4.4	＜0.001	7(6)	Nimustine (5%) + doxorubicin	36±6.6	＜0.01
8(6)	Nimustine (10%) + doxorubicin	26±4.4	＜0.001	9(6)	Nimustine (15%) + doxorubicin	16±2.2	＜0.01
10(6)	Nimustine (30%) + doxorubicin	10±1.4	＜0.001	9(6)	Nimustine (15%) + doxorubicin	16±2.2	＜0.01

The results show that the used nimustine has obvious inhibition effect on the growth of various tumor cells, the inhibition effect is related to the dosage, and the nimustine synergist (adriamycin) can show obvious synergistic effect when being used in combination. This finding constitutes a further important feature of the present invention.

Experiment seven, the tumor inhibition effect of nimustine and nimustine synergist (slow release injection)

Using white rat as test object, 2X 10⁵Individual prostate tumor cells were injected subcutaneously into the quaternary costal region and were divided into negative controls (blank), monotherapy (nimustine or nimustine potentiator) and combination therapy (nimustine and nimustine potentiator) after 14 days of tumor growth. The slow release injection is injected 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 5).

TABLE 5

Test set (n)	Is treated by	Tumor inhibition ratio (%)	P value
Test set (n)	Is treated by	Tumor inhibition ratio (%)	P value	1(6)	Control
2(6)	Nimustine (5%)	48	＜0.05	1(6)	Control
2(6)	Nimustine (5%)	48	＜0.05	3(6)	Nimustine (10%)	56	＜0.01
4(6)	Nimustine (15%)	62	＜0.01	3(6)	Nimustine (10%)	56	＜0.01
4(6)	Nimustine (15%)	62	＜0.01	5(6)	Nimustine (20%)	70	＜0.01
6(6)	Carboplatin (10%)	40	＜0.01	5(6)	Nimustine (20%)	70	＜0.01
6(6)	Carboplatin (10%)	40	＜0.01	7(6)	Nimustine (5%) + carboplatin	70	＜0.001
8(6)	Nimustine (10%) + carboplatin	78	＜0.001	7(6)	Nimustine (5%) + carboplatin	70	＜0.001
8(6)	Nimustine (10%) + carboplatin	78	＜0.001	9(6)	Nimustine (15%) + carboplatin	88	＜0.001
10(6)	Nimustine (20%) + carboplatin	98	＜0.001	9(6)	Nimustine (15%) + carboplatin	88	＜0.001

The results show that the used nimustine and nimustine synergist (carboplatin) have obvious inhibition effect on the growth of various tumors when being used independently at the concentration, can show obvious synergistic effect when being used jointly, and has obvious dose-effect relationship.

Experiment eight, the tumor inhibition effect of nimustine and nimustine synergist (slow 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 slow release injection (the auxiliary material is PLA with the molecular weight of 20000-40000) is injected in tumor. 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
Test set (n)	Is treated by	Tumor inhibition ratio (%)	P value	1(6)	Control
2(6)	Nimustine (5%)	48	＜0.05	1(6)	Control
2(6)	Nimustine (5%)	48	＜0.05	3(6)	Nimustine (10%)	56	＜0.01
4(6)	Nimustine (15%)	62	＜0.01	3(6)	Nimustine (10%)	56	＜0.01
4(6)	Nimustine (15%)	62	＜0.01	5(6)	Nimustine (20%)	70	＜0.01
6(6)	Methotrexate (15%)	40	＜0.01	5(6)	Nimustine (20%)	70	＜0.01
6(6)	Methotrexate (15%)	40	＜0.01	7(6)	Nimustine (5%) + methotrexate	68	＜0.001
8(6)	Nimustine (10%) + methotrexate	74	＜0.001	7(6)	Nimustine (5%) + methotrexate	68	＜0.001
8(6)	Nimustine (10%) + methotrexate	74	＜0.001	9(6)	Nimustine (15%) + methotrexate	86	＜0.001
10(6)	Nimustine (20%) + methotrexate	96	＜0.001	9(6)	Nimustine (15%) + methotrexate	86	＜0.001

The results show that the used nimustine and the nimustine synergist (methotrexate) have obvious inhibition effect on the growth of various tumors when being used independently at the concentration, and can show obvious synergistic effect when being used jointly, and have obvious dose-effect relationship. This finding constitutes a further important feature of the present invention.

Experiments prove that the nine drugs, the nimustine and the nimustine synergist (slow release injection) have the tumor inhibition effect

Using white rat as test object, 2X 10⁵Each rectal tumor cell was injected subcutaneously into the quaternary costal region and was divided into the following 10 groups 14 days after tumor growth (see table 7). The first group is the control group, the groups 2 to 10 are the treatment groups, and the sustained-release implant is placed in the tumor (containing 5-30% ACNU, PLGA (50: 50) with molecular weight of 20000-40000 is used as adjuvant). Tumor volume was measured on day 20 after treatment and the effect of treatment was compared (see table 7).

TABLE 7

Test set (n)	Therapeutic amounts	Tumor volume (cm)³)	P value
Test set (n)	Therapeutic amounts	Tumor volume (cm)³)	P value	1(6)	Control	52±12
2(6)	Carboplatin (5%)	44±8.2	＜0.05	1(6)	Control	52±12
2(6)	Carboplatin (5%)	44±8.2	＜0.05	3(6)	Carboplatin (10%)	36±6.6	＜0.01
4(6)	Carboplatin (15%)	28±4.0	＜0.001	3(6)	Carboplatin (10%)	36±6.6	＜0.01
4(6)	Carboplatin (15%)	28±4.0	＜0.001	5(6)	Carboplatin (30)	24±3.2	＜0.01
6(6)	Nimustine (10%)	22±4.2	＜0.001	5(6)	Carboplatin (30)	24±3.2	＜0.01
6(6)	Nimustine (10%)	22±4.2	＜0.001	7(6)	(5%) Carboplatin + nimustine	14±3.2	＜0.01
8(6)	(10%) Carboplatin + nimustine	10±2.6	＜0.001	7(6)	(5%) Carboplatin + nimustine	14±3.2	＜0.01
8(6)	(10%) Carboplatin + nimustine	10±2.6	＜0.001	9(6)	(15%) Carboplatin + nimustine	6±1.0	＜0.01
10(6)	(30%) Carboplatin + nimustine	2±0.8	＜0.001	9(6)	(15%) Carboplatin + nimustine	6±1.0	＜0.01

The results show that the used nimustine synergist (carboplatin) has inhibition effect on the growth of tumor cells, the inhibition effect and the dosage are related, and the nimustine synergist can show obvious synergistic effect when being combined with nimustine. This finding constitutes a further important feature of the present invention.

Experiment shows that the tumor inhibiting effect of nimustine and its synergist

The tumor cells include pancreatic cancer, esophageal cancer, gastric gland epithelial cancer (SA), bone tumor (BC), breast cancer (BA), lung cancer (LH), papillary thyroid adenocarcinoma (PAT), and liver cancer. The nimustine and the nimustine synergist are added into various tumor cells cultured in vitro for 24 hours according to the concentration ratio of 1: 1, and the total number of the cells is counted after the tumor cells are continuously cultured for 48 hours. The tumor cell growth inhibitory effect is shown in Table 8.

TABLE 8

Tumor cell	Nimustine	Gemcitabine	Oxaliplatin	Epirubicin	Nimustine + gemcitabine	Nimustine + oxaliplatin	Nimustine + epirubicin
Tumor cell	Nimustine	Gemcitabine	Oxaliplatin	Epirubicin	Nimustine + gemcitabine	Nimustine + oxaliplatin	Nimustine + epirubicin	Pancreatic cancer	48％	40％	54％	44％	72％	82％	80％
Esophageal cancer	60％	50％	60％	54％	74％	82％	78％	Pancreatic cancer	48％	40％	54％	44％	72％	82％	80％
Esophageal cancer	60％	50％	60％	54％	74％	82％	78％	SA	48％	52％	66％	42％	68％	84％	82％
BC	52％	42％	54％	64％	66％	86％	80％	SA	48％	52％	66％	42％	68％	84％	82％
BC	52％	42％	54％	64％	66％	86％	80％	BA	54％	50％	52％	42％	68％	82％	88％
LH	52％	52％	62％	48％	60％	84％	82％	BA	54％	50％	52％	42％	68％	82％	88％
LH	52％	52％	62％	48％	60％	84％	82％	PAT	46％	42％	52％	58％	68％	80％	82％

The results show that the used nimustine synergist (gemcitabine, oxaliplatin and epirubicin) and nimustine have obvious inhibition effect on the growth of a plurality of tumor cells when the nimustine synergist and the nimustine are used alone at the concentration, and can show obvious synergistic effect when the nimustine synergist and the nimustine are used in combination. The same effect can be seen in other types of tumors, such as brain glioma, osteosarcoma, esophageal cancer, ovarian cancer, pancreatic cancer, intestinal cancer, etc.

Experiment shows the tumor inhibiting effect of undecylenic acid, nimustine and nimustine synergist

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 9). The first group is the control group, the groups 2 to 10 are the treatment groups, and the sustained-release implant is placed in the tumor (containing 5-30% ACNU, PLGA (50: 50) with molecular weight of 30000-50000 as adjuvant). Tumor volume was measured on day 20 after treatment and the effect was compared (see table 9).

TABLE 9

Test set (n)	Therapeutic amounts	Tumor volume (cm)³)	P value
Test set (n)	Therapeutic amounts	Tumor volume (cm)³)	P value	1(6)	Control	54±12
2(6)	Nimustine (5%)	46±8.0	＜0.05	1(6)	Control	54±12
2(6)	Nimustine (5%)	46±8.0	＜0.05	3(6)	Nimustine (10%)	38±6.0	＜0.01
4(6)	Nimustine (15%)	28±4.4	＜0.001	3(6)	Nimustine (10%)	38±6.0	＜0.01
4(6)	Nimustine (15%)	28±4.4	＜0.001	5(6)	Nimustine (30)	18±3.2	＜0.01
6(6)	Epirubicin (10%)	48±8.2	＜0.001	5(6)	Nimustine (30)	18±3.2	＜0.01
6(6)	Epirubicin (10%)	48±8.2	＜0.001	7(6)	Nimustine (5%) + epirubicin	26±6.6	＜0.01
8(6)	Nimustine (10%) + epirubicin	22±4.4	＜0.001	7(6)	Nimustine (5%) + epirubicin	26±6.6	＜0.01
8(6)	Nimustine (10%) + epirubicin	22±4.4	＜0.001	9(6)	Nimustine (15%) + epirubicin	22±2.2	＜0.01
10(6)	Nimustine (30%) + epirubicin	18±4.4	＜0.001	9(6)	Nimustine (15%) + epirubicin	22±2.2	＜0.01

The results show that the used nimustine has obvious inhibition effect on the growth of various tumor cells, the inhibition effect is related to the dosage, and the nimustine synergist (epirubicin) can show obvious synergistic effect when being combined for application. This finding constitutes a further important feature of the present invention.

Experiment on the tumor inhibition effect of Dolomustine, nimustine and nimustine synergist (slow release injection)

Using white rat as test object, 2X 10⁵Individual prostate tumor cells were injected subcutaneously into the quaternary costal region and were divided into negative controls (blank), monotherapy (nimustine or nimustine potentiator) and combination therapy (nimustine and nimustine potentiator) after 14 days of tumor growth. The slow release injection is injected 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 10).

Watch 10

Test set (n)	Is treated by	Tumor inhibition ratio (%)	P value
Test set (n)	Is treated by	Tumor inhibition ratio (%)	P value	1(6)	Control
2(6)	Nimustine (5%)	48	＜0.05	1(6)	Control
2(6)	Nimustine (5%)	48	＜0.05	3(6)	Nimustine (10%)	56	＜0.01
4(6)	Nimustine (15%)	62	＜0.01	3(6)	Nimustine (10%)	56	＜0.01
4(6)	Nimustine (15%)	62	＜0.01	5(6)	Nimustine (20%)	70	＜0.01
6(6)	Oxaliplatin (10%)	40	＜0.01	5(6)	Nimustine (20%)	70	＜0.01
6(6)	Oxaliplatin (10%)	40	＜0.01	7(6)	Nimustine (5%) + oxaliplatin	78	＜0.001
8(6)	Nimustine (10%) + oxaliplatin	84	＜0.001	7(6)	Nimustine (5%) + oxaliplatin	78	＜0.001
8(6)	Nimustine (10%) + oxaliplatin	84	＜0.001	9(6)	Nimustine (15%) + oxaliplatin	82	＜0.001
10(6)	Nimustine (20%) + oxaliplatin	88	＜0.001	9(6)	Nimustine (15%) + oxaliplatin	82	＜0.001

The results show that the nimustine and the nimustine synergist (oxaliplatin) have obvious inhibition effect on the growth of various tumors when being used independently at the concentration, and can show obvious synergistic effect when being used jointly, and have obvious dose-effect relationship.

Thirteen experiments show that the tumor inhibition effect of the nimustine and the nimustine synergist (sustained release injection)

Using white rat as test object, 2X 10⁵Each breast tumor cell was injected subcutaneously into the costal region of the patient, and the tumor was divided into a negative control (blank), a single drug treatment group, and a combination treatment group 14 days after the tumor had grown. The slow release injection (the auxiliary material is PLA with the molecular weight of 20000-40000) is injected in tumor. Tumor volume was measured on day 20 after treatment, and the therapeutic effect was compared using tumor growth inhibition as an index (see table 11).

TABLE 11

Test set (n)	Is treated by	Tumor inhibition ratio (%)	P value
Test set (n)	Is treated by	Tumor inhibition ratio (%)	P value	1(6)	Control
2(6)	Nimustine (5%)	48	＜0.05	1(6)	Control
2(6)	Nimustine (5%)	48	＜0.05	3(6)	Nimustine (10%)	56	＜0.01
4(6)	Nimustine (15%)	62	＜0.01	3(6)	Nimustine (10%)	56	＜0.01
4(6)	Nimustine (15%)	62	＜0.01	5(6)	Nimustine (20%)	70	＜0.01
6(6)	Methotrexate (15%)	40	＜0.01	5(6)	Nimustine (20%)	70	＜0.01
6(6)	Methotrexate (15%)	40	＜0.01	7(6)	Nimustine (5%) + methotrexate	80	＜0.001
8(6)	Nimustine (10%) + methotrexate	84	＜0.001	7(6)	Nimustine (5%) + methotrexate	80	＜0.001
8(6)	Nimustine (10%) + methotrexate	84	＜0.001	9(6)	Nimustine (15%) + methotrexate	82	＜0.001
10(6)	Nimustine (20%) + methotrexate	90	＜0.001	9(6)	Nimustine (15%) + methotrexate	82	＜0.001

Experiment on the tumor inhibition effect of fourteen nimustine and nimustine synergist (slow release injection)

Using white rat as test object, 2X 10⁵Each rectal tumor cell was injected subcutaneously into the quaternary costal region and was divided into the following 10 groups 14 days after tumor growth (see table 12). The first group is the control group, the groups 2 to 10 are the treatment groups, and the sustained-release implant is placed in the tumor (containing 5-30% ACNU, PLGA (50: 50) with molecular weight of 20000-40000 is used as adjuvant). Tumor volume was measured on day 20 after treatment and the effect of treatment was compared (see table 12).

TABLE 12

Test set (n)	Therapeutic amounts	Tumor volume (cm)³)	P value
Test set (n)	Therapeutic amounts	Tumor volume (cm)³)	P value	1(6)	Control	52±12
2(6)	Oxaliplatin (5%)	44±8.2	＜0.05	1(6)	Control	52±12
2(6)	Oxaliplatin (5%)	44±8.2	＜0.05	3(6)	Oxaliplatin (10%)	36±6.6	＜0.01
4(6)	Oxaliplatin (15%)	28±4.0	＜0.001	3(6)	Oxaliplatin (10%)	36±6.6	＜0.01
4(6)	Oxaliplatin (15%)	28±4.0	＜0.001	5(6)	Oxaliplatin (30)	24±3.2	＜0.01
6(6)	Nimustine (10%)	22±4.2	＜0.001	5(6)	Oxaliplatin (30)	24±3.2	＜0.01
6(6)	Nimustine (10%)	22±4.2	＜0.001	7(6)	(5%) oxaliplatin + nimustine	14±3.2	＜0.01
8(6)	(10%) oxaliplatin + nimustine	10±2.6	＜0.001	7(6)	(5%) oxaliplatin + nimustine	14±3.2	＜0.01
8(6)	(10%) oxaliplatin + nimustine	10±2.6	＜0.001	9(6)	(15%) oxaliplatin + nimustine	6±1.0	＜0.01
10(6)	(30%) oxaliplatin + nimustine	2±0.8	＜0.001	9(6)	(15%) oxaliplatin + nimustine	6±1.0	＜0.01

The results show that the used nimustine synergist (oxaliplatin) has inhibition effect on the growth of tumor cells, the inhibition effect and the dosage are related, and the nimustine synergist can show obvious synergistic effect when being combined with nimustine. This finding constitutes a further important feature of the present invention.

Fifteen experiments show that the in vivo release of the nimustine sustained release implant prepared by the polylactic acid with different molecular weights is compared

Rats were used as test subjects, and divided into groups (3 mice/group) and subcutaneously administered with equal amounts of nimustine sustained release implants loaded with polylactic acid (PLA) of different Molecular Weights (MW). Then, the remaining amount of the drug in the implant was measured on days 1, 3, 7, 14, 21, 28 and 35, respectively, to obtain the in vivo release rate (%). The results show that the release with molecular weight 20000 is: 1 day (10%), 3 (26%), 7 (54%), 14 (80%), 21 (90%), 28(92) and 35 (94%). Comparing in vivo release of nimustine sustained release implants made of different molecular weight polylactic acids, it was found that the release was slowed down with increasing molecular weight, and compared with the systemic administration group, the tumor inhibition rate was increased with increasing molecular weight of polylactic acids, as exemplified by day 7, 66% (MW: 5000), 64% (MW: 15000), 58% (MW: 25000), 54% (MW: 40000) and 46 (MW: 60000), in this order.

The same result is also seen in the drug sustained release preparation prepared by taking polylactic acid as an auxiliary material, which contains the combination of nimustine and the synergist thereof.

Particularly, the sustained-release preparation, particularly the sustained-release injection, has simple and convenient operation and good repeatability. Not only has good curative effect, but also has little toxic and side effect.

Different drug packages differ from different biodegradable polymers in their essential characteristics. Further research shows that the slow release auxiliary materials most suitable for the slow release of the drug are one of or a combination of racemic polylactic acid, racemic polylactic acid/glycolic acid copolymer, monomethyl polyethylene glycol/polylactic acid copolymer, polyethylene glycol/polylactic acid copolymer, terminal carboxyl polylactic acid/glycolic acid copolymer, polifeprosan, di-fatty acid and sebacic acid copolymer, poly (erucic aciddipolymer-sebacic acid), poly (fumaric acid-sebacic acid), ethylene vinyl acetate copolymer, polylactic acid, polyglycolic acid and glycolic acid copolymer, xylitol, oligosaccharide, chondroitin, chitin, hyaluronic acid, collagen, gelatin and albumin glue. The sustained release preparation prepared by the sustained release auxiliary materials has no obvious phenomenon of sudden drug release; the most suitable suspending agent is one or more of methylcellulose, hydroxymethyl cellulose, sodium carboxymethylcellulose, (iodine) glycerol, dimethicone, propylene glycol, carbomer, mannitol, sorbitol, surfactant, Tween 20, Tween 40, Tween 80, or their combination.

In a word, the used nimustine and various nimustine synergists have obvious inhibition effect on the growth of various tumor cells when being used independently, and can show obvious synergistic effect when being used jointly. Therefore, the active ingredients of the invention are nimustine and any nimustine 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

The first embodiment is as follows:

putting 90mg of polylactic acid (PLA) with the medical auxiliary material molecular weight of 20000-40000 into a container, adding 100 ml of dichloromethane into the container to dissolve and mix evenly, adding 10mg of nimustine into the mixture, shaking the mixture evenly again, and then drying the mixture in vacuum to remove the organic solvent. Shaking up again, and vacuum drying to remove organic solvent. Freeze-pulverizing the dried solid composition containing drug to obtain micropowder containing nimustine 10 wt%, and suspending in physiological saline containing 1.5% sodium carboxymethylcellulose to obtain suspension type sustained-release injection with viscosity of 360-480 cp (at 25-30 deg.C). The subcutaneous drug release time is 25-30 days.

Example two:

75mg of polylactic acid (PLA) with the medical auxiliary material molecular weight of 30000-50000 is put into a container, 100 ml of dichloromethane is added to dissolve and mix evenly, 25mg of nimustine is added, the mixture is shaken up again and dried in vacuum to remove the organic solvent. And immediately forming the dried solid composition, subpackaging and sterilizing by rays to obtain the anticancer in-vivo implant containing the nimustine with the weight percentage of 25 percent for treating the solid tumors. The subcutaneous drug release time is 35-40 days.

Example three:

putting 95mg of polylactic acid (PLA) with the medical auxiliary material molecular weight of 15000-30000 into a container, adding 100 ml of dichloromethane into the container to dissolve and mix evenly, adding 5mg of nimustine, shaking up again and drying in vacuum to remove the organic solvent. And immediately forming the dried solid composition, subpackaging and sterilizing by rays to obtain the anticancer in-vivo implant containing 5 weight percent of nimustine for treating the solid tumors. The subcutaneous drug release time is 30-40 days.

Example four:

as described in examples one to three, except that the component is one of the following, all in weight percent:

(A) 5% of nimustine and 95% of polylactic acid;

(B) 10% nimustine and 90% polylactic acid;

(C) 20% of nimustine and 80% of polylactic acid;

(D) 35% of nimustine and 65% of polylactic acid.

Example five:

85mg of polyglycolic acid-glycolic acid copolymer (PLGA, 50: 50) with the molecular weight of the pharmaceutic adjuvant 15000-35000 is weighed and put into a container, 100 ml of organic solvent is added to dissolve and mix evenly, 15mg of nimustine is added to the mixture, and the mixture is shaken again and dried in vacuum to remove the organic solvent. Freeze-pulverizing the dried solid composition containing drug to obtain micropowder containing nimustine 15 wt%, and suspending in physiological saline containing 1.0% sodium carboxymethylcellulose and 5% mannitol to obtain suspension type sustained-release injection with viscosity of 420-480 cp (at 25-30 deg.C). The subcutaneous drug release time of the rat is 40-45 days.

Example six:

weighing 90mg of PLGA (50: 50) with the pharmaceutic adjuvant molecular weight of 25000-50000, putting the PLGA into a container, adding 100 ml of organic solvent to dissolve and uniformly mix, adding 10mg of nimustine, shaking uniformly again, and drying in vacuum to remove the organic solvent. The dried solid composition is immediately formed, subpackaged and sterilized by rays to obtain the solid tumor treating pharmaceutical composition containing 10 weight percent of nimustine, which is used as an anticancer in vivo implant. The subcutaneous drug release time of the rat is 45-50 days.

Example seven:

weighing 80mg of PLGA (75: 25) with the molecular weight of 20000-40000 as a pharmaceutic adjuvant, adding 100 ml of dichloromethane into the weighed materials, dissolving and uniformly mixing the materials, adding 20mg of nimustine, shaking the mixture uniformly again, and drying the mixture in vacuum to remove the organic solvent. And immediately forming the dried solid composition, subpackaging and sterilizing by rays to obtain the solid tumor treating pharmaceutical composition containing 20 weight percent of nimustine, which is used as an anticancer in vivo implant. The subcutaneous drug release time of the rat is 50-55 days.

Example eight: as described in examples five to seven, except that the component is one of the following, all in weight percent:

(A) 5% nimustine and 95% polyglycolic acid and glycolic acid copolymer;

(B) 10% nimustine and 90% polyglycolic acid and glycolic acid copolymer;

(C) 15% nimustine and 85% polyglycolic acid and glycolic acid copolymer;

(D) 20% nimustine and 80% polyglycolic acid and glycolic acid copolymer;

(E) 35% nimustine and 75% polyglycolic acid and glycolic acid copolymer.

Example nine:

the ethylene vinyl acetate copolymer (EVAc) with 95mg of pharmaceutical excipients of which the molecular weight is 35000-55000 is weighed and put into a container, 100 ml of dichloromethane is added to dissolve and mix evenly, 5mg of nimustine is added to the mixture, and the mixture is shaken again and evenly and then dried in vacuum to remove the organic solvent. The dried solid composition is immediately formed, subpackaged and sterilized by rays to obtain the solid tumor treating pharmaceutical composition containing 5 weight percent of nimustine, which is used as an anticancer in vivo implant. The subcutaneous drug release time of the rat is 35 to 45 days.

Example ten: as described in example nine, except that the component is one of the following, all in weight percent:

(A) 10% nimustine and 90% EVAc;

(B) 15% nimustine and 85% EVAc;

(C) 20% nimustine and 80% EVAc;

(D) 25% nimustine and 75% EVAc;

(E) 30% nimustine and 70% EVAc.

Example eleven:

placing 80mg of polifeprosan (p-carboxyphenylpropane: sebacic acid at a weight ratio of 20: 80) into a container, adding 100 ml of dichloromethane, dissolving, mixing, adding 10mg of nimustine and 10mg of carboplatin, shaking again, and vacuum drying to remove the organic solvent. Freeze-pulverizing the dried solid composition containing the medicine to obtain micropowder containing 10 wt% of nimustine and 10 wt% of carboplatin, and suspending the micropowder in physiological saline containing 2.5% of sodium carboxymethylcellulose to obtain corresponding suspension type sustained-release injection with viscosity of 480-560 cp (at 25-30 deg.C), drug release time in vitro physiological saline of 25-30 days, and drug release time under mouse skin of 25-40 days.

Example twelve: as described in example eleven, except that the component is one of the following, all in weight percent:

(A) 5% nimustine and 35% carboplatin;

(B) 10% nimustine and 25% carboplatin;

(C) 15% nimustine and 15% carboplatin;

(D) 20% nimustine and 10% carboplatin;

(E) 25% nimustine and 5% carboplatin.

Example thirteen:

weighing 80mg of PLGA (50: 50) with the molecular weight of 20000-40000 as a pharmaceutic adjuvant, putting the PLGA into a container, adding 100 ml of dichloromethane to dissolve and mix evenly, adding 10mg of nimustine and 10mg of methotrexate, shaking up again, and drying in vacuum to remove the organic solvent. And immediately forming the dried solid composition, subpackaging and sterilizing by rays to obtain the solid tumor treating pharmaceutical composition containing 10 weight percent of nimustine and 10 weight percent of methotrexate, and taking the pharmaceutical composition as an anticancer in vivo implant. The in vivo implant has the release time of 15-25 days in vitro physiological saline and the release time of 25-40 days under mouse skin.

Example fourteen:

80mg of PLGA (75: 25) with the molecular weight of 20000-60000 as a pharmaceutic adjuvant is weighed and put into a container, 100 ml of dichloromethane is added to dissolve and mix evenly, 15mg of nimustine and 5mg of adriamycin are added to the mixture, the mixture is shaken again and dried in vacuum to remove the organic solvent. The dried solid composition is immediately formed, subpackaged and sterilized by rays to obtain the solid tumor treating pharmaceutical composition containing 15 weight percent of nimustine and 5 weight percent of adriamycin, which is used as an anticancer in vivo implant. The in vivo implant has a release time of 15-20 days in vitro physiological saline and a release time of 30-40 days under the skin of a mouse.

Example fifteen:

weighing 40mg of PLA with the molecular weight of 20000-40000 as a pharmaceutical excipient and 40mg of polifeprosan (the weight ratio of p-carboxyphenylpropane to sebacic acid is 50: 50) into a container, adding 100 ml of dichloromethane to dissolve and mix uniformly, adding 5mg of nimustine and 15mg of epirubicin, shaking uniformly again, and drying in vacuum to remove the organic solvent. The dried solid composition is immediately formed, subpackaged and sterilized by rays to obtain the solid tumor treating pharmaceutical composition containing 5 weight percent of nimustine and 15 weight percent of epirubicin, which is used as an anticancer in vivo implant. The in vivo implant has a release time of 15-20 days in vitro physiological saline and a release time of 30-40 days under the skin of a mouse.

Example sixteen: as in examples thirteen to fifteen, except that the component is one of the following, all in weight percent:

(A) 5% nimustine and 35% doxorubicin or epirubicin;

(B) 10% nimustine and 25% doxorubicin or epirubicin;

(C) 15% nimustine and 15% doxorubicin or epirubicin;

(D) 20% nimustine and 10% doxorubicin or epirubicin;

(E) 25% nimustine and 5% doxorubicin or epirubicin.

Example seventeen:

40mg of PLGA (50: 50) with the molecular weight of 20000-40000 as a pharmaceutic adjuvant and 40mg of polifeprosan (the weight ratio of p-carboxyphenylpropane to sebacic acid is 20: 80) are weighed and put into a container, 100 ml of dichloromethane is added to dissolve and mix evenly, 10mg of nimustine and 10mg of oxaliplatin are added, the mixture is shaken again evenly and dried in vacuum to remove the organic solvent. The dried solid composition is immediately formed, subpackaged and sterilized by rays to obtain the solid tumor treating pharmaceutical composition containing 10 weight percent of nimustine and 10 weight percent of oxaliplatin, which is used as an anticancer in vivo implant. The in vivo implant has the release time of 15-25 days in vitro physiological saline and the release time of 25-40 days under mouse skin.

Example eighteen:

80mg of PLGA (75: 25) with the molecular weight of 20000-60000 as a pharmaceutic adjuvant is weighed and put into a container, 100 ml of dichloromethane is added to dissolve and mix evenly, 15mg of nimustine and 5mg of methotrexate are added, the mixture is shaken again and dried in vacuum to remove the organic solvent. The dried drug-containing solid composition is frozen and crushed into micro powder containing 15 percent of nimustine and 5 percent of methotrexate by weight percentage, and then the micro powder is suspended in physiological saline containing 5 percent of mannitol to prepare a corresponding suspension type sustained-release injection, the viscosity is 380cp-460cp (at 25-30 ℃), the drug release time in the in vitro physiological saline is 15-20 days, and the drug release time under the skin of a mouse is 30-40 days.

Example nineteenth:

and (2) putting 80mg of PLA with the molecular weight of 20000-40000 as a pharmaceutical adjuvant into a container, adding 100 ml of dichloromethane, dissolving and uniformly mixing, adding 5mg of nimustine and 15mg of gemcitabine, shaking uniformly again, and drying in vacuum to remove the organic solvent. The dried solid composition is immediately formed, subpackaged and sterilized by rays to obtain the solid tumor treating pharmaceutical composition containing 5 weight percent of nimustine and 15 weight percent of gemcitabine, which is used as an anticancer in vivo implant. The in vivo implant has a release time of 15-20 days in vitro physiological saline and a release time of 30-40 days under the skin of a mouse.

Example twenty: as in examples seventeen to nineteen, except that the component is one of the following, all in weight percent:

(A) 5% nimustine and 35% methotrexate or gemcitabine;

(B) 10% nimustine and 25% methotrexate or gemcitabine;

(C) 15% nimustine and 15% methotrexate or gemcitabine;

(D) 20% nimustine and 10% methotrexate or gemcitabine;

(E) 25% nimustine and 5% methotrexate or gemcitabine.

Example twenty one:

the pharmaceutical composition for treating solid tumors as described in examples one to nineteenth, wherein the pharmaceutical excipients are selected from one or a combination of the following:

a) polylactic acid (PLA) with molecular weight of 5000-15000, 10000-25000, 25000-35000 or 30000-50000;

b) a copolymer of polyglycolic acid and glycolic acid (PLGA) having a molecular weight of 5000-;

c) ethylene vinyl acetate copolymer (EVAc);

d) polifeprosan (p-carboxyphenylpropane (p-CPP): Sebacic Acid (SA)) copolymer, wherein the weight percentage of the p-carboxyphenylpropane (p-CPP) to the Sebacic Acid (SA) is 10: 90, 20: 80, 30: 70, 40: 60, 50: 50 or 60: 40;

e) xylitol, oligosaccharide, chitin, potassium salt, sodium salt, hyaluronic acid, collagen, gelatin or albumin.

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.

In addition, the slow release implant for implanting the nimustine into the tumor has good treatment effect on glioma, bone tumor, lymphoma, gastric cancer, bladder cancer, testicular cancer, colon cancer, rectal cancer, ovarian cancer, endometrial cancer, cervical cancer, kidney cancer, prostate cancer and other solid tumors, and the effect of the slow release implant is obviously better than that of a nimustine abdominal cavity injection group and a nimustine local injection group. This unexpected discovery constitutes a major technical feature of the present invention, providing yet another new choice for therapeutic drugs for solid tumors.

Claims

1. A nimustine sustained release agent for treating solid tumor is a sustained release injection, which comprises the following components:

(A) a sustained release microsphere comprising:

0.5-60% of anticancer active ingredient

Sustained release auxiliary materials 40-99%

0.0 to 30 percent of suspending agent

The above are weight percentages

And

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

Wherein,

the anticancer active ingredient is nimustine or the combination of nimustine and nimustine synergist selected from carboplatin, oxaliplatin, methotrexate, gemcitabine, epirubicin or adriamycin;

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) a di-fatty acid and sebacic acid copolymer;

f) poly (erucic acid dimer-sebacic acid) copolymer;

g) poly (fumaric acid-sebacic acid) copolymer;

h) racemic polylactic acid, racemic polylactic acid/glycolic acid copolymer, monomethyl polyethylene glycol/polylactic acid copolymer, polyethylene glycol/polylactic acid copolymer, carboxyl-terminated polylactic acid or carboxyl-terminated polylactic acid/glycolic acid copolymer; or

i) Polifeprosan in combination with polylactic acid or a copolymer of polyglycolic acid and glycolic acid.

The suspending agent is selected from one or more of sodium carboxymethylcellulose, iodoglycerol, dimethicone, propylene glycol, carbomer, mannitol, sorbitol, surface active substance, Tween 20, Tween 40 and Tween 80.

The viscosity of the suspending agent is 100cp-3000cp (at 20-30 ℃), and the viscosity of the menstruum is 10cp-650cp (at 20-30 ℃).

2. The slow release formulation of nimustine for treating solid tumor as claimed in claim 1, wherein the anticancer active constituents and excipients are selected from one of the following, all by weight:

(A) 5-15% nimustine and 85-95% polyglycolic acid and glycolic acid copolymer;

(B) 15-35% nimustine and 65-85% polyglycolic acid and glycolic acid copolymer;

(C) 5-15% of nimustine and 85-95% of polylactic acid;

(D) 15-35% of nimustine and 65-85% of polylactic acid;

(E) 5-25% nimustine and 75-95% polifeprosan;

(F) 5-35% of nimustine and 65-95% of ethylene vinyl acetate copolymer.

3. The slow release nimustine anticancer active ingredients of claim 1, which are selected from the following groups, all by weight:

(1) 5-25% nimustine and 5-35% methotrexate or gemcitabine;

(2) 5-25% nimustine and 5-35% carboplatin or oxaliplatin;

(3) 5-25% of nimustine and 5-35% of adriamycin or epiadriamycin.

4. The sustained-release injection for treating solid tumor according to claims 1 and 2, characterized in that the molecular weight peak of polylactic acid is 5000-15000, 10000-25000, 25000-35000 or 30000-60000.

5. The sustained-release injection for treating solid tumors as claimed in claims 1 and 2, wherein the molecular weight peak of the copolymer of polyglycolic acid and glycolic acid is 5000-; the weight ratio of polyglycolic acid to glycolic acid is 10: 90, 20: 80, 30: 70, 40: 60, 50: 50 or 60: 40.

6. The sustained-release injection for treating solid tumors as claimed in claims 1 and 2, wherein the weight ratio of p-carboxyphenylpropane to sebacic acid in polifeprosan is 10: 90, 20: 80, 30: 70, 40: 60, 50: 50 or 60: 40.

7. The sustained-release nimustine injection for treating solid tumors as claimed in claim 1, wherein the anticancer active ingredient is formulated as a sustained-release implant.

8. The slow release implant of nimustine for treating solid tumor as claimed in claim 7, wherein the anticancer active constituents and excipients are selected from one of the following, all by weight:

(A) 5-15% nimustine and 85-95% polyglycolic acid and glycolic acid copolymer;

(B) 15-35% nimustine and 65-85% polyglycolic acid and glycolic acid copolymer;

(C) 5-15% of nimustine and 85-95% of polylactic acid;

(D) 15-35% of nimustine and 65-85% of polylactic acid;

(E) 5-25% nimustine and 75-95% polifeprosan;

(F) 5-35% of nimustine and 65-95% of ethylene vinyl acetate copolymer.

9. The slow release implant of nimustine for treating solid tumors as claimed in claim 7, wherein the anticancer active ingredient is further selected from one of the following:

(1) 5-25% of nimustine and 5-35% of methotrexate;

(2) 5-25% nimustine and 5-35% carboplatin;

(3) 5-25% nimustine and 5-35% adriamycin;

(4) 5-25% nimustine and 5-35% gemcitabine;

(5) 5-25% nimustine and 5-35% oxaliplatin; or

(6) 5-25% of nimustine and 5-35% of epirubicin.

The 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) a di-fatty acid and sebacic acid copolymer;

f) poly (erucic acid dimer-sebacic acid) copolymer;

g) poly (fumaric acid-sebacic acid) copolymer;

10. The slow release implant of nimustine for the treatment of solid tumors as claimed in claim 1, for the preparation of a medicament for the treatment of solid tumors including brain tumor, glioma, osteosarcoma, lymphoma, liver cancer, lung cancer, esophageal cancer, stomach cancer, breast cancer, pancreatic cancer, thyroid cancer, nasopharyngeal cancer, ovarian cancer, endometrial cancer, cervical cancer, kidney cancer, prostate cancer, bladder cancer, colon cancer, rectal cancer, testicular cancer, skin cancer, head and neck tumors and solid tumors originating from the gall bladder, oral cavity, peripheral nervous system, mucosa, glands, blood vessels, bone tissue, lymph nodes, primary or secondary cancer of the eye, sarcoma or carcinosarcoma.