CN1969828A - Anticancer sustained release injection containing mesenchyme hydrolytic agent - Google Patents

Abstract

Disclosed is a anti-cancer slow release injection containing mesenchyme hydrolytic reagent which comprises slow release microspheres 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 anticancer active constituent being the combination of mesenchyme hydrolytic reagent and alkylating agent, purine analogues and/or hormones anti-cancer drugs, the slow release auxiliary materials are selected from polylactic acid and its copolymer, Polifeprosan, polylactic acid copolymer or mixture, EVAc or their combination, The suspending agent is selected from carboxymethylcellulose, the viscosity of the suspension adjuvant is 80-3000cp (at 20-30 deg C). The slow release microspheres can also be prepared into slow release implanting agent. When used for in-tumor or around-tumor injection or placement, the slow release agent can achieve and maintain medicinal concentration in the solid tumor, the effect for chemotherapy can also be improved.

Description

Anticancer sustained-release injection containing interstitial hydrolytic agent

(I) technical field

The invention relates to an anticancer sustained-release injection containing an interstitial hydrolytic agent, belonging to the technical field of medicines. Specifically, the invention provides a sustained-release injection or sustained-release implant carrying an interstitial hydrolytic agent and an anticancer drug, wherein the anticancer drug is an alkylating agent, a purine derivative and/or a hormone anticancer drug. The anticancer sustained release agent can effectively inhibit or destroy solid tumor stroma and tumor blood vessel, inhibit tumor neovascularization, effectively reduce tension, interstitial pressure and interstitial viscosity in tumor, further improve the interstitial fluid conductivity, and facilitate the effective diffusion of the drug into solid tumor and in tumor.

(II) background of the invention

The treatment of cancer mainly comprises methods such as surgery, radiotherapy, chemotherapy and the like. Wherein the surgical treatment can not eliminate scattered tumor cells, so that the tumor cells are frequently relapsed or caused to spread and metastasize due to surgical stimulation; radiotherapy and traditional chemotherapy have no selectivity, are difficult to form effective drug concentration or therapeutic dose locally on tumors, have poor effect and high toxicity, and are limited by systemic toxicity reaction when the drug or radiation dose is simply increased. See, e.g., "Intratumoral Placement of cisplatin plus systemic Carmustine in rat brain tumors" J.Takema.69, pp 76-82, 1998 (Kong Q et al, J Surg Oncol.1998 Oct; 69 (2): 76-82).

Low dose anti-cancer drug therapy can not only increase drug tolerance of cancer cells, but also promote invasive growth thereof, see Beam et al, "anti-cancer drug pulsed screening increases drug tolerance and in vitro infiltration capacity of human lung cancer cells with concomitant changes in gene expression" [ International journal of cancer (Liang Y, et al, Int Jcancer. 2004; 111 (4): 484-93) ].

The local placement of the antitumor drug can better overcome the defects, not only can obviously improve the local drug concentration of the tumor, but also can obviously reduce the systemic toxic reaction. A number of in vitro and in vivo experiments have shown therapeutic efficacy against solid tumors, see Kongqing et al, "cisplatin placement in tumors plus systemic carmustine for treatment of rat brain tumors" [ J.Oncork.69, 76-82 ], 1998 (Kong Q et al, J Surg Oncol.1998 Oct; 69 (2): 76-82) ] and Kongqing et al, "cisplatin placement in tumors for cure of rat primary brain tumors" [ J.Oncork.64, 268-273 (1997) (Kong Q et al, JSURg Oncol.1997 Oct; 64: 268-273). See also Chinese patent (ZL 00111093.4; ZL 96115937.5; application Nos. 001111264, 001111272) and U.S. patent Nos. 6,376,525B 1; 5,651,986; 5,626,862).

However, solid tumors are composed of tumor cells and tumor stroma, wherein blood vessels in the tumor stroma not only provide a scaffold and essential nutrients for the growth of tumor cells, but also influence the penetration and diffusion of chemotherapeutic drugs around tumors and in tumor tissues, see Niti et al, "influence of extracellular stroma conditions on drug transport in solid tumors" [ Cancer research ] No. 60, No. 2497, No. 503, 2000 (Netti PA, Cancer Res.2000, No. 60 (9): 2497, No. 503).

The components of fibrin and collagen in blood vessels and connective tissues in tumor stroma and hyperproliferative tumor cells cause high interstitial pressure (interstitial pressure), high interstitial viscosity (interstitial viscosity), high tissue tension coefficient (tissue tension module) and low interstitial fluid conductivity (hydralic con) of solid tumors. These factors greatly limit the effective diffusion of drugs into solid tumors and within tumors, and thus constitute a major obstacle to tumor chemotherapy.

Moreover, blood vessels in the tumor stroma are insensitive to conventional chemotherapeutic drugs, often resulting in increased resistance of tumor cells to anticancer drugs, with consequent failure of the treatment.

Disclosure of the invention

The invention provides an anti-cancer sustained-release injection containing an interstitial hydrolytic agent aiming at the defects of the prior art, belonging to the technical field of medicines. Specifically, the invention provides a sustained-release injection or sustained-release implant carrying an interstitial hydrolytic agent and an anticancer drug, wherein the anticancer drug is an alkylating agent, a purine derivative and/or a hormone anticancer drug.

The interstitial hydrolytic agent, the alkylating agent, the purine derivative and/or the hormone anticancer drug can inhibit the growth of tumors when being used independently, and can also increase the sensitivity of tumor cells to each other when being used together. Has been widely used for treating various solid tumors at home and abroad. However, during the application process, the obvious systemic toxicity greatly limits the application of the medicine.

In addition, the interstitial hydrolytic agent and/or the anticancer drug are prepared into the sustained release agent (mainly a sustained release injection and a sustained release implant), so that not only can the local drug concentration of the tumor be greatly improved, the drug concentration of the drug in a circulatory system be reduced, the toxicity of the drug to normal tissues be reduced, but also the drug injection can be greatly facilitated, the complication of the operation can be reduced, and the cost of a patient can be reduced. The above unexpected findings constitute the subject of the present invention.

The anti-solid tumor sustained release agent comprises anti-cancer active ingredients and pharmaceutic adjuvants, wherein interstitial hydrolytic agents in the anti-cancer active ingredients are vascular inhibitors and/or proteolytic enzymes. The blood vessel inhibitor has the functions of inhibiting the growth of tumor cells, effectively inhibiting or destroying blood vessels of tumors and inhibiting the formation of new blood vessels of the tumors, so that the tumor cells lose the sources of the stent and nutrient substances required by the growth, and the combination or the independent application of the blood vessel inhibitor and proteolytic enzyme can obviously promote the penetration and the diffusion of chemotherapeutic drugs into the tumors, the tumor periphery and the tumor tissues; the proteolytic enzyme can effectively degrade fibrin, collagen and other components in blood vessels and connective tissues in tumor interstitium, effectively reduce tension, interstitial pressure and interstitial viscosity in the tumor, further improve interstitial fluid conductivity, and facilitate the penetration and diffusion of the medicine into solid tumor and around the tumor and in the tumor tissue. The above unexpected findings constitute the subject of the present invention.

The compound pharmaceutical composition of the present invention can be prepared into any preparation form, such as, but not limited to, capsules, sustained release preparations, granules, pills, tablets, powders, injections, ointments, patches, implants, sustained release injections, etc. Among them, sustained release preparations are preferable, and sustained release implants and sustained release injections are most preferable.

Aiming at the defects of the prior art, the invention provides a novel sustained-release injection containing an interstitial hydrolytic agent and an anticancer drug.

The invention relates to a slow release injection of interstitial hydrolytic agent, which is composed of slow release microspheres and dissolvent. Specifically, the anticancer sustained-release injection consists of the following components:

(A) a sustained release microsphere comprising:

0.5-60% of anticancer active ingredient

Sustained release auxiliary materials 40-99%

0.0 to 30 percent of suspending agent

The above are weight percentages

And

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

The menstruum is divided into common menstruum and special menstruum.

The anticancer active component is the combination of interstitial hydrolytic agent and anticancer drugs, the interstitial hydrolytic agent is selected from vascular inhibitor andor proteolytic enzyme, and the anticancer drugs are alkylating agent, purine derivative and/or hormone anticancer drugs.

The medicine prepared from the interstitial hydrolytic agent is mainly administrated by conventional ways such as oral administration or intravenous injection, and the administration mode of the invention is local sustained-release administration, so that the systemic toxicity of the medicine is obviously reduced while the treatment effect of the medicine is obviously enhanced. In the case of interstitial hydrolytical agents with anticancer activity, not all sustained-release excipients can achieve a sustained-release effect of effective release. 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 selected interstitial hydrolytic agent in a human body or an animal body 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 above unexpected findings constitute the subject of the present invention.

The interstitial hydrolytic agent is a vascular inhibitor and/or proteolytic enzyme, the vascular inhibitor can effectively inhibit or destroy the blood vessels of the tumor and inhibit the formation of new blood vessels of the tumor besides the function of inhibiting the growth of the tumor cells, thereby not only leading the tumor cells to lose the sources of the stent and nutrient substances required by the growth, but also obviously promoting the penetration and the diffusion of chemotherapeutic drugs into the tumor, the periphery of the tumor and the tumor tissues when being used together with or independently applied with the proteolytic enzyme; the proteolytic enzyme can effectively degrade fibrin, collagen and other components in blood vessels and connective tissues in tumor interstitium, effectively reduce tension, interstitial pressure and interstitial viscosity in the tumor, further improve interstitial fluid conductivity, and facilitate the penetration and diffusion of the medicine into solid tumor and around the tumor and in the tumor tissue.

The proteolytic enzyme is selected from one or a combination of elastase, pancreatic elastase, metalloprotease, trypsin, chymotrypsin, pepsin, pronase, dispase, bromelain, chymotrypsin, clostripain, thermolysin, subtilisin, papain, chymopapain, plasmin, serenethiopeptidase, pancreatin, cathepsin-G, cysteine protease, thioesterase, amidotransferase, transesterase activity, plasminogen activator, collagenase, polymorphonuclear leukocyte serine protease, nuclease, lipase, esterase, streptokinase, glycosidase, hyaluronidase, neuraminidase, amylase, relaxin, interferon (gamma-interferon), and fibrin.

Among them, elastase, trypsin, pepsin, pronase, dispase, bromelain, chymotrypsin, clostripain, plasmin, cathepsin-G, plasminogen activator, collagenase, streptokinase, glycosidase, hyaluronidase, lysozyme, relaxin, interferon (γ -interferon), and trypsin are preferable.

The blood vessel inhibitor is selected from one or the combination of gefitinib, erlotinib, lapatinib, vatalanib, pelitinib, carboxyamidotriazole, thalidomide, ranolamine, angiostatin, endostatin, imatinib mesylate, sematinib, dasatinib, avastin, canatinib, sorafenib, sunitinib, teoslata, panitoma, marimastat, SU5416, SU6668, fumagillin, TNP-470.

The above neovascularization inhibitors also include their salts, such as, but not limited to, sulfate, phosphate, hydrochloride, lactobionate, acetate, aspartate, nitrate, citrate, purine or pyrimidine salts, succinate, maleate, and the like.

The proportion of the angiogenesis inhibitor in the sustained release preparation is determined by specific conditions, and can be 0.1-50%, preferably 1-40%, and most preferably 5-30%.

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

the biological effective component is 0.5-60%

The sustained-release auxiliary material is 41 to 99.9 percent

0.0 to 30 percent of suspending agent

(B) 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 slow release particles comprise a medicinal active ingredient and a slow release auxiliary material and/or a suspending agent, wherein the active ingredient can be an interstitial hydrolytic agent, an alkylating agent, a purine derivative and/or a hormone anticancer drug.

The alkylating agent is selected from one or a combination of the following: cyclophosphamide (CTX), Melphalan (Melphalan), tumorigenin (chlorambucil), 4H-peroxycyclophosphamide (4H-CTX), Ifosfamide (Ifosfamide, pipapine), tris-mustard cyclophosphamide, sultamide (Sufosfamide), desphosphoramide (Defosfamide), macsfamide (Mafosfamide), Perfosfamide (Perfosfamide), triamcinolone (Trofosfamide), carbazolomide, metafaram (Metalfalan), formazan (Formylermalan), hexametholamine (hexamethylmamelamine), amethoquinone, thymopentin, clomiphene, letrozole, sodium cantharidine, cantharidine (cantharidine), sodium methamphetamine, cantharidine, cantharidin (Norcantharidin), mannomustine (Mannosum), treosun (Tresulosin), trexodine (Etodoxadine), ethiprolide (Etopodium bromide, piposulfan), carcinonine (triethyleneamine), epoxypiperazine (epoxypiperazine), benzotepa (Benzodepa), puripea (Pumitepa), Meturedepa (Meturedepa), azatepa (Aza-TEPA), Uredepa (Uredepa) or salts thereof.

The alkylating agent is preferably cyclophosphamide, melphalan, oncoclonine, ifosfamide, 4H-peroxycyclophosphamide, cyclophosphamide, macsfamide, cyclophosphamide, hexamethyl-pyriminone, cantharidin, norcantharidin, mannosylfan, trooshusuo, ritrosufen, improsulfan, etogrel, pipobroman, piposulfan, canonin, epoxy piperazine, benzotepa, purepipipa, meltutepa, uretepa or azatepa.

Salts of the above alkylating agents include: sulphate, phosphate, hydrochloride, lactobionate, acetate, aspartate, nitrate, citrate, purine or pyrimidine salt, succinate or maleate.

The weight percentage of the alkylating agent in the sustained-release agent is 0.01-90%, preferably 1-50%, and most preferably 5-30%.

The guanine analog is selected from benzylguanine, O6-benzylguanine, O6-butylguanine, O6-methylguanine, O6-alkylguanine, 2-amino-6-oxopurine, O6-benzyl 2' -deoxyguanosine, guanine (2-amino-6-hydroxypurine), 8-amino-O6-benzylguanine, 8-methyl-O6-benzylguanine, 8-hydroxy-O6-benzylguanine, 8-bromo-O6-benzylguanine, 8-oxy-O6-benzylguanine, 8-trifluoromethyl-O6-benzylguanine, O6-benzyluric acid, O6-benzylxanthine, O6-benzyl-2-fluorohypoxanthine, diacetyl-O6-benzyl-8-oxoguanine, O6-benzyl-8-methylguanine, O6-benzyl-8-oxoguanine, O6-benzyl-8-bromoguanine, O6-benzyl-8-trifluoromethylguanine, O6-benzyl-N2-methylguanine, O6-benzyl-N2N 2-dimethylguanine, O6-benzyl-8-trifluoromethyl-9-methylguanine, O6-benzyl-8-bromo-9-methylguanine, O6-benzyl-8-bromo-9-pivaloyloxymethylguanine, O6-benzyl-7-pivaloyloxymethylguanine, O6-benzyl-8-bromo-7-pivaloyloxymethylguanine, O6-benzyl-8-bromo-benzyl-4-pivaloyloxymethylguanine, O6-benzyl-8-bromo-methyl-4-pivaloyloxymethylguanine, 8-aza-O6-benzyl-7-pivaloyloxymethylguanine, 8-aza-O6-benzyl-7-pivaloyloxymethylguanine, 8-aza-O6-benzylguanine, 8-aza-O6-benzyl-9-methylguanine, or acetyl-O6-benzyl-8-oxoguanine, O6-benzyl-N2-methylguanine, O6-benzyl-N2N 2-dimethylguanine, 2-amino-6-chloro-8-methylpurine, 2, 8-diamino-6-chloropurine, O6-benzyl-N2-guanosine, N (7) -methylguanine, O6-benzyl-9-cyanoguanine, O6-benzyl-N2-guanosine, O6-cycloalkenyl-guanine, 1-cyclobutenylmethyl-guanine, 1-cyclopentenylmethyl-guanine, and O6-bromothiapiprolidinyl-guanine, or a combination thereof.

The proportion of guanine analogues in the composition is determined by the particular circumstances, and in general, may be from 0.1% to 50%, preferably from 2% to 40%, and most preferably from 5% to 30%. All are weight percent.

Hormonal anti-cancer agents are primarily steroid hormones and hormone antagonists including, but not limited to, triptorelin, goserelin, leuprorelin, anastrozole, idoxifene, mirtaxifene, tamoxifen, 4-monohydroxytamoxifen (OH-TAM), comoxifene, raloxifene, sterculigenol, 4-hydroxyttamoxifen, flutamide, aminoglutethimide, pirglutethimide, megestrol, medroxyprogesterone, clomiphene, toremifene, letrozole, anastrozole, exemestane, bicalutamide.

The hormone anticancer drugs can be used for various hormone-dependent tumors, but different drugs have relative tumor selectivity, such as tamoxifen, pirimid, rubitecan, and toremifene, which are mainly used for treating estrogen-dependent tumors, such as breast cancer and endometrial cancer; flutamide, quart monosilicon blue, and bicalutamide are used primarily to treat androgen dependent tumors, such as prostate cancer; triptorelin, goserelin, leuprorelin, tamoxifen, raloxifene, aminoglutethimide, clomiphene, toremifene, letrozole, anastrozole and exemestane are used to treat breast cancer, prostate cancer and endometrial cancer.

The content of the hormone anticancer drug in the composition is 0.01-60%, preferably 1-40%, and most preferably 5-30%, all of which are weight percentages.

The invention relates to a plurality of available pharmaceutical excipients, in particular to a plurality of slow release excipients screened from hundreds of excipients, wherein the selected slow release excipients can release the selected drug in human and animal bodies for tens of days, and the release lasts for 30-50 days from hours (see the examples in the specification). The obtained product is an anticancer sustained release agent. The choice of sustained release excipients, particularly the combination with different drugs, is not obvious because it can be determined by limited experiments but by a great deal of creative work.

The viscosity range IV (dl/g) of the sustained-release auxiliary material is 0.1-1.0, and the sustained-release auxiliary material is selected from racemic polylactic acid (D, L-PLA), racemic polylactic acid/glycollic acid copolymer (D, L-PLGA), monomethyl polyethylene glycol/polylactic acid (MPEG-PLA), monomethyl polyethylene glycol/polylactic acid copolymer (MPEG-PLGA), polyethylene glycol/polylactic acid (PLA-PEG-PLA), polyethylene glycol/polylactic acid copolymer (PLGA-PEG-PLGA), carboxyl-terminated polylactic acid (PLA-COOH), carboxyl-terminated polylactic acid/glycollic acid copolymer (PLGA-COOH), polifeprosan, difatty fatty acid and sebacic acid copolymer (PFAD-SA), poly (erucic acid dimer-sebacic acid) [ P (EAD-SA) ], poly (fumaric acid-sebacic acid) [ P (FA-SA) ], poly (FA-sebacic acid) ], and the like, Ethylene vinyl acetate copolymer (EVAc), polylactic acid (PLA), polyglycolic acid and glycolic acid copolymer (PLGA), poly-dioxanone (PDO), polytrimethylene carbonate (PTMC), xylitol, oligosaccharide, chondroitin, chitin, hyaluronic acid, collagen, gelatin, albumin glue or one of the combination thereof; 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 anticancer active ingredients in the anticancer sustained-release injection microsphere are preferably as follows:

elastase, trypsin, pepsin, pronase, dispase, bromelain, chymotrypsin, clostripain, plasmin, cathepsin-G, plasminogen activator, collagenase, streptokinase, glycosidase, hyaluronidase, lysozyme, relaxin, interferon, fibrin, gefitinib, erlotinib, lapatinib, vatalanib, pelitinib, carboxyamidotriazole, thalidomide, ranolamine, angiostatin, endostatin, angioendostatin, imatinib mesylate, sematinib, dasatinib, avastin, canatinib, sorafenib, sunitinib, telosta, panitoma or marimastat with 1-40% cyclophosphamide, melphalan, tumorigenin, ifosfamide, 4H-peroxycyclophosphamide, ifosfamide, macsfamide, mazinostatin, mazoxan, and mazinostat, Perphosphoramide, hexamethylpyriminol, cantharidin, norcantharidin, mannosuman, troosufen, ritrosufen, improsulfan, etoglut, pipobroman, piposulfan, canonine, epoxy piperazine, benzotepa, puripeline, metotepipa, uredepa, azatepa, benzyl guanine, O6-benzyl guanine, O6-butyl guanine, O6-methyl guanine, O6-alkylguanine, 2-amino-6-oxopurine, O6-benzyluric acid, O6-benzyl xanthine, triptorelin, goserelin, leuprorelin, anastrozole, idoxifene, mirtafluxifene, tamoxifen, 4-monohydroxytamoxifene, comoxifene, raloxifene, antiestrol, anti-cancer sterenol, 4-hydroxytamoxifene, flutamifene, tamoxifen, flutolnafide, tamoxifen, tolnafil, tolnaftate, a combination of pirimid, megestrol, medroxyprogesterone, clomiphene, toremifene, letrozole, anastrozole, exemestane or bicalutamide.

The slow release auxiliary material is biocompatible and (or non-) degradable absorption polymer, preferably one or a combination of silicone rubber, 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 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 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.

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-mentioned adjuvants, other substances can be selected and used as described in detail in U.S. Pat. Nos. 4757128, 4857311, 4888176 and 4789724 and "pharmaceutical adjuvants" in general (p. 123, published by Sichuan scientific and technical Press 1993, compiled by Luoming and high-tech). In addition, Chinese patent (application No. 96115937.5; 91109723.6; 9710703.3; 01803562.0) and U.S. patent No. 5,651,986) also list some pharmaceutical excipients, including fillers, solubilizers, absorption promoters, film-forming agents, gelling agents, pore-forming agents, excipients or retarders.

In order to adjust the drug release rate or change other characteristics of the present invention, the monomer component or molecular weight of the polymer can be changed, and the composition and ratio of the pharmaceutical excipients can be added or adjusted, and water-soluble low molecular compounds such as, but not limited to, various sugars or salts can be added. 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.

The suspending agent is used for preparing and/or effectively suspending, stabilizing and/or protecting various medicaments or sustained-release microspheres (or microcapsules), so that the prepared injection has good injectability, difficult blockage, good stability, difficult layering and high viscosity.

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 suspending agent is 100cp-3000cp (at 20-30 ℃), preferably 1000cp-3000cp (at 20-30 ℃), and most preferably 1500cp-3000cp (at 20-30 ℃).

The application of the solvent mainly refers to the application of the special solvent in effectively suspending, stabilizing and/or protecting various medicines or sustained-release microspheres (or microcapsules) so as to prepare corresponding injections. The application of the special solvent can lead the prepared injection to have better injection property, good stability and higher viscosity.

The common solvent can be, but is not limited to, distilled water, water for injection, physiological saline, absolute ethyl alcohol or buffer solution prepared from various salts, and the pharmacopoeia has corresponding regulations; the special solvent in the invention is a common solvent containing a suspending agent, and the suspending agent can be, but is not limited to, sodium carboxymethylcellulose, (iodine) glycerol, simethicone, propylene glycol, carbomer, mannitol, sorbitol, a surface active substance, Tween 20, Tween 40 and Tween 80 or a combination thereof. The content of the suspending agent in the special solvent is 0.1-30% by volume weight, preferably as follows:

a) 0.5-5% sodium carboxymethylcellulose; or

b) 0.5-5% sodium carboxymethylcellulose and 0.1-0.5% tween 80; or

c) 5-20% mannitol; or

d) 5-20% mannitol and 0.1-0.5% tween 80; or

e) 0.5-5% of sodium carboxymethylcellulose, 5-20% of sorbitol and 0.1-0.5% of tween 80.

The above-mentioned all are volume weight percentages, and the weight of suspending agent in the common solvent of unit volume, for example, g/ml, kg/l. The same applies below.

The content of the suspending agent depends on the composition, nature and required amount of the medicine suspended in the solvent, the sustained-release microspheres (or microcapsules), the preparation method of the injection, the kind and composition of the suspending agent, for example, the content of the sodium carboxymethylcellulose can be 0.5-5%, but 1-3% is preferred, the content of mannitol and/or sorbitol is 5-30%, but 10-20% is preferred, and the content of Tween 20, Tween 40 or Tween 80 is 0.05-2%, but 0.10-0.5% is preferred. In most cases, the sustained-release particles are composed of active ingredients and sustained-release excipients, and the solvent is a special solvent. When the solvent is common solvent, the suspended drug or sustained release microsphere (or microcapsule) is composed of effective components, sustained release adjuvant and/or suspending agent. In other words, when the suspending agent in sustained release particle (A) is "0", solvent (B) is a special solvent, and when the suspending agent in sustained release particle (A) is not "0", solvent (B) can be a common solvent or a special solvent. The viscosity of the suspending agent is 100cp-3000cp (at 20-30 ℃), preferably 1000cp-3000cp (at 20-30 ℃), and most preferably 1500cp-3000cp (at 20-30 ℃).

The preparation of the injection comprises the preparation of sustained release microspheres or drug particles, the preparation of a solvent, the suspension of the sustained release microspheres or drug particles in the solvent and the final preparation of the injection.

Wherein, the sustained release microspheres or drug microparticles can be prepared by several methods: such as, but not limited to, mixing, melting, dissolving, spray-drying to prepare microspheres, dissolving in combination with freeze (dry) milling, liposome encapsulation, and emulsification. Among them, the dissolution method (i.e., solvent evaporation method), the freeze (dry) pulverization method, the drying method, the spray drying method and the emulsification method are preferable. The microspheres can be used for preparing the various sustained-release injections. The particle size of the suspension drug or sustained release microspheres (or microcapsules) is determined by specific needs and can be, but is not limited to, 1-300um, but is preferably 20-200um, and most preferably 30-150 um. The drug or the sustained-release microspheres can be prepared into microspheres, submicron spheres, micro-emulsion, nanospheres, granules or spherical pellets. The slow release auxiliary material is the above-mentioned biocompatible, biodegradable or non-biodegradable polymer.

The preparation of the solvent depends on the kind of the solvent, and common solvents are commercially available or self-made, such as distilled water, water for injection, physiological saline, absolute ethanol or buffers prepared from various salts, but the preparation must strictly follow the relevant standards. The special solvent should be selected from the type and composition of suspending agent, the composition, properties and required amount of the medicine suspended in the solvent, sustained release microsphere (or microcapsule), and the preparation method of injection, for example, sodium carboxymethylcellulose (1.5%) + mannitol and/or sorbitol (15%) and/or Tween-80 (0.1%) are dissolved in physiological saline to obtain corresponding solvent with viscosity of 10-650 cp (at 20-30 deg.C).

The invention discovers that the key factor influencing the suspension and/or injection of the medicament and/or the sustained-release microspheres is the viscosity of the solvent, and the higher the viscosity is, the better the suspension effect is and the stronger the injectability is. This unexpected finding constitutes one of the main exponential features of the present invention. The viscosity of the solvent depends on the viscosity of the suspending agent, and the viscosity of the suspending agent is 100cp-3000cp (at 20-30 ℃), preferably 1000cp-3000cp (at 20-30 ℃), and most preferably 1500cp-3000cp (at 20-30 ℃). The viscosity of the solvent prepared according to the condition is 10cp-650cp (at 20-30 ℃), preferably 20cp-650cp (at 20-30 ℃), and most preferably 60cp-650cp (at 20-30 ℃).

The preparation of injection has several methods, one is that the slow release particles (A) whose suspending agent is '0' are directly mixed in special solvent to obtain correspondent slow release particle injection; the other is that the slow release particles (A) of which the suspending agent is not 0 are mixed in a special solvent or a common solvent to obtain the corresponding slow release particle injection; and the other one is that the slow release particles (A) are mixed in common dissolvent, then suspending agent is added and mixed evenly, and the corresponding slow release particle injection is obtained. Besides, the sustained-release particles (A) can be mixed in special solvent to prepare corresponding suspension, then the water in the suspension is removed by methods such as vacuum drying, and then the suspension is suspended by special solvent or common solvent to obtain the corresponding sustained-release particle injection. The above methods are merely illustrative and not restrictive of the invention. It is noted that the concentration of the suspended drug or the sustained release microspheres (or microcapsules) in the injection may be, but is not limited to, 10-400mg/ml, but is preferably 30-300mg/ml, and most preferably 50-200mg/ml, depending on the particular need. The viscosity of the injection is 50-1000 cp (at 20-30 deg C), preferably 100-1000 cp (at 20-30 deg C), and most preferably 200-650 cp (at 20-30 deg C). This viscosity is suitable for 18-22 gauge needles and specially made needles with larger (to 3 mm) inside diameters.

The route of administration of the injection depends on various factors. Can be administered intravenously, lymphatically, subcutaneously, intramuscularly, intracavity (such as intraperitoneal, thoracic, intraarticular and intraspinal), intrahistologically, intratumorally, peritumorally, by selective arterial injection, intranodal and intramedullally. For solid tumors, selective arterial, intracavitary, intratumoral, or peritumoral injection is preferred, although administration can be by the routes described above. In order to obtain effective concentration at the site of primary or metastatic tumor, it can also be administered by combination of multiple routes, such as intravenous, lymphatic, subcutaneous, intramuscular, intracavity (such as intraperitoneal, thoracic, intraarticular and intraspinal) or selective arterial injection in combination with local injection. Such combination administration is particularly useful for solid tumors. For example, the injection is combined with the systemic injection at the same time of intratumoral injection and peritumoral injection.

The injection is prepared by making drug-containing particles (spheres), especially slow-release particles, into corresponding slow-release injection with special solvent with high viscosity, so that the corresponding drug can be injected into the body of a patient or mammal with the required drug. The injected drug may be, but is not limited to, the above drug fine powder or drug sustained-release fine particles.

The application of the injection comprises the application of sustained-release microspheres or drug particles, the application of a solvent and the application of the injection prepared by suspending the sustained-release microspheres or the drug particles in the solvent.

In the slow release injection, the drug slow release system can be prepared into microspheres, submicron spheres, micro emulsion, nanospheres, granules or spherical pellets, and then the injection is prepared after the drug slow release system is mixed with an injection solvent. The suspension type sustained-release injection is preferably selected from various sustained-release injections, the suspension type sustained-release injection is a preparation obtained by suspending a drug sustained-release system containing an anticancer component in injection, the used auxiliary materials are one or the combination of the sustained-release auxiliary materials, and the used solvent is a common solvent or a special solvent containing a suspending agent. Common solvents are, but not limited to, distilled water, water for injection, physiological saline, absolute ethanol or buffers formulated with various salts. The suspending agent is intended to effectively suspend the microspheres containing the drug, thereby facilitating injection.

The anticancer effective components mainly comprise interstitial hydrolytic agent and anticancer drug. When the anticancer drug in the drug sustained-release microspheres is only interstitial hydrolytic agent or anticancer drug, the anticancer sustained-release injection is mainly used for increasing the effect of the anticancer drug or the interstitial hydrolytic agent applied in other ways or for the synergy of radiotherapy or other therapies. When the anticancer drug in the drug sustained-release microspheres is only interstitial hydrolytic agent or anticancer drug, the application and synergy mode of the anticancer sustained-release injection is as follows:

(1) the slow release injection containing the interstitial hydrolytic agent is locally injected to be combined with other anticancer drugs applied by other ways;

(2) the slow release injection containing the anticancer drug is locally injected to be combined with interstitial hydrolytic agents applied by other ways; or

(3) The combination of a sustained-release injection containing an anticancer drug for local injection and a sustained-release injection containing an interstitial hydrolytic agent for local application.

The slow released anticancer injection for local application may be also used in raising the effect of radiotherapy and other treatment. Other routes refer, but are not limited to, arterial, venous, intraperitoneal, subcutaneous, intraluminal administration.

The weight percentage of the anticancer drug in the sustained release microspheres is 0.5-60%, preferably 2-40%, and most preferably 5-30%. When the interstitial hydrolytic agent and the anti-cancer drug are used together, the weight ratio of the interstitial hydrolytic agent to the alkylating agent and/or the hormone anti-cancer drug is 1-19: 1 to 1: 1-19, preferably 1-9: 1 to 1-9: 1, and most preferably 1-5: 1 to 1-5: 1.

The microsphere is used for preparing sustained release injection, such as suspension sustained release injection, gel injection, and block copolymer micelle injection. Among various injections, a suspension type sustained-release injection is preferable. The suspension type sustained-release injection is a preparation obtained by suspending medicament sustained-release microspheres or medicament particles containing active ingredients in a solvent, the used auxiliary material is one or the combination of the sustained-release auxiliary materials, and the used solvent is a common solvent or a special solvent containing a suspending agent. Common solvent is, but not limited to, distilled water, water for injection, physiological saline, absolute ethyl alcohol or buffer solution prepared by various salts; the block copolymer micelle is formed by a hydrophobic-hydrophilic block copolymer in an aqueous solution and has a spherical core-shell structure, wherein the hydrophobic block forms a core, and the hydrophilic block forms a shell. The drug-loaded micelle is injected into the body to achieve the purpose of controlling the release of the drug or targeting therapy. The drug carrier is any one of the above or the combination thereof. 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 1 to 300um, but preferably 20 to 200um, most preferably 30 to 150 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, and the water-soluble high molecular polymer is selected from various high molecular polymers, such as polifeprosan, di-fatty acid and sebacic acid copolymer (PFAD-SA), poly (erucic acid dimmer-sebacic acid) [ P (EAD-SA) ], poly (fumaric acid-sebacic acid) [ P (FA-SA) ], ethylene vinyl acetate copolymer (EVAc), polylactic acid (PLA), polyglycolic acid and glycolic acid copolymer (PLGA), xylitol, oligosaccharide, chondroitin, chitin, hyaluronic acid, collagen, gelatin and albumin or a combination thereof.

The preferable slow release auxiliary materials can be various water-soluble or water-insoluble polymer polymers. The sustained-release auxiliary materials in the sustained-release implant and the weight percentage thereof are most preferably 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.

Therefore, 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 such as, but not limited to, a capsule, a sustained-release agent, an implant, a sustained-release agent implant, etc.; 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.

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 application of the anticancer sustained-release implant is the same as the sustained-release injection, the anticancer active ingredients and the weight percentage of the anticancer active ingredients of the sustained-release implant are the same as the sustained-release injection, but the anticancer active ingredients are preferably:

(1) 1-40% of an interstitial hydrolytic agent in combination with 1-40% of cyclophosphamide, melphalan, tumorigenin, ifosfamide, 4H-peroxycyclophosphamide, cyclophosphamide, macsfamide, phosphoramide, hexamethyl-pyrimethanil, cantharidin, norcantharidin, mannosuman, troosufan, ritrosufan, improsulfan, etoglut, pipobroman, piposulfan, cancinonin, epoxy piperazine, zotepa, purothiopipene, metotepipa, uretepa or azatepa; or

(2) 1-40% of an interstitial hydrolytic agent in combination with 1-40% of benzylguanine, O6-benzylguanine, O6-butylguanine, O6-methylguanine, O6-alkylguanine, 2-amino-6-oxopurine, O6-benzyluric acid or O6-benzylxanthine; or

(3) 1-40% of an interstitial hydrolytic agent in combination with 1-40% of triptorelin, goserelin, leuprorelin, anastrozole, idoxifene, mirtaoxifene, tamoxifen, 4-monohydroxytamoxifen, comoxifene, raloxifene, sterculia, anticancer sterenol, 4-hydroxyttamoxifen, flutamide, aminoglutethimide, pirimimide, megestrol, medroxyprogesterone, clomiphene, toremifene, letrozole, anastrozole, exemestane, or bicalutamide.

The interstitial hydrolytic agent is preferably elastase, trypsin, pepsin, pronase, dispase, bromelain, chymotrypsin, clostripain, plasmin, cathepsin-G, plasminogen activator, collagenase, streptokinase, glycosidase, hyaluronidase, lysozyme, relaxin, fibrin, gefitinib, erlotinib, lapatinib, vatalanib, pelitinib, carboxyamidotriazole, thalidomide, ranolamine, angiostatin, endostatin, angioendostatin, imatinib mesylate, semasnib, dasatinib, avastin, canatinib, sorafenib, sunitinib, telostab, panitoma, marimastat.

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. In addition, the active ingredients of the anticancer sustained-release implant can also be uniformly packaged in liposome or made into microspheres by the prior art method.

The anticancer implant is in various shapes such as, but not limited to, granules, tablets, powders, spheres, blocks, needles, rods, columns and films. The optimal preparation form is a biocompatible and degradable and absorbable implant sustained-release agent, and can be prepared into various shapes and various preparation forms according to different clinical requirements, such as, but not limited to, sustained-release implant tablets, granules, capsules, balls, pills, powders and rods. 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 and the weight percentage of the anticancer sustained-release implant can refer to sustained-release injection. When the anticancer drug in the drug sustained-release microspheres is only interstitial hydrolytic agent or anticancer drug, the application and the synergy mode of the anticancer sustained-release implant are the same as those of sustained-release injection.

The anticancer sustained-release implant can be administered by various routes, and in various routes, local administration is mainly performed, such as selective arterial, intracavity, intratumoral and peritumoral placement, and a slow release form in intratumoral, peritumoral or tumor cavity is preferred, and direct placement in tumor body is optimal.

The amount of the anti-cancer agent to be administered depends on many factors, such as, but not limited to, tumor volume, patient weight, mode of administration, disease progression, and response to treatment. In general, the amount of interstitial hydrolytic agent and anticancer agent is preferably 0.01-1000 mg/kg body weight, more preferably 1-800 mg/kg body weight, most preferably 5-80 mg/kg body weight, and the amount of hormone anticancer agent is preferably 0.01-500 mg/kg body weight, more preferably 1-100 mg/kg body weight, most preferably 5-50 mg/kg body weight

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 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. When the anticancer drug in the drug sustained-release microspheres is only interstitial hydrolytic agent or anticancer drug, the application and the synergy mode of the anticancer sustained-release implant are the same as those of sustained-release injection.

The invention can be used for preparing pharmaceutical preparations for treating various tumors of human and animals, mainly sustained-release injections or sustained-release implants, wherein the tumors comprise primary or metastatic cancers or sarcomas or carcinosarcomas originated from brain, central nervous system, kidney, liver, gall bladder, head and neck, oral cavity, thyroid, skin, mucous membrane, gland, blood vessel, bone tissue, lymph node, lung, esophagus, stomach, mammary gland, pancreas, eye, nasopharynx, uterus, ovary, endometrium, cervix, prostate, bladder, colon and rectum.

The 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 with different modes of use of alkylating agents (melphalan)

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 per group was 2.5mg/kg melphalan. The results of measuring the content (%) of the medicament in the tumor at different times show that the local medicament concentration difference of melphalan applied in different modes is obvious, the effective medicament concentration of the part where the tumor is located 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. This finding constitutes an important feature of the present invention. This is further confirmed by the following relevant tumor inhibition test.

Test 2 comparison of the in vivo tumor-inhibiting action of the drug (collagenase) applied in different ways

Using white rat as test object, 2X 10⁵Individual breast tumor cells were injected subcutaneously into the quaternary costal region and grouped after tumors grew to 0.5 cm diameter. Each group was dosed with 5mg/kg collagenase. 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 difference of the tumor inhibition effect of collagenase 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. Repeated experiments with interstitial hydrolytic agent can obtain the same experimental results.

Test 3 antitumor Effect of interstitial hydrolytic Agents (Hyaluronidase) and anticancer drugs

Using white rat as test object, 2X 10⁵The pancreatic tumor cells were subcutaneously injected into the costal region of the patient, and the tumor was divided into control and treatment groups (1-11) 14 days after the tumor had grown). The therapeutic components include interstitial hydrolytic agent and anticancer drug. The dosage of the medicine is 5mg/kg, the interstitial hydrolytic agent is injected intratumorally, and the anticancer medicine is injected intraperitoneally. Tumor volume was measured on day 20 after treatment and the effect was compared (see table 1).

TABLE 1

Group of	Interstitial hydrolytic agent	Synergist	Tumor inhibition ratio (%)	P value
					1	+	-	46	*
2	-	Triptorelin	40	*
					3	-	Goserelin	36	*
4	-	Leuprorelin	44	*
					5	-	Anastrozole	46	*
6	-	Idoxifene	38	*
					7	+	Triptorelin	78	**
8	+	Goserelin	84	**
					9	+	Leuprorelin	82	**
10	+	Anastrozole	78	**
					11	+	Idoxifene	88	**

The results show that the interstitial hydrolytic agent and the used anti-cancer drugs (triptorelin, goserelin, leuprorelin, anastrozole and idoxifene) have obvious inhibition effect on the growth of the tumor when being used at the concentration alone (P value is less than 0.05), and can show very obvious synergistic effect when being used in combination (P value is less than 0.001).

Test 4 tumor-inhibiting action of interstitial hydrolytic agent (collagenase) and anticancer drug (sustained release injection)

The anti-tumor effects of collagenase and the sustained-release injection of anticancer drugs were measured according to the method described in test 3, and the tumor cells used include CNS-1, C6, 9L, gastric gland epithelial cancer (SA), bone tumor (BC), breast cancer (BA), lung cancer (LH), papillary thyroid cancer (PAT), liver cancer, etc. 15mg/kg except for 2.5mg/kg of collagenase. The tumor cell growth inhibitory effect (%) is shown in Table 2.

TABLE 2

Tumor cell	Collagenase	A	B	C	D	E	Collagenase + A	Collagenase + B	Collagenase + C	Collagenase + D	Collagenase + E
												CNS	30	50	56	38	52	42	82	70	86	88	88
C6	22	52	46	36	64	40	90	84	84	84	90
												SA	26	52	58	42	62	42	84	84	80	82	86
BC	36	58	40	44	52	54	88	82	78	76	84
												BA	18	48	38	48	60	56	82	80	90	90	82
LH	26	56	44	54	58	60	92	80	94	76	84
												PAT	30	54	50	52	50	62	80	78	82	88	84

The above results indicate that the interstitial hydrolytic agent is collagenase, and the anticancer drug is B: mirbexifene, B: tamoxifen, C: domoxifene, D: raloxifene, E: can be used for resisting female. The concentration has 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.

Test 5 antitumor Effect of interstitial hydrolytic Agents and anticancer drugs (sustained-Release injection)

The anti-tumor effects of collagenase and the sustained-release injection of anticancer drugs were measured according to the method described in test 3, and the tumor cells used include CNS-1, C6, 9L, gastric gland epithelial cancer (SA), bone tumor (BC), breast cancer (BA), lung cancer (LH), papillary thyroid cancer (PAT), liver cancer, etc. The dosage of the interstitial hydrolytic agent (trypsin) and the anticancer drug is 10mg/kg, and the treatment lasts for 30 days. The results show that the interstitial hydrolytic agent and the anti-cancer drugs (cyclophosphamide, melphalan, oncoclonine, ifosfamide and 4H-peroxy-cyclophosphamide) have obvious inhibition effect (P is less than 0.05) on the growth of various tumors when being used independently, and can show obvious synergistic effect (P is less than 0.01) when being used in combination. Further experiments have shown that such significant synergy is seen in pepsin, pronase, dispase, bromelain, chymotrypsin, clostripain, plasmin, cathepsin-G, plasminogen activator, collagenase, streptokinase, glycosidase, hyaluronidase, lysozyme, relaxin, fibrin, gefitinib, erlotinib, lapatinib, vatalanib, pelitinib, carboxyamidotriazole, thalidomide, ranolamine, angiostatin, endostatin, imatinib mesylate, sematinib, dasatinib, avastin, canatinib, sorafenib, sunitinib, teosta, panitoma, marimastat, etc. interstitial hydrolytics with cyclophosphamide, macsfamide, phosphoramide, hexamethylpyrimethanil, cantharidin, gansufang, Combinations of trooshusulfan, ritrosufan, improsulfan, etoglut, pipobroman, piposulfan, carcinosine, epoxy piperazine, benzotepa, puripeline, metotepipa, uretepa, or azatepa.

Test 6 antitumor Effect of interstitial hydrolytic agent (Gefitinib) and anticancer drug (sustained-release injection)

Using white rat as test object, 2X 10⁵Individual pancreatic tumor cells were injected subcutaneously into the costal region of the patient and 14 days after tumor growth were assigned to negative controls (blank), single drug treatment groups (interstitial hydrolytic agents or anti-cancer drugs) and combination treatment groups (interstitial hydrolytic agents and anti-cancer drugs). The medicine is injected intratumorally. The dosage is 5 mg/kg. The volume of the tumor was measured on the 20 th day after the treatment, and the therapeutic effect was compared using the tumor growth inhibition rate as an index. The results show that the interstitial hydrolytic agent and the anticancer drugs (benzylguanine, O6-benzylguanine, O6-butylguanine and O6-methylguanine) have obvious inhibition effect (P is less than 0.05) on the growth of a plurality of tumor cells when being used independently, and can show obvious synergistic effect (P is less than 0.01) when being used in combination. Further experiments have shown that such a pronounced synergistic effect is also seen in the combination of erlotinib with benzylguanine, O6-benzylguanine, O6-butylguanine, O6-methylguanine, O6-alkylguanine, 2-amino-6-oxopurine, O6-benzyluric acid or O6-benzylxanthine.

Test 7 tumor-inhibiting action of interstitial hydrolytic agent (relaxin) and anticancer drug (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 anticancer medicine is injected intratumorally, and the interstitial hydrolytic agent is injected intraperitoneally. The dosage is 5 mg/kg. The volume of the tumor was measured on the 10 th day after the treatment, and the therapeutic effect was compared using the tumor growth inhibition rate as an index (see Table 3).

TABLE 3

Test set (n)	Is treated by	Tumor inhibition ratio (%)	P value
				1(6)	Control	-
2(6)	Interstitial hydrolytic agent	48	＜0.05
				3(6)	O6-benzyl guanine	54	＜0.01
4(6)	O6-butylguanine	42	＜0.01
				5(6)	O6-alkylguanine	54	＜0.01
6(6)	O6-methylguanine	50	＜0.01
				7(6)	Interstitial hydrolytic agent + O6-benzyl guanine	80	＜0.001
8(6)	Interstitial hydrolytic agent + O6-butyl guanine	86	＜0.001
				9(6)	Interstitial hydrolytic agent + O6-methylguanine	82	＜0.001
10(6)	Interstitial hydrolytic agent + O6-alkylguanine	84	＜0.001

The results show that the interstitial hydrolytic agent and the anticancer drugs (benzylguanine, O6-benzylguanine, O6-butylguanine, O6-methylguanine and O6-alkylguanine) have obvious inhibition effect on the growth of a plurality of tumor cells when being singly applied at the concentration, and can show obvious synergistic effect when being jointly applied.

The same synergistic effect is seen in lysozyme with O6-benzyl guanine, O6-butyl guanine, O6-methyl guanine, O6-alkyl guanine, 2-amino-6-oxy purine, O6-benzyl uric acid or O6-benzyl xanthine.

Experiment 8, the antitumor effects of interstitial hydrolytic agent (plasmin) and anticancer drug (sustained release implant)

Using white rat as test object, 2X 10⁵Injecting the breast tumor cells into the costal region of the patient subcutaneously, and classifying the tumor into negative control (blank) and single drug treatment groups after the tumor grows for 14 daysAnd a combination treatment group. The sustained release implant is placed intratumorally. The dosage is 15mg/kg except 5mg/kg of plasmin. Tumor volume was measured on day 20 after treatment, and the therapeutic effect was compared using tumor growth inhibition as an index (see table 4).

TABLE 4

Test set (n)	Is treated by	Tumor inhibition ratio (%)	P value
				1(6)	Control	-
2(6)	Interstitial hydrolytic agent	50	＜0.05
				3(6)	Diphosphamide	48	＜0.05
4(6)	Malachite	38	＜0.05
				5(6)	Pesphamide	40	＜0.05
6(6)	Hexamethyl pyrimidine	36	＜0.01
				7(6)	Interstitial hydrolytic agent + phosphoramide	80	＜0.01
8(6)	Interstitial hydrolytic agent + phosphoramide	86	＜0.01
				9(6)	Interstitial hydrolytic agent + pephosphoramide	84	＜0.01
10(6)	Interstitial hydrolytic agent + hexamethyl-pyrimethanil	86	＜0.001

The results show that the interstitial hydrolytic agent and the anti-cancer drugs (cyclophosphamide, macsfamide, cyclophosphamide and hexamethyl-pyrimethanil) have obvious inhibition effect on the growth of a plurality of tumor cells when being singly applied at the concentration, and can show obvious synergistic effect when being combined.

Test 9 tumor-inhibiting action of interstitial hydrolytic agent (lipase) and anticancer drug (sustained-release implant)

The tumor-inhibiting effects of the interstitial hydrolytic agent and the anticancer drug (sustained release implant) were measured as described in test 8, and the tumor growth inhibition rates are shown in Table 5.

TABLE 5

Test set (n)	Is treated by	Tumor inhibition ratio (%)	P value
				1(6)	Control	-
2(6)	Interstitial hydrolytic agent	60	＜0.05
				3(6)	Triptorelin	52	＜0.01
4(6)	Goserelin	54	＜0.01
				5(6)	Leuprorelin	60	＜0.01
6(6)	Anastrozole	52	＜0.01
				7(6)	Interstitial hydrolytic agent + triptorelin	82	＜0.001
8(6)	Interstitial hydrolytic agent + goserelin	86	＜0.001
				9(6)	Interstitial hydrolytic agent + leuprorelin	80	＜0.001
10(6)	Interstitial hydrolytic agent + anastrozole	86	＜0.001

The results show that the interstitial hydrolytic agent and the anti-cancer drugs (triptorelin, goserelin, leuprorelin and anastrozole) have obvious inhibition effect on the growth of various tumor cells when being used independently at the concentration, and can show obvious synergistic effect when being used in combination.

Test 10 tumor inhibition of plasminogen activator and anti-cancer drugs (sustained release implant)

The tumor-inhibiting effects of the interstitial hydrolytic agent and the anticancer drug (sustained release implant) were measured as described in test 8, and the tumor growth inhibition rates are shown in Table 6.

TABLE 6

Test set (n)	Is treated by	Tumor inhibition ratio (%)	P value
				1(6)	Control	-
2(6)	Interstitial hydrolytic agent	50	＜0.05
				3(6)	Idoxifene	48	＜0.01
4(6)	Mipcifen	38	＜0.01
				5(6)	Tamoxifen	42	＜0.01
6(6)	Sunitinib	52	＜0.01
				7(6)	Interstitial hydrolytic agent + idoxifene	78	＜0.01
8(6)	Interstitial hydrolytic agent + milbexifene	82	＜0.001
				9(6)	Interstitial hydrolytic agent + tamoxifen	82	＜0.001
10(6)	Interstitial hydrolytic agent + sunitinib	80	＜0.001

The results show that the interstitial hydrolytic agent and the anti-cancer drugs (idoxifene, milbexifene, tamoxifen and sunitinib) have obvious inhibition effect on the growth of a plurality of tumor cells when being singly used at the concentration, and can show obvious synergistic effect when being jointly used.

Test 11 antitumor Effect of interstitial hydrolytic Agents and anticancer drugs (sustained Release injections)

The results of the tumor-inhibiting effects of the interstitial hydrolyzates and the anticancer drugs (sustained release injections) were determined as described in test 7, and the results showed that the interstitial hydrolyzates (collagenase, hyaluronidase, erlotinib) significantly enhanced the tumor-inhibiting effects of the anticancer drugs triptorelin, goserelin, leuprolide, anastrozole, idoxifene, miprofecoxifene, tamoxifen, 4-monohydroxytamoxifen, comoxifene, raloxifene, sterculia, anticancer sterenol, 4-hydroxyttamoxifen, flutamide, aminoglutethimide, pirglutethimide, megestrol, medroxyprogesterone, clomiphene, toremifene, letrozole, exemestane, or bicalutamide, and the like, and the potentiating effects were 50-88% (P < 0.01).

In conclusion, the interstitial hydrolytic agent and various anti-cancer drugs have obvious inhibition effect on the growth of various tumor cells when being applied independently, and can show obvious synergistic effect when being applied in combination. Therefore, the active ingredients of the invention are the combination of interstitial hydrolytic agents and/or any one anti-cancer drug. The medicine containing the effective components can be prepared into sustained-release microspheres and further prepared into sustained-release injection and implant, wherein the suspension injection formed by combining the suspension injection with a special solvent containing a suspending agent is preferred, and the viscosity of the solvent of the suspension injection is 10cp-650cp (at 20-30 ℃), preferably 20cp-650cp (at 20-30 ℃), and most preferably 60cp-650cp (at 20-30 ℃).

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 a polifeprosan (p-carboxyphenylpropane (p-CPP): Sebacic Acid (SA) 20: 80) copolymer is put into a container, 100ml of dichloromethane is added, after the mixture is dissolved and mixed evenly, 10mg of collagenase and 10mg of leuprorelin 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 collagenase and 10% of leuprorelin. Then suspending the microspheres in physiological saline containing 15 percent mannitol to prepare the corresponding suspension type sustained-release injection with the viscosity of 20-300 cp (at 20-30 ℃). 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.

The steps of the method for processing the sustained-release injection are the same as the example 1, but the difference is that the p-CPP: SA in the polifeprosan is 50: 50, and the anticancer active ingredients and the weight percentage thereof are as follows: the combination of 5% of collagenase, hyaluronidase, gefitinib or erlotinib and 15% of cyclophosphamide, melphalan, oncoclonine, ifosfamide, 4H-peroxy cyclophosphamide, norcantharidin, meltupipa, uretepa or azatepa, and the viscosity of the sustained-release injection is 10-650 cp (at 20-30 ℃).

Example 3.

70mg of polylactic acid (PLGA, 75: 25) with a molecular weight peak of 20000-40000 is put into a container, 100ml of dichloromethane is added, after dissolving and mixing evenly, 15mg of hyaluronidase and 15mg of melphalan are added, shaking up again and vacuum drying is carried out to remove the organic solvent. Freeze-pulverizing dried solid composition containing drug to obtain micropowder containing 15% hyaluronidase and 15% melphalan, and suspending in physiological saline containing 1.5% sodium carboxymethylcellulose to obtain suspension type sustained-release injection with viscosity of 220-340 cp (at 20-30 deg.C). The slow release injection has the release time of 10-15 days in-vitro physiological saline and the release time of about 20-30 days under the skin of a mouse.

Example 4

The steps of the method for processing the sustained-release injection are the same as the example 3, but the difference is that the used auxiliary material is polylactic acid (PLGA, 50: 50) with the molecular weight peak of 40000-60000, and the anti-cancer active ingredients and the weight percentage thereof are as follows: a combination of 10% pepsin, dispase, chymotrypsin, clostripain or plasmin and 10% cyclophosphamide, melphalan, busulfan, ifosfamide, 4H-peroxycyclophosphamide or norcantharidin; 100cp-690cp (at 20 ℃ -30 ℃).

Example 5.

70mg of ethylene-vinyl acetate copolymer (EVAc) is put into a container, 100ml of dichloromethane is added to dissolve and mix evenly, 20mg of plasmin and 10mg of tamoxifen are added, after shaking up again, the microspheres for injection containing 20% of plasmin and 10% of tamoxifen are prepared by a spray drying method. Then suspending the microspheres in injection containing 5-15% sorbitol to obtain corresponding suspension type sustained release injection with viscosity of 100-160 cp (at 25-30 deg.C). The slow release injection has the release time of 10-15 days in-vitro physiological saline and the release time of about 20-30 days under the skin of a mouse.

Example 6.

The steps of the method for processing the sustained-release injection are the same as the example 5, but the difference is that the anticancer active ingredients and the weight percentage thereof are as follows: 20% plasmin, cathepsin-G, plasminogen activator, streptokinase or glycosidase in combination with 10% triptorelin, goserelin, leuprolide, tamoxifen, toremifene, letrozole, anastrozole, exemestane or bicalutamide; the viscosity of the slow release injection is 10cp-650cp (at 20 ℃ -30 ℃).

Example 7.

70mg of polylactic acid (PLA) with the molecular weight peak value of 20000-40000 is put into a container, 100ml of dichloromethane is added, 20mg of streptokinase and 10mg of letrozole are added after the mixture is dissolved and mixed evenly, and the microspheres for injection containing 20% of streptokinase and 10% of letrozole are prepared by a spray drying method after the mixture is shaken again. 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 with the viscosity of 180cp-260cp (at the temperature of 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 8.

The steps of the method for processing the sustained-release injection are the same as the example 7, but the difference is polylactic acid (PLA) with the molecular weight peak of 40000-60000, which contains the effective anticancer components in percentage by weight: a combination of 15% streptokinase, glycosidase, hyaluronidase, lysozyme, relaxin or plasmin and 15% triptorelin, goserelin, leuprolide, anastrozole, idoxifene, tamoxifen, letrozole, anastrozole, exemestane, or bicalutamide; the viscosity is 200cp-560cp (at 25 ℃ -30 ℃).

Example 9

70mg of polifeprosan (20: 80) copolymer is put into a container, 100ml of dichloromethane is added, after dissolving and mixing evenly, 20mg of interstitial hydrolytic agent and 10mg of O6-butyl guanine are added, after shaking up again, the microspheres for injection containing 20% of interstitial hydrolytic agent and 10% of O6-butyl guanine 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 with the viscosity of 100cp-160cp (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 10

The steps of the method for processing the sustained-release injection are the same as the example 9, but the difference is that the polifeprosan is 20: 80, and the anticancer active ingredients and the weight percentage thereof are as follows: 20% lysozyme, relaxin, fibrin, gefitinib, erlotinib, lapatinib, voltalanib or pelitinib in combination with 10% benzylguanine, O6-benzylguanine, O6-butylguanine, O6-methylguanine, O6-alkylguanine, O6-benzyluric acid or O6-benzylxanthine; the viscosity is 560cp-640cp (at 25 ℃ -30 ℃).

Example 11

The steps of the method for processing the sustained-release injection are the same as those of the examples 9 and 10, but the different anticancer active ingredients and the weight percentages thereof are as follows: 15% of vascular endothelial chalone, imatinib mesylate, semasinib, dasatinib, avastin, canatinib, sorafenib or sunitinib in combination with 15% of cyclophosphamide, melphalan, onconine, ifosfamide, 4H-peroxycyclophosphamide, norcantharidin, meltupipa, uredepa or azatepa, the viscosity being 260cp to 680cp (at 25 ℃ to 30 ℃).

Example 12

The procedure of the process for preparing a sustained release implant was the same as in example 11, except that the sustained release excipients used were:

(1) 60-95% of a copolymer of di-fatty acids and sebacic acid (PFAD-SA);

(2) 75-95% poly (erucic acid dimer-sebacic acid) [ P (EAD-SA) ]; or

(3) 70-95% of poly (fumaric-sebacic acid) [ P (FA-SA) ].

Example 13

70mg of polylactic acid (PLGA, 50: 50) with the molecular weight peak of 25000-45000 is put into a container, 100ml of dichloromethane is added, after the dissolution and the uniform mixing, 10mg of collagenase, 10mg of hyaluronidase and 10mg of melphalan are added, after the uniform shaking again, the spray drying method is used for preparing the microspheres for injection containing 10% of collagenase, 10% of hyaluronidase and 10% of melphalan. Then the microspheres are prepared into the corresponding sustained-release implant by a tabletting method. The slow release implant has the release time of 10-15 days in vitro physiological saline and the release time of about 35-50 days under the skin of a mouse.

Example 14

The steps of the method for processing the sustained-release implant are the same as the examples 11 to 13, but the difference is that the sustained-release implant comprises the following effective anticancer components in percentage by weight:

(1) a combination of 10% collagenase and 10% hyaluronidase with 10% cyclophosphamide, melphalan, onconine, ifosfamide, 4H-peroxycyclophosphamide, norcantharidin, benzotepa, purinethol, meltutepa, uretepa, or azatepa; or

(2) 10% collagenase and 10% hyaluronidase in combination with 10% benzylguanine, O6-benzylguanine, O6-butylguanine, O6-methylguanine, O6-alkylguanine, 2-amino-6-oxopurine, O6-benzyluric acid or O6-benzylxanthine; or

(3) 10% collagenase and 10% hyaluronidase in combination with 1-40% triptorelin, goserelin, leuprorelin, anastrozole, idoxifene, tamoxifen, letrozole, anastrozole, exemestane, or bicalutamide.

Example 15

The procedure of processing into sustained release preparation is the same as that of examples 1-14, except that the sustained release excipient is one or a combination of the following:

a) polylactic acid (PLA) with a molecular weight peak of 10000-;

b) a copolymer (PLGA) of polyglycolic acid and glycolic acid, wherein the ratio of the polyglycolic acid to the glycolic acid is 50-95: 50-50, and the peak value of the molecular weight is 10000-30000, 300000-60000, 60000-100000 or 100000-150000;

c) ethylene vinyl acetate copolymer (EVAc);

d) polifeprosan, p-carboxyphenylpropane (p-CPP) to Sebacic Acid (SA) in a ratio of 10: 90, 20: 80, 30: 70, 40: 60, 50: 50 or 60: 40;

e) di-fatty acid and sebacic acid copolymer (PFAD-SA);

f) poly (erucic acid dimer-sebacic acid) [ P (EAD-SA) ];

g) poly (fumaric-sebacic acid) [ P (FA-SA) ];

h) xylitol, oligosaccharide, chondroitin, chitin, hyaluronic acid, collagen, gelatin or albumin glue;

i) 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.

Example 16

The procedure for preparing a sustained release injection is the same as in examples 1 to 10, 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 further describe the technical process of the present invention. Are intended to be illustrative and not limiting of the scope of the invention. Indeed, various modifications of the invention in addition to those shown and described herein will become apparent to those skilled in the art from the foregoing description and accompanying drawings. Such modifications are, of course, intended to be within the scope of the appended claims. It should be understood, therefore, that the foregoing description focuses on certain specific embodiments of the invention and that equivalent alterations and substitutions made thereto are within the spirit and scope of the appended claims.

Claims (10)

1. An anticancer sustained-release injection containing interstitial hydrolytic agent, which consists of the following components:

(A) a sustained release microsphere comprising:

the biological effective component is 0.5-60%

The sustained-release auxiliary material is 41 to 99.9 percent

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 the combination of an effective anticancer amount of interstitial hydrolytic agent and an effective anticancer amount of anticancer drugs, and the anticancer drugs are alkylating agent, purine analogues and/or hormone anticancer drugs; the interstitial hydrolytic agent is selected from vascular inhibitor and/or proteolytic enzyme;

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

i) 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.

The suspending agent is selected from sodium carboxymethylcellulose, iodoglycerol, dimethicone, propylene glycol, carbomer, mannitol, sorbitol, surfactant, Tween-20, Tween-40 and Tween-80 or their combination, and has viscosity of 100-3000 cp (at 20-30 deg.C).

2. The sustained-release anticancer injection as claimed in claim 1, wherein the alkylating agent is selected from one or a combination of cyclophosphamide, melphalan, tumorigenin, ifosfamide, 4H-peroxycyclophosphamide, cyclophosphamide, macsfamide, perfosfamide, hexamethylpyrimidineamine, cantharidin, norcantharidin, mannosuman, troosulfan, ritrosufan, improsulfan, etoglut, pipobroman, piposulfan, canonin, epoxy piperazine, zotepa, purepitepa, metotepipa, uretepa or azatepa.

3. The sustained-release anticancer injection according to claim 1, wherein the purine analogues are selected from the group consisting of benzylguanine, O6-benzylguanine, O6-butylguanine, O6-methylguanine, O6-alkylguanine, 2-amino-6-oxopurine, O6-benzyl 2' -deoxyguanosine, guanine (2-amino-6-hydroxypurine), 8-amino-O6-benzylguanine, 8-methyl-O6-benzylguanine, 8-hydroxy-O6-benzylguanine, 8-bromo-O6-benzylguanine, 8-oxy-O6-benzylguanine, 8-trifluoromethyl-O6-benzylguanine, O6-benzyluric acid, O6-benzylxanthine, O6-benzyl-2-fluorohypoxanthine, diacetyl-O6-benzyl-8-oxoguanine, O6-benzyl-8-methylguanine, O6-benzyl-8-oxoguanine, O6-benzyl-8-bromoguanine, O6-benzyl-8-trifluoromethylguanine, O6-benzyl-N2-methylguanine, O6-benzyl-N2N 2-dimethylguanine, O6-benzyl-8-trifluoromethyl-9-methylguanine, O6-benzyl-8-bromo-9-methylguanine, O6-benzyl-8-bromo-9-pivaloyloxymethylguanine, O6-benzyl-7-pivaloyloxymethylguanine, O6-benzyl-8-bromo-7-pivaloyloxymethylguanine, 8-aza-O6-benzyl-7-pivaloyloxymethylguanine, 8-aza-O6-benzyl-7-pivaloyloxymethylguanine, 8-aza-O6-benzylguanine, 8-aza-O6-benzyl-9-methylguanine, or acetyl-O6-benzyl-8-oxoguanine, O6-benzyl-N2-methylguanine, O6-benzyl-N2N 2-dimethylguanine, 2-amino-6-chloro-8-methylpurine, 2, 8-diamino-6-chloropurine, O6-benzyl-N2-guanosine, N (7) -methylguanine, O6-benzyl-9-cyanoguanine, O6-benzyl-N2-guanosine, O6-cycloalkenyl guanine, 1-cyclobutenylmethyl guanine, 1-cyclopentenylmethyl guanine or O6-bromothiapiprolidinyl guanine, or a combination thereof.

4. The sustained-release anticancer injection according to claim 1, wherein the hormone anticancer drug is anastrozole, idoxifene, milbexifene, tamoxifen, 4-monohydroxytamoxifen, comoxifene, steroidal antiestrogen, 7- α - [9- (4, 4, 5, 5, 5-pentafluoropentylsulfinyl) nonyl ] estra-1, 3, 5(10) -triene-3, 17 β diol, anticancer sterenol, 4-hydroxyttamoxifen, γ -linoleic acid, 2-methoxyestradiol, methoxy norgestriene diol, 4-hydroxytamoxifene, hexachlorocyclohexane, raloxifene, diethylstilbestrol, estradiol, estrone, 17 α -estradiol, 2-hydroxyestrone, 5, 7, 4-trihydroxyisoflavone, progesterone, or a mixture thereof, The composition comprises at least one of meperidine, androgen, pirglutethimide, rubitecan, billezifene, flutamide, quart monosilicon blue, bicalutamide, aminoglutethimide, betamethasone benzoate, carroterone, triptorelin, goserelin, leuprorelin, megestrol, medroxyprogesterone, dartostigmine, epitioandrostanol, bromoacetate estrene, hyssoprene, clomiphene, toremifene, letrozole, anastrozole and exemestane or testolactone.

5. The sustained-release anticancer injection according to claim 1, wherein the proteolytic enzyme is selected from one or a combination of elastase, trypsin, pepsin, pronase, dispase, bromelain, chymotrypsin, clostripain, plasmin, cathepsin-G, plasminogen activator, collagenase, streptokinase, glycosidase, hyaluronidase, lysozyme, relaxin, interferon, and fibrin;

the blood vessel inhibitor is selected from one or the combination of gefitinib, erlotinib, lapatinib, vatalanib, pelitinib, carboxyamidotriazole, thalidomide, ranolamine, angiostatin, endostatin, imatinib mesylate, sematinib, dasatinib, avastin, canatinib, sorafenib, sunitinib, teoslata, panitoma, marimastat and fumagillin.

6. The sustained-release anticancer injection according to claim 1, wherein the weight ratio of the interstitial hydrolytic agent to the anticancer drug is 1-19: 1 to 1: 1-19.

7. 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;

f) (iodine) glycerol, dimethicone, propylene glycol or carbomer;

g) 0.5-5% of sodium carboxymethylcellulose and 0.1-0.5% of Tween 80;

h) 5-20% of mannitol and 0.1-0.5% of Tween 80;

i)0.5 to 5 percent of sodium carboxymethylcellulose, 5 to 20 percent of sorbitol and 0.1 to 0.5 percent of Tween 80.

8. The sustained-release anticancer injection according to claim 1, wherein the pharmaceutical preparation is a sustained-release agent, implant or sustained-release implant made of sustained-release microspheres.

9. The sustained-release anticancer implant according to claim 8, characterized in that the sustained-release excipients used in the sustained-release implant are 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) a di-fatty acid and sebacic acid copolymer;

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

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

h) xylitol, oligosaccharide, chondroitin, chitin, hyaluronic acid, collagen, gelatin or albumin glue;

i) 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;

the weight ratio of the interstitial hydrolytic agent to the anticancer drug is 1-19: 1 to 1: 1-19.

10. The sustained-release anticancer agent according to claims 1 and 8, characterized in that the sustained-release agent is used for preparing a drug for treating primary or secondary cancer, sarcoma or carcinosarcoma originated from brain, central nervous system, 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, and is administered by intratumoral or peritumoral injection or placement.