CN1857210A

CN1857210A - Slow released anticancer medicine with both antimetabolite and its synergist

Info

Publication number: CN1857210A
Application number: CNA2006102002596A
Authority: CN
Inventors: 孔庆忠; 孙娟; 苏红清; 栾永祖
Original assignee: Shandong Lanjin Pharmaceuticals Co Ltd
Current assignee: Shandong Lanjin Pharmaceuticals Co Ltd
Priority date: 2006-03-17
Filing date: 2006-03-17
Publication date: 2006-11-08

Abstract

The slow released anticancer injection with both antimetabolite and its synergist consists of slow released microsphere and solvent. The slow released microsphere includes effective anticancer component and slow releasing supplementary material, and the solvent is special solvent containing suspending agent. The effective anticancer component is antimetabolite Zalcitabine, Emtricitabine, etc and/or antimetabolite synergist selected from antimitotic medicine and/or alkylating agent. The slow releasing supplementary material is selected from difatty acid-sebacic acid copolymer, EVAc, etc. The suspending agent is carboxymethyl cellulose sodium, etc. and has viscosity of 100-3000 cp at 20-30 deg.c. The slow released microsphere may be also prepared into slow released implanting agent for raising the local medicine concentration and raising the effect of chemotherapeutic medicine, radiotherapeutic medicine, etc.

Description

The anticancer sustained-release agent of a kind of both antimetabolite and synergist thereof

(1) technical field

The present invention relates to a kind of compound anti-cancer medicinal slow release agent that contains antimetabolite, belong to technical field of pharmaceuticals.Particularly, the invention provides a kind of anticancer medicine slow-release preparation containing that contains antimetabolite and/or its synergist, be mainly slow releasing injection and sustained-release implant.

(2) background technology

Treatment for cancer mainly comprises methods such as operation, radiotherapy and chemotherapy.Therefore wherein operative treatment can not be removed the oncocyte that is dispersed in, and often recurs or causes tumor cell to stimulate diffusion transfer because of operation; Radiotherapy and traditional chemotherapy are not had a selectivity, and be difficult to tumor by local and form effective drug level or therapeutic dose, weak effect, toxicity is big, improves the restriction that medicine or radiological dose are subjected to general toxic reaction again merely.Referring to " placing cisplatin adding system carmustine treatment rat brain tumor in the tumor " " surgery tumor magazine " 69 phase 76-82 pages or leaves (1998) (Kong Q et al., J Surg Oncol.1998 Oct such as Kong Qingzhongs; 69 (2): 76-82).

The local placement of antitumor drug can overcome above defective preferably, not only can obviously improve the drug level of tumor by local, and can significantly reduce general toxic reaction.A large amount of internal and external tests have demonstrated the therapeutic effect to entity tumor, referring to " placing cisplatin adding system carmustine treatment rat brain tumor in the tumor " " surgery tumor magazine " 69 phase 76-82 pages or leaves (1998) (Kong Q et al., J Surg Oncol.1998 Oct such as Kong Qingzhongs; 69 (2): 76-82) and Kong Qingzhong etc. " place cisplatin in the tumor and cure the former carbuncle in the occipital region tumor of rat " " surgery tumor magazine " 64 phase 268-273 pages or leaves (1997) (Kong Q et al., JSurg Oncol.1997 Oct; 64:268-273).Also can be referring to Chinese patent (ZL00111093.4; ZL96115937.5; Application number 001111264,001111272) and U.S.'s patent of invention (patent No. 6,376,525B1; 5,651,986; 5,626,862).

Yet there is great difference in tumor cell to the sensitivity of chemotherapeutics.Many tumor cell medicines are also insensitive, and the tumor cell that has is in the early stage sensitivity of chemotherapy, but very fast tolerance.Particularly work as cancer therapy drug, as antimetabolite, when using separately, the enhancing of toleration usually causes the treatment failure.

In addition, the cancer drug therapy of low dosage not only can increase the Drug tolerance of cancerous cell, but also can promote its infiltrative growth "; referring to beam etc. " increased the Drug tolerance of human lung carcinoma cell and external wetting capacity after the cancer therapy drug pulse screening and with the change of gene expression " " international journal of cancer " 111 phase 484-93 page or leaf (2004) (Liang Y; etal., Int J Cancer.2004; 111 (4): 484-93).

Therefore, the present invention is directed to the deficiencies in the prior art, a kind of anticancer pharmaceutical composition is provided, more specifically, be entity-tumor-resistant medicine composition, this pharmaceutical composition can suppress growth of tumour cell effectively by the generation that reduces toleration, thereby can better treat tumor, reduce recurrence.

(3) summary of the invention

The present invention is directed to the deficiencies in the prior art, a kind of slow-releasing anticarcinogen injection is provided, more specifically, is entity-tumor-resistant medicine composition, comprises slow releasing injection and sustained-release implant.

Anti-cancer medicine sustained-release injection of the present invention is made up of sustained-release micro-spheres and solvent.Particularly, this slow-releasing anticarcinogen injection is grouped into by following one-tenth:

(A) sustained-release microparticle, the one-tenth following by percentage by weight is grouped into:

Anticancer effective component 0.5-60%

Slow-release auxiliary material 41-99.9%

Suspending agent 0.0-30%

(B) solvent is divided into common solvent and special solvent.

Anticancer effective component is antimetabolite and/or antimetabolite synergist.The antimetabolite synergist is anti-mitosis medicine and/or alkylating agent.The anticancer effective component decapacitation suppresses can also increase the sensitivity of tumor cell to cancer therapy drug outside the tumor growth.

Antimetabolitas can stop the synthetic of DNA in different links respectively, suppresses cell division propagation, and cell cycle and DNA are synthetic to play a role by influencing.

Antimetabolitas is selected from one of following or combination: as pemetrexed, pemetrexed disodium, Rumi Qu Sai, thunder for song account for, his shore of Raltitrexed, 2-Amino-6-methyl-5-(pyridin-4-ylsulfanyl)-3H-quinazolin-4-one, carmofur, dexrazoxane, ftorafur, temozolomide, zalcitabine, emtricitabine, galocitabine, ibacitabine, ancitabine, decitabine, flurocitabine, enocitabine, imidazoles, capecitabine, gemcitabine, fludarabine, cladribine.

The percentage by weight of above-mentioned antimetabolitas in compositions is good from 1%-50% with 5%-30%.

Antimetabolite is selected from one of following or combination: above antimetabolite also comprises their salt, as, but be not limited to sulfate, phosphate, hydrochlorate, Lactobionate, acetate, aspat, nitrate, citrate, purine or pyrimidine salt, succinate and maleate etc.

Anti-mitosis medicine will make tumor cell stop at the different links of cell cycle.Anti-mitosis medicine mainly is selected from a kind of or its combination in cytochalasin, mitoclomine, mitoflaxone, mitoguazone, mitonafide, mitopodozide, mitoquidone, mitosper, mitotane, mitotenamine, mitozolomide, Flavone acetic acid, colchisal, colchicine, Demecolcine, B cytochalasin B, naphthols, alpha-Naphthol, betanaphthol, alpha-phosphate naphthols, acodazole, procodazole, arsenicum, giracodazole and the nocodazole.Serve as preferred wherein with colchicine, B cytochalasin B, alpha-Naphthol, betanaphthol, acodazole, procodazole, arsenicum, giracodazole and nocodazole.

The percentage by weight of above-mentioned anti-mitosis medicine in slow releasing agent can be 0.01%-80%, is good with 1%-50%, and 5%-30% is best.

Above-mentioned alkylating agent is selected from a kind of or its combination in ifosfamide, 4H-peroxide cyclophosphamide, defosfamide, Mafosfamide, perfosfamide, hexamethylmelamine, cantharidin, norcantharidin, mannomustine, treosulfan, ritrosulfan, an improsulfan, etoglucid, pipobroman, piposulfan, triethylenemelaine, epoxypiperazine, benzene assistant TEPA, Phopurine, meturedepa, urethimine, the Ah bundle's TEPA.

Above alkylating agent also comprises their salt, as, but be not limited to sulfate, phosphate, hydrochlorate, Lactobionate, acetate, aspat, nitrate, citrate, purine or pyrimidine salt, succinate and maleate etc.

The percentage by weight of above-mentioned alkylating agent in slow releasing agent is good from 0.01%-99.99% with 1%-50%, is best with 5%-30%.

Anticancer effective component is mainly antimetabolite and/or its synergist.When the cancer therapy drug in the medicament slow-release microsphere only is antimetabolite or antimetabolite synergist, slow-releasing anticarcinogen injection is mainly used in the antimetabolite of other approach application of increase or the action effect of antimetabolite synergist, or is used for the potentiation to radiotherapy or other therapies.When the cancer therapy drug in the medicament slow-release microsphere only was antimetabolite or its synergist, the application of slow-releasing anticarcinogen injection and potentiation mode were:

(1) contain the slow releasing injection local injection of antimetabolite, other approach of antimetabolite synergist are used;

(2) local injection contains the slow releasing injection of antimetabolite synergist, and other approach are used antimetabolite;

(3) local injection contains the slow releasing injection and the slow releasing injection that contains the antimetabolite synergist of antimetabolite; Or

(4) local injection contains the slow releasing injection of antimetabolite and synergist.

The slow-releasing anticarcinogen injection of topical application also is used for the potentiation to radiotherapy or other therapies.Other approach refer to, but are not limited to tremulous pulse, vein, abdominal cavity, subcutaneous, intracavitary administration.

Percentage by weight in medicament slow-release microsphere is 0.5%-60%, is good with 2%-40%, is best with 5%-30%.The weight ratio of antimetabolite and antimetabolite synergist is 1-9: 1 to 1: 1-9.With 1-2: 1 serves as preferred.

Anticancer effective component percentage by weight in the anticancer slow-release microsphere of the present invention is preferably as follows:

(a) pemetrexed of 1-50%, pemetrexed disodium, Rumi Qu Sai, thunder for song account for, his shore of Raltitrexed, 2-Amino-6-methyl-5-(pyridin-4-ylsulfanyl)-3H-quinazolin-4-one, carmofur, dexrazoxane, ftorafur, temozolomide, zalcitabine, emtricitabine, galocitabine, ibacitabine, ancitabine, decitabine, flurocitabine, enocitabine, imidazoles, capecitabine, gemcitabine, fludarabine or cladribine;

(b) colchicine of 1-50%, B cytochalasin B, alpha-Naphthol, betanaphthol, acodazole, procodazole, arsenicum, giracodazole or nocodazole;

(c) ifosfamide of 1-50%, 4H-peroxide cyclophosphamide, defosfamide, Mafosfamide, perfosfamide, etoglucid, benzene assistant TEPA, Phopurine, meturedepa, urethimine or Ah bundle's TEPA;

(d) pemetrexed of 1-50%, pemetrexed disodium, Rumi Qu Sai, thunder accounts for for song, Raltitrexed, 2-Amino-6-methyl-5-(pyridin-4-ylsulfanyl)-3H-quinazolin-4-one, carmofur, dexrazoxane, ftorafur, the temozolomide, zalcitabine, emtricitabine, galocitabine, ibacitabine, ancitabine, decitabine, flurocitabine, enocitabine, his shore of imidazoles, capecitabine, gemcitabine, the colchicine of fludarabine or cladribine and 1-50%, B cytochalasin B, alpha-Naphthol, betanaphthol, acodazole, procodazole, arsenicum, the combination of giracodazole or nocodazole;

(e) pemetrexed of 1-50%, pemetrexed disodium, Rumi Qu Sai, thunder accounts for for song, Raltitrexed, 2-Amino-6-methyl-5-(pyridin-4-ylsulfanyl)-3H-quinazolin-4-one, carmofur, dexrazoxane, ftorafur, the temozolomide, zalcitabine, emtricitabine, galocitabine, ibacitabine, ancitabine, decitabine, flurocitabine, enocitabine, his shore of imidazoles, capecitabine, gemcitabine, the ifosfamide of fludarabine or cladribine and 1-50%, 4H-peroxide cyclophosphamide, defosfamide, Mafosfamide, perfosfamide, etoglucid, benzene assistant TEPA, Phopurine, meturedepa, the combination of urethimine or Ah bundle's TEPA;

(f) combination of the ifosfamide of the colchicine of 1-50%, B cytochalasin B, alpha-Naphthol, betanaphthol, acodazole, procodazole, arsenicum, giracodazole or nocodazole and 1-50%, 4H-peroxide cyclophosphamide, defosfamide, Mafosfamide, perfosfamide, etoglucid, benzene assistant TEPA, Phopurine, meturedepa, urethimine or Ah bundle's TEPA; Or

(g) pemetrexed of 1-50%, pemetrexed disodium, Rumi Qu Sai, thunder accounts for for song, Raltitrexed, 2-Amino-6-methyl-5-(pyridin-4-ylsulfanyl)-3H-quinazolin-4-one, carmofur, dexrazoxane, ftorafur, the temozolomide, zalcitabine, emtricitabine, galocitabine, ibacitabine, ancitabine, decitabine, flurocitabine, enocitabine, his shore of imidazoles, capecitabine, gemcitabine, the colchicine of fludarabine or cladribine and 1-50%, B cytochalasin B, alpha-Naphthol, betanaphthol, acodazole, procodazole, arsenicum, the ifosfamide of giracodazole or nocodazole and 1-50%, 4H-peroxide cyclophosphamide, defosfamide, Mafosfamide, perfosfamide, etoglucid, benzene assistant TEPA, Phopurine, meturedepa, the combination of urethimine or Ah bundle's TEPA.

One of the copolymer (PLGA) of the preferred polylactic acid of slow-release auxiliary material (PLA), polyglycolic acid and hydroxyacetic acid, ethylene vinyl acetate copolymer (EVAc), bis-fatty acid and decanedioic acid copolymer, poly-(erucic acid dimer-decanedioic acid) copolymer, poly-(fumaric acid-decanedioic acid) copolymer, polifeprosan or its combination.When selecting the copolymer (PLGA) of polylactic acid (PLA), polyglycolic acid (PGA), polylactic acid (PLA) and mixture, glycolic and the hydroxy carboxylic acid of polyglycolic acid for use, PLA and PLGA content percentage by weight are respectively 0.1-99.9% and 99.9-0.1%.The molecular weight peak value of polylactic acid can be, but is not limited to, 5000-100, and 000, but with 20,000-60,000 is preferred, with 30,000-50,000 for most preferably; The molecular weight of polyglycolic acid can be, but is not limited to, 5000-100, and 000, but with 20,000-60,000 is preferred, with 30,000-50,000 for most preferably; Above polyhydroxy acid can singly select or multiselect.When singly selecting, serve as preferred with the copolymer (PLGA) of polylactic acid (PLA) or hydroxy carboxylic acid and glycolic, the molecular weight of copolymer can be, but is not limited to, 5000-100,000, but with 20,000-60,000 be preferably, with 30,000-50,000 for most preferably; When multiselect, compound polymer or the copolymer formed with macromolecule polymer or different macromolecule polymer serve as preferred, with the compound polymer that contains different molecular weight polylactic acid or decanedioic acid or copolymer for most preferably, as, but be not limited to, molecular weight is 1000 to 30000 polylactic acid with molecular weight is that 20000 to 50000 polylactic acid mixes, molecular weight is 10000 to 30000 polylactic acid with molecular weight is that 30000 to 80000 PLGA mixes, molecular weight is that 20000 to 30000 polylactic acid mixes with decanedioic acid, molecular weight is that 30000 to 80000 PLGA mixes with decanedioic acid.

In various high molecular polymers, with polylactic acid, decanedioic acid, the mixture or the copolymer that contain the macromolecule polymer of polylactic acid or certain herbaceous plants with big flowers diacid is first-selection, mixture and copolymer can be selected from, but be not limited to the mixture or the copolymer of the mixture of PLA, PLGA, glycolic and hydroxy carboxylic acid, certain herbaceous plants with big flowers diacid and fragrant polyanhydride or aliphatic polyanhydride.The blend ratio of glycolic and hydroxy carboxylic acid is 10/90-90/10 (weight), preferably 25/75-75/25 (weight).The method of blend is arbitrarily.Content when glycolic and hydroxy carboxylic acid copolymerization is respectively percentage by weight 10-90% and 90-10%.The representative of fragrance polyanhydride is polifeprosan [poly-(1,3-two (to the carboxyl phenoxy group) propane-decanedioic acid) (p (CPP-SA)), bis-fatty acid-decanedioic acid copolymer (PFAD-SA)], poly-(erucic acid dimer-decanedioic acid) [P (EAD-SA)] and poly-(fumaric acid-decanedioic acid) [P (FA-SA)] etc.Content during to carboxylic phenoxypropane (p-CPP) and decanedioic acid copolymerization is respectively percentage by weight 10-60% and 20-90%, and the blend weight ratio is 10-40: 50-90, preferably weight ratio 15-30: 65-85.

Except that above-mentioned adjuvant, also can select for use other materials to see the United States Patent (USP) (patent No. 4757128; 4857311; 4888176; 4789724) and in " pharmaceutic adjuvant complete works " (the 123rd page, Sichuan science tech publishing house published in 1993, Luo Mingsheng and Gao Tianhui chief editor) have a detailed description.In addition, Chinese patent (application number 96115937.5; 91109723.6; 9710703.3; 01803562.0) and U.S.'s patent of invention (patent No. 5,651,986) also enumerated some pharmaceutic adjuvant, comprise filler, solubilizing agent, absorption enhancer, film former, gellant, system (or causing) hole agent, excipient or blocker etc.

For regulating drug releasing rate or changing other characteristic of the present invention, can change the composition and the proportioning of monomer component or molecular weight, interpolation or the adjusting pharmaceutic adjuvant of polymer, add the water-soluble low-molecular chemical compound, as, but be not limited to various sugar or salt etc.Wherein sugar can be, but is not limited to, xylitol, oligosaccharide, (sulphuric acid) chrondroitin and chitin etc., and wherein salt can be, but is not limited to, potassium salt and sodium salt etc.

In the slow releasing injection, drug sustained release system can be made into microsphere, sub-micro ball, microemulsion, nanosphere, granule or spherical piller, makes the injection use then with after the injection solvent mixes.In various slow releasing injection, serve as preferred with the suspension type slow releasing injection, the suspension type slow releasing injection is the preparation that the drug sustained release system that will contain anticancer component is suspended in gained in the injection, used adjuvant is a kind of or its combination in the above-mentioned slow-release auxiliary material, and used solvent is common solvent or the special solvent that contains suspending agent.Common solvent is, but is not limited to the buffer that distilled water, water for injection, physiology are prepared towards liquid, dehydrated alcohol or various salt.The purpose of suspending agent is the pastille microsphere that effectively suspends, thereby is beneficial to the usefulness of injection.

Suspending agent is selected from one of sodium carboxymethyl cellulose, (iodine) glycerol, simethicone, propylene glycol, carbomer, mannitol, sorbitol, surfactant, soil temperature 20, soil temperature 40 and soil temperature 80 or its combination.

The content of suspending agent in common solvent is decided because of its characteristic, can be 0.1-30% and decides because of concrete condition.Consisting of of preferred suspending agent:

A) 0.5-5% sodium carboxymethyl cellulose+0.1-0.5% soil temperature 80; Or

B) 5-20% mannitol+0.1-0.5% soil temperature 80; Or.

C) 0.5-5% sodium carboxymethyl cellulose+5-20% sorbitol+0.1-0.5% soil temperature 80.

The preparation method of slow releasing injection is arbitrarily, available some kinds of methods preparation: as, but be not limited to, mixing method, fusion method, dissolution method, spray drying method for preparation microsphere, dissolution method are made micropowder, liposome bag medicine method and emulsion process etc. in conjunction with freezing (drying) comminuting method.Serve as preferred wherein with dissolution method (being the solvent volatility process), seasoning, spray drying method and emulsion process.Microsphere then can be used for preparing above-mentioned various slow releasing injection, and its method is arbitrarily.The particle size range of used microsphere can be between 5-400um, serving as preferred between the 10-300um, with between the 20-200um for most preferably.

Microsphere also can be used for preparing other slow releasing injection, as gel injection, block copolymer micelle injection.Wherein, block copolymer micelle is formed in aqueous solution by hydrophobic-hydrophilic block copolymers, has spherical inner core-shell mechanism, and hydrophobic block forms kernel, and hydrophilic block forms shell.The carrier micelle injection enters the purpose that reaches control drug release or targeted therapy in the body.Used pharmaceutical carrier is above-mentioned any one or its combination.Wherein preferred molecular weight is the hydrophilic block of the Polyethylene Glycol (PEG) of 1000-15000 as the micelle copolymer, and preferred biological degradation polyalcohol (as PLA, polylactide, polycaprolactone and copolymer thereof (molecular weight 1500-25000)) is as the hydrophobic block of micelle copolymer.The particle size range of block copolymer micelle can be between 10-300um, between the 20-200um serving as preferred.Gel injection system is dissolved in some amphipathic solvent with biological degradation polyalcohol (as PLA, PLGA or DL-LA and epsilon-caprolactone copolymer), adds medicine miscible with it (or suspendible) back again and forms flowability gel preferably, can be through tumor week or intratumor injection.In case inject, amphipathic solvent diffuses to body fluid very soon, the moisture in the body fluid then infiltrates gel, makes polymer cure, slowly discharges medicine.

Sustained-release micro-spheres also can be used for preparing sustained-release implant, used pharmaceutic adjuvant can be any or multiple material in the above-mentioned pharmaceutic adjuvant, but with the high molecular weight water soluble polymer is main separation, in various high molecular polymers, with polylactic acid, certain herbaceous plants with big flowers diacid, the mixture or the copolymer that contain the macromolecule polymer of polylactic acid or certain herbaceous plants with big flowers diacid is first-selection, mixture and copolymer can be selected from, but be not limited to the mixture or the copolymer of the mixture of PLA, PLGA, PLA and PLGA, certain herbaceous plants with big flowers diacid and fragrant polyanhydride or aliphatic polyanhydride.Polylactic acid (PLA) and polyglycolic acid the blend ratio be 10/90-90/10 (weight), 25/75-75/25 (weight) preferably.The method of blend is arbitrarily.Content when glycolic and lactic acid copolymerization is respectively percentage by weight 10-90% and 90-10%.The representative of fragrance polyanhydride is to carboxy phenyl propane (p-CPP), content during to carboxy phenyl propane (p-CPP) and the copolymerization of certain herbaceous plants with big flowers diacid is respectively percentage by weight 10-60% and 20-90%, the blend weight ratio is 10-40: 50-90, preferably weight ratio 15-30: 65-85.

Another form of anticancer medicine slow-release preparation containing of the present invention is that anticancer medicine slow-release preparation containing is a sustained-release implant.The effective ingredient of anticancer implant can be packaged in the whole pharmaceutic adjuvant equably, also can be packaged in carrier holder center or its surface; Can effective ingredient be discharged by direct diffusion and/or the mode of degrading through polymer.

The present invention finds to influence medicine and/or sustained-release micro-spheres suspends and/or the key factor of injection is the viscosity of solvent, and viscosity is big more, and suspension effect is good more, and syringeability is strong more.This unexpected one of main index characteristic of the present invention of finding to have constituted.The viscosity of solvent depends on the viscosity of suspending agent, and the viscosity of suspending agent is 100cp-3000cp (20 ℃-30 ℃ time), preferred 1000cp-3000cp (20 ℃-30 ℃ time), most preferably 1500cp-3000cp (20 ℃-30 ℃ time).According to the viscosity of the prepared solvent of this condition is 10cp-650cp (20 ℃-30 ℃ time), preferred 20cp-650cp (20 ℃-30 ℃ time), most preferably 60cp-650cp (20 ℃-30 ℃ time).

The preparation of injection has several different methods, and a kind of is that the sustained-release microparticle (A) of suspending agent for " 0 " directly mixed in special solvent, obtains corresponding sustained-release microparticle injection; Another kind is that suspending agent is not mixed in special solvent or common solvent for the sustained-release microparticle (A) of " 0 ", obtains corresponding sustained-release microparticle injection; Another is that sustained-release microparticle (A) is mixed in common solvent, adds the suspending agent mixing then, obtains corresponding sustained-release microparticle injection.Except, also can earlier sustained-release microparticle (A) be mixed and in special solvent, make corresponding suspension, with the moisture in ways such as the vacuum drying removal suspension, special solvent of reuse or common solvent suspendible obtain corresponding sustained-release microparticle injection afterwards then.Above method just is illustrative rather than definitive thereof the present invention.It should be noted that suspended drug or sustained-release micro-spheres (or microcapsule) concentration in injection decide because of specifically needing, can be, but be not limited to, 10-400mg/ml, but be preferably with 30-300mg/ml, with 50-200mg/ml most preferably.The viscosity of injection is 50cp-1000cp (20 ℃-30 ℃ time), preferred 100cp-1000cp (20 ℃-30 ℃ time), most preferably 200cp-650cp (20 ℃-30 ℃ time).This viscosity is applicable to 18-22 injection needle and special bigger (to 3 millimeters) injection needle of internal diameter.

The characteristics of sustained-release implant are that used slow-release auxiliary material removes the high molecular polymerization beyond the region of objective existence, also contain above-mentioned any one or multiple other adjuvant.The pharmaceutic adjuvant that adds is referred to as additive.Additive can be divided into filler, porogen, excipient, dispersant, isotonic agent, preservative agent, blocker, solubilizing agent, absorption enhancer, film former, gellant etc. according to its function.

The Main Ingredients and Appearance of sustained-release implant can be made into multiple dosage form.As, but be not limited to capsule, slow releasing agent, implant, slow releasing agent implant etc.; Be multiple shape, as, but be not limited to granule, pill, tablet, powder, granule, sphere, bulk, needle-like, bar-shaped, column and membranaceous.In various dosage forms, serve as preferred slowly to discharge implant in the body.Its volume is decided because of clinical needs, can be 0.5-2.0cm (diameter) * 0.01-0.5cm (thickness) as tablet, serves as preferred with 1-1.5 * 0.1-0.3cm; Stick can be 0.1-2.0cm (length) * 0.05-0.8cm (external diameter), serves as preferred with 0.3-1.0cm * 0.1-0.5cm.

The most preferred dosage form of sustained-release implant is that the slow releasing agent that biocompatibility, degradable absorb is implanted, and can make different shape and various dosage form because of the clinical needs of difference.The packing method of its Main Ingredients and Appearance and step in United States Patent (USP) (US5651986) have a detailed description, comprise the some kinds of methods that prepare slow releasing preparation: as, but be not limited to, (i) carrier holder powder and medicament mixed be pressed into implant then, promptly so-called mixing method; (ii) carrier holder fusing, mix solid cooled then, promptly so-called fusion method mutually with medicine to be packaged; (iii) the carrier holder is dissolved in the solvent, medicine dissolution to be packaged or be scattered in the polymer solution, evaporating solvent then, drying, promptly so-called dissolution method; (iv) spray drying method; And (v) freeze-drying etc.

The anticancer effective component and the percentage by weight of anti-cancer sustained-released implantation agent of the present invention are preferably as follows:

The present invention can be used to prepare the pharmaceutical preparation of the various tumors for the treatment of people and animal, is mainly slow releasing injection or sustained-release implant.Prepared tumor comprises various entity tumors.Comprise former of originating from brain and central nervous system or shift; And originate from the outer various entity tumors of cranium, as kidney, liver, gallbladder, incidence, the oral cavity, thyroid, skin, mucosa, body of gland, blood vessel, osseous tissue, lymph node, lungs, esophagus, stomach, mammary gland, pancreas, eyes, nasopharynx part, the uterus, ovary, endometrium, cervix uteri, prostate, bladder, colon, former or cancer or sarcoma or the carcinosarcoma that shifts of rectum are wherein with the cerebral tumor, renal carcinoma, tumor of head and neck, thyroid carcinoma, pulmonary carcinoma, the esophageal carcinoma, gastric cancer, breast carcinoma, cancer of pancreas, cervical cancer, ovarian cancer, carcinoma of prostate, bladder cancer, colorectal former or metastatic carcinoma are preferred.

Route of administration depends on multiple factor, for obtain valid density in former or position, metastatic tumour place, medicine can give through number of ways, as in subcutaneous, intracavity (in abdominal cavity, thoracic cavity and canalis spinalis), the tumor, in all injections of tumor or placement, selective arterial injection, the lymph node and injection in the bone marrow.With in selective arterial injection, intracavity, the tumor, tumor week injection or be placed as preferred.Can be in when operation or perioperatively tumor, tumor week injection or place; Can with radiation and systemic chemotherapy simultaneously or front and back separate applications, but sustained-release implant with in the tumor, tumor week inject or be placed as preferably.When the cancer therapy drug in the medicament slow-release microsphere only is antimetabolite or its synergist, the application of anti-cancer sustained-released implantation agent and the same slow releasing injection of potentiation mode.

Also can add other medicinal ingredient in slow releasing injection that the present invention is made or the sustained-release implant, as, but be not limited to antibiotics, antalgica, anticoagulant medicine, hemorrhage etc.

By following test and embodiment technical method of the present invention is further described:

The local drug concentration that test 1, different modes are used behind the antimetabolite (pemetrexed) compares

With the rat is subjects, with 2 * 10 ⁵Individual prostate tumor cells subcutaneous injection is in its hypochondrium, treats behind tumor growth to 1 cm diameter its grouping.Every group of dosage is the 5mg/kg pemetrexed.Measure medicament contg (%) in the different time tumor, the result shows, the local drug concentration significant difference of pemetrexed after different modes is used, topical can obviously improve and effectively keep the active drug concentration at position, tumor place, and is wherein best with the effect of placing sustained-release implant and intratumor injection slow releasing injection in the tumor.Yet, intratumor injection slow releasing injection operation most convenient, easy.This discovery constitutes key character of the present invention.Following relevant inhibition test has further confirmed this point.

The interior tumor-inhibiting action of body that test 2, different modes are used behind the antimetabolite (Raltitrexed) compares

With the rat is subjects, with 2 * 10 ⁵Individual prostate tumor cells subcutaneous injection is in its hypochondrium, treats behind tumor growth to 0.5 cm diameter its grouping.Every group of dosage is the 5mg/kg Raltitrexed.The treatment back was measured gross tumor volume size, relatively therapeutic effect on the 10th day.The result shows, the tumor-inhibiting action significant difference of Raltitrexed after different modes is used, topical can obviously improve and effectively keep the active drug concentration at position, tumor place, and is wherein best with the effect of placing sustained-release implant and intratumor injection slow releasing injection in the tumor.Yet, intratumor injection slow releasing injection operation most convenient, easy.Good effect not only, toxic and side effects is also little.

Test 3, contain tumor-inhibiting action in the body of antimetabolite and antimetabolite synergist (slow releasing injection)

With the rat is subjects, with 2 * 10 ⁵Individual pancreatic tumor cell subcutaneous injection is in its hypochondrium, treats that tumor growth after 14 days is divided into it following 10 groups (seeing Table 1).First group is contrast, and the 2nd to 10 group is the treatment group, and antimetabolite is through intratumor injection, and the antimetabolite synergist is through lumbar injection.Dosage is 5mg/kg.The treatment back was measured gross tumor volume size, relatively therapeutic effect (seeing Table 1) on the 10th day.

Table 1

Test group (n)	Suffered treatment	Gross tumor volume (cm ³)	The P value
Test group (n)	Suffered treatment	Gross tumor volume (cm ³)	The P value	1(6)	Contrast	60±10
2(6)	Antimetabolite	24±2.0	＜0.05	1(6)	Contrast	60±10
2(6)	Antimetabolite	24±2.0	＜0.05	3(6)	Procodazole	46±5.0	＜0.01
4(6)	Arsenicum	48±4.0	＜0.01	3(6)	Procodazole	46±5.0	＜0.01
4(6)	Arsenicum	48±4.0	＜0.01	5(6)	Acodazole	54±6.6	＜0.01
6(6)	B cytochalasin B	62±3.0	＜0.01	5(6)	Acodazole	54±6.6	＜0.01
6(6)	B cytochalasin B	62±3.0	＜0.01	7(6)	Antimetabolite+procodazole	20±2.2	＜0.001
8(6)	Antimetabolite+arsenicum	16±2.0	＜0.001	7(6)	Antimetabolite+procodazole	20±2.2	＜0.001
8(6)	Antimetabolite+arsenicum	16±2.0	＜0.001	9(6)	Antimetabolite+acodazole	16±1.4	＜0.001
10(6)	Antimetabolite+B cytochalasin B	12±2.0	＜0.001	9(6)	Antimetabolite+acodazole	16±1.4	＜0.001

Above result shows, growth all has the obvious suppression effect to kinds of tumors when this concentration is used separately for antimetabolite (carmofur) and used antimetabolite synergist-anti-mitosis medicine (procodazole, arsenicum, acodazole, B cytochalasin B), and is obvious with administering effect in the tumor.When use in conjunction, can show significant potentiation.

The tumor-inhibiting action of test 4, antimetabolite and antimetabolite synergist (slow releasing injection)

Used tumor cell comprises CNS-1, C6,9L, gastric gland epithelial cancer (SA), bone tumor (BC), breast carcinoma (BA), pulmonary carcinoma (LH), papillary adenocarcinoma of thyroid (PAT), hepatocarcinoma etc.Antimetabolite and antimetabolite synergist are added in 24 hours the various tumor cells of In vitro culture by 10ug/ml concentration, continue to cultivate counting cells sum after 48 hours.Its growth of tumour cell suppresses effect and is shown in Table 2.

Table 2

Oncocyte	Antimetabolite	Giracodazole	Arsenicum	Nocodazole	Antimetabolite+giracodazole	Antimetabolite+arsenicum	Antimetabolite+nocodazole
Oncocyte	Antimetabolite	Giracodazole	Arsenicum	Nocodazole	Antimetabolite+giracodazole	Antimetabolite+arsenicum	Antimetabolite+nocodazole	CNS	48％	58％	60％	60％	84％	86％	90％
C6	44％	60％	64％	54％	92％	90％	92％	CNS	48％	58％	60％	60％	84％	86％	90％
C6	44％	60％	64％	54％	92％	90％	92％	SA	34％	50％	56％	62％	86％	92％	90％
BC	40％	52％	56％	64％	92％	80％	86％	SA	34％	50％	56％	62％	86％	92％	90％
BC	40％	52％	56％	64％	92％	80％	86％	BA	38％	60％	62％	62％	94％	96％	84％
LH	30％	54％	60％	58％	90％	86％	84％	BA	38％	60％	62％	62％	94％	96％	84％
LH	30％	54％	60％	58％	90％	86％	84％	PAT	34％	46％	64％	50％	88％	86％	78％

Above result shows, growth all has the obvious suppression effect to kinds of tumor cells when this concentration is used separately for used antimetabolite (Raltitrexed) and antimetabolite synergist-anti-mitosis medicine (giracodazole, arsenicum, nocodazole), and is obvious with administering effect in the tumor.When use in conjunction, can show significant potentiation.

The tumor-inhibiting action of test 5, antimetabolite and antimetabolite synergist (sustained-release implant)

With the rat is subjects, with 2 * 10 ⁵Individual tumor cell of liver subcutaneous injection is in its hypochondrium, treats that tumor growth after 14 days is divided into it following 10 groups (seeing Table 3).First group is contrast, and the 2nd to 10 group is the treatment group, and antimetabolite and antimetabolite synergist sustained-release implant are all placed in tumor.Dosage is 5mg/kg.The treatment back was measured gross tumor volume size, relatively therapeutic effect (seeing Table 3) on the 10th day.

Table 3

Test group (n)	Suffered treatment	Gross tumor volume (cm ³)	The P value
Test group (n)	Suffered treatment	Gross tumor volume (cm ³)	The P value	1(6)	Contrast	70±10
2(6)	Ifosfamide	48±5.0	＜0.05	1(6)	Contrast	70±10
2(6)	Ifosfamide	48±5.0	＜0.05	3(6)	Rumi Qu Sai	44±4.0	＜0.01
4(6)	Ifosfamide+Rumi Qu Sai	24±2.4	＜0.001	3(6)	Rumi Qu Sai	44±4.0	＜0.01
4(6)	Ifosfamide+Rumi Qu Sai	24±2.4	＜0.001	5(6)	Urethimine	46±3.0	＜0.01
6(6)	Urethimine+Rumi Qu Sai	26±2.2	＜0.001	5(6)	Urethimine	46±3.0	＜0.01
6(6)	Urethimine+Rumi Qu Sai	26±2.2	＜0.001	7(6)	Ah bundle's TEPA	38±3.8	＜0.01
8(6)	Ah bundle's TEPA+Rumi Qu Sai	20±2.4	＜0.001	7(6)	Ah bundle's TEPA	38±3.8	＜0.01
8(6)	Ah bundle's TEPA+Rumi Qu Sai	20±2.4	＜0.001	9(6)	4H-peroxide cyclophosphamide	46±4.8	＜0.01
10(6)	4H-peroxide cyclophosphamide+Rumi Qu Sai	18±2.2	＜0.001	9(6)	4H-peroxide cyclophosphamide	46±4.8	＜0.01

Above result shows, growth all has the obvious suppression effect to kinds of tumor cells when this concentration is used separately for the bent plug of used antimetabolite-Rumi and antimetabolite synergist-alkylating agent (ifosfamide, urethimine, Ah bundle's TEPA, 4H-peroxide cyclophosphamide), can show significant potentiation when use in conjunction.

The tumor-inhibiting action of test 6, antimetabolite and antimetabolite synergist (slow releasing injection)

With the rat is subjects, with 2 * 10 ⁵Individual prostate tumor cells subcutaneous injection is in its hypochondrium, treats that tumor growth after 14 days is divided into it negative control (blank), single therapy group (antimetabolite or antimetabolite synergist) and therapeutic alliance group (antimetabolite and antimetabolite synergist).Antimetabolite is through intratumor injection, and the antimetabolite synergist is through lumbar injection.Dosage is 5mg/kg.The treatment back was measured the gross tumor volume size on the 10th day, made relatively therapeutic effect (seeing Table 4) of index with inhibition rate of tumor growth.

Table 4

Test group (n)	Suffered treatment	Tumor control rate (%)	The P value
Test group (n)	Suffered treatment	Tumor control rate (%)	The P value	1(6)	Contrast	-
2(6)	Ftorafur	56	＜0.05	1(6)	Contrast	-
2(6)	Ftorafur	56	＜0.05	3(6)	4H-peroxide cyclophosphamide	20	＜0.01
4(6)	Defosfamide	16	＜0.01	3(6)	4H-peroxide cyclophosphamide	20	＜0.01
4(6)	Defosfamide	16	＜0.01	5(6)	Mafosfamide	14	＜0.01
6(6)	Perfosfamide	16	＜0.01	5(6)	Mafosfamide	14	＜0.01
6(6)	Perfosfamide	16	＜0.01	7(6)	Ftorafur+4H-peroxide cyclophosphamide	88	＜0.001
8(6)	Ftorafur+defosfamide	86	＜0.001	7(6)	Ftorafur+4H-peroxide cyclophosphamide	88	＜0.001
8(6)	Ftorafur+defosfamide	86	＜0.001	9(6)	Ftorafur+Mafosfamide	80	＜0.001
10(6)	Ftorafur+perfosfamide	92	＜0.001	9(6)	Ftorafur+Mafosfamide	80	＜0.001

Above result shows, growth all has the obvious suppression effect to kinds of tumor cells when this concentration is used separately for used antimetabolite (ftorafur) and antimetabolite synergist-alkylating agent (4H-peroxide cyclophosphamide, defosfamide, Mafosfamide, perfosfamide), can show significant potentiation when use in conjunction.

The tumor-inhibiting action of test 7, antimetabolite and antimetabolite synergist (slow releasing injection)

With the rat is subjects, with 2 * 10 ⁵Individual breast tumor cell subcutaneous injection is in its hypochondrium, treats that tumor growth after 14 days is divided into it negative control (blank), single therapy group, therapeutic alliance group.Antimetabolite is through lumbar injection, and the antimetabolite synergist is through intratumor injection.Dosage is 5mg/kg.The treatment back was measured the gross tumor volume size on the 10th day, made relatively therapeutic effect (seeing Table 5) of index with inhibition rate of tumor growth.

Table 5

Test group (n)	Suffered treatment	Tumor control rate (%)	The P value
Test group (n)	Suffered treatment	Tumor control rate (%)	The P value	1(6)	Contrast	-
2(6)	Antimetabolite	38	＜0.05	1(6)	Contrast	-
2(6)	Antimetabolite	38	＜0.05	3(6)	Hexamethylmelamine	52	＜0.01
4(6)	Cantharidin	58	＜0.01	3(6)	Hexamethylmelamine	52	＜0.01
4(6)	Cantharidin	58	＜0.01	5(6)	Norcantharidin	60	＜0.01
6(6)	Mannomustine	60	＜0.01	5(6)	Norcantharidin	60	＜0.01
6(6)	Mannomustine	60	＜0.01	7(6)	Antimetabolite+hexamethylmelamine	80	＜0.001
8(6)	Antimetabolite+cantharidin	88	＜0.01	7(6)	Antimetabolite+hexamethylmelamine	80	＜0.001
8(6)	Antimetabolite+cantharidin	88	＜0.01	9(6)	Antimetabolite+norcantharidin	84	＜0.001
10(6)	Antimetabolite+mannomustine	86	＜0.001	9(6)	Antimetabolite+norcantharidin	84	＜0.001

Above result shows, growth all has the obvious suppression effect to kinds of tumor cells when this concentration is used separately for used antimetabolite (gemcitabine) and antimetabolite synergist-alkylating agent (hexamethylmelamine, cantharidin, norcantharidin, mannomustine), can show significant potentiation when use in conjunction.

The tumor-inhibiting action of test 8, antimetabolite and antimetabolite synergist (sustained-release implant)

With the rat is subjects, with 2 * 10 ⁵Individual breast tumor cell subcutaneous injection is in its hypochondrium, treats that tumor growth after 14 days is divided into it negative control (blank), single therapy group, therapeutic alliance group.Sustained-release implant is all placed in tumor.Dosage is 5mg/kg.The treatment back was measured the gross tumor volume size on the 10th day, made relatively therapeutic effect (seeing Table 6) of index with inhibition rate of tumor growth.

Table 6

Test group (n)	Suffered treatment	Tumor control rate (%)	The P value
Test group (n)	Suffered treatment	Tumor control rate (%)	The P value	1(6)	Contrast	-
2(6)	Antimetabolite	66	＜0.05	1(6)	Contrast	-
2(6)	Antimetabolite	66	＜0.05	3(6)	Treosulfan	58	＜0.05
4(6)	Ritrosulfan	56	＜0.05	3(6)	Treosulfan	58	＜0.05
4(6)	Ritrosulfan	56	＜0.05	5(6)	An improsulfan	54	＜0.05
6(6)	Etoglucid	52	＜0.01	5(6)	An improsulfan	54	＜0.05
6(6)	Etoglucid	52	＜0.01	7(6)	Antimetabolite+treosulfan	88	＜0.01
8(6)	Antimetabolite+ritrosulfan	84	＜0.05	7(6)	Antimetabolite+treosulfan	88	＜0.01
8(6)	Antimetabolite+ritrosulfan	84	＜0.05	9(6)	Antimetabolite+improsulfan	76	＜0.01
10(6)	Antimetabolite+etoglucid	92	＜0.001	9(6)	Antimetabolite+improsulfan	76	＜0.01

Above result shows, growth all has the obvious suppression effect to kinds of tumor cells when this concentration is used separately for used antimetabolite (emtricitabine) and antimetabolite synergist-alkylating agent (treosulfan, ritrosulfan, an improsulfan, etoglucid), can show significant potentiation when use in conjunction.

The tumor-inhibiting action of test 9, antimetabolite and antimetabolite synergist (sustained-release implant)

By the tumor-inhibiting action of test 8 described methods mensuration antimetabolites and antimetabolite synergist (sustained-release implant), its inhibition rate of tumor growth sees Table 7.

Table 7

Test group (n)	Suffered treatment	Tumor control rate (%)	The P value
Test group (n)	Suffered treatment	Tumor control rate (%)	The P value	1(6)	Contrast	-
2(6)	Antimetabolite	44	＜0.05	1(6)	Contrast	-
2(6)	Antimetabolite	44	＜0.05	3(6)	Triethylenemelaine	40	＜0.01
4(6)	Epoxypiperazine	48	＜0.01	3(6)	Triethylenemelaine	40	＜0.01
4(6)	Epoxypiperazine	48	＜0.01	5(6)	Urethimine	44	＜0.01
6(6)	Ah bundle's TEPA	42	＜0.01	5(6)	Urethimine	44	＜0.01
6(6)	Ah bundle's TEPA	42	＜0.01	7(6)	Antimetabolite+triethylenemelaine	82	＜0.001
8(6)	Antimetabolite+epoxypiperazine	84	＜0.001	7(6)	Antimetabolite+triethylenemelaine	82	＜0.001
8(6)	Antimetabolite+epoxypiperazine	84	＜0.001	9(6)	Antimetabolite+urethimine	80	＜0.001
10(6)	Antimetabolite+Ah bundle's TEPA	88	＜0.001	9(6)	Antimetabolite+urethimine	80	＜0.001

Above result shows, growth all has the obvious suppression effect to kinds of tumor cells when this concentration is used separately for used antimetabolite (capecitabine) and antimetabolite synergist-alkylating agent (triethylenemelaine, epoxypiperazine, urethimine, Ah bundle's TEPA), can show significant potentiation when use in conjunction.

The tumor-inhibiting action of test 10, antimetabolite and antimetabolite synergist (slow releasing injection)

Measure the tumor-inhibiting action of antimetabolite synergist (slow releasing injection) by test 7 described methods, the result shows and is selected from pemetrexed, pemetrexed disodium, Rumi Qu Sai, thunder accounts for for song, Raltitrexed, 2-Amino-6-methyl-5-(pyridin-4-ylsulfanyl)-3H-quinazolin-4-one, carmofur, dexrazoxane, ftorafur, the temozolomide, zalcitabine, emtricitabine, galocitabine, ibacitabine, ancitabine, decitabine, flurocitabine, enocitabine, his shore of imidazoles, capecitabine, gemcitabine, the antimetabolite of fludarabine or cladribine can significantly strengthen ifosfamide, 4H-peroxide cyclophosphamide, etoglucid, benzene assistant TEPA, Phopurine, meturedepa, urethimine, the tumor killing effect of Ah bundle's TEPA, potentiation is in 48-78% (P＜0.01).

The tumor-inhibiting action of test 11, antimetabolite synergist (slow releasing injection)

Measure the tumor-inhibiting action of antimetabolite synergist (slow releasing injection) by test 7 described methods, the result shows and is selected from the tumor killing effect that colchicine, B cytochalasin B, alpha-Naphthol, betanaphthol, acodazole, procodazole, arsenicum, giracodazole or nocodazole can significantly strengthen ifosfamide, 4H-peroxide cyclophosphamide, etoglucid, benzene assistant TEPA, Phopurine, meturedepa, urethimine, Ah bundle's TEPA that potentiation is in 50-80% (P＜0.05).

The tumor-inhibiting action of test 12, antimetabolite and antimetabolite synergist (sustained-release implant)

Used tumor cell comprises CNS-1, C6,9L, gastric gland epithelial cancer (SA), bone tumor (BC), breast carcinoma (BA), pulmonary carcinoma (LH), papillary adenocarcinoma of thyroid (PAT), hepatocarcinoma etc.Antimetabolite and antimetabolite synergist are added in 24 hours the various tumor cells of In vitro culture by 5ug/ml concentration, continue to cultivate counting cells sum after 48 hours.Its growth of tumour cell suppresses effect (%) and is shown in Table 8.

Table 8

Oncocyte	Ftorafur	Arsenicum	Ifosfamide	Ftorafur+arsenicum	Ftorafur+ifosfamide	Arsenicum+ifosfamide	Ftorafur+arsenicum+ifosfamide
Oncocyte	Ftorafur	Arsenicum	Ifosfamide	Ftorafur+arsenicum	Ftorafur+ifosfamide	Arsenicum+ifosfamide	Ftorafur+arsenicum+ifosfamide	CNS	26	22	38	58	58	58	84
C6	32	42	48	68	64	62	86	CNS	26	22	38	58	58	58	84
C6	32	42	48	68	64	62	86	SA	36	40	50	62	62	72	88
BC	46	42	42	54	62	64	92	SA	36	40	50	62	62	72	88
BC	46	42	42	54	62	64	92	BA	28	26	32	46	46	48	86
LH	28	36	44	54	68	66	94	BA	28	26	32	46	46	48	86
LH	28	36	44	54	68	66	94	PAT	32	42	42	56	62	60	86

Above result shows, growth all has certain inhibitory action to kinds of tumor cells when this concentration is used separately for used antimetabolite (carmofur) and antimetabolite synergist (lobaplatin and goserelin), but the community of the two obviously strengthens its inhibitory action.And three's use in conjunction shows the most significant potentiation.

Further test shows that so potentiation also sees 5% pemetrexed, Raltitrexed, 2-Amino-6-methyl-5-(pyridin-4-ylsulfanyl)-3H-quinazolin-4-one, carmofur, dexrazoxane, ftorafur, the temozolomide, zalcitabine, emtricitabine, galocitabine, ibacitabine, ancitabine, decitabine, flurocitabine, enocitabine, his shore of imidazoles, capecitabine, gemcitabine, fludarabine or cladribine and 5% ifosfamide, 4H-peroxide cyclophosphamide, defosfamide, Mafosfamide, perfosfamide, etoglucid, benzene assistant TEPA, Phopurine, meturedepa, the colchicine of urethimine or Ah bundle's TEPA and 5%, B cytochalasin B, alpha-Naphthol, betanaphthol, acodazole, procodazole, arsenicum, the combination of giracodazole or nocodazole.

In a word, growth all had the obvious suppression effect to kinds of tumor cells when used antimetabolite and various antimetabolite synergist were used separately, can show significant potentiation when use in conjunction.Therefore, effective ingredient of the present invention is the combination of antimetabolite and any one antimetabolite synergist.The medicine that contains above effective ingredient can be made into sustained-release micro-spheres, and then makes slow releasing injection and implant, serves as preferred with the suspensoid injectio that is combined to form with the special solvent that contains suspending agent wherein.

Slow releasing injection or sustained-release implant also can be further specified by following embodiment.Just the invention will be further described for the foregoing description and following examples, is not its content and use are imposed any restrictions.

(4) specific embodiment

Embodiment 1.

With 90,90 and 80mg polifeprosan (to carboxy phenyl propane (p-CPP): certain herbaceous plants with big flowers diacid (SA) is 20: 80) copolymer put into (first), (second) and (the third) three container respectively, add 100 milliliters of dichloromethane then in each, behind the dissolving mixing, add 10m pemetrexed, 10mg colchicine, 10mg pemetrexed and 10mg colchicine respectively, shake up the back contains 10% pemetrexed, 10% colchicine and 10% pemetrexed and 10% colchicine with spray drying method for preparation injectable microsphere again.Then microsphere is suspended in the normal saline that contains 15% mannitol, makes corresponding suspension type slow releasing injection.The viscosity of injection is 300cp-600cp (20 ℃-30 ℃ time).The drug release time of this slow releasing injection in external normal saline is 10-15 days, is about 20-30 days at the subcutaneous drug release time of mice.

Embodiment 2.

The method step that is processed into slow releasing injection is identical with embodiment 1, but different is that contained anticancer effective component and percentage by weight thereof are:

(a) his shore of the pemetrexed of 2-40%, Raltitrexed, 2-Amino-6-methyl-5-(pyridin-4-ylsulfanyl)-3H-quinazolin-4-one, carmofur, dexrazoxane, ftorafur, temozolomide, zalcitabine, emtricitabine, galocitabine, ibacitabine, ancitabine, decitabine, flurocitabine, enocitabine, imidazoles, capecitabine, gemcitabine, fludarabine or cladribine;

(b) colchicine of 2-40%, B cytochalasin B, alpha-Naphthol, betanaphthol, acodazole, procodazole, arsenicum, giracodazole or nocodazole; Or

(c) pemetrexed of 2-40%, Raltitrexed, 2-Amino-6-methyl-5-(pyridin-4-ylsulfanyl)-3H-quinazolin-4-one, carmofur, dexrazoxane, ftorafur, the temozolomide, zalcitabine, emtricitabine, galocitabine, ibacitabine, ancitabine, decitabine, flurocitabine, enocitabine, his shore of imidazoles, capecitabine, gemcitabine, the colchicine of fludarabine or cladribine and 2-40%, B cytochalasin B, alpha-Naphthol, betanaphthol, acodazole, procodazole, arsenicum, the combination of giracodazole or nocodazole.

Embodiment 3.

With 70mg molecular weight peak value 65000 polylactic acid (PLGA, 75: 25) put into (first), (second) and (the third) three container respectively, add 100 milliliters of dichloromethane then in each, behind the dissolving mixing, in three containers, add 30mg Raltitrexed, 30mg ifosfamide, 15mg Raltitrexed and 15mg ifosfamide respectively, shake up the back contains 30% Raltitrexed, 30% ifosfamide, 15% Raltitrexed and 15% ifosfamide with spray drying method for preparation injectable microsphere again.Dried microsphere is suspended in the normal saline that contains 1.5% sodium carboxymethyl cellulose, makes corresponding suspension type slow releasing injection.The viscosity of injection is 300cp-600cp (20 ℃-30 ℃ time).The drug release time of this slow releasing injection in external normal saline is 10-15 days, is about 20-30 days at the subcutaneous drug release time of mice.

Embodiment 4

The method step that is processed into slow releasing injection is identical with embodiment 3, but different is that contained anticancer effective component and percentage by weight thereof are:

(1) ifosfamide of 2-40%, 4H-peroxide cyclophosphamide, defosfamide, Mafosfamide, perfosfamide, etoglucid, benzene assistant TEPA, Phopurine, meturedepa, urethimine or Ah bundle's TEPA; Or

(2) pemetrexed of 2-40%, Raltitrexed, 2-Amino-6-methyl-5-(pyridin-4-ylsulfanyl)-3H-quinazolin-4-one, carmofur, dexrazoxane, ftorafur, the temozolomide, zalcitabine, emtricitabine, galocitabine, ibacitabine, ancitabine, decitabine, flurocitabine, enocitabine, his shore of imidazoles, capecitabine, gemcitabine, the ifosfamide of fludarabine or cladribine and 2-40%, 4H-peroxide cyclophosphamide, defosfamide, Mafosfamide, perfosfamide, etoglucid, benzene assistant TEPA, Phopurine, meturedepa, the combination of urethimine or Ah bundle's TEPA.

Embodiment 5.

(EVAc) puts into container with the 70mg ethylene vinyl acetate copolymer, after adding 100 milliliters of dichloromethane dissolving mixings, add 20 milligrams of 4H-peroxide cyclophosphamide and 10 milligrams of acodazoles, shake up the back contains 20%4H-peroxide cyclophosphamide and 10% acodazole with spray drying method for preparation injectable microsphere again.Then microsphere is suspended in the injection that contains the 5-15% sorbitol, makes corresponding suspension type slow releasing injection.The drug release time of this slow releasing injection in external normal saline is 10-15 days, is about 20-30 days at the subcutaneous drug release time of mice.

Embodiment 6.

The method step that is processed into slow releasing injection is identical with embodiment 5, but different is that contained anticancer effective component is:

The combination of colchicine, B cytochalasin B, alpha-Naphthol, betanaphthol, acodazole, procodazole, arsenicum, giracodazole or the nocodazole of the ifosfamide of 10-20%, 4H-peroxide cyclophosphamide, defosfamide, Mafosfamide, perfosfamide, etoglucid, benzene assistant TEPA, Phopurine, meturedepa, urethimine or Ah bundle's TEPA and 10-20%.

Embodiment 7.

70mg polifeprosan (to carboxy phenyl propane (p-CPP): certain herbaceous plants with big flowers diacid (SA) is 20: 80) copolymer is put into container, add 100 milliliters of dichloromethane, behind the dissolving mixing, add 20mg temozolomide and 10mg etoglucid, shake up the back contains 20% temozolomide and 10% etoglucid with spray drying method for preparation injectable microsphere again.Microsphere is suspended in the normal saline that contains 1.5% sodium carboxymethyl cellulose and 0.5% Tween 80 then, makes corresponding suspension type slow releasing injection.The drug release time of this slow releasing injection in external normal saline is 10-15 days, is about 20-30 days at the subcutaneous drug release time of mice.

Embodiment 8.

The method step that is processed into slow releasing injection is identical with embodiment 7, but different is that contained anticancer effective component is:

The pemetrexed of 10-20%, Raltitrexed, 2-Amino-6-methyl-5-(pyridin-4-ylsulfanyl)-3H-quinazolin-4-one, carmofur, dexrazoxane, ftorafur, the temozolomide, zalcitabine, emtricitabine, galocitabine, ibacitabine, ancitabine, decitabine, flurocitabine, enocitabine, his shore of imidazoles, capecitabine, gemcitabine, the ifosfamide of fludarabine or cladribine and 10-20%, 4H-peroxide cyclophosphamide, defosfamide, Mafosfamide, perfosfamide, etoglucid, benzene assistant TEPA, Phopurine, meturedepa, the combination of urethimine or Ah bundle's TEPA.

Embodiment 9

70mg polifeprosan (to carboxy phenyl propane (p-CPP): certain herbaceous plants with big flowers diacid (SA) is 20: 80) copolymer is put into container, add 100 milliliters of dichloromethane, behind the dissolving mixing, add 15mg emtricitabine and 15mg nocodazole, shake up the back contains 15% emtricitabine and 15% with spray drying method for preparation nocodazole injectable microsphere again.Then microsphere is suspended in the normal saline that contains 1.5% sodium carboxymethyl cellulose and 15% sorbitol and 0.2% Tween 80, makes corresponding suspension type slow releasing injection.The drug release time of this slow releasing injection in external normal saline is 10-15 days, is about 20-30 days at the subcutaneous drug release time of mice.

Embodiment 10

The method step that is processed into slow releasing injection is identical with embodiment 9, but different is that contained anticancer effective component is:

The combination of cytochalasin, acodazole, procodazole, arsenicum, giracodazole or the nocodazole of his shore of 15% pemetrexed, Raltitrexed, 2-Amino-6-methyl-5-(pyridin-4-ylsulfanyl)-3H-quinazolin-4-one, carmofur, dexrazoxane, ftorafur, temozolomide, zalcitabine, emtricitabine, galocitabine, ibacitabine, ancitabine, decitabine, flurocitabine, enocitabine, imidazoles, capecitabine, gemcitabine, fludarabine or cladribine and 15%.

Embodiment 11

70mg polifeprosan (to carboxy phenyl propane (p-CPP): certain herbaceous plants with big flowers diacid (SA) is 20: 80) copolymer is put into container, add 100 milliliters of dichloromethane, behind the dissolving mixing, add 10mg meturedepa and 20mg galocitabine, shake up the back contains 10% meturedepa and 20% galocitabine with spray drying method for preparation injectable microsphere again.Then microsphere is made corresponding sustained-release implant through pressed disc method.The drug release time of this sustained-release implant in external normal saline is 10-15 days, is about 30-40 days at the subcutaneous drug release time of mice.

Embodiment 12

The method step that is processed into sustained-release implant is identical with embodiment 11, but different is that contained anticancer effective component is:

The ifosfamide of 10-20%, 4H-peroxide cyclophosphamide, defosfamide, Mafosfamide, perfosfamide, etoglucid, benzene assistant TEPA, Phopurine, meturedepa, the pemetrexed of urethimine or Ah bundle's TEPA and 10-20%, Raltitrexed, 2-Amino-6-methyl-5-(pyridin-4-ylsulfanyl)-3H-quinazolin-4-one, carmofur, dexrazoxane, ftorafur, the temozolomide, zalcitabine, emtricitabine, galocitabine, ibacitabine, ancitabine, decitabine, flurocitabine, enocitabine, his shore of imidazoles, capecitabine, gemcitabine, the combination of fludarabine or cladribine.

Embodiment 13

With 70mg molecular weight peak value 45000 polylactic acid (PLGA, 50: 50) put into container, add 100 milliliters of dichloromethane, behind the dissolving mixing, add 10mg decitabine and 20mg4H-peroxide cyclophosphamide, shake up the back contains 10% decitabine and 20%4H-peroxide cyclophosphamide with spray drying method for preparation injectable microsphere again.Then microsphere is made corresponding sustained-release implant through pressed disc method.The drug release time of this sustained-release implant in external normal saline is 15-25 days, is about 35-50 days at the subcutaneous drug release time of mice.

Embodiment 14

The method step that is processed into sustained-release implant is identical with embodiment 11,13, but different is that contained anticancer effective component and percentage by weight are:

(a) his shore of the pemetrexed of 2-30%, Raltitrexed, 2-Amino-6-methyl-5-(pyridin-4-ylsulfanyl)-3H-quinazolin-4-one, carmofur, dexrazoxane, ftorafur, temozolomide, zalcitabine, emtricitabine, galocitabine, ibacitabine, ancitabine, decitabine, flurocitabine, enocitabine, imidazoles, capecitabine, gemcitabine, fludarabine or cladribine;

(b) colchicine of 2-30%, B cytochalasin B, alpha-Naphthol, betanaphthol, acodazole, procodazole, arsenicum, giracodazole or nocodazole;

(c) ifosfamide of 2-30%, 4H-peroxide cyclophosphamide, defosfamide, Mafosfamide, perfosfamide, etoglucid, benzene assistant TEPA, Phopurine, meturedepa, urethimine or Ah bundle's TEPA;

(d) pemetrexed of 2-30%, Raltitrexed, 2-Amino-6-methyl-5-(pyridin-4-ylsulfanyl)-3H-quinazolin-4-one, carmofur, dexrazoxane, ftorafur, the temozolomide, zalcitabine, emtricitabine, galocitabine, ibacitabine, ancitabine, decitabine, flurocitabine, enocitabine, his shore of imidazoles, capecitabine, gemcitabine, the colchicine of fludarabine or cladribine and 2-30%, B cytochalasin B, alpha-Naphthol, betanaphthol, acodazole, procodazole, arsenicum, the combination of giracodazole or nocodazole;

(e) pemetrexed of 2-30%, Raltitrexed, 2-Amino-6-methyl-5-(pyridin-4-ylsulfanyl)-3H-quinazolin-4-one, carmofur, dexrazoxane, ftorafur, the temozolomide, zalcitabine, emtricitabine, galocitabine, ibacitabine, ancitabine, decitabine, flurocitabine, enocitabine, his shore of imidazoles, capecitabine, gemcitabine, the ifosfamide of fludarabine or cladribine and 2-30%, 4H-peroxide cyclophosphamide, defosfamide, Mafosfamide, perfosfamide, etoglucid, benzene assistant TEPA, Phopurine, meturedepa, the combination of urethimine or Ah bundle's TEPA;

(f) combination of the ifosfamide of the colchicine of 2-30%, B cytochalasin B, alpha-Naphthol, betanaphthol, acodazole, procodazole, arsenicum, giracodazole or nocodazole and 2-30%, 4H-peroxide cyclophosphamide, defosfamide, Mafosfamide, perfosfamide, etoglucid, benzene assistant TEPA, Phopurine, meturedepa, urethimine or Ah bundle's TEPA; Or

(g) pemetrexed of 2-30%, Raltitrexed, 2-Amino-6-methyl-5-(pyridin-4-ylsulfanyl)-3H-quinazolin-4-one, carmofur, dexrazoxane, ftorafur, the temozolomide, zalcitabine, emtricitabine, galocitabine, ibacitabine, ancitabine, decitabine, flurocitabine, enocitabine, his shore of imidazoles, capecitabine, gemcitabine, the colchicine of fludarabine or cladribine and 2-30%, B cytochalasin B, alpha-Naphthol, betanaphthol, acodazole, procodazole, arsenicum, the ifosfamide of giracodazole or nocodazole and 2-30%, 4H-peroxide cyclophosphamide, defosfamide, Mafosfamide, perfosfamide, etoglucid, benzene assistant TEPA, Phopurine, meturedepa, the combination of urethimine or Ah bundle's TEPA.

Embodiment 15

The method step that is processed into slow releasing agent is identical with embodiment 1-14, but different is used slow-release auxiliary material is one of following or its combination:

A) the molecular weight peak value is the polylactic acid (PLA) of 10000-30000,30000-60000,60000-100000 or 100000-150000;

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

C) ethylene vinyl acetate copolymer (EVAc);

D) 10: 90,20: 80,30: 70,40: 60,50: 50 or 60: 40 to carboxy phenyl propane (p-CPP): certain herbaceous plants with big flowers diacid (SA) copolymer (polifeprosan);

E) bis-fatty acid and decanedioic acid copolymer;

F) poly-(erucic acid dimer-decanedioic acid) copolymer;

G) poly-(fumaric acid-decanedioic acid) copolymer;

H) xylitol, oligosaccharide, chrondroitin, chitin, potassium salt, sodium salt, hyaluronic acid, collagen protein, gelatin or white tempera.

Embodiment 16

The method step that is processed into slow releasing injection is identical with embodiment 1-10, but different is used suspending agent is respectively one of following or its combination:

A) 0.5-3.0% carboxymethyl cellulose (sodium);

B) 5-15% mannitol;

C) 5-15% sorbitol;

D) 0.1-1.5% surfactant;

E) 0.1-0.5% polysorbas20;

F) (iodine) glycerol, simethicone, propylene glycol or carbomer;

G) 0.5-5% sodium carboxymethyl cellulose+0.1-0.5% soil temperature 80;

H) 5-20% mannitol+0.1-0.5% soil temperature 80; Or

I) 0.5-5% sodium carboxymethyl cellulose+5-20% sorbitol+0.1-0.5% soil temperature 80.

Above embodiment only is used for explanation, and is not limitation application of the present invention.

The present invention disclosed and the protection the content see claim.

Claims

1. the anticancer sustained-release agent of both antimetabolite and synergist thereof is a slow releasing injection, is grouped into by following one-tenth:

(A) sustained-release micro-spheres comprises:

Anticancer effective component 0.5-60%

Slow-release auxiliary material 40-99%

Suspending agent 0.0-30%

More than be weight percentage

With

(B) solvent is for common solvent or contain the special solvent of suspending agent.

Wherein,

Anticancer effective component is antimetabolite and/or is selected from anti-mitosis medicine and/or the antimetabolite synergist of alkylating agent;

The viscosity of suspending agent is 100cp-3000cp (20 ℃-30 ℃ time), is selected from one of sodium carboxymethyl cellulose, iodine glycerol, simethicone, propylene glycol, carbomer, mannitol, sorbitol, surfactant, soil temperature 20, soil temperature 40 and soil temperature 80 or its combination.

2. the slow-releasing anticarcinogen injection according to claim 1 is characterized in that antimetabolite is selected from one of his shore of pemetrexed, Raltitrexed, 2-Amino-6-methyl-5-(pyridin-4-ylsulfanyl)-3H-quinazolin-4-one, carmofur, dexrazoxane, ftorafur, temozolomide, zalcitabine, emtricitabine, galocitabine, ibacitabine, ancitabine, decitabine, flurocitabine, enocitabine, imidazoles, capecitabine, gemcitabine, fludarabine and cladribine or its combination.

3. the slow-releasing anticarcinogen injection according to claim 1 is characterized in that anti-mitosis medicine is selected from one of cytochalasin, mitoclomine, mitoflaxone, mitoguazone, mitonafide, mitopodozide, mitoquidone, mitosper, mitotane, mitotenamine, mitozolomide, Flavone acetic acid, colchisal, colchicine, Demecolcine, B cytochalasin B, naphthols, alpha-Naphthol, betanaphthol, alpha-phosphate naphthols, acodazole, procodazole, arsenicum, giracodazole, nocodazole or its combination.

4. the slow-releasing anticarcinogen injection according to claim 1 is characterized in that alkylating agent is selected from a kind of or its combination in ifosfamide, 4H-peroxide cyclophosphamide, defosfamide, Mafosfamide, perfosfamide, hexamethylmelamine, cantharidin, norcantharidin, mannomustine, treosulfan, ritrosulfan, an improsulfan, etoglucid, pipobroman, piposulfan, triethylenemelaine, epoxypiperazine, benzene assistant TEPA, Phopurine, meturedepa, urethimine, the Ah bundle's TEPA.

5. the slow-releasing anticarcinogen injection according to claim 1 is characterized in that the anticancer effective component of slow-releasing anticarcinogen injection and percentage by weight thereof are:

(1) pemetrexed of 1-50%, pemetrexed disodium, Rumi Qu Sai, thunder for song account for, his shore of Raltitrexed, 2-Amino-6-methyl-5-(pyridin-4-ylsulfanyl)-3H-quinazolin-4-one, carmofur, dexrazoxane, ftorafur, temozolomide, zalcitabine, emtricitabine, galocitabine, ibacitabine, ancitabine, decitabine, flurocitabine, enocitabine, imidazoles, capecitabine, gemcitabine, fludarabine or cladribine;

(2) colchicine of 1-50%, B cytochalasin B, alpha-Naphthol, betanaphthol, acodazole, procodazole, arsenicum, giracodazole or nocodazole;

(3) ifosfamide of 1-50%, 4H-peroxide cyclophosphamide, defosfamide, Mafosfamide, perfosfamide, etoglucid, benzene assistant TEPA, Phopurine, meturedepa, urethimine or Ah bundle's TEPA;

(4) pemetrexed of 1-50%, pemetrexed disodium, Rumi Qu Sai, thunder accounts for for song, Raltitrexed, 2-Amino-6-methyl-5-(pyridin-4-ylsulfanyl)-3H-quinazolin-4-one, carmofur, dexrazoxane, ftorafur, the temozolomide, zalcitabine, emtricitabine, galocitabine, ibacitabine, ancitabine, decitabine, flurocitabine, enocitabine, his shore of imidazoles, capecitabine, gemcitabine, the colchicine of fludarabine or cladribine and 1-50%, B cytochalasin B, alpha-Naphthol, betanaphthol, acodazole, procodazole, arsenicum, the combination of giracodazole or nocodazole;

(5) pemetrexed of 1-50%, pemetrexed disodium, Rumi Qu Sai, thunder accounts for for song, Raltitrexed, 2-Amino-6-methyl-5-(pyridin-4-ylsulfanyl)-3H-quinazolin-4-one, carmofur, dexrazoxane, ftorafur, the temozolomide, zalcitabine, emtricitabine, galocitabine, ibacitabine, ancitabine, decitabine, flurocitabine, enocitabine, his shore of imidazoles, capecitabine, gemcitabine, the ifosfamide of fludarabine or cladribine and 1-50%, 4H-peroxide cyclophosphamide, defosfamide, Mafosfamide, perfosfamide, etoglucid, benzene assistant TEPA, Phopurine, meturedepa, the combination of urethimine or Ah bundle's TEPA;

(6) combination of the ifosfamide of the colchicine of 1-50%, B cytochalasin B, alpha-Naphthol, betanaphthol, acodazole, procodazole, arsenicum, giracodazole or nocodazole and 1-50%, 4H-peroxide cyclophosphamide, defosfamide, Mafosfamide, perfosfamide, etoglucid, benzene assistant TEPA, Phopurine, meturedepa, urethimine or Ah bundle's TEPA; Or

(7) pemetrexed of 1-50%, pemetrexed disodium, Rumi Qu Sai, thunder accounts for for song, Raltitrexed, 2-Amino-6-methyl-5-(pyridin-4-ylsulfanyl)-3H-quinazolin-4-one, carmofur, dexrazoxane, ftorafur, the temozolomide, zalcitabine, emtricitabine, galocitabine, ibacitabine, ancitabine, decitabine, flurocitabine, enocitabine, his shore of imidazoles, capecitabine, gemcitabine, the colchicine of fludarabine or cladribine and 1-50%, B cytochalasin B, alpha-Naphthol, betanaphthol, acodazole, procodazole, arsenicum, the ifosfamide of giracodazole or nocodazole and 1-50%, 4H-peroxide cyclophosphamide, defosfamide, Mafosfamide, perfosfamide, etoglucid, benzene assistant TEPA, Phopurine, meturedepa, the combination of urethimine or Ah bundle's TEPA.

6. the slow-releasing anticarcinogen injection according to claim 1 is characterized in that slow-release auxiliary material is selected from one of following or its combination:

A) polylactic acid;

B) copolymer of polyglycolic acid and hydroxyacetic acid;

C) polifeprosan;

D) ethylene vinyl acetate copolymer;

E) bis-fatty acid and decanedioic acid copolymer;

F) poly-(erucic acid dimer-decanedioic acid) copolymer;

G) poly-(fumaric acid-decanedioic acid) copolymer;

7. the slow-releasing anticarcinogen injection according to claim 1 is characterized in that used suspending agent is respectively one of following:

A) 0.5-3.0% carboxymethyl cellulose (sodium);

B) 5-15% mannitol;

C) 5-15% sorbitol;

D) 0.1-1.5% surfactant;

E) 0.1-0.5% polysorbas20;

F) (iodine) glycerol, simethicone, propylene glycol or carbomer;

G) 0.5-5% sodium carboxymethyl cellulose+0.1-0.5% soil temperature 80;

H) 5-20% mannitol+0.1-0.5% soil temperature 80; Or

8. be used to prepare the sustained-release implant that treatment originates from people and animal entity tumor according to the described anticancer slow-release microsphere of claim 1.

9. described according to Claim 8 anti-cancer sustained-released implantation agent is characterized in that anticancer effective component and percentage by weight are:

Slow-release auxiliary material is selected from one of following or its combination:

A) polylactic acid;

B) copolymer of polyglycolic acid and hydroxyacetic acid;

C) polifeprosan;

D) ethylene vinyl acetate copolymer;

E) bis-fatty acid and decanedioic acid copolymer;

F) poly-(erucic acid dimer-decanedioic acid) copolymer;

G) poly-(fumaric acid-decanedioic acid) copolymer;

10. described according to Claim 8 described anti-cancer sustained-released implantation agent is characterized in that in the slow-release auxiliary material:

A) the molecular weight peak value of polylactic acid is selected from 10000-30000,300000-60000,60000-100000 or 100000-150000;

B) in the copolymer of polyglycolic acid and hydroxyacetic acid, the ratio of polyglycolic acid and hydroxyacetic acid is 50-95: 50-50, and the molecular weight peak value is 10000-30000,300000-60000,60000-100000 or 100000-150000;

C) in the polifeprosan, to carboxy phenyl propane: the certain herbaceous plants with big flowers diacid is 10: 90,20: 80,30: 70,40: 60,50: 50 or 60: 40.