CN1973817A

CN1973817A - Solid tumor treating slow releasing prepn containing chemotherapy synergist

Info

Publication number: CN1973817A
Application number: CNA200610201336XA
Authority: CN
Inventors: 孔庆忠; 刘玉燕
Original assignee: Shandong Lanjin Pharmaceuticals Co Ltd
Current assignee: Shandong Lanjin Pharmaceuticals Co Ltd
Priority date: 2006-12-20
Filing date: 2006-12-20
Publication date: 2007-06-06

Abstract

The solid tumor treating slow releasing preparation containing chemotherapeutic medicine and its synergist is one kind of slow releasing injection comprising slow released microsphere and solvent. The slow released microsphere includes effective anticancer component and slow releasing supplementary material. The effective anticancer component is composition of chemotherapeutic synergist and antitumor antiseptic and/or antimetabolite. The solvent is special solvent containing suspending agent. The chemotherapeutic synergist is rapamycin; the slow releasing supplementary material is selected from lactic acid copolymer, polyethylene glycol/polylactic acid, glycolic acid copolymer, etc; the suspending agent has viscosity of 80cp-3000cp at 20-30 deg.c and is selected from carboxymethyl cellulose, etc. The slow released microsphere may be also prepared into slow releasing implant. The slow releasing injection and the slow releasing implant may release medicine locally for 30-50 days.

Description

A kind of controlled release formulation for anti entity tumour that contains chemical-therapy synergistic agent

(1) technical field

The present invention relates to a kind of controlled release formulation for anti entity tumour, belong to technical field of pharmaceuticals.Particularly, the invention provides a kind of slow releasing injection and sustained-release implant that contains chemical-therapy synergistic agent.Chemical-therapy synergistic agent in this anticancer sustained-release agent can suppress or destroy matter and tumor vessel between entity tumor effectively, the new vessels that can not only suppress tumor, effectively reduce tension force, a matter pressure, a matter viscosity in the tumor, and then improve its interstitial fluid conductance, help medicine and enter entity tumor and the effective diffusion in tumor, also can increase the sensitivity of tumor chemotherapeutics.

(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 such as hole, (Kong Q et al., J Surg Oncol.1998 Oct in 1998; 69 (2): 76-82).

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; et al., Int JCancer.2004; 111 (4): 484-93).

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 such as Kong Qingzhongs, (Kong Q et al., J Surg Oncol.1998 Oct in 1998; 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, entity tumor is made up of tumor cell and mesenchyma stroma of tumors, wherein the blood vessel in the mesenchyma stroma of tumors not only provides support and requisite nutrient substance for the growth of tumor cell, also influenced chemotherapeutics around tumor and infiltration and diffusion in the tumor tissues, " situation of extracellular matrix is to the influence of medicine running in the entity tumor " " cancer research " 60 phase 2497-503 page or leaf such as carry referring to the Buddhist nun, (Netti PA, Cancer Res.2000,60 (9): 2497-503) in 2000.

The tumor cell of composition such as the blood vessel in the mesenchyma stroma of tumors and fibrin in the connective tissue and collagen protein and hyperplasia cause entity tumor between matter pressure (interstitial pressure) high, a matter viscosity (interstitialviscosity) is big, tissue tension coefficient (tissue tensile modulus) is big, (hydraulicconductance) is low for the interstitial fluid conductance.Above factors have limited medicine greatly and have entered entity tumor and the effective diffusion in tumor, therefore constitute the major obstacle of chemotherapy of tumors.

Moreover, the blood vessel in the mesenchyma stroma of tumors often causes tumor cell to cancer therapy drug to conventional chemotherapy medicine and insensitive, the enhancing of the toleration of particularly single medicine chemotherapy, consequently treatment failure.

(3) summary of the invention

The present invention is directed to the deficiencies in the prior art, a kind of new pharmaceutical composition is provided, contain chemical-therapy synergistic agent and cancer therapy drug.More specifically, be the slow releasing agent of anti entity tumour, be mainly sustained-release implant and slow releasing injection.Chemical-therapy synergistic agent in this anticancer sustained-release agent can suppress or destroy matter and tumor vessel between entity tumor effectively, the new vessels that can not only suppress tumor, effectively reduce tension force, a matter pressure, a matter viscosity in the tumor, and then improve its interstitial fluid conductance, help medicine and enter entity tumor and the effective diffusion in tumor, also can increase the sensitivity of tumor chemotherapeutics.

Chemical-therapy synergistic agent and cancer therapy drug are made drug level that slow releasing agent (being mainly slow releasing injection and sustained-release implant) not only can greatly improve tumor by local, reduce the drug level of medicine in blood circulation, are reduced the toxicity of medicine to normal structure, can also greatly make things convenient for the medicine injection, reduce operation technique complication, reduce patient's expense.The chemical-therapy synergistic agent decapacitation suppresses can also increase the sensitivity of tumor cell to cancer therapy drug outside the tumor growth.The above unexpected main contents of the present invention of finding to constitute.

Controlled release formulation for anti entity tumour of the present invention comprises anticancer effective component and pharmaceutic adjuvant, and anticancer effective component is selected from the cancer therapy drug and the chemical-therapy synergistic agent of antitumor antibiotics and/or antimetabolitas.Chemical-therapy synergistic agent is a rapamycin, except that having the effect that suppresses growth of tumour cell, the blood vessel that can suppress or destroy tumor effectively also can suppress the formation of the new vessels of tumor, and then not only make tumor cell lose the required support of growth and the source of nutrient substance, also can obviously promote chemotherapeutics to enter tumor and reach around tumor and infiltration and diffusion in the tumor tissues

The above unexpected main contents of the present invention of finding to constitute.

Compound medicament composition of the present invention can be made into any dosage form, as, but be not limited to capsule, slow releasing agent, granule, pill, tablet, powder, injection, ointment, patch, implant, slow releasing agent implant, slow releasing agent injection etc.Wherein be preferred with the slow releasing agent, with slow releasing agent implant and slow releasing agent injection for most preferably.

The present invention is directed to the deficiencies in the prior art, a kind of new slow releasing injection that contains chemical-therapy synergistic agent and cancer therapy drug is provided.

Chemical-therapy synergistic agent slow releasing 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 micro-spheres comprises:

Anticancer effective component 0.01-60%

Slow-release auxiliary material 40-99.99%

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.

Solvent is divided into common solvent and special solvent.

Anticancer effective component is the combination of chemical-therapy synergistic agent and antitumor antibiotics and/or antimetabolitas.

The drug main that chemical-therapy synergistic agent, antitumor antibiotics and/or antimetabolitas are made is wanted conventional route administrations such as oral administration or intravenous injection.Administering mode of the present invention is the local sustained release administration, obviously reduces the toxic action of its whole body in the therapeutic effect that significantly strengthens medicine.With regard to chemical-therapy synergistic agent and cancer therapy drug, be not the slow release effect that all slow-release auxiliary material all can reach effective release with active anticancer.Pharmaceutic adjuvant have hundreds of more than, pharmaceutic adjuvant with slow releasing function, particularly the pharmaceutic adjuvant that selected chemical-therapy synergistic agent among the present invention slowly can be discharged in the regular hour in human body or animal body must could obtain through a large amount of creationary experiments, specific slow-release auxiliary material and can need be passed through a large amount of creative works by the selection of the compositions of slow releasing pharmaceutical and proportioning thereof and could determine.Discharged and be not enough to obtain active drug concentration slowly, thereby effective kill tumor cell; Cause prominent releasing if discharge too fast meeting, then cause general toxic reaction as conventional injection easily.The data of release characteristics need could obtain through a large amount of creationary experiments in inside and outside in the related data, particularly animal body, are not just can determine to have unobviousness through limited experiment.

Chemical-therapy synergistic agent mainly is selected from rapamycin and derivant thereof.Rapamycin 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.

Above-mentioned rapamycin shared ratio in slow releasing agent is decided because of concrete condition, can be 0.001%-50%, is good with 0.01%-20%, and 0.1%-10% is best.

Antitumor antibiotics mainly is selected from Epothilones (epothilone), epothilone B, doxorubicin hydrochloride (adriamycin), triferricdoxorubicin, epirubicin (epiadriamycin), 7-O-methyl Nuo Jia-4 '-epirubicin (7-o-methylnogallol-4 '-epiadriamycin), diethoxy acetyl amycin, mitomycin (Mitomycin), ametycin (mitomycin C), NSC-69529, actinomycin D (Dactinomycin), actinomycin C, cyclosporin A.Serve as preferred wherein with Epothilones, epothilone B, amycin, epirubicin, ametycin, actinomycin D, dactinomycin.Above antitumor antibiotics medicine also comprises its salt, as, but be not limited to sulfate, phosphate, hydrochlorate, Lactobionate, acetate, aspat, nitrate, citrate, purine or pyrimidine salt, succinate or maleate.

Above-mentioned antitumor antibiotic shared ratio in slow releasing injection is decided because of concrete condition, can be 0.1%-50%, is good with 1%-40%, and 2%-30% is best.

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: floxuridine (fluridine), doxifluridine (Doxifloridine, fortulon), the 5-doxifluridine, propylthiouracil, fluorouracil (Fluoracil, 5-FU), the fluorobutane uracil, tegadifurum, the 5-fluoxydin, sulfomercaprine sodium, mercaptopurine (Mercaptopurine, happy disease is peaceful, 6-MP), mercapto miaow purine, Ismipur, the adenine hydrochlorate, Benin, thioguanine (thioguanine, 6-TG), methotrexate methotrexate, MTX), fluoromethotrexate, the dioxy methotrexate, folic acid, 10-ethyl denitrification aminopterin (deaza-aminopterin), fluoromethotrexate, the dioxy methotrexate, 5, the 10-lonetrexol, N5-Methyltetrahydrohmofotic Acid, carmofur (Carmofur), ftorafur (Tegafur, tegafur, FT-207), UFT (Tegafur-Uracil, UFT), Tegafur-uracil mixt., 8-azaguanine (8-azaguanine), uracil, 5-mercaptomethyluracil, calcium levofolinate, calcium folinate (Calcium Levofolinate, calcium leucovorin), hycamtin, topotecan hydrochloride, cytosine arabinoside (cytosine arabinoside, Cytarabine (Ara-C)), ancitabine (cyclotidine, Cyclocytidine), ancitabine (cyclotidine, Cyclocytidine), hydroxyurea (Hydroxycarbamide, hydroxyurea), the hydroxyl guanidine.

In the above antimetabolite with floxuridine, doxifluridine, the 5-doxifluridine, propylthiouracil, fluorouracil, the fluorobutane uracil, tegadifurum, the 5-fluoxydin, sulfomercaprine sodium, mercaptopurine, mercapto miaow purine, Ismipur, the adenine hydrochlorate, Benin, thioguanine, methotrexate, fluoromethotrexate, the dioxy methotrexate, 10-ethyl denitrification aminopterin, the dioxy methotrexate, N5-Methyltetrahydrohmofotic Acid, folic acid, 5, the 10-lonetrexol, calcium levofolinate, calcium folinate, carmofur, ftorafur, UFT, Tegafur-uracil mixt., the 8-azaguanine, uracil, 5-mercaptomethyluracil, hycamtin, topotecan hydrochloride, cytosine arabinoside, ancitabine, hydroxyurea, the hydroxyl guanidine is preferred.

The percentage by weight of above-mentioned antimetabolitas in slow releasing injection is 0.1%-50%, is good with 1%-40%, and 2%-30% is best.

Slow-release auxiliary material range of viscosities IV (dl/g) is 0.1～0.8, be selected from poly-dl-lactide (D, L-PLA), poly-dl-lactide/ethanol copolymer (D, L-PLGA), monomethyl polyethylene glycol (MPEG-PLA), monomethyl polyethylene glycol copolymer (MPEG-PLGA), polyethylene glycol (PLA-PEG-PLA), polyethylene glycol copolymer (PLGA-PEG-PLGA), end carboxyl polylactic acid (PLA-COOH), end carboxyl polylactic acid/ethanol copolymer (PLGA-COOH), polifeprosan, bis-fatty acid and decanedioic acid copolymer (PFAD-SA), poly-(erucic acid dimer-decanedioic acid) [P (EAD-SA)], poly-(fumaric acid-decanedioic acid) [P (FA-SA)], ethylene vinyl acetate copolymer (EVAc), polylactic acid (PLA), the copolymer of polyglycolic acid and hydroxyacetic acid (PLGA), PPDO (PDO), PTMC (PTMC), xylitol, oligosaccharide, chrondroitin, chitin, hyaluronic acid, collagen protein, gelatin, chitosan, poloxamer, one of albumin glue or its combination; 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.

When the anticancer effective component in the medicament slow-release microsphere only was chemical-therapy synergistic agent or cancer therapy drug, slow-releasing anticarcinogen injection was mainly used in the chemical-therapy synergistic agent of other approach application of increase or the action effect of cancer therapy drug, or was used for the potentiation to radiotherapy or other therapies.When the cancer therapy drug in the medicament slow-release microsphere only was chemical-therapy synergistic agent or cancer therapy drug, the application of slow-releasing anticarcinogen injection and potentiation mode were:

(1) contain the slow releasing injection local injection of chemical-therapy synergistic agent, and cancer therapy drug is used through other approach;

(2) local injection contains the slow releasing injection of cancer therapy drug, other approach treatment with chemotherapy synergists;

(3) local injection contains the slow releasing injection and the slow releasing injection that contains cancer therapy drug of chemical-therapy synergistic agent; Or

(4) local injection contains the slow releasing injection of chemical-therapy synergistic agent and cancer therapy drug.

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

Anticancer effective component chemical-therapy synergistic agent and/or the cancer therapy drug percentage by weight in medicament slow-release microsphere is 0.1%-50%, is good with 1%-40%, and 2%-30% is best.The weight ratio of chemical-therapy synergistic agent and cancer therapy drug is 1-99: 1 to 1: 1-19, with 1-19: 1 to 1: 1-19 serves as preferred.

Anticancer effective component is a kind of or the combination of several chemical-therapy synergistic agents and/or a kind of or several anticarcinogens in the anticancer pharmaceutical composition of the present invention, and the anticancer effective component preferred compositions is as follows:

(1) combination of the Epothilones of the rapamycin of 0.01%-20% and 1-40%, epothilone B, amycin, epirubicin, ametycin, actinomycin D or dactinomycin; Or

(2) combination of the fluorouracil of the rapamycin of 0.01%-20% and 1-40% (5-FU), mercaptopurine, Ismipur, methotrexate, folic acid, calcium levofolinate, calcium folinate, carmofur, ftorafur, UFT, Tegafur-uracil mixt., hycamtin, cytosine arabinoside, ancitabine or hydroxyurea.

Slow-release auxiliary material of the present invention can be through enzyme, soda acid or tissue fluid hydrolysis or degraded, comprises one of following or its combination:

(1) biocompatibility polymer comprises biodegradable or biological nondegradable polymer and composition thereof or copolymer;

(2) water-soluble low-molecular chemical compound; Or/and

(3) be used to realize the suitable additive and the excipient of pharmaceutical dosage forms such as injection and slow releasing agent.

Slow-release auxiliary material can be various water solublity or water-insoluble macromolecule polymer, and slow-release auxiliary material is selected from poly-dl-lactide, poly-dl-lactide/ethanol copolymer, the monomethyl polyethylene glycol, monomethyl polyethylene glycol copolymer, polyethylene glycol, the polyethylene glycol copolymer, end carboxyl polylactic acid, end carboxyl polylactic acid/ethanol copolymer, polifeprosan, bis-fatty acid and decanedioic acid copolymer, poly-(erucic acid dimer-decanedioic acid), poly-(fumaric acid-decanedioic acid), polylactic acid, the copolymer of polyglycolic acid and hydroxyacetic acid, xylitol, oligosaccharide, chrondroitin, chitin, hyaluronic acid, collagen protein, gelatin, chitosan, one of poloxamer and albumin glue or its combination.

Slow-release auxiliary material and percentage by weight thereof are most preferably as follows in the sustained-release micro-spheres of the present invention:

(1) copolymer of the PLA of 50-99% or PLGA or PLA and PLGA or mixture;

(2) copolymer of the Polyethylene Glycol of 50-99% and PLA or PLGA;

(3) polifeprosan of 50-99%;

(4) bis-fatty acid of 55-99% and decanedioic acid copolymer;

(5) PLGA of the PLA of the polifeprosan of 30-60% and 30-60% or 30-60%;

(6) xylitol of 40-95%, oligosaccharide, chrondroitin, chitin, hyaluronic acid, collagen protein, gelatin, chitosan, poloxamer or white tempera; Or

(7) poly-dl-lactide of 40-95%, poly-dl-lactide/ethanol copolymer, monomethyl polyethylene glycol, monomethyl polyethylene glycol copolymer, end carboxyl polylactic acid or end carboxyl polylactic acid/ethanol copolymer.

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.

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 5,000-30,000 for most preferably; The molecular weight of polyglycolic acid can be, but is not limited to, 5000-100, and 000, but with 5,000-50,000 is preferred, with 10,000-30,000 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.Used polylactic acid serves as preferred with Poly-L-lactic acid (L-PLA).Poly-L-lactic acid (L-PLA) range of viscosities IV (dl/g) is 0.2～0.8, and glass transition temperature range is 55～65 ℃, 175～185 ℃ of fusing points.

Except that above-mentioned slow-release auxiliary material, 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.; Also can add other pharmaceutic adjuvant, as but be not limited to filler, solubilizing agent, absorption enhancer, film former, gellant, system (or causing) hole agent, excipient or blocker 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 slow-release auxiliary material 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.Be convenient injection, the viscosity of suspending agent is 100cp-3000cp (20 ℃-30 ℃ time), preferred 1000cp-3000cp (20 ℃-30 ℃ time), most preferably 1500cp-3000cp (20 ℃-30 ℃ time).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 kind of solvent is then depended in the preparation of solvent, and common solvent has commercially available, also can make by oneself, and as distilled water, water for injection, physiology buffer towards liquid, dehydrated alcohol or the preparation of various salt, but must be in strict accordance with related standards.Special solvent need be considered the kind of suspending agent and the medicine that composition, solvent suspended, composition, character and the requirement thereof of sustained-release micro-spheres (or microcapsule) and the preparation method of injection, as sodium carboxymethyl cellulose (1.5%)+mannitol and/or sorbitol (15%) and/or Tween 80 (0.1%) are dissolved in the normal saline corresponding solvent, viscosity is at 10cp-650cp (20 ℃-30 ℃ time).

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 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 the 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, the 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 are first-selection, mixture and copolymer can be selected from, but be not limited to PLA, PLGA, the mixture of PLA and PLGA, the mixture or the copolymer of certain herbaceous plants with big flowers diacid and fragrant polyanhydride or aliphatic polyanhydride, bis-fatty acid and decanedioic acid copolymer (PFAD-SA), poly-(erucic acid dimer-decanedioic acid) [P (EAD-SA)], poly-(fumaric acid-decanedioic acid) [P (FA-SA)].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 weight hundred than 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 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, sphere, bulk, needle-like, bar-shaped, column and membranaceous.In various dosage forms, serve as preferred slowly to discharge implant in the body.Can be the bar-shaped of 0.1-5mm (slightly) * 1-10mm (length), also can be other shapes such as lamellar.

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.Used organic solvent is known, can be, but is not limited to, dehydrated alcohol, acetone, chloroform, dichloromethane.

The anticancer effective component of sustained-release implant is the combination of rapamycin and above-mentioned cancer therapy drug, but is preferably as follows, and all is weight percentage:

Sustained-release micro-spheres also can be used for preparing sustained-release implant, and used slow-release auxiliary material can be any or multiple material in the above-mentioned pharmaceutic adjuvant, is main separation with the high molecular weight water soluble polymer in various high molecular polymers.

Slow-release auxiliary material and percentage by weight thereof are most preferably as follows in the sustained-release implant of the present invention:

(1) copolymer of the PLA of 50-99% or PLGA or PLA and PLGA or mixture;

(2) copolymer of the Polyethylene Glycol of 50-99% and PLA or PLGA;

(3) polifeprosan of 50-99%;

(4) bis-fatty acid of 55-99% and decanedioic acid copolymer;

(5) PLGA of the PLA of the polifeprosan of 30-60% and 30-60% or 30-60%;

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.

The application of sustained-release implant and the same slow-releasing anticarcinogen injection of potentiation mode, the cancer therapy drug that place the associating of the chemical-therapy synergistic agent of the associating of the cancer therapy drug of the promptly local chemical-therapy synergistic agent of placing and other administration, the local cancer therapy drug of placing and other administration, part and the associating of the local chemical-therapy synergistic agent of placing.Wherein the cancer therapy drug of topical application and chemical-therapy synergistic agent can be separately or Joint Production, packing, sale, use.Packing refers to medicine carrying process and pastille slow-release agent the exterior and interior packing for transport and/or store of medicine for adjuvant.The medicine carrying process includes, but not limited to weighing, dissolving, mixing, drying, shaping, coating, spraying, granulation etc.

The present invention can be used to prepare the pharmaceutical preparation of the various tumors for the treatment of people and animal, be mainly slow releasing injection or sustained-release implant, the indication tumor comprises former or cancer or sarcoma or the carcinosarcoma that shifts that originates from brain, central nervous system, kidney, liver, gallbladder, incidence, oral cavity, thyroid, skin, mucosa, body of gland, blood vessel, osseous tissue, lymph node, lungs, esophagus, stomach, mammary gland, pancreas, eyes, nasopharynx part, uterus, ovary, endometrium, cervix uteri, prostate, bladder, colon, rectum.

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 the technology of composition for treating solid tumor of the present invention is further described:

Tumor-inhibiting action in the body of test one, chemical-therapy synergistic agent (rapamycin) and cancer therapy drug.

With the rat is subjects, with 2 * 10 ⁵Individual colon cancer 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 wherein, the 2nd group is chemical-therapy synergistic agent, and the 3rd to 6 group is respectively amycin, epirubicin, ametycin, actinomycin D.The the 7th to 10 group of associating that is respectively chemical-therapy synergistic agent and amycin, epirubicin, ametycin, actinomycin D.Except that chemical-therapy synergistic agent was placed in tumor, amycin, epirubicin, ametycin, actinomycin D were intraperitoneal administration.Except that being 0.5mg/kg, chemical-therapy synergistic agent is 15mg/kg.The treatment back was measured gross tumor volume size, relatively therapeutic effect (seeing Table 1) on the 30th 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	58±12
2(6)	Chemical-therapy synergistic agent	44±10	＜0.05	1(6)	Contrast	58±12
2(6)	Chemical-therapy synergistic agent	44±10	＜0.05	3(6)	Amycin	32±8	＜0.05
4(6)	Epirubicin	46±10	＜0.05	3(6)	Amycin	32±8	＜0.05
4(6)	Epirubicin	46±10	＜0.05	5(6)	Ametycin	44±10	＜0.01
6(6)	Actinomycin D	38±6	＜0.01	5(6)	Ametycin	44±10	＜0.01
6(6)	Actinomycin D	38±6	＜0.01	7(6)	Chemical-therapy synergistic agent+amycin	18±4	＜0.001
8(6)	Chemical-therapy synergistic agent+epirubicin	24±6	＜0.001	7(6)	Chemical-therapy synergistic agent+amycin	18±4	＜0.001
8(6)	Chemical-therapy synergistic agent+epirubicin	24±6	＜0.001	9(6)	Chemical-therapy synergistic agent+ametycin	28±4	＜0.001
10(6)	Chemical-therapy synergistic agent+actinomycin D	26±4	＜0.001	9(6)	Chemical-therapy synergistic agent+ametycin	28±4	＜0.001

Annotate: amycin, epirubicin, ametycin, actinomycin D are antitumor antibiotic.The result shows, compares with matched group, and chemical-therapy synergistic agent (the 2nd group) and antitumor antibiotic (the 3rd to 6 group) application separately all have certain tumor-inhibiting action (P＜0.05), particularly topical.And use in conjunction (the 7th to 10 group) has obvious synergistic effect (P＜0.001).

Tumor-inhibiting action in the body of test two, chemical-therapy synergistic agent (rapamycin) and cancer therapy drug.

Measure tumor-inhibiting action in the body of chemical-therapy synergistic agent and cancer therapy drug according to testing a described method, the result shows that cancer therapy drugs such as epothilone B, amycin, epirubicin, ametycin, actinomycin D or dactinomycin can obviously strengthen the tumor-inhibiting action (P＜0.05) of chemical-therapy synergistic agent.The two uses separately particularly that topical all has certain tumor-inhibiting action (P＜0.05) to cancer of pancreas, and use in conjunction has obvious synergistic effect (P＜0.001).

The tumor-inhibiting action of test three, topical application anti-metabolism cancer therapy drug and chemical-therapy synergistic agent (rapamycin).

With the rat is subjects, with 2 * 10 ⁵Individual breast cancer cell subcutaneous injection is in its hypochondrium, treats that tumor growth after 14 days is divided into it following 10 groups (seeing Table 2).First group is contrast, and the 2nd to 10 group is the treatment group, and wherein, the 2nd group is chemical-therapy synergistic agent, and the 3rd to 6 group is respectively 5-fluorouracil, Ismipur, methotrexate and hycamtin.The the 7th to 10 group of associating that is respectively chemical-therapy synergistic agent and 5-fluorouracil, Ismipur, methotrexate and hycamtin.All medicines are placed in being tumor, and are equal except that chemical-therapy synergistic agent is 0.25mg/kg, and the anti-metabolism cancer therapy drug is 5mg/kg.The treatment back was measured gross tumor volume size, relatively therapeutic effect (seeing Table 2) on the 30th day.

Table 2

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	58±12
2(6)	Chemical-therapy synergistic agent	42±10	＜0.05	1(6)	Contrast	58±12
2(6)	Chemical-therapy synergistic agent	42±10	＜0.05	3(6)	5-fluorouracil	42±10	＜0.01
4(6)	Ismipur	42±8	＜0.01	3(6)	5-fluorouracil	42±10	＜0.01
4(6)	Ismipur	42±8	＜0.01	5(6)	Methotrexate	38±8	＜0.01
6(6)	Hycamtin	38±8	＜0.01	5(6)	Methotrexate	38±8	＜0.01
6(6)	Hycamtin	38±8	＜0.01	7(6)	Chemical-therapy synergistic agent+5-fluorouracil	20±4.6	＜0.001
8(6)	Chemical-therapy synergistic agent+Ismipur	20±4.2	＜0.001	7(6)	Chemical-therapy synergistic agent+5-fluorouracil	20±4.6	＜0.001
8(6)	Chemical-therapy synergistic agent+Ismipur	20±4.2	＜0.001	9(6)	Chemical-therapy synergistic agent+methotrexate	26±4	＜0.001
10(6)	Chemical-therapy synergistic agent+hycamtin	24±3	＜0.001	9(6)	Chemical-therapy synergistic agent+methotrexate	26±4	＜0.001

Annotate: 5-fluorouracil, Ismipur, methotrexate and hycamtin are the anti-metabolism cancer therapy drug.The result shows, compares with matched group, and chemical-therapy synergistic agent (the 2nd group) and anti-metabolism cancer therapy drug (the 3rd to 6 group) application separately all have certain tumor-inhibiting action (P＜0.05).Yet use in conjunction (the 7th to 10 group) has obvious synergistic effect (P＜0.001).

Tumor-inhibiting action in the body of test four, chemical-therapy synergistic agent (rapamycin) and anti-metabolism cancer therapy drug.

Detected tumor-inhibiting action in the body of chemical-therapy synergistic agent and anti-metabolism cancer therapy drug according to test three method.The result shows chemical-therapy synergistic agent and is selected from fluorouracil, Ismipur, methotrexate that the anti-metabolism cancer therapy drug of fluoromethotrexate, dioxy methotrexate, calcium levofolinate, calcium folinate, carmofur, ftorafur, UFT, topotecan, cytosine arabinoside, ancitabine, ancitabine, hydroxyurea, hydroxyl guanidine is used separately all has obvious tumor-inhibiting action (P＜0.05) to colon cancer.And use in conjunction has obvious synergistic effect (P＜0.001).

Tumor-inhibiting action in the body of test five, chemical-therapy synergistic agent (rapamycin) and anti-metabolism cancer therapy drug.

With the rat is subjects, with 2 * 10 ⁵Individual ovarian cancer cell subcutaneous injection is in its hypochondrium, treats that tumor growth after 14 days is divided into it following 10 groups (seeing Table 3).The 1st group is contrast, and the 2nd to 10 group is the treatment group, and wherein, the 2nd group is chemical-therapy synergistic agent; The the 3rd to 6 group is respectively the antimetabolic anticarcinoma agent thing.The the 7th to 10 group of associating that is respectively chemical-therapy synergistic agent and different antimetabolic anticarcinoma agent things.Except that chemical-therapy synergistic agent was placed in tumor, carmofur, ftorafur, UFT and topotecan hydrochloride were intraperitoneal administration.Except that being 5mg/kg, chemical-therapy synergistic agent is 5mg/kg.The treatment back was measured gross tumor volume size, relatively therapeutic effect (seeing Table 3) on the 30th 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	56±10
2(6)	Chemical-therapy synergistic agent	44±5	＜0.05	1(6)	Contrast	56±10
2(6)	Chemical-therapy synergistic agent	44±5	＜0.05	3(6)	Carmofur	44±8	＜0.01
4(6)	Ftorafur	42±8	＜0.01	3(6)	Carmofur	44±8	＜0.01
4(6)	Ftorafur	42±8	＜0.01	5(6)	UFT	42±9	＜0.01
6(6)	Topotecan hydrochloride	42±6	＜0.01	5(6)	UFT	42±9	＜0.01
6(6)	Topotecan hydrochloride	42±6	＜0.01	7(6)	Chemical-therapy synergistic agent+carmofur	28±3.2	＜0.001
8(6)	Chemical-therapy synergistic agent+ftorafur	22±3.2	＜0.001	7(6)	Chemical-therapy synergistic agent+carmofur	28±3.2	＜0.001
8(6)	Chemical-therapy synergistic agent+ftorafur	22±3.2	＜0.001	9(6)	Chemical-therapy synergistic agent+UFT	20±3.0	＜0.001
10(6)	Chemical-therapy synergistic agent+topotecan hydrochloride	18±3.0	＜0.001	9(6)	Chemical-therapy synergistic agent+UFT	20±3.0	＜0.001

Annotate: carmofur, ftorafur, UFT and topotecan hydrochloride are the anti-metabolism cancer therapy drug.

Tumor-inhibiting action in the body of test six, chemical-therapy synergistic agent (rapamycin) and anti-metabolism cancer therapy drug.

With the rat is subjects, with 2 * 10 ⁵Individual lung carcinoma cell subcutaneous injection is in its hypochondrium, treats that tumor growth after 14 days is divided into it following 10 groups (seeing Table 4).The 1st group is contrast, and the 2nd to 10 group is the treatment group, and wherein, the 2nd group is chemical-therapy synergistic agent; The the 3rd to 6 group is respectively the anti-metabolism cancer therapy drug.The the 7th to 10 group of associating that is respectively chemical-therapy synergistic agent and different anti-metabolism cancer therapy drugs.Except that chemical-therapy synergistic agent was placed in tumor, carmofur, ftorafur, 8-azaguanine and cytosine arabinoside were intraperitoneal administration.Except that being 4mg/kg, chemical-therapy synergistic agent is 16mg/kg.The treatment back was measured gross tumor volume size, relatively therapeutic effect (seeing Table 4) on the 30th day.

Table 4

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	62±14
2(6)	Chemical-therapy synergistic agent	50±10	＜0.05	1(6)	Contrast	62±14
2(6)	Chemical-therapy synergistic agent	50±10	＜0.05	3(6)	Carmofur	46±6.3	＜0.05
4(6)	Ftorafur	48±6.0	＜0.05	3(6)	Carmofur	46±6.3	＜0.05
4(6)	Ftorafur	48±6.0	＜0.05	5(6)	The 8-azaguanine	42±6.4	＜0.05
6(6)	Cytosine arabinoside	40±4.8	＜0.05	5(6)	The 8-azaguanine	42±6.4	＜0.05
6(6)	Cytosine arabinoside	40±4.8	＜0.05	7(6)	Chemical-therapy synergistic agent+carmofur	28±2.8	＜0.001
8(6)	Chemical-therapy synergistic agent+ftorafur	26±3.6	＜0.001	7(6)	Chemical-therapy synergistic agent+carmofur	28±2.8	＜0.001
8(6)	Chemical-therapy synergistic agent+ftorafur	26±3.6	＜0.001	9(6)	Chemical-therapy synergistic agent+8-azaguanine	18±2.0	＜0.001
10(6)	Chemical-therapy synergistic agent+cytosine arabinoside	14±2.0	＜0.001	9(6)	Chemical-therapy synergistic agent+8-azaguanine	18±2.0	＜0.001

Annotate: carmofur, ftorafur, 8-azaguanine and cytosine arabinoside are the anti-metabolism cancer therapy drug.

Tumor-inhibiting action in the body of test seven, chemical-therapy synergistic agent (rapamycin) and cancer therapy drug.

With the rat is subjects, with 2 * 10 ⁵Individual gastric cancer tumor cell subcutaneous injection is in its hypochondrium, treats that tumor growth after 14 days is divided into it following 10 groups (seeing Table 5).First group is contrast, and the 2nd to 10 group is the treatment group, and wherein, the 2nd group is chemical-therapy synergistic agent, and the 3rd to 6 group is respectively amycin, epirubicin, ametycin, actinomycin D.The the 7th to 10 group of associating that is respectively chemical-therapy synergistic agent and amycin, epirubicin, ametycin, actinomycin D.Except that chemical-therapy synergistic agent was placed in tumor, amycin, epirubicin, ametycin, actinomycin D were intraperitoneal administration.Except that being 2.5mg/kg, chemical-therapy synergistic agent is 15mg/kg.The treatment back was measured gross tumor volume size, relatively therapeutic effect (seeing Table 5) on the 30th day.

Table 5

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	56±12
2(6)	Chemical-therapy synergistic agent	46±10	＜0.05	1(6)	Contrast	56±12
2(6)	Chemical-therapy synergistic agent	46±10	＜0.05	3(6)	Amycin	42±8	＜0.05
4(6)	Epothilone B	50±10	＜0.05	3(6)	Amycin	42±8	＜0.05
4(6)	Epothilone B	50±10	＜0.05	5(6)	Ametycin	44±10	＜0.01
6(6)	Actinomycin D	38±6	＜0.01	5(6)	Ametycin	44±10	＜0.01
6(6)	Actinomycin D	38±6	＜0.01	7(6)	Chemical-therapy synergistic agent+amycin	26±4	＜0.001
8(6)	Chemical-therapy synergistic agent+epothilone B	24±6	＜0.001	7(6)	Chemical-therapy synergistic agent+amycin	26±4	＜0.001
8(6)	Chemical-therapy synergistic agent+epothilone B	24±6	＜0.001	9(6)	Chemical-therapy synergistic agent+ametycin	20±4	＜0.001
10(6)	Chemical-therapy synergistic agent+actinomycin D	18±4	＜0.001	9(6)	Chemical-therapy synergistic agent+ametycin	20±4	＜0.001

The tumor-inhibiting action of test eight, topical application anti-metabolism cancer therapy drug and chemical-therapy synergistic agent (rapamycin).

With the rat is subjects, with 2 * 10 ⁵Individual hepatoma carcinoma cell subcutaneous injection is in its hypochondrium, treats that tumor growth after 14 days is divided into it following 10 groups (seeing Table 6).First group is contrast, and the 2nd to 10 group is the treatment group, and wherein, the 2nd group is chemical-therapy synergistic agent, and the 3rd to 6 group is respectively 5-fluorouracil, Ismipur, methotrexate and hycamtin.The the 7th to 10 group of associating that is respectively chemical-therapy synergistic agent and 5-fluorouracil, Ismipur, methotrexate and hycamtin.All medicines are placed in being tumor, and are equal except that chemical-therapy synergistic agent is 2.5mg/kg, and the anti-metabolism cancer therapy drug is 17.5mg/kg.The treatment back was measured gross tumor volume size, relatively therapeutic effect (seeing Table 6) on the 30th day.

Table 6

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	58±12
2(6)	Chemical-therapy synergistic agent	48±10	＜0.05	1(6)	Contrast	58±12
2(6)	Chemical-therapy synergistic agent	48±10	＜0.05	3(6)	5-fluorouracil	38±10	＜0.01
4(6)	Ismipur	40±8	＜0.01	3(6)	5-fluorouracil	38±10	＜0.01
4(6)	Ismipur	40±8	＜0.01	5(6)	Methotrexate	38±8	＜0.01
6(6)	Hycamtin	36±8	＜0.01	5(6)	Methotrexate	38±8	＜0.01
6(6)	Hycamtin	36±8	＜0.01	7(6)	Chemical-therapy synergistic agent+5-fluorouracil	22±4.6	＜0.001
8(6)	Chemical-therapy synergistic agent+Ismipur	20±4.2	＜0.001	7(6)	Chemical-therapy synergistic agent+5-fluorouracil	22±4.6	＜0.001
8(6)	Chemical-therapy synergistic agent+Ismipur	20±4.2	＜0.001	9(6)	Chemical-therapy synergistic agent+methotrexate	16±4	＜0.001
10(6)	Chemical-therapy synergistic agent+hycamtin	14±3	＜0.001	9(6)	Chemical-therapy synergistic agent+methotrexate	16±4	＜0.001

Similar potentiation also sees the associating of other chemical-therapy synergistic agent and other anti-metabolism cancer therapy drug, as: fluorouracil, Ismipur, methotrexate, fluoromethotrexate, calcium levofolinate, calcium folinate, carmofur, ftorafur, UFT, hycamtin, topotecan hydrochloride, cytosine arabinoside, ancitabine, ancitabine, anti-metabolism cancer therapy drug and gefitinibs such as hydroxyurea or hydroxyl guanidine, Erlotinib, Lapatinib, votaranib, WAY-EKB 569, NSC 609974, thalidomide, LS-2616, angiostatin, the combination of Endostatin or blood vessel endothelium chalone, and epothilone B, amycin, epirubicin, ametycin, antibiotics such as actinomycin D or dactinomycin cancer therapy drug and imatinib mesylate, Sugen 5416, BMS 354825, Avastin, Cl 1033, Sorafenib, Sutent, TLK286, the combination of ABX-EGF or Marimastat.The tumor cell that tries comprises the cerebral tumor (CNS-1, C6,9L), gastric gland epithelial cancer (SA), bone tumor (BC), breast carcinoma (BA), papillary adenocarcinoma of thyroid (PAT), hepatocarcinoma, cancer of pancreas, renal carcinoma and the esophageal carcinoma etc.

Release ratio in the body of the chemical-therapy synergistic agent sustained-release implant that test nine, different molecular weight polylactic acid are made

With the rat is subjects, grouping (3/group) and the equivalent chemical-therapy synergistic agent sustained-release implant that carries in the subcutaneous polylactic acid (PLA) that contains different molecular weight (MW).Survey the surplus of medicine in implant respectively at 1,3,7,14,21,28 and 35 day then, and then draw rate of release (%) in its body.The result shows, molecular weight is 20000 is released to: 1 day (8%), 3 (28%), 7 (56%), 14 (82%), 21 (90), 28 (94) and 35 (98%).Discharge in the body of chemical-therapy synergistic agent (rapamycin) sustained-release implant that comparison different molecular weight polylactic acid is made and find, slack-off with the molecular weight increase, with the 7th day was example, compare with whole body administration group, tumor control rate increases with the polylactic acid molecule amount and improves, and is followed successively by 72% (MW:5000), 68% (MW:15000), 56% (MW:25000), 52% (MW:40000) and 46 (MW:60000).

The tumor-inhibiting action of test ten, topical application anti-metabolism cancer therapy drug and chemical-therapy synergistic agent (rapamycin).

With the rat is subjects, with 2 * 10 ⁵Individual esophageal cancer cell subcutaneous injection is in its hypochondrium, treats that tumor growth after 14 days is divided into it following 10 groups (seeing Table 7).First group is contrast, and the 2nd to 10 group is the treatment group, and wherein, the 2nd group is chemical-therapy synergistic agent, and the 3rd to 6 group is respectively 5-fluorouracil, epothilone B, methotrexate and hycamtin.The the 7th to 10 group of associating that is respectively chemical-therapy synergistic agent and 5-fluorouracil, epothilone B, methotrexate and hycamtin.All medicines are placed in being tumor, and are equal except that chemical-therapy synergistic agent is 2.5mg/kg, and the anti-metabolism cancer therapy drug is 17.5mg/kg.The treatment back was measured gross tumor volume size, relatively therapeutic effect (seeing Table 7) on the 30th day.

Table 7

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	56±12
2(6)	Chemical-therapy synergistic agent	48±10	＜0.05	1(6)	Contrast	56±12
2(6)	Chemical-therapy synergistic agent	48±10	＜0.05	3(6)	5-fluorouracil	38±10	＜0.01
4(6)	Epothilones	40±8	＜0.01	3(6)	5-fluorouracil	38±10	＜0.01
4(6)	Epothilones	40±8	＜0.01	5(6)	Methotrexate	38±8	＜0.01
6(6)	Hycamtin	36±8	＜0.01	5(6)	Methotrexate	38±8	＜0.01
6(6)	Hycamtin	36±8	＜0.01	7(6)	Chemical-therapy synergistic agent+5-fluorouracil	22±4.6	＜0.001
8(6)	Chemical-therapy synergistic agent+Epothilones	14±2.2	＜0.001	7(6)	Chemical-therapy synergistic agent+5-fluorouracil	22±4.6	＜0.001
8(6)	Chemical-therapy synergistic agent+Epothilones	14±2.2	＜0.001	9(6)	Chemical-therapy synergistic agent+methotrexate	16±4	＜0.001
10(6)	Chemical-therapy synergistic agent+hycamtin	18±4	＜0.001	9(6)	Chemical-therapy synergistic agent+methotrexate	16±4	＜0.001

Annotate: 5-fluorouracil, Epothilones, methotrexate and hycamtin are the anti-metabolism cancer therapy drug.The result shows, compares with matched group, and chemical-therapy synergistic agent (the 2nd group) and anti-metabolism cancer therapy drug (the 3rd to 6 group) application separately all have certain tumor-inhibiting action (P＜0.05).Yet use in conjunction (the 7th to 10 group) has obvious synergistic effect (P＜0.001).

Test 11, the tumor-inhibiting action of topical application anti-metabolism cancer therapy drug and rapamycin.

With the rat is subjects, with 2 * 10 ⁵Individual esophageal cancer cell subcutaneous injection is in its hypochondrium, treats that tumor growth after 14 days is divided into it following 10 groups (seeing Table 8).First group is contrast, and the 2nd to 10 group is the treatment group, and wherein, the 2nd group is rapamycin, and the 3rd to 6 group is respectively 5-fluorouracil, epothilone B, methotrexate and hycamtin.The the 7th to 10 group of associating that is respectively chemical-therapy synergistic agent (rapamycin) and 5-fluorouracil, epothilone B, methotrexate and hycamtin.All medicines are placed in being tumor, and are equal except that chemical-therapy synergistic agent is 5mg/kg, and the anti-metabolism cancer therapy drug is 15mg/kg.The treatment back was measured gross tumor volume size, relatively therapeutic effect (seeing Table 8) on the 30th day.

Table 8

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	54±10
2(6)	Chemical-therapy synergistic agent	46±80	＜0.05	1(6)	Contrast	54±10
2(6)	Chemical-therapy synergistic agent	46±80	＜0.05	3(6)	5-fluorouracil	38±10	＜0.01
4(6)	Epothilone B	44±8	＜0.01	3(6)	5-fluorouracil	38±10	＜0.01
4(6)	Epothilone B	44±8	＜0.01	5(6)	Methotrexate	34±8	＜0.01
6(6)	Hycamtin	34±8	＜0.01	5(6)	Methotrexate	34±8	＜0.01
6(6)	Hycamtin	34±8	＜0.01	7(6)	Chemical-therapy synergistic agent+5-fluorouracil	22±4.6	＜0.001
8(6)	Chemical-therapy synergistic agent+Epothilones	14±2.2	＜0.001	7(6)	Chemical-therapy synergistic agent+5-fluorouracil	22±4.6	＜0.001
8(6)	Chemical-therapy synergistic agent+Epothilones	14±2.2	＜0.001	9(6)	Chemical-therapy synergistic agent+methotrexate	20±4	＜0.001
10(6)	Chemical-therapy synergistic agent+hycamtin	18±4	＜0.001	9(6)	Chemical-therapy synergistic agent+methotrexate	20±4	＜0.001

Annotate: 5-fluorouracil, epothilone B, methotrexate and hycamtin are the anti-metabolism cancer therapy drug.The result shows, compares with matched group, and chemical-therapy synergistic agent (the 2nd group) and anti-metabolism cancer therapy drug (the 3rd to 6 group) application separately all have certain tumor-inhibiting action (P＜0.05).Yet use in conjunction (the 7th to 10 group) has obvious synergistic effect (P＜0.001).

It is the slow releasing agent that adjuvant is made that same result also sees with polylactic acid, comprise fluorouracil, mercaptopurine, Ismipur, methotrexate, folic acid, calcium folinate, carmofur, ftorafur, UFT, Tegafur-uracil mixt., the 8-azaguanine, hycamtin, topotecan hydrochloride, cytosine arabinoside, the combination of anti-metabolism cancer therapy drugs such as hydroxyurea or hydroxyl guanidine and chemical-therapy synergistic agent, and Epothilones, epothilone B, amycin, epirubicin, ametycin, the combination of antibiotics such as actinomycin D or dactinomycin cancer therapy drug and chemical-therapy synergistic agent.

That pays special attention to is simple to operation, the good reproducibility of slow releasing agent of the present invention, particularly slow releasing injection.Good effect not only, toxic and side effects is little.

Different drug packages is different with the drug release feature of different Biodegradable high moleculars.Discover that further the slow-release auxiliary material that is most appropriate to medicament slow release of the present invention is a poly-dl-lactide, poly-dl-lactide/ethanol copolymer, the monomethyl polyethylene glycol, monomethyl polyethylene glycol copolymer, polyethylene glycol, the polyethylene glycol copolymer, end carboxyl polylactic acid, end carboxyl polylactic acid/ethanol copolymer, polifeprosan, bis-fatty acid and decanedioic acid copolymer, poly-(erucic acid dimer-decanedioic acid), poly-(fumaric acid-decanedioic acid), polylactic acid, the copolymer of polyglycolic acid and hydroxyacetic acid, xylitol, oligosaccharide, chrondroitin, chitin, hyaluronic acid, collagen protein, gelatin, chitosan, poloxamer, one of albumin glue or its combination; Optimum suspending agent is one of methylcellulose, hydroxy methocel, sodium carboxymethyl cellulose, (iodine) glycerol, simethicone, propylene glycol, carbomer, mannitol, sorbitol, surfactant, soil temperature 20, soil temperature 40, soil temperature 80 or its combination.

In a word, experimental result shows that chemical-therapy synergistic agent among the present invention is to the potentiation of listed anti-metabolism cancer therapy drug or antibiotics cancer therapy drug.Therefore, the effective ingredient of anticancer compound of the present invention is the associating of chemical-therapy synergistic agent and any one (or multiple) anti-metabolism cancer therapy drug or antibiotics cancer therapy drug or packs separately.Above effective ingredient can be made into any dosage form or shape, but serves as preferred with the agent for slow releasing type, is mainly slow releasing injection or sustained-release implant.

(4) specific embodiment

Embodiment 1.

With 90mg molecular weight peak value is that the polylactic acid (PLGA, 50: 50) of 25000-40000 is put into container, adds 100 milliliters of dichloromethane, behind the dissolving mixing, adds 2mg rapamycin and 8mg methotrexate, shakes up the dry organic solvent of removing of final vacuum again.Dried solid composite is shaped immediately, and ray sterilizing after the packing must contain the anticancer slow-release of 2% rapamycin and 8% methotrexate.All be weight percentage.The drug release time of this entity-tumor-resistant medicine composition in external normal saline is 15-25 days, is 25-50 days at the subcutaneous drug release time of mice.

Embodiment 2.

As described in embodiment 1, the molecular weight peak value of different is polylactic acid is 35000-60000 (PLGA, 75: 25), and anticancer effective component and percentage by weight are one of following:

(1) combination of the Epothilones of the rapamycin of 0.01-5% and 5-20%, epothilone B, amycin, epirubicin, ametycin, actinomycin D or dactinomycin; Or

(2) fluorouracil of the rapamycin of 0.01-5% and 5-20%, Ismipur, methotrexate, the combination of fluoromethotrexate, calcium levofolinate, calcium folinate, carmofur, ftorafur, UFT, hycamtin, topotecan hydrochloride, cytosine arabinoside, ancitabine or hydroxyurea.

Embodiment 3.

80mg polifeprosan (to carboxy phenyl propane (p-CPP): decanedioic acid (SA) is 20: 80) copolymer is put into container, add the 100ml dichloromethane, behind the dissolving mixing, add 1mg rapamycin and 19mg fluorouracil, shake up the back contains 1% rapamycin and 19% fluorouracil 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, viscosity is 20cp-300cp (20 ℃-30 ℃ time).The drug release time of this slow releasing injection in external normal saline is 15-25 days, is about 30-40 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: the combination of the rapamycin of 5-20% and the fluorouracil of 5-25%; Used slow-release auxiliary material is: polifeprosan (50: 50), poly-dl-lactide (the molecular weight peak value is 20000-60000), PLGA (75: 25 or 50: 50), poly-dl-lactide/ethanol copolymer, monomethyl polyethylene glycol, monomethyl polyethylene glycol copolymer, polyethylene glycol, polyethylene glycol copolymer, end carboxyl polylactic acid or end carboxyl polylactic acid/ethanol copolymer.The viscosity of slow releasing injection is 200cp-600cp (20 ℃-30 ℃ time).

Embodiment 5.

With 70mg molecular weight peak value is that the polylactic acid (PLA) of 20000-60000 is put into container, adds 100 milliliters of dichloromethane, behind the dissolving mixing, adds 15mg amycin and 15mg rapamycin, shakes up the dry organic solvent of removing of final vacuum again.Dried pastille solid composite freezing and pulverizing is made the micropowder that contains 15% amycin and 15% rapamycin, be suspended in then in the normal saline that contains 1.5% sodium carboxymethyl cellulose, make corresponding suspension type slow releasing injection, viscosity is 200cp-360cp (20 ℃-30 ℃ time).The drug release time of this slow releasing injection in external normal saline is 20-25 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 the molecular weight peak value is the polylactic acid of 10000-20000, and contained anticancer effective component and percentage by weight thereof are:

The combination of (1) 5% Epothilones, epothilone B, amycin, epirubicin, ametycin or actinomycin D and 10% rapamycin;

(2) 10% Epothilones, epothilone B, amycin or epirubicin and 10% the mould combination of thunder handkerchief;

The combination of (3) 15% ametycin or actinomycin D and 5% rapamycin;

The combination of (4) 25% amycin, epirubicin, ametycin or actinomycin D and 1% rapamycin.

The viscosity of injection is 10cp-650cp (20 ℃-30 ℃ time).

Embodiment 7.

With 30mg polifeprosan (to carboxy phenyl propane (p-CPP): decanedioic acid (SA) is 20: 80) and 40mg molecular weight peak value is that the polylactic acid (PLA) of 20000-40000 is put into container, add 100 milliliters of dichloromethane, behind the dissolving mixing, add 25mg epirubicin and 5mg rapamycin, shake up the back contains 25% epirubicin and 5% rapamycin 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, viscosity is 120cp-280cp (25 ℃-30 ℃ time).The drug release time of this slow releasing injection in external normal saline is 18-25 days, is about 30-35 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 used adjuvant is 50mg polifeprosan (to carboxy phenyl propane (p-CPP): decanedioic acid (SA) is 40: 60) and 30mg molecular weight peak value are the polylactic acid (PLA) of 10000-20000, contain anticancer effective component and are: the combination of the rapamycin of 0.1-10% and the Epothilones of 1-19%, epothilone B, amycin, epirubicin, ametycin, actinomycin D or dactinomycin; The slow releasing injection viscosity is 440cp-650cp (25 ℃-30 ℃ time).

Embodiment 9

With 40mg polifeprosan (50: 50) and 40mg molecular weight peak value is the polylactic acid (PLGA of 20000-40000,50: 50) put into container, add 100 milliliters of dichloromethane, behind the dissolving mixing, add 7.5mg Epothilones and 12.5mg lysozyme, shake up the back contains 7.5% Epothilones and 12.5% rapamycin with spray drying method for preparation 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, viscosity is 100cp-160cp (25 ℃-30 ℃ time).The drug release time of this slow releasing injection in external normal saline is 20-25 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 used adjuvant is 30mg polifeprosan (to carboxy phenyl propane (p-CPP): decanedioic acid (SA) is 40: 60) and 50mg molecular weight peak value are the polylactic acid (PLGA of 20000-40000,75: 25), contained anticancer effective component is: the combination of the rapamycin of the Epothilones of 1-15%, epothilone B, amycin, epirubicin, ametycin, actinomycin D or dactinomycin and 1-5%; Viscosity is 560cp-640cp (25 ℃-30 ℃ time).

Embodiment 11

With 50mg molecular weight peak value is that the PLGA (75: 25) of 10000-20000 and PLA that 40mg molecular weight peak value is 20000-40000 put into container, add 100 milliliters of dichloromethane, behind the dissolving mixing, add 8mg amycin and 2mg rapamycin, shake up the back contains 8% amycin and 2% rapamycin 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 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 used slow-release auxiliary material is: the monomethyl polyethylene glycol of 60-95%, monomethyl polyethylene glycol copolymer, polyethylene glycol or polyethylene glycol copolymer, contained anticancer effective component is: the combination of 10% amycin, Epothilones, epothilone B and 5-20% rapamycin.

Embodiment 13

70 parts of bis-fatty acids and decanedioic acid copolymer (PFAD-SA) are put into container, after adding an amount of dichloromethane dissolving mixing, add 10 parts of Epothilones and 20 parts of rapamycins, shake up the back contains 10% Epothilones and 20% rapamycin 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 15-20 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 used adjuvant is poly-(erucic acid dimer-decanedioic acid) [P (EAD-SA)] or poly-(fumaric acid-decanedioic acid) [P (FA-SA)], contains anticancer effective component and percentage by weight to be:

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) polylactic acid (PLA), the molecular weight peak value is 10000-30000,300000-60000,60000-100000 or 100000-150000;

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

C) mixture or the copolymer of polylactic acid (PLA) and PLGA;

D) polifeprosan, to carboxy phenyl propane (p-CPP): decanedioic acid (SA) is 10: 90,20: 80,30: 70,40: 60,50: 50 or 60: 40;

E) bis-fatty acid and decanedioic acid copolymer (PFAD-SA);

F) poly-(erucic acid dimer-decanedioic acid) [P (EAD-SA)];

G) poly-(fumaric acid-decanedioic acid) [P (FA-SA)];

H) xylitol, oligosaccharide, chrondroitin, chitin, hyaluronic acid, collagen protein, gelatin, chitosan, poloxamer or white tempera;

I) poly-dl-lactide, poly-dl-lactide/ethanol copolymer, monomethyl polyethylene glycol, monomethyl polyethylene glycol copolymer, polyethylene glycol, polyethylene glycol copolymer, end carboxyl polylactic acid or end carboxyl polylactic acid/ethanol copolymer.

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.

Embodiment 17.

The polylactic acid (PLA) that 70 parts of molecular weight peak values are 20000-60000 is put into container, add an amount of dichloromethane, add 25 portions of fluorouracil and 5 parts of rapamycins behind the dissolving mixing, shake up the dry organic solvent of removing of final vacuum again.Dried pastille solid composite freezing and pulverizing is made the micropowder that contains 25% fluorouracil and 5% rapamycin, be suspended in then in the normal saline that contains 1.5% sodium carboxymethyl cellulose, make corresponding suspension type slow releasing injection, viscosity is 220cp-340cp (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 18

The method step that is processed into slow releasing injection is identical with embodiment 5, but different is that contained anticancer effective component and percentage by weight thereof are:

(1) combination of the Epothilones of the rapamycin of 0.1%-20% and 1-40%, epothilone B, amycin, epirubicin, ametycin, actinomycin D or dactinomycin; Or

(2) combination of the fluorouracil of the rapamycin of 0.1%-20% and 1-40%, mercaptopurine, Ismipur, methotrexate, folic acid, calcium levofolinate, calcium folinate, carmofur, ftorafur, UFT, Tegafur-uracil mixt., hycamtin, cytosine arabinoside, ancitabine or hydroxyurea.

The viscosity of injection is 200cp-650cp (20 ℃-30 ℃ time).

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.

Above result shows that the chemical-therapy synergistic agent that the present invention is used and the combination and the consequent anticancer synergia effect of its cancer therapy drug are of universal significance, and is to be used for various entity tumors.Dosage when therefore, chemical-therapy synergistic agent and its cancer therapy drug are united is selected and can be released according to relevant data of the present invention.

The foregoing description has been done further description to technical method of the present invention.Be to illustrate for example rather than will limit scope of the present invention.In fact, except that shown in this paper and the of the present invention various changes described, to those skilled in the art all can be from description and chart apparent.Certainly these changes should be in the scope of appended claim.Therefore, to disclose some specific implementations of the present invention emphatically and its being equal to of making is changed or replaces all be in described design of appended claims and scope to the description that should be realized that the front.

Claims

1. a controlled release formulation for anti entity tumour that contains chemotherapeutics and synergist thereof is characterized in that chemotherapeutics is selected from antitumor antibiotics and/or antimetabolitas, and synergist is a rapamycin.

2. the controlled release formulation for anti entity tumour according to claim 1 is characterized in that controlled release formulation for anti entity tumour is a slow releasing injection, is grouped into by following one-tenth:

(A) sustained-release micro-spheres comprises:

Anticancer effective component 0.01-60%

Slow-release auxiliary material 41-99.99%

Suspending agent 0.0-30%

More than be weight percentage

With

Wherein,

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, and the viscosity of suspending agent is 100cp 3000cp (20 ℃ 30 ℃ time).

3. the slow releasing injection according to claim 2 is characterized in that used suspending agent is selected from 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.

4. the controlled release formulation for anti entity tumour according to claim 1 is characterized in that controlled release formulation for anti entity tumour is a sustained-release implant, is made up of anticancer effective component and slow-release auxiliary material.

5. the slow releasing agent according to claim 1 is characterized in that described antitumor antibiotics is selected from Epothilones, epothilone B, amycin, epirubicin, ametycin, actinomycin D, dactinomycin and salt thereof.

6. the slow releasing agent according to claim 1 is characterized in that described anti-metabolism cancer therapy drug is selected from floxuridine, doxifluridine, 5-doxifluridine, propylthiouracil, fluorouracil, Ismipur, methotrexate, folic acid, carmofur, ftorafur, UFT, Tegafur-uracil mixt., 8-azaguanine, hycamtin, topotecan hydrochloride, cytosine arabinoside, ancitabine, ancitabine, hydroxyurea, hydroxyl guanidine and salt thereof.

7. the slow releasing agent according to claim 1 is characterized in that anticancer effective component is one of following:

8. the anticancer sustained-release agent according to claim 1 is characterized in that described slow-release auxiliary material is selected from one of following or its combination:

(1) copolymer of PLA or PLGA or PLA and PLGA or mixture;

(2) copolymer of Polyethylene Glycol and PLA or PLGA;

(3) polifeprosan;

(4) bis-fatty acid and decanedioic acid copolymer;

(5) combination of polifeprosan and PLA or PLGA;

(6) xylitol, oligosaccharide, chrondroitin, chitin, hyaluronic acid, collagen protein, gelatin, chitosan, poloxamer or white tempera; Or

(7) poly-dl-lactide, poly-dl-lactide/ethanol copolymer, monomethyl polyethylene glycol, monomethyl polyethylene glycol copolymer, end carboxyl polylactic acid or end carboxyl polylactic acid/ethanol copolymer.

9. the anticancer sustained-release agent according to claim 1 is characterized in that described slow-release auxiliary material is selected from one of following or its combination:

A) the molecular weight peak value of polylactic acid is 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: decanedioic acid is 10: 90,20: 80,30: 70,40: 60,50: 50 or 60: 40.

10. the anticancer sustained-release agent according to claim 1, it is characterized in that described slow releasing agent is used to prepare the slow releasing agent that treatment originates from cancer, sarcoma or the carcinosarcoma of people and animal brain, central nervous system, kidney, liver, gallbladder, incidence, oral cavity, thyroid, skin, mucosa, body of gland, blood vessel, osseous tissue, lymph node, lungs, esophagus, stomach, mammary gland, pancreas, eyes, nasopharynx part, uterus, ovary, endometrium, cervix uteri, prostate, bladder, colon or rectum former or secondary, in tumor or tumor week injection or place administration.