CN101416938A

CN101416938A - Slow-released injection containing nolatrexed dihydrochloride and synergist thereof

Info

Publication number: CN101416938A
Application number: CNA2008103014829A
Authority: CN
Inventors: 孔庆忠; 孙娟; 贺润萍; 张志霞
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: 2009-04-29

Abstract

The invention relates to a slow-release injection containing nolatrexed and a synergistic agent of the nolatrexed, which consists of a slow-release microballoon sphere and a solution medium, wherein, the slow-release microballoon sphere comprises active anti-cancer ingredients and slow-release accessories; and the solution medium is a special solution medium containing a suspending agent. The active anti-cancer ingredients are antimetabolites, such as pemetrexed, rumitrexed, raltitrexed, nolatrexed, carmofur, dexrazoxane, tegafur, zalcitabine, emtricitabine, ibatabine, ancitabine, decitabine, flurocitabine, enocitabine, imidazoletabine, capecitabine, gemcitabine, fludarabine or cladribine, and the like, and synergistic agents of the antimetabolites selected from topoisomerase inhibitors and/or tetrazine compounds; the slow-release accessories are selected from one of polifeprosan, di-fatty acid and decanedioic acid copolymer, polylactic acid copolymer and EVAC or the combination thereof; the viscosity of the suspending agent is 100cp to 3000cp (at the temperature of 20 DEG C to 30 DEG C) and the suspending agent is selected from carboxymethylcellulose sodium and the like. The slow-release microballoon sphere can also be prepared into a slow-release implant used for being injected or put in tumors or the surrounding of the tumors so as to enhance the effects of radiotherapy and chemotherapy.

Description

The slow releasing injection that contains 2-Amino-6-methyl-5-(pyridin-4-ylsulfanyl)-3H-quinazolin-4-one and synergist thereof

(1) technical field

The present invention relates to a kind of slow releasing injection that contains antimetabolite and/or its synergist and preparation method thereof, belong to technical field of pharmaceuticals.

(2) background technology

As a kind of chemotherapeutics commonly used, antimetabolite has been widely used in the treatment of multiple malignant tumor.Yet its beat all toxic reaction and chemical sproof generation have greatly limited the application of such medicine medicine.Because blood vessel, connective tissue, stromatin, fibrin and collagen protein etc. in the mesenchyma stroma of tumors not only provide support and requisite nutrient substance for the growth of tumor cell, also influenced chemotherapeutics around tumor and the infiltration in the tumor tissues and diffusion (carry and to wait " situation of extracellular matrix to entity tumor in the medicine influence of turning round " " cancer research " 60 phase 2497-503 page or leaf (2000) (Netti PA referring to the Buddhist nun, Cancer Res.2000,60 (9): 2497-503)).Moreover, entity tumor excessive expansion hypertrophy, the viscosity of matter was high than its normal surrounding tissue all between matter pressure, tissue elasticity pressure, fluid pressure reached therebetween, therefore, conventional chemotherapy, be difficult to tumor by local and form effective drug level, 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 SurgOncol.1998 Oct such as Kong Qingzhongs; 69 (2): 76-82), improve the restriction that dosage is subjected to general reaction again merely.Pharmaceutical topical application may solve the problem of drug level to a certain extent, yet operation techniques such as medicine implantation are complicated, traumatic big, the various complication such as, infection hemorrhage, immunity reduction, also can cause or quicken the diffusion and the transfer of tumor except that easily causing.In addition, the preparation of perioperatively itself and expensive expense usually influence its effective enforcement.

The obvious increase after chemotherapy of DNA repair function in the tumor cell often causes the enhancing of tumor cell to the toleration of cancer therapy drug, consequently 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, be convenient to keep high drug level and increase tumor cell the preparation and the method for the sensitivity of medicine just become an important subject at tumor by local.

(3) summary of the invention

The present invention is directed to the deficiencies in the prior art, a kind of slow releasing injection that contains antimetabolite and/or its synergist is provided.

Antimetabolite is mainly used in entity tumors such as treatment intestinal cancer, hepatocarcinoma and digestive tract tumor abroad as a kind of new cancer therapy drug.Yet the generation born of the same parents of medicine general toxicity and tumor cell toleration have greatly limited the application of this medicine.

The present invention is through discovering in a large number, medicine that has and antimetabolite share and can make its antitumaous effect strengthen (the following medicine that the antimetabolite antitumaous effect will be increased mutually is referred to as the antimetabolite synergist) mutually, yet its toxic reaction does not obviously increase; In addition, the compositions of antimetabolite or antimetabolite and its synergist is made drug level that anticancer medicine slow-release preparation containing (being mainly slow releasing injection and sustained-release implant) not only can greatly improve tumor by local, reduces the drug level of medicine in blood circulation, is 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 above unexpected main contents of the present invention of finding to constitute.

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:

Biological effective components 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.

Wherein, common solvent comprises the buffer that distilled water, water for injection, physiology are prepared towards liquid, dehydrated alcohol or various salt; Special solvent is the common solvent that contains suspending agent, and 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 suspending agent in the sustained-release microparticle (A) was " 0 ", solvent (B) was special solvent.

Sustained-release microparticle of the present invention is made up of effective medicinal components and slow-release auxiliary material and/or suspending agent, wherein, effective ingredient can be antimetabolite and/or antimetabolite synergist, and the antimetabolite synergist is selected from topoenzyme inhibitor and/or tetrazine class medicine.

The percentage by weight of effective ingredient in medicament slow-release microsphere is 0.5%-60%, is good with 2%-40%, is best with 5%-30%.

Slow-release auxiliary material is selected from one of copolymer (PLGA), xylitol, oligosaccharide, chrondroitin, chitin, hyaluronic acid, collagen protein, gelatin and white tempera of 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), polyglycolic acid and hydroxyacetic acid 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.

Antimetabolite is selected from one of following or combination: 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 etc.

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.

Above-mentioned antimetabolite shared percentage by weight in slow releasing agent is decided because of concrete condition, can be 0.1%-50%, is good with 1%-40%, and 5%-30% is best.

Topoenzyme inhibitor is selected from one of following or combination: Camptothecin (camptothecin, CPT), the derivant of Camptothecin, lurtotecan (Lurtotecan), topotecan (10-hydroxy-9-dimethylaminomethyl-(S)-camptothecin, topotecan), irinotecan (irinotecan, IRT), 9-nitro Camptothecin (9-nitrocamptothecin, 9NC), 7-ethyl-10-hydroxyl-Camptothecin (7-ethyl-10-hydroxy-camptothecin, SN-38), 7-ethyl-10-[4-(1-piperidino)-1-piperidino] and the carbonyl Camptothecin (7-ethyl-10-[4-(1-pyperidino)-1-piperidino] carbonyloxycamptothecin, CPT-11), 10-hydroxyl-Camptothecin (10-Hydroxycamptothecin, HCPT), Homocamptothecins (Homocamptothecins), MD-CPT (10,11-methylenedioxy, MD-CPT), (RS)-MD-CPT (10,11-MD-20 (RS)-CPT), (S)-MD-CPT glycinate (10,11-MD-20 (S)-CPTglycinate ester (Gly) .HCl), 9-amino-(S)-MD-CPT glycinate (9-amino-10,11-MD-20 (S)-CPT-Gly), N-[2-(dimethylamino) ethyl] and pyridine-4-carboxylic acid amides (N-[2-(dimethylamino) ethyl] acridine-4-carboxamide, DACA) and the derivant of 5 or 7 replacements, podophyllotoxin (podophyllotoxin), etoposide (Etoposide, epipodophyllotoxins, etoposide, etoposide, VP-16), teniposide (Teniposide, teniposide, VM-26), Podophyllinic acid, podophyllotoxin, trihydroxy-isoflavone (Genistein), the 14-doxorubicin, amrubicin (Amrubicin), Ai Rou is than star (4 '-(acridinylamino) methansulfon-m-anisidide (amsacrine, m-AMSA)), the nor-oxygen daunorubicin of 4-(4-demeth oxydaunorubicin), detorubicin, 7-O-methyl Nuo Jia-4 '-epirubicin (7-o-methylnogallol-4 '-epiadriamycin), esorubicin (Esorubicin), carubicin, idarubicin (idarubicin, IDA), rodorubicin, leurubicin (Leurubicin), medorubicin, Nemorubicin (Nemorubicin), doxorubicin, valrubicin (N-trifluoro toxin-14-valerate, N-trifluoroacetyladriamycin-14-valerate, AD32, valrubicin), 2-[4-(7-chloro-2-quinoxalinyl phenoxy base]-propanoic acid ((2-[4-(7-chloro-2-quinoxalinyloxyphenoxy]-propionic acid, XK469), zorubicin (Zorubicin), N-(2-ethyl chloride)-N-nitroso-group urea groups daunorubicin (N-(2-Chloroethyl)-N-nitrosoureidodaunorubicin, AD 312), pyrazoles [1,5-a] indole derivatives, as, but be not limited to, GS-2,-3,-4, GS-5; The dioxy piperazine oxazine derivatives, as, but be not limited to, pair (3, the 5-dioxo piperazinyl) propane ((+)-1, (+)-1,2,2-bis (3,5-dioxopiperazinyl-1-yl) propane, ICRF-187) ,-2,3-two (3,5-dioxo piperazine-1-yl) butane (meso-2,3-bis (3,5-dioxopiperazine-1-yl) butane, ICRF-193), two dioxo piperazine (bisdioxopiperazine); Suramin (Suramin), deoxyguanosine (Deoxyguanosine), lithocholic acid (lithocholic acid, LCA) or Hydrazoic acid,sodium salt (sodium azide).

In the above topology enzyme inhibitor, serve as preferred than star, detorubicin, esorubicin, rodorubicin, leurubicin or zorubicin with Camptothecin, hydroxy-camptothecin alkali, 9-nitro Camptothecin, podophyllotoxin, trihydroxy-isoflavone, lurtotecan, topotecan, irinotecan, etoposide, teniposide, 14-doxorubicin, amrubicin, Ai Rou.

Topoenzyme inhibitor shared ratio in compositions is decided because of concrete condition, generally speaking, can be good with 1%-40% from 0.01%-50%, is best with 5%-30%.All be weight percentage.

Tetrazine kind compound is selected from one of following or combination: procarbazine (procarbazine, PCB), mitozolomide (mitozolomide, MTZ), temozolomide (Temozolomide or 8-Carbamoyl-3-methylimidazo[5,1-d]-1,2,3,5-tetrazin-4 (3H)-one or NSC362856)), 4-carboxyl temozolomide [4--carbonyl] temozolomide], 3N methyl temozolomide [3-N-methyl] temozolomide), the pyrroles [2,1-d] [1,2,3,5] tetrazine-4 (3H)-temozolomide (Pyrrolo[2,1-d] [1,2,3,5] tetrazine-4 (3H) ones), the pyrroles [2,1-d] [1,2,3,5] tetrazine 10a-o (Pyrrolo[2,1-d] [1,2,3,5] tetrazinones10a-o), 5-(3-N-methyl three nitrogen-1-yl)-imidazo-4-carboxylic acid amides (MTIC, 5-(3-N-methyltriazen-1-yl)-imidazole-4-carboxamide), 8-nitro-3-methyl-phendioxin, 2,3,5-four azatropylidenes-4-temozolomide (8-nitro-3-methyl-benzo-1,2,3,5-tetrazepin-4 (3H)-one, NIME), 3,5-dimethyl-pyrido-1,2,3,5-four azatropylidenes-4-temozolomide (3,5-dimethyl-pyrido-1,2,3,5-tetrazepin-4-one, PYRZ) or 3-(2-ethyl chloride)-N, N dimethyl-4-oxygen-3,4-glyoxalidine [5,1-d]-1,2,3,5-tetrazine-8-carboxylic acid amides (3-(2-chloroethyl)-N, N-dimethyl-4-oxo-3,4-is dihydroimidazo[5 just, 1-d]-1,2,3,5-tetrazine-8-arboxamide, CDODTC).

Serve as preferred with imidazo procarbazine, mitozolomide, 4-carboxyl temozolomide or temozolomide in the above-mentioned tetrazine kind compound.

Tetrazine kind compound shared ratio in slow releasing agent is decided because of concrete condition, generally speaking, can be good with 1%-40% from 0.01%-55%, is best with 5%-30%.All be weight percentage.

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, the antimetabolite synergist is used through other approach;

(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.

The percentage by weight of cancer therapy drug 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 be 1-9:1 to 1:1-9, be preferred with 1-2:1.

Anticancer effective component in the slow-releasing anticarcinogen injection microsphere of the present invention is preferably as follows, and all is weight percentage:

(a) pemetrexed of 2-40%, 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) Camptothecin of 2-40%, hydroxy-camptothecin alkali, 9-nitro Camptothecin, podophyllotoxin, trihydroxy-isoflavone, lurtotecan, topotecan, irinotecan, etoposide, teniposide, 14-doxorubicin, amrubicin, Ai Rou are than star, detorubicin, esorubicin, rodorubicin, leurubicin or zorubicin;

(c) pemetrexed of 2-40%, 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 Camptothecin of fludarabine or cladribine and 2-40%, hydroxy-camptothecin alkali, lurtotecan, topotecan, irinotecan, etoposide, teniposide, amrubicin, Ai Rou compares star, rodorubicin, the combination of leurubicin or zorubicin;

(d) procarbazine of 2-40%, mitozolomide, 4-carboxyl temozolomide or temozolomide;

(e) pemetrexed of 2-40%, 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 procarbazine of fludarabine or cladribine and 2-40%, mitozolomide, 4-carboxyl temozolomide or temozolomide's combination;

(f) Camptothecin of 2-40%, hydroxy-camptothecin alkali, 9-nitro Camptothecin, podophyllotoxin, trihydroxy-isoflavone, lurtotecan, topotecan, irinotecan, etoposide, teniposide, 14-doxorubicin, amrubicin, Ai Rou are than procarbazine, mitozolomide, 4-carboxyl temozolomide or the temozolomide's of star, detorubicin, esorubicin, rodorubicin, leurubicin or zorubicin and 2-40% combination; Or

(g) pemetrexed of 2-40%, 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 pemetrexed of fludarabine or cladribine and 2-40%, 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 combination of fludarabine or cladribine.

Slow-release auxiliary material be bio-capacitivity, can (or non-) the degraded polymer, copolymer (PLGA), ethylene vinyl acetate copolymer (EVAc), poly-(erucic acid dimer-decanedioic acid) copolymer of preferred polifeprosan, bis-fatty acid and decanedioic acid copolymer, polylactic acid (PLA), polyglycolic acid and hydroxyacetic acid, gather one of (fumaric acid-decanedioic acid) copolymer or its combination.Its percentage by weight in medicament slow-release microsphere is 41-99.9%.

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, 5000-300, and 000, but with 20,000-100,000 is preferred, with 30,000-50,000 for most preferably; The molecular weight of polyglycolic acid can be, but is not limited to, 5000-300, and 000, but with 20,000-100,000 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, 5000-300,000, but with 20,000-10,000 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 addition, 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.

Suspending agent be used for preparation and/or effectively suspend, stable and/or protect various medicines or sustained-release micro-spheres (or microcapsule), thereby make prepared injection injectivity good, be not easy obstruction, good stability, be difficult for layering, the viscosity height.

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 is decided because of the medicine that solvent suspended, composition, character and the requirement thereof of sustained-release micro-spheres (or microcapsule), the preparation method of injection and the kind and the composition thereof of suspending agent, as, sodium carboxymethyl cellulose can be 0.5-5%, but with 1-3% is preferred, mannitol and/or sorbitol are 5-30%, but is preferred with 10-20%, and soil temperature 20, soil temperature 40 or soil temperature 80 are 0.05-2%, but are preferred with 0.10-0.5%.In most cases, sustained-release microparticle is made up of effective ingredient and slow-release auxiliary material, and solvent is special solvent.When solvent was common solvent, medicine that is suspended or sustained-release micro-spheres (or microcapsule) then were made up of effective ingredient, slow-release auxiliary material and/or suspending agent.In other words, when the suspending agent in the sustained-release microparticle (A) was " 0 ", solvent (B) was special solvent, and when the suspending agent in the sustained-release microparticle (A) was not " 0 ", solvent (B) can be common solvent or special solvent.The viscosity of suspending agent is 100cp-3000cp (20 ℃-30 ℃ time), preferred 1000cp-3000cp (20 ℃-30 ℃ time), most preferably 1500cp-3000cp (20 ℃-30 ℃ time).

Common solvent can be, but is not limited to, the buffer that distilled water, water for injection, physiology are prepared towards liquid, dehydrated alcohol or various salt, and pharmacopeia has respective specified; The special solvent of indication of the present invention is the common solvent that contains suspending agent, suspending agent can be, but be not limited to 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 is 0.1-30% volume weight percentage ratio in the special solvent, is preferably as follows:

(a) 0.5-5% sodium carboxymethyl cellulose; Or

(b) 0.5-5% sodium carboxymethyl cellulose and 0.1-0.5% Tween 80; Or

(c) 5-20% mannitol; Or

(d) 5-20% mannitol and 0.1-0.5% Tween 80; Or.

(e) 0.5-5% sodium carboxymethyl cellulose, 5-20% sorbitol and 0.1-0.5% Tween 80.

The above-mentioned volume weight percentage ratio that is contains the weight of suspending agent in the common solvent of unit volume, as g/ml, and kg/l.Down together.

The preparation of injection comprises that the preparation of preparation, solvent of sustained-release micro-spheres or drug microparticles and sustained-release micro-spheres or drug microparticles suspend, and make injection at last in solvent.

Wherein, sustained-release micro-spheres or drug microparticles can prepare with some kinds of methods: as, but be not limited to, mixing method, fusion method, dissolution method, spray drying method for preparation microsphere, dissolution method are in conjunction with freezing (drying) comminuting method, liposome bag medicine method and emulsion process etc.Serve as preferred wherein with dissolution method (being the solvent volatility process), freezing (drying) comminuting method, seasoning, spray drying method and emulsion process.Microsphere then can be used for preparing above-mentioned various slow releasing injection.The particle diameter of suspended drug or sustained-release micro-spheres (or microcapsule) decide because of specifically needing, and can be, but be not limited to, 1-300um, but be that preferably 30-150um most preferably with 20-200um.Medicine or sustained-release micro-spheres can be made into microsphere, sub-micro ball, microemulsion, nanosphere, granule or spherical piller.Slow-release auxiliary material is above-mentioned bio-capacitivity, biodegradable or non-biodegradation polymer.

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 soil temperature 80 (0.1%) are dissolved in the normal saline mutually deserved 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 application of injection comprises the application of the injection of making after the application of application, solvent of sustained-release micro-spheres or drug microparticles and sustained-release micro-spheres or drug microparticles suspend in solvent.

Microsphere is used to prepare slow releasing injection, as suspension type slow releasing injection, gel injection, block copolymer micelle injection.In various injections, serve as preferred with the suspension type slow releasing injection.The suspension type slow releasing injection is to contain the medicament slow-release microsphere of effective composition or the preparation that drug microparticles is suspended in gained in the solvent, and 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; 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 at 1-300um, but is preferred with 20-200um, and 30-150um most preferably; 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.

The application of solvent refers to that mainly the application of special solvent is effective suspension, stablizes and/or protects various medicines or sustained-release micro-spheres (or microcapsule), thereby prepares corresponding injection.The application of special solvent can make prepared injection have better injectivity, stability and higher viscosity.

The application of injection be with full-bodied special solvent with pastille microgranule, particularly sustained-release microparticle, make corresponding slow releasing injection, thus make corresponding medicine can with the injection mode import in the patient or mammalian body of required medicine.The medicine that is injected can be, but is not limited to, said medicine micropowder or medicament slow release microgranule.

The route of administration of injection depends on multiple factor.Can be in vein, lymphatic vessel, subcutaneous, muscle, intracavity (in as abdominal cavity, thoracic cavity, articular cavity and in the canalis spinalis), tissue, tumor in, reach in the bone marrow in all, the selective arterial injection of tumor, lymph node and inject.For entity tumor, though can be through above-mentioned administration, with in selective arterial, intracavity, the tumor, the injection of tumor week serves as preferred.

For obtaining valid density in former or position, metastatic tumour place, also can unite and give through number of ways, in the time of as vein, lymphatic vessel, subcutaneous, muscle, intracavity (as in abdominal cavity, thoracic cavity, the articular cavity and in the canalis spinalis) or selective arterial injection in conjunction with local injection.So administering drug combinations is specially adapted to entity tumor.As in the tumor, tumor week injection time is in conjunction with systemic injection.

The present invention can be used to prepare the medicine of the various entity tumors for the treatment of people and animal, is mainly slow releasing injection.

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, 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 application of anti-cancer sustained-released implantation agent and the same slow releasing injection of potentiation mode, sustained-release implant anticancer effective component and the same slow releasing injection of percentage by weight thereof, but be preferably:

(f) Camptothecin of 2-40%, hydroxy-camptothecin alkali, 9-nitro Camptothecin, podophyllotoxin, trihydroxy-isoflavone, lurtotecan, topotecan, irinotecan, etoposide, teniposide, 14-doxorubicin, amrubicin, Ai Rou are than procarbazine, mitozolomide, 4 carboxyl temozolomides or the temozolomide's of star, detorubicin, esorubicin, rodorubicin, leurubicin or zorubicin and 2-40% combination; Or

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.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.

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 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 medicine is through intratumor 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	66±80
2(6)	Decitabine	38±4.0	<0.05	1(6)	Contrast	66±80
2(6)	Decitabine	38±4.0	<0.05	3(6)	Camptothecin	48±2.0	<0.01
4(6)	Hydroxy-camptothecin alkali	46±2.2	<0.01	3(6)	Camptothecin	48±2.0	<0.01
4(6)	Hydroxy-camptothecin alkali	46±2.2	<0.01	5(6)	Topotecan	42±3.2	<0.01
6(6)	Irinotecan	44±3.0	<0.01	5(6)	Topotecan	42±3.2	<0.01
6(6)	Irinotecan	44±3.0	<0.01	7(6)	Decitabine+Camptothecin	22±2.0	<0.001
8(6)	Decitabine+hydroxy-camptothecin alkali	20±3.4	<0.001	7(6)	Decitabine+Camptothecin	22±2.0	<0.001
8(6)	Decitabine+hydroxy-camptothecin alkali	20±3.4	<0.001	9(6)	Decitabine+topotecan	20±3.0	<0.001
10(6)	Decitabine+irinotecan	16±2.0	<0.001	9(6)	Decitabine+topotecan	20±3.0	<0.001

Above result shows, growth all has the obvious suppression effect to kinds of tumor cells when this concentration is used separately for antimetabolite (decitabine) and used antimetabolite synergist topoenzyme inhibitor (Camptothecin, hydroxy-camptothecin alkali, topotecan, irinotecan), can show significant potentiation when use in conjunction.

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	Carmofur	Lurtotecan	Etoposide	Teniposide	Carmofur+lurtotecan	Carmofur+etoposide	Carmofur+teniposide
Oncocyte	Carmofur	Lurtotecan	Etoposide	Teniposide	Carmofur+lurtotecan	Carmofur+etoposide	Carmofur+teniposide	CNS	30％	52％	60％	62％	88％	88％	90％
C6	44％	62％	62％	62％	94％	84％	96％	CNS	30％	52％	60％	62％	88％	88％	90％
C6	44％	62％	62％	62％	94％	84％	96％	SA	38％	60％	56％	62％	86％	90％	92％
BC	32％	64％	56％	64％	94％	84％	82％	SA	38％	60％	56％	62％	86％	90％	92％
BC	32％	64％	56％	64％	94％	84％	82％	BA	38％	62％	62％	60％	98％	90％	92％
LH	30％	58％	62％	58％	90％	86％	86％	BA	38％	62％	62％	60％	98％	90％	92％
LH	30％	58％	62％	58％	90％	86％	86％	PAT	30％	52％	64％	58％	82％	88％	94％

Above result shows, growth all has the obvious suppression effect to kinds of tumor cells when this concentration is used separately for used carmofur and antimetabolite synergist topoenzyme inhibitor (lurtotecan, etoposide, teniposide), can show significant potentiation when use in conjunction.

The tumor-inhibiting action of test 5, antimetabolite and antimetabolite synergist (slow releasing injection)

With the rat is subjects, with 2 * 10 ⁵Individual tumor cell of liver subcutaneous injection is in its hypochondrium, treat tumor growth after 14 days sustained-release implant in tumor, place.Dosage is 5mg/kg.The treatment back was measured gross tumor volume size, relatively therapeutic effect on the 10th day.The result shows, 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, antimetabolite such as fludarabine or cladribine can also obviously strengthen the tumor killing effect of other topoenzyme inhibitor, as Camptothecin, hydroxy-camptothecin alkali, 9-nitro Camptothecin, podophyllotoxin, trihydroxy-isoflavone, lurtotecan, topotecan, irinotecan, etoposide, teniposide, the 14-doxorubicin, amrubicin, Ai Rou compares star, detorubicin, esorubicin, rodorubicin, leurubicin or zorubicin etc.

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, antimetabolite synergist intraperitoneal administration.Dosage is 5mg/kg.The treatment back was measured the gross tumor volume size on the 10th day, made relatively therapeutic effect (seeing Table 3) of index with inhibition rate of tumor growth.

Table 3

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	72	<0.05	1(6)	Contrast	-
2(6)	Antimetabolite	72	<0.05	3(6)	Procarbazine	40	<0.01
4(6)	Mitozolomide	36	<0.01	3(6)	Procarbazine	40	<0.01
4(6)	Mitozolomide	36	<0.01	5(6)	4-carboxyl temozolomide	34	<0.01
6(6)	The temozolomide	32	<0.01	5(6)	4-carboxyl temozolomide	34	<0.01
6(6)	The temozolomide	32	<0.01	7(6)	Antimetabolite+procarbazine	86	<0.001
8(6)	Antimetabolite+mitozolomide	88	<0.001	7(6)	Antimetabolite+procarbazine	86	<0.001
8(6)	Antimetabolite+mitozolomide	88	<0.001	9(6)	Antimetabolite+4-carboxyl temozolomide	86	<0.001
10(6)	Antimetabolite+temozolomide	94	<0.001	9(6)	Antimetabolite+4-carboxyl temozolomide	86	<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 (emtricitabine) and antimetabolite synergist-tetrazine kind compound (procarbazine, mitozolomide, 4-carboxyl temozolomide, temozolomide), 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.The antimetabolite synergist is through intratumor injection, and antimetabolite is through intraperitoneal administration.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)	Camptothecin	26	<0.05	1(6)	Contrast	-
2(6)	Camptothecin	26	<0.05	3(6)	His shore of imidazoles	53	<0.01
4(6)	Capecitabine	64	<0.01	3(6)	His shore of imidazoles	53	<0.01
4(6)	Capecitabine	64	<0.01	5(6)	Gemcitabine	50	<0.01
6(6)	Fludarabine	54	<0.01	5(6)	Gemcitabine	50	<0.01
6(6)	Fludarabine	54	<0.01	7(6)	His shore of Camptothecin+imidazoles	86	<0.001
8(6)	Camptothecin+capecitabine	88	<0.001	7(6)	His shore of Camptothecin+imidazoles	86	<0.001
8(6)	Camptothecin+capecitabine	88	<0.001	9(6)	Camptothecin+gemcitabine	92	<0.001
10(6)	Camptothecin+fludarabine	92	<0.001	9(6)	Camptothecin+gemcitabine	92	<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 (his shore of imidazoles, capecitabine, gemcitabine, fludarabine) and antimetabolite synergist-topoenzyme inhibitor (Camptothecin), 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 of index with inhibition rate of tumor growth.The result shows, growth all has the obvious suppression effect to kinds of tumor cells when this concentration is used separately for used antimetabolite (galocitabine, ibacitabine, ancitabine, decitabine) and antimetabolite synergist-hydroxy-camptothecin alkali, can show significant potentiation when use in conjunction.

The tumor-inhibiting action of test 9, 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 Camptothecin, hydroxy-camptothecin alkali, lurtotecan, topotecan, irinotecan, etoposide, teniposide, amrubicin, Ai Rou compares star, rodorubicin, leurubicin, zorubicin, procarbazine, mitozolomide, 4-carboxyl temozolomide or temozolomide's tumor killing effect, potentiation is in 65-80% (P＜0.01).

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 procarbazine, mitozolomide, 4-carboxyl temozolomide or temozolomide's tumor killing effect, potentiation is in 60-85% (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 Camptothecin, hydroxy-camptothecin alkali, 9-nitro Camptothecin, podophyllotoxin, trihydroxy-isoflavone, lurtotecan, topotecan, irinotecan, etoposide, teniposide, the 14-doxorubicin, amrubicin, Ai Rou compares star, detorubicin, esorubicin, rodorubicin, leurubicin or zorubicin antimetabolite synergist can significantly strengthen procarbazine, mitozolomide, 4-carboxyl temozolomide or temozolomide's tumor killing effect, potentiation is in 50-80% (P＜0.01).

Similar potentiation also sees other antimetabolite and the associating of other antimetabolite synergist and the combination between different antimetabolite synergist, as: pemetrexed, pemetrexed disodium, Rumi Qu Sai, carmofur, ftorafur, the temozolomide, zalcitabine, emtricitabine, galocitabine, ibacitabine, ancitabine, decitabine, flurocitabine, enocitabine, his shore of imidazoles, capecitabine, gemcitabine, fludarabine, thunder accounts for for song, Raltitrexed, dexrazoxane, cladribine or 2-Amino-6-methyl-5-(pyridin-4-ylsulfanyl)-3H-quinazolin-4-one and Camptothecin, hydroxy-camptothecin alkali, 9-nitro Camptothecin, podophyllotoxin, trihydroxy-isoflavone, lurtotecan, topotecan, irinotecan, etoposide, teniposide, the 14-doxorubicin, amrubicin, Ai Rou compares star, detorubicin, esorubicin, rodorubicin, antimetabolite such as leurubicin or zorubicin synergist and procarbazine, mitozolomide, the combination of antimetabolite synergists such as 4-carboxyl temozolomide or temozolomide.

With multiple other tumor cell (comprising 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, pulmonary carcinoma, intestinal cancer, renal carcinoma, ovarian cancer and the esophageal carcinoma etc.) is that subjects draws similar results.

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 (or the more than one) antimetabolite that is any one and/or any one (or more than 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.

80mg 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 pemetrexed and 10mg Camptothecin, shake up the back contains 10% pemetrexed and 10% Camptothecin 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 200cp-650cp (20 ℃-30 ℃ time).The drug release time of this slow releasing injection in external normal saline is 20-30 days, is about 30-40 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) Camptothecin of 2-40%, hydroxy-camptothecin alkali, 9-nitro Camptothecin, podophyllotoxin, trihydroxy-isoflavone, lurtotecan, topotecan, irinotecan, etoposide, teniposide, 14-doxorubicin, amrubicin, Ai Rou are than star, detorubicin, esorubicin, rodorubicin, leurubicin or zorubicin;

(b) his shore of the pemetrexed of 2-40%, pemetrexed disodium, Rumi Qu Sai, carmofur, ftorafur, temozolomide, zalcitabine, emtricitabine, galocitabine, ibacitabine, ancitabine, decitabine, flurocitabine, enocitabine, imidazoles, capecitabine, gemcitabine, fludarabine, thunder for song account for, Raltitrexed, dexrazoxane, cladribine or 2-Amino-6-methyl-5-(pyridin-4-ylsulfanyl)-3H-quinazolin-4-one; Or

(c) pemetrexed of 2-40%, pemetrexed disodium, Rumi Qu Sai, carmofur, ftorafur, the temozolomide, zalcitabine, emtricitabine, galocitabine, ibacitabine, ancitabine, decitabine, flurocitabine, enocitabine, his shore of imidazoles, capecitabine, gemcitabine, fludarabine, thunder accounts for for song, Raltitrexed, dexrazoxane, the Camptothecin of cladribine or 2-Amino-6-methyl-5-(pyridin-4-ylsulfanyl)-3H-quinazolin-4-one and 2-40%, hydroxy-camptothecin alkali, lurtotecan, topotecan, irinotecan, etoposide, teniposide, amrubicin, Ai Rou compares star, rodorubicin, the combination of leurubicin or zorubicin.

Embodiment 3.

With 70mg molecular weight peak value is that (PLGA 75:25) puts into container, adds 100 milliliters of dichloromethane, behind the dissolving mixing, adds 15mg emtricitabine and 15mg hydroxy-camptothecin alkali, shakes up the dry organic solvent of removing of final vacuum again for 25000 polylactic acid.Dried pastille solid composite freezing and pulverizing is made the micropowder that contains 15% emtricitabine and 15% hydroxy-camptothecin alkali, be suspended in then in the normal saline that contains 1.5% sodium carboxymethyl cellulose, make corresponding suspension type slow releasing injection.The viscosity of injection is 300cp-650cp (20 ℃-30 ℃ time).The drug release time of this slow releasing injection in external normal saline is 10-15 days, is about 30-35 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:

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 teniposides and 10 milligrams of ftorafur, shake up the back contains 20% teniposide and 10% ftorafur 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 viscosity of injection is 200cp-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 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:

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 ibacitabine and 10mg mitozolomide, shake up the back contains 20% ibacitabine and 10% mitozolomide 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 viscosity of injection is 500cp-800cp (20 ℃-30 ℃ time).The drug release time of this slow releasing injection in external normal saline is 15-25 days, is about 20-35 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 that contained anticancer effective component is:

(a) procarbazine of 2-40%, mitozolomide, 4-carboxyl temozolomide or temozolomide; Or

(b) pemetrexed of 2-40%, pemetrexed disodium, Rumi Qu Sai, carmofur, ftorafur, the temozolomide, zalcitabine, emtricitabine, galocitabine, ibacitabine, ancitabine, decitabine, flurocitabine, enocitabine, his shore of imidazoles, capecitabine, gemcitabine, fludarabine, thunder accounts for for song, Raltitrexed, dexrazoxane, the procarbazine of cladribine or 2-Amino-6-methyl-5-(pyridin-4-ylsulfanyl)-3H-quinazolin-4-one and 2-40%, mitozolomide, 4-carboxyl temozolomide or temozolomide's combination.

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 20mg hydroxy-camptothecin alkali and 10mg mitozolomide, shake up the back contains 20% hydroxy-camptothecin alkali and 10% mitozolomide 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.The viscosity of injection is 500cp-700cp (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 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 Camptothecin of 5-30%, hydroxy-camptothecin alkali, 9-nitro Camptothecin, podophyllotoxin, trihydroxy-isoflavone, lurtotecan, topotecan, irinotecan, etoposide, teniposide, 14-doxorubicin, amrubicin, Ai Rou are than procarbazine, mitozolomide, 4-carboxyl temozolomide or the temozolomide's of star, detorubicin, esorubicin, rodorubicin, leurubicin or zorubicin and 5-30% combination.

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 procarbazine and 20mg camptothecine, shake up the back contains 10% procarbazine and 20% camptothecine 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 Camptothecin of 10-30%, hydroxy-camptothecin alkali, 9-nitro Camptothecin, podophyllotoxin, trihydroxy-isoflavone, lurtotecan, topotecan, irinotecan, etoposide, teniposide, 14-doxorubicin, amrubicin, Ai Rou are than procarbazine, mitozolomide, 4-carboxyl temozolomide or the temozolomide's of star, detorubicin, esorubicin, rodorubicin, leurubicin or zorubicin and 10-30% combination.

Embodiment 13

With 70mg molecular weight peak value 35000 polylactic acid (PLGA, 50:50) put into container, add 100 milliliters of dichloromethane, behind the dissolving mixing, add 10mg etoposide and 20mg mitozolomide, shake up the back contains 10% etoposide and 20% mitozolomide 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 3550 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 is: 15% Camptothecin, hydroxy-camptothecin alkali, 9-nitro Camptothecin, podophyllotoxin, trihydroxy-isoflavone, lurtotecan, topotecan, irinotecan, etoposide, teniposide, 14-doxorubicin, amrubicin, Ai Rou are than procarbazine, mitozolomide, 4-carboxyl temozolomide or the temozolomide's of star, detorubicin, esorubicin, rodorubicin, leurubicin or zorubicin and 15% combination.

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, molecular weight peak value are 10000-30000,300000-60000,60000-100000 or 100000-150000;

B) copolymer of polyglycolic acid and hydroxyacetic acid, 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) ethylene vinyl acetate copolymer;

D) 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;

E) bis-fatty acid and decanedioic acid copolymer;

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

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

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

Embodiment 16

The method step that is processed into slow releasing injection is identical with embodiment 1-15, 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.

Embodiment 17

The method step that is processed into slow releasing injection is identical with embodiment 1-15, but different is that contained anticancer effective component is:

(b) his shore of the pemetrexed of 2-40%, pemetrexed disodium, Rumi Qu Sai, carmofur, ftorafur, temozolomide, zalcitabine, emtricitabine, galocitabine, ibacitabine, ancitabine, decitabine, flurocitabine, enocitabine, imidazoles, capecitabine, gemcitabine, fludarabine, thunder for bently account for, procarbazine, mitozolomide, 4-carboxyl temozolomide or the temozolomide of Raltitrexed, dexrazoxane, cladribine or 2-Amino-6-methyl-5-(pyridin-4-ylsulfanyl)-3H-quinazolin-4-one and 2-40%;

(c) pemetrexed of 2-40%, pemetrexed disodium, Rumi Qu Sai, carmofur, ftorafur, the temozolomide, zalcitabine, emtricitabine, galocitabine, ibacitabine, ancitabine, decitabine, flurocitabine, enocitabine, his shore of imidazoles, capecitabine, gemcitabine, fludarabine, thunder accounts for for song, Raltitrexed, dexrazoxane, the procarbazine of cladribine or 2-Amino-6-methyl-5-(pyridin-4-ylsulfanyl)-3H-quinazolin-4-one and 2-40%, mitozolomide, the Camptothecin of 4-carboxyl temozolomide or temozolomide and 2-40%, hydroxy-camptothecin alkali, lurtotecan, topotecan, irinotecan, etoposide, teniposide, amrubicin, Ai Rou compares star, rodorubicin, the combination of leurubicin or zorubicin;

(e) pemetrexed of 2-40%, pemetrexed disodium, Rumi Qu Sai, carmofur, ftorafur, the temozolomide, zalcitabine, emtricitabine, galocitabine, ibacitabine, ancitabine, decitabine, flurocitabine, enocitabine, his shore of imidazoles, capecitabine, gemcitabine, fludarabine, thunder accounts for for song, Raltitrexed, dexrazoxane, the procarbazine of cladribine or 2-Amino-6-methyl-5-(pyridin-4-ylsulfanyl)-3H-quinazolin-4-one and 2-40%, mitozolomide, the procarbazine of 4-carboxyl temozolomide or temozolomide and 2-40%, mitozolomide, 4-carboxyl temozolomide or temozolomide's combination; Or

(f) Camptothecin of 2-40%, hydroxy-camptothecin alkali, 9-nitro Camptothecin, podophyllotoxin, trihydroxy-isoflavone, lurtotecan, topotecan, irinotecan, etoposide, teniposide, 14-doxorubicin, amrubicin, Ai Rou are than procarbazine, mitozolomide, 4 carboxyl temozolomides or the temozolomide's of star, detorubicin, esorubicin, rodorubicin, leurubicin or zorubicin and 2-40% combination;

(g) pemetrexed of 2-40%, pemetrexed disodium, Rumi Qu Sai, carmofur, ftorafur, the temozolomide, zalcitabine, emtricitabine, galocitabine, ibacitabine, ancitabine, decitabine, flurocitabine, enocitabine, his shore of imidazoles, capecitabine, gemcitabine, fludarabine, thunder accounts for for song, Raltitrexed, dexrazoxane, the procarbazine of cladribine or 2-Amino-6-methyl-5-(pyridin-4-ylsulfanyl)-3H-quinazolin-4-one and 2-40%, mitozolomide, the Camptothecin of 4-carboxyl temozolomide or temozolomide and 2-40%, hydroxy-camptothecin alkali, 9-nitro Camptothecin, podophyllotoxin, trihydroxy-isoflavone, lurtotecan, topotecan, irinotecan, etoposide, teniposide, the 14-doxorubicin, amrubicin, Ai Rou compares star, detorubicin, esorubicin, rodorubicin, the procarbazine of leurubicin or zorubicin and 2-40%, mitozolomide, 4-carboxyl temozolomide or temozolomide's combination.

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

[claim 1] a kind of slow releasing injection that contains antimetabolite and its synergist is grouped into by following one-tenth:

(A) sustained-release microparticle:

Anticancer effective component

Slow-release auxiliary material

(B) solvent;

Wherein, anticancer effective component is antimetabolite and tetrazine kind compound;

The component of described slow releasing injection is one of following combination:

Anticancer effective component is 20% ibacitabine and 10% mitozolomide, and slow-release auxiliary material is to carboxy phenyl propane: decanedioic acid is the polifeprosan of 20:80, and solvent is the normal saline that contains 1.5% sodium carboxymethyl cellulose and 0.5% Tween 80;

Below all be weight percentage.