CN1868454A - Slow-release injection contg. platinum compounds and its potentiator - Google Patents

Slow-release injection contg. platinum compounds and its potentiator Download PDF

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CN1868454A
CN1868454A CNA2006102005931A CN200610200593A CN1868454A CN 1868454 A CN1868454 A CN 1868454A CN A2006102005931 A CNA2006102005931 A CN A2006102005931A CN 200610200593 A CN200610200593 A CN 200610200593A CN 1868454 A CN1868454 A CN 1868454A
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platinum
acid
copolymer
slow
release
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孔庆忠
俞建江
苏红清
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Shandong Lanjin Pharmaceuticals Co Ltd
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Shandong Lanjin Pharmaceuticals Co Ltd
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Abstract

A slow-release anticancer injection is composed of the slow-release micro-balls containing active component and slow-releasing auxiliary and the special solvent containing the suspending aid. Said active component is the combination of Pt compound chosen from dicycloplatinum, etc and the topological enzyme inhibitor and/or tetraazine compound. Said slow-releasing auxiliary is chosen from polylactic acid or its copolymer, monoethyl polyethanediol or its copolymer, EVAc, etc.

Description

The slow releasing injection that contains platinum-like compounds and synergist thereof
(1) technical field
The present invention relates to a kind of slow releasing injection that contains platinum-like compounds and/or its synergist and preparation method thereof, belong to technical field of pharmaceuticals.
(2) background technology
As a kind of chemotherapeutics commonly used, platinum-like compounds has been widely used in the treatment of multiple malignant tumor, and action effect is comparatively obvious.Yet its beat all neurotoxicity has greatly limited the application of this medicine.Blood vessel in the mesenchyma stroma of tumors, connective tissue, stromatin, fibrin and collagen protein etc. 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)).Because 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 Surg Oncol.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 (Chinese patent) 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.
In addition, the DNA repair function in many tumor cells obviously increases after chemotherapy.The latter 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 platinum-like compounds and its synergist is provided.
Platinum-like compounds and platinum-like compounds synergist be as new cancer therapy drug, has been widely used in the multiple entity tumor of treatment both at home and abroad, as the cerebral tumor etc.Yet in application process, its tangible general toxicity has greatly limited the application of this medicine.
Be effectively to improve tumor by local drug level, reduce the drug level of medicine in blood circulation, people have studied the slow-released system that contains cancer therapy drug, comprise that sustained-release micro-spheres (capsule) (sees: (China Patent No. ZL00809160.9; Application number 91109723.6), Ciftci K etc. " with the polylactic acid microsphere treatment entity tumor that contains fluorouracil and the research of drug release " " drug development technology " (Pharm Dev Technol.) 2 (2): 151-60,1997), sustained-release implant (sees: China Patent No. ZL96115937.5; ZL97107076.8) etc.Yet, solid sustained-release implant (China Patent No. ZL96115937.5; ZL97107076.8) and existing as be used for the treatment of the cerebral tumor (ZL00809160.9) sustained-release micro-spheres or United States Patent (USP) (US5,651,986) and all have problem such as be not easy more than operation, weak curative effect, the complication.In addition, the sensitivity that many entity tumors are drawn together platinum-like compounds to anticancer medicated bag is relatively poor, and is easy to generate drug resistance in therapeutic process.The present invention finds that medicine of mentioning among the present invention and platinum-like compounds share and can make its antitumaous effect strengthen (the following medicine that the platinum-like compounds antitumaous effect will be increased mutually is referred to as the platinum-like compounds synergist) mutually.In addition, with the assembly packaging of platinum-like compounds and its synergist in specific slow-release auxiliary material and be equipped with special solvent and make drug level that anti-cancer medicine sustained-release injection not only can greatly improve tumor by local, reduce the drug level of medicine in blood circulation, reduce 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 decapacitation of platinum-like compounds synergist suppresses can also increase the sensitivity of tumor cell to cancer therapy drug outside the tumor growth.
The drug main that platinum-like compounds is made is wanted conventional route administrations such as oral administration or intravenous injection, and 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.Existing several thousand new platinum family chemical compounds are entered the screening back find to have only 28 chemical compounds to enter clinical research, have 4 chemical compounds to get the Green Light and come into the market, also have 2～3 chemical compounds will obtain to produce certification.Therefore, in having the platinum-like compounds of active anticancer, be not all slow release effects that all can in slow-release auxiliary material of the present invention, reach effective release.Pharmaceutic adjuvant have hundreds of more than, pharmaceutic adjuvant with slow releasing function, particularly the pharmaceutic adjuvant that selected platinum-like compounds 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 combination of slow releasing pharmaceutical and could determine.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.
The above unexpected main contents of the present invention of finding to constitute.
The present invention is directed to the deficiencies in the prior art, a kind of new slow releasing injection that contains platinum-like compounds and platinum-like compounds synergist is provided.
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:
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%
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 platinum-like compounds and/or platinum-like compounds synergist, and the platinum-like compounds 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 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, 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.
Platinum-like compounds is selected from one of following or combination: the platinum (sunpla) that relaxes, bicycloplatin (bicycloplatin), according to platinum (eptalatin), picoplatin, citricplatin (citricplatin), ZD 0473 (picoplatin).
Above-mentioned platinum-like compounds shared ratio in compositions is decided because of concrete condition, can be 0.1%-50%, is good with 1%-30%, and 5%-20% 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)-cpT-glycinate 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, 7-0-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, AD 32, 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, (+)-1, two (3, the 5-dioxo piperazinyl) propane ((+)-1 of 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: imidazo tetrazine (imidazotetrazine), imidazopyrazine (imidazopyrazine), 1H-imidazo [b] piperazine (1H-imidazo[b] pyrazine), imidazopyridine (imidazopyridine), 1H-imidazo [1,2-a] pyridine (1H-imidazo[1,2-a] pyridinum), procarbazine (procarbazine, PCB), mitozolomide (mitozolomide, MTZ), temozolomide (Temozolomideor 8-Carbamoyl-3-methyl imidazo[5,1-d]-1,2,3,5-tetrazin-4 (3H)-one or NSC362856)), 4-carboxyl temozolomide [4--carbonyl] temozolomide], 3-N-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] tetrazinones 10a-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-carboxamide, CDODTC).
Serve as preferred with imidazo procarbazine, mitozolomide, 4-carboxyl temozolomide or temozolomide in the above-mentioned tetrazine kind compound.Above tetrazine kind compound 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.
Tetrazine kind compound shared ratio in slow releasing agent is decided because of concrete condition, generally speaking, can be good with 1%-40% from 0.1%-50%, is best with 5%-30%.All be weight percentage.
Anticancer effective component is mainly platinum-like compounds and/or its synergist.When the cancer therapy drug in the medicament slow-release microsphere only is platinum-like compounds or platinum-like compounds synergist, slow-releasing anticarcinogen injection is mainly used in the platinum-like compounds of other approach application of increase or the action effect of platinum-like compounds 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 platinum-like compounds or its synergist, the application of slow-releasing anticarcinogen injection and potentiation mode were:
(1) contain the slow releasing injection local injection of platinum-like compounds, other approach of platinum-like compounds synergist are used;
(2) local injection contains the slow releasing injection of platinum-like compounds synergist, and other approach are used platinum-like compounds;
(3) local injection contains the slow releasing injection and the slow releasing injection that contains the platinum-like compounds synergist of platinum-like compounds; Or
(4) local injection contains the slow releasing injection of platinum-like compounds 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, be 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 platinum-like compounds and platinum-like compounds synergist is 1-9: 1 to 1: 1-9, with 1-2: 1 serves as preferred.
Anticancer effective component in the slow-releasing anticarcinogen injection microsphere of the present invention is preferably as follows, and all is weight percentage:
(a) the easypro platinum of 2-40%, bicycloplatin, the Camptothecin according to platinum, picoplatin, citricplatin or ZD 0473 and 2-40%, hydroxy-camptothecin alkali, lurtotecan, topotecan, irinotecan, etoposide, teniposide, amrubicin, Ai Rou are than the combination of star, rodorubicin, leurubicin or zorubicin; Or
(b) the easypro platinum of 2-40%, bicycloplatin, procarbazine, mitozolomide, 4-carboxyl temozolomide or temozolomide's combination according to platinum, picoplatin, citricplatin or ZD 0473 and 2-40%.
Slow-release auxiliary material is a bio-capacitivity, can (or non-) the degraded polymer, preferred 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), ethylene vinyl acetate copolymer, polylactic acid, the copolymer of polyglycolic acid and hydroxyacetic acid, xylitol, oligosaccharide, chrondroitin, chitin, hyaluronic acid, collagen protein, one of gelatin and albumin glue or its combination.Its percentage by weight in medicament slow-release microsphere is 41-99.9%.
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) PLA of 55-90%;
(2) PLGA of 50-90%;
(3) polifeprosan of 50-85%;
(4) bis-fatty acid of 55-90% and decanedioic acid copolymer;
(5) EVAc of 55-90%;
(6) xylitol of 40-95%, oligosaccharide, chrondroitin, chitin, hyaluronic acid, collagen protein, gelatin or white tempera; Or
(7) poly-dl-lactide of 40-95%, 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.
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 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 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).So 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 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, 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.
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 the slow releasing agent implant that biocompatibility, degradable absorb, 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, the same slow releasing injection of the anticancer effective component of sustained-release implant and percentage by weight thereof, but be preferably:
(a) the easypro platinum of 2-40%, bicycloplatin, the Camptothecin according to platinum, picoplatin, citricplatin or ZD 0473 and 2-40%, hydroxy-camptothecin alkali, lurtotecan, topotecan, irinotecan, etoposide, teniposide, amrubicin, Ai Rou are than the combination of star, rodorubicin, leurubicin or zorubicin; Or
(b) the easypro platinum of 2-40%, bicycloplatin, procarbazine, mitozolomide, 4-carboxyl temozolomide or temozolomide's combination according to platinum, picoplatin, citricplatin or ZD 0473 and 2-40%.
Slow-release auxiliary material and percentage by weight thereof are most preferably as follows in the sustained-release implant of the present invention:
(1) PLA of 55-90%;
(2) PLGA of 50-90%;
(3) polifeprosan of 50-85%;
(4) bis-fatty acid of 55-90% and decanedioic acid copolymer;
(5) EVAc of 55-90%;
(6) xylitol of 40-95%, oligosaccharide, chrondroitin, chitin, hyaluronic acid, collagen protein, gelatin or albumin glue; Or
(7) poly-dl-lactide of 40-95%, 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.
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 platinum-like compounds 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 technology of the present invention is further described:
The local drug concentration that test 1, different modes are used behind the platinum-like compounds (according to platinum) 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 5mg/kg according to platinum.Measure medicament contg (%) in the different time tumor, the result shows, according to the local drug concentration significant difference of platinum 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 platinum-like compounds (platinum relaxes) 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 easypro platinum of 5mg/kg.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 platinum after different modes is used relaxes, 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 platinum-like compounds and platinum-like compounds 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
1(6) Contrast 66±8.0
2(6) Bicycloplatin 44±4.8 ＜0.05
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
7(6) Bicycloplatin+Camptothecin 22±2.2 ＜0.001
8(6) Bicycloplatin+hydroxy-camptothecin alkali 20±3.0 ＜0.001
9(6) Bicycloplatin+topotecan 22±3.2 ＜0.001
10(6) Bicycloplatin+irinotecan 16±2.0 ＜0.001
Above result shows, growth all has the obvious suppression effect to kinds of tumor cells when this concentration is used separately for platinum-like compounds (bicycloplatin) and used platinum-like compounds synergist-topoenzyme inhibitor (Camptothecin, hydroxy-camptothecin alkali, topotecan, irinotecan), can show significant potentiation when use in conjunction.
The tumor-inhibiting action of test 4, platinum-like compounds and platinum-like compounds 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.Platinum-like compounds and platinum-like compounds 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 Citricplatin Lurtotecan Etoposide Teniposide Citricplatin+lurtotecan Citricplatin+etoposide Citricplatin+teniposide
CNS 42％ 52％ 62％ 60％ 90％ 86％ 92％
C6 44％ 62％ 62％ 62％ 94％ 84％ 96％
SA 38％ 62％ 56％ 62％ 86％ 92％ 90％
BC 32％ 64％ 56％ 54％ 94％ 84％ 84％
BA 38％ 62％ 62％ 52％ 98％ 92％ 92％
LH 30％ 58％ 62％ 58％ 90％ 86％ 86％
PAT 34％ 56％ 62％ 56％ 86％ 88％ 90％
Above result shows, growth all has the obvious suppression effect to kinds of tumor cells when this concentration is used separately for used citricplatin and platinum-like compounds synergist-topoenzyme inhibitor (lurtotecan, etoposide, teniposide), can show significant potentiation when use in conjunction.
The tumor-inhibiting action of test 5, platinum-like compounds and platinum-like compounds 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, can obviously strengthen the tumor killing effect of other topoenzyme inhibitor according to platinum-like compounds such as platinum, the platinum that relaxes, picoplatin, ZD 0473, as Camptothecin, hydroxy-camptothecin alkali, 9-nitro Camptothecin, podophyllotoxin, trihydroxy-isoflavone, lurtotecan, topotecan, irinotecan, etoposide, teniposide, 14-doxorubicin, amrubicin, Ai Rou than star, detorubicin, esorubicin, rodorubicin, leurubicin or zorubicin etc.
The tumor-inhibiting action of test 6, platinum-like compounds and platinum-like compounds 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 (platinum-like compounds or platinum-like compounds synergist) and therapeutic alliance group (platinum-like compounds and platinum-like compounds synergist).Platinum-like compounds is through intratumor injection, platinum-like compounds 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
1(6) Contrast -
2(6) Platinum-like compounds 66 ＜0.05
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
7(6) Platinum-like compounds+procarbazine 86 ＜0.001
8(6) Platinum-like compounds+mitozolomide 80 ＜0.001
9(6) Platinum-like compounds+4-carboxyl temozolomide 76 ＜0.001
10(6) Platinum-like compounds+temozolomide 90 ＜0.001
Above result shows that used platinum-like compounds is a ZD 0473, and the platinum-like compounds synergist is tetrazine kind compound (procarbazine, mitozolomide, 4-carboxyl temozolomide, temozolomide).Growth all had the obvious suppression effect to kinds of tumor cells when said medicine was used separately, can show significant potentiation when use in conjunction.
The tumor-inhibiting action of test 7, platinum-like compounds and platinum-like compounds 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 platinum-like compounds synergist is through intratumor injection, and platinum-like compounds 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
1(6) Contrast -
2(6) Camptothecin 66 ＜0.05
3(6) Platinum relaxes 33 ＜0.01
4(6) According to platinum 34 ＜0.01
5(6) Bicycloplatin 40 ＜0.01
6(6) Picoplatin 44 ＜0.01
7(6) Camptothecin+platinum relaxes 82 ＜0.001
8(6) Camptothecin+according to platinum 84 ＜0.001
9(6) Camptothecin+bicycloplatin 92 ＜0.001
10(6) Camptothecin+picoplatin 88 ＜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 platinum-like compounds (relax platinum, according to platinum, bicycloplatin, picoplatin) and platinum class chemical combination example synergist-topoenzyme inhibitor (Camptothecin), can show significant potentiation when use in conjunction.
The tumor-inhibiting action of test 8, platinum-like compounds and platinum-like compounds 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 platinum-like compounds (relax platinum, according to platinum, bicycloplatin, picoplatin, citricplatin, ZD 0473) and platinum-like compounds synergist-hydroxy-camptothecin alkali, can show significant potentiation when use in conjunction.
The tumor-inhibiting action of test 9, platinum-like compounds and platinum-like compounds synergist (slow releasing injection)
Measure the tumor-inhibiting action of platinum-like compounds synergist (slow releasing injection) by test 7 described methods, the result shows to be selected from according to platinum-like compounds such as platinum, the platinum that relaxes, bicycloplatin, citricplatin, picoplatin or ZD 0473 and can significantly strengthen Camptothecin, hydroxy-camptothecin alkali, lurtotecan, topotecan, irinotecan, etoposide, teniposide, amrubicin, the Ai Rou tumor killing effect than star, rodorubicin, leurubicin, zorubicin, procarbazine, mitozolomide, 4-carboxyl temozolomide or temozolomide that potentiation is in 68-85% (P＜0.01).
The tumor-inhibiting action of test 10, platinum-like compounds and platinum-like compounds synergist (slow releasing injection)
Measure the tumor-inhibiting action of platinum-like compounds synergist (slow releasing injection) by test 7 described methods, the result shows to be selected from according to platinum-like compounds such as platinum, the platinum that relaxes, bicycloplatin, citricplatin and can significantly strengthen procarbazine, mitozolomide, 4-carboxyl temozolomide or temozolomide's tumor killing effect that potentiation is in 62-82% (P＜0.01).
The test 11, the different molecular weight polylactic acid make according to release ratio in the body of platinum sustained-release implant
With the rat is subjects, grouping (3/group) and in the equivalent of subcutaneous polylactic acid (PLA) carrying that contains different molecular weight (MW) according to the platinum sustained-release implant.Then respectively at 1,3,7,14,21,28
With the surplus of 35 days survey medicines in implant, 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%).What relatively the different molecular weight polylactic acid was made finds according to discharging in the body of platinum sustained-release implant, slack-off with the molecular weight increase, with the 7th day was example, compare with whole body administration group, the bacteriostatic rate increases with the polylactic acid molecule amount and improves, and is followed successively by 68% (MW:5000), 66% (MW:15000), 54% (MW:25000), 50% (MW:40000) and 48 (MW:60000).
Same result also sees the slow releasing agent made from other medicinal slow-release auxiliary material.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), ethylene vinyl acetate copolymer, polylactic acid, the copolymer of polyglycolic acid and hydroxyacetic acid, xylitol, oligosaccharide, chrondroitin, chitin, hyaluronic acid, collagen protein, gelatin, 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, growth all had the obvious suppression effect to kinds of tumor cells when used platinum-like compounds and various platinum-like compounds synergist were used separately, can show significant potentiation when use in conjunction.Therefore, effective ingredient of the present invention (or the more than one) platinum-like compounds that is any one and any one (or more than one) platinum-like compounds 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.
Further discover 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.
It should be noted that especially, in slow releasing agent of the present invention, the drug release characteristic of the slow releasing agent that different medicines is made not only depends on the characteristic of medicine, also be subjected to the influence of slow-release auxiliary material characteristic, comprise ratio, fusing point, water solublity, vitrification point, acid-base value, stability of molecular weight, viscosity, the polymer monomer of Biodegradable high molecular etc.That is to say, be not arbitrarily medicine just can be made into ideal medicinal slow release agent with adjuvant arbitrarily.Specific slow-release auxiliary material with can need could be determined through a large amount of creative work by the selection of the combination of slow releasing pharmaceutical.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.
Slow releasing injection or sustained-release implant also can be further specified by following embodiment.Just the invention will be further described for above-mentioned experiment 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 according to platinum and 10mg Camptothecin, shake up the back again and contain 10% injectable microsphere according to platinum and 10% Camptothecin with spray drying method for preparation.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) the easypro platinum of 2-40%, bicycloplatin, the Camptothecin according to platinum, picoplatin, citricplatin or ZD 0473 and 2-40%, hydroxy-camptothecin alkali, lurtotecan, topotecan, irinotecan, etoposide, teniposide, amrubicin, Ai Rou are than the combination of star, rodorubicin, leurubicin or zorubicin; Or
(b) the easypro platinum of 2-40%, bicycloplatin, procarbazine, mitozolomide, 4-carboxyl temozolomide or temozolomide's combination according to platinum, picoplatin, citricplatin or ZD 0473 and 2-40%.
Used adjuvant is: 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; The viscosity of slow releasing injection is 10cp-650cp (20 ℃-30 ℃ time).
Embodiment 3.
With 70mg molecular weight peak value is that 25000 polylactic acid (PLGA, 75: 25) is put into container, adds 100 milliliters of dichloromethane, behind the dissolving mixing, adds 15mg relax platinum and 15mg hydroxy-camptothecin alkali, 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% easypro platinum 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:
(a) the easypro platinum of 2-40%, bicycloplatin, the Camptothecin according to platinum, picoplatin, citricplatin or ZD 0473 and 2-40%, hydroxy-camptothecin alkali, lurtotecan, topotecan, irinotecan, etoposide, teniposide, amrubicin, Ai Rou are than the combination of star, rodorubicin, leurubicin or zorubicin; Or
(b) the easypro platinum of 2-40%, bicycloplatin, procarbazine, mitozolomide, 4-carboxyl temozolomide or temozolomide's combination according to platinum, picoplatin, citricplatin or ZD 0473 and 2-40%.
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 bicycloplatin, shake up the back contains 20% teniposide and 10% bicycloplatin 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: the easypro platinum of 5-30%, bicycloplatin, the Camptothecin according to platinum, picoplatin, citricplatin or ZD 0473 and 2-40%, hydroxy-camptothecin alkali, lurtotecan, topotecan, irinotecan, etoposide, teniposide, amrubicin, Ai Rou are than the combination of star, rodorubicin, leurubicin or zorubicin.
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 easypro platinum of 20mg and 10mg mitozolomide, shake up the back contains 20% easypro platinum 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: the easypro platinum of 5-30%, bicycloplatin, the procarbazine according to platinum, picoplatin, citricplatin or ZD 0473 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 according to platinum, shake up the back again and contain 20% hydroxy-camptothecin alkali and 10% injectable microsphere according to platinum with spray drying method for preparation.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 easypro platinum of 5-30%, bicycloplatin, the Camptothecin according to platinum, picoplatin, citricplatin or ZD 0473 and 2-40%, hydroxy-camptothecin alkali, lurtotecan, topotecan, irinotecan, etoposide, teniposide, amrubicin, Ai Rou are than the combination of star, rodorubicin, leurubicin or zorubicin.
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 the easypro platinum of 10mg procarbazine and 20mg, shake up the back contains 10% procarbazine and 20% easypro platinum 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 the easypro platinum of the 5-30% of star, detorubicin, esorubicin, rodorubicin, leurubicin or zorubicin and 10-30%, bicycloplatin, according to the combination of platinum, picoplatin, citricplatin or ZD 0473.
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 citricplatin, shake up the back contains 10% etoposide and 20% citricplatin 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 35-50 days at the subcutaneous drug release time of mice.
Embodiment 14
The method step that is processed into sustained-release implant is identical with embodiment 11,13, but different is that contained anticancer effective component is: 15% Camptothecin, hydroxy-camptothecin alkali, 9-nitro Camptothecin, podophyllotoxin, trihydroxy-isoflavone, lurtotecan, topotecan, irinotecan, etoposide, teniposide, 14-doxorubicin, amrubicin, Ai Rou are than the easypro platinum of the 5-30% of star, detorubicin, esorubicin, rodorubicin, leurubicin or zorubicin and 15%, bicycloplatin, according to the combination of platinum, picoplatin, citricplatin or ZD 0473.
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;
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 1-15, 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:
(a) the easypro platinum of 2-40%, bicycloplatin, the Camptothecin according to platinum, picoplatin, citricplatin or ZD 0473 and 2-40%, hydroxy-camptothecin alkali, lurtotecan, topotecan, irinotecan, etoposide, teniposide, amrubicin, Ai Rou are than the combination of star, rodorubicin, leurubicin or zorubicin; Or
(b) the easypro platinum of 2-40%, bicycloplatin, procarbazine, mitozolomide, 4-carboxyl temozolomide or temozolomide's combination according to platinum, picoplatin, citricplatin or ZD 0473 and 2-40%.
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 (10)

1. a slow releasing injection that contains platinum-like compounds and its synergist is become to be grouped into by following:
(A) sustained-release microparticle, the one-tenth following by percentage by weight is grouped into:
Anticancer effective component 0.5-60%
Slow-release auxiliary material 41-99.9%
Suspending agent 0.0-30%
(B) solvent is divided into common solvent and special solvent.
Wherein, effective ingredient can be and be selected from easypro platinum, according to the platinum-like compounds of platinum, bicycloplatin, picoplatin, citricplatin or ZD 0473 and the combination that is selected from the platinum-like compounds synergist of topoenzyme inhibitor and/or tetrazine kind compound;
Slow-release auxiliary material is selected from one of following or its combination:
A) polylactic acid;
B) copolymer of polyglycolic acid and hydroxyacetic acid;
C) polifeprosan;
D) ethylene vinyl acetate copolymer;
E) bis-fatty acid and decanedioic acid copolymer;
F) poly-(erucic acid dimer-decanedioic acid) copolymer;
G) poly-(fumaric acid-decanedioic acid) copolymer, xylitol, oligosaccharide, chrondroitin, chitin, hyaluronic acid, collagen protein, gelatin, white tempera;
H) 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.
Special solvent is the common solvent that contains suspending agent, the suspending agent viscosity is 100cp-3000cp (20 ℃-30 ℃ time), is selected from one of sodium carboxymethyl cellulose, (iodine) glycerol, simethicone, propylene glycol, carbomer, mannitol, sorbitol, surfactant, soil temperature 20, soil temperature 40 and soil temperature 80 or its combination.
2. the anticancer medicine slow-release preparation containing according to claim 1 is characterized in that topoenzyme inhibitor is selected from Camptothecin, hydroxy-camptothecin alkali, 9-nitro Camptothecin, podophyllotoxin, trihydroxy-isoflavone, lurtotecan, topotecan, irinotecan, etoposide, teniposide, 14-doxorubicin, amrubicin, Ai Rou than one of star, detorubicin, esorubicin, rodorubicin, leurubicin, zorubicin or its combination.
3. the anticancer medicine slow-release preparation containing according to claim 1 is characterized in that tetrazine kind compound is selected from one of procarbazine, mitozolomide, 4-carboxyl temozolomide, temozolomide or its combination.
4. the anti-cancer medicine sustained-release injection according to claim 1 is characterized in that the anticancer effective component of slow-releasing anticarcinogen injection and percentage by weight are:
(a) the easypro platinum of 2-40%, bicycloplatin, the Camptothecin according to platinum, picoplatin, citricplatin or ZD 0473 and 2-40%, hydroxy-camptothecin alkali, lurtotecan, topotecan, irinotecan, etoposide, teniposide, amrubicin, Ai Rou are than the combination of star, rodorubicin, leurubicin or zorubicin; Or
(b) the easypro platinum of 2-40%, bicycloplatin, procarbazine, mitozolomide, 4-carboxyl temozolomide or temozolomide's combination according to platinum, picoplatin, citricplatin or ZD 0473 and 2-40%.
5. the slow-releasing anticarcinogen injection according to claim 1 is characterized in that slow-release auxiliary material is selected from one of following or its combination:
A) polylactic acid, 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;
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.
6. the slow-releasing anticarcinogen injection according to claim 1 is characterized in that used suspending agent is respectively:
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.
7. the slow-releasing anticarcinogen injection according to claim 1 is characterized in that sustained-release micro-spheres and/or the anticancer effective component in the slow-releasing anticarcinogen injection is used to prepare sustained-release implant.
8. the anti-cancer sustained-released implantation agent according to claim 7 is characterized in that the anticancer effective component of anti-cancer sustained-released implantation agent and percentage by weight thereof are:
(a) the easypro platinum of 2-40%, bicycloplatin, the Camptothecin according to platinum, picoplatin, citricplatin or ZD 0473 and 2-40%, hydroxy-camptothecin alkali, lurtotecan, topotecan, irinotecan, etoposide, teniposide, amrubicin, Ai Rou are than the combination of star, rodorubicin, leurubicin or zorubicin; Or
(b) the easypro platinum of 2-40%, bicycloplatin, procarbazine, mitozolomide, 4-carboxyl temozolomide or temozolomide's combination according to platinum, picoplatin, citricplatin or ZD 0473 and 2-40%.
Slow-release auxiliary material is selected from one of following or its combination:
A) polylactic acid;
B) copolymer of polyglycolic acid and hydroxyacetic acid;
C) polifeprosan;
D) ethylene vinyl acetate copolymer;
E) bis-fatty acid and decanedioic acid copolymer;
F) poly-(erucic acid dimer-decanedioic acid) copolymer;
G) poly-(fumaric acid-decanedioic acid) copolymer, xylitol, oligosaccharide, chrondroitin, chitin, hyaluronic acid, collagen protein, gelatin, white tempera;
H) 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.
9. the anti-cancer sustained-released implantation agent according to claim 7 is characterized in that,
In the slow-release auxiliary material:
A) the molecular weight peak value of polylactic acid is selected from 10000-30000,300000-60000,60000-100000 or 100000-150000;
B) in the copolymer of polyglycolic acid and hydroxyacetic acid, the ratio of polyglycolic acid and hydroxyacetic acid is 50-95: 50-50, and the molecular weight peak value is 10000-30000,300000-60000,60000-100000 or 100000-150000;
C) in the polifeprosan, to carboxy phenyl propane: the certain herbaceous plants with big flowers diacid is 10: 90,20: 80,30: 70,40: 60,50: 50 or 60: 40.
10. the anti-cancer sustained-released implantation agent according to claim 7 is characterized in that,
Anticancer effective component and percentage by weight thereof are:
(a) the easypro platinum of 5-30%, bicycloplatin, the Camptothecin according to platinum, picoplatin, citricplatin or ZD 0473 and 5-30%, hydroxy-camptothecin alkali, lurtotecan, topotecan, irinotecan, etoposide, teniposide, amrubicin, Ai Rou are than the combination of star, rodorubicin, leurubicin or zorubicin; Or
(b) the easypro platinum of 5-30%, bicycloplatin, procarbazine, mitozolomide, 4-carboxyl temozolomide or temozolomide's combination according to platinum, picoplatin, citricplatin or ZD 0473 and 5-30%.
CNA2006102005931A 2006-06-21 2006-06-21 Slow-release injection contg. platinum compounds and its potentiator Pending CN1868454A (en)

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8168661B2 (en) 2006-11-06 2012-05-01 Poniard Pharmaceuticals, Inc. Use of picoplatin to treat colorectal cancer
US8168662B1 (en) 2006-11-06 2012-05-01 Poniard Pharmaceuticals, Inc. Use of picoplatin to treat colorectal cancer
US8173686B2 (en) 2006-11-06 2012-05-08 Poniard Pharmaceuticals, Inc. Use of picoplatin to treat colorectal cancer
US8178564B2 (en) 2006-11-06 2012-05-15 Poniard Pharmaceuticals, Inc. Use of picoplatin to treat colorectal cancer

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8168661B2 (en) 2006-11-06 2012-05-01 Poniard Pharmaceuticals, Inc. Use of picoplatin to treat colorectal cancer
US8168662B1 (en) 2006-11-06 2012-05-01 Poniard Pharmaceuticals, Inc. Use of picoplatin to treat colorectal cancer
US8173686B2 (en) 2006-11-06 2012-05-08 Poniard Pharmaceuticals, Inc. Use of picoplatin to treat colorectal cancer
US8178564B2 (en) 2006-11-06 2012-05-15 Poniard Pharmaceuticals, Inc. Use of picoplatin to treat colorectal cancer

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