CN101249067A - Anticancer sustained-release injection containing tumour medicament-resistant reverse agent and cell toxicity medicament - Google Patents

Abstract

An anticancer sustained-release injection is provided, which contains tumor multidrug resistance reversal agent and cytotoxic drugs. The anticancer sustained-release injection comprises sustained-release microspheres and solvents, wherein the sustained-release microspheres contain anticancer active components and sustained-release adjuvant, and the solvents are special solvents containing a suspending agent. The anticancer active components comprise a tumor multidrug resistance reversal agent selected from nelarabine, zarnestra, ropinirole and valspodar and/or a cytotoxic drug selected from cyclophosphamide, carmustine, nimustine, camptothecin, paclitaxel, cisplatin, carboplatin, vincristine, buthionine sulfoximine, O6-benzyladenine and O4-benzyl folic acid. The sustained-release adjuvant is selected from polifeprosan, di-fatty acid-decanedioic acid copolymer, polylactic acid and EVAc. The suspending agent has a viscocity of 100-3000 cp (25-30 DEG C) and is preferably sodium carboxymethylcellulose. The sustained-release microspheres can also be formulated as sustained-release implants or gel injections for injection or implantation in tumors or around tumors, to inhibit tumor cells and selectively enhance the therapeutic effect of nonoperative treatment such as chemotherapy.

Description

The slow-releasing anticarcinogen injection that contains tumor drug resistance reversal agent and cell toxicity medicament

(1) technical field

The present invention relates to a kind of slow-releasing anticarcinogen injection that contains tumor drug resistance reversal agent and cell toxicity medicament and preparation method thereof, belong to technical field of pharmaceuticals.Particularly, the invention provides a kind of anticancer medicine slow-release preparation containing that contains tumor drug resistance reversal agent and/or cell toxicity medicament, be mainly slow releasing injection and sustained-release implant.

(2) background technology

As one of cancer conventional treatments, the medicine chemotherapy has been widely used in the treatment of multiple malignant tumor, and action effect is comparatively obvious.Yet its tangible general toxicity and chemical sproof generation have greatly limited the application of this medicine.Wherein, tumor cell produces the major reason that drug resistance is the clinical chemotherapy failure to chemotherapeutics.Therefore, seeking reversal agent of drug resistance (RRA) is one of Critical policies of antitumor drug research.

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

Moreover, 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)).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

Cancer therapy drug especially cell toxicity medicament has been widely used in the multiple entity tumor of treatment both at home and abroad, as the cerebral tumor, pulmonary carcinoma, digestive tract tumor etc. as cancer therapy drug commonly used.Yet in application process, its tangible general toxicity has greatly limited the application of this medicine, and chemical sproof generation often causes the treatment failure.

The major reason of clinical chemotherapy failure is that tumor cell produces drug resistance to chemotherapeutics, and the cause of the death of most of tumour patients is directly or indirectly relevant with drug resistance.Therefore, seeking reversal agent of drug resistance is one of Critical policies of antitumor drug research.

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, many entity tumors are relatively poor to the sensitivity of anticarcinogen, and are easy to generate drug resistance in therapeutic process, and the latter often is the main cause of treatment failure.The present invention finds that through a large amount of experiments cell toxicity medicament of mentioning among the present invention and tumor drug resistance reversal agent (RRA) share its antitumaous effect is strengthened mutually.In addition, with the said medicine assembly packaging 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.Medicine can suppress effectively or destroy outside the tumor tumor cell tumor growth, can also increase the sensitivity of tumor cell to cancer therapy drug.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 tumor drug resistance reversal agent (RRA) and/or cell toxicity medicament is provided.

Tumor drug resistance reversal agent slow releasing injection of the present invention is made up of sustained-release micro-spheres and solvent.Particularly, this slow-releasing anticarcinogen injection is grouped into by following one-tenth:

(A) sustained-release micro-spheres comprises:

Anticancer effective component 0.5-60%

Slow-release auxiliary material 40-99%

Suspending agent 0.0-30%

More than be weight percentage

With

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

Wherein,

Anticancer effective component is tumor drug resistance reversal agent and/or cell toxicity medicament; 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.

Tumor drug resistance reversal agent is selected from one of following or combination: as nelarabine 506u (nelarabine), Zarnestra (Tipifarnib, trade name Zarnestra), SCH-66336 (Lonafarnib, have another name called SCH-66336), Valspodar (valspodar, commodity are called Amdray), pemetrexed, Raltitrexed, 2-Amino-6-methyl-5-(pyridin-4-ylsulfanyl)-3H-quinazolin-4-one.Above tumor drug resistance reversal agent also comprises their salt, as, but be not limited to sulfate, phosphate, hydrochlorate, Lactobionate, acetate, aspat, nitrate, citrate, purine or pyrimidine salt, succinate and maleate etc.

Above-mentioned tumor drug resistance reversal agent shared ratio 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.

Cell toxicity medicament comprises and is selected from Camptothecin, procarbazine, paclitaxel, cisplatin, carboplatin, Chlorambucil, cyclophosphamide, carmustine, nimustine, irinotecan, vincristine, leuprorelin, colchicine, aminotriazole(ATA), DL-Buthionine-(S,R)-sulfoximine BSO [DL-Buthionine-(S, R)-sulfoximine, be called for short BSO], one of O6-benzyl guanine, O4-benzyl folic acid (O4-benzylfolic acid) or its combination.

The percentage by weight of above-mentioned cell toxicity medicament in slow releasing agent is good from 0.01%-80% with 1%-40%, is best with 5%-30%.

When the anticancer effective component in the medicament slow-release microsphere only is tumor drug resistance reversal agent or cell toxicity medicament, slow-releasing anticarcinogen injection is mainly used in the tumor drug resistance reversal agent of other approach application of increase or the action effect of cell toxicity medicament, or is used for the potentiation to radiotherapy or other therapies.When the anticancer effective component in the medicament slow-release microsphere only was tumor drug resistance reversal agent or its synergist (cell toxicity medicament), the application of slow-releasing anticarcinogen injection and potentiation mode were:

(1) contain the slow releasing injection local injection of tumor drug resistance reversal agent, and cell toxicity medicament is used through other approach;

(2) local injection contains the slow releasing injection of cell toxicity medicament, and other approach are used tumor drug resistance reversal agent;

(3) local injection contains the slow releasing injection and the slow releasing injection that contains cell toxicity medicament of tumor drug resistance reversal agent; Or

(4) local injection contains the slow releasing injection of tumor drug resistance reversal agent and cell toxicity medicament.

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

Anticancer effective component tumor drug resistance reversal agent and/or the cell toxicity medicament percentage by weight in medicament slow-release microsphere is 0.5%-60%, is good with 2%-40%, is best with 5%-30%.The weight ratio of tumor drug resistance reversal agent and cell toxicity medicament 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) nelarabine 506u of 1-40%, Zarnestra, SCH-66336, Valspodar, 2-Amino-6-methyl-5-(pyridin-4-ylsulfanyl)-3H-quinazolin-4-one, pemetrexed or Raltitrexed;

(b) Camptothecin of 1-40%, procarbazine, paclitaxel, cisplatin, carboplatin, Chlorambucil, cyclophosphamide, carmustine, nimustine, irinotecan, vincristine, leuprorelin, colchicine, aminotriazole(ATA), DL-Buthionine-(S,R)-sulfoximine BSO, O6-benzyl guanine or O4-benzyl folic acid; Or

(c) combination of the Camptothecin of the nelarabine 506u of 1-40%, Zarnestra, SCH-66336, Valspodar, 2-Amino-6-methyl-5-(pyridin-4-ylsulfanyl)-3H-quinazolin-4-one, pemetrexed or Raltitrexed and 1-40%, procarbazine, paclitaxel, cisplatin, carboplatin, Chlorambucil, cyclophosphamide, carmustine, nimustine, irinotecan, vincristine, leuprorelin, colchicine, aminotriazole(ATA), DL-Buthionine-(S,R)-sulfoximine BSO, O6-benzyl guanine or O4-benzyl folic acid.

Slow-release auxiliary material can be various water solublity or water-insoluble macromolecule polymer, copolymer (PLGA), ethylene vinyl acetate copolymer (EVAc), polifeprosan, bis-fatty acid and the decanedioic acid copolymer (PFAD-SA) of preferred polylactic acid (PLA), polyglycolic acid and hydroxyacetic acid, one of poly-(erucic acid dimer-decanedioic acid) [P (EAD-SA)], poly-(fumaric acid-decanedioic acid) [P (FA-SA)] or its combination in multiple slow-release auxiliary material.

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 be for arbitrarily, but preferably 1-99% and 99-1%.The molecular weight peak value of polylactic acid can be, but is not limited to, 5000-200, and 000, but with 20,000-60,000 is preferred, with 30,000-50,000 for most preferably; The molecular weight of polyglycolic acid can be, but is not limited to, 5000-200, and 000, but with 20,000-60,000 is preferred, with 30,000-50,000 for most preferably; Above polyhydroxy acid can singly select or multiselect.When singly selecting, serve as preferred with the copolymer (PLGA) of polylactic acid (PLA) or hydroxy carboxylic acid and glycolic, the molecular weight of copolymer can be, but is not limited to, 5000-200,000, 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 10000 to 100000 polylactic acid with molecular weight is that 20000 to 150000 polylactic acid mixes, molecular weight is 10000 to 100000 polylactic acid with molecular weight is that 30000 to 80000 PLGA mixes, molecular weight is that 20000 to 30000 polylactic acid mixes with decanedioic acid, molecular weight is that 30000 to 80000 PLGA mixes with decanedioic acid.

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

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

For regulating drug releasing rate or changing other characteristic of the present invention, can change the composition and the proportioning of monomer component or molecular weight, interpolation or the adjusting pharmaceutic adjuvant of polymer, add the water-soluble low-molecular chemical compound, as, but be not limited to various sugar or salt etc.Wherein sugar can be, but is not limited to, xylitol, oligosaccharide, (sulphuric acid) chrondroitin and chitin etc., and wherein salt can be, but is not limited to, potassium salt and sodium salt etc.; Also can add other pharmaceutic adjuvant, as but be not limited to filler, solubilizing agent, absorption enhancer, film former, gellant, system (or causing) hole agent, excipient or blocker etc.

In the slow releasing injection, drug sustained release system can be made into microsphere, sub-micro ball, microemulsion, nanosphere, granule or spherical piller, makes the injection use then with after the injection solvent mixes.In various slow releasing injection, serve as preferred with the suspension type slow releasing injection, the suspension type slow releasing injection is the preparation that the drug sustained release system that will contain anticancer component is suspended in gained in the injection, used slow-release auxiliary material is a kind of or its combination in the above-mentioned slow-release auxiliary material, and used solvent is common solvent or the special solvent that contains suspending agent.Common solvent is, but is not limited to the buffer that distilled water, water for injection, physiology are prepared towards liquid, dehydrated alcohol or various salt.The purpose of suspending agent is the pastille microsphere that effectively suspends, thereby is beneficial to the usefulness of injection.Be convenient injection, the viscosity of suspending agent is 100cp-3000cp (20 ℃-30 ℃ time), preferred 1000cp-3000cp (20 ℃-30 ℃ time), most preferably 1500cp-3000cp (20 ℃-30 ℃ time).Suspending agent is selected from one of sodium carboxymethyl cellulose, (iodine) glycerol, simethicone, propylene glycol, carbomer, mannitol, sorbitol, surfactant, soil temperature 20, soil temperature 40 and soil temperature 80 or its combination.

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

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

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

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

The kind of solvent is then depended in the preparation of solvent, and common solvent has commercially available, also can make by oneself, and as distilled water, water for injection, physiology buffer towards liquid, dehydrated alcohol or the preparation of various salt, but must be in strict accordance with related standards.Special solvent need be considered the kind of suspending agent and the medicine that composition, solvent suspended, composition, character and the requirement thereof of sustained-release micro-spheres (or microcapsule) and the preparation method of injection, as sodium carboxymethyl cellulose (1.5%)+mannitol and/or sorbitol (15%) and/or Tween 80 (0.1%) are dissolved in the normal saline corresponding solvent, viscosity is at 10cp-650cp (20 ℃-30 ℃ time).

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

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

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

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

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

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

The 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 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, is 0.5-1.0,1.0-1.5,1.5-2.0cm as the diameter of tablet, and thickness is 0.01-0.05,0.05-0.1,0.1-0.5cm; The stick external diameter is 0.05-0.1,0.1-0.3,0.3-0.8cm, and length is 0.1-0.3,0.3-1.0,1-2cm.

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 potentiation mode of sustained-release implant, anticancer effective component form and the percentage by weight in preparation can be preferably as follows with reference to slow releasing injection:

(a) nelarabine 506u of 5-30%, Zarnestra, SCH-66336, Valspodar, 2-Amino-6-methyl-5-(pyridin-4-ylsulfanyl)-3H-quinazolin-4-one, pemetrexed or Raltitrexed;

(b) Camptothecin of 5-30%, procarbazine, paclitaxel, cisplatin, carboplatin, Chlorambucil, cyclophosphamide, carmustine, nimustine, irinotecan, vincristine, leuprorelin, colchicine, aminotriazole(ATA), DL-Buthionine-(S,R)-sulfoximine BSO, O6-benzyl guanine or O4-benzyl folic acid; Or

(c) combination of the Camptothecin of the nelarabine 506u of 5-30%, Zarnestra, SCH-66336, Valspodar, 2-Amino-6-methyl-5-(pyridin-4-ylsulfanyl)-3H-quinazolin-4-one, pemetrexed or Raltitrexed and 5-30%, procarbazine, paclitaxel, cisplatin, carboplatin, Chlorambucil, cyclophosphamide, carmustine, nimustine, irinotecan, vincristine, leuprorelin, colchicine, aminotriazole(ATA), DL-Buthionine-(S,R)-sulfoximine BSO, O6-benzyl guanine or O4-benzyl folic acid.

Slow-release auxiliary material can be various water solublity or water-insoluble macromolecule polymer, copolymer (PLGA), ethylene vinyl acetate copolymer (EVAc), polifeprosan, bis-fatty acid and the decanedioic acid copolymer (PFAD-SA) of preferred polylactic acid (PLA), polyglycolic acid and hydroxyacetic acid, one of poly-(erucic acid dimer-decanedioic acid) [P (EAD-SA)], poly-(fumaric acid-decanedioic acid) [P (FA-SA)] or its combination in multiple slow-release auxiliary material.

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 tumor drug resistance reversal agent or its synergist (cytotoxic drug), 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 tumor drug resistance reversal agent (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 1 cm diameter its grouping.Every group of dosage is the 5mg/kg Raltitrexed.Measure medicament contg (%) in the different time tumor, the result shows, the local drug concentration 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.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 tumor drug resistance reversal agent (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 0.5 cm diameter its grouping.Every group of dosage is the 5mg/kg pemetrexed.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 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.Good effect not only, toxic and side effects is also little.

Tumor-inhibiting action in the body of test 3, tumor drug resistance reversal agent and cell toxicity medicament (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	68±10
2(6)	Paclitaxel	44±5.2	＜0.05
				3(6)	Nelarabine 506u	42±2.0	＜0.01
4(6)	Zarnestra	46±4.2	＜0.01
				5(6)	SCH-66336	38±2.2	＜0.01
6(6)	Valspodar	42±3.4	＜0.01
				7(6)	Paclitaxel+nelarabine 506u	18±2.0	＜0.001
8(6)	Paclitaxel+Zarnestra	24±2.4	＜0.001
				9(6)	Paclitaxel+SCH-66336	22±2.2	＜0.001
10(6)	Paclitaxel+Valspodar	20±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 tumor drug resistance reversal agent (nelarabine 506u, Zarnestra, SCH-66336, Valspodar) and its synergist (paclitaxel), can show significant potentiation when use in conjunction.This discovery constitutes the another key character of the present invention.

The tumor-inhibiting action of test 4, tumor drug resistance reversal agent and cell toxicity medicament (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.Tumor drug resistance reversal agent and cell toxicity medicament 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	Camptothecin	Nelarabine 506u	Zarnestra	SCH-66336	Camptothecin+nelarabine 506u	Camptothecin+Zarnestra	Camptothecin+SCH-66336
								CNS	38％	42％	42％	36％	90％	86％	88％
C6	40％	52％	38％	24％	84％	88％	92％
								SA	38％	42％	42％	20％	88％	88％	90％
BC	48％	46％	34％	34％	88％	86％	80％
								BA	44％	42％	42％	16％	88％	78％	88％
LH	38％	52％	28％	38％	80％	86％	82％
								PAT	42％	42％	36％	38％	80％	88％	82％

Above result shows, growth all has the obvious suppression effect to kinds of tumor cells when this concentration is used separately for used cell toxicity medicament (Camptothecin) and tumor drug resistance reversal agent (nelarabine 506u, Zarnestra, SCH-66336), can show significant potentiation when use in conjunction.

The tumor-inhibiting action of test 5, tumor drug resistance reversal agent and cell toxicity medicament (slow releasing injection)

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

Table 3

Test group (n)	Suffered treatment	Gross tumor volume (cm 3)	The P value
				1(6)	Contrast	60±10
2(6)	Pemetrexed	42±4.2	＜0.05
				3(6)	Nimustine	34±2.0	＜0.01
4(6)	Pemetrexed+nimustine	20±2.0	＜0.001
				5(6)	Carmustine	36±3.2	＜0.01
6(6)	Pemetrexed+carmustine	18±1.6	＜0.001
				7(6)	Cisplatin	32±2.8	＜0.01
8(6)	Pemetrexed+cisplatin	22±2.4	＜0.001
				9(6)	Carboplatin	40±4.0	＜0.01
10(6)	Pemetrexed+carboplatin	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 used tumor drug resistance reversal agent (pemetrexed) and cell toxicity medicament (nimustine, carmustine, cisplatin, carboplatin), can show significant potentiation when use in conjunction.This discovery constitutes the another key character of the present invention.

The tumor-inhibiting action of test 6, tumor drug resistance reversal agent and cell toxicity medicament (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 (tumor drug resistance reversal agent or cell toxicity medicament) and therapeutic alliance group (tumor drug resistance reversal agent and cell toxicity medicament).Medicine is through intratumor injection.Dosage is 5mg/kg.The treatment back was measured the gross tumor volume size on the 10th day, made relatively therapeutic effect (seeing Table 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)	Raltitrexed	48	＜0.05
				3(6)	Aminotriazole(ATA)	38	＜0.01
4(6)	DL-Buthionine-(S,R)-sulfoximine BSO	40	＜0.01
				5(6)	O6-benzyl guanine	50	＜0.01
6(6)	O4-benzyl folic acid	40	＜0.01
				7(6)	Raltitrexed+aminotriazole(ATA)	78	＜0.001
8(6)	Raltitrexed+DL-Buthionine-(S,R)-sulfoximine BSO	64	＜0.001
				9(6)	Raltitrexed+O6-benzyl guanine	68	＜0.001
10(6)	Raltitrexed+O4-benzyl folic acid	72	＜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 tumor drug resistance reversal agent (Raltitrexed) and cell toxicity medicament (aminotriazole(ATA), DL-Buthionine-(S,R)-sulfoximine BSO, O6-benzyl guanine, O4-benzyl folic acid), can show significant potentiation when use in conjunction.

The tumor-inhibiting action of test 7, tumor drug resistance reversal agent and cell toxicity medicament (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.Medicine is through intratumor injection.Dosage is 5mg/kg.The treatment back was measured the gross tumor volume size on the 10th day, made relatively therapeutic effect (seeing Table 5) of index with inhibition rate of tumor growth.

Table 5

Test group (n)	Suffered treatment	Tumor control rate (%)	The P value
				1(6)	Contrast
2(6)	2-Amino-6-methyl-5-(pyridin-4-ylsulfanyl)-3H-quinazolin-4-one	48	＜0.05
				3(6)	Chlorambucil	44	＜0.01
4(6)	Carmustine	66	＜0.01
				5(6)	Cyclophosphamide	48	＜0.01
6(6)	Nimustine	64	＜0.01
				7(6)	2-Amino-6-methyl-5-(pyridin-4-ylsulfanyl)-3H-quinazolin-4-one+Chlorambucil	88	＜0.001
8(6)	2-Amino-6-methyl-5-(pyridin-4-ylsulfanyl)-3H-quinazolin-4-one+carmustine	84	＜0.001
				9(6)	2-Amino-6-methyl-5-(pyridin-4-ylsulfanyl)-3H-quinazolin-4-one+cyclophosphamide	80	＜0.001
10(6)	2-Amino-6-methyl-5-(pyridin-4-ylsulfanyl)-3H-quinazolin-4-one+nimustine	76	＜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 tumor drug resistance reversal agent (2-Amino-6-methyl-5-(pyridin-4-ylsulfanyl)-3H-quinazolin-4-one) and cell toxicity medicament (Chlorambucil, carmustine, cyclophosphamide, nimustine), can show significant potentiation when use in conjunction.This discovery constitutes the another key character of the present invention.

The tumor-inhibiting action of test 8, tumor drug resistance reversal agent and cell toxicity medicament (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.Sustained-release implant is placed in tumor.Dosage is 5mg/kg.The treatment back was measured the gross tumor volume size on the 10th day, made relatively therapeutic effect (seeing Table 6) of index with inhibition rate of tumor growth.

Table 6

Test group (n)	Suffered treatment	Tumor control rate (%)	The P value
				1(6)	Contrast
2(6)	Valspodar	38	＜0.05
				3(6)	Vincristine	48	＜0.01
4(6)	Irinotecan	46	＜0.01
				5(6)	Leuprorelin	42	＜0.01
6(6)	Colchicine	38	＜0.01
				7(6)	Valspodar+vincristine	88	＜0.001
8(6)	Valspodar+irinotecan	80	＜0.001
				9(6)	Valspodar+leuprorelin	82	＜0.001
10(6)	Valspodar+colchicine	84	＜0.001

Above result shows, growth all has the obvious suppression effect to kinds of tumor cells when this concentration is used separately for used tumor drug resistance reversal agent (Valspodar) and cell toxicity medicament (irinotecan, vincristine, leuprorelin, colchicine), can show significant potentiation when use in conjunction.This discovery constitutes the another key character of the present invention.

The tumor-inhibiting action of test 9, tumor drug resistance reversal agent and cell toxicity medicament (slow releasing injection)

Measure the tumor-inhibiting action of cell toxicity medicament (slow releasing injection) by test 7 described methods, the result shows the Camptothecin that is selected from, procarbazine, paclitaxel, cisplatin, carboplatin, Chlorambucil, cyclophosphamide, carmustine, nimustine, irinotecan, vincristine, leuprorelin, colchicine, aminotriazole(ATA), DL-Buthionine-(S,R)-sulfoximine BSO, cell toxicity medicaments such as O6-benzyl guanine or O4-benzyl folic acid can significantly strengthen nelarabine 506u, Zarnestra, SCH-66336, Valspodar, 2-Amino-6-methyl-5-(pyridin-4-ylsulfanyl)-3H-quinazolin-4-one, the tumor killing effect of tumor drug resistance reversal agent such as pemetrexed or Raltitrexed, potentiation is in 38-60% (P＜0.01).

Significant potentiation also sees the potentiation to Camptothecin, procarbazine, paclitaxel, cisplatin, carboplatin, Chlorambucil, cyclophosphamide, carmustine, nimustine, irinotecan, vincristine, leuprorelin or colchicine of aminotriazole(ATA), DL-Buthionine-(S,R)-sulfoximine BSO, O6-benzyl guanine or O4-benzyl folic acid; Camptothecin, procarbazine, paclitaxel, cisplatin, carboplatin or Chlorambucil are to the potentiation of cyclophosphamide, carmustine, nimustine, irinotecan, vincristine, leuprorelin or colchicine.

In a word, growth all had the obvious suppression effect to kinds of tumor cells when used tumor drug resistance reversal agent and/or various cell toxicity medicament were used separately, can show significant potentiation when use in conjunction.Therefore, effective ingredient of the present invention be any one tumor drug resistance reversal agent and/or with any one or several cell toxicity medicament.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 paclitaxel and 10mg pemetrexed, shake up the back contains 10% paclitaxel and 10% pemetrexed with spray drying method for preparation injectable microsphere again.Then microsphere is suspended in the normal saline that contains 15% mannitol, makes corresponding suspension type slow releasing injection, viscosity is 220cp-460cp (20 ℃-30 ℃ time).The drug release time of this slow releasing injection in external normal saline is 10-15 days, is about 20-30 days at the subcutaneous drug release time of mice.

Embodiment 2.

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

(1) Camptothecin of 2-40%, procarbazine, paclitaxel, cisplatin, carboplatin, Chlorambucil, cyclophosphamide, carmustine, nimustine, irinotecan, vincristine, leuprorelin, colchicine, aminotriazole(ATA), DL-Buthionine-(S,R)-sulfoximine BSO, O6-benzyl guanine or O4-benzyl folic acid;

(2) nelarabine 506u of 2-40%, Zarnestra, SCH-66336, Valspodar, 2-Amino-6-methyl-5-(pyridin-4-ylsulfanyl)-3H-quinazolin-4-one, pemetrexed or Raltitrexed; Or

(3) combination of nelarabine 506u, Zarnestra, SCH-66336, Valspodar, 2-Amino-6-methyl-5-(pyridin-4-ylsulfanyl)-3H-quinazolin-4-one, pemetrexed or the Raltitrexed of the Camptothecin of 2-40%, procarbazine, paclitaxel, cisplatin, carboplatin, Chlorambucil, cyclophosphamide, carmustine, nimustine, irinotecan, vincristine, leuprorelin, colchicine, aminotriazole(ATA), DL-Buthionine-(S,R)-sulfoximine BSO, O6-benzyl guanine, O4-benzyl folic acid and 2-40%.

Embodiment 3.

With 70mg molecular weight peak value is that 65000 polylactic acid (PLGA, 75: 25) is put into container, adds 100 milliliters of dichloromethane, behind the dissolving mixing, adds 15mg Raltitrexed and 15mg nimustine, 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% Raltitrexed and 15% nimustine, be suspended in then in the normal saline that contains 1.5% sodium carboxymethyl cellulose, make corresponding suspension type slow releasing injection, viscosity is 300cp-400cp (20 ℃-30 ℃ time).The drug release time of this slow releasing injection in external normal saline is 10-15 days, is about 20-30 days at the subcutaneous drug release time of mice.

Embodiment 4

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

(1) Camptothecin of 2-40%, paclitaxel, cisplatin, carboplatin, cyclophosphamide, nimustine or carmustine;

(2) combination of the Camptothecin of the nelarabine 506u of 2-40%, Zarnestra, SCH-66336, Valspodar, 2-Amino-6-methyl-5-(pyridin-4-ylsulfanyl)-3H-quinazolin-4-one, pemetrexed or Raltitrexed and 2-40%, paclitaxel, cisplatin, carboplatin, cyclophosphamide, nimustine or carmustine.

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 vincristine and 10 milligrams of 2-Amino-6-methyl-5-(pyridin-4-ylsulfanyl)-3H-quinazolin-4-ones, shake up the back contains 20% vincristine and 10% 2-Amino-6-methyl-5-(pyridin-4-ylsulfanyl)-3H-quinazolin-4-one 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, viscosity is 100cp-200cp (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 combination of nelarabine 506u, Zarnestra, SCH-66336, Valspodar, 2-Amino-6-methyl-5-(pyridin-4-ylsulfanyl)-3H-quinazolin-4-one, pemetrexed or the Raltitrexed of the vincristine of 2-40%, leuprorelin, colchicine, aminotriazole(ATA), DL-Buthionine-(S,R)-sulfoximine BSO, O6-benzyl guanine, O4-benzyl folic acid and 2-40%.

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 Valspodar and 10mg camptothecine, shake up the back contains 20% Valspodar and 10% camptothecine with spray drying method for preparation injectable microsphere again.Microsphere is suspended in the normal saline that contains 1.5% sodium carboxymethyl cellulose and 0.5% Tween 80 then, makes corresponding suspension type slow releasing injection, viscosity is 80cp-150cp (20 ℃-25 ℃ 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 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 combination of the Camptothecin of the nelarabine 506u of 2-40%, Zarnestra, SCH-66336, Valspodar, 2-Amino-6-methyl-5-(pyridin-4-ylsulfanyl)-3H-quinazolin-4-one, pemetrexed or Raltitrexed and 2-40%, paclitaxel, cisplatin, carboplatin, cyclophosphamide, nimustine or carmustine.

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 pemetrexed and 10mg carmustine, shake up the back contains 20% pemetrexed and 10% with spray drying method for preparation carmustine injectable microsphere again.Then microsphere is suspended in the normal saline that contains 1.5% sodium carboxymethyl cellulose and 15% sorbitol and 0.2% Tween 80, makes corresponding suspension type slow releasing injection, viscosity is 560cp-640cp (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 combination of 20% nelarabine 506u, Zarnestra, SCH-66336, Valspodar, 2-Amino-6-methyl-5-(pyridin-4-ylsulfanyl)-3H-quinazolin-4-one, pemetrexed or Raltitrexed and 10% Camptothecin, paclitaxel, cisplatin, carboplatin, cyclophosphamide, nimustine or carmustine.

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 carmustine and 20mg paclitaxel, shake up the back contains 10% carmustine and 20% paclitaxel 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 combination of Chlorambucil, cyclophosphamide, nimustine or the carmustine of 15% Camptothecin, procarbazine, paclitaxel, cisplatin, carboplatin, irinotecan, vincristine, leuprorelin, colchicine, aminotriazole(ATA), DL-Buthionine-(S,R)-sulfoximine BSO, O6-benzyl guanine or O4-benzyl folic acid paclitaxel and 10%.

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 nimustine and 20mg camptothecine, shake up the back contains 10% nimustine 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 35-50 days at the subcutaneous drug release time of mice.

Embodiment 14

Be processed into the method step and the embodiment 11 of sustained-release implant, 13 is identical, but different is that contained anticancer effective component is: 15% Camptothecin, procarbazine, paclitaxel, cisplatin, carboplatin, Chlorambucil, cyclophosphamide, carmustine, nimustine, irinotecan, vincristine, leuprorelin, colchicine, aminotriazole(ATA), DL-Buthionine-(S,R)-sulfoximine BSO, the pemetrexed of O6-benzyl guanine or O4-benzyl folic acid and 15%, 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.

Embodiment 15.

With 70mg molecular weight peak value is that 35000 polylactic acid (PLA) is put into container, adds 100 milliliters of dichloromethane, behind the dissolving mixing, adds 15mg paclitaxel and 15mg vincristine, 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% paclitaxel and 15% vincristine, be suspended in then in the normal saline that contains 1.5% sodium carboxymethyl cellulose, make corresponding suspension type slow releasing injection, viscosity is 220cp-260cp (25 ℃-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 16

The method step that is processed into slow releasing injection is identical with embodiment 15, but different is that contained anticancer effective component and percentage by weight thereof are:

15% Camptothecin, procarbazine, paclitaxel, cisplatin, carboplatin, Chlorambucil, cyclophosphamide, carmustine, nimustine, irinotecan, vincristine, leuprorelin, colchicine or aminotriazole(ATA) and combination 15%, DL-Buthionine-(S,R)-sulfoximine BSO, O6-benzyl guanine or O4-benzyl folic acid.

Embodiment 17.

With 70mg molecular weight peak value is that 30000 bis-fatty acid and certain herbaceous plants with big flowers diacid (SA) copolymer (bis-fatty acid: the certain herbaceous plants with big flowers diacid is 20: 80) are put into container, add 100 milliliters of dichloromethane, behind the dissolving mixing, add 15mg nimustine and 15mg vincristine, shake up the dry organic solvent of removing of final vacuum again.Dried pastille solid composite freezing and pulverizing is made the micropowder that contains 15% nimustine and 15% vincristine, be suspended in then in the normal saline that contains 1.5% sodium carboxymethyl cellulose, make corresponding suspension type slow releasing injection, viscosity is 380cp-460cp (25 ℃-30 ℃ time).The drug release time of this slow releasing injection in external normal saline is 10-15 days, is about 20-30 days at the subcutaneous drug release time of mice.

Embodiment 18.

The method step that is processed into slow releasing injection is identical with embodiment 17, but different is that contained anticancer effective component and percentage by weight thereof are:

The combination of the combination of 15% nimustine or carmustine and 15% DL-Buthionine-(S,R)-sulfoximine BSO, O6-benzyl guanine or O4-benzyl folic acid.

Embodiment 19

The method step that is processed into slow releasing agent is identical with embodiment 1-18, but different is used slow-release auxiliary material is one of following or its combination:

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

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

C) ethylene vinyl acetate copolymer (EVAc);

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

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

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

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

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

Embodiment 20

The method step that is processed into slow releasing injection is identical with embodiment 1-19, but different is used suspending agent is respectively one of following or its combination:

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

B) 5-15% mannitol;

C) 5-15% sorbitol;

D) 0.1-1.5% surfactant;

E) 0.1-0.5% polysorbas20.

Embodiment 21

The method step that is processed into slow releasing injection is identical with embodiment 1-20, but different is that contained anticancer effective component is: 15% nelarabine 506u, Zarnestra, SCH-66336, Valspodar, 2-Amino-6-methyl-5-(pyridin-4-ylsulfanyl)-3H-quinazolin-4-one, pemetrexed, Raltitrexed, Camptothecin, procarbazine, paclitaxel, cisplatin, carboplatin, Chlorambucil, cyclophosphamide, carmustine, nimustine, irinotecan, vincristine, leuprorelin, colchicine, aminotriazole(ATA), DL-Buthionine-(S,R)-sulfoximine BSO, O6-benzyl guanine or O4-benzyl folic acid.

Embodiment 22

The method step that is processed into slow releasing injection is identical with embodiment 1-20, but different is that contained anticancer effective component is:

(a) nelarabine 506u of 5-30%, Zarnestra, SCH-66336, Valspodar, 2-Amino-6-methyl-5-(pyridin-4-ylsulfanyl)-3H-quinazolin-4-one, pemetrexed or Raltitrexed;

(b) Camptothecin of 5-30%, procarbazine, paclitaxel, cisplatin, carboplatin, Chlorambucil, cyclophosphamide, carmustine, nimustine, irinotecan, vincristine, leuprorelin, colchicine, aminotriazole(ATA), DL-Buthionine-(S,R)-sulfoximine BSO, O6-benzyl guanine or O4-benzyl folic acid; Or

(c) combination of nelarabine 506u, Zarnestra, SCH-66336, Valspodar, 2-Amino-6-methyl-5-(pyridin-4-ylsulfanyl)-3H-quinazolin-4-one, pemetrexed or the Raltitrexed of the Camptothecin of 5-30%, procarbazine, paclitaxel, cisplatin, carboplatin, Chlorambucil, irinotecan, vincristine, leuprorelin, colchicine, aminotriazole(ATA), DL-Buthionine-(S,R)-sulfoximine BSO, O6-benzyl guanine or O4-benzyl folic acid and 5-30% and 15% nimustine, carmustine, cyclophosphamide or melphalan.

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 (4)

1. slow-releasing anticarcinogen injection that contains tumor drug resistance reversal agent and cell toxicity medicament is grouped into by following one-tenth:

(A) sustained-release micro-spheres comprises:

Anticancer effective component 0.5-60%

Slow-release auxiliary material 40-99%

More than be weight percentage

With

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

Wherein,

Anticancer effective component is tumor drug resistance reversal agent and cell toxicity medicament;

Described tumor drug resistance reversal agent is selected from Zarnestra or SCH-66336;

Described cell toxicity medicament is selected from paclitaxel;

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

A) polylactic acid, its molecular weight peak value is 10000-30000,30000-60000,60000-100000 or 100000-150000;

B) copolymer of polylactic acid and hydroxyacetic acid, wherein, the ratio of polylactic acid and hydroxyacetic acid is 10/90-90/10, the molecular weight peak value is 10000-30000,30000-60000,60000-100000 or 100000-150000;

C) polifeprosan, wherein, to carboxy phenyl propane: decanedioic acid is 10: 90,20: 80,30: 70,40: 60,50: 50 or 60: 40;

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;

The viscosity of suspending agent is 100cp-3000cp (20 ℃-30 ℃ time), is selected from one of following or its combination:

A) 0.5-3.0% sodium carboxymethyl cellulose;

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% Tween 80;

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

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

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

The combination of the paclitaxel of the Zarnestra of 2-40% or SCH-66336 and 2-40%.

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

4. the anti-cancer sustained-released implantation agent according to claim 3 is characterized in that the anticancer effective component of sustained-release implant is:

The combination of the paclitaxel of the Zarnestra of 5-30% or SCH-66336 and 5-30%.