CN1887262A - Slow released anticancer medicine injection containing bendamustine and its synergist - Google Patents
Slow released anticancer medicine injection containing bendamustine and its synergist Download PDFInfo
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- CN1887262A CN1887262A CNA2006102007284A CN200610200728A CN1887262A CN 1887262 A CN1887262 A CN 1887262A CN A2006102007284 A CNA2006102007284 A CN A2006102007284A CN 200610200728 A CN200610200728 A CN 200610200728A CN 1887262 A CN1887262 A CN 1887262A
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Abstract
The slow released compound anticancer injection containing bendamustine and its synergist consists of slow released microsphere and solvent. The slow released microsphere includes effective anticancer component and slow releasing supplementary material, and the solvent is special solvent containing suspending agent. The effective anticancer component is the composition of bendamustine and bendamustine synergist selected from phosphoinositide 3-kinase inhibitor, pyrimidine analog and DNA repairase inhibitor. The slow releasing supplementary material is polylactic acid and its copolymer, polifeprosan, EVAc or other biocompatible polymer. The .suspending agent is carboxymethyl cellulose, etc. and has viscosity of 100-3000 cp at 20-30 deg.c. The slow released microsphere may be also prepared into slow released implanting agent. The present invention can inhibit the growth of tumor and enhance the curative effect of chemotherapy, radiotherapy and other non-operative treatment.
Description
(1) technical field
The present invention relates to a kind of compound anti-cancer medicament slow release injection, belong to technical field of pharmaceuticals.Particularly, the invention provides a kind of compound anti-cancer medicinal slow release agent that contains bendamustine and its synergist, be mainly slow releasing injection and sustained-release implant.
(2) background technology
Treatment for cancer is still based on chemotherapy at present.Yet traditional chemotherapy mode is not had a selectivity, be difficult to tumor by local and form effective drug level or therapeutic dose, and weak effect, toxicity is big, improves the restriction that medicine or radiological dose are subjected to general toxic reaction again merely.Referring to " placing cisplatin adding system carmustine treatment rat brain tumor in the tumor " " surgery tumor magazine " 69 phase 76-82 pages or leaves (1998) (Kong Q et al., J Surg Oncol.1998 Oct such as Kong Qingzhongs; 69 (2): 76-82).
The local placement of chemotherapeutics can overcome above defective preferably, not only can obviously improve the drug level of tumor by local, and can significantly reduce general toxic reaction.A large amount of internal and external tests have demonstrated the therapeutic effect to entity tumor, referring to " placing cisplatin adding system carmustine treatment rat brain tumor in the tumor " " surgery tumor magazine " 69 phase 76-82 pages or leaves (1998) (Kong Q et al., J Surg Oncol.1998 Oct such as Kong Qingzhongs; 69 (2): 76-82) and Kong Qingzhong etc. " place cisplatin in the tumor and cure the former carbuncle in the occipital region tumor of rat " " surgery tumor magazine " 64 phase 268-273 pages or leaves (1997) (Kong Q et al., JSurg Oncol.1997 Oct; 64:268-273).Also can be referring to Chinese patent (ZL00111093.4; ZL96115937.5; Application number 001111264,001111272) and U.S.'s patent of invention (patent No. 6,376,525B1; 5,651,986; 5,626,862).
Yet, entity tumor is made up of tumor cell and mesenchyma stroma of tumors, wherein the blood vessel in the mesenchyma stroma of tumors not only provides support and requisite nutrient substance for the growth of tumor cell, also influenced chemotherapeutics around tumor and the infiltration in the tumor tissues and diffusion (carry and to wait " situation of extracellular matrix to entity tumor in the medicine influence of turning round " " cancer research " 60 phase 2497-503 page or leaf (2000) (Netti PA referring to the Buddhist nun, Cancer Res.2000,60 (9): 2497-503)).Moreover, the blood vessel in the mesenchyma stroma of tumors often causes the enhancing of tumor cell to the toleration of cancer therapy drug to conventional chemotherapy medicine and insensitive, 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, develop a kind of effective cancer therapy drug or Therapeutic Method and just become a current important topic.The present invention provides a kind of new anticancer pharmaceutical composition just at the deficiencies in the prior art, can suppress growth of tumour cell effectively, and can strengthen the treatment tumor effect of other medicines, reduces recurrence.
(3) summary of the invention
The present invention is directed to the deficiencies in the prior art, a kind of compound recipe bendamustine slow releasing agent is provided.Particularly, the invention provides a kind of anticancer medicine slow-release preparation containing that contains bendamustine and its synergist, be mainly slow releasing injection and sustained-release implant.
Bendamustine is mainly used in the multiple entity tumor of treatment as a kind of new cancer therapy drug.Yet the tangible general toxicity that shows in application process has greatly limited the application of such medicine.
The present invention finds that cancer therapy drug that has and bendamustine share its antitumaous effect is strengthened mutually, below the bendamustine antitumaous effect will be increased mutually medicine be referred to as the bendamustine synergist, be mainly cell toxicity medicament; In addition, bendamustine or bendamustine synergist are made drug level that anticancer medicine slow-release preparation containing (being mainly slow releasing injection and sustained-release implant) not only can greatly improve tumor by local, reduce the drug level of medicine in blood circulation, are reduced the toxicity of medicine to normal structure, can also greatly make things convenient for the medicine injection, reduce operation technique complication, reduce patient's expense.The cancer therapy drug decapacitation suppresses can also increase the sensitivity of tumor cell to cancer therapy drug outside the tumor growth.The above unexpected main contents of the present invention of finding to constitute.
A kind of form of bendamustine slow releasing agent of the present invention is a slow releasing injection, 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 bendamustine and its synergist, and the bendamustine synergist is selected from phosphoinositide 3-kinase (PI3K) inhibitor, pyrimidine analogue and/or DNA repairase inhibitor; 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.
Conventional route administrations such as main oral administration of cancer therapy drug or intravenous injection, administering mode of the present invention is the local sustained release administration, obviously reduces the toxic action of its whole body in the therapeutic effect that significantly strengthens medicine.In addition, pharmaceutic adjuvant have hundreds of more than, pharmaceutic adjuvant with slow releasing function, it is not apparent particularly selected bendamustine among the present invention slowly being discharged in the regular hour in human body or animal body, but specific slow-release auxiliary material need could be determined through a large amount of creative works with the selection of slow releasing pharmaceutical combination.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.
Bendamustine shared ratio in compositions is decided because of concrete condition, can be 1%-50%, is good with 2%-40%, and 5%-30% is best.
Phosphoinositide 3-kinase (phosphoinositide 3-kinase, being called for short PI3K) inhibitor is selected from one of following or combination: 7-(hydroxy-star shaped spore native (7-hydroxyl-staurosporine, UCN-01), 7-O-alkyl-star shaped spore native (UCN-02), the beta-methoxy-star shaped spore native, alkyl phosphate choline (alkylphosphocholines), hexa-decyl choline phosphate (hexadecylphosphocholine, MIL, HPC, Miltefosine), octadecyl-(1, the 1-dimethyl-4-piperidine) (Octadecyl-(1 for phosphate, 1-dimethyl-4-piperidylio) phosphate, perifosine, D-21266), 1-O-six decyls-2-O-methyl-rac-glyceryl-3-phosphocholine (AMG-PC, 1-O-hexadecyl-2-O-methyl-rac-glycero-3-phosphocholine, ET-16-OCH3), 1-O-octadecyl-2-O-methyl-rac-glyceryl-3-phosphocholine (1-O-Octadecyl-2-O-methyl-rac-glycerophosphocholine, ET-18-OCH3, edelfosine), 1-O-octadecyl-2-O-methyl-sn-glyceryl-3-phosphocholine (1-O-octadecyl-2-O-methyl-sn-glycero-3-phosphocholine, ilmofosine, L-ET-18-OCH (3)), inositolpolyphosphates (inositol polyphosphates), basic phosphocholine (the Tetradecylphosphocholine of 14 (alkane), TPC), six certain herbaceous plants with big flowers base phosphoric acid (N-N-N-trimethyl) hexanol amine (hexadecylphospho (N-N-N-trimethyl) hexanolamine, HPC6), D 19391 (octadecylphosphocholine, OPC), octadecyl-[2-(N-methyl piperidine) ethyl]-phosphate (octadecyl-[2-(N-methyl piperidinio) ethyl]-phosphate, D-20133 or OMPEP).
In the above phosphoinositide 3-kinase inhibitor, with 7-hydroxy-star shaped spore native, 7-O-alkyl-star shaped spore native, the beta-methoxy-star shaped spore native, alkyl phosphate choline, hexa-decyl choline phosphate, octadecyl-(1, the 1-dimethyl-4-piperidine) phosphate, 1-O-six decyls-2-O-methyl-rac-glyceryl-3-phosphocholine, 1-O-octadecyl-2-O-methyl-rac-glyceryl-3-phosphocholine, 1-O-octadecyl-2-O-methyl-sn-glyceryl-3-phosphocholine, inositolpolyphosphates, the basic phosphocholine of 14 (alkane), six certain herbaceous plants with big flowers base phosphoric acid (N-N-N-trimethyl) hexanol amine, D 19391 or octadecyl-[2-(N-methyl piperidine) ethyl]-phosphate.Serve as preferred wherein with 7-hydroxy-star shaped spore native, 7-O-alkyl-star shaped spore native, beta-methoxy-star shaped spore native, alkyl phosphate choline, hexa-decyl choline phosphate.
Pyrimidine analogue mainly is selected from O4-benzyl folic acid, 2,4,5-triamido-6-benzyloxy pyrimidine, 2,4-diaminourea-6-benzyloxy-5-nitroso-group pyrimidine, 2,4-diaminourea-6-benzyloxy-5-bromo pyrimidine, 2-amino-4-benzyloxy-5-nitro-pyrimidine, 2-amino-4-benzyloxy-6-methyl-5-nitro pyrimidine, 2, one or more of 4-diaminourea-6-benzyloxy-s-triazine, 2-amino-O4-benzyl pteridine.
DNA repairase inhibitor can be kinases inhibitor and/or poly-(ADP-ribose) AG14361 that any DNA-relies on, but with imidazopyrazine, imidazopyridine, wortmannin, .alpha.-5:6-benzopyran, 6-aromatic radical-2-morphol-4-base-pyrans-4-base, 2-(4-Lin Ji)-8-phenylchromone, 7-ethyl-10-hydroxycamptothecine, 3-cyano group-6-hydrazono-methyl-5-(4-pyridine radicals) pyridine-[1H]-2-1, phenylbutyric acid, methoxamine, hydroxylamine, inositolpolyphosphates, the basic phosphocholine of 14 (alkane), six certain herbaceous plants with big flowers base phosphoric acid (N-N-N-trimethyl) hexanol amine, D 19391, octadecyl-[2-(N-methyl piperidine) ethyl]-phosphate, aminotriazole(ATA) (AT) and DL-Buthionine-(S,R)-sulfoximine BSO are preferred.
When the cancer therapy drug in the medicament slow-release microsphere only was bendamustine or its synergist, the application of slow-releasing anticarcinogen injection and potentiation mode were:
(1) contain the slow releasing injection local injection of bendamustine, other approach of bendamustine synergist are used;
(2) local injection contains the slow releasing injection of bendamustine synergist, and other approach are used bendamustine;
(3) local injection contains the slow releasing injection and the slow releasing injection that contains the bendamustine synergist of bendamustine; Or
(4) local injection contains the slow releasing injection of bendamustine and synergist.
The slow-releasing anticarcinogen injection of topical application also is used for the potentiation to radiotherapy or other therapies.Other approach refer to, but are not limited to tremulous pulse, vein, abdominal cavity, subcutaneous, intracavitary administration.
The percentage by weight of bendamustine synergist in medicament slow-release microsphere is 0.5%-60%, is good with 1%-40%, is best with 5%-30%.The weight ratio of bendamustine and bendamustine 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:
(1) combination of 7-hydroxy-star shaped spore native of the bendamustine of 2-40% and 1-40%, 7-O-alkyl-star shaped spore native, beta-methoxy-star shaped spore native, alkyl phosphate choline or hexa-decyl choline phosphate;
(2) the O4-benzyl folic acid, 2 of the bendamustine of 2-40% and 1-40%, 4,5-triamido-6-benzyloxy pyrimidine, 2,4-diaminourea-6-benzyloxy-5-nitroso-group pyrimidine, 2,4-diaminourea-6-benzyloxy-5-bromo pyrimidine, 2-amino-4-benzyloxy-5-nitro-pyrimidine, 2-amino-4-benzyloxy-6-methyl-5-nitro pyrimidine, 2, the combination of 4-diaminourea-6-benzyloxy-s-triazine or 2-amino-O4-benzyl pteridine; Or
(3) imidazopyrazine of the bendamustine of 2-40% and 1-40%, imidazopyridine, wortmannin, .alpha.-5:6-benzopyran, 6-aromatic radical-2-morphol-4-base-pyrans-4-base, 2-(4-Lin Ji)-8-phenylchromone, 7-ethyl-10-hydroxycamptothecine, 3-cyano group-6-hydrazono-methyl-5-(4-pyridine radicals) pyridine-[1H]-2-1, phenylbutyric acid, methoxamine, hydroxylamine, inositolpolyphosphates, the basic phosphocholine of 14 (alkane), six certain herbaceous plants with big flowers base phosphoric acid (N-N-N-trimethyl) hexanol amine, D 19391, octadecyl-[2-(N-methyl piperidine) ethyl]-phosphate, the combination of aminotriazole(ATA) or DL-Buthionine-(S,R)-sulfoximine BSO.
Slow-release auxiliary material is selected from poly-dl-lactide, poly-dl-lactide/ethanol copolymer, the monomethyl polyethylene glycol, monomethyl polyethylene glycol copolymer, polyethylene glycol, the polyethylene glycol copolymer, end carboxyl polylactic acid, end carboxyl polylactic acid/ethanol copolymer, polifeprosan, bis-fatty acid and decanedioic acid copolymer, poly-(erucic acid dimer-decanedioic acid), poly-(fumaric acid-decanedioic acid), 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.
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.
In the slow releasing injection, drug sustained release system can be made into microsphere, sub-micro ball, microemulsion, nanosphere, granule or spherical piller, makes the injection use then with after the injection solvent mixes.In various slow releasing injection, serve as preferred with the suspension type slow releasing injection, the suspension type slow releasing injection is the preparation that the drug sustained release system that will contain anticancer component is suspended in gained in the injection, used adjuvant is a kind of or its combination in the above-mentioned slow-release auxiliary material, and used solvent is common solvent or the special solvent that contains suspending agent.Common solvent is, but is not limited to the buffer that distilled water, water for injection, physiology are prepared towards liquid, dehydrated alcohol or various salt.The purpose of suspending agent is the pastille microsphere that effectively suspends, thereby is beneficial to the usefulness of injection.
Suspending agent is selected from one of sodium carboxymethyl cellulose, (iodine) glycerol, simethicone, propylene glycol, carbomer, mannitol, sorbitol, surfactant, soil temperature 20, soil temperature 40 and soil temperature 80 or its combination.
The content of suspending agent in common solvent is decided because of its characteristic, can be 0.1-30% and decides because of concrete condition.Consisting of of preferred suspending agent:
A) 0.5-5% sodium carboxymethyl cellulose+0.1-0.5% soil temperature 80; Or
B) 5-20% mannitol+0.1-0.5% soil temperature 80; Or.
C) 0.5-5% sodium carboxymethyl cellulose+5-20% sorbitol+0.1-0.5% soil temperature 80.
The 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 preparation method of slow releasing injection is arbitrarily, available some kinds of methods preparation: as, but be not limited to, mixing method, fusion method, dissolution method, spray drying method for preparation microsphere, dissolution method are made micropowder, liposome bag medicine method and emulsion process etc. in conjunction with freezing (drying) comminuting method.Serve as preferred wherein with dissolution method (being the solvent volatility process), seasoning, spray drying method and emulsion process.Microsphere then can be used for preparing above-mentioned various slow releasing injection, and its method is arbitrarily.The particle size range of used microsphere can be between 5-400um, serving as preferred between the 10-300um, with between the 20-200um for most preferably.
Microsphere also can be used for preparing other slow releasing injection, as gel injection, block copolymer micelle injection.Wherein, block copolymer micelle is formed in aqueous solution by hydrophobic-hydrophilic block copolymers, has spherical inner core-shell mechanism, and hydrophobic block forms kernel, and hydrophilic block forms shell.The carrier micelle injection enters the purpose that reaches control drug release or targeted therapy in the body.Used pharmaceutical carrier is above-mentioned any one or its combination.Wherein preferred molecular weight is the hydrophilic block of the Polyethylene Glycol (PEG) of 1000-15000 as the micelle copolymer, and preferred biological degradation polyalcohol (as PLA, polylactide, polycaprolactone and copolymer thereof (molecular weight 1500-25000)) is as the hydrophobic block of micelle copolymer.The particle size range of block copolymer micelle can be between 10-300um, between the 20-200um serving as preferred.Gel injection system is dissolved in some amphipathic solvent with biological degradation polyalcohol (as PLA, PLGA or DL-LA and epsilon-caprolactone copolymer), adds medicine miscible with it (or suspendible) back again and forms flowability gel preferably, can be through tumor week or intratumor injection.In case inject, amphipathic solvent diffuses to body fluid very soon, the moisture in the body fluid then infiltrates gel, makes polymer cure, slowly discharges medicine.
Sustained-release micro-spheres also can be used for preparing sustained-release implant, used pharmaceutic adjuvant can be any or multiple material in the above-mentioned pharmaceutic adjuvant, but with the high molecular weight water soluble polymer is main separation, in various high molecular polymers, with polylactic acid, certain herbaceous plants with big flowers diacid, the mixture or the copolymer that contain the macromolecule polymer of polylactic acid or certain herbaceous plants with big flowers diacid is first-selection, mixture and copolymer can be selected from, but be not limited to the mixture or the copolymer of the mixture of PLA, PLGA, PLA and PLGA, certain herbaceous plants with big flowers diacid and fragrant polyanhydride or aliphatic polyanhydride.Polylactic acid (PLA) 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 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 volume size depends on factors such as the position, size of focus.Can be the bar-shaped of 0.1-5mm (slightly) * 1-10mm (length), also can be other shapes such as lamellar.
The most preferred dosage form of sustained-release implant is that the slow releasing agent that biocompatibility, degradable absorb is implanted, and can make different shape and various dosage form because of the clinical needs of difference.The packing method of its Main Ingredients and Appearance and step in United States Patent (USP) (US5651986) have a detailed description, comprise the some kinds of methods that prepare slow releasing preparation: as, but be not limited to, (i) carrier holder powder and medicament mixed be pressed into implant then, promptly so-called mixing method; (ii) carrier holder fusing, mix solid cooled then, promptly so-called fusion method mutually with medicine to be packaged; (iii) the carrier holder is dissolved in the solvent, medicine dissolution to be packaged or be scattered in the polymer solution, evaporating solvent then, drying, promptly so-called dissolution method; (iv) spray drying method; And (v) freeze-drying etc.
Anticancer effective component and percentage by weight in the sustained-release implant are preferably as follows:
(1) combination of 7-hydroxy-star shaped spore native of the bendamustine of 2-40% and 1-40%, 7-O-alkyl-star shaped spore native, beta-methoxy-star shaped spore native, alkyl phosphate choline or hexa-decyl choline phosphate;
(2) the O4-benzyl folic acid, 2 of the bendamustine of 2-40% and 1-40%, 4,5-triamido-6-benzyloxy pyrimidine, 2,4-diaminourea-6-benzyloxy-5-nitroso-group pyrimidine, 2,4-diaminourea-6-benzyloxy-5-bromo pyrimidine, 2-amino-4-benzyloxy-5-nitro-pyrimidine, 2-amino-4-benzyloxy-6-methyl-5-nitro pyrimidine, 2, the combination of 4-diaminourea-6-benzyloxy-s-triazine or 2-amino-O4-benzyl pteridine; Or
(3) imidazopyrazine of the bendamustine of 2-40% and 1-40%, imidazopyridine, wortmannin, .alpha.-5:6-benzopyran, 6-aromatic radical-2-morphol-4-base-pyrans-4-base, 2-(4-Lin Ji)-8-phenylchromone, 7-ethyl-10-hydroxycamptothecine, 3-cyano group-6-hydrazono-methyl-5-(4-pyridine radicals) pyridine-[1H]-2-1, phenylbutyric acid, methoxamine, hydroxylamine, inositolpolyphosphates, the basic phosphocholine of 14 (alkane), six certain herbaceous plants with big flowers base phosphoric acid (N-N-N-trimethyl) hexanol amine, D 19391, octadecyl-[2-(N-methyl piperidine) ethyl]-phosphate, the combination of aminotriazole(ATA) or DL-Buthionine-(S,R)-sulfoximine BSO.
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.
When the cancer therapy drug in the medicament slow-release microsphere only is bendamustine or its synergist, the application of anti-cancer sustained-released implantation agent and the same slow releasing injection of potentiation mode.
Route of administration depends on multiple factor, for obtain valid density in former or position, metastatic tumour place, medicine can give through number of ways, as in subcutaneous, intracavity (in abdominal cavity, thoracic cavity and canalis spinalis), the tumor, in all injections of tumor or placement, selective arterial injection, the lymph node and injection in the bone marrow.With in selective arterial injection, intracavity, the tumor, tumor week injection or be placed as preferred.
The 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 bendamustine 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 bendamustine.Measure medicament contg (%) in the different time tumor, the result shows, the local drug concentration significant difference of bendamustine 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 bendamustine 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 bendamustine.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 bendamustine after different modes is used, topical can obviously improve and effectively keep the active drug concentration at position, tumor place, and is wherein best with the effect of placing sustained-release implant and intratumor injection slow releasing injection in the tumor.Yet, intratumor injection slow releasing injection operation most convenient, easy.Good effect not only, toxic and side effects is also little.
Test 3, contain tumor-inhibiting action in the body of bendamustine and bendamustine 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).The-to organize be contrast, and the 2nd to 10 group is the treatment group, and medicine is all 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 | 58±8.0 | |
| 2(6) | Bendamustine | 44±5.0 | ＜0.05 |
| 3(6) | UCN-01 | 46±2.0 | ＜0.01 |
| 4(6) | UCN-02 | 38±2.4 | ＜0.01 |
| 5(6) | MIL | 40±5.2 | ＜0.01 |
| 6(6) | D-21266 | 42±3.0 | ＜0.01 |
| 7(6) | Bendamustine+UCN-01 | 22±2.2 | ＜0.001 |
| 8(6) | Bendamustine+UCN-02 | 28±3.6 | ＜0.001 |
| 9(6) | Bendamustine+MIL | 24±3.2 | ＜0.001 |
| 10(6) | Bendamustine+D-21266 | 24±2.2 | ＜0.001 |
Above result shows, bendamustine and used bendamustine synergist-phosphoinositide 3-kinase (PI3K) inhibitor (UCN-01:7-hydroxy-star shaped spore native wherein; UCN-02:7-O-alkyl-star shaped spore native; MIL:Miltefosine; D-21266: octadecyl-(1, the 1-dimethyl-4-piperidine) phosphate or perifosine) growth all has the obvious suppression effect to kinds of tumor cells when this concentration is used separately, can show significant potentiation when use in conjunction.
The tumor-inhibiting action of test 4, bendamustine and bendamustine 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.Bendamustine and bendamustine 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 | Bendamustine | O4-BA | UCN-01 | UCN-02 | Bendamustine+O4-BA | Bendamustine+UCN-01 | Bendamustine+UCN-02 |
| CNS | 32％ | 52％ | 62％ | 62％ | 86％ | 88％ | 84％ |
| C6 | 34％ | 64％ | 60％ | 64％ | 94％ | 80％ | 94％ |
| SA | 38％ | 60％ | 50％ | 62％ | 86％ | 92％ | 92％ |
| BC | 36％ | 62％ | 54％ | 64％ | 94％ | 82％ | 82％ |
| BA | 38％ | 60％ | 62％ | 60％ | 92％ | 92％ | 92％ |
| LH | 42％ | 56％ | 62％ | 58％ | 90％ | 86％ | 84％ |
| PAT | 48％ | 52％ | 66％ | 52％ | 92％ | 84％ | 86％ |
Above result shows, used bendamustine and bendamustine synergist (O4-BA:O4-benzyl uric acid; UCN-01:7-hydroxy-star shaped spore native; UCN-02:7-O-alkyl-star shaped spore native) growth all has the obvious suppression effect to kinds of tumor cells when this concentration is used separately, can show significant potentiation when use in conjunction.
The tumor-inhibiting action of test 5, bendamustine and bendamustine synergist (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 | 62±8.0 | |
| 2(6) | ilmofosine | 40±5.0 | ＜0.05 |
| 3(6) | Bendamustine | 42±2.2 | ＜0.01 |
| 4(6) | The ilmofosine+ bendamustine | 30±2.6 | ＜0.001 |
| 5(6) | AMG-PC | 48±3.2 | ＜0.01 |
| 6(6) | The AMG-PC+ bendamustine | 24±3.0 | ＜0.001 |
| 7(6) | edelfosine | 30±2.6 | ＜0.01 |
| 8(6) | The Edelfosine+ bendamustine | 22±2.4 | ＜0.001 |
| 9(6) | IDOU | 30±3.4 | ＜0.01 |
| 10(6) | The IDOU+ bendamustine | 22±2.2 | ＜0.001 |
Above result shows, used bendamustine and bendamustine synergist-PI3K inhibitor (wherein, AMG-PC:1-O-six decyls-2-O-methyl-rac-glyceryl-3-phosphocholine; Edelfosine:1-O-octadecyl-2-O-methyl-rac-glyceryl-3-phosphocholine; Ilmofosine:1-O-octadecyl-2-O-methyl-sn-glyceryl-3-phosphocholine; IDOU:5-iodo-2 '-deoxyguanosine) growth all has the obvious suppression effect to kinds of tumor cells when this concentration is used separately, can show significant potentiation when use in conjunction.
The tumor-inhibiting action of test 6, bendamustine and bendamustine 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 (bendamustine or bendamustine synergist) and therapeutic alliance group (bendamustine and bendamustine synergist).Bendamustine is through intratumor injection, and the bendamustine synergist is through lumbar injection.Dosage is 5mg/kg.The treatment back was measured the gross tumor volume size on the 10th day, made relatively therapeutic effect (seeing Table 4) of index with inhibition rate of tumor growth.
Table 4
| Test group (n) | Suffered treatment | Tumor control rate (%) | The P value |
| 1(6) | Contrast | - | |
| 2(6) | Bendamustine | 40 | ＜0.05 |
| 3(6) | Imidazopyrazine | 30 | ＜0.01 |
| 4(6) | Imidazopyridine | 34 | ＜0.01 |
| 5(6) | Wortmannin | 34 | ＜0.01 |
| 6(6) | .alpha.-5:6-benzopyran | 38 | ＜0.01 |
| 7(6) | Bendamustine+imidazopyrazine | 80 | ＜0.001 |
| 8(6) | Bendamustine+imidazopyridine | 72 | ＜0.001 |
| 9(6) | Bendamustine+wortmannin | 80 | ＜0.001 |
| 10(6) | Bendamustine+.alpha.-5:6-benzopyran | 78 | ＜0.001 |
Above result shows, the kinases inhibitor that used bendamustine and bendamustine synergist-DNA-relies on (wherein, imidazopyrazine, imidazopyridine, wortmannin .alpha.-5:6-benzopyran) growth all has the obvious suppression effect to kinds of tumor cells when this concentration is used separately, can show significant potentiation when use in conjunction.
The tumor-inhibiting action of test 7, bendamustine and bendamustine 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.Bendamustine is through lumbar injection, and the bendamustine synergist is through the injection of tumor week.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) | Bendamustine | 46 | ＜0.05 |
| 3(6) | LY294002 | 50 | ＜0.01 |
| 4(6) | SU11752 | 46 | ＜0.01 |
| 5(6) | SN-38 | 54 | ＜0.01 |
| 6(6) | OK-1035 | 46 | ＜0.01 |
| 7(6) | Bendamustine+LY294002 | 78 | ＜0.001 |
| 8(6) | Bendamustine+SU11752 | 82 | ＜0.001 |
| 9(6) | Bendamustine+SN-38 | 80 | ＜0.001 |
| 10(6) | Bendamustine+OK-1035 | 76 | ＜0.001 |
Above result shows, kinases inhibitor (wherein, LY294002:2-(4-Lin Ji)-8-phenylchromone that used bendamustine and bendamustine synergist-DNA-relies on; SU11752: inhibitors of kinases; SN-38:7-ethyl-10-hydroxycamptothecine; Growth all has the obvious suppression effect to OK-1035:3-cyano group-6-hydrazono-methyl-5-(4-pyridine radicals) pyridine-[1H]-2-1) to kinds of tumor cells when this concentration is used separately, can show significant potentiation when use in conjunction.
The tumor-inhibiting action of test 8, bendamustine and bendamustine synergist (sustained-release implant)
With the rat is subjects, with 2 * 10
5Individual pancreatic tumour cell subcutaneous injection is in its hypochondrium, treats that tumor growth after 14 days is divided into it negative control (blank), single therapy group, therapeutic alliance group.Sustained-release implant is all placed in tumor.Dosage is 5mg/kg.The treatment back was measured the gross tumor volume size on the 10th day, made relatively therapeutic effect (seeing Table 6) of index with inhibition rate of tumor growth.
Table 6
| Test group (n) | Suffered treatment | Tumor control rate (%) | The P value |
| 1(6) | Contrast | - | |
| 2(6) | Bendamustine | 48 | ＜0.05 |
| 3(6) | Methoxamine | 30 | ＜0.05 |
| 4(6) | Minocycline | 38 | ＜0.05 |
| 5(6) | Hydroxylamine | 34 | ＜0.05 |
| 6(6) | O-methyl hydroxylamine | 32 | ＜0.01 |
| 7(6) | Bendamustine+methoxamine | 74 | ＜0.01 |
| 8(6) | Bendamustine+minocycline | 76 | ＜0.01 |
| 9(6) | Bendamustine+hydroxylamine | 82 | ＜0.01 |
| 10(6) | Bendamustine+O-methyl hydroxylamine | 80 | ＜0.001 |
Above result shows, growth all has the obvious suppression effect to the kinases inhibitor that used bendamustine and bendamustine synergist-DNA-relies on to kinds of tumor cells when this concentration is used separately, can show significant potentiation when use in conjunction.
The tumor-inhibiting action of test 9, bendamustine and bendamustine synergist (sustained-release implant)
By the tumor-inhibiting action of test 8 described methods mensuration bendamustines and bendamustine synergist (sustained-release implant), its inhibition rate of tumor growth sees Table 7.
Table 7
| Test group (n) | Suffered treatment | Tumor control rate (%) | The P value |
| 1(6) | Contrast | - | |
| 2(6) | Bendamustine | 42 | ＜0.05 |
| 3(6) | 3-AB | 42 | ＜0.01 |
| 4(6) | Benzoylamide | 46 | ＜0.01 |
| 5(6) | PD128763 | 40 | ＜0.01 |
| 6(6) | AG14361 | 36 | ＜0.01 |
| 7(6) | Bendamustine+3-AB | 72 | ＜0.001 |
| 8(6) | Bendamustine+Benzoylamide | 76 | ＜0.001 |
| 9(6) | Bendamustine+PD128763 | 84 | ＜0.001 |
| 10(6) | Bendamustine+AG14361 | 84 | ＜0.001 |
Above result shows, used bendamustine and bendamustine synergist-poly-(ADP-ribose) AG14361 (wherein, 3-AB:3-aminobenzamide; Benzoylamide; PD 128763:3,4-dihydro methoxy isoquinolin-1 (2H)-Benzoylamide; AG14361: AG14361) growth all has the obvious suppression effect to kinds of tumor cells when this concentration is used separately, can show significant potentiation when use in conjunction.
The tumor-inhibiting action of test 10, bendamustine and bendamustine synergist (slow releasing injection)
By the tumor-inhibiting action of test 8 described methods mensuration bendamustines and bendamustine synergist (sustained-release implant), its inhibition rate of tumor growth sees Table 8.
Table 8
| Test group (n) | Suffered treatment | Tumor control rate (%) | The P value |
| 1(6) | Contrast | - | |
| 2(6) | Bendamustine | 46 | ＜0.05 |
| 3(6) | BZ1-6 | 50 | ＜0.01 |
| 4(6) | TI1-5 | 38 | ＜0.01 |
| 5(6) | TBC | 46 | ＜0.01 |
| 6(6) | Benzimidazole | 44 | ＜0.01 |
| 7(6) | Bendamustine+BZ1-6 | 78 | ＜0.001 |
| 8(6) | Bendamustine+TI1-5 | 80 | ＜0.001 |
| 9(6) | Bendamustine+TBC | 78 | ＜0.001 |
| 10(6) | Bendamustine+benzimidazole | 84 | ＜0.001 |
Above result shows, used bendamustine and bendamustine synergist-poly-(ADP-ribose) AG14361 (wherein, BZ1-6: benzimidazole-4-carboxamides BZ1-6; TI1-5: tricyclic lactam hydrogen sulfide; TBC: three ring benzimidazole carboxylic acid amides, benzimidazole) growth all has the obvious suppression effect to kinds of tumor cells when this concentration is used separately, can show significant potentiation when use in conjunction.
The tumor-inhibiting action of test 11, bendamustine and/or bendamustine synergist (sustained-release implant)
By the tumor-inhibiting action of test 8 described methods mensuration bendamustines and/or bendamustine synergist (sustained-release implant), its inhibition rate of tumor growth sees Table 9.
Table 9
| Test group (n) | Suffered treatment | Tumor control rate (%) | The P value |
| 1(6) | Contrast | - | |
| 2(6) | Bendamustine | 44 | ＜0.05 |
| 3(6) | NU1025 | 56 | ＜0.01 |
| 4(6) | PBC | 42 | ＜0.01 |
| 5(6) | MPBC | 40 | ＜0.01 |
| 6(6) | NU1085 | 46 | ＜0.01 |
| 7(6) | Bendamustine+NU1025 | 86 | ＜0.001 |
| 8(6) | Bendamustine+PBC | 82 | ＜0.001 |
| 9(6) | Bendamustine+MPBC | 78 | ＜0.001 |
| 10(6) | Bendamustine+NU1085 | 80 | ＜0.001 |
Above result shows, used bendamustine and bendamustine synergist-poly-(ADP-ribose) AG14361 (wherein, PBC:2-phenyl-1H-benzimidazole-4-carboxamides BZ1-6; MPBC:2-(3-anisyl)-1H-benzimidazole-4-carboxamides BZ1-6 (2-(3-methoxyphenyl)-1H-benzimidazole-4-carboxamide); NU1025:8-hydroxy-2-methyl quinazolinone; NU1085:2-(4-hydroxyphenyl) benzimidazole-4-carboxamides BZ1-6) growth all has the obvious suppression effect to kinds of tumor cells when this concentration is used separately, can show significant potentiation when use in conjunction.
The tumor-inhibiting action of test 12, bendamustine and/or bendamustine synergist (sustained-release implant)
By the tumor-inhibiting action of test 6 described methods mensuration bendamustines and/or bendamustine synergist (sustained-release implant), its inhibition rate of tumor growth sees Table 10.
Table 10
| Test group (n) | Suffered treatment | Tumor control rate (%) | The P value |
| 1(6) | Contrast | - | |
| 2(6) | Bendamustine | 50 | ＜0.05 |
| 3(6) | BSO | 46 | ＜0.01 |
| 4(6) | Aminotriazole(ATA) | 38 | ＜0.01 |
| 5(6) | Cavatic acid | 42 | ＜0.01 |
| 6(6) | New podophyllotoxin | 30 | ＜0.01 |
| 7(6) | Bendamustine+BSO | 80 | ＜0.001 |
| 8(6) | Bendamustine+aminotriazole(ATA) | 76 | ＜0.001 |
| 9(6) | Bendamustine+cavatic acid | 82 | ＜0.001 |
| 10(6) | Bendamustine+new podophyllotoxin | 80 | ＜0.001 |
Above result shows, used bendamustine and bendamustine synergist-poly-(ADP-ribose) AG14361 (wherein, BSO is a DL-Buthionine-(S,R)-sulfoximine BSO) growth all has the obvious suppression effect to kinds of tumor cells when this concentration is used separately, can show significant potentiation when use in conjunction.
Release ratio in the body of the bendamustine sustained-release implant that test 13, different molecular weight polylactic acid are made
With the rat is subjects, grouping (3/group) and the equivalent bendamustine sustained-release implant that carries in the subcutaneous polylactic acid (PLA) that contains different molecular weight (MW).Survey the surplus of medicine in implant respectively at 1,3,7,14,21,28 and 35 day then, and then draw rate of release (%) in its body.The result shows, molecular weight is 20000 is released to: 1 day (12%), 3 (26%), 7 (54%), 14 (80%), 21 (86), 28 (92) and 35 (95%).Discharge in the body of the sustained-release implant that comparison different molecular weight polylactic acid is made and find, slack-off with the molecular weight increase, with the 7th day was example, compare with whole body administration group, 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).
It is the slow releasing agent that contains bendamustine and its synergist that adjuvant is made that same result also sees with polylactic acid.
That pays special attention to is simple to operation, the good reproducibility of slow releasing agent of the present invention, particularly slow releasing injection.Good effect not only, toxic and side effects is little.
Different drug packages is different with the drug release feature of different Biodegradable high moleculars.Discover that further the slow-release auxiliary material that is most appropriate to medicament slow release of the present invention is a poly-dl-lactide, poly-dl-lactide/ethanol copolymer, the monomethyl polyethylene glycol, monomethyl polyethylene glycol copolymer, polyethylene glycol, the polyethylene glycol copolymer, end carboxyl polylactic acid, end carboxyl polylactic acid/ethanol copolymer, polifeprosan, bis-fatty acid and decanedioic acid copolymer, poly-(erucic acid dimer-decanedioic acid), poly-(fumaric acid-decanedioic acid), 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 bendamustine and various bendamustine synergist were used separately, can show significant potentiation when use in conjunction.Therefore, effective ingredient of the present invention is the combination of bendamustine and any one (or more than one) bendamustine synergist.The medicine that contains above effective ingredient can be made into sustained-release micro-spheres, and then makes slow releasing injection and implant, serves as preferred with the suspensoid injectio that is combined to form with the special solvent that contains suspending agent wherein.
Slow releasing injection or sustained-release implant also can be further specified by following embodiment.Just the invention will be further described for the foregoing description and following examples, is not its content and use are imposed any restrictions.
(4) specific embodiment
Embodiment 1.
80mg polifeprosan (to carboxy phenyl propane (p-CPP): certain herbaceous plants with big flowers diacid (SA) is 20: 80) copolymer is put into container, add 100 milliliters of dichloromethane, behind the dissolving mixing, add 10mg bendamustine and 7-hydroxy-star shaped spore native, shake up the back contains 10% bendamustine and 10%7-hydroxy-star shaped spore native with spray drying method for preparation injectable microsphere again.Then microsphere is suspended in the normal saline that contains 15% mannitol, makes corresponding suspension type slow releasing injection.The drug release time of this slow releasing injection in external normal saline is 14-20 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:
(1) combination of 7-hydroxy-star shaped spore native of the bendamustine of 2-40% and 1-40%, 7-O-alkyl-star shaped spore native, beta-methoxy-star shaped spore native, alkyl phosphate choline or hexa-decyl choline phosphate;
(2) the O4-benzyl folic acid, 2 of the bendamustine of 2-40% and 1-40%, 4,5-triamido-6-benzyloxy pyrimidine, 2,4-diaminourea-6-benzyloxy-5-nitroso-group pyrimidine, 2,4-diaminourea-6-benzyloxy-5-bromo pyrimidine, 2-amino-4-benzyloxy-5-nitro-pyrimidine, 2-amino-4-benzyloxy-6-methyl-5-nitro pyrimidine, 2, the combination of 4-diaminourea-6-benzyloxy-s-triazine or 2-amino-O4-benzyl pteridine; Or
(3) imidazopyrazine of the bendamustine of 2-40% and 1-40%, imidazopyridine, wortmannin, .alpha.-5:6-benzopyran, 6-aromatic radical-2-morphol-4-base-pyrans-4-base, 2-(4-Lin Ji)-8-phenylchromone, 7-ethyl-10-hydroxycamptothecine, 3-cyano group-6-hydrazono-methyl-5-(4-pyridine radicals) pyridine-[1H]-2-1, phenylbutyric acid, methoxamine, hydroxylamine, inositolpolyphosphates, the basic phosphocholine of 14 (alkane), six certain herbaceous plants with big flowers base phosphoric acid (N-N-N-trimethyl) hexanol amine, D 19391, octadecyl-[2-(N-methyl piperidine) ethyl]-phosphate, the combination of aminotriazole(ATA) or DL-Buthionine-(S,R)-sulfoximine BSO.
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.
Embodiment 3.
With 70mg molecular weight peak value 65000 polylactic acid (PLGA, 75: 25) put into container, add 100 milliliters of dichloromethane, behind the dissolving mixing, add 15mg bendamustine and 15mg7-ethyl-10-hydroxycamptothecine, 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% bendamustine and 15%7-ethyl-10-hydroxycamptothecine, be suspended in then in the normal saline that contains 1.5% sodium carboxymethyl cellulose, make corresponding suspension type slow releasing injection.The drug release time of this slow releasing injection in external normal saline is 20-35 days, is about 35-50 days at the subcutaneous drug release time of mice.
Embodiment 4
The method step that is processed into slow releasing injection is identical with embodiment 3, but different is that contained anticancer effective component and percentage by weight thereof are: the combination of 7-hydroxy-star shaped spore native of the bendamustine of 2-40% and 1-40%, 7-O-alkyl-star shaped spore native, beta-methoxy-star shaped spore native, alkyl phosphate choline or hexa-decyl choline phosphate.
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 bendamustines and 10 milligrams of benzimidazoles, shake up the back contains 20% bendamustine and 10% benzimidazole with spray drying method for preparation injectable microsphere again.Then microsphere is suspended in the injection that contains the 5-15% sorbitol, makes corresponding suspension type slow releasing injection.The drug release time of this slow releasing injection in external normal saline is 10-15 days, is about 20-30 days at the subcutaneous drug release time of mice.
Embodiment 6.
The method step that is processed into slow releasing injection is identical with embodiment 5, but different is that contained anticancer effective component is: the O4-benzyl folic acid, 2 of the bendamustine of 1-40% and 1-40%, 4,5-triamido-6-benzyloxy pyrimidine, 2,4-diaminourea-6-benzyloxy-5-nitroso-group pyrimidine, 2,4-diaminourea-6-benzyloxy-5-bromo pyrimidine, 2-amino-4-benzyloxy-5-nitro-pyrimidine, 2-amino-4-benzyloxy-6-methyl-5-nitro pyrimidine, 2, the combination of 4-diaminourea-6-benzyloxy-s-triazine or 2-amino-O4-benzyl pteridine.
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 bendamustine and 10mg DL-Buthionine-(S,R)-sulfoximine BSO, shake up the back contains 20% bendamustine and 10% DL-Buthionine-(S,R)-sulfoximine BSO with spray drying method for preparation injectable microsphere again.Microsphere is suspended in the normal saline that contains 1.5% sodium carboxymethyl cellulose and 0.5% Tween 80 then, makes corresponding suspension type slow releasing injection.The drug release time of this slow releasing injection in external normal saline is 10-15 days, is about 20-30 days at the subcutaneous drug release time of mice.
Embodiment 8.
The method step that is processed into slow releasing injection is identical with embodiment 7, but different is that contained anticancer effective component is: the bendamustine of 1-40% and the imidazopyrazine of 1-40%, imidazopyridine, wortmannin, .alpha.-5:6-benzopyran, 6-aromatic radical-2-morphol-4-base-pyrans-4-base, 2-(4-Lin Ji)-8-phenylchromone, 7-ethyl-10-hydroxycamptothecine, 3-cyano group-6-hydrazono-methyl-5-(4-pyridine radicals) pyridine-[1H]-2-1, phenylbutyric acid, methoxamine, hydroxylamine, inositolpolyphosphates, the basic phosphocholine of 14 (alkane), six certain herbaceous plants with big flowers base phosphoric acid (N-N-N-trimethyl) hexanol amine, D 19391, octadecyl-[2-(N-methyl piperidine) ethyl]-phosphate, the combination of aminotriazole(ATA) or DL-Buthionine-(S,R)-sulfoximine BSO.
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 bendamustine and 10mgO4-benzyl folic acid, shake up the back contains 20% bendamustine and 10%O4-benzyl folic acid with spray drying method for preparation injectable microsphere again.Then microsphere is suspended in the normal saline that contains 1.5% sodium carboxymethyl cellulose and 15% sorbitol and 0.2% Tween 80, makes corresponding suspension type slow releasing injection.The 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 O4-benzyl folic acid, 2 of the bendamustine of 10-30% and 10-40%, 4,5-triamido-6-benzyloxy pyrimidine, 2,4-diaminourea-6-benzyloxy-5-nitroso-group pyrimidine, 2,4-diaminourea-6-benzyloxy-5-bromo pyrimidine, 2-amino-4-benzyloxy-5-nitro-pyrimidine, 2-amino-4-benzyloxy-6-methyl-5-nitro pyrimidine, 2, the combination of 4-diaminourea-6-benzyloxy-s-triazine or 2-amino-O4-benzyl pteridine.
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 10mg7-hydroxy-star shaped spore native and 20mg bendamustine, shake up the back contains 10%7-hydroxy-star shaped spore native and 20% bendamustine 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 20% bendamustine and 10% 7-hydroxy-star shaped spore native, 7-O-alkyl-star shaped spore native, beta-methoxy-star shaped spore native, alkyl phosphate choline or hexa-decyl choline phosphate.
Embodiment 13
With 70mg molecular weight peak value 80000 polylactic acid (PLGA, 50: 50) put into container, add 100 milliliters of dichloromethane, behind the dissolving mixing, add 10mg bendamustine and the new podophyllotoxin of 20mg, shake up the back contains 10% bendamustine and 20% new podophyllotoxin 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 25-30 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: the combination of 10% bendamustine and 20% aminotriazole(ATA), DL-Buthionine-(S,R)-sulfoximine BSO, cavatic acid, S-hexyl glutathion, new podophyllotoxin, Exatecan mesylate or TAN-1518.
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 following it-or its combination:
A) the molecular weight peak value is the polylactic acid (PLA) of 5000-10000,10000-30000,30000-60000,60000-100000 or 100000-150000;
B) the molecular weight peak value is the polyglycolic acid of 5000-10000,10000-30000,30000-60000,60000-100000 or 100000-150000 and the copolymer of hydroxyacetic acid (PLGA), wherein, the ratio of polyglycolic acid and hydroxyacetic acid is 50-95: 50-50;
C) ethylene vinyl acetate copolymer (EVAc);
D) 10: 90,20: 80,30: 70,40: 60,50: 50 or 60: 40 to carboxy phenyl propane (p-CPP): certain herbaceous plants with big flowers diacid (SA) copolymer (polifeprosan);
E) bis-fatty acid and decanedioic acid copolymer;
F) poly-(erucic acid dimer-decanedioic acid) copolymer;
G) poly-(fumaric acid-decanedioic acid) copolymer;
H) xylitol, oligosaccharide, chrondroitin, chitin, potassium salt, sodium salt, hyaluronic acid, collagen protein, gelatin or albumin glue;
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.
Embodiment 17
The method step that is processed into slow releasing injection is identical with embodiment 11-15, but different is that contained anticancer effective component is:
(1) combination of 7-hydroxy-star shaped spore native of the bendamustine of 5-30% and 5-30%, 7-O-alkyl-star shaped spore native, beta-methoxy-star shaped spore native, alkyl phosphate choline or hexa-decyl choline phosphate;
(2) the O4-benzyl folic acid, 2 of the bendamustine of 5-30% and 5-30%, 4,5-triamido-6-benzyloxy pyrimidine, 2,4-diaminourea-6-benzyloxy-5-nitroso-group pyrimidine, 2,4-diaminourea-6-benzyloxy-5-bromo pyrimidine, 2-amino-4-benzyloxy-5-nitro-pyrimidine, 2-amino-4-benzyloxy-6-methyl-5-nitro pyrimidine, 2, the combination of 4-diaminourea-6-benzyloxy-s-triazine or 2-amino-O4-benzyl pteridine; Or
(3) imidazopyrazine of the bendamustine of 5-30% and 5-30%, imidazopyridine, wortmannin, .alpha.-5:6-benzopyran, 6-aromatic radical-2-morphol-4-base-pyrans-4-base, 2-(4-Lin Ji)-8-phenylchromone, 7-ethyl-10-hydroxycamptothecine, 3-cyano group-6-hydrazono-methyl-5-(4-pyridine radicals) pyridine-[1H]-2-1, phenylbutyric acid, methoxamine, hydroxylamine, inositolpolyphosphates, the basic phosphocholine of 14 (alkane), six certain herbaceous plants with big flowers base phosphoric acid (N-N-N-trimethyl) hexanol amine, D 19391, octadecyl-[2-(N-methyl piperidine) ethyl]-phosphate, the combination of aminotriazole(ATA) or DL-Buthionine-(S,R)-sulfoximine BSO.
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. anti-cancer medicine sustained-release injection with carrying bendamustine spit of fland and synergist thereof 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 bendamustine and its synergist, and the bendamustine synergist is selected from phosphoinositide 3-kinase inhibitor, pyrimidine analogue and/or DNA repairase inhibitor;
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;
Slow-release auxiliary material range of viscosities IV (dl/g) is 0.1～0.8, 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;
H) xylitol, oligosaccharide, chrondroitin, chitin, hyaluronic acid, collagen protein, gelatin or albumin glue;
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.
The viscosity of suspending agent is 100cp-3000cp (20 ℃-30 ℃ time), is selected from one of sodium carboxymethyl cellulose, hydroxy methocel, iodine glycerol, simethicone, propylene glycol, carbomer, mannitol, sorbitol, surfactant, soil temperature 20, soil temperature 40 and soil temperature 80 or its combination.
2. the slow-releasing anticarcinogen injection according to claim 1, the weight ratio that it is characterized in that bendamustine and bendamustine synergist is 1-9: 1 to 1: 1-9.
3. the slow-releasing anticarcinogen injection according to claim 1, it is characterized in that phosphoinositide 3-kinase inhibitor is selected from 7-hydroxy-star shaped spore native, 7-O-alkyl-star shaped spore native, the beta-methoxy-star shaped spore native, alkyl phosphate choline, hexa-decyl choline phosphate, octadecyl-(1, the 1-dimethyl-4-piperidine) phosphate, 1-O-six decyls-2-O-methyl-rac-glyceryl-3-phosphocholine, 1-O-octadecyl-2-O-methyl-rac-glyceryl-3-phosphocholine, 1-O-octadecyl-2-O-methyl-sn-glyceryl-3-phosphocholine, inositolpolyphosphates, cyclosporin A, the basic phosphocholine of 14 (alkane), six certain herbaceous plants with big flowers base phosphoric acid (N-N-N-trimethyl) hexanol amine, D 19391, one of octadecyl-[2-(N-methyl piperidine) ethyl]-phosphate or its combination.
4. the slow-releasing anticarcinogen injection according to claim 1, it is characterized in that pyrimidine analogue is selected from O4-benzyl folic acid, 2,4,5-triamido-6-benzyloxy pyrimidine, 2,4-diaminourea-6-benzyloxy-5-nitroso-group pyrimidine, 2,4-diaminourea-6-benzyloxy-5-bromo pyrimidine, 2-amino-4-benzyloxy-5-nitro-pyrimidine, 2-amino-4-benzyloxy-6-methyl-5-nitro pyrimidine, 2, one of 4-diaminourea-6-benzyloxy-s-triazine, 2-amino-O4-benzyl pteridine or its combination.
5. the slow-releasing anticarcinogen injection according to claim 1 is characterized in that DNA repairase inhibitor is selected from one of following or its combination:
(a) 2-(morphol-4-yl)-.alpha.-5:6-benzopyran-4-base, 2-(4-Lin Ji)-8-phenylchromone, 1-(2-hydroxyl-4-morphol-4-base-phenyl)-ethano-, inhibitors of kinases, 2-aminopurine, 7-ethyl-10-hydroxycamptothecine, phenylbutyric acid salt, methylamine, methoxamine, hydroxylamine, minocycline, O-hydroxylamine, O-methyl hydroxylamine or O-δ-ammonia oxygen-butyl hydroxylamine;
(b) 3-aminobenzamide, Benzoylamide, 3,4-dihydro methoxy isoquinolin-1 (2H)-Benzoylamide, AG14361, the poly synthase inhibitor, the amino 2-aromatic radical benzimidazole-4-carboxamides BZ1-6 that replaces, benzimidazole-4-carboxamides BZ1-6, tricyclic lactam hydrogen sulfide, three ring benzimidazole carboxylic acid amides, benzimidazole, 1H-three ring benzimidazole carboxylic acid amides, 2-aromatic radical-1H-benzimidazole-4-carboxamides BZ1-6,2-phenyl-1H-benzimidazole-4-carboxamides BZ1-6,2-(4-hydroxymethyl phenyl)-1H-benzimidazole-4-carboxamides BZ1-6,2-(3-anisyl)-1H-benzimidazole-4-carboxamides BZ1-6,8-hydroxy-2-methyl quinazolinone or 2-(4-hydroxyphenyl) benzimidazole-4-carboxamides BZ1-6;
(c) aminotriazole(ATA), DL-Buthionine-(S,R)-sulfoximine BSO, cavatic acid, S-hexyl glutathion, new podophyllotoxin, Exatecan mesylate or TAN-1518.
6. 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:
(1) combination of 7-hydroxy-star shaped spore native of the bendamustine of 2-40% and 1-40%, 7-O-alkyl-star shaped spore native, beta-methoxy-star shaped spore native, alkyl phosphate choline or hexa-decyl choline phosphate;
(2) the O4-benzyl folic acid, 2 of the bendamustine of 2-40% and 1-40%, 4,5-triamido-6-benzyloxy pyrimidine, 2,4-diaminourea-6-benzyloxy-5-nitroso-group pyrimidine, 2,4-diaminourea-6-benzyloxy-5-bromo pyrimidine, 2-amino-4-benzyloxy-5-nitro-pyrimidine, 2-amino-4-benzyloxy-6-methyl-5-nitro pyrimidine, 2, the combination of 4-diaminourea-6-benzyloxy-s-triazine or 2-amino-O4-benzyl pteridine; Or
(3) imidazopyrazine of the bendamustine of 2-40% and 1-40%, imidazopyridine, wortmannin, .alpha.-5:6-benzopyran, 6-aromatic radical-2-morphol-4-base-pyrans-4-base, 2-(4-Lin Ji)-8-phenylchromone, 7-ethyl-10-hydroxycamptothecine, 3-cyano group-6-hydrazono-methyl-5-(4-pyridine radicals) pyridine-[1H]-2-1, phenylbutyric acid, methoxamine, hydroxylamine, inositolpolyphosphates, the basic phosphocholine of 14 (alkane), six certain herbaceous plants with big flowers base phosphoric acid (N-N-N-trimethyl) hexanol amine, D 19391, octadecyl-[2-(N-methyl piperidine) ethyl]-phosphate, the combination of aminotriazole(ATA) or DL-Buthionine-(S,R)-sulfoximine BSO.
7. the slow-releasing anticarcinogen injection according to claim 1 is characterized in that in the selected slow-release auxiliary material,
(1) the molecular weight peak value of polylactic acid is selected from 5000-10000,10000-30000,300000-60000,60000-100000 or 100000-150000;
(2) 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 5000-10000,10000-30000,300000-60000,60000-100000 or 100000-150000;
(3) 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.
8. the slow-releasing anticarcinogen injection according to claim 1 is characterized in that 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.
9. the slow-releasing anticarcinogen injection according to claim 1, it is characterized in that slow-releasing anticarcinogen injection 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 suspensoid injectio of sarcoma or carcinosarcoma or sustained-release implant are in tumor or tumor week injection or place administration.
10. the slow-releasing anticarcinogen injection according to claim 9 is characterized in that the anticancer effective component of described anti-cancer sustained-released implantation agent is:
(1) combination of 7-hydroxy-star shaped spore native of the bendamustine of 5-30% and 5-30%, 7-O-alkyl-star shaped spore native, beta-methoxy-star shaped spore native, alkyl phosphate choline or hexa-decyl choline phosphate;
(2) the O4-benzyl folic acid, 2 of the bendamustine of 5-30% and 5-30%, 4,5-triamido-6-benzyloxy pyrimidine, 2,4-diaminourea-6-benzyloxy-5-nitroso-group pyrimidine, 2,4-diaminourea-6-benzyloxy-5-bromo pyrimidine, 2-amino-4-benzyloxy-5-nitro-pyrimidine, 2-amino-4-benzyloxy-6-methyl-5-nitro pyrimidine, 2, the combination of 4-diaminourea-6-benzyloxy-s-triazine or 2-amino-O4-benzyl pteridine; Or
(3) imidazopyrazine of the bendamustine of 5-30% and 5-30%, imidazopyridine, wortmannin, .alpha.-5:6-benzopyran, 6-aromatic radical-2-morphol-4-base-pyrans-4-base, 2-(4-Lin Ji)-8-phenylchromone, 7-ethyl-10-hydroxycamptothecine, 3-cyano group-6-hydrazono-methyl-5-(4-pyridine radicals) pyridine-[1H]-2-1, phenylbutyric acid, methoxamine, hydroxylamine, inositolpolyphosphates, the basic phosphocholine of 14 (alkane), six certain herbaceous plants with big flowers base phosphoric acid (N-N-N-trimethyl) hexanol amine, D 19391, octadecyl-[2-(N-methyl piperidine) ethyl]-phosphate, the combination of aminotriazole(ATA) or DL-Buthionine-(S,R)-sulfoximine BSO.
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.
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| CNA2008103014886A Division CN101439016A (en) | 2006-07-25 | 2006-07-25 | Bendamustine and potentiating agent thereof carried by anti-cancer medicine sustained-release injection |
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