CN101637444B - Anti-cancer drug slow release injection containing gemcitabine - Google Patents
Anti-cancer drug slow release injection containing gemcitabine Download PDFInfo
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Abstract
The invention relates to an anti-cancer drug slow release injection containing gemcitabine, which comprises slow release microspheres and a menstruum, wherein the microsphere comprises anti-cancer active ingredients and slow release auxiliary materials, and the menstruum is a special menstruum containing a suspending agent; the anti-cancer active ingredients are gemcitabine, or antimetabolites selected from zalcitabine, emtricitabine, galocitabine, ibacitabine, ancitabine, decitabine, flurocitabine, enocitabine, imidazole gemcitabine, capecitabine, gemcitabine, fludarabine or cladribine, and/or antimetabolite potentiating agents selected from phosphoinositide 3-kinase inhibitor, pyrimidine analogue and/or DNA repair enzyme inhibitor; the slow release auxiliary materials are polifeprosan, dienoic fatty acid, decanedioic acid copolymer, polylactic acid copolymer, EVAc and the like; the suspending agent has a viscosity of 100cp-3000cp (20-30 DEG C), and is selected from sodium carboxymethylcellulose and the like. The slow release microspheres can be prepared into slow release implants. When injected or placed into tumors or at peripheries of tumors, the slow release microspheres can enhance the treatment effect of non-operative treatment methods, such as radiotherapy, chemotherapy, etc.
Description
(1) technical field
The present invention relates to a kind of compound anti-cancer medicament slow release preparation, belong to technical field of pharmaceuticals.Particularly, the present invention provides a kind of compound anti-cancer medicinal slow release agent that contains antimetabolite and/or its synergist, is mainly slow releasing injection and sustained-release implant.
(2) background technology
Treatment for cancer mainly comprises methods such as operation, radiotherapy and chemotherapy.Therefore wherein operative treatment can not be removed the oncocyte that is dispersed in, and often recurs or causes tumor cell to stimulate diffusion transfer because of operation; Radiotherapy and traditional chemotherapy are not had a selectivity, and be difficult to tumor by local and form effective drug level or therapeutic dose, weak effect, toxicity is big, improves the restriction that medicine or radiological dose receive general toxic reaction again merely.Referring to " placing cisplatin adding system carmustine treatment rat brain tumor in the tumor " " surgery tumor journal 69 phase 76-82 page or leaf (1998) (Kong Q et al., J Surg Oncol.1998Oct such as Kong Qingzhongs; 69 (2): 76-82).
The local placement of antitumor drug can overcome above defective preferably, not only can obviously improve the drug level of tumor by local, and can significantly reduce general toxic reaction.A large amount of internal and external tests have demonstrated the therapeutic effect to entity tumor; Referring to " placing cisplatin adding system carmustine treatment rat brain tumor in the tumor " " surgery tumor journal 69 phase 76-82 page or leaf (1998) (Kong Q et al., J Surg Oncol.1998Oct such as Kong Qingzhongs; 69 (2): 76-82) " place cisplatin in the tumor and cure the former carbuncle in the occipital region tumor of rat " " surgery tumor journal 64 phase 268-273 page or leaf (1997) (Kong Q et al., JSurg Oncol.1997Oct with Kong Qingzhong etc.; 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 there is great difference in tumor cell to the sensitivity of chemotherapeutics.Many tumor cell medicines are also insensitive, and the tumor cell that has is in the early stage sensitivity of chemotherapy, but tolerance very soon.Particularly work as cancer therapy drug, like antimetabolite, when using separately, the enhancing of toleration usually causes the 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 Drug tolerance and the external wetting capacity of human lung carcinoma cell after the cancer therapy drug pulse screening and with the change of gene expression " " international journal of cancer " 111 phase 48-493 page or leaf (2004) (Liang Y, etal., Int J Cancer.2004; 111 (4): 484-93).
Therefore, the present invention is directed to the deficiency of prior art, a kind of anticancer pharmaceutical composition is provided; More specifically, be entity-tumor-resistant medicine composition, this pharmaceutical composition can suppress growth of tumour cell effectively through the generation that reduces toleration; Thereby can better treat tumor, reduce recurrence.
(3) summary of the invention
The present invention is directed to the deficiency of prior art, a kind of slow-releasing anticarcinogen injection is provided, more specifically, is entity-tumor-resistant medicine composition, comprises slow releasing injection and sustained-release implant.
Antimetabolite is mainly used in entity tumors such as treatment ovarian cancer, pulmonary carcinoma and digestive tract tumor abroad as one type of cancer therapy drug commonly used.Yet the application that tangible general toxicity that shows in application process and Drug tolerance have greatly limited such medicine.
The present invention finds that cancer therapy drug that has and antimetabolite share its antitumaous effect is strengthened each other, below the antimetabolite antitumaous effect will be increased each other medicine be referred to as the antimetabolite synergist, be mainly cell toxicity medicament; In addition; Antimetabolite or antimetabolite synergist are processed 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 antimetabolite 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 antimetabolite and/or its synergist, and the antimetabolite synergist is selected from phosphoinositide 3-kinase (PI3K) inhibitor, pyrimidine analogue and/or DNA repairase inhibitor; Slow-release auxiliary material is selected from polifeprosan, bis-fatty acid and decanedioic acid copolymer (PFAD-SA), one of gather (erucic acid dimer-decanedioic acid) [P (EAD-SA)], the copolymer (PLGA) that gathers (fumaric acid-decanedioic acid) [P (FA-SA)], EVAc (EVAc), polylactic acid (PLA), polyglycolic acid and hydroxyacetic acid, xylitol, oligosaccharide, chrondroitin, chitin, hyaluronic acid, collagen protein, gelatin and white tempera 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.
Antimetabolitas can stop the synthetic of DNA in different links respectively, suppresses cell division propagation, and cell cycle and DNA are synthetic to play a role through influencing.
Antimetabolitas is selected from one of following or combination: as pemetrexed, pemetrexed disodium, Rumi Qu Sai, thunder for song account for, his shore of Raltitrexed, 2-Amino-6-methyl-5-(pyridin-4-ylsulfanyl)-3H-quinazolin-4-one, carmofur, dexrazoxane, ftorafur, temozolomide, zalcitabine, emtricitabine, galocitabine, ibacitabine, ancitabine, decitabine, flurocitabine, enocitabine, imidazoles, capecitabine, gemcitabine, fludarabine, cladribine.
Antimetabolite is selected from one of following or combination: above antimetabolite also comprises their salt; As; But be not limited to sulfate, phosphate, hydrochlorate, Lactobionate, acetate, aspat, nitrate, citrate, purine or pyrimidine salt, succinate and maleate etc.
Above-mentioned antimetabolite shared ratio in slow releasing agent is decided because of concrete condition, can be 0.1%-50%, is good with 1%-40%, and 2%-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-shape sporidesmin (7-hydroxyl-staurosporine; UCN-01), 7-O-alkyl-star shaped spore native (UCN-02), 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), the basic phosphocholine of 14 (alkane) (Tetradecylphosphocholine, 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, β 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, the basic phosphocholine of inositolpolyphosphates, 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.Be 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, octadecyl-(1, the 1-dimethyl-4-piperidine) phosphate, 1-O-octadecyl-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.
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 the kinases inhibitor that any DNA-relies on and/or gathers (ADP-ribose) AG14361, but serves as preferred 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-cyanic acid-6-hydrazono-methyl-5-(4-pyridine radicals) pyridine-[1H]-2-1, phenylbutyric acid, methoxamine, hydroxylamine, the basic phosphocholine of inositolpolyphosphates, 14 (alkane), basic phosphoric acid (N-N-N-trimethyl) the hexanol amine of six certain herbaceous plants with big flowers, D 19391, octadecyl-[2-(N-methyl piperidine) ethyl]-phosphate, aminotriazole(ATA) (AT) and DL-Buthionine-(S,R)-sulfoximine BSO.
When the cancer therapy drug in the medicament slow-release microsphere is merely antimetabolite or antimetabolite synergist; Slow-releasing anticarcinogen injection is mainly used in the antimetabolite of other approach application of increase or the action effect of antimetabolite synergist, or is used for the potentiation to radiotherapy or other therapies.
When the cancer therapy drug in the medicament slow-release microsphere was merely antimetabolite or its synergist, the application of slow-releasing anticarcinogen injection and potentiation mode were:
(1) contain the slow releasing injection local injection of antimetabolite, the antimetabolite synergist is used through other approach;
(2) local injection contains the slow releasing injection of antimetabolite synergist, and other approach are used antimetabolite;
(3) local injection contains the slow releasing injection and the slow releasing injection that contains the antimetabolite synergist of antimetabolite; Or
(4) local injection contains the slow releasing injection of antimetabolite and synergist.
Therefore, antimetabolite and antimetabolite synergist can be packed individually or simultaneously, can be successively, simultaneously or alternate application.
The slow-releasing anticarcinogen injection of topical application also is used for the potentiation to radiotherapy, microwave or other therapies.Other approach refer to, but, be not limited to tremulous pulse, vein, abdominal cavity, subcutaneous, intracavitary administration.
The percentage by weight of antimetabolite synergist in medicament slow-release microsphere is 0.5%-60%, is good with 1%-40%, is best with 5%-30%.The weight ratio of antimetabolite and antimetabolite 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 following, all is weight percentage:
(a) pemetrexed of 1-40%, pemetrexed disodium, Rumi Qu Sai, thunder for song account for, his shore of Raltitrexed, 2-Amino-6-methyl-5-(pyridin-4-ylsulfanyl)-3H-quinazolin-4-one, carmofur, dexrazoxane, ftorafur, temozolomide, zalcitabine, emtricitabine, galocitabine, ibacitabine, ancitabine, decitabine, flurocitabine, enocitabine, imidazoles, capecitabine, gemcitabine, fludarabine or cladribine;
(b) the 7 hydroxy star shaped spore natives of 1-40%, 7-O-alkyl-star shaped spore native, beta-methoxy-star shaped spore native, alkyl phosphate choline, hexa-decyl choline phosphate, octadecyl-(1, the 1-dimethyl-4-piperidine) phosphate, 1-O-octadecyl-2-O-methyl-rac-glyceryl-3-phosphocholine, 1-O-octadecyl-2-O-methyl-rac-glyceryl-3-phosphocholine or 1-O-octadecyl-2-O-methyl-sn-glyceryl-3-phosphocholine;
(c) the O4-benzyl folic acid, 2 of 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, 2,4-diaminourea-6-benzyloxy-s-triazine or 2-amino-O4-benzyl pteridine;
(d) 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-cyanic acid-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) or DL-Buthionine-(S,R)-sulfoximine BSO;
(e) pemetrexed of 1-40%, pemetrexed disodium, Rumi Qu Sai, thunder for bently account for, 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, octadecyl-(1, the 1-dimethyl-4-piperidine) phosphate, 1-O-octadecyl-2-O-methyl-rac-glyceryl-3-phosphocholine, 1-O-octadecyl-2-O-methyl-rac-glyceryl-3-phosphocholine or the 1-O-octadecyl-2-O-methyl-sn-glyceryl-3-phosphocholine of his shore of Raltitrexed, 2-Amino-6-methyl-5-(pyridin-4-ylsulfanyl)-3H-quinazolin-4-one, carmofur, dexrazoxane, ftorafur, temozolomide, zalcitabine, emtricitabine, galocitabine, ibacitabine, ancitabine, decitabine, flurocitabine, enocitabine, imidazoles, capecitabine, gemcitabine, fludarabine or cladribine and 1-40%;
(f) pemetrexed of 1-40%, pemetrexed disodium, Rumi Qu Sai, thunder for bently account for, the O4-benzyl folic acid, 2 of his shore of Raltitrexed, 2-Amino-6-methyl-5-(pyridin-4-ylsulfanyl)-3H-quinazolin-4-one, carmofur, dexrazoxane, ftorafur, temozolomide, zalcitabine, emtricitabine, galocitabine, ibacitabine, ancitabine, decitabine, flurocitabine, enocitabine, imidazoles, capecitabine, gemcitabine, fludarabine or cladribine 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
(j) pemetrexed; Pemetrexed disodium; Rumi Qu Sai; Thunder accounts for for song; Raltitrexed; 2-Amino-6-methyl-5-(pyridin-4-ylsulfanyl)-3H-quinazolin-4-one; Carmofur; Dexrazoxane; Ftorafur; The temozolomide; Zalcitabine; Emtricitabine; Galocitabine; Ibacitabine; Ancitabine; Decitabine; Flurocitabine; Enocitabine; His shore of imidazoles; Capecitabine; Gemcitabine; The imidazopyrazine of fludarabine or cladribine 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-cyanic acid-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.
The preferred polifeprosan of slow-release auxiliary material, bis-fatty acid and decanedioic acid copolymer, gather (erucic acid dimer-decanedioic acid) copolymer, gather (fumaric acid-decanedioic acid) copolymer, one of copolymer (PLGA) of polylactic acid (PLA), polyglycolic acid and hydroxyacetic acid, EVAc (EVAc) or its combination.
When selecting the copolymer (PLGA) of polylactic acid (PLA), polyglycolic acid (PGA), polylactic acid (PLA) and mixture, glycolic and the hydroxy carboxylic acid of polyglycolic acid for use, PLA and PLGA content percentage by weight are respectively 0.1-99.9% and 99.9-0.1%.The molecular weight peak value of polylactic acid can be, but is not limited to, 5000-100, 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, 5000-100, 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, 5000-100,000, 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, to be 1000 to 30000 polylactic acid be with molecular weight that 20000 to 50000 polylactic acid mixes to molecular weight, to be 10000 to 30000 polylactic acid be with molecular weight that 30000 to 80000 PLGA mixes to molecular weight, 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 [gathering (1,3-two (to the carboxyl phenoxy group) propane-decanedioic acid) (p (CPP-SA)), bis-fatty acid-decanedioic acid copolymer (PFAD-SA)], gathers (erucic acid dimer-decanedioic acid) [P (EAD-SA)] and gather (fumaric acid-decanedioic acid) [P (FA-SA)] etc.Content during to carboxylic phenoxypropane (p-CPP) and decanedioic acid copolymerization is respectively percentage by weight 10-60% and 20-90%, and the blend weight ratio is 10-40: 50-90, preferably weight ratio 15-30: 65-85.
Except that above-mentioned adjuvant, also can select for use other materials to see the United States Patent (USP) (patent No. 4757128; 4857311; 4888176; 4789724) reach existing detailed description in " pharmaceutic adjuvant is complete works of " (the 123rd page, Sichuan science tech publishing house published in 1993, Luo Mingsheng and Gao Tianhui chief editor).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, processes 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 contains 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 does, 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 like 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 method for preparing 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, remove the moisture in the suspension with ways such as vacuum dryings then, special solvent of reuse or common solvent suspendible obtain corresponding sustained-release microparticle injection afterwards.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 method for preparing 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 combine freezing (drying) comminuting method to process micropowder, liposome bag medicine method and emulsion process etc.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, like 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 gets into 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 (like 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 (like 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, be first-selection 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, 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 through 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.Its volume is decided because of clinical needs, can be 0.5-2.0cm (diameter) * 0.01-0.5cm (thickness) like tablet, serves as preferred with 1-1.5 * 0.1-0.3cm; Stick can be 0.1-2.0cm (length) * 0.05-0.8cm (external diameter), serves as preferred with 0.3-1.0cm * 0.1-0.5cm.
The most preferred dosage form of sustained-release implant is that the slow releasing agent that biocompatibility, degradable absorb is implanted, and can process different shape and various dosage form because of the clinical needs of difference.The existing detailed description in detail of the packing method of its Main Ingredients and Appearance and step in United States Patent (USP) (US5651986); Comprise the some kinds of methods that prepare slow releasing preparation: as; But be not limited to, (i) be pressed into implant to carrier holder powder and medicament mixed then, promptly so-called mixing method; (ii), mix solid cooled then, promptly so-called fusion method mutually with medicine to be packaged carrier holder fusing; (iii) be dissolved in the carrier holder 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 in the sustained-release implant and percentage by weight can be with reference to slow releasing injection, but preferred as follows:
(a) pemetrexed of 5-30%, pemetrexed disodium, Rumi Qu Sai, thunder for song account for, his shore of Raltitrexed, 2-Amino-6-methyl-5-(pyridin-4-ylsulfanyl)-3H-quinazolin-4-one, carmofur, dexrazoxane, ftorafur, temozolomide, zalcitabine, emtricitabine, galocitabine, ibacitabine, ancitabine, decitabine, flurocitabine, enocitabine, imidazoles, capecitabine, gemcitabine, fludarabine or cladribine;
(b) 7-of 5-30% hydrogen-oxygen-Ji star shaped spore native, 7-O-alkyl-star shaped spore native, beta-methoxy-star shaped spore native, alkyl phosphate choline, hexa-decyl choline phosphate, octadecyl-(1, the 1-dimethyl-4-piperidine) phosphate, 1-O-octadecyl-2-O-methyl-rac-glyceryl-3-phosphocholine, 1-O-octadecyl-2-O-methyl-rac-glyceryl-3-phosphocholine or 1-O-octadecyl-2-O-methyl-sn-glyceryl-3-phosphocholine;
(c) the O4-benzyl folic acid, 2 of 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, 2,4-diaminourea-6-benzyloxy-s-triazine or 2-amino-O4-benzyl pteridine;
(d) imidazopyrazine of 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-cyanic acid-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) or DL-Buthionine-(S,R)-sulfoximine BSO;
(e) pemetrexed of 1-40%, pemetrexed disodium, Rumi Qu Sai, thunder for bently account for, 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, octadecyl-(1, the 1-dimethyl-4-piperidine) phosphate, 1-O-octadecyl-2-O-methyl-rac-glyceryl-3-phosphocholine, 1-O-octadecyl-2-O-methyl-rac-glyceryl-3-phosphocholine or the 1-O-octadecyl-2-O-methyl-sn-glyceryl-3-phosphocholine of his shore of Raltitrexed, 2-Amino-6-methyl-5-(pyridin-4-ylsulfanyl)-3H-quinazolin-4-one, carmofur, dexrazoxane, ftorafur, temozolomide, zalcitabine, emtricitabine, galocitabine, ibacitabine, ancitabine, decitabine, flurocitabine, enocitabine, imidazoles, capecitabine, gemcitabine, fludarabine or cladribine and 1-40%;
(f) pemetrexed of 1-40%, pemetrexed disodium, Rumi Qu Sai, thunder for bently account for, the O4-benzyl folic acid, 2 of his shore of Raltitrexed, 2-Amino-6-methyl-5-(pyridin-4-ylsulfanyl)-3H-quinazolin-4-one, carmofur, dexrazoxane, ftorafur, temozolomide, zalcitabine, emtricitabine, galocitabine, ibacitabine, ancitabine, decitabine, flurocitabine, enocitabine, imidazoles, capecitabine, gemcitabine, fludarabine or cladribine 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
(j) pemetrexed of 1-40%; Pemetrexed disodium; Rumi Qu Sai; Thunder accounts for for song; Raltitrexed; 2-Amino-6-methyl-5-(pyridin-4-ylsulfanyl)-3H-quinazolin-4-one; Carmofur; Dexrazoxane; Ftorafur; The temozolomide; Zalcitabine; Emtricitabine; Galocitabine; Ibacitabine; Ancitabine; Decitabine; Flurocitabine; Enocitabine; His shore of imidazoles; Capecitabine; Gemcitabine; The imidazopyrazine of fludarabine or cladribine 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-cyanic acid-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.
When the cancer therapy drug in the medicament slow-release microsphere is merely antimetabolite 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 obtaining valid density in position, former or 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 of treating 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.
Through following test and embodiment technical method of the present invention is done further to describe:
The local drug concentration that test 1, different modes are used behind the antimetabolite (gemcitabine) 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 gemcitabine.Measure medicament contg (%) in the different time tumor; The result shows; The local drug concentration significant difference of gemcitabine after different modes is used; Topical can obviously improve and effectively keep the active drug concentration at position, tumor place, and is wherein best with the effect of placing sustained-release implant and intratumor injection slow releasing injection in the tumor.Yet, intratumor injection slow releasing injection operation most convenient, easy.This discovery constitutes key character of the present invention.Following relevant inhibition test has further confirmed this point.
The interior tumor-inhibiting action of body that test 2, different modes are used behind the antimetabolite (ftorafur) 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 ftorafur.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 ftorafur after different modes is used; Topical can obviously improve and effectively keep the active drug concentration at position, tumor place, and is wherein best with the effect of placing sustained-release implant and intratumor injection slow releasing injection in the tumor.Yet, intratumor injection slow releasing injection operation most convenient, easy.Good effect not only, toxic and side effects is also little.
Test 3, contain tumor-inhibiting action in the body of antimetabolite and antimetabolite synergist (slow releasing injection)
With the rat is subjects, with 2 * 10
5Individual pancreatic tumour cell skin injected treats that in its hypochondrium tumor growth was divided into following 10 groups (seeing table 1) with it after 14 days.First group is 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 | 68±10 | |
| 2(6) | Antimetabolite | 52±5.0 | ?＜0.05 |
| 3(6) | UCN-01 | 52±2.0 | ?＜0.01 |
| 4(6) | UCN-02 | 48±2.2 | ?＜0.01 |
| 5(6) | MIL | 58±5.2 | ?＜0.01 |
| 6(6) | D-21266 | 40±3.0 | ?＜0.01 |
| 7(6) | Antimetabolite+UCN-01 | 18±2.2 | ?＜0.001 |
| 8(6) | Antimetabolite+UCN-02 | 30±3.2 | ?＜0.001 |
| 9(6) | Antimetabolite+MIL | 20±2.2 | ?＜0.001 |
| 10(6) | Antimetabolite+D-21266 | 16±2.0 | ?＜0.001 |
Above result shows, antimetabolite (pemetrexed) and used antimetabolite 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, when Combined application, can show significant potentiation.
The tumor-inhibiting action of test 4, antimetabolite and antimetabolite synergist (slow releasing injection)
Used tumor cell comprises CNS-1, C6,9L, gastric gland epithelial cancer (SA), bone tumor (BC), breast carcinoma (BA), pulmonary carcinoma (LH), papillary adenocarcinoma of thyroid (PAT), hepatocarcinoma etc.Antimetabolite and antimetabolite synergist are added in 24 hours the various tumor cells of In vitro culture by 10ug/ml concentration, continue to cultivate counting cells sum after 48 hours.Its growth of tumour cell suppresses effect to be seen shown in the table 2.
Table 2
| Oncocyte | Raltitrexed | ?O4-BA | UCN-01 | UCN-02 | Raltitrexed+O4-BA | Raltitrexed+UCN-1 | Raltitrexed+UCN-2 |
| CNS | 32％ | ?52％ | 60％ | 60％ | 86％ | 88％ | 86％ |
| C6 | 30％ | ?60％ | 60％ | 64％ | 94％ | 80％ | 94％ |
| SA | 36％ | ?60％ | 50％ | 62％ | 86％ | 92％ | 90％ |
| BC | 38％ | ?62％ | 54％ | 64％ | 94％ | 82％ | 82％ |
| BA | 38％ | ?50％ | 60％ | 60％ | 90％ | 92％ | 90％ |
| LH | 40％ | ?56％ | 62％ | 58％ | 90％ | 86％ | 84％ |
| PAT | 42％ | ?52％ | 62％ | 54％ | 92％ | 84％ | 84％ |
Above result shows, used antimetabolite (Raltitrexed) and antimetabolite 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, when Combined application, can show significant potentiation.
The tumor-inhibiting action of test 5, antimetabolite and antimetabolite synergist (slow releasing injection)
With the rat is subjects, with 2 * 10
5Individual tumor cell of liver subcutaneous injection treats that in its hypochondrium tumor growth was divided into following 10 groups (seeing table 3) with it after 14 days.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 | 72±10 | |
| 2(6) | ilmofosine | 46±5.0 | ?＜0.05 |
| 3(6) | Antimetabolite | 44±2.4 | ?＜0.01 |
| 4(6) | The ilmofosine+ antimetabolite | 30±2.4 | ?＜0.001 |
| 5(6) | AMG-PC | 48±3.2 | ?＜0.01 |
| 6(6) | The AMG-PC+ antimetabolite | 24±3.0 | ?＜0.001 |
| 7(6) | edelfosine | 32±2.6 | ?＜0.01 |
| 8(6) | The Edelfosine+ antimetabolite | 20±2.4 | ?＜0.001 |
| 9(6) | IDOU | 32±3.4 | ?＜0.01 |
| 10(6) | The IDOU+ antimetabolite | 18±2.0 | ?＜0.001 |
Above result shows, used antimetabolite (capecitabine) and antimetabolite 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, when Combined application, can show significant potentiation.
The tumor-inhibiting action of test 6, antimetabolite and antimetabolite synergist (slow releasing injection)
With the rat is subjects, with 2 * 10
5Individual prostate tumor cells subcutaneous injection treats that in its hypochondrium tumor growth was divided into negative control (blank), single therapy group (antimetabolite or antimetabolite synergist) and therapeutic alliance group (antimetabolite and antimetabolite synergist) with it after 14 days.Antimetabolite is through intratumor injection, and the antimetabolite 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) | Antimetabolite | 58 | ?＜0.05 |
| 3(6) | Imidazopyrazine | 28 | ?＜0.01 |
| 4(6) | Imidazopyridine | 38 | ?＜0.01 |
| 5(6) | Wortmannin | 34 | ?＜0.01 |
| 6(6) | .alpha.-5:6-benzopyran | 30 | ?＜0.01 |
| 7(6) | Antimetabolite+imidazopyrazine | 82 | ?＜0.001 |
| 8(6) | Antimetabolite+imidazopyridine | 78 | ?＜0.001 |
| 9(6) | Antimetabolite+wortmannin | 84 | ?＜0.001 |
| 10(6) | Antimetabolite+.alpha.-5:6-benzopyran | 74 | ?＜0.001 |
Above result shows; The kinases inhibitor that used antimetabolite (ftorafur) and antimetabolite 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, when Combined application, can show significant potentiation.
The tumor-inhibiting action of test 7, antimetabolite and antimetabolite synergist (slow releasing injection)
With the rat is subjects, with 2 * 10
5Individual breast tumor cell subcutaneous injection treats that in its hypochondrium tumor growth was divided into negative control (blank), single therapy group, therapeutic alliance group with it after 14 days.Antimetabolite is through lumbar injection, and the antimetabolite 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) | Antimetabolite | 40 | ?＜0.05 |
| 3(6) | LY294002 | 70 | ?＜0.01 |
| 4(6) | SU11752 | 66 | ?＜0.01 |
| 5(6) | SN-38 | 74 | ?＜0.01 |
| 6(6) | OK-1035 | 66 | ?＜0.01 |
| 7(6) | Antimetabolite+LY294002 | 82 | ?＜0.001 |
| 8(6) | Antimetabolite+SU11752 | 90 | ?＜0.001 |
| 9(6) | Antimetabolite+SN-38 | 82 | ?＜0.001 |
| 10(6) | Antimetabolite+OK-1035 | 88 | ?＜0.001 |
Above result shows, kinases inhibitor (wherein, LY294002:2-(4-Lin Ji)-8-phenylchromone that used antimetabolite (Rumi Qu Sai) and antimetabolite 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-cyanic acid-6-hydrazono-methyl-5-(4-pyridine radicals) pyridine-[1H]-2-1) to kinds of tumor cells when this concentration is used separately, when Combined application, can show significant potentiation.
The tumor-inhibiting action of test 8, antimetabolite and antimetabolite synergist (sustained-release implant)
With the rat is subjects, with 2 * 10
5Individual breast tumor cell subcutaneous injection treats that in its hypochondrium tumor growth was divided into negative control (blank), single therapy group, therapeutic alliance group with it after 14 days.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) | Antimetabolite | 58 | ?＜0.05 |
| 3(6) | Methoxamine | 60 | ?＜0.05 |
| 4(6) | Minocycline | 68 | ?＜0.05 |
| 5(6) | Hydroxylamine | 52 | ?＜0.05 |
| 6(6) | O-methyl hydroxylamine | 60 | ?＜0.01 |
| 7(6) | Antimetabolite+methoxamine | 84 | ?＜0.01 |
| 8(6) | Antimetabolite+minocycline | 84 | ?＜0.01 |
| 9(6) | Antimetabolite+hydroxylamine | 86 | ?＜0.01 |
| 10(6) | Antimetabolite+O-methyl hydroxylamine | 90 | ?＜0.001 |
Above result shows; Growth all has the obvious suppression effect to the kinases inhibitor that used antimetabolite (temozolomide) and antimetabolite synergist-DNA-relies on to kinds of tumor cells when this concentration is used separately, when Combined application, can show significant potentiation.
The tumor-inhibiting action of test 9, antimetabolite and antimetabolite synergist (sustained-release implant)
By the tumor-inhibiting action of test 8 said methods mensuration antimetabolites and antimetabolite synergist (sustained-release implant), its inhibition rate of tumor growth is seen table 7.
Table 7
| Test group (n) | Suffered treatment | Tumor control rate (%) | The P value |
| 1(6) | Contrast | - | |
| 2(6) | Antimetabolite | 52 | ?＜0.05 |
| 3(6) | ?3-AB | 46 | ?＜0.01 |
| 4(6) | Benzoylamide | 46 | ?＜0.01 |
| 5(6) | ?PD128763 | 42 | ?＜0.01 |
| 6(6) | ?AG14361 | 38 | ?＜0.01 |
| 7(6) | Antimetabolite+3-AB | 88 | ?＜0.001 |
| 8(6) | Antimetabolite+Benzoylamide | 78 | ?＜0.001 |
| 9(6) | Antimetabolite+PD128763 | 86 | ?＜0.001 |
| 10(6) | Antimetabolite+AG14361 | 86 | ?＜0.001 |
Above result shows, used antimetabolite (emtricitabine) and antimetabolite synergist-gather (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, when Combined application, can show significant potentiation.
The tumor-inhibiting action of test 10, antimetabolite and antimetabolite synergist (slow releasing injection)
By the tumor-inhibiting action of test 8 said methods mensuration antimetabolites and antimetabolite synergist (sustained-release implant), its inhibition rate of tumor growth is seen table 8.
Table 8
| Test group (n) | Suffered treatment | Tumor control rate (%) | The P value |
| 1(6) | Contrast | - | |
| 2(6) | Antimetabolite | 52 | ?＜0.05 |
| 3(6) | ?BZ1-6 | 52 | ?＜0.01 |
| 4(6) | ?TI1-5 | 38 | ?＜0.01 |
| 5(6) | ?TBC | 44 | ?＜0.01 |
| 6(6) | Benzimidazole | 48 | ?＜0.01 |
| 7(6) | Antimetabolite+BZ1-6 | 88 | ?＜0.001 |
| 8(6) | Antimetabolite+TI1-5 | 84 | ?＜0.001 |
| 9(6) | Antimetabolite+TBC | 78 | ?＜0.001 |
| 10(6) | Antimetabolite+benzimidazole | 80 | ?＜0.001 |
Above result shows, used antimetabolite (galocitabine) and antimetabolite synergist-gather (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, when Combined application, can show significant potentiation.
The tumor-inhibiting action of test 11, antimetabolite and/or antimetabolite synergist (sustained-release implant)
By the tumor-inhibiting action of test 8 said methods mensuration antimetabolites and/or antimetabolite synergist (sustained-release implant), its inhibition rate of tumor growth is seen table 9.
Table 9
| Test group (n) | Suffered treatment | Tumor control rate (%) | The P value |
| 1(6) | Contrast | - | |
| 2(6) | Antimetabolite | 40 | ?＜0.05 |
| 3(6) | ?NU1025 | 50 | ?＜0.01 |
| 4(6) | ?PBC | 40 | ?＜0.01 |
| 5(6) | ?MPBC | 36 | ?＜0.01 |
| 6(6) | ?NU1085 | 42 | ?＜0.01 |
| 7(6) | Antimetabolite+NU1025 | 90 | ?＜0.001 |
| 8(6) | Antimetabolite+PBC | 80 | ?＜0.001 |
| 9(6) | Antimetabolite+MPBC | 72 | ?＜0.001 |
| 10(6) | Antimetabolite+NU1085 | 92 | ?＜0.001 |
Above result shows, used antimetabolite (2-Amino-6-methyl-5-(pyridin-4-ylsulfanyl)-3H-quinazolin-4-one) and antimetabolite synergist-gather (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, when Combined application, can show significant potentiation.
The tumor-inhibiting action of test 12, antimetabolite and/or antimetabolite synergist (sustained-release implant)
By the tumor-inhibiting action of test 6 said methods mensuration antimetabolites and/or antimetabolite synergist (sustained-release implant), its inhibition rate of tumor growth is seen table 10.
Table 10
| Test group (n) | Suffered treatment | Tumor control rate (%) | The P value |
| 1(6) | Contrast | - | |
| 2(6) | Antimetabolite | 52 | ?＜0.05 |
| 3(6) | ?BSO | 36 | ?＜0.01 |
| 4(6) | Aminotriazole(ATA) | 34 | ?＜0.01 |
| 5(6) | Cavatic acid | 32 | ?＜0.01 |
| 6(6) | New podophyllotoxin | 30 | ?＜0.01 |
| 7(6) | Antimetabolite+BSO | 80 | ?＜0.001 |
| 8(6) | Antimetabolite+aminotriazole(ATA) | 80 | ?＜0.001 |
| 9(6) | Antimetabolite+cavatic acid | 72 | ?＜0.001 |
| 10(6) | Antimetabolite+new podophyllotoxin | 82 | ?＜0.001 |
Above result shows; Used antimetabolite (enocitabine) and antimetabolite synergist-AG14361 (wherein to gather (ADP-ribose); 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, when Combined application, can show significant potentiation.
Further test shows, pemetrexed, pemetrexed disodium, Rumi Qu Sai, thunder for song account for, his shore of Raltitrexed, 2-Amino-6-methyl-5-(pyridin-4-ylsulfanyl)-3H-quinazolin-4-one, carmofur, dexrazoxane, ftorafur, temozolomide, zalcitabine, emtricitabine, galocitabine, ibacitabine, ancitabine, decitabine, flurocitabine, enocitabine, imidazoles, capecitabine, gemcitabine, fludarabine or cladribine strengthen the action effect that gathers (ADP-ribose) AG14361 and other antimetabolite synergist to some extent.
In a word, growth all had the obvious suppression effect to kinds of tumor cells when used antimetabolite and various antimetabolite synergist were used separately, when Combined application, can show significant potentiation.Yet in the mutual synergic while, its toxic action does not have obvious increase.Therefore, effective ingredient of the present invention (or the more than one) antimetabolite that is any one and/or any one (or more than one) antimetabolite synergist.The medicine that contains above effective ingredient can be made into sustained-release micro-spheres, and then processes 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 able to further specify through following embodiment.The foregoing description and following examples just are described further the present invention, are not its content is used as any restriction with making.
(4) specific embodiment
Embodiment 1.
80mg polifeprosan (to carboxy phenyl propane (p-CPP): certain herbaceous plants with big flowers diacid (SA) is 20: 80) copolymer is put into container; Add 100 milliliters of dichloromethane; Behind the dissolving mixing; Add 10mg pemetrexed and 7 hydroxy star shaped spore natives, shake up the back contains 10% pemetrexed 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 10-15 days, is about 20-30 days at the subcutaneous drug release time of mice.The viscosity of injection is 400cp-600cp (20 ℃-30 ℃ time).
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) pemetrexed of 1-40%, pemetrexed disodium, Rumi Qu Sai, thunder for song account for, his shore of Raltitrexed, 2-Amino-6-methyl-5-(pyridin-4-ylsulfanyl)-3H-quinazolin-4-one, carmofur, dexrazoxane, ftorafur, temozolomide, zalcitabine, emtricitabine, galocitabine, ibacitabine, ancitabine, decitabine, flurocitabine, enocitabine, imidazoles, capecitabine, gemcitabine, fludarabine or cladribine;
(2) 7-of 1-40% hydrogen-oxygen-Ji star shaped spore native, 7-O-alkyl-star shaped spore native, 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 cyclosporin A, 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; Or
(3) 1-40% pemetrexed, pemetrexed disodium, Rumi Qu Sai, thunder for bently account for, basic phosphoric acid (N-N-N-trimethyl) the hexanol amine of 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, 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 cyclosporin A, 14 (alkane), six certain herbaceous plants with big flowers, D 19391 or octadecyl-[2-(N-methyl piperidine) the ethyl]-phosphatic combination of his shore of Raltitrexed, 2-Amino-6-methyl-5-(pyridin-4-ylsulfanyl)-3H-quinazolin-4-one, carmofur, dexrazoxane, ftorafur, temozolomide, zalcitabine, emtricitabine, galocitabine, ibacitabine, ancitabine, decitabine, flurocitabine, enocitabine, imidazoles, capecitabine, gemcitabine, fludarabine or cladribine 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 15mg7-ethyl-10-hydroxycamptothecine, shakes up the dry removal of final vacuum organic solvent again.Dried pastille solid composite freezing and pulverizing is processed the micropowder that contains 15% Raltitrexed 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.The viscosity of injection is 480cp-620cp (20 ℃-30 ℃ time)
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) imidazopyrazine of 1-40%; Imidazopyridine; Wortmannin; .alpha.-5:6-benzopyran; 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; Vanillin; 2-aminopurine; 7-ethyl-10-hydroxycamptothecine; Phenylbutyric acid salt; Methylamine; Methoxamine; Hydroxylamine; Minocycline; The O-hydroxylamine; O-methyl hydroxylamine or O-δ-ammonia oxygen-butyl hydroxylamine; Or
(2) pemetrexed of 1-40%; Pemetrexed disodium; Rumi Qu Sai; Thunder accounts for for song; Raltitrexed; 2-Amino-6-methyl-5-(pyridin-4-ylsulfanyl)-3H-quinazolin-4-one; Carmofur; Dexrazoxane; Ftorafur; The temozolomide; Zalcitabine; Emtricitabine; Galocitabine; Ibacitabine; Ancitabine; Decitabine; Flurocitabine; Enocitabine; His shore of imidazoles; Capecitabine; Gemcitabine; The imidazopyrazine of fludarabine or cladribine and 1-40%; Imidazopyridine; Wortmannin; .alpha.-5:6-benzopyran; 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; Vanillin; 2-aminopurine; 7-ethyl-10-hydroxycamptothecine; Phenylbutyric acid salt; Methylamine; Methoxamine; Hydroxylamine; Minocycline; The O-hydroxylamine; The combination of O-methyl hydroxylamine or O-δ-ammonia oxygen-butyl hydroxylamine.
Embodiment 5.
(EVAc) puts into container with the 70mg EVAc; After adding 100 milliliters of dichloromethane dissolving mixings; Add 20 milligrams of carmofurs and 10 milligrams of benzimidazoles, shake up the back contains 20% carmofur 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.The viscosity of injection is 440cp-640cp (20 ℃-30 ℃ time)
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:
(1) the 3-aminobenzamide of 1-40%, Benzoylamide, 3,4-dihydro methoxy isoquinolin-1 (2H)-Benzoylamide, AG14361, poly polymerase inhibitor, amino substituted 2-aromatic radical benzimidazole-4-carboxamides BZ1-6, 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; Or
(2) pemetrexed of 1-40%, pemetrexed disodium, Rumi Qu Sai, thunder for bently account for, 3-aminobenzamide, the Benzoylamide, 3 of his shore of Raltitrexed, 2-Amino-6-methyl-5-(pyridin-4-ylsulfanyl)-3H-quinazolin-4-one, carmofur, dexrazoxane, ftorafur, temozolomide, zalcitabine, emtricitabine, galocitabine, ibacitabine, ancitabine, decitabine, flurocitabine, enocitabine, imidazoles, capecitabine, gemcitabine, fludarabine or cladribine and 1-40%, 4-dihydro methoxy isoquinolin-1 (2H)-Benzoylamide, AG14361, poly polymerase inhibitor, amino substituted 2-aromatic radical benzimidazole-4-carboxamides BZ1-6, benzimidazole-4-carboxamides BZ1-6, tricyclic lactam hydrogen sulfide, three ring benzimidazole carboxylic acid amides, benzimidazole, 1H-three encircle the combination of 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.
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 ftorafur and 10mg DL-Buthionine-(S,R)-sulfoximine BSO, shake up the back contains 20% ftorafur and 10% DL-Buthionine-(S,R)-sulfoximine BSO 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 0.5% 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.The viscosity of injection is 480cp-660cp (20 ℃-30 ℃ time)
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:
(1) glutathione bisulphide of 1-40%, tetramethylthiuram disulfide, aminotriazole(ATA), DL-Buthionine-(S,R)-sulfoximine BSO, cavatic acid, S-hexyl glutathion, new podophyllotoxin; Or
(2) pemetrexed of 1-40%; Pemetrexed disodium; Rumi Qu Sai; Thunder accounts for for song; Raltitrexed; 2-Amino-6-methyl-5-(pyridin-4-ylsulfanyl)-3H-quinazolin-4-one; Carmofur; Dexrazoxane; Ftorafur; The temozolomide; Zalcitabine; Emtricitabine; Galocitabine; Ibacitabine; Ancitabine; Decitabine; Flurocitabine; Enocitabine; His shore of imidazoles; Capecitabine; Gemcitabine; The glutathione bisulphide of fludarabine or cladribine and 2-40%; Tetramethylthiuram disulfide; Aminotriazole(ATA); DL-Buthionine-(S,R)-sulfoximine BSO; Cavatic acid; S-hexyl glutathion; New podophyllotoxin; The combination of Exatecan mesylate or TAN-1518.
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 zalcitabine and 10mgO4-benzyl folic acid, shake up the back contains 20% zalcitabine 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.The viscosity of injection is 420cp-680cp (20 ℃-30 ℃ time)
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:
(1) the O4-benzyl folic acid, 2 of 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, 2,4-diaminourea-6-benzyloxy-s-triazine or 2-amino-O4-benzyl pteridine; Or
(2) pemetrexed of 10-30%, pemetrexed disodium, Rumi Qu Sai, thunder for bently account for, the O4-benzyl folic acid, 2 of his shore of Raltitrexed, 2-Amino-6-methyl-5-(pyridin-4-ylsulfanyl)-3H-quinazolin-4-one, carmofur, dexrazoxane, ftorafur, temozolomide, zalcitabine, emtricitabine, galocitabine, ibacitabine, ancitabine, decitabine, flurocitabine, enocitabine, imidazoles, capecitabine, gemcitabine, fludarabine or cladribine 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 gemcitabine, shake up the back contains 10%7-hydroxy-star shaped spore native and 20% gemcitabine 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:
20% pemetrexed; Pemetrexed disodium; Rumi Qu Sai; Thunder accounts for for song; Raltitrexed; 2-Amino-6-methyl-5-(pyridin-4-ylsulfanyl)-3H-quinazolin-4-one; Carmofur; Dexrazoxane; Ftorafur; The temozolomide; Zalcitabine; Emtricitabine; Galocitabine; Ibacitabine; Ancitabine; Decitabine; Flurocitabine; Enocitabine; His shore of imidazoles; Capecitabine; Gemcitabine; Fludarabine or cladribine and 7-hydroxy-star shaped spore native of 10%; 7-O-alkyl-star shaped spore native; The beta-methoxy-star shaped spore native; The combination of 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 cladribine and the new podophyllotoxin of 20mg, shake up the back contains 10% cladribine 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: 10% pemetrexed, pemetrexed disodium, Rumi Qu Sai, thunder for bently account for, aminotriazole(ATA), DL-Buthionine-(S,R)-sulfoximine BSO, cavatic acid, S-hexyl glutathion, the combination of podophyllotoxin, Exatecan mesylate or TAN-1518 newly of his shore of Raltitrexed, 2-Amino-6-methyl-5-(pyridin-4-ylsulfanyl)-3H-quinazolin-4-one, carmofur, dexrazoxane, ftorafur, temozolomide, zalcitabine, emtricitabine, galocitabine, ibacitabine, ancitabine, decitabine, flurocitabine, enocitabine, imidazoles, capecitabine, gemcitabine, fludarabine or cladribine and 20%.
Embodiment 15
The method step that is processed into slow releasing agent is identical with embodiment 1-14, but different is used slow-release auxiliary material is one of following or its combination:
A) polylactic acid, molecular weight peak value are 10000-30000,300000-60000,60000-100000 or 100000-150000;
B) copolymer of polyglycolic acid and hydroxyacetic acid, wherein, the ratio of polyglycolic acid and hydroxyacetic acid is 50-95: 50-50, the molecular weight peak value is 10000-30000,300000-60000,60000-100000 or 100000-150000;
C) EVAc;
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) gather (erucic acid dimer-decanedioic acid);
G) gather (fumaric acid-decanedioic acid);
H) xylitol, oligosaccharide, chrondroitin, chitin, hyaluronic acid, collagen protein, gelatin or white tempera.
Embodiment 16
The method step that is processed into slow releasing injection is identical with embodiment 1-15, but different is used suspending agent is respectively one of following or its combination:
A) 0.5-3.0% carboxymethyl cellulose (sodium);
B) 5-15% mannitol;
C) 5-15% sorbitol;
D) 0.1-1.5% surfactant;
E) 0.1-0.5% polysorbas20.
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:
(a) pemetrexed of 1-40%, pemetrexed disodium, Rumi Qu Sai, thunder for song account for, his shore of Raltitrexed, 2-Amino-6-methyl-5-(pyridin-4-ylsulfanyl)-3H-quinazolin-4-one, carmofur, dexrazoxane, ftorafur, temozolomide, zalcitabine, emtricitabine, galocitabine, ibacitabine, ancitabine, decitabine, flurocitabine, enocitabine, imidazoles, capecitabine, gemcitabine, fludarabine or cladribine;
(b) 7-of 1-40% hydrogen-oxygen-Ji 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;
(c) the O4-benzyl folic acid of 1-40%;
(d) methoxamine of 1-40%, hydroxylamine, inositolpolyphosphates, aminotriazole(ATA) or DL-Buthionine-(S,R)-sulfoximine BSO;
(e) pemetrexed of 1-40%; Pemetrexed disodium; Rumi Qu Sai; Thunder accounts for for song; Raltitrexed; 2-Amino-6-methyl-5-(pyridin-4-ylsulfanyl)-3H-quinazolin-4-one; Carmofur; Dexrazoxane; Ftorafur; The temozolomide; Zalcitabine; Emtricitabine; Galocitabine; Ibacitabine; Ancitabine; Decitabine; Flurocitabine; Enocitabine; His shore of imidazoles; Capecitabine; Gemcitabine; 7-hydroxy-star shaped spore native of fludarabine or cladribine and 1-40%; 7-O-alkyl-star shaped spore native; The beta-methoxy-star shaped spore native; The combination of alkyl phosphate choline or hexa-decyl choline phosphate;
(f) pemetrexed of 1-40%, pemetrexed disodium, Rumi Qu Sai, thunder for bently account for, the combination of the O4-benzyl folic acid of his shore of Raltitrexed, 2-Amino-6-methyl-5-(pyridin-4-ylsulfanyl)-3H-quinazolin-4-one, carmofur, dexrazoxane, ftorafur, temozolomide, zalcitabine, emtricitabine, galocitabine, ibacitabine, ancitabine, decitabine, flurocitabine, enocitabine, imidazoles, capecitabine, gemcitabine, fludarabine or cladribine and 1-40%;
(j) pemetrexed of 1-40%, pemetrexed disodium, Rumi Qu Sai, thunder for bently account for, the combination of methoxamine, hydroxylamine, aminotriazole(ATA) or the DL-Buthionine-(S,R)-sulfoximine BSO of his shore of Raltitrexed, 2-Amino-6-methyl-5-(pyridin-4-ylsulfanyl)-3H-quinazolin-4-one, carmofur, dexrazoxane, ftorafur, temozolomide, zalcitabine, emtricitabine, galocitabine, ibacitabine, ancitabine, decitabine, flurocitabine, enocitabine, imidazoles, capecitabine, gemcitabine, fludarabine or cladribine and 1-40%.
Above embodiment only is used for explanation, and is not limitation application of the present invention.
The present invention disclosed with the protection the content see claim.
Claims (1)
1. slow releasing injection that contains antimetabolite and its synergist, process by following method:
70mg polifeprosan copolymer is put into container; In the polifeprosan copolymer to carboxy phenyl propane: decanedioic acid is 20:80; Add 100 milliliters of dichloromethane; Behind the dissolving mixing, add 20mg zalcitabine and 10mgO4-benzyl folic acid, shake up the back contains 20% zalcitabine 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.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2008103014848A CN101637444B (en) | 2006-03-17 | 2006-03-17 | Anti-cancer drug slow release injection containing gemcitabine |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2008103014848A CN101637444B (en) | 2006-03-17 | 2006-03-17 | Anti-cancer drug slow release injection containing gemcitabine |
Related Parent Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA2006102002562A Division CN1861049A (en) | 2006-03-17 | 2006-03-17 | Slow-releasing injection contg anticarcinogen of Jixitabin |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN101637444A CN101637444A (en) | 2010-02-03 |
| CN101637444B true CN101637444B (en) | 2012-08-15 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2008103014848A Expired - Fee Related CN101637444B (en) | 2006-03-17 | 2006-03-17 | Anti-cancer drug slow release injection containing gemcitabine |
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| Country | Link |
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| CN (1) | CN101637444B (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| PT2750768T (en) * | 2011-08-30 | 2018-12-19 | Astex Pharmaceuticals Inc | Decitabine derivative formulations |
| CN102512387B (en) * | 2011-12-26 | 2013-11-27 | 天津市嵩锐医药科技有限公司 | Zalcitabine drug composition |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1634586A (en) * | 2004-11-22 | 2005-07-06 | 山东蓝金生物工程有限公司 | Anti-cancer medicine composition |
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Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1634586A (en) * | 2004-11-22 | 2005-07-06 | 山东蓝金生物工程有限公司 | Anti-cancer medicine composition |
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| Publication number | Publication date |
|---|---|
| CN101637444A (en) | 2010-02-03 |
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