CN1846677A - Slow-released injection containing fluoroplex synergist - Google Patents
Slow-released injection containing fluoroplex synergist Download PDFInfo
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- CN1846677A CN1846677A CNA2006102000459A CN200610200045A CN1846677A CN 1846677 A CN1846677 A CN 1846677A CN A2006102000459 A CNA2006102000459 A CN A2006102000459A CN 200610200045 A CN200610200045 A CN 200610200045A CN 1846677 A CN1846677 A CN 1846677A
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Abstract
The slow released anticancer injection containing fluoroplex consists of slow released microballoon and solvent. The slow released microballoon includes effective anticancer component and slow releasing supplementary material, and the solvent is common solvent or special solvent containing suspending agent. The effective anticancer component is 5-FU and/or 5-FU synergist selected from platinum compound, topoisomerase inhibitor, guanine analogue and tetrazine compound; the slow releasing supplementary material is PLA, PLGA, EVAc, etc or their composition; and the suspending agent is sodium carboxymethyl cellulose, Tween-40 and/or Tween-80. Injecting the slow released injection to tumor can lower the systematic toxic reaction of the medicine and raise the medicine concentration of local tumor part selectively to raise the treating effect.
Description
(1) technical field
The present invention relates to a kind of slow releasing injection that contains fluorouracil (5-FU) synergist and preparation method thereof, belong to technical field of pharmaceuticals.
(2) background technology
As a kind of chemotherapeutics commonly used, 5-fluorouracil (5-FU) has been widely used in the treatment of multiple malignant tumor, and action effect is comparatively obvious.Yet its beat all neurotoxicity has greatly limited the application of this medicine.Blood vessel in the mesenchyma stroma of tumors, connective tissue, stromatin, fine micro protein and collagen protein etc. not only provide support and requisite nutrient substance for the growth of tumor cell, also influenced chemotherapeutics around tumor and the infiltration in the tumor tissues and diffusion (carry and to wait " situation of extracellular matrix to entity tumor in the medicine influence of turning round " " cancer research " 60 phase 2497-503 page or leaf (2000) (Netti PA referring to the Buddhist nun, Cancer Res.2000,60 (9): 2497-503).Because entity tumor excessive expansion hypertrophy, the viscosity of matter was high than its normal surrounding tissue all between matter pressure, tissue elasticity pressure, fluid pressure reached therebetween, therefore, conventional chemotherapy, be difficult to tumor by local and form effective drug level, referring to " placing cisplatin adding system carmustine treatment rat brain tumor in the tumor " " surgery tumor magazine " 69 phase 76-82 pages or leaves (1998) (Kong Q et al., J SurgOncol.1998 Oct such as Kong Qingzhongs; 69 (2): 76-82), improve the restriction that dosage is subjected to general reaction again merely.Pharmaceutical topical application may solve the problem (Chinese patent) of drug level to a certain extent, yet operation techniques such as medicine implantation are complicated, traumatic big, the various complication such as, infection hemorrhage, immunity reduction, also can cause or quicken the diffusion and the transfer of tumor except that easily causing.In addition, the preparation of perioperatively itself and expensive expense usually influence its effective enforcement.
In addition, the DNA repair function in many tumor cells obviously increases after chemotherapy.The latter often causes the enhancing of tumor cell to the toleration of cancer therapy drug, consequently treatment failure.
In addition, the cancer drug therapy of low dosage not only can increase the Drug tolerance of cancerous cell, but also can promote its infiltrative growth " (referring to beam etc. " increased the Drug tolerance of human lung carcinoma cell and external wetting capacity after the cancer therapy drug pulse screening and with the change of gene expression " " international journal of cancer " 111 phase 484-93 page or leaf (2004) (Liang Y; etal., Int J Cancer.2004; 111 (4): 484-93).
Therefore, be convenient to keep high drug level and increase tumor cell the preparation and the method for the sensitivity of medicine just become an important subject at tumor by local.
(3) summary of the invention
5-fluorouracil has been widely used in the treatment kinds of tumors as a kind of cancer therapy drug commonly used, as cerebral tumor etc.Yet in application process, its tangible general toxicity has greatly limited the application of this medicine.
Be effectively to improve tumor by local drug level, reduce the drug level of medicine in blood circulation, people have studied the drug sustained release system that contains 5-fluorouracil, comprise that sustained-release micro-spheres (capsule) (sees: (China Patent No. ZL00809160.9; Application number 91109723.6), Ciftci K etc. " with the polylactic acid microsphere treatment entity tumor that contains fluorouracil and the research of drug release " " (see: China Patent No. ZL96115937.5 by drug development technology (Pharm Dev Technol.2 (2): 151-60,1997), sustained-release implant; ZL97107076.8) etc.Yet, solid sustained-release implant (China Patent No. ZL96115937.5; ZL97107076.8) and existing as be used for the treatment of the cerebral tumor (ZL00809160.9) sustained-release micro-spheres or United States Patent (USP) (US5,651,986) and all have problem such as be not easy more than operation, weak curative effect, the complication.In addition, the sensitivity that many entity tumors are drawn together 5-fluorouracil to anticancer medicated bag is relatively poor, and is easy to generate drug resistance in therapeutic process.The present invention finds that medicine of mentioning among the present invention and 5-FU share and can make its antitumaous effect strengthen (the following medicine that the 5-FU antitumaous effect will be increased mutually is referred to as the 5-FU synergist) mutually.In addition, with the assembly packaging of 5-FU or 5-FU and its synergist in specific slow-release auxiliary material and be equipped with special solvent and make drug level that anti-cancer medicine sustained-release injection not only can greatly improve tumor by local, reduce the drug level of medicine in blood circulation, reduce the toxicity of medicine to normal structure, can also greatly make things convenient for the medicine injection, reduce operation technique complication, reduce patient's expense.The above unexpected main contents of the present invention of finding to constitute.
The present invention is directed to the deficiencies in the prior art, a kind of new slow releasing injection that contains fluorouracil and/or 5-fluorouracil synergist is provided.
Anti-cancer medicine sustained-release injection of the present invention is made up of sustained-release micro-spheres and solvent.Particularly, this slow-releasing anticarcinogen injection is grouped into by following one-tenth:
(A) sustained-release micro-spheres comprises:
Anticancer effective component 0.5-50%
Slow-release auxiliary material 50-99%
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 the combination or the 5-fluorouracil synergist of 5-fluorouracil and 5-fluorouracil synergist, and the 5-fluorouracil synergist is selected from platinum-like compounds, topoenzyme inhibitor, guanine class medicine and/or tetrazine class medicine; Suspending agent helps the suspension of slow releasing pharmaceutical and then makes things convenient for drug administration by injection, is selected from one of sodium carboxymethyl cellulose, (iodine) glycerol, simethicone, propylene glycol, carbomer, mannitol, sorbitol, soil temperature 20, soil temperature 40 and soil temperature 80 or its combination.
5-fluorouracil shared ratio in compositions is decided because of concrete condition, generally speaking, can be good with 1%-50% from 0.01%-55%, is best with 2%-40%.All be weight percentage.
Topoenzyme inhibitor is selected from one of following or combination: Camptothecin (camptothecin, CPT), the derivant of Camptothecin, lurtotecan (Lurtotecan), topotecan (10-hydroxy-9-dimethylaminomethyl-(S)-camptothecin, topotecan), irinotecan (irinotecan, IRT), 9-nitro Camptothecin (9-nitrocamptothecin, 9NC), 7-ethyl-10-hydroxyl-Camptothecin (7-ethyl-10-hydroxy-camptothecin, SN-38), 7-ethyl-10-[4-(1-piperidino)-1-piperidino] and the carbonyl Camptothecin (7-ethyl-10-[4-(1-pyperidino)-1-piperidino] carbonyloxycamptothecin, CPT-11), 10-hydroxyl-Camptothecin (10-Hydroxycamptothecin, HCPT), Homocamptothecins (Homocamptothecins), MD-CPT (10,11-methylenedioxy, MD-CPT), (RS)-MD-CPT (10,11-MD-20 (RS)-CPT), (S)-MD-CPT glycinate (10,11-MD-20 (S)-cpT-glycinate ester (Gly) .HCl), 9-amino-(S)-MD-CPT glycinate (9-amino-10,11-MD-20 (S)-CPT-Gly), N-[2-(dimethylamino) ethyl] and pyridine-4-carboxylic acid amides (N-[2-(dimethylamino) ethyl] acridine-4-carboxamide, DACA) and the derivant of 5 or 7 replacements, podophyllotoxin (podophyllotoxin), etoposide (Etoposide, epipodophyllotoxins, etoposide, etoposide, VP-16), teniposide (Teniposide, teniposide, VM-26), Podophyllinic acid, podophyllotoxin, trihydroxy-isoflavone (Genistein), the 14-doxorubicin, amrubicin (Amrubicin), Ai Rou is than star (4 '-(acridinylamino) methansulfon-m-anisidide (amsacrine, m-AMSA)), the nor-oxygen daunorubicin of 4-(4-demeth oxydaunorubicin), detorubicin, 7-O-methyl Nuo Jia-4 '-epirubicin (7-o-methylnogallol-4 '-epiadriamycin), esorubicin (Esorubicin), carubicin, idarubicin (idarubicin, IDA), rodorubicin, leurubicin (Leurubicin), medorubicin, Nemorubicin (Nemorubicin), doxorubicin, valrubicin (N-trifluoro toxin-14-valerate, N-trifluoroacetyladriamycin-14-valerate, AD 32, valrubicin), 2-[4-(7-chloro-2-quinoxalinyl phenoxy base]-propanoic acid ((2-[4-(7-chloro-2-quinoxalinyloxyphenoxy]-propionic acid, XK469), zorubicin (Zorubicin), N-(2-ethyl chloride)-N-nitroso-group urea groups daunorubicin (N-(2-Chloroethyl)-N-nitrosoureidodaunorubicin, AD 312), pyrazoles [1,5-a] indole derivatives, as, but be not limited to, GS-2,-3,-4, GS-5; The dioxy piperazine oxazine derivatives, as, but be not limited to, (+)-1, two (3, the 5-dioxo piperazinyl) propane ((+)-1 of 2-, 2-bis (3,5-dioxopiperazinyl-1-yl) propane, ICRF-187) ,-2,3-two (3,5-dioxo piperazine-1-yl) butane (meso-2,3-bis (3,5-dioxopiperazine-1-yl) butane, ICRF-193), two dioxo piperazine (bisdioxopiperazine); Suramin (Suramin), deoxyguanosine (Deoxyguanosine), lithocholic acid (lithocholic acid, LCA) or Hydrazoic acid,sodium salt (sodium azide).
In the above topology enzyme inhibitor, serve as preferred than star, rodorubicin, leurubicin, zorubicin, valrubicin or idarubicin with Camptothecin, hydroxy-camptothecin alkali, lurtotecan, topotecan, irinotecan, etoposide, teniposide, amrubicin, Ai Rou.
Topoenzyme inhibitor shared ratio in compositions is decided because of concrete condition, generally speaking, can be good with 1%-40% from 0.01%-50%, is best with 5%-30%.All be weight percentage.
Guanine analog comprises 2-amino-6-oxypurine (2-amino-6-oxypurine); guanine (guanine); benzyl guanine (benzylguanine); O6-benzyl guanine (O6-BG); O6-butyl guanine (O6-butylguanines; O6-BuG); O6-methyl guanine (O6-MG); O6-alkyl guanine (O6-Alkylguanine; O6-AG); O6-benzyl-2 '-deoxyguanosine (O6-benzyl-2 '-deoxyguanosine); 8-amino-O6-benzyl guanine (8-Amino-O.sup.6-benzylguanine); 8-methyl-O6-benzyl guanine (8-methyl-O.sup.6-benzylguanine); 8-hydroxyl-O6-benzyl guanine (8-hydroxy-O.sup.6-benzylguanine); 8-bromo-O6-benzyl guanine (8-bromo-O.sup.6-benzylguanine); 8-oxygen-O6-benzyl guanine (8-Oxo-O.sup.6-benzylguanine); 8-trifluoromethyl-O6-benzyl guanine (8-trifluoromethyl-O.sup.6-benzylguanine); O6-benzyl uric acid (O.sup.6-Benzyluricacid; O6-BA); O6-benzyl xanthine (O.sup.6-Benzylxanthine); O6-benzyl-2-fluorine hypoxanthine (O.sup.6-Benzyl-2-fluorohypoxanthine); Diacetyl-O.sup.6-benzyl-8-oxoguanine (Diacetyl-O.sup.6-benzyl-8-oxoguanine); O6-benzyl-8-methyl guanine (O.sup.6-Benzyl-8-methylguanine); O6-benzyl-8-oxo guanine (O.sup.6-Benzyl-8-oxoguanine); O6-benzyl-8-bromination guanine (O.sup.6-Benzyl-8-bromoguanine); O6-benzyl-8-trifluoromethyl guanine (O.sup.6-Benzyl-8-trifluoromethylguanine); O6-benzyl-N2-methyl guanine (O.sup.6-benzyl-N.sup.2-methylguanine); O6-benzyl-N2N2-dimethylguanine (O.sup.6-benzyl-N.sup.2; N.sup.2-dimethylguanine); O6-benzyl-8-trifluoromethyl-9-methyl guanine (O.sup.6-benzyl-8-trifluoromethyl-9-methylguanine); O6-benzyl-8-bromo-9-methyl guanine (O.sup.6-benzyl-8-bromo-9-methylguanine); O6-benzyl-8-bromo-9-pivaloyl oxygen methyl guanine (O.sup.6-benzyl-8-bromo-9-(pivaloyloxymethyl) guanine); O6-benzyl-7-pivaloyl oxygen methyl guanine (O.sup.6-benzyl-7-(pivaloyloxymethyl) guanine); O6-benzyl-8-bromo-7-pivaloyl oxygen methyl guanine (O.sup.6-benzyl-8-bromo-7-(pivaloyloxymethyl) guanine); 8-azepine-O6-benzyl-7-pivaloyl oxygen methyl guanine (8-Aza-O.sup.6-benzyl-9-(pivaloyloxymethyl) guanine); 8-azepine-O6-benzyl-7-pivaloyl oxygen methyl guanine (8-Aza-O.sup.6-benzyl-7-(pivaloyloxymethyl) guanine); 8-azepine-O6-benzyl guanine (8-Aza-O.sup.6-benzylguanine); 8-azepine-O6-benzyl-9-methyl guanine (8-Aza-O.sup.6-benzyl-9-methylguanine); N.sup.2-Acetyl-O.sup.6-benzyl-8-oxoguanine (N.sup.2-Acetyl-O.sup.6-benzyl-8-oxoguanine); O6-benzyl-N2-methyl guanine (O.sup.6-Benzyl-N.sup.2-methylguanine); O6-benzyl-N2N2-dimethylguanine (O.sup.6-Benzyl-N.sup.2; N.sup.2-dimethylguanine); 2-amino-6-chloro-8-methyl purine (2-Amino-6-chloro-8-methylpurine); 2; 8-diaminourea-6-chloropurine (2; 8-Diamino-6-chloropurine); O6-benzyl-N2-guanosine (O6-benzyl-N2-acetylguanosine); O6-benzyl-9-cyano group guanine (O6-benzyl-9-cyanomethylguanine (CMBG)); N (7)-methyl guanine (N (7)-methylguanine); O6-benzyl-N2-guanosine (O6-benzylguanosine (BGS)); O6-cycloalkyl guanine (O (6)-cycloalkylguanines); O6-pi-allyl guanine (O (6)-allylguanine); O6-(2-oxyalkyl guanine (O (6)-(2-oxoalkyl) guanine); O6-cycloalkenyl guanine (O (6)-Cycloalkenylguanines; O6-CAG); 1-cyclobutane methyl guanine (1-cyclobutenylmethylguanine; CBMG); 1-cyclopentenyl methyl guanine (1-cyclopentenylmethylguanine; cpMG) and O6-bromothen base guanine (O (6)-(4-bromothenyl) guanine, O6-BTG).
Guanine analog can be one or more in the above medicine; but preferred benzyl guanine; O6-benzyl guanine; O6-butyl guanine; the O6-methyl guanine; O6-alkyl guanine; 2-amino-6-oxypurine; O6-benzyl 2 '-deoxyguanosine; guanine (guanine); 8-amino-O6-benzyl guanine; 8-methyl-O6-benzyl guanine; 8-hydroxyl-O6-benzyl guanine; 8-bromo-O6-benzyl guanine; 8-oxygen-O6-benzyl guanine; 8-trifluoromethyl-O6-benzyl guanine; O6-benzyl uric acid; O6-benzyl xanthine; O6-benzyl-2-fluorine hypoxanthine; Diacetyl-O.sup.6-benzyl-8-oxoguanine; O6-benzyl-8-methyl guanine; O6-benzyl-8-oxo guanine; O6-benzyl-8-bromination guanine; O6-benzyl-8-trifluoromethyl guanine; O6-benzyl-N2-methyl guanine; O6-benzyl-N2N2-dimethylguanine; O6-benzyl-8-trifluoromethyl-9-methyl guanine; O6-benzyl-8-bromo-9-methyl guanine; O6-benzyl-8-bromo-9-pivaloyl oxygen methyl guanine; O6-benzyl-7-pivaloyl oxygen methyl guanine; O6-benzyl-8-bromo-7-pivaloyl oxygen methyl guanine; 8-azepine-O6-benzyl-7-pivaloyl oxygen methyl guanine; 8-azepine-O6-benzyl-7-pivaloyl oxygen methyl guanine; 8-azepine-O6-benzyl guanine; 8-azepine-O6-benzyl-9-methyl guanine; or N.sup.2-Acetyl-O.sup.6-benzyl-8-oxoguanine; O6-benzyl-N2-methyl guanine; O6-benzyl-N2N2-dimethylguanine; 2-amino-6-chloro-8-methyl purine; 2,8-diaminourea-6-chloropurine; O6-benzyl-N2-guanosine; N (7)-methyl guanine; O6-benzyl-9-cyano group guanine; O6-benzyl-N2-guanosine; O6-cycloalkenyl guanine; 1-cyclobutane methyl guanine; a kind of or its combination in 1-cyclopentenyl methyl guanine and the O6-bromothen base guanine.
Guanine analog shared ratio in compositions is decided because of concrete condition, generally speaking, can be good with 2%-40% from 0.1%-50%, is best with 5%-30%.All be weight percentage.
Tetrazine kind compound is selected from one of following or combination: imidazo tetrazine (imidazotetrazine), imidazopyrazine (imidazopyrazine), 1H-imidazo [b] piperazine (1H-imidazo[b] pyrazine), imidazopyridine (imidazopyridine), 1H-imidazo [1,2-a] pyridine (1H-imidazo[1,2-a] pyridinum), procarbazine (procarbazine, PCB), mitozolomide (mitozolomide, MTZ), dacarbazine (dacarbazine, DCB), temozolomide (Temozolomide or 8-Carbamoyl-3-methylimidazo[5,1-d]-1,2,3,5-tetrazin-4 (3H)-one or NSC 362856)), 4-carboxyl temozolomide [4--carbonyl] temozolomide], 3-N-methyl temozolomide [3-N-methyl] temozolomide), the pyrroles [2,1-d] [1,2,3,5] tetrazine-4 (3H)-temozolomide (Pyrrolo[2,1-d] [1,2,3,5] tetrazine-4 (3H)-ones), the pyrroles [2,1-d] [1,2,3,5] tetrazine l0a-o (Pyrrolo[2,1-d] [1,2,3,5] tetrazinones 10a-o), 5-(3-N-methyl three nitrogen-1-yl)-imidazo-4-carboxylic acid amides (MTIC, 5-(3-N-methyltriazen-1-yl)-imidazole-4-carboxamide), 8-nitro-3-methyl-phendioxin, 2,3,5-four azatropylidenes-4-temozolomide (8-nitro-3-methyl-benzo-1,2,3,5-tetrazepin-4 (3H)-one, NIME), 3,5-dimethyl-pyrido-1,2,3,5-four azatropylidenes-4-temozolomide (3,5-dimethyl-pyrido-1,2,3,5-tetrazepin-4-one, PYRZ) or 3-(2-ethyl chloride)-N, N dimethyl-4-oxygen-3,4-glyoxalidine [5,1-d]-1,2,3,5-tetrazine-8-carboxylic acid amides (3-(2-chloroethyl)-N, N-dimethyl-4-oxo-3,4-dihydroimidazo[5,1-d]-1,2,3,5-tetrazine-8-carboxamide, CDODTC).
Be preferred with imidazo tetrazine, imidazopyrazine, 1H-imidazo [b] piperazine, imidazopyridine, 1H-imidazo [1,2-a] pyridine, procarbazine, mitozolomide, dacarbazine or temozolomide in the above-mentioned tetrazine kind compound.
Tetrazine kind compound shared ratio in slow releasing agent is decided because of concrete condition, generally speaking, can be good with 1%-40% from 0.01%-55%, is best with 5%-30%.All be weight percentage.
Platinum-like compounds is selected from one of following or combination: cisplatin (cisplatin, DDP), carboplatin (Carboplatin, carboplatin), ring platinum (Cycloplatin), platinum in heptan (sunplatinum), DNA-2114 (dacarbazine; Dacarbazine; NSC-45388; Dacarbazine), cis-Dichlorobis(cyclopentylamine)platinum, platinum blue, cis-Dichlorobis(cyclopropylamine)platinum, Ethylenediammineplatinum(II) malonate, CL 286558., enloplatin (Enloplatin), sulfatodiamino cyclohexane platinum (ring ethylenediamine platinic sulfate, Sulfatodiaminocy clohexane platinum, SHP), Spiroplatin (spiral shell sulphur platinum amine), dexormaplatin (Dexormaplatin), iproplatin (Iproplatin), lobaplatin (Lobaplatin, happy platinum), rice platinum (Miboplatin), pick up platinum (picoplatin), nedaplatin (Nedaplatin), ormaplatin (Ormaplatin), oxaliplatin (Oxaliplatin, Oxaloplatin), sebriplatin (Sebriplatin, briplatin), spiroplatin (Spiroplatin) or zeniplatin (Zeniplatin).
Above platinum-like compounds with cisplatin, carboplatin, ormaplatin, dexormaplatin, heptan platinum, lobaplatin, nedaplatin or oxaliplatin serve as preferred.
The percentage by weight of above-mentioned platinum-like compounds in compositions can be 0.1%-50%, is good with 1%-30%, and 5%-20% is best.
Anticancer effective component is the combination of 5-FU synergist or 5-FU and its synergist.When the cancer therapy drug in the medicament slow-release microsphere only was the 5-FU synergist, slow-releasing anticarcinogen injection was mainly used in the action effect that increases the 5-FU that other approach use or is used for potentiation to radiotherapy or other therapies.When being used to increase the action effect of the 5-FU that other approach use, 5-FU can be through tremulous pulse, vein or local injection, placement administration.
The percentage by weight of antitumor drug in medicament slow-release microsphere is 0.5%-60%, is good with 2%-40%, is best with 5%-30%.When use in conjunction, the weight ratio of 5-fluorouracil and 5-fluorouracil synergist is 1-9: 1 to 1: 1-9, and with 1-2: 1 and 2-1: 1 serves as preferred, 1: 1 for most preferably.
Anticancer effective component in the slow-releasing anticarcinogen injection microsphere of the present invention is preferably as follows, and all is weight percentage:
(a) 5-fluorouracil of 1-40%;
(b) cisplatin of 1-40%, carboplatin, heptan platinum, dexormaplatin, lobaplatin, nedaplatin, ormaplatin, oxaliplatin or zeniplatin;
(c) Camptothecin of 1-40%, hydroxy-camptothecin alkali, lurtotecan, topotecan, irinotecan, etoposide, teniposide, amrubicin, Ai Rou are than star, rodorubicin, leurubicin, zorubicin, valrubicin or idarubicin;
(d) the O6-benzyl guanine of 1-40%, O6-butyl guanine, O6-methyl guanine, O6-alkyl guanine, O6-benzyl uric acid, O6-benzyl xanthine;
(e) procarbazine of 1-40%, mitozolomide, dacarbazine or temozolomide; Or
(f) cisplatin of the 5-fluorouracil of 1-40% and 1-40%, carboplatin, heptan platinum, dexormaplatin, lobaplatin, nedaplatin, ormaplatin, oxaliplatin or zeniplatin combination;
(g) Camptothecin of the 5-fluorouracil of 1-40% and 1-40%, hydroxy-camptothecin alkali, lurtotecan, topotecan, irinotecan, etoposide, teniposide, amrubicin, Ai Rou are than the combination of star, rodorubicin, leurubicin, zorubicin, valrubicin or idarubicin;
(h) the O6-benzyl guanine of the 5-fluorouracil of 1-40% and 1-40%, O6-butyl guanine, O6-methyl guanine, O6-alkyl guanine, O6-benzyl uric acid or the xanthic combination of O6-benzyl; Or
(i) procarbazine of the 5-fluorouracil of 1-40% and 1-40%, mitozolomide, dacarbazine or temozolomide.
The slow-release auxiliary material slow-release auxiliary material is selected from one of copolymer (PL6A), ethylene vinyl acetate copolymer (EVAc), polifeprosan, FAD and decanedioic acid copolymer, xylitol, oligosaccharide, chrondroitin, chitin, hyaluronic acid, collagen protein, gelatin and white tempera of polylactic acid (PLA), polyglycolic acid and hydroxyacetic acid or its combination, one of copolymer (PLGA), ethylene vinyl acetate copolymer (EVAc), FAD and the decanedioic acid copolymer of wherein preferred polylactic acid (PLA), polyglycolic acid and hydroxyacetic acid, polifeprosan 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, 5000-200, and 000, but with 20,000-80,000 is preferred, with 30,000-50,000 for most preferably; The molecular weight of polyglycolic acid can be, but is not limited to, 5000-200, and 000, but with 20,000-100,000 is preferred, with 30,000-50,000 for most preferably; Above polyhydroxy acid can singly select or multiselect.When singly selecting, serve as preferred with the copolymer (PLGA) of polylactic acid (PLA) or hydroxy carboxylic acid and glycolic, the molecular weight of copolymer can be, but is not limited to, 5000-200,000, but with 20,000-60,000 be preferably, with 30,000-50,000 for most preferably; The blend ratio of glycolic and hydroxy carboxylic acid is 10/90-90/10 (weight), preferred 25/75-75/25 (weight), most preferably 75: 25.The method of blend is arbitrarily.Content when glycolic and hydroxy carboxylic acid copolymerization is respectively percentage by weight 10-90% and 90-10%.When multiselect, compound polymer or the copolymer formed with macromolecule polymer or different macromolecule polymer serve as preferred, with the compound polymer that contains different molecular weight polylactic acid or decanedioic acid or copolymer for most preferably, as, but be not limited to, molecular weight is 1000 to 30000 polylactic acid with molecular weight is that 20000 to 50000 polylactic acid mixes, molecular weight is 10000 to 30000 polylactic acid with molecular weight is that 30000 to 80000 PLGA mixes, molecular weight is that 20000 to 30000 polylactic acid mixes with decanedioic acid, molecular weight is that 30000 to 80000 PLGA mixes with decanedioic acid.In 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, PLA, the mixture or the copolymer of the mixture of PLGA, glycolic and hydroxy carboxylic acid, certain herbaceous plants with big flowers diacid and fragrant polyanhydride or aliphatic polyanhydride.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 one decanedioic acid copolymer (PFAD-SA)], poly-(erucic acid dimer one decanedioic acid) [P (EAD-SA)] and poly-(fumaric acid one 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.
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.
Except that above-mentioned adjuvant, also can select for use other materials to see United States Patent (USP) (4757128; 4857311; 4888176; 4789724) and in " pharmaceutic adjuvant complete works " (the 123rd page, Sichuan science tech publishing house published in 1993, Luo Mingsheng and Gao Tianhui chief editor) have a detailed description.In addition, Chinese patent (application number 96115937.5; 91109723.6; 9710703.3; 01803562.0) and U.S.'s patent of invention (patent No. 5,651,986) also enumerated some pharmaceutic adjuvant, comprise filler, solubilizing agent, absorption enhancer, film former, gellant, system (or causing) hole agent, excipient or blocker etc.
The content of suspending agent is decided because of the medicine that solvent suspended, composition, character and the requirement thereof of sustained-release micro-spheres (or microcapsule), the preparation method of injection and the kind and the composition thereof of suspending agent, as, sodium carboxymethyl cellulose can be 0.5-5%, but with 1-3% is preferred, mannitol and or sorbitol be 5-30%, but is preferred with 10-20%, and polysorbas20, polysorbate40 or Tween 80 are 0.05-2%, but are preferred with 0.10-0.5%.In most cases, sustained-release microparticle is made up of effective ingredient and slow-release auxiliary material, and solvent is special solvent.When solvent was common solvent, medicine that is suspended or sustained-release micro-spheres (or microcapsule) then were made up of effective ingredient, slow-release auxiliary material and/or suspending agent.In other words, when the suspending agent in the sustained-release microparticle (A) was " 0 ", solvent (B) was special solvent, and when the suspending agent in the sustained-release microparticle (A) was not " 0 ", solvent (B) can be common solvent or special solvent.The viscosity of suspending agent is 100cp-3000cp (20 ℃-30 ℃ time), preferred 1000cp-3000cp (20 ℃-30 ℃ time), most preferably 1500cp-3000cp (20 ℃-30 ℃ time).
Common solvent can be, but is not limited to, the buffer that distilled water, water for injection, physiology are prepared towards liquid, dehydrated alcohol or various salt, and pharmacopeia has respective specified; The special solvent of indication of the present invention is the common solvent that contains suspending agent, suspending agent can be, but be not limited to one of sodium carboxymethyl cellulose, (iodine) glycerol, simethicone, propylene glycol, carbomer, mannitol, sorbitol, surfactant, polysorbas20, polysorbate40 and Tween 80 or its combination.The content of suspending agent is 0.1-30% volume weight percentage ratio in the special solvent, is preferably as follows:
(a) 0.5-5% sodium carboxymethyl cellulose; Or
(b) 0.5-5% sodium carboxymethyl cellulose and 0.1-0.5% Tween 80; Or
(c) 5-20% mannitol; Or
(d) 5-20% mannitol and 0.1-0.5% Tween 80; Or.
(e) 0.5-5% sodium carboxymethyl cellulose, 5-20% sorbitol and 0.1-0.5% Tween 80.
The above-mentioned volume weight percentage ratio that is contains the weight of suspending agent in the common solvent of unit volume, as g/ml, kg/L down with.
The preparation of injection comprises that the preparation of preparation, solvent of sustained-release micro-spheres or drug microparticles and sustained-release micro-spheres or drug microparticles suspend, and make injection at last in solvent.
Wherein, sustained-release micro-spheres or drug microparticles can prepare with some kinds of methods: as, but be not limited to, mixing method, fusion method, dissolution method, spray drying method for preparation microsphere, dissolution method are in conjunction with freezing (drying) comminuting method, liposome bag medicine method and emulsion process etc.Serve as preferred wherein with dissolution method (being the solvent volatility process), freezing (drying) comminuting method, seasoning, spray drying method and emulsion process.Microsphere then can be used for preparing above-mentioned various slow releasing injection.The particle diameter of suspended drug or sustained-release micro-spheres (or microcapsule) decide because of specifically needing, and can be, but be not limited to, 1-300um, but be that preferably 30-150um most preferably with 20-200um.Medicine or sustained-release micro-spheres can be made into microsphere, sub-micro ball, microemulsion, nanosphere, granule or spherical piller.Slow-release auxiliary material is above-mentioned bio-capacitivity, biodegradable or non-biodegradation polymer.
The kind of solvent is then depended in the preparation of solvent, and common solvent has commercially available, also can make by oneself, and as distilled water, water for injection, physiology buffer towards liquid, dehydrated alcohol or the preparation of various salt, but must be in strict accordance with related standards.Special solvent need be considered the kind of suspending agent and the medicine that composition, solvent suspended, composition, character and the requirement thereof of sustained-release micro-spheres (or microcapsule) and the preparation method of injection, as with sodium carboxymethyl cellulose (1.5%)+mannitol with or sorbitol (15%) and/or Tween 80 (0.1%) be dissolved in the normal saline mutually deserved solvent, viscosity is at 10cp-650cp (20 ℃-30 ℃ time).
The present invention finds to influence medicine and/or sustained-release micro-spheres suspends and/or the key factor of injection is the viscosity of solvent, and viscosity is big more, and suspension effect is good more, and syringeability is strong more.This unexpected one of main index characteristic of the present invention of finding to have constituted.The viscosity of solvent depends on the viscosity of suspending agent, and the viscosity of suspending agent is 100cp-3000cp (20 ℃-30 ℃ time), preferred 1000cp-3000cp (20 ℃-30 ℃ time), most preferably 1500cp-3000cp (20 ℃-30 ℃ time).According to the viscosity of the prepared solvent of this condition is 10cp-650cp (20 ℃-30 ℃ time), preferred 20cp-650cp (20 ℃-30 ℃ time), most preferably 60cp-650cp (20 ℃-30 ℃ time).
The preparation of injection has several different methods, and a kind of is that the sustained-release microparticle (A) of suspending agent for " 0 " directly mixed in special solvent, obtains corresponding sustained-release microparticle injection; Another kind is that suspending agent is not mixed in special solvent or common solvent for the sustained-release microparticle (A) of " 0 ", obtains corresponding sustained-release microparticle injection; Another is that sustained-release microparticle (A) is mixed in common solvent, adds the suspending agent mixing then, obtains corresponding sustained-release microparticle injection.Except, also can earlier sustained-release microparticle (A) be mixed and in special solvent, make corresponding suspension, with the moisture in ways such as the vacuum drying removal suspension, special solvent of reuse or common solvent suspendible obtain corresponding sustained-release microparticle injection afterwards then.Above method just is illustrative rather than definitive thereof the present invention.It should be noted that suspended drug or sustained-release micro-spheres (or microcapsule) concentration in injection decide because of specifically needing, can be, but be not limited to, 10-400mg/ml, but be preferably with 30-300mg/ml, with 50-200mg/ml most preferably.The viscosity of injection is 50cp-1000cp (20 ℃-30 ℃ time), preferred 100cp-1000cp (20 ℃-30 ℃ time), most preferably 200cp-650cp (20 ℃-30 ℃ time).This viscosity is applicable to 18-22 injection needle and special bigger (to 3 millimeters) injection needle of internal diameter.
The application of injection comprises the application of the injection of making after the application of application, solvent of sustained-release micro-spheres or drug microparticles and sustained-release micro-spheres or drug microparticles suspend in solvent.
Microsphere is used to prepare slow releasing injection, as suspension type slow releasing injection, gel injection, block copolymer micelle injection.In various injections, serve as preferred with the suspension type slow releasing injection.The suspension type slow releasing injection is to contain the medicament slow-release microsphere of effective composition or the preparation that drug microparticles is suspended in gained in the solvent, and used adjuvant is a kind of or its combination in the above-mentioned slow-release auxiliary material, and used solvent is common solvent or the special solvent that contains suspending agent.Common solvent is, but is not limited to the buffer that distilled water, water for injection, physiology are prepared towards liquid, dehydrated alcohol or various salt; Block copolymer micelle is formed in aqueous solution by hydrophobic-hydrophilic block copolymers, has 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 is (as PLA, polylactide, polycaprolactone and copolymer thereof (molecular weight 1500-25000) hydrophobic block as the micelle copolymer.The particle size range of block copolymer micelle can be at 1-300um, but is preferred with 20-200um, and 30-150um most preferably; Gel injection system is dissolved in some amphipathic solvent with biological degradation polyalcohol (as PLA, PLGA or DL-LA and epsilon-caprolactone copolymer), adds medicine miscible with it (or suspendible) back again and forms flowability gel preferably, can be through tumor week or intratumor injection.In case inject, amphipathic solvent diffuses to body fluid very soon, the moisture in the body fluid then infiltrates gel, makes polymer cure, slowly discharges medicine.
The application of solvent refers to that mainly the application of special solvent is effective suspension, stablizes and/or protects various medicines or sustained-release micro-spheres (or microcapsule), thereby prepares corresponding injection.The application of special solvent can make prepared injection have better injectivity, good stability and higher viscosity.
The application of injection be with full-bodied special solvent with pastille microgranule, particularly sustained-release microparticle, make corresponding slow releasing injection, thus make corresponding medicine can with the injection mode import in the patient or mammalian body of required medicine.The medicine that is injected can be, but is not limited to, said medicine micropowder or medicament slow release microgranule.
The route of administration of injection depends on multiple factor.For the non-proliferative pathological changes, can be in vein, lymphatic vessel, subcutaneous, muscle, intracavity (in as abdominal cavity, thoracic cavity, articular cavity and in the canalis spinalis), tissue, tumor in, reach in the bone marrow in all, the selective arterial injection of tumor, lymph node and inject.For proliferative lesion, as the entity tumor, though can be through above-mentioned administration, with in selective arterial, intracavity, the tumor, the injection of tumor week serves as preferred.
For obtaining valid density in former or position, metastatic tumour place, also can unite and give through number of ways, in the time of as vein, lymphatic vessel, subcutaneous, muscle, intracavity (as in abdominal cavity, thoracic cavity, the articular cavity and in the canalis spinalis) or selective arterial injection in conjunction with local injection.So administering drug combinations is specially adapted to entity tumor.As in the tumor, tumor week injection time is in conjunction with systemic injection.
The present invention can be used to prepare the medicine of the various tumors for the treatment of people and animal, is mainly slow releasing injection.
The present invention is example with the antitumor drug, by following test and embodiment technical scheme of the present invention is further described:
Route of administration depends on multiple factor, for obtaining 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, the selective arterial injection of tumor, lymph node and injection in the bone marrow.With in selective arterial, intracavity, the tumor, tumor week injection serves as preferred.
The present invention can be used to prepare the medicine of the various tumors for the treatment of people and animal, be mainly slow releasing injection, 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.
Sustained-release micro-spheres among the present invention can be used to prepare the sustained-release implant of the various tumors for the treatment of people and animal.
Also can add other medicinal ingredient in the made slow releasing injection of the present invention, as, but be not limited to antibiotics, antalgica, anticoagulant medicine, hemorrhage etc.
By following test and embodiment technology side of the present invention is further described:
The local drug concentration of 5-FU relatively after test 1, the different modes administration
With the rat is subjects, with 2 * 10
5Individual prostate tumor cells subcutaneous injection is treated behind tumor growth to 1 cm diameter it to be divided into following 8 groups (seeing Table 1) in its hypochondrium.Every group of dosage is 5mg/kg5-FU.Measure 5-FU content (%) in the different time tumor.
Table 1
| Test group (n) | Administering mode | Medication amount in the 1st day tumor | Medicament contg in the 3rd day tumor | Medicament contg in the 7th day tumor |
| 1(3) | The agent of tail vein injection normal injection | 0.63 | 0.34 | 0.13 |
| 2(3) | The agent of lumbar injection normal injection | 0.56 | 0.32 | 0.08 |
| 3(3) | The agent of tumor week injection normal injection | 2.8 | 1.4 | 0.3 |
| 4(3) | Tumor week injection slow releasing injection | 18 | 28 | 30 |
| 5(3) | Tumor week is placed sustained-release implant | 20 | 30 | 32 |
| 6(3) | The agent of intratumor injection normal injection | 6 | 4 | 1 |
| 7(3) | The intratumor injection slow releasing injection | 94 | 88 | 76 |
| 8(3) | Place sustained-release implant in the tumor | 94 | 90 | 86 |
Above result shows, the local drug concentration significant difference of 5-FU 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, easily.This discovery constitutes key character of the present invention.Following relevant inhibition test has further confirmed this point.
Tumor-inhibiting action relatively in the body after test 2, the different modes administration
With the rat is subjects, with 2 * 10
5Individual prostate tumor cells subcutaneous injection is treated behind tumor growth to 0.5 cm diameter it to be divided into following 9 groups (seeing Table 2) in its hypochondrium.Every group of dosage is 5mg/kg5-FU and 2mg/kgO6-BG.The treatment back was measured gross tumor volume size, relatively therapeutic effect on the 10th day.
Table 2
| Test group (n) | Administering mode | Gross tumor volume (cm 3) | The P value |
| 1(6) | - | 70 | |
| 2(6) | The agent of tail vein injection normal injection | 67 | 0.06 |
| 3(6) | The agent of lumbar injection normal injection | 66 | 0.06 |
| 4(6) | The agent of tumor week injection normal injection | 58 | 0.03 |
| 5(6) | Tumor week injection slow releasing injection | 30 | ＜0.01 |
| 6(6) | Tumor week is placed sustained-release implant | 22 | ＜0.01 |
| 7(6) | The agent of intratumor injection normal injection | 54 | 0.04 |
| 8(6) | The intratumor injection slow releasing injection | 20 | ＜0.001 |
| 9(6) | Place sustained-release implant in the tumor | 18 | ＜0.001 |
Above result shows, 5-FU and O6-BG (O6-benzyl guanine) the tumor-inhibiting action significant difference after different modes is used, topical can obviously improve its tumor-inhibiting action, 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, easily.Good effect not only, toxic and side effects is also little.
The tumor-inhibiting action of test 3,5-FU and 5-FU 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.Medicine is through intratumor injection.Dosage is 5mg/kg.The treatment back was measured the gross tumor volume size on the 10th day, made relatively therapeutic effect (seeing Table 3) of index with inhibition rate of tumor growth.
Table 3
| Test group (n) | Suffered treatment | Tumor control rate (%) | The P value |
| 1(6) | Contrast | - | |
| 2(6) | 5-FU | 58 | ＜0.05 |
| 3(6) | Cisplatin | 50 | ＜0.01 |
| 4(6) | Carboplatin | 52 | ＜0.01 |
| 5(6) | Ormaplatin | 48 | ＜0.01 |
| 6(6) | Dexormaplatin | 52 | ＜0.01 |
| 7(6) | The 5-FU+ cisplatin | 82 | ＜0.001 |
| 8(6) | The 5-FU+ carboplatin | 86 | ＜0.001 |
| 9(6) | The 5-FU+ ormaplatin | 92 | ＜0.001 |
| 10(6) | The 5-FU+ dexormaplatin | 90 | ＜0.001 |
Above result shows, growth all has the obvious suppression effect to kinds of tumor cells when this concentration is used separately for used 5-FU and 5-FU synergist-platinum-like compounds (cisplatin, carboplatin, ormaplatin, dexormaplatin), can show significant potentiation when use in conjunction.
The tumor-inhibiting action of test 4,5-FU and 5-FU 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.Sustained-release implant is placed in tumor.Dosage is 5mg/kg.The treatment back was measured the gross tumor volume size on the 10th day, made relatively therapeutic effect (seeing Table 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) | 5-FU | 58 | ＜0.05 |
| 3(6) | Heptan platinum | 50 | ＜0.05 |
| 4(6) | Lobaplatin | 48 | ＜0.05 |
| 5(6) | Nedaplatin | 56 | ＜0.05 |
| 6(6) | Oxaliplatin | 52 | ＜0.01 |
| 7(6) | 5-FU+ platinum in heptan | 84 | ＜0.01 |
| 8(6) | The 5-FU+ lobaplatin | 80 | ＜0.01 |
| 9(6) | The 5-FU+ nedaplatin | 92 | ＜0.01 |
| 10(6) | The 5-FU+ oxaliplatin | 94 | ＜0.001 |
Above result shows, 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 for used 5-FU and 5-FU synergist-platinum-like compounds (heptan platinum, lobaplatin, nedaplatin, oxaliplatin)
Test 5, contain tumor-inhibiting action in the body of 5-FU and 5-FU 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 3).First group is contrast, and the 2nd to 10 group is the treatment group, and medicine is through intratumor injection.Dosage is 5mg/kg.The treatment back was measured gross tumor volume size, relatively therapeutic effect (seeing Table 5) on the 10th day.
Table 5
| Test group (n) | Suffered treatment | Gross tumor volume (cm 3) | The P value |
| 1(6) | Contrast | 72±10 | |
| 2(6) | 5-FU | 48±5.4 | ＜0.05 |
| 3(6) | Camptothecin | 48±2.0 | ＜0.01 |
| 4(6) | Hydroxy-camptothecin alkali | 46±2.2 | ＜0.01 |
| 5(6) | Topotecan | 42±3.2 | ＜0.01 |
| 6(6) | Irinotecan | 44±3.0 | ＜0.01 |
| 7(6) | The 5-FU+ Camptothecin | 22±2.0 | ＜0.001 |
| 8(6) | 5-FU+ hydroxy-camptothecin alkali | 30±3.6 | ＜0.001 |
| 9(6) | The 5-FU+ topotecan | 32±3.6 | ＜0.001 |
| 10(6) | The 5-FU+ irinotecan | 18±2.2 | ＜0.001 |
Above result shows, growth all has the obvious suppression effect to kinds of tumor cells when this concentration is used separately for 5-FU and used 5-FU synergist-topoenzyme inhibitor (Camptothecin, hydroxy-camptothecin alkali, topotecan, irinotecan), can show significant potentiation when use in conjunction.
The tumor-inhibiting action of test 6,5-FU and 5-FU 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.5-FU and 5-FU 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 6.
Table 6
| Oncocyte | 5-FU | Lurtotecan | Etoposide | Teniposide | The 5-FU+ lurtotecan | The 5-FU+ etoposide | The 5-FU+ teniposide |
| CNS | 62％ | 58％ | 64％ | 68％ | 92％ | 88％ | 98％ |
| C6 | 64％ | 64％ | 60％ | 64％ | 94％ | 84％ | 96％ |
| SA | 58％ | 62％ | 56％ | 62％ | 88％ | 92％ | 92％ |
| BC | 54％ | 64％ | 54％ | 64％ | 94％ | 84％ | 82％ |
| BA | 58％ | 60％ | 62％ | 60％ | 98％ | 92％ | 92％ |
| LH | 60％ | 58％ | 62％ | 58％ | 90％ | 88％ | 88％ |
| PAT | 64％ | 54％ | 62％ | 58％ | 92％ | 88％ | 92％ |
Above result shows, used 5-FU and 5-FU synergist-topoenzyme inhibitor (lurtotecan, etoposide, teniposide) phosphate) 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.Further experiment shows that 5-FU can also obviously strengthen the tumor killing effect of other topoenzyme inhibitor, as amrubicin, Ai Rou than star, rodorubicin, leurubicin, zorubicin, valrubicin, idarubicin etc.
The tumor-inhibiting action of test 7,5-FU and 5-FU 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 5).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 7) on the 10th day.
Table 7
| Test group (n) | Suffered treatment | Gross tumor volume (cm 3) | The P value |
| 1(6) | Contrast | 80±10 | |
| 2(6) | 5-FU | 48±5.3 | ＜0.05 |
| 3(6) | O6-BG | 60±6.3 | ＜0.01 |
| 4(6) | O6-BuG | 62±3.6 | ＜0.001 |
| 5(6) | O6-MG | 64±5.0 | ＜0.01 |
| 6(6) | O6-AG | 62±4.0 | ＜0.001 |
| 7(6) | 5-FU+O6-BG | 36±3.8 | ＜0.01 |
| 8(6) | 5-FU+O6-BuG | 20±2.6 | ＜0.001 |
| 9(6) | 5-FU+O6-MG | 26±3.8 | ＜0.01 |
| 10(6) | 5-FU+O6-AG | 20±2.4 | ＜0.001 |
Above result shows, used 5-FU and 5-FU thing synergist-guanine analog (O6-BG:O6-benzyl guanine; O6-BuG:O6-butyl guanine; The O6-MG:O6-methyl guanine; O6-AG:O6-alkyl guanine) 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.Further experiment shows that 5-FU can also obviously strengthen the tumor killing effect of guanine analogs such as O6-benzyl uric acid.
The tumor-inhibiting action of test 8,5-FU and 5-FU 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 (5-FU or 5-FU synergist) and therapeutic alliance group (5-FU and 5-FU synergist).Medicine is through intratumor injection.Dosage is 5mg/kg.The treatment back was measured the gross tumor volume size on the 10th day, made relatively therapeutic effect (seeing Table 8) of index with inhibition rate of tumor growth.
Table 8
| Test group (n) | Suffered treatment | Tumor control rate (%) | The P value |
| 1(6) | Contrast | - | |
| 2(6) | 5-FU | 42 | ＜0.05 |
| 3(6) | Procarbazine | 40 | ＜0.01 |
| 4(6) | Mitozolomide | 36 | ＜0.01 |
| 5(6) | Dacarbazine | 34 | ＜0.01 |
| 6(6) | The temozolomide | 32 | ＜0.01 |
| 7(6) | The 5-FU+ procarbazine | 86 | ＜0.001 |
| 8(6) | The 5-FU+ mitozolomide | 84 | ＜0.001 |
| 9(6) | The 5-FU+ dacarbazine | 86 | ＜0.001 |
| 10(6) | The 5-FU+ temozolomide | 92 | ＜0.001 |
Above result shows, growth all has the obvious suppression effect to kinds of tumor cells when this concentration is used separately for used 5-FU and 5-FU synergist-tetrazine kind compound (procarbazine, mitozolomide, dacarbazine, temozolomide), can show significant potentiation when use in conjunction.
In a word, growth all had the obvious suppression effect to kinds of tumor cells when the various 5-FU synergists of used 5-FU were used separately, can show significant potentiation when use in conjunction.Therefore, effective ingredient of the present invention is the combination of 5-FU and any one 5-FU 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.
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 20mg5-FU and 10mg cisplatin, shake up the back contains 20%5-FU and 10% cisplatin 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 2.
The method step that is processed into slow releasing injection is identical with embodiment 1, but different is that contained anticancer effective component is:
(1) cisplatin of the 5-FU of 2-40% and 1-30%, carboplatin, ormaplatin, dexormaplatin, heptan platinum, lobaplatin, nedaplatin or oxaliplatin combination;
(2) 5-FU of 5-30%; Or
(3) cisplatin of 1-30%, carboplatin, ormaplatin, dexormaplatin, heptan platinum, lobaplatin, nedaplatin or oxaliplatin.
Embodiment 3.
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 10mg5-FU and 10mg Camptothecin, shake up the back contains 10%5-FU and 10% Camptothecin with spray drying method for preparation injectable microsphere again.Then microsphere is suspended in the normal saline that contains 15% mannitol, makes corresponding suspension type slow releasing injection.The drug release time of this slow releasing injection in external normal saline is 15-25 days, is about 30-40 days at the subcutaneous drug release time of mice.
Embodiment 4.
The method step that is processed into slow releasing injection is identical with embodiment 3, but different is that contained anticancer effective component and percentage by weight thereof are:
(1) 5-FU of 2-40%;
(2) Camptothecin of 5-30%, hydroxy-camptothecin alkali, lurtotecan, topotecan, irinotecan, etoposide, teniposide, amrubicin, Ai Rou are than star, rodorubicin, leurubicin, zorubicin, valrubicin or idarubicin;
(3) Camptothecin of the 5-FU of 2-40% and 5-30%, hydroxy-camptothecin alkali, lurtotecan, topotecan, irinotecan, etoposide, teniposide, amrubicin, Ai Rou are than the combination of star, rodorubicin, leurubicin, zorubicin, valrubicin or idarubicin.
Embodiment 5.
With 70mg molecular weight peak value is that 25000 polylactic acid (PLGA, 75: 25) is put into container, adds 100 milliliters of dichloromethane, behind the dissolving mixing, adds 15mg5-FU and 15mgO6-benzyl guanine, shakes up the dry organic solvent of removing of final vacuum again.Dried pastille solid composite freezing and pulverizing is made the micropowder that contains 10%5-FU and 10%O6-benzyl guanine, 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 10-15 days, is about 30-35 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 and percentage by weight thereof are:
(1) 5-FU of 2-40%;
(2) the O6-benzyl guanine of 2-40%, O6-butyl guanine, O6-methyl guanine, O6-alkyl guanine, O6-benzyl uric acid, the xanthic combination of O6-benzyl;
(3) the O6-benzyl guanine of the 5-FU of 2-40% and 2-40%, O6-butyl guanine, O6-methyl guanine, O6-alkyl guanine, O6-benzyl uric acid, the xanthic combination of O6-benzyl.
Embodiment 7.
(EVAc) puts into container with the 70mg ethylene vinyl acetate copolymer, after adding 100 milliliters of dichloromethane dissolving mixings, add 20 milligrams of 5-FU and 10 milligrams of temozolomides, shake up the back contains 20%5-FU and 10% temozolomide 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 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) 5-FU of 2-40%;
(2) the imidazo tetrazine of 2-40%, imidazopyrazine, 1H-imidazo [b] piperazine, imidazopyridine, 1H-imidazo [1,2-a] pyridine, procarbazine, mitozolomide, dacarbazine or temozolomide;
(3) the imidazo tetrazine of the 5-FU of 2-40% and 2-40%, imidazopyrazine, 1H-imidazo [b] piperazine, imidazopyridine, 1H-imidazo [1,2-a] pyridine, procarbazine, mitozolomide, dacarbazine or temozolomide's combination.
Embodiment 9
70mg polifeprosan (to carboxy phenyl propane (p-CPP): certain herbaceous plants with big flowers diacid (SA) is 20: 80) copolymer is put into container, add 100 milliliters of dichloromethane, behind the dissolving mixing, add 20mg5-FU and 10mg etoposide, shake up the back contains 20%5-FU and 10% etoposide 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:
(1) 5-FU of 2-40%;
(2) Camptothecin of 5-30%, hydroxy-camptothecin alkali, lurtotecan, topotecan, irinotecan, etoposide, teniposide, amrubicin, Ai Rou are than star, rodorubicin, leurubicin, zorubicin, valrubicin or idarubicin;
(3) Camptothecin of the 5-FU of 2-40% and 5-30%, hydroxy-camptothecin alkali, lurtotecan, topotecan, irinotecan, etoposide, teniposide, amrubicin, Ai Rou are than the combination of star, rodorubicin, leurubicin, zorubicin, valrubicin or idarubicin.
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 10mgO6-benzyl uric acid and 20mg5-FU, shake up the back contains 10%O6-benzyl uric acid and 20%5-FU 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 the benzyl guanine of the 5-FU of 2-40% and 2-40%, O6-benzyl guanine, O6-butyl guanine, O6-methyl guanine, O6-alkyl guanine or O6-benzyl uric acid.
Embodiment 13
With 70mg molecular weight peak value is that 35000 polylactic acid (PLA) is put into container, add 100 milliliters of dichloromethane, behind the dissolving mixing, add 10mg5-FU and 20mg mitozolomide, shake up the back contains 10%5-FU and 20% mitozolomide with spray drying method for preparation injectable microsphere again.Then microsphere is made corresponding sustained-release implant through pressed disc method.The drug release time of this sustained-release implant in external normal saline is 10-15 days, is about 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% 5-FU and 20% mitozolomide, cisplatin, carboplatin, ormaplatin, dexormaplatin, heptan platinum, lobaplatin, nedaplatin or oxaliplatin combination.
Embodiment 15
The method step that is processed into slow releasing agent is identical with embodiment 1-14, but different is used slow-release auxiliary material is one of following or its combination:
A) the molecular weight peak value is the polylactic acid (PLA) of 5000-30000,30000-60000,60000-100000 or 100000-150000;
B) the molecular weight peak value is the polyglycolic acid of 5000-30000,30000-60000,60000-100000 or 100000-150000 and the copolymer of hydroxyacetic acid (PLGA), and 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);
D) FAD and certain herbaceous plants with big flowers diacid (SA) copolymer;
E) xylitol, oligosaccharide, chrondroitin, chitin, potassium salt, sodium salt, 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
With 90mg molecular weight peak value is that 25000 polylactic acid (PLGA, 75: 25) is put into container, adds 100 milliliters of dichloromethane, behind the dissolving mixing, adds the 10mg oxaliplatin, shakes up the dry organic solvent of removing of final vacuum again.Dried pastille solid composite freezing and pulverizing is made the micropowder that contains 10% oxaliplatin, 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 10-15 days, is about 20-30 days at the subcutaneous drug release time of mice.
Embodiment 18.
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 the 20mg5-fluorouracil, shake up the back contains the 20%5-fluorouracil 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.
Embodiment 19.
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 the 20mg Camptothecin, shake up the back contains 20% Camptothecin 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 20.
The method step that is processed into slow releasing injection is identical with embodiment 1-19, but different is that contained anticancer effective component is:
(a) 15% 5-FU; Or
(b) 10% cisplatin, carboplatin, heptan platinum, DNA-2114, enloplatin, sulfatodiamino cyclohexane platinum, Spiroplatin, dexormaplatin, oxaliplatin, iproplatin, lobaplatin, rice platinum, nedaplatin, ormaplatin, sebriplatin, spiroplatin or zeniplatin; Or
(c) 15% Camptothecin, hydroxy-camptothecin alkali, lurtotecan, topotecan, irinotecan, etoposide, teniposide, amrubicin, Ai Rou are than star, rodorubicin, leurubicin, zorubicin, valrubicin or idarubicin; Or
(d) 15% O6-benzyl guanine, O6-butyl guanine, O6-methyl guanine, O6-alkyl guanine or O6-benzyl uric acid; Or
(e) 15% procarbazine, mitozolomide, dacarbazine or temozolomide; Or
(f) 15% 5-FU and 10% cisplatin, carboplatin, ormaplatin, dexormaplatin, heptan platinum, lobaplatin, nedaplatin or oxaliplatin combination; Or
(g) 15% 5-FU and 15% Camptothecin, hydroxy-camptothecin alkali, lurtotecan, topotecan, irinotecan, etoposide, teniposide, amrubicin, Ai Rou are than the combination of star, rodorubicin, leurubicin, zorubicin, valrubicin or idarubicin; Or
(h) combination of 15% 5-FU and 15% O6-benzyl guanine, O6-butyl guanine, O6-methyl guanine, O6-alkyl guanine or O6-benzyl uric acid; Or
(i) 15% 5-FU and 15% procarbazine, mitozolomide, dacarbazine or temozolomide's combination.
Embodiment 21.
The method step that is processed into slow releasing injection is identical with embodiment 1-20, but different is slow-release auxiliary material is selected from one of following or its combination:
A) polylactic acid, molecular weight peak value are 10000-30000,30000-60000,60000-100000 or 100000-150000;
B) copolymer of polyglycolic acid and hydroxyacetic acid, molecular weight peak value are 10000-30000,30000-60000,60000-100000 or 100000-150000, and wherein, the ratio of polyglycolic acid and hydroxyacetic acid is 75: 25;
C) FAD and certain herbaceous plants with big flowers diacid copolymer;
D) in the polifeprosan to carboxy phenyl propane (p-CPP): certain herbaceous plants with big flowers diacid (SA) is 10: 90,20: 80,30: 70,40: 60,50: 50 or 60: 40;
The viscosity of suspending agent is 100cp-2000cp (20 ℃-30 ℃ time), is selected from one of following or its combination:
A) 1% sodium carboxymethyl cellulose;
B) 10% mannitol;
C) 5% sorbitol;
D) 0.3% polysorbas20;
E) 1% sodium carboxymethyl cellulose+0.5% soil temperature 80;
F) 12% mannitol+0.5% soil temperature 80;
G) 1.5% sodium carboxymethyl cellulose+10% sorbitol+0.5% soil temperature 80;
H) 1% sodium carboxymethyl cellulose+15% mannitol+0.5% soil temperature 20.
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 that contains fluorouracil is characterized in that slow releasing 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 be 5-FU and be selected from topoenzyme inhibitor, guanine analog, tetrazine kind compound and or the 5-FU synergist of platinum-like compounds;
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 viscosity of suspending agent is 100cp-3000cp (20 ℃-30 ℃ time).
2. the anti-cancer medicine sustained-release injection according to claim 1 is characterized in that topoenzyme inhibitor is selected from Camptothecin, hydroxy-camptothecin alkali, lurtotecan, topotecan, irinotecan, etoposide, teniposide, amrubicin, Ai Rou than one of star, rodorubicin, leurubicin, zorubicin, valrubicin, idarubicin or its combination.
3. the anticancer medicine slow-release preparation containing according to claim 1 is characterized in that guanine analog is selected from one of O6-benzyl guanine, O6-butyl guanine, O6-methyl guanine, O6-alkyl guanine, O6-benzyl uric acid, O6-benzyl xanthine or its combination.
4. the anti-cancer medicine sustained-release injection according to claim 1 is characterized in that tetrazine kind compound is selected from one of procarbazine, mitozolomide, dacarbazine, temozolomide or its combination.
5. the anticancer medicine slow-release preparation containing according to claim 1 is characterized in that platinum-like compounds is selected from cisplatin, carboplatin, heptan platinum, DNA-2114, enloplatin, sulfatodiamino cyclohexane platinum, Spiroplatin, dexormaplatin, iproplatin, lobaplatin, nedaplatin, ormaplatin, oxaliplatin, spiroplatin or zeniplatin.
6. the anti-cancer medicine sustained-release injection according to claim 1 is characterized in that the anticancer effective component of slow-releasing anticarcinogen injection is:
(1) 5-fluorouracil of 1-40%;
(2) cisplatin of 1-40%, carboplatin, heptan platinum, dexormaplatin, lobaplatin, nedaplatin, ormaplatin, oxaliplatin or zeniplatin;
(3) Camptothecin of 1-40%, hydroxy-camptothecin alkali, lurtotecan, topotecan, irinotecan, etoposide, teniposide, amrubicin, Ai Rou are than star, rodorubicin, leurubicin, zorubicin, valrubicin or idarubicin;
(4) the O6-benzyl guanine of 1-40%, O6-butyl guanine, O6-methyl guanine, O6-alkyl guanine, O6-benzyl uric acid, O6-benzyl xanthine;
(5) procarbazine of 1-40%, mitozolomide, dacarbazine or temozolomide;
(6) cisplatin of the 5-fluorouracil of 1-40% and 1-40%, carboplatin, heptan platinum, dexormaplatin, lobaplatin, nedaplatin, ormaplatin, oxaliplatin or zeniplatin combination;
(7) Camptothecin of the 5-fluorouracil of 1-40% and 1-40%, hydroxy-camptothecin alkali, lurtotecan, topotecan, irinotecan, etoposide, teniposide, amrubicin, Ai Rou are than the combination of star, rodorubicin, leurubicin, zorubicin, valrubicin or idarubicin;
(8) the O6-benzyl guanine of the 5-fluorouracil of 1-40% and 1-40%, O6-butyl guanine, O6-methyl guanine, O6-alkyl guanine, O6-benzyl uric acid or the xanthic combination of O6-benzyl; Or
(9) procarbazine of the 5-fluorouracil of 1-40% and 1-40%, mitozolomide, dacarbazine or temozolomide's combination.
Below all be weight percentage.
7. the slow-releasing anticarcinogen injection according to claim 1 is characterized in that slow-release auxiliary material is selected from one of following or its combination:
A) polylactic acid;
B) copolymer of polyglycolic acid and hydroxyacetic acid;
C) polifeprosan;
D) ethylene vinyl acetate copolymer;
E) FAD and certain herbaceous plants with big flowers diacid copolymer.
8. the slow-releasing anticarcinogen injection according to claim 1 is characterized in that:
A) the molecular weight peak value of polylactic acid (PLA) is 5000-30000,30000-60000,60000-100000 or 100000-150000;
B) copolymer of polyglycolic acid and hydroxyacetic acid (PLGA) weight molecule amount peak value is 5000-30000,30000-60000,60000-100000 or 100000-150000, and wherein, the ratio of polyglycolic acid and hydroxyacetic acid is 50-95: 50;
C) in the polifeprosan to carboxy phenyl propane (p-CPP): certain herbaceous plants with big flowers diacid (SA) is 10: 90,20: 80,30: 70,40: 60,50: 50 or 60: 40.
9. the slow-releasing anticarcinogen injection according to claim 1 is characterized in that used suspending agent is respectively:
A) 0.5-3.0% carboxymethyl cellulose (sodium);
B) 5-15% mannitol;
C) 5-15% sorbitol;
D) 0.1-1.5% surfactant;
E) 0.1-0.5% polysorbas20;
F) (iodine) glycerol, simethicone, propylene glycol or carbomer;
G) 0.5-5% sodium carboxymethyl cellulose+0.1-0.5% soil temperature 80;
H) 5-20% mannitol+0.1-0.5% soil temperature 80; Or
I) 0.5-5% sodium carboxymethyl cellulose+5-20% sorbitol+0.1-0.5% soil temperature 80.
10. the slow-releasing anticarcinogen injection according to claim 1 is characterized in that:
Anticancer effective component in the slow-releasing anticarcinogen injection is:
(a) 15% 5-FU; Or
(b) 10% cisplatin, carboplatin, heptan platinum, lobaplatin, oxaliplatin or nedaplatin; Or
(c) 15% Camptothecin, hydroxy-camptothecin alkali, lurtotecan, topotecan, irinotecan, etoposide, teniposide, amrubicin, Ai Rou are than star, rodorubicin, leurubicin, zorubicin, valrubicin or idarubicin; Or
(d) 15% O6-benzyl guanine, O6-butyl guanine, O6-methyl guanine, O6-alkyl guanine or O6-benzyl uric acid; Or
(e) 15% procarbazine, mitozolomide, dacarbazine or temozolomide; Or
(f) 15% 5-FU and 10% cisplatin, carboplatin, heptan platinum, lobaplatin, nedaplatin or oxaliplatin combination; Or
(g) 15% 5-FU and 15% Camptothecin, hydroxy-camptothecin alkali, lurtotecan, topotecan, irinotecan, etoposide, teniposide, amrubicin, Ai Rou are than the combination of star, rodorubicin, leurubicin, zorubicin, valrubicin or idarubicin; Or
(h) combination of 15% 5-FU and 15% O6-benzyl guanine, O6-butyl guanine, O6-methyl guanine, O6-alkyl guanine or O6-benzyl uric acid; Or
(i) 15% 5-FU and 15% procarbazine, mitozolomide, dacarbazine or temozolomide's combination.
Slow-release auxiliary material is selected from one of following or its combination:
A) polylactic acid, weight molecule amount peak value is 5000-30000,30000-60000,60000-100000 or 100000-150000;
B) copolymer of polyglycolic acid and hydroxyacetic acid, weight molecule amount peak value is 5000-30000,30000-60000,60000-100000 or 100000-150000, wherein, the ratio of polyglycolic acid and hydroxyacetic acid is 75: 25;
C) FAD and certain herbaceous plants with big flowers diacid copolymer;
D) in the polifeprosan to carboxy phenyl propane (p-CPP): certain herbaceous plants with big flowers diacid (SA) is 10: 90,20: 80,30: 70,40: 60,50: 50 or 60: 40;
The viscosity of suspending agent is 100cp-2000cp (20 ℃-30 ℃ time), is selected from one of following or its combination:
A) 1% sodium carboxymethyl cellulose;
B) 10% mannitol;
C) 5% sorbitol;
D) 0.3% polysorbas20;
E) 1% sodium carboxymethyl cellulose+0.5% soil temperature 80;
F) 12% mannitol+0.5% soil temperature 80;
G) 1.5% sodium carboxymethyl cellulose+10% sorbitol+0.5% soil temperature 80;
H) 1% sodium carboxymethyl cellulose+15% mannitol+0.5% soil temperature 20.
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| CNA2006102000459A CN1846677A (en) | 2006-01-18 | 2006-01-18 | Slow-released injection containing fluoroplex synergist |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100500682C (en) * | 2007-02-14 | 2009-06-17 | 江苏奥赛康药业有限公司 | Method of purifying medaplatin |
| CN1957920B (en) * | 2006-09-28 | 2010-05-19 | 山东蓝金生物工程有限公司 | Anti cancer slow release agent carrying fluorouracil and synergist |
-
2006
- 2006-01-18 CN CNA2006102000459A patent/CN1846677A/en active Pending
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1957920B (en) * | 2006-09-28 | 2010-05-19 | 山东蓝金生物工程有限公司 | Anti cancer slow release agent carrying fluorouracil and synergist |
| CN100500682C (en) * | 2007-02-14 | 2009-06-17 | 江苏奥赛康药业有限公司 | Method of purifying medaplatin |
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