CN101380308A - Anticancer sustained-release preparation loaded with anti-cancer medicine and synergist thereof - Google Patents
Anticancer sustained-release preparation loaded with anti-cancer medicine and synergist thereof Download PDFInfo
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- CN101380308A CN101380308A CNA2008103045155A CN200810304515A CN101380308A CN 101380308 A CN101380308 A CN 101380308A CN A2008103045155 A CNA2008103045155 A CN A2008103045155A CN 200810304515 A CN200810304515 A CN 200810304515A CN 101380308 A CN101380308 A CN 101380308A
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Abstract
An anticarcinogenic slow release formulation carrying an anticancer drug and a synergist is a slow release injection or a slow release implant, and the slow release injection is made from slow release microspheres and a dissolvant. The slow release microspheres comprise anticancer active components and a slow adjuvant, and the dissolvant is a special dissolvant containing a suspending agent which is selected from sodium carboxymethyl cellulose and the like, and the viscosity of the suspending agent is 80cp-3,000cp (at room temperature). The anticancer active components are alkylating agents such as melphalan, ifosfamide and the like, purine analogues such as O6-BG and the like, and/or hormones anticancer drugs selected from triptorelin, goserelin, leuprorelin and a composition selected from epothilone (A-F) and derivatives thereof; the slow release adjuvant is chosen from one of or the copolymer or the mixture of polylactic acid and a copolymer thereof, polifeprosan and the copolymer or the mixture of polylactic acid and sebacic acid copolymer; the slow release implant and the slow release injection are injected or put in tumors or around the tumors, which is beneficial to diffusing the drug in the solid tumors, maintaining high concentration, reducing drug tolerance, being capable of mutual synergy and enhancing curative effects of chemotherapy and/or radiotherapy.
Description
(1) technical field
The present invention relates to a kind of anticancer sustained-release agent that contains synergist, belong to technical field of pharmaceuticals.Particularly, the invention provides a kind of slow releasing injection or sustained-release implant with year synergist and cancer therapy drug, cancer therapy drug wherein is alkylating agent, purine derivative and/or hormone anti-cancer medicine.
(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 are subjected to general toxic reaction again merely.Referring to " placing cisplatin adding system carmustine treatment rat brain tumor in the tumor " " surgery tumor magazine " 69 phase 76-82 pages or leaves such as hole, (Kong Q et al., J Surg Oncol.1998Oct in 1998; 69 (2): 76-82).
The cancer drug therapy of low dosage not only can increase the Drug tolerance of cancerous cell, but also can promote its infiltrative growth "; referring to beam etc. " increased the Drug tolerance of human lung carcinoma cell and external wetting capacity after the cancer therapy drug pulse screening and with the change of gene expression " " international journal of cancer " 111 phase 484-93 page or leaf; 2004 (Liang Y; et al., Int JCancer.2004; 111 (4): 484-93).
Entity tumor is made up of tumor cell and mesenchyma stroma of tumors, wherein the blood vessel in the mesenchyma stroma of tumors not only provides support and requisite nutrient substance for the growth of tumor cell, also influenced chemotherapeutics around tumor and infiltration and diffusion in the tumor tissues, " situation of extracellular matrix is to the influence of medicine running in the entity tumor " " cancer research " 60 phase 2497-503 page or leaf such as carry referring to the Buddhist nun, (Netti PA in 2000, Cancer Res.2000,60 (9): 2497-503).
The tumor cell of composition such as the blood vessel in the mesenchyma stroma of tumors and fibrin in the connective tissue and collagen protein and hyperplasia cause entity tumor between matter pressure (interstitial pressure) high, a matter viscosity (interstitialviscosity) is big, tissue tension coefficient (tissue tensile modulus) is big, (hydraulicconductance) is low for the interstitial fluid conductance.Above factors have limited medicine greatly and have entered entity tumor and the effective diffusion in tumor, therefore constitute the major obstacle of chemotherapy of tumors.
Antitumor drug local injection or placement can overcome above defective preferably, not only can obviously improve the drug level of tumor by local, and can significantly reduce general toxic reaction.A large amount of internal and external tests have demonstrated the therapeutic effect to entity tumor, referring to " placing cisplatin adding system carmustine treatment rat brain tumor in the tumor " " surgery tumor magazine " 69 phase 76-82 pages or leaves such as Kong Qingzhongs, (Kong Q et al., J Surg Oncol.1998 Oct in 1998; 69 (2): 76-82) and Kong Qingzhong etc. " place cisplatin in the tumor and cure the former carbuncle in the occipital region tumor of rat " " surgery tumor magazine " 64 phase 268-273 pages or leaves (1997) (Kong Q etal., J Surg Oncol.1997Oct; 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 single medicine chemotherapy often causes tumor cell that the toleration of cancer therapy drug is increased, consequently treatment failure.
(3) summary of the invention
The present invention is directed to the deficiencies in the prior art, a kind of anticancer sustained-release agent that contains synergist is provided, belong to technical field of pharmaceuticals.Particularly, the invention provides a kind of slow releasing injection or sustained-release implant with year synergist and cancer therapy drug, cancer therapy drug wherein is alkylating agent, purine derivative and/or hormone anti-cancer medicine.
Cancer therapy drug such as alkylating agent, purine derivative and/or hormone anti-cancer medicine have been widely used in the treatment of kinds of tumors.Yet in application process, its tangible general toxicity has greatly limited the application of this medicine.Conventional route administrations such as main oral administration of the cancer therapy drug that this type of medicine is made or intravenous injection, its tangible toxic action often makes the treatment premature termination.Low dose of effect is bad, measures big body and is difficult to tolerance.
Administering mode of the present invention is the local sustained release administration, obviously reduces the toxic action of its whole body in the therapeutic effect that significantly strengthens medicine.
With synergist and or cancer therapy drug make drug level that slow releasing agent (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, reduce the toxicity of medicine normal structure, can also greatly make things convenient for the medicine injection, reduce operation technique complication, reduce patient's expense.Yet, with regard to medicine, be not the slow release effect that all slow-release auxiliary material all can reach effective release with active anticancer.Pharmaceutic adjuvant have hundreds of more than, pharmaceutic adjuvant with slow releasing function, particularly the pharmaceutic adjuvant that selected synergist among the present invention slowly can be discharged in the regular hour in human body or animal body must could obtain through a large amount of creationary experiments, specific slow-release auxiliary material and can need be passed through a large amount of creative works by the selection of the combination of slow releasing pharmaceutical and could determine.The data of release characteristics need could obtain through a large amount of creationary experiments in inside and outside in the related data, particularly animal body, are not just can determine to have unobviousness through limited experiment.
In addition, all can suppress tumor growth when alkylating agent, purine derivative and/or hormone anti-cancer medicine are used separately, but be easy to generate tolerance.Behind big quantity research, the present invention find Epothilones and derivant thereof can strengthen alkylating agent, purine derivative and or the tumor killing effect of hormone anti-cancer medicine (following can strengthen alkylating agent, purine derivative and or the material or the medicine of the tumor killing effect of hormone anti-cancer medicine be referred to as synergist).All tumor growth can be suppressed when synergist and alkylating agent, purine derivative and/or hormone anti-cancer medicine are used separately, tumor cell can be obviously increased during use in conjunction its sensitivity.The above unexpected another main contents of the present invention of finding to constitute.
Anticancer sustained-release agent of the present invention comprises anticancer effective component and pharmaceutic adjuvant, can be made into any dosage form, as, but be not limited to capsule, slow releasing agent, granule, pill, tablet, powder, injection, ointment, patch, implant, slow releasing agent implant, slow releasing agent injection etc.Wherein be preferred with the slow releasing agent, with slow releasing agent implant and slow releasing agent injection for most preferably.
Synergist slow releasing injection of the present invention is made up of sustained-release micro-spheres and solvent.Particularly, this slow-releasing anticarcinogen injection is grouped into by following one-tenth:
(A) sustained-release micro-spheres comprises:
Anticancer effective component 0.5-60%
Slow-release auxiliary material 40-99%
Suspending agent 0.0-30%
More than be weight percentage
With
(B) solvent is for common solvent or contain the special solvent of suspending agent.
Solvent is divided into common solvent and special solvent.
Anticancer effective component is the combination of synergist and cancer therapy drug, and synergist is selected from Epothilones and derivant thereof, and cancer therapy drug is alkylating agent, purine derivative and/or hormone anti-cancer medicine.
Wherein, common solvent comprises the buffer that distilled water, water for injection, physiology are prepared towards liquid, dehydrated alcohol or various salt; Special solvent is the common solvent that contains suspending agent, and suspending agent is selected from one of sodium carboxymethyl cellulose, (iodine) glycerol, simethicone, propylene glycol, carbomer, mannitol, sorbitol, surfactant, soil temperature 20, soil temperature 40 and soil temperature 80 or its combination.When the suspending agent in the sustained-release microparticle (A) was " 0 ", solvent (B) was special solvent.
Epothilones is, but be not limited to, Epothilones (A-F) and epothilone derivate, be selected from one of following or combination: Epothilones (Epothilone) or epothilone derivate, be selected from Epothilones A, epothilone B (Patupilone, EPO-906), Epothilone C (-)-Deoxyepothilone A (Epothilone C, desoxyepothilone), epothilone d (epothilone D (EpoD), 12,13-desoxyepothilone B, Epothilone C B, dEpoB, KOS-862 or NSC-703147), Epothilone E (-)-Epothilone E., Epothilone F (-)-Epothilone F. etc. and their derivant.
Wherein, the derivant of Epothilone C (-)-Deoxyepothilone A as, but be not limited to 4-demethyl-9-ketone-Epothilone C (-)-Deoxyepothilone A, 12,13-dihydro-13-oxygen Epothilone C (-)-Deoxyepothilone A (12,13-dihydro-13-oxoepothilone C);
The derivant of epothilone B as, but be not limited to, 21 and 26 difference or the epothilone B that is replaced by amino simultaneously, 9,10 dehydrogenation epothilone Bs, 10,11 dehydrogenation epothilone Bs, 26,27 epothilone Bs that replaced by halogen, 9,10,11,14,21,26 epothilone Bs that replaced by hydroxyl respectively, 21,26-dihydroxy epothilone B, 21-hydroxyl-10,11 dehydrogenation epothilone Bs, 4-demethyl-9-ketone-epothilone B, 4-demethyl-9,10-two dehydrogenation epothilone Bs, 4 demethyls-10,11-two dehydrogenation epothilone Bs, 6-demethyl-10,11-two dehydrogenation epothilone Bs, the amino epothilone B of 21-, 21-hydroxyl epothilone B, 26-hydroxyl epothilone B, 26-fluorine epothilone B, the amino epothilone B of 26-, 12,13 cyclopropyl epothilone Bs, 12,13 cyclobutyl epothilone Bs, ixabepilone (BMS-247550), Azaepothilone B (Azaepothilone B, oxygen in the lactone ring is replaced by nitrogen), 26-three fluoro-(E)-9,10-dehydrogenation-12,13-Epothilone C B (26-Trifluoro-(E)-9,10-dehydro-12,13-desoxyepothilone B[Fludelone (Flu)]); The derivant of epothilone d as, but be not limited to, 21 and 26 difference or the epothilone d that is replaced by amino simultaneously, 9 and 10 dehydrogenation epothilone ds, 10,11 dehydrogenation epothilone ds, 26,27 epothilone ds that replaced by halogen, 9,10,11,14,21,26 epothilone ds that replaced by hydroxyl respectively, 21,26-dihydroxy epothilone d, 21-hydroxyl-10,11 dehydrogenation epothilone ds, 4-demethyl-9-ketone-epothilone d, 4-demethyl-9,10-two dehydrogenation epothilone ds, 4-demethyl-10,11-two dehydrogenation epothilone ds, 6-demethyl-10,11-two dehydrogenation epothilone ds, 21-hydroxyl epothilone d, the amino epothilone d of 21-, 26-hydroxyl epothilone d, the amino epothilone d of 26-, 26-fluorine epothilone d, the 6-ethyl, the 16-fluorine, 17-pyridine Epothilones (or isoesperamicin), isoesperamicin D, 9,10 dehydrogenation epothilone ds, 10,11 dehydrogenation epothilone ds, furan epothilone d (furano-epothilone D), (E)-9,10-dehydrogenation-12,13-Epothilone C D (E)-9,10-dehydro-12,13-desoxyepothiloneD), BMS-310705, the 6-ethyl, the 16-fluorine, 17-pyridine Epothilones (ZK-EPO), 11,12-dehydrogenation-12,13-dehydrogenation-13-Epothilone C D11,12-dehydro-12,13-dihydro-13-oxoepothilone D, 12,13-dehydrogenation-13-Epothilone C D (12,13-dihydro-13-oxoepothilone D), 9-oxygen base epothilone d (9-oxoepothilone D), 8-table-9-oxygen base epothilone d (8-epi-9-oxoepothilone D), the salt of said medicine.
Above-mentioned salt as, but be not limited to sulfate, phosphate, hydrochlorate, Lactobionate, acetate, aspat, nitrate, citrate, purine or pyrimidine salt, succinate or maleate.
A kind of or its combination among the preferred Epothilones of above-mentioned Epothilones and epothilone derivate, Epothilones A, epothilone B, Epothilone C (-)-Deoxyepothilone A, epothilone d, isoesperamicin D, Epothilone E (-)-Epothilone E., Epothilone F (-)-Epothilone F., BMS-247550, Azaepothilone B, furan epothilone d, the BMS-310705.With epothilone B, epothilone d, isoesperamicin D, BMS-247550, Azaepothilone B, furan epothilone d and BMS-310705 serves as preferred.
Epothilones and epothilone derivate shared ratio in compositions is decided because of concrete condition, can be 0.1%-60%, is good with 1%-40%, and 5%-20% is best.
Alkylating agent is selected from one of following or combination: cyclophosphamide (CTX), melphalan (Melphalan), Chlorambucil (chlorambucil), 4H-peroxide cyclophosphamide (4H-CTX), ifosfamide (Ifosfamide, Isophosphamide), three mustard cyclophosphamide, sufosfamide (Sufosfamide), defosfamide (Defosfamide), Mafosfamide (Mafosfamide), perfosfamide (Perfosfamide), trofosfamide (Trofosfamide), thiocarzolamide, metamelfalan (Metamelfalan), formylmerphalan (Formylmerphalan), hexamethylmelamine (hexamethylmelamine), Ametantrone, Thymopentin, clomifene, letrozole, disodium cantharidinate, cantharidin (cantharidine), N-methylcantharidimide, N-hydroxycantharidin, norcantharidin (Norcantharidin), mannomustine (Mannosulfan), treosulfan (Treosulfan), ritrosulfan (Ritrosulfan), an improsulfan (Improsulfan), etoglucid (etoglucid, Ethoglucid, Etoglucid), pipobroman (pipobroman, Pipobroman), piposulfan (A-20968, Piposulfan), triethylenemelaine (triethylenemelamine), epoxypiperazine (epoxypiperazine), benzene assistant TEPA (Benzodepa), Phopurine (Pumitepa), meturedepa (Meturedepa), Ah bundle's TEPA (Aza-TEPA), the salt of urethimine (Uredepa) or said medicine.
Above-mentioned alkylating agent serves as preferred with cyclophosphamide, melphalan, Chlorambucil, ifosfamide, 4H-peroxide cyclophosphamide, defosfamide, Mafosfamide, perfosfamide, hexamethylmelamine, cantharidin, norcantharidin, mannomustine, treosulfan, ritrosulfan, an improsulfan, etoglucid, pipobroman, piposulfan, triethylenemelaine, epoxypiperazine, benzene assistant TEPA, Phopurine, meturedepa, urethimine or Ah bundle's TEPA.
The salt of above-mentioned alkylating agent comprises: sulfate, phosphate, hydrochlorate, Lactobionate, acetate, aspat, nitrate, citrate, purine or pyrimidine salt, succinate or maleate.
The percentage by weight of alkylating agent in slow releasing agent is good from 0.01%-90% with 1%-50%, is best with 5%-30%.
Guanine analog is selected from the 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-N2 N2-dimethylguanine; 2-amino-6-chloro-8 methyl purines; 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.
Steroids anti-cancer drugs is mainly steroid hormone and hormone antagonist, comprise, but be not limited to, triptorelin, goserelin, leuprorelin, Anastrozole, idoxifene, Miproxifene, tamoxifen, 4-monohydroxy tamoxifen (OH-TAM), not former times sweet smell, raloxifene, ICI-M 164384, anticancer steroid alkene phenol, 4-trans-Hydroxytamoxifen, Drogenil, aminoglutethimide, (.+-.)-Pyridoglutethimide, megestrol, medroxyprogesterone, clomifene, toremifene, letrozole, Anastrozole, exemestane, bicalutamide.
Above steroids anti-cancer drugs can be used for the tumor that various hormones rely on, but different pharmaceutical has relative tumor-selective, as, tamoxifen, (.+-.)-Pyridoglutethimide, rubitecan, Acapodene etc. mainly rely on estrogenic tumor in order to treatment, as breast carcinoma and carcinoma of endometrium; Drogenil, overstate that single silicon indigo plant and bicalutamide mainly rely on androgenic tumor in order to treatment, as carcinoma of prostate; Triptorelin, goserelin, leuprorelin, tamoxifen, raloxifene, aminoglutethimide, clomifene, toremifene, letrozole, Anastrozole and exemestane are then in order to treatment breast carcinoma, carcinoma of prostate and carcinoma of endometrium.
The content of steroids anti-cancer drugs in compositions is 0.01%-60%, is good with 1%-40%, is best with 5%-30%, more than all be weight percentage.
Available pharmaceutic adjuvant is a lot, the present invention is several slow-release auxiliary material of screening from hundreds of adjuvants, selected slow-release auxiliary material can discharge the selected medicine of the present invention tens of days in people and animal body, discharge since a few hours, continues 30-50 days (seeing the embodiment in the description).Resulting product is an anticancer sustained-release agent.The selection of slow-release auxiliary material particularly need could be determined through a large amount of creative works with the combination of different pharmaceutical, is not just can determine through limited experiment, thereby has unobviousness.
Slow-release auxiliary material range of viscosities IV (dl/g) is 0.1～1.0, be selected from poly-dl-lactide (D, L-PLA), poly-dl-lactide/ethanol copolymer (D, L-PLGA), monomethyl polyethylene glycol (MPEG-PLA), monomethyl polyethylene glycol copolymer (MPEG-PLGA), polyethylene glycol (PLA-PEG-PLA), polyethylene glycol copolymer (PLGA-PEG-PLGA), end carboxyl polylactic acid (PLA-COOH), end carboxyl polylactic acid/ethanol copolymer (PLGA-COOH), polifeprosan, bis-fatty acid and decanedioic acid copolymer (PFAD-SA), poly-(erucic acid dimer-decanedioic acid) [P (EAD-SA)], poly-(fumaric acid-decanedioic acid) [P (FA-SA)], polylactic acid (PLA), the copolymer of polyglycolic acid and hydroxyacetic acid (PLGA), poly-to dioxy cyclohexanone (PDO), PTMC (PTMC), xylitol, oligosaccharide, chrondroitin, chitin, chitosan, chitosan, hyaluronic acid, collagen protein, gelatin, poloxamer, one of albumin glue or its combination; Suspending agent is selected from one of sodium carboxymethyl cellulose, (iodine) glycerol, simethicone, propylene glycol, carbomer, mannitol, sorbitol, surfactant, soil temperature 20, soil temperature 40 and soil temperature 80 or its combination.
Anticancer effective component in the slow-releasing anticarcinogen injection microsphere of the present invention is preferably as follows:
Epothilone B, epothilone d, isoesperamicin D, BMS-247550, Azaepothilone B, the cyclophosphamide of furan epothilone d and BMS-310705 and 1-40%, melphalan, Chlorambucil, ifosfamide, 4H-peroxide cyclophosphamide, defosfamide, Mafosfamide, perfosfamide, hexamethylmelamine, cantharidin, norcantharidin, mannomustine, treosulfan, ritrosulfan, an improsulfan, etoglucid, pipobroman, piposulfan, triethylenemelaine, epoxypiperazine, benzene assistant TEPA, Phopurine, meturedepa, urethimine, Ah bundle's TEPA, the benzyl guanine, O6-benzyl guanine, O6-butyl guanine, the O6-methyl guanine, O6-alkyl guanine, 2-amino-6-oxypurine, O6-benzyl uric acid, O6-benzyl xanthine, triptorelin, goserelin, leuprorelin, Anastrozole, idoxifene, Miproxifene, tamoxifen, 4-monohydroxy tamoxifen, not former times sweet smell, raloxifene, ICI-M 164384, anticancer steroid alkene phenol, the 4-trans-Hydroxytamoxifen, Drogenil, aminoglutethimide, (.+-.)-Pyridoglutethimide, megestrol, medroxyprogesterone, clomifene, toremifene, letrozole, Anastrozole, the combination of exemestane or bicalutamide.
Slow-release auxiliary material is a bio-capacitivity, can (or non-) degraded and absorbed polymer, preferred silicone rubber, poly-dl-lactide, poly-dl-lactide/ethanol copolymer, the monomethyl polyethylene glycol, monomethyl polyethylene glycol copolymer, polyethylene glycol, the polyethylene glycol copolymer, end carboxyl polylactic acid, end carboxyl polylactic acid/ethanol copolymer, polifeprosan, bis-fatty acid and decanedioic acid copolymer, poly-(erucic acid dimer-decanedioic acid), poly-(fumaric acid-decanedioic acid), polylactic acid, the copolymer of polyglycolic acid and hydroxyacetic acid, xylitol, oligosaccharide, chrondroitin, chitin, chitosan, hyaluronic acid, collagen protein, one of gelatin and albumin glue or its combination.
Slow-release auxiliary material and percentage by weight thereof are most preferably as follows in the sustained-release micro-spheres of the present invention:
(1) PLA of 55-90%;
(2) PLGA of 50-90%;
(3) polifeprosan of 50-85%;
(4) bis-fatty acid of 55-90% and decanedioic acid copolymer;
(5) combination of the PLA of the polifeprosan of 40-60% and 30-60% or 30-60%;
(6) xylitol of 40-95%, oligosaccharide, chrondroitin, chitin, chitosan, chitosan, hyaluronic acid, collagen protein, gelatin or white tempera; Or
(7) poly-dl-lactide of 40-95%, poly-dl-lactide/ethanol copolymer, monomethyl polyethylene glycol, monomethyl polyethylene glycol copolymer, polyethylene glycol, polyethylene glycol copolymer, end carboxyl polylactic acid or end carboxyl polylactic acid/ethanol copolymer.
In various high molecular polymers, with polylactic acid, decanedioic acid, the mixture or the copolymer that contain the macromolecule polymer of polylactic acid or certain herbaceous plants with big flowers diacid is first-selection, mixture and copolymer can be selected from, but be not limited to the mixture or the copolymer of the mixture of PLA, PLGA, glycolic and hydroxy carboxylic acid, certain herbaceous plants with big flowers diacid and fragrant polyanhydride or aliphatic polyanhydride.The blend ratio of glycolic and hydroxy carboxylic acid is 10/90-90/10 (weight), preferably 25/75-75/25 (weight).The method of blend is arbitrarily.Content when glycolic and hydroxy carboxylic acid copolymerization is respectively percentage by weight 10-90% and 90-10%.The representative of fragrance polyanhydride is polifeprosan [poly-(1,3-two (to the carboxyl phenoxy group) propane-decanedioic acid) (p (CPP-SA)), bis-fatty acid-decanedioic acid copolymer (PFAD-SA)], poly-(erucic acid dimer-decanedioic acid) [P (EAD-SA)] and poly-(fumaric acid-decanedioic acid) [P (FA-SA)] etc.Content during to carboxylic phenoxypropane (p-CPP) and decanedioic acid copolymerization is respectively percentage by weight 10-60% and 20-90%, and the blend weight ratio is 10-40:50-90, preferably weight ratio 15-30:65-85.
The molecular weight peak value of polylactic acid can be, but is not limited to, 5000-100, and 000, but with 20,000-60,000 is preferred, with 5,000-30,000 for most preferably; The molecular weight of polyglycolic acid can be, but is not limited to, 5000-100, and 000, but with 5,000-50,000 is preferred, with 10,000-30,000 for most preferably; Above polyhydroxy acid can singly select or multiselect.When singly selecting, serve as preferred with the copolymer (PLGA) of polylactic acid (PLA) or hydroxy carboxylic acid and glycolic, the molecular weight of copolymer can be, but is not limited to, 5000-100,000, but with 20,000-60,000 be preferably, with 30,000-50,000 for most preferably; When multiselect, compound polymer or the copolymer formed with macromolecule polymer or different macromolecule polymer serve as preferred, with the compound polymer that contains different molecular weight polylactic acid or decanedioic acid or copolymer for most preferably, as, but be not limited to, molecular weight is 1000 to 30000 polylactic acid with molecular weight is that 20000 to 50000 polylactic acid mixes, molecular weight is 10000 to 30000 polylactic acid with molecular weight is that 30000 to 80000 PLGA mixes, molecular weight is that 20000 to 30000 polylactic acid mixes with decanedioic acid, molecular weight is that 30000 to 80000 PLGA mixes with decanedioic acid.Used polylactic acid serves as preferred with Poly-L-lactic acid (L-PLA).Poly-L-lactic acid (L-PLA) range of viscosities IV (dl/g) is 0.2～0.8, and glass transition temperature range is 55～65 ℃, 175～185 ℃ of fusing points.
Except that above-mentioned adjuvant, also can select for use other materials to see the United States Patent (USP) (patent No. 4757128; 4857311; 4888176; 4789724) and in " pharmaceutic adjuvant complete works " (the 123rd page, Sichuan science tech publishing house published in 1993, Luo Mingsheng and Gao Tianhui chief editor) have a detailed description.In addition, Chinese patent (application number 96115937.5; 91109723.6; 9710703.3; 01803562.0) and U.S.'s patent of invention (patent No. 5,651,986) also enumerated some pharmaceutic adjuvant, comprise filler, solubilizing agent, absorption enhancer, film former, gellant, system (or causing) hole agent, excipient or blocker etc.
For regulating drug releasing rate or changing other characteristic of the present invention, can change the composition and the proportioning of monomer component or molecular weight, interpolation or the adjusting pharmaceutic adjuvant of polymer, add the water-soluble low-molecular chemical compound, as, but be not limited to various sugar or salt etc.Wherein sugar can be, but is not limited to, xylitol, oligosaccharide, (sulphuric acid) chrondroitin and chitin etc., and wherein salt can be, but is not limited to, potassium salt and sodium salt etc.
Suspending agent be used for preparation and/or effectively suspend, stable and/or protect various medicines or sustained-release micro-spheres (or microcapsule), thereby make prepared injection injectivity good, be not easy obstruction, good stability, be difficult for layering, the viscosity height.
Suspending agent is selected from one of sodium carboxymethyl cellulose, (iodine) glycerol, simethicone, propylene glycol, carbomer, mannitol, sorbitol, surfactant, soil temperature 20, soil temperature 40 and soil temperature 80 or its combination.
The viscosity of suspending agent is 100cp-3000cp (20 ℃-30 ℃ time), preferred 1000cp-3000cp (20 ℃-30 ℃ time), most preferably 1500cp-3000cp (20 ℃-30 ℃ time).
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.
Common solvent can be, but is not limited to, the buffer that distilled water, water for injection, physiology are prepared towards liquid, dehydrated alcohol or various salt, and pharmacopeia has respective specified; The special solvent of indication of the present invention is the common solvent that contains suspending agent, suspending agent can be, but be not limited to one of sodium carboxymethyl cellulose, (iodine) glycerol, simethicone, propylene glycol, carbomer, mannitol, sorbitol, surfactant, soil temperature 20, soil temperature 40 and soil temperature 80 or its combination.The content of suspending agent is 0.1-30% volume weight percentage ratio in the special solvent, is preferably as follows:
A) 0.5-5% sodium carboxymethyl cellulose; Or
B) 0.5-5% sodium carboxymethyl cellulose and 0.1-0.5% Tween 80; Or
C) 5-20% mannitol; Or
D) 5-20% mannitol and 0.1-0.5% Tween 80; Or
E) 0.5-5% sodium carboxymethyl cellulose, 5-20% sorbitol and 0.1-0.5% Tween 80.
The above-mentioned volume weight percentage ratio that is contains the weight of suspending agent in the common solvent of unit volume, as g/ml, and kg/l.Down together.
The content of suspending agent is decided because of the medicine that solvent suspended, composition, character and the requirement thereof of sustained-release micro-spheres (or microcapsule), the preparation method of injection and the kind and the composition thereof of suspending agent, as, sodium carboxymethyl cellulose can be 0.5-5%, but with 1-3% is preferred, mannitol and/or sorbitol are 5-30%, but is preferred with 10-20%, and soil temperature 20, soil temperature 40 or soil temperature 80 are 0.05-2%, but are preferred with 0.10-0.5%.In most cases, sustained-release microparticle is made up of effective ingredient and slow-release auxiliary material, and solvent is special solvent.When solvent was common solvent, medicine that is suspended or sustained-release micro-spheres (or microcapsule) then were made up of effective ingredient, slow-release auxiliary material and/or suspending agent.In other words, when the suspending agent in the sustained-release microparticle (A) was " 0 ", solvent (B) was special solvent, and when the suspending agent in the sustained-release microparticle (A) was not " 0 ", solvent (B) can be common solvent or special solvent.The viscosity of suspending agent is 100cp-3000cp (20 ℃-30 ℃ time), preferred 1000cp-3000cp (20 ℃-30 ℃ time), most preferably 1500cp-3000cp (20 ℃-30 ℃ time).
The preparation of injection comprises that the preparation of preparation, solvent of sustained-release micro-spheres or drug microparticles and sustained-release micro-spheres or drug microparticles suspend, and make injection at last in solvent.
Wherein, sustained-release micro-spheres or drug microparticles can prepare with some kinds of methods: as, but be not limited to, mixing method, fusion method, dissolution method, spray drying method for preparation microsphere, dissolution method are in conjunction with freezing (drying) comminuting method, liposome bag medicine method and emulsion process etc.Serve as preferred wherein with dissolution method (being the solvent volatility process), freezing (drying) comminuting method, seasoning, spray drying method and emulsion process.Microsphere then can be used for preparing above-mentioned various slow releasing injection.The particle diameter of suspended drug or sustained-release micro-spheres (or microcapsule) decide because of specifically needing, and can be, but be not limited to, 1-300um, but be that preferably 30-150um most preferably with 20-200um.Medicine or sustained-release micro-spheres can be made into microsphere, sub-micro ball, microemulsion, nanosphere, granule or spherical piller.Slow-release auxiliary material is above-mentioned bio-capacitivity, biodegradable or non-biodegradation polymer.
The kind of solvent is then depended in the preparation of solvent, and common solvent has commercially available, also can make by oneself, and as distilled water, water for injection, physiology buffer towards liquid, dehydrated alcohol or the preparation of various salt, but must be in strict accordance with related standards.Special solvent need be considered the kind of suspending agent and the medicine that composition, solvent suspended, composition, character and the requirement thereof of sustained-release micro-spheres (or microcapsule) and the preparation method of injection, as sodium carboxymethyl cellulose (1.5%)+mannitol and/or sorbitol (15%) and/or soil temperature 80 (0.1%) are dissolved in the normal saline 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 route of administration of injection depends on multiple factor.Can be in vein, lymphatic vessel, subcutaneous, muscle, intracavity (in as abdominal cavity, thoracic cavity, articular cavity and in the canalis spinalis), tissue, tumor in, reach in the bone marrow in all, the selective arterial injection of tumor, lymph node and inject.For entity tumor, though can be through above-mentioned administration, with in selective arterial, intracavity, the tumor, the injection of tumor week serves as preferred.For obtaining valid density in former or position, metastatic tumour place, also can unite and give through number of ways, in the time of as vein, lymphatic vessel, subcutaneous, muscle, intracavity (as in abdominal cavity, thoracic cavity, the articular cavity and in the canalis spinalis) or selective arterial injection in conjunction with local injection.So administering drug combinations is specially adapted to entity tumor.As in the tumor, tumor week injection time is in conjunction with systemic injection.
The application of injection is to utilize full-bodied special solvent with pastille microgranule (ball), particularly sustained-release microparticle, makes corresponding slow releasing injection, thereby corresponding medicine can be imported in the patient or mammalian body of required medicine in the mode of injection.The medicine that is injected can be, but is not limited to, said medicine micropowder or medicament slow release microgranule.
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.
In the slow releasing injection, drug sustained release system can be made into microsphere, sub-micro ball, microemulsion, nanosphere, granule or spherical piller, makes the injection use then with after the injection solvent mixes.In various slow releasing injection, serve as preferred with the suspension type slow releasing injection, the suspension type slow releasing injection is the preparation that the drug sustained release system that will contain anticancer component is suspended in gained in the injection, used adjuvant is a kind of or its combination in the above-mentioned slow-release auxiliary material, and used solvent is common solvent or the special solvent that contains suspending agent.Common solvent is, but is not limited to the buffer that distilled water, water for injection, physiology are prepared towards liquid, dehydrated alcohol or various salt.The purpose of suspending agent is the pastille microsphere that effectively suspends, thereby is beneficial to the usefulness of injection.
Anticancer effective component is mainly synergist and cancer therapy drug.When the cancer therapy drug in the medicament slow-release microsphere only was synergist or cancer therapy drug, slow-releasing anticarcinogen injection was mainly used in the cancer therapy drug of other approach application of increase or the action effect of synergist, or was used for the potentiation to radiotherapy or other therapies.When the cancer therapy drug in the medicament slow-release microsphere only was synergist or cancer therapy drug, the application of slow-releasing anticarcinogen injection and potentiation mode were:
(1) local injection contains the slow releasing injection of synergist and the cancer therapy drug associating that other approach are used;
(2) local injection contains the slow releasing injection of cancer therapy drug and the synergist associating that other approach are used; Or
(3) local injection contains the associating of the slow releasing injection that contains synergist of the slow releasing injection of cancer therapy drug and topical application.
The slow-releasing anticarcinogen injection of topical application also is used for the potentiation to radiotherapy or other therapies.Other approach refer to, but, be not limited to tremulous pulse, vein, abdominal cavity, subcutaneous, intracavitary administration.
The percentage by weight of cancer therapy drug in sustained-release micro-spheres is 0.5%-60%, is good with 2%-40%, is best with 5%-30%.When synergist and cancer therapy drug use in conjunction, the weight ratio of synergist and alkylating agent and/or steroids anti-cancer drugs for for 1-19:1 to 1:1-19, serve as preferably with 1-9:1 to 1-9:1, arrive 1-5:1 for most preferably with 1-5:1.
Microsphere is used to prepare slow releasing injection, as suspension type slow releasing injection, gel injection, block copolymer micelle injection.In various injections, serve as preferred with the suspension type slow releasing injection.The suspension type slow releasing injection is to contain the medicament slow-release microsphere of effective composition or the preparation that drug microparticles is suspended in gained in the solvent, and used adjuvant is a kind of or its combination in the above-mentioned slow-release auxiliary material, and used solvent is common solvent or the special solvent that contains suspending agent.Common solvent is, but is not limited to the buffer that distilled water, water for injection, physiology are prepared towards liquid, dehydrated alcohol or various salt; Block copolymer micelle is formed in aqueous solution by hydrophobic-hydrophilic block copolymers, has spherical inner core-shell mechanism, and hydrophobic block forms kernel, and hydrophilic block forms shell.The carrier micelle injection enters the purpose that reaches control drug release or targeted therapy in the body.Used pharmaceutical carrier is above-mentioned any one or its combination.Wherein preferred molecular weight is the hydrophilic block of the Polyethylene Glycol (PEG) of 1000-15000 as the micelle copolymer, and preferred biological degradation polyalcohol (as PLA, polylactide, polycaprolactone and copolymer thereof (molecular weight 1500-25000)) is as the hydrophobic block of micelle copolymer.The particle size range of block copolymer micelle can be at 1-300um, but is preferred with 20-200um, and 30-150um most preferably; Gel injection system is dissolved in some amphipathic solvent with biological degradation polyalcohol (as PLA, PLGA or DL-LA and epsilon-caprolactone copolymer), adds medicine miscible with it (or suspendible) back again and forms flowability gel preferably, can be through tumor week or intratumor injection.In case inject, amphipathic solvent diffuses to body fluid very soon, the moisture in the body fluid then infiltrates gel, makes polymer cure, slowly discharges medicine.
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, in various high molecular polymers, be main separation, as polifeprosan with the high molecular weight water soluble polymer, bis-fatty acid and decanedioic acid copolymer (PFAD-SA), poly-(erucic acid dimer-decanedioic acid) [P (EAD-SA)], poly-(fumaric acid [decanedioic acid) [P (FA-SA)], ethylene vinyl acetate copolymer (EVAc), polylactic acid (PLA), the copolymer of polyglycolic acid and hydroxyacetic acid (PLGA), xylitol, oligosaccharide, chrondroitin, chitin, chitosan, hyaluronic acid, collagen protein, one of gelatin and white tempera or its combination.
Preferred slow-release auxiliary material can be various water solublity or water-insoluble macromolecule polymer.Slow-release auxiliary material and percentage by weight thereof are most preferably as follows in the sustained-release implant of the present invention:
(1) PLA of 55-90%;
(2) PLGA of 50-90%;
(3) polifeprosan of 50-85%;
(4) bis-fatty acid of 55-90% and decanedioic acid copolymer;
(5) combination of the PLA of the polifeprosan of 40-60% and 30-60% or 30-60%;
(6) xylitol of 40-95%, oligosaccharide, chrondroitin, chitin, chitosan, chitosan, hyaluronic acid, collagen protein, gelatin or albumin glue; Or
(7) poly-dl-lactide of 40-95%, poly-dl-lactide/ethanol copolymer, monomethyl polyethylene glycol, monomethyl polyethylene glycol copolymer, polyethylene glycol, polyethylene glycol copolymer, end carboxyl polylactic acid or end carboxyl polylactic acid/ethanol copolymer.
Therefore, another form of anticancer medicine slow-release preparation containing of the present invention is that anticancer medicine slow-release preparation containing is a sustained-release implant, as, but be not limited to capsule, slow releasing agent, implant, slow releasing agent implant etc.; Be multiple shape, as, but be not limited to granule, pill, tablet, powder, sphere, bulk, needle-like, bar-shaped, column and membranaceous.In various dosage forms, serve as preferred slowly to discharge implant in the body.
The most preferred dosage form of sustained-release implant is the slow releasing agent implant that biocompatibility, degradable absorb, and can make different shape and various dosage form because of the clinical needs of difference.The packing method of its Main Ingredients and Appearance and step in United States Patent (USP) (US5651986) have a detailed description, comprise the some kinds of methods that prepare slow releasing preparation: as, but be not limited to, (i) carrier holder powder and medicament mixed be pressed into implant then, promptly so-called mixing method; (ii) carrier holder fusing, mix solid cooled then, promptly so-called fusion method mutually with medicine to be packaged; (iii) the carrier holder is dissolved in the solvent, medicine dissolution to be packaged or be scattered in the polymer solution, evaporating solvent then, drying, promptly so-called dissolution method; (iv) spray drying method; And (v) freeze-drying etc.
The same slow releasing injection of application formula of anti-cancer sustained-released implantation agent, the wherein preferred Epothilones of synergist, Epothilones A, epothilone B, Epothilone C (-)-Deoxyepothilone A, epothilone d, isoesperamicin D, Epothilone E (-)-Epothilone E., Epothilone F (-)-Epothilone F., BMS-247550, Azaepothilone B, furan epothilone d or BMS-310705.
Therefore, sustained-release implant anticancer effective component and percentage by weight thereof be preferably:
(1) Epothilones of 1-40%, Epothilones A, epothilone B, Epothilone C (-)-Deoxyepothilone A, epothilone d, isoesperamicin D, Epothilone E (-)-Epothilone E., Epothilone F (-)-Epothilone F., BMS-247550, Azaepothilone B, the cyclophosphamide of furan epothilone d or BMS-310705 and 1-40%, melphalan, Chlorambucil, ifosfamide, 4H peroxide cyclophosphamide, defosfamide, Mafosfamide, perfosfamide, hexamethylmelamine, cantharidin, norcantharidin, mannomustine, treosulfan, ritrosulfan, an improsulfan, etoglucid, pipobroman, piposulfan, triethylenemelaine, epoxypiperazine, benzene assistant TEPA, Phopurine, meturedepa, the combination of urethimine or Ah bundle's TEPA; Or
(2) the benzyl guanine of the Epothilones of 1-40%, Epothilones A, epothilone B, Epothilone C (-)-Deoxyepothilone A, epothilone d, isoesperamicin D, Epothilone E (-)-Epothilone E., Epothilone F (-)-Epothilone F., BMS-247550, Azaepothilone B, furan epothilone d or BMS-310705 and 1-40%, O6-benzyl guanine, O6-butyl guanine, O6-methyl guanine, O6-alkyl guanine, 2 amino-6-hypoxanthine, O6-benzyl uric acid or the xanthic combination of O6-benzyl; Or
(3) Epothilones of 1-40%, Epothilones A, epothilone B, Epothilone C (-)-Deoxyepothilone A, epothilone d, isoesperamicin D, Epothilone E (-)-Epothilone E., Epothilone F (-)-Epothilone F., BMS-247550, Azaepothilone B, the triptorelin of furan epothilone d or BMS-310705 and 1-40%, goserelin, leuprorelin, Anastrozole, idoxifene, Miproxifene, tamoxifen, 4 monohydroxy tamoxifens, not former times sweet smell, raloxifene, ICI-M 164384, anticancer steroid alkene phenol, the 4-trans-Hydroxytamoxifen, Drogenil, aminoglutethimide, (.+-.)-Pyridoglutethimide, megestrol, medroxyprogesterone, clomifene, toremifene, letrozole, Anastrozole, the combination of exemestane or bicalutamide.
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 be packaged in respectively is shaped behind the same adjuvant of different adjuvants or tool different molecular weight simultaneously makes homogeneous agent or layering implant, can effective ingredient be discharged by direct diffusion and/or through the mode of polymer degraded.In addition, the effective ingredient of anti-cancer sustained-released implantation agent also can be packaged in the liposome equably, or makes microsphere with art methods.
Anticancer implant is multiple shape, as, but be not limited to granule, tablet, powder, sphere, bulk, needle-like, bar-shaped, column and membranaceous.Its most preferred dosage form is the implantation slow release agent that biocompatibility, degradable absorb, and can make different shape and various dosage form because of the clinical needs of difference, as, but be not limited to slow releasing agent implant, granule, capsule, ball, ball, diffusing, excellent.The packing method of its Main Ingredients and Appearance and step in United States Patent (USP) (US5651986) have a detailed description, comprise the some kinds of methods that prepare slow releasing preparation: as, but be not limited to, (i) carrier holder powder and medicament mixed be pressed into implant then, promptly so-called mixing method; (ii) carrier holder fusing, mix solid cooled then, promptly so-called fusion method mutually with medicine to be packaged; (iii) the carrier holder is dissolved in the solvent, medicine dissolution to be packaged or be scattered in the polymer solution, evaporating solvent then, drying, promptly so-called dissolution method; (iv) spray drying method; And (v) freeze-drying etc.
The anticancer effective component of anti-cancer sustained-released implantation agent of the present invention and percentage by weight are preferably as slow releasing injection.When the cancer therapy drug in the medicament slow-release microsphere only is synergist or cancer therapy drug, the application of anti-cancer sustained-released implantation agent and the same slow releasing injection of potentiation mode.
Anti-cancer sustained-released implantation agent of the present invention can give through number of ways, in number of ways, with topical, as with in selective arterial, intracavity, the tumor, tumor week be placed as the master, with in the tumor, the form that slowly discharges of tumor week or tumor chamber serve as preferred, is the best directly to place or to inject in the tumor body.
The consumption of cancer therapy drug depends on several factors, as, but be not limited to gross tumor volume, patient body weight, administering mode, disease progression situation and therapeutic response.Generally speaking, synergist and cancer therapy drug can be 0.01-1000 milligram/kg body weight, with 1-800 milligram/kg body weight is ideal, with 5-80 milligram/kg body weight for the most desirable, hormone anti-cancer medicine can be 0.01-500 milligram/kg body weight, with 1-100 milligram/kg body weight is ideal, with 5-50 milligram/kg body weight for the most desirable.
The Main Ingredients and Appearance of sustained-release implant can be made into multiple dosage form.As, but be not limited to capsule, slow releasing agent, implant, slow releasing agent implant etc.; Be multiple shape, as, but be not limited to granule, pill, tablet, powder, sphere, bulk, needle-like, bar-shaped, column and membranaceous.In various dosage forms, serve as preferred slowly to discharge implant in the body.Can be the bar-shaped of 0.1-5mm (slightly) * 1-10mm (length), also can be other shapes such as lamellar.
Route of administration depends on multiple factor, for obtain valid density in former or position, metastatic tumour place, medicine can give through number of ways, as in subcutaneous, intracavity (in abdominal cavity, thoracic cavity and canalis spinalis), the tumor, in all injections of tumor or placement, selective arterial injection, the lymph node and injection in the bone marrow.With in selective arterial injection, intracavity, the tumor, tumor week injection or be placed as preferred.When the cancer therapy drug in the medicament slow-release microsphere only is synergist or cancer therapy drug, the application of anti-cancer sustained-released implantation agent and the same slow releasing injection of potentiation mode.
The present invention can be used to prepare the pharmaceutical preparation of the various tumors for the treatment of people and animal, be mainly slow releasing injection or sustained-release implant, the indication tumor comprises former or cancer or sarcoma or the carcinosarcoma that shifts that originates from brain, central nervous system, kidney, liver, gallbladder, incidence, oral cavity, thyroid, skin, mucosa, body of gland, blood vessel, osseous tissue, lymph node, lungs, esophagus, stomach, mammary gland, pancreas, eyes, nasopharynx part, uterus, ovary, endometrium, cervix uteri, prostate, bladder, colon, rectum.
Also can add other medicinal ingredient in slow releasing injection that the present invention is made or the sustained-release implant, as, but be not limited to antibiotics, antalgica, anticoagulant medicine, hemorrhage etc.
By following test and embodiment technical method of the present invention is further described:
The local drug concentration that test 1, different modes are used alkylating agent (epothilone d) 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 2.5mg/kg epothilone d.Measure medicament contg (%) in the different time tumor, the result shows, the local drug concentration significant difference of epothilone d 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.
Tumor-inhibiting action relatively in the body of the medicine (epothilone B) that test 2, different modes are used
With the rat is subjects, with 2 * 10
5Individual breast tumor cell 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 epothilone B.The treatment back was measured gross tumor volume size, relatively therapeutic effect on the 20th day.The result shows, the tumor-inhibiting action significant difference of epothilone B 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.Make repeated experiments with synergist, get same experimental result.
The tumor-inhibiting action of test 3, synergist (epothilone d) and cancer therapy drug
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 matched group and treatment group (1-11).The treatment component is synergist (2.5mg/kg) and cancer therapy drug (17.5mg/kg) group.Synergist is through intratumor injection, and cancer therapy drug is through lumbar injection.The treatment back was measured gross tumor volume size, relatively therapeutic effect (seeing Table 1) on the 20th day.
Table 1
| Group | Synergist | Cancer therapy drug | Tumor control rate (%) | The P value |
| 1 | + | - | 46 | * |
| 2 | - | Triptorelin | 40 | * |
| 3 | - | Goserelin | 36 | * |
| 4 | - | Leuprorelin | 44 | * |
| 5 | - | Anastrozole | 46 | * |
| 6 | - | Idoxifene | 38 | * |
| 7 | + | Triptorelin | 70 | ** |
| 8 | + | Goserelin | 74 | ** |
| 9 | + | Leuprorelin | 80 | ** |
| 10 | + | Anastrozole | 76 | ** |
| 11 | + | Idoxifene | 82 | ** |
Above result shows, synergist (epothilone d) and used cancer therapy drug (triptorelin, goserelin, leuprorelin, Anastrozole, idoxifene) all have significant inhibitory effect (*: the P value is less than 0.05) to tumor growth when this concentration is used separately, can show the potentiation (* *: the P value is less than 0.001) of highly significant when use in conjunction.
The tumor-inhibiting action of test 4, synergist (epothilone d) and cancer therapy drug (slow releasing injection)
According to the tumor-inhibiting action of test 3 described methods mensuration epothilone ds and anti-cancer medicine sustained-release 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.Except that being 2.5mg/kg, epothilone d is 15mg/kg.Its growth of tumour cell suppresses effect (%) and is shown in Table 2.
Table 2
| Oncocyte | Epothilone d | A | B | C | D | E | Epothilone d+A | Epothilone d+B | Epothilone d+C | Epothilone d+D | Epothilone d+E |
| CNS | 32 | 50 | 56 | 38 | 52 | 42 | 82 | 70 | 86 | 88 | 82 |
| C6 | 22 | 52 | 46 | 36 | 64 | 40 | 90 | 84 | 84 | 84 | 90 |
| SA | 26 | 52 | 58 | 42 | 62 | 42 | 84 | 84 | 80 | 82 | 86 |
| BC | 36 | 58 | 40 | 44 | 52 | 54 | 88 | 82 | 78 | 76 | 84 |
| BA | 18 | 48 | 38 | 48 | 60 | 56 | 82 | 80 | 90 | 90 | 88 |
| LH | 26 | 56 | 44 | 54 | 58 | 60 | 92 | 80 | 94 | 76 | 84 |
| PAT | 34 | 54 | 50 | 52 | 50 | 62 | 80 | 78 | 82 | 88 | 84 |
Above result shows that synergist is an epothilone d, and cancer therapy drug is A: Miproxifene, B: tamoxifen, C: not former times sweet smell, D: raloxifene, E: ICI-M 164384.Above-mentioned growth all has the obvious suppression effect to kinds of tumor cells when this concentration is used separately, can show significant potentiation when use in conjunction.
The tumor-inhibiting action of test 5, synergist and cancer therapy drug (slow releasing injection)
According to the tumor-inhibiting action of test 3 described methods mensuration isoesperamicin D and anti-cancer medicine sustained-release 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.The dosage of synergist (isoesperamicin D) and cancer therapy drug is 10mg/kg, treats 30 days.The result shows, growth all has obvious suppression effect (P＜0.05) to kinds of tumors when using separately for used synergist and cancer therapy drug (cyclophosphamide, melphalan, Chlorambucil, ifosfamide, 4H-peroxide cyclophosphamide), can show significant potentiation (P＜0.01) when use in conjunction.
Further test shows, so obvious synergistic effect also sees the combination that synergist such as BMS-247550 and defosfamide, Mafosfamide, perfosfamide, hexamethylmelamine, cantharidin, norcantharidin, mannomustine, treosulfan, ritrosulfan, an improsulfan, etoglucid, pipobroman, piposulfan, triethylenemelaine, epoxypiperazine, benzene are helped TEPA, Phopurine, meturedepa, urethimine or Ah bundle's TEPA.
The tumor-inhibiting action of test 6, synergist (Azaepothilone B) and cancer therapy drug (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 negative control (blank), single therapy group (synergist Azaepothilone B or cancer therapy drug) and therapeutic alliance group (synergist Azaepothilone B and cancer therapy drug).Medicine is through intratumor injection.Dosage is 5mg/kg.The treatment back was measured the gross tumor volume size on the 20th day, made relatively therapeutic effect of index with inhibition rate of tumor growth.The result shows, growth all has obvious suppression effect (P＜0.05) to kinds of tumor cells when using separately for used synergist and cancer therapy drug (benzyl guanine, O6-benzyl guanine, O6-butyl guanine, O6-methyl guanine), can show significant potentiation (P＜0.01) when use in conjunction.Further test shows, so obvious synergistic effect also sees the combination of furan epothilone d and benzyl guanine, O6-benzyl guanine, O6-butyl guanine, O6-methyl guanine, O6-alkyl guanine, 2-amino-6-oxypurine, O6-benzyl uric acid or the combination of O6-benzyl xanthine.
The tumor-inhibiting action of test 7, synergist and cancer therapy drug (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.Cancer therapy drug is through intratumor injection, and synergist is through lumbar injection.Dosage is 5mg/kg.The treatment back was measured the gross tumor volume size on the 20th 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) | Synergist | 46 | <0.05 |
| 3(6) | O6-benzyl bird is fast | 54 | <0.01 |
| 4(6) | O6-butyl guanine | 42 | <0.01 |
| 5(6) | O6-alkyl guanine | 54 | <0.01 |
| 6(6) | The O6-methyl guanine | 50 | <0.01 |
| 7(6) | Synergist+O6-benzyl bird is fast | 82 | <0.001 |
| 8(6) | Synergist+O6-butyl guanine | 88 | <0.001 |
| 9(6) | Synergist+O6-methyl guanine | 72 | <0.001 |
| 10(6) | Synergist+O6-alkyl guanine | 80 | <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 synergist (Azaepothilone B) and cancer therapy drug (benzyl guanine, O6-benzyl guanine, O6-butyl guanine, O6-methyl guanine, O6-alkyl guanine), can show significant potentiation when use in conjunction.
Same potentiation also sees furan epothilone d or BMS-310705 and O6-benzyl guanine, O6-butyl guanine, O6-methyl guanine, O6-alkyl guanine, 2-amino-6-oxypurine, O6-benzyl uric acid or the xanthic associating of O6-benzyl.
The tumor-inhibiting action of test 8, synergist (furan epothilone d) and cancer therapy drug (sustained-release implant)
With the rat is subjects, with 2 * 10
5Individual breast tumor cell subcutaneous injection is in its hypochondrium, treats that tumor growth after 14 days is divided into it negative control (blank), single therapy group, therapeutic alliance group.Sustained-release implant is placed in tumor.Dosage is except that being 15mg/kg for the 5mg/kg.The treatment back was measured the gross tumor volume size on the 20th 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) | Synergist | 52 | <0.05 |
| 3(6) | Defosfamide | 48 | <0.05 |
| 4(6) | Mafosfamide | 38 | <0.05 |
| 5(6) | Perfosfamide | 40 | <0.05 |
| 6(6) | Hexamethylmelamine | 36 | <0.01 |
| 7(6) | Synergist+defosfamide | 78 | <0.01 |
| 8(6) | Synergist+Mafosfamide | 82 | <0.01 |
| 9(6) | Synergist+perfosfamide | 84 | <0.01 |
| 10(6) | Synergist+hexamethylmelamine | 82 | <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 synergist (furan epothilone d) and cancer therapy drug (defosfamide, Mafosfamide, perfosfamide, hexamethylmelamine), can show significant potentiation when use in conjunction.
The tumor-inhibiting action of test 9, synergist (furan epothilone d) and cancer therapy drug (sustained-release implant)
By the tumor-inhibiting action of test 8 described methods mensuration synergists and cancer therapy drug (sustained-release implant), its inhibition rate of tumor growth sees Table 5.
Table 5
| Test group (n) | Suffered treatment | Tumor control rate (%) | The P value |
| 1(6) | Contrast | - | |
| 2(6) | Synergist | 60 | <0.05 |
| 3(6) | Triptorelin | 52 | <0.01 |
| 4(6) | Goserelin | 54 | <0.01 |
| 5(6) | Leuprorelin | 60 | <0.01 |
| 6(6) | Anastrozole | 52 | <0.01 |
| 7(6) | Synergist+triptorelin | 82 | <0.001 |
| 8(6) | Synergist+goserelin | 86 | <0.001 |
| 9(6) | Synergist+leuprorelin | 80 | <0.001 |
| 10(6) | Synergist+Anastrozole | 86 | <0.001 |
Above result shows, used synergist (furan epothilone d) and and cancer therapy drug (triptorelin, goserelin, leuprorelin, Anastrozole) when this concentration is used separately, kinds of tumor cells grown the obvious suppression effect all arranged, when use in conjunction, can show significant potentiation.
The tumor-inhibiting action of test 10, epothilone d and cancer therapy drug (sustained-release implant)
By the tumor-inhibiting action of test 8 described methods mensuration synergists and cancer therapy drug (sustained-release implant), its inhibition rate of tumor growth sees Table 6.
Table 6
| Test group (n) | Suffered treatment | Tumor control rate (%) | The P value |
| 1(6) | Contrast | - | |
| 2(6) | Synergist | 50 | <0.05 |
| 3(6) | Cyclophosphamide | 42 | <0.01 |
| 4(6) | Melphalan | 36 | <0.01 |
| 5(6) | Ifosfamide | 40 | <0.01 |
| 6(6) | 4H-peroxide cyclophosphamide | 42 | <0.01 |
| 7(6) | Synergist+cyclophosphamide | 76 | <0.01 |
| 8(6) | Synergist+melphalan | 86 | <0.001 |
| 9(6) | Synergist+ifosfamide | 80 | <0.001 |
| 10(6) | Synergist+4H peroxide cyclophosphamide | 86 | <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 synergist (epothilone d) and cancer therapy drug (cyclophosphamide, melphalan, ifosfamide, 4H-peroxide cyclophosphamide), can show significant potentiation when use in conjunction.
The tumor-inhibiting action of test 11, synergist and cancer therapy drug (slow releasing injection)
Measure the tumor-inhibiting action of synergist and cancer therapy drug (slow releasing injection) by test 7 described methods, the result shows that synergist (epothilone d) can significantly strengthen triptorelin, goserelin, leuprorelin, Anastrozole, idoxifene, Miproxifene, tamoxifen, 4-monohydroxy tamoxifen, not former times sweet smell, raloxifene, ICI-M 164384, anticancer steroid alkene phenol, the 4-trans-Hydroxytamoxifen, Drogenil, aminoglutethimide, (.+-.)-Pyridoglutethimide, megestrol, medroxyprogesterone, clomifene, toremifene, letrozole, the tumor killing effect of cancer therapy drug such as exemestane or bicalutamide, potentiation is in 50-88% (P＜0.01).
The tumor-inhibiting action of test 12, epothilone B and cancer therapy drug (sustained-release implant)
By the tumor-inhibiting action of test 8 described methods mensuration synergists and cancer therapy drug (sustained-release implant), its inhibition rate of tumor growth sees Table 7.
Table 7
| Test group (n) | Suffered treatment | Tumor control rate (%) | The P value |
| 1(6) | Contrast | - | |
| 2(6) | Synergist | 50 | <0.05 |
| 3(6) | Cyclophosphamide | 32 | <0.01 |
| 4(6) | Melphalan | 36 | <0.01 |
| 5(6) | Ifosfamide | 40 | <0.01 |
| 6(6) | Norcantharidin | 40 | <0.01 |
| 7(6) | Synergist+cyclophosphamide | 74 | <0.01 |
| 8(6) | Synergist+melphalan | 86 | <0.001 |
| 9(6) | Synergist+ifosfamide | 80 | <0.001 |
| 10(6) | Synergist+norcantharidin | 82 | <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 synergist (epothilone B) and cancer therapy drug (cyclophosphamide, melphalan, ifosfamide), can show significant potentiation when use in conjunction.
In a word, growth all had the obvious suppression effect to kinds of tumor cells when used synergist and various cancer therapy drug were used separately, can show significant potentiation when use in conjunction.Therefore, effective ingredient of the present invention is the combination of synergist and/or any one cancer therapy drug.The medicine that contains above effective ingredient can be made into sustained-release micro-spheres, and then make slow releasing injection and implant, serve as preferred wherein with the suspensoid injectio that is combined to form with the special solvent that contains suspending agent, the viscosity of the solvent of suspensoid injectio is 10cp-650cp (20 ℃-30 ℃ time), preferred 20cp-650cp (20 ℃-30 ℃ time), most preferably 60cp-650cp (20 ℃-30 ℃ time).
Slow releasing injection or sustained-release implant also can be further specified by following embodiment.Just the invention will be further described for the foregoing description and following examples, is not its content and use are imposed any restrictions.
(4) specific embodiment
Embodiment 1.
80mg polifeprosan (to carboxy phenyl propane (p-CPP): decanedioic acid (SA) is 20:80) copolymer is put into container, add the 100ml dichloromethane, behind the dissolving mixing, add 10mg epothilone d and leuprorelin, shake up the back contains 10% epothilone d and 10% leuprorelin with spray drying method for preparation injectable microsphere again.Then microsphere is suspended in the normal saline that contains 15% mannitol, makes corresponding suspension type slow releasing injection, viscosity is 20cp-300cp (20 ℃-30 ℃ time).The drug release time of this slow releasing injection in external normal saline is 24-30 days, is about 2532 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 p-CPP:SA is 50:50 in the polifeprosan, and contained anticancer effective component and percentage by weight thereof are:
The combination of the cyclophosphamide of (1) 5% epothilone B or isoesperamicin D and 15%, melphalan, Chlorambucil, ifosfamide, 4H peroxide cyclophosphamide, norcantharidin, meturedepa, urethimine or Ah bundle's TEPA;
The combination of (2) 15% epothilone d or BMS-247550 and 5% cyclophosphamide, melphalan, Chlorambucil, ifosfamide, 4H peroxide cyclophosphamide, norcantharidin, meturedepa, urethimine or Ah bundle's TEPA; Or
The combination of the cyclophosphamide of (3) 10% Azaepothilone B, furan epothilone d or BMS-310705 and 5%, melphalan, Chlorambucil, ifosfamide, 4H-peroxide cyclophosphamide, norcantharidin, meturedepa, urethimine or Ah bundle's TEPA.The viscosity of made slow releasing injection is 80cp-600cp (20 ℃-30 ℃ time).
Embodiment 3.
With 70mg molecular weight peak value is that (PLGA 75:25) puts into container, adds 100 milliliters of dichloromethane, behind the dissolving mixing, adds 15mg epothilone B and 15mg melphalan, shakes up the dry organic solvent of removing of final vacuum again for the polylactic acid of 20000-40000.Dried pastille solid composite freezing and pulverizing is made the micropowder that contains 15% epothilone B and 15% melphalan, be suspended in then in the normal saline that contains 1.5% sodium carboxymethyl cellulose, make corresponding suspension type slow releasing injection, viscosity is 200cp-380cp (20 ℃-30 ℃ time).The drug release time of this slow releasing injection in external normal saline is 28-35 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 used adjuvant for the molecular weight peak value be 40000-60000 polylactic acid (PLGA, 50:50), contained anticancer effective component and percentage by weight thereof are:
The combination of (1) 10% epothilone B or epothilone d and 10% cyclophosphamide, melphalan, Chlorambucil, ifosfamide, 4H peroxide cyclophosphamide, norcantharidin, meturedepa, urethimine or Ah bundle's TEPA;
The combination of (2) 15% epothilone d and 5% melphalan or norcantharidin, meturedepa, urethimine or Ah bundle's TEPA; Or
The combination of (3) 25% Azaepothilone B and 5% melphalan, Chlorambucil, ifosfamide, 4H-peroxide cyclophosphamide or norcantharidin.
The viscosity of made slow releasing injection is 100cp-690cp (20 ℃-30 ℃ time).
Embodiment 5.
With 70mg molecular weight peak value is that the polylactic acid (PLA) of 20000-40000 is put into container, after adding 100 milliliters of dichloromethane dissolving mixings, add 20 milligrams of Azaepothilone Bs and 10 milligrams of tamoxifens, shake up the back contains 20% Azaepothilone B and 10% tamoxifen with spray drying method for preparation injectable microsphere again.Then microsphere is suspended in the injection that contains the 5-15% sorbitol, makes corresponding suspension type slow releasing injection, viscosity is 100cp-160cp (25 ℃-30 ℃ time).The drug release time of this slow releasing injection in external normal saline is 10-15 days, is about 20-30 days at the subcutaneous drug release time of mice.
Embodiment 6.
The method step that is processed into slow releasing injection is identical with embodiment 5, but different is that used adjuvant is the polylactic acid (PLA) of 10000-20000 for the molecular weight peak value, and contained anticancer effective component and percentage by weight thereof are: the combination of 20% epothilone d and 10% triptorelin, goserelin, leuprorelin, tamoxifen, toremifene, letrozole, Anastrozole, exemestane or bicalutamide; The viscosity of slow releasing injection is 100cp-440cp (20 ℃-30 ℃ time).
Embodiment 7.
With 40mg molecular weight peak value is that polylactic acid (PLA) and the 30mg polifeprosan (20:80) of 20000-40000 put into container, add 100 milliliters of dichloromethane, behind the dissolving mixing, add 20mg furan epothilone d and 10mg letrozole, shake up the back contains 20% furan epothilone d and 10% letrozole with spray drying method for preparation injectable microsphere again.Microsphere is suspended in the normal saline that contains 1.5% sodium carboxymethyl cellulose and 0.5% Tween 80 then, makes corresponding suspension type slow releasing injection, viscosity is 180cp-260cp (25 ℃-30 ℃ time).The drug release time of this slow releasing injection in external normal saline is 20-25 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 polylactic acid (PLA) and 40mg polifeprosan (50:50) the molecular weight peak value of different is used adjuvant is 30mg molecular weight peak value is 10000-20000 are the polylactic acid (PLA) of 40000-60000, and contained anticancer effective component and percentage by weight thereof are: the combination of 15% the furan epothilone d or triptorelin, goserelin, leuprorelin, Anastrozole, idoxifene, tamoxifen, letrozole, Anastrozole, exemestane or the bicalutamide of BMS-310705 and 15%; Viscosity is 200cp-560cp (25 ℃-30 ℃ time).
Embodiment 9
With 40mg molecular weight peak value is the polylactic acid (PLGA of 20000-40000,75:25) put into container with 30mg polifeprosan (20:80), add 100 milliliters of dichloromethane, behind the dissolving mixing, add 20mg BMS-310705 and 10mg O6-butyl guanine, shake up the back contains 20% BMS-310705 and 10% O6-butyl guanine 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, viscosity is 100cp-160cp (25 ℃-30 ℃ time).The drug release time of this slow releasing injection in external normal saline is 30-35 days, is about 30-38 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 polifeprosan is 50:50, PLGA is 75:25, MW is 40000-55000, contained anticancer effective component and percentage by weight thereof are: 20% epothilone d and 10% benzyl guanine, O6-benzyl guanine, O6-butyl guanine, O6-methyl guanine, O6-alkyl guanine, O6-benzyl uric acid or the xanthic combination of O6-benzyl, viscosity are 560cp-640cp (25 ℃-30 ℃ time).
Embodiment 11
The method step that is processed into slow releasing injection is identical with embodiment 7 and 9, but different contained anticancer effective component and percentage by weights thereof be: the combination of the cyclophosphamide of 15% epothilone B, epothilone d, isoesperamicin D, BMS-247550, Azaepothilone B, furan epothilone d or BMS-310705 and 15%, melphalan, Chlorambucil, ifosfamide, 4H peroxide cyclophosphamide, norcantharidin, meturedepa, urethimine or Ah bundle's TEPA, viscosity are 260cp-680cp (25 ℃ 30 ℃ time).
Embodiment 12
The method step that is processed into sustained-release implant is identical with embodiment 7 or 9, but different is that used slow-release auxiliary material is:
(1) bis-fatty acid of 60-95% and decanedioic acid copolymer p [FAD-SA)];
(2) poly-(erucic acid dimer-decanedioic acid) [P (EAD-SA)] of 75-95%; Or
(3) poly-(fumaric acid-decanedioic acid) [P (FA-SA)] of 70-95%.
Embodiment 13
With 40mg molecular weight peak value is the polylactic acid (PLGA of 25000-45000,50:50) put into container with 40mg P (FAD-SA), add 100 milliliters of dichloromethane, behind the dissolving mixing, add 10mg epothilone d and 10mg melphalan, shake up the back contains 10% epothilone d and 10% melphalan 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 18-25 days, is about 25-30 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 13, but different is used adjuvant and contained anticancer effective component and percentage by weight are:
The combination of (1) 80% P (EAD-SA) and 10% epothilone d and 10% cyclophosphamide, melphalan, Chlorambucil, ifosfamide, 4H-peroxide cyclophosphamide, norcantharidin, benzene assistant TEPA, Phopurine, meturedepa, urethimine or Ah bundle's TEPA; Or
(2) 70% P (FA-SA) and 10% epothilone d and 20% benzyl guanine, O6-benzyl guanine, O6-butyl guanine, O6-methyl guanine, O6-alkyl guanine, 2-amino-6-oxypurine, O6-benzyl uric acid or the combination of O6-benzyl xanthine; Or
The combination of triptorelin, goserelin, leuprorelin, Anastrozole, idoxifene, tamoxifen, letrozole, Anastrozole, exemestane or the bicalutamide of (3) 70% P (FA-SA) and 20% epothilone d and 1-40%.
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 (PLA), the molecular weight peak value is 10000-30000,300000-60000,60000-100000 or 100000-150000;
B) copolymer of polyglycolic acid and hydroxyacetic acid (PLGA), wherein, the ratio of polyglycolic acid and hydroxyacetic acid is 40-90:25:75, the molecular weight peak value is 10000-30000,300000-60000,60000-100000 or 100000-150000;
C) combination of polifeprosan and PLA or PLGA;
D) polifeprosan, to carboxy phenyl propane (p-CPP): decanedioic acid (SA) is 10:90,20:80,30:70,40:60,50:50 or 60:40;
E) bis-fatty acid and decanedioic acid copolymer (PFAD-SA);
F) poly-(erucic acid dimer-decanedioic acid) [P (EAD-SA)];
G) poly-(fumaric acid-decanedioic acid) [P (FA-SA)];
H) xylitol, oligosaccharide, chrondroitin, chitin, chitosan, chitosan, hyaluronic acid, collagen protein, gelatin or white tempera;
I) poly-dl-lactide, poly-dl-lactide/ethanol copolymer, monomethyl polyethylene glycol, monomethyl polyethylene glycol copolymer, polyethylene glycol, polyethylene glycol copolymer, end carboxyl polylactic acid or end carboxyl polylactic acid/ethanol copolymer.
Embodiment 16
The method step that is processed into slow releasing injection is identical with embodiment 1-10, 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 sustained-release implant is identical with embodiment 13, but different is used adjuvant and contained anticancer effective component and percentage by weight are:
The combination of (1) 80% P (EAD-SA) and 10% epothilone B and 10% cyclophosphamide, melphalan, Chlorambucil, ifosfamide, 4H-peroxide cyclophosphamide, norcantharidin, benzene assistant TEPA, Phopurine, meturedepa, urethimine or Ah bundle's TEPA; Or
(2) 70% P (FA-SA) and 10% epothilone B and 20% benzyl guanine, O6-benzyl guanine, O6-butyl guanine, O6-methyl guanine, O6-alkyl guanine, 2-amino-6-oxypurine, O6-benzyl uric acid or the combination of O6-benzyl xanthine; Or
The combination of triptorelin, goserelin, leuprorelin, Anastrozole, idoxifene, tamoxifen, letrozole, Anastrozole, exemestane or the bicalutamide of (3) 70% P (FA-SA) and 20% epothilone B and 1-40%.
The foregoing description has been done further description to technical method of the present invention.Be to illustrate for example rather than will limit scope of the present invention.In fact, except that shown in this paper and the of the present invention various changes described, to those skilled in the art all can be from description and chart apparent.Certainly these changes should be in the scope of appended claim.Therefore, to disclose some specific implementations of the present invention emphatically and its being equal to of making is changed or replaces all be in described design of appended claims and scope to the description that should be realized that the front.
Claims (5)
- The anticancer sustained-release agent of [claim 1] a kind of anticancer medicine and synergist is characterized in that this slow releasing agent is a 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 41-99.9%Suspending agent 0.0-30%More than be weight percentageWith(B) solvent is for common solvent or contain the special solvent of suspending agent;Wherein,Anticancer effective component is the combination of the synergist of the cancer therapy drug of effective anticancer and effective anticancer, and cancer therapy drug is a purine analogue; Synergist is selected from epothilone derivate;Described purine analogue is selected from the 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, one of 1-cyclopentenyl methyl guanine or O6-bromothen base guanine or its combination;Described epothilone derivate is selected from Epothilones, Epothilones A, epothilone B, Epothilone C (-)-Deoxyepothilone A, epothilone d, Epothilone E (-)-Epothilone E., Epothilone F (-)-Epothilone F., 4-demethyl-9-ketone-Epothilone C (-)-Deoxyepothilone A, 12,13-dihydro-13-oxygen Epothilone C (-)-Deoxyepothilone A, the amino epothilone B of 21-, the amino epothilone B of 26-, 21,26-diaminourea epothilone B, 9,10-dehydrogenation epothilone B, 10,11-hydrogen epothilone B, 26,27-halogen epothilone B, 9,10,11,14,21,26 epothilone Bs that replaced by hydroxyl respectively, 21,26-dihydroxy epothilone B, 21-hydroxyl-10,11 dehydrogenation epothilone Bs, 4-demethyl-9-ketone-epothilone B, 4 demethyls-9,10-two dehydrogenation epothilone Bs, 4-demethyl-10,11-two dehydrogenation epothilone Bs, 6-demethyl-10,11-two dehydrogenation epothilone Bs, the amino epothilone B of 21-, 21-hydroxyl epothilone B, 26-hydroxyl epothilone B, 26-fluorine epothilone B, the amino epothilone B of 26-, 12,13 cyclopropyl epothilone Bs, 12,13 cyclobutyl epothilone Bs, ixabepilone, Azaepothilone B, 26-three fluoro-(E) 9,10-dehydrogenation-12,13-Epothilone C B, 21 and 26 difference or the epothilone d that is replaced by amino simultaneously, 9 and 10 dehydrogenation epothilone ds, 10,11 dehydrogenation epothilone ds, 26,27 epothilone ds that replaced by halogen, 9,10,11,14,21,26 epothilone ds that replaced by hydroxyl respectively, 21,26-dihydroxy epothilone d, 21-hydroxyl-10,11 dehydrogenation epothilone ds, 4-demethyl-9-ketone-epothilone d, 4-demethyl-9,10-two dehydrogenation epothilone ds, 4-demethyl-10,11-two dehydrogenation epothilone ds, 6-demethyl-10,11-two dehydrogenation epothilone ds, 21-hydroxyl epothilone d, the amino epothilone d of 21-, 26-hydroxyl epothilone d, the amino epothilone d of 26-, 26-fluorine epothilone d, isoesperamicin, isoesperamicin D, 9,10 dehydrogenation epothilone ds, 10,11 dehydrogenation epothilone ds, the furan epothilone d, (E)-9,10-dehydrogenation-12,13-Epothilone C D, BMS-310705, the 6-ethyl, the 16-fluorine, 17-pyridine Epothilones, 11,12-dehydrogenation-12,13-dehydrogenation-13-Epothilone C D, 12,13-dehydrogenation-13-Epothilone C D, 9 oxygen base epothilone ds or 8-table-9-oxygen base epothilone d;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) combination of the copolymer of polifeprosan and polylactic acid or polyglycolic acid and hydroxyacetic acid;E) bis-fatty acid and decanedioic acid copolymer;F) poly-(erucic acid dimer-decanedioic acid) copolymer;G) poly-(fumaric acid-decanedioic acid) copolymer;H) xylitol, oligosaccharide, chrondroitin, chitin, chitosan, chitosan, hyaluronic acid, collagen protein, gelatin or white tempera;I) poly-dl-lactide, poly-dl-lactide/ethanol copolymer, monomethyl polyethylene glycol, monomethyl polyethylene glycol copolymer, polyethylene glycol, polyethylene glycol copolymer, end carboxyl polylactic acid or end carboxyl polylactic acid/ethanol copolymer;Suspending agent is selected from one of following or its combination:A) 0.5-3.0% sodium carboxymethyl cellulose;B) 5-15% mannitol;C) 5-15% sorbitol;D) 0.1-1.5% surfactant;E) 0.1-0.5% polysorbas20;F) iodine glycerol, simethicone, propylene glycol or carbomer;G) 0.5-5% sodium carboxymethyl cellulose+0.1-0.5% Tween 80;H) 5-20% mannitol+0.1-0.5% Tween 80;I) 0.5-5% sodium carboxymethyl cellulose+5-20% sorbitol+0.1-0.5% Tween 80;The viscosity of suspending agent is 100cp-3000cp (20 ℃-30 ℃ time).
- The anticancer sustained-release agent that [claim 2] is according to claim 1, the weight ratio that it is characterized in that synergist and cancer therapy drug are that 1-19:1 is to 1:1-19.
- The anticancer sustained-release agent that [claim 3] is according to claim 1 is characterized in that described anticancer sustained-release agent is a sustained-release implant, and the used slow-release auxiliary material of sustained-release implant is selected from one of following or its combination:A) polylactic acid;B) copolymer of polyglycolic acid and hydroxyacetic acid;C) polifeprosan;D) combination of the copolymer of polifeprosan and polylactic acid or polyglycolic acid and hydroxyacetic acid;E) bis-fatty acid and decanedioic acid copolymer;F) poly-(erucic acid dimer-decanedioic acid) copolymer;G) poly-(fumaric acid-decanedioic acid) copolymer;H) xylitol, oligosaccharide, chrondroitin, chitin, chitosan, hyaluronic acid, collagen protein, gelatin or white tempera;I) poly-dl-lactide, poly-dl-lactide/ethanol copolymer, monomethyl polyethylene glycol, monomethyl polyethylene glycol copolymer, polyethylene glycol, polyethylene glycol copolymer, end carboxyl polylactic acid or end carboxyl polylactic acid/ethanol copolymer;The weight ratio of synergist and cancer therapy drug is that 1-19:1 is to 1:1-19.
- The anticancer sustained-release agent that [claim 4] is according to claim 1 is characterized in that described slow releasing agent is used to prepare the medicine that treatment originates from cancer, sarcoma or the carcinosarcoma of people and animal 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 or rectum former or secondary.
- The anticancer sustained-release agent that [claim 5] is according to claim 1 is characterized in that the anticancer effective component of described slow releasing agent and percentage by weight thereof are preferably:The benzyl guanine of the Epothilones of 1-40%, Epothilones A, epothilone B, Epothilone C (-)-Deoxyepothilone A, epothilone d, isoesperamicin D, Epothilone E (-)-Epothilone E., Epothilone F (-)-Epothilone F., BMS-247550, Azaepothilone B, furan epothilone d or BMS-310705 and 1-40%, O6-benzyl guanine, O6-butyl guanine, O6-methyl guanine, O6-alkyl guanine, 2-amino-6-oxypurine, O6-benzyl uric acid or the xanthic combination of O6-benzyl.
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| CNA2008103045155A CN101380308A (en) | 2006-12-12 | 2006-12-12 | Anticancer sustained-release preparation loaded with anti-cancer medicine and synergist thereof |
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| CNA2008103045155A CN101380308A (en) | 2006-12-12 | 2006-12-12 | Anticancer sustained-release preparation loaded with anti-cancer medicine and synergist thereof |
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