CN1957913A - Composition of anti cancer medication prepared from carried platinum category compound and consubstantial hydrolytic agent - Google Patents
Composition of anti cancer medication prepared from carried platinum category compound and consubstantial hydrolytic agent Download PDFInfo
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Abstract
A slowly-release anticancer medicine in the form of injection or implant is disclosed. Said slowly-release injection is composed of a special solvent containing suspending aid and the slowly-release microballs consisting Pt compound, iterstitial hydrolyte and slowly-releasing auxiliary. Said Pt compound is chosen from cisplatin, carboplatin, etc. Said interstitial hydrolyte is chosen from collagenase, relaxin, etc. Said slowly-releasing auxiliary is chosen from polylactic acid, polyethanediol, etc.
Description
(1) technical field
The present invention relates to a kind of anticancer sustained-release agent that contains mesenchyme hydrolytic agent, belong to technical field of pharmaceuticals.Particularly, the invention provides a kind of slow releasing injection and sustained-release implant that contains mesenchyme hydrolytic agent.This anticancer sustained-release agent can suppress or destroy matter and tumor vessel between entity tumor effectively, and can suppress the new vessels of tumor, effectively reduce tension force, a matter pressure, a matter viscosity in the tumor, and then improve its interstitial fluid conductance, help medicine and enter entity tumor and the effective diffusion in tumor.
(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.1998 Oct 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).
The local placement of antitumor drug can overcome above defective preferably, not only can obviously improve the drug level of tumor by local, and can significantly reduce general toxic reaction.A large amount of internal and external tests have demonstrated the therapeutic effect to entity tumor, referring to " placing cisplatin adding system carmustine treatment rat brain tumor in the tumor " " surgery tumor 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 et al., J Surg Oncol.1997 Oct; 64:268-273).Also can be referring to Chinese patent (ZL00111093.4; ZL96115937.5; Application number 001111264,001111272) and U.S.'s patent of invention (patent No. 6,376,525B1; 5,651,986; 5,626,862).
Yet, entity tumor is made up of tumor cell and mesenchyma stroma of tumors, wherein the blood vessel in the mesenchyma stroma of tumors not only provides support and requisite nutrient substance for the growth of tumor cell, also influenced chemotherapeutics around tumor and 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, Cancer Res.2000,60 (9): 2497-503) in 2000.
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.
Moreover, the blood vessel in the mesenchyma stroma of tumors often causes the enhancing of tumor cell to the toleration of cancer therapy drug to conventional chemotherapy medicine and insensitive, consequently treatment failure.
(3) summary of the invention
The present invention is directed to the deficiencies in the prior art, a kind of new pharmaceutical composition is provided, contain mesenchyme hydrolytic agent and/or cancer therapy drug.More specifically, be the slow releasing agent of anti entity tumour, be mainly sustained-release implant and slow releasing injection.Topical application can suppress or destroy the blood vessel of tumor effectively and can suppress the new vessels of tumor; Decapacitation suppresses can also increase the sensitivity of tumor cell to cancer therapy drug outside the tumor growth; This controlled release formulation for anti entity tumour also effectively reduces tension force, a matter pressure, the matter viscosity in the tumor, and then improves its interstitial fluid conductance, helps medicine and enters entity tumor and the effective diffusion in tumor.
In addition, mesenchyme hydrolytic agent and/or cancer therapy drug are made 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, are reduced the toxicity of medicine to normal structure, can also greatly make things convenient for the medicine injection, reduce operation technique complication, reduce patient's expense.The cancer therapy drug decapacitation suppresses can also increase the sensitivity of tumor cell to cancer therapy drug outside the tumor growth.The above unexpected main contents of the present invention of finding to constitute.
Controlled release formulation for anti entity tumour of the present invention comprises anticancer effective component and pharmaceutic adjuvant, and anticancer effective component is selected from platinum-like compounds and mesenchyme hydrolytic agent.Mesenchyme hydrolytic agent is vasoinhibitor and/or proteolytic enzyme, vasoinhibitor is except that having the effect that suppresses growth of tumour cell, the blood vessel that can suppress or destroy tumor effectively also can suppress the formation of the new vessels of tumor, and then not only make tumor cell lose the required support of growth and the source of nutrient substance, share with proteolytic enzyme or use separately and also can obviously promote chemotherapeutics to enter tumor and around tumor and infiltration and diffusion in the tumor tissues; Proteolytic enzyme can effectively degrade blood vessel and compositions such as fibrin in the connective tissue and collagen protein in the mesenchyma stroma of tumors, effectively reduce tension force, a matter pressure, a matter viscosity in the tumor, and then improve its interstitial fluid conductance, help that medicine enters entity tumor and around the tumor and infiltration and diffusion in the tumor tissues.
The present invention finds, the anticancer medicine slow-release preparation containing that platinum-like compounds and mesenchyme hydrolytic agent are made (being mainly slow releasing injection and sustained-release implant) not only can greatly improve tumor by local drug level, 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.The cancer therapy drug decapacitation suppresses can also increase the sensitivity of tumor cell to cancer therapy drug outside the tumor growth.Proteolytic enzyme can effectively degrade blood vessel and compositions such as fibrin in the connective tissue and collagen protein in the mesenchyma stroma of tumors, effectively reduce tension force, a matter pressure, a matter viscosity in the tumor, and then improve its interstitial fluid conductance, help that medicine enters entity tumor and around the tumor and infiltration and diffusion in the tumor tissues.The above unexpected main contents of the present invention of finding to constitute.
Compound medicament composition of the present invention 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.
A kind of preferred form of the present invention is a slow releasing injection, is made up of sustained-release micro-spheres and solvent.Particularly, this slow-releasing anticarcinogen injection is grouped into by following one-tenth:
(A) sustained-release micro-spheres comprises:
Anticancer effective component 0.5-60%
Slow-release auxiliary material 40-99%
Suspending agent 0.0-30%
More than be weight percentage
With
(B) solvent is for common solvent or contain the special solvent of suspending agent.
Wherein,
Anticancer effective component be mesenchyme hydrolytic agent or and platinum-like compounds; Slow-release auxiliary material range of viscosities IV (dl/g) is 0.1～0.8, be selected from poly-dl-lactide (D, L-PLA), poly-dl-lactide/ethanol copolymer (D, L-PLGA), monomethyl polyethylene glycol (MPEG-PLA), monomethyl polyethylene glycol copolymer (MPEG-PLGA), polyethylene glycol (PLA-PEG-PLA), polyethylene glycol copolymer (PLGA-PEG-PLGA), end carboxyl polylactic acid (PLA-COOH), end carboxyl polylactic acid/ethanol copolymer (PLGA-COOH), polifeprosan, bis-fatty acid and decanedioic acid copolymer (PFAD-SA), poly-(erucic acid dimer-decanedioic acid) [P (EAD-SA)], poly-(fumaric acid-decanedioic acid) [P (FA-SA)], ethylene vinyl acetate copolymer (EVAc), polylactic acid (PLA), the copolymer of polyglycolic acid and hydroxyacetic acid (PLGA), poly-to dioxy cyclohexanone (PDO), PTMC (PTMC), xylitol, oligosaccharide, chrondroitin, chitin, hyaluronic acid, collagen protein, gelatin, one of albumin glue or its combination; Suspending agent is selected from one of sodium carboxymethyl cellulose, (iodine) glycerol, simethicone, propylene glycol, carbomer, mannitol, sorbitol, surfactant, soil temperature 20, soil temperature 40 and soil temperature 80 or its combination.
Conventional route administrations such as main oral administration of platinum family cancer therapy drug or intravenous injection, administering mode of the present invention is the local sustained release administration, obviously reduces the toxic action of its whole body in the therapeutic effect that significantly strengthens medicine.The platinum-like compounds of having reported of using through the slow release approach has cisplatin and carboplatin etc., yet existing several thousand new platinum family chemical compounds are entered the screening back to be found, have only 28 chemical compounds to enter clinical research, there are 4 chemical compounds to get the Green Light and come into the market, also have 2～3 chemical compounds will obtain to produce certification.Therefore, in having the platinum-like compounds of active anticancer, be not all slow release effects that all can in slow-release auxiliary material of the present invention, reach effective release yet.Pharmaceutic adjuvant have hundreds of more than, pharmaceutic adjuvant with slow releasing function, it is not apparent particularly selected platinum-like compounds among the present invention slowly being discharged in the regular hour in human body or animal body, but specific slow-release auxiliary material need could be determined through a large amount of creative works with the selection of slow releasing pharmaceutical combination.The data of release characteristics need could obtain through a large amount of creationary experiments in inside and outside in the related data, particularly animal body, are not just can determine to have unobviousness through limited experiment.
Mesenchyme hydrolytic agent is vasoinhibitor and/or proteolytic enzyme, vasoinhibitor is except that having the effect that suppresses growth of tumour cell, the blood vessel that can suppress or destroy tumor effectively also can suppress the formation of the new vessels of tumor, and then not only make tumor cell lose the required support of growth and the source of nutrient substance, share with proteolytic enzyme or use separately and also can obviously promote chemotherapeutics to enter tumor and around tumor and infiltration and diffusion in the tumor tissues; Proteolytic enzyme can effectively degrade blood vessel and compositions such as fibrin in the connective tissue and collagen protein in the mesenchyma stroma of tumors, effectively reduce tension force, a matter pressure, a matter viscosity in the tumor, and then improve its interstitial fluid conductance, help that medicine enters entity tumor and around the tumor and infiltration and diffusion in the tumor tissues.
Platinum-like compounds is selected from one of following or combination: cisplatin (cisplatin, DDP), carboplatin (Carboplatin, carboplatin), ring platinum (Cycloplatin), platinum in heptan (sunplatinum), DNA-2114 (dacarbazine; Dacarbazine; NSC-45388; Dacarbazine), cis-Dichlorobis(cyclopentylamine)platinum, platinum blue, cis-Dichlorobis(cyclopropylamine)platinum, Ethylenediammineplatinum(II) malonate, CL 286558., enloplatin (Enloplatin), sulfatodiamino cyclohexane platinum (ring ethylenediamine platinic sulfate, Sulfatodiaminocy clohexane platinum, SHP), Spiroplatin (spiral shell sulphur platinum amine), dexormaplatin (Dexormaplatin), iproplatin (Iproplatin), lobaplatin (Lobaplatin, happy platinum), rice platinum (Miboplatin), pick up platinum (picoplatin), nedaplatin (Nedaplatin), ormaplatin (Ormaplatin), oxaliplatin (Oxaliplatin, Oxaloplatin), sebriplatin (Sebriplatin, briplatin), spiroplatin (Spiroplatin), platinum (sunpla) relaxes, bicycloplatin (bicycloplatin), according to platinum (eptalatin), picoplatin, citricplatin (citricplatin), ZD 0473 (picoplatin) or zeniplatin (Zeniplatin).
Above platinum-like compounds with cisplatin, carboplatin, ormaplatin, dexormaplatin, heptan platinum, lobaplatin, nedaplatin or oxaliplatin serve as preferred.
Above-mentioned platinum-like compounds shared ratio in compositions is decided because of concrete condition, can be 0.1%-50%, is good with 1%-30%, and 5%-20% is best.
Proteolytic enzyme is selected from elastoser, pancreatic elastase, metalloproteases, trypsin, chymase, pepsin, pronase, Bacillus polymyxa Neutral proteinase, bromelain, Chymotrypsin, clostripain, thermolysin, subtilisin, carase, papain, chymopapain, fibrinolysin, house thunder sulfo-peptidase, pancreatin, cathepsin-G, cysteine proteinase, thioesterase, amide transferase, the transesterification enzymatic activity, plasminogen activator, collagenase, the polymorphonuclear leukocyte serine protease, nuclease, lipase, esterase, streptokinase, glycosidase, hyaluronidase, neuraminidase, amylase, Cervilaxin, a kind of or its combination in interferon (gamma interferon) and the brinase.
Serve as preferred wherein with elastoser, trypsin, pepsin, pronase, Bacillus polymyxa Neutral proteinase, bromelain, Chymotrypsin, clostripain, fibrinolysin, cathepsin-G, plasminogen activator, collagenase, streptokinase, glycosidase, hyaluronidase, lysozyme, Cervilaxin, interferon (gamma interferon) and brinase.
Vasoinhibitor is selected from a kind of or its combination among gefitinib, Erlotinib, Lapatinib, votaranib, WAY-EKB 569, NSC 609974, thalidomide, LS-2616, angiostatin, Endostatin, blood vessel endothelium chalone, imatinib mesylate, Sugen 5416, BMS 354825, Avastin, Cl 1033, Sorafenib, Sutent, TLK286, ABX-EGF, Marimastat, SU5416, SU6668, Amebacilin, the TNP-470.
Above newborn neovascularization inhibitor also comprises their salt, as, but be not limited to sulfate, phosphate, hydrochlorate, Lactobionate, acetate, aspat, nitrate, citrate, purine or pyrimidine salt, succinate and maleate etc.
Above-mentioned neovascularization inhibitor shared ratio in slow releasing agent is decided because of concrete condition, can be 0.1%-50%, is good with 1%-40%, and 5%-30% is best.
Cancer therapy drug in medicament slow-release microsphere only is platinum-like compounds or mesenchyme hydrolytic agent, and the application of slow-releasing anticarcinogen injection and potentiation mode are:
(1) contain the slow releasing injection local injection of platinum-like compounds, mesenchyme hydrolytic agent is used through other approach;
(2) local injection contains the slow releasing injection of mesenchyme hydrolytic agent, and other approach are used platinum-like compounds;
(3) local injection contains the slow releasing injection and the slow releasing injection that contains mesenchyme hydrolytic agent of platinum-like compounds; Or
(4) local injection contains the slow releasing injection of platinum-like compounds and synergist.
The slow-releasing anticarcinogen injection of topical application also is used for the potentiation to radiotherapy or other therapies.Other approach refer to, but are not limited to tremulous pulse, vein, abdominal cavity, subcutaneous, intracavitary administration.
Mesenchyme hydrolytic agent shared ratio in compositions is decided because of concrete condition, can be 0.1%-60%, is good with 2%-40%, and 5%-30% is best.
The weight ratio of platinum-like compounds and mesenchyme hydrolytic agent is 1-9: 1 to 1: 1-9.With 1-2: 1 serves as preferred.
Anticancer effective component in the slow-releasing anticarcinogen injection microsphere of the present invention is preferably as follows, and all is weight percentage:
(1) elastoser of 2-40%, trypsin, pepsin, pronase, Bacillus polymyxa Neutral proteinase, bromelain, Chymotrypsin, clostripain, fibrinolysin, cathepsin-G, plasminogen activator, collagenase, streptokinase, glycosidase, hyaluronidase, lysozyme, Cervilaxin, gamma interferon, brinase, gefitinib, Erlotinib, Lapatinib, votaranib, WAY-EKB 569, NSC 609974, thalidomide, LS-2616, angiostatin, Endostatin, the blood vessel endothelium chalone, imatinib mesylate, Sugen 5416, BMS 354825, Avastin, Cl 1033, Sorafenib, Sutent, TLK286, ABX-EGF, Marimastat, SU5416, SU6668, Amebacilin or TNP-470; Or
(2) elastoser of 2-40%, trypsin, pepsin, pronase, Bacillus polymyxa Neutral proteinase, bromelain, Chymotrypsin, clostripain, fibrinolysin, cathepsin-G, plasminogen activator, collagenase, streptokinase, glycosidase, hyaluronidase, lysozyme, Cervilaxin, gamma interferon, brinase, gefitinib, Erlotinib, Lapatinib, votaranib, WAY-EKB 569, NSC 609974, thalidomide, LS-2616, angiostatin, Endostatin, the blood vessel endothelium chalone, imatinib mesylate, Sugen 5416, BMS 354825, Avastin, Cl 1033, Sorafenib, Sutent, TLK286, ABX-EGF, Marimastat, SU5416, SU6668, the cisplatin of Amebacilin or TNP-470 and 1-30%, carboplatin, ring platinum, heptan platinum, DNA-2114, cis-Dichlorobis(cyclopentylamine)platinum, platinum blue, cis-Dichlorobis(cyclopropylamine)platinum, Ethylenediammineplatinum(II) malonate, CL 286558., enloplatin, sulfatodiamino cyclohexane platinum, Spiroplatin, dexormaplatin, iproplatin, lobaplatin, rice platinum, pick up platinum, nedaplatin, ormaplatin, oxaliplatin, sebriplatin, spiroplatin, platinum relaxes, bicycloplatin, according to platinum, picoplatin, citricplatin, the combination of ZD 0473 or zeniplatin.
Slow-release auxiliary material is selected from poly-dl-lactide, poly-dl-lactide/ethanol copolymer, the monomethyl polyethylene glycol, monomethyl polyethylene glycol copolymer, polyethylene glycol, the polyethylene glycol copolymer, end carboxyl polylactic acid, end carboxyl polylactic acid/ethanol copolymer, polifeprosan, bis-fatty acid and decanedioic acid copolymer, poly-(erucic acid dimer-decanedioic acid), poly-(fumaric acid-decanedioic acid), ethylene vinyl acetate copolymer, polylactic acid, the copolymer of polyglycolic acid and hydroxyacetic acid, xylitol, oligosaccharide, chrondroitin, chitin, hyaluronic acid, collagen protein, one of gelatin and albumin glue or its combination.
Slow-release auxiliary material and percentage by weight thereof are most preferably as follows in the sustained-release micro-spheres of the present invention:
(1) PLA of 55-90%;
(2) PLGA of 50-90%;
(3) polifeprosan of 50-85%;
(4) bis-fatty acid of 55-90% and decanedioic acid copolymer;
(5) EVAc of 55-90%;
(6) xylitol of 40-95%, oligosaccharide, chrondroitin, chitin, hyaluronic acid, collagen protein, gelatin or white tempera; Or
(7) poly-dl-lactide of 40-95%, poly-dl-lactide/ethanol copolymer, monomethyl polyethylene glycol, monomethyl polyethylene glycol copolymer, polyethylene glycol, polyethylene glycol copolymer, end carboxyl polylactic acid or end carboxyl polylactic acid/ethanol copolymer.
In various high molecular polymers, with polylactic acid, decanedioic acid, the mixture or the copolymer that contain the macromolecule polymer of polylactic acid or certain herbaceous plants with big flowers diacid is first-selection, mixture and copolymer can be selected from, but be not limited to the mixture or the copolymer of the mixture of PLA, PLGA, glycolic and hydroxy carboxylic acid, certain herbaceous plants with big flowers diacid and fragrant polyanhydride or aliphatic polyanhydride.The blend ratio of glycolic and hydroxy carboxylic acid is 10/90-90/10 (weight), preferably 25/75-75/25 (weight).The method of blend is arbitrarily.Content when glycolic and hydroxy carboxylic acid copolymerization is respectively percentage by weight 10-90% and 90-10%.The representative of fragrance polyanhydride is polifeprosan [poly-(1,3-two (to the carboxyl phenoxy group) propane-decanedioic acid) (p (CPP-SA)), bis-fatty acid-decanedioic acid copolymer (PFAD-SA)], poly-(erucic acid dimer-decanedioic acid) [P (EAD-SA)] and poly-(fumaric acid-decanedioic acid) [P (FA-SA)] etc.Content during to carboxylic phenoxypropane (p-CPP) and decanedioic acid copolymerization is respectively percentage by weight 10-60% and 20-90%, and the blend weight ratio is 10-40: 50-90, preferably weight ratio 15-30: 65-85.
The molecular weight peak value of polylactic acid can be, but is not limited to, 5000-100, and 000, but with 20,000-60,000 is preferred, with 5,000-30,000 for most preferably; The molecular weight of polyglycolic acid can be, but is not limited to, 5000-100, and 000, but with 5,000-50,000 is preferred, with 10,000-30,000 for most preferably; Above polyhydroxy acid can singly select or multiselect.When singly selecting, serve as preferred with the copolymer (PLGA) of polylactic acid (PLA) or hydroxy carboxylic acid and glycolic, the molecular weight of copolymer can be, but is not limited to, 5000-100,000, but with 20,000-60,000 be preferably, with 30,000-50,000 for most preferably; When multiselect, compound polymer or the copolymer formed with macromolecule polymer or different macromolecule polymer serve as preferred, with the compound polymer that contains different molecular weight polylactic acid or decanedioic acid or copolymer for most preferably, as, but be not limited to, molecular weight is 1000 to 30000 polylactic acid with molecular weight is that 20000 to 50000 polylactic acid mixes, molecular weight is 10000 to 30000 polylactic acid with molecular weight is that 30000 to 80000 PLGA mixes, molecular weight is that 20000 to 30000 polylactic acid mixes with decanedioic acid, molecular weight is that 30000 to 80000 PLGA mixes with decanedioic acid.Used polylactic acid serves as preferred with Poly-L-lactic acid (L-PLA).Poly-L-lactic acid (L-PLA) range of viscosities IV (dl/g) is 0.2～0.8, and glass transition temperature range is 55～65 ℃, 175～185 ℃ of fusing points.
Except that above-mentioned adjuvant, also can select for use other materials to see the United States Patent (USP) (patent No. 4757128; 4857311; 4888176; 4789724) and in " pharmaceutic adjuvant complete works " (the 123rd page, Sichuan science tech publishing house published in 1993, Luo Mingsheng and Gao Tianhui chief editor) have a detailed description.In addition, Chinese patent (application number 96115937.5; 91109723.6; 9710703.3; 01803562.0) and U.S.'s patent of invention (patent No. 5,651,986) also enumerated some pharmaceutic adjuvant, comprise filler, solubilizing agent, absorption enhancer, film former, gellant, system (or causing) hole agent, excipient or blocker etc.
For regulating drug releasing rate or changing other characteristic of the present invention, can change the composition and the proportioning of monomer component or molecular weight, interpolation or the adjusting pharmaceutic adjuvant of polymer, add the water-soluble low-molecular chemical compound, as, but be not limited to various sugar or salt etc.Wherein sugar can be, but is not limited to, xylitol, oligosaccharide, (sulphuric acid) chrondroitin and chitin etc., and wherein salt can be, but is not limited to, potassium salt and sodium salt etc.
In the slow releasing injection, drug sustained release system can be made into microsphere, sub-micro ball, microemulsion, nanosphere, granule or spherical piller, makes the injection use then with after the injection solvent mixes.In various slow releasing injection, serve as preferred with the suspension type slow releasing injection, the suspension type slow releasing injection is the preparation that the drug sustained release system that will contain anticancer component is suspended in gained in the injection, used adjuvant is a kind of or its combination in the above-mentioned slow-release auxiliary material, and used solvent is common solvent or the special solvent that contains suspending agent.Common solvent is, but is not limited to the buffer that distilled water, water for injection, physiology are prepared towards liquid, dehydrated alcohol or various salt.The purpose of suspending agent is the pastille microsphere that effectively suspends, thereby is beneficial to the usefulness of injection.
Suspending agent is selected from one of sodium carboxymethyl cellulose, (iodine) glycerol, simethicone, propylene glycol, carbomer, mannitol, sorbitol, surfactant, soil temperature 20, soil temperature 40 and soil temperature 80 or its combination.
The content of suspending agent in common solvent is decided because of its characteristic, can be 0.1-30% and decides because of concrete condition.Consisting of of preferred suspending agent:
A) 0.5-5% sodium carboxymethyl cellulose+0.1-0.5% soil temperature 80; Or
B) 5-20% mannitol+0.1-0.5% soil temperature 80; Or.
C) 0.5-5% sodium carboxymethyl cellulose+5-20% sorbitol+0.1-0.5% soil temperature 80.
The kind of solvent is then depended in the preparation of solvent, and common solvent has commercially available, also can make by oneself, and as distilled water, water for injection, physiology buffer towards liquid, dehydrated alcohol or the preparation of various salt, but must be in strict accordance with related standards.Special solvent need be considered the kind of suspending agent and the medicine that composition, solvent suspended, composition, character and the requirement thereof of sustained-release micro-spheres (or microcapsule) and the preparation method of injection, as sodium carboxymethyl cellulose (1.5%)+mannitol and/or sorbitol (15%) and/or soil temperature 80 (0.1%) are dissolved in the normal saline corresponding solvent, viscosity is at 10cp-650cp (20 ℃-30 ℃ time).
The present invention finds to influence medicine and/or sustained-release micro-spheres suspends and/or the key factor of injection is the viscosity of solvent, and viscosity is big more, and suspension effect is good more, and syringeability is strong more.This unexpected one of main index characteristic of the present invention of finding to have constituted.The viscosity of solvent depends on the viscosity of suspending agent, and the viscosity of suspending agent is 100cp-3000cp (20 ℃-30 ℃ time), preferred 1000cp-3000cp (20 ℃-30 ℃ time), most preferably 1500cp-3000cp (20 ℃-30 ℃ time).According to the viscosity of the prepared solvent of this condition is 10cp-650cp (20 ℃-30 ℃ time), preferred 20cp-650cp (20 ℃-30 ℃ time), most preferably 60cp-650cp (20 ℃-30 ℃ time).
The preparation of injection has several different methods, and a kind of is that the sustained-release microparticle (A) of suspending agent for " 0 " directly mixed in special solvent, obtains corresponding sustained-release microparticle injection; Another kind is that suspending agent is not mixed in special solvent or common solvent for the sustained-release microparticle (A) of " 0 ", obtains corresponding sustained-release microparticle injection; Another is that sustained-release microparticle (A) is mixed in common solvent, adds the suspending agent mixing then, obtains corresponding sustained-release microparticle injection.Except, also can earlier sustained-release microparticle (A) be mixed and in special solvent, make corresponding suspension, with the moisture in ways such as the vacuum drying removal suspension, special solvent of reuse or common solvent suspendible obtain corresponding sustained-release microparticle injection afterwards then.Above method just is illustrative rather than definitive thereof the present invention.It should be noted that suspended drug or sustained-release micro-spheres (or microcapsule) concentration in injection decide because of specifically needing, can be, but be not limited to, 10-400mg/ml, but be preferably with 30-300mg/ml, with 50-200mg/ml most preferably.The viscosity of injection is 50cp-1000cp (20 ℃-30 ℃ time), preferred 100cp-1000cp (20 ℃-30 ℃ time), most preferably 200cp-650cp (20 ℃-30 ℃ time).So viscosity is applicable to 18-22 injection needle and special bigger (to 3 millimeters) injection needle of internal diameter.
The preparation method of slow releasing injection is arbitrarily, available some kinds of methods preparation: as, but be not limited to, mixing method, fusion method, dissolution method, spray drying method for preparation microsphere, dissolution method are made micropowder, liposome bag medicine method and emulsion process etc. in conjunction with freezing (drying) comminuting method.Serve as preferred wherein with dissolution method (being the solvent volatility process), seasoning, spray drying method and emulsion process.Microsphere then can be used for preparing above-mentioned various slow releasing injection, and its method is arbitrarily.The particle size range of used microsphere can be between 5-400um, serving as preferred between the 10-300um, with between the 20-200um for most preferably.
Microsphere also can be used for preparing other slow releasing injection, as gel injection, block copolymer micelle injection.Wherein, block copolymer micelle is formed in aqueous solution by hydrophobic-hydrophilic block copolymers, has spherical inner core-shell mechanism, and hydrophobic block forms kernel, and hydrophilic block forms shell.The carrier micelle injection enters the purpose that reaches control drug release or targeted therapy in the body.Used pharmaceutical carrier is above-mentioned any one or its combination.Wherein preferred molecular weight is the hydrophilic block of the Polyethylene Glycol (PEG) of 1000-15000 as the micelle copolymer, and preferred biological degradation polyalcohol (as PLA, polylactide, polycaprolactone and copolymer thereof (molecular weight 1500-25000)) is as the hydrophobic block of micelle copolymer.The particle size range of block copolymer micelle can be between 10-300um, between the 20-200um serving as preferred.Gel injection system is dissolved in some amphipathic solvent with biological degradation polyalcohol (as PLA, PLGA or DL-LA and epsilon-caprolactone copolymer), adds medicine miscible with it (or suspendible) back again and forms flowability gel preferably, can be through tumor week or intratumor injection.In case inject, amphipathic solvent diffuses to body fluid very soon, the moisture in the body fluid then infiltrates gel, makes polymer cure, slowly discharges medicine.
Sustained-release micro-spheres also can be used for preparing sustained-release implant, used pharmaceutic adjuvant can be any or multiple material in the above-mentioned pharmaceutic adjuvant, but with the high molecular weight water soluble polymer is main separation, in various high molecular polymers, with polylactic acid, certain herbaceous plants with big flowers diacid, the mixture or the copolymer that contain the macromolecule polymer of polylactic acid or certain herbaceous plants with big flowers diacid is first-selection, mixture and copolymer can be selected from, but be not limited to the mixture or the copolymer of the mixture of PLA, PLGA, PLA and PLGA, certain herbaceous plants with big flowers diacid and fragrant polyanhydride or aliphatic polyanhydride.Polylactic acid (PLA) is 10/90-90/10 (weight) with the blend ratio of polyglycolic acid, preferably 25/75-75/25 (weight).The method of blend is arbitrarily.Content when glycolic and lactic acid copolymerization is respectively percentage by weight 10-90% and 90-10%.The representative of fragrance polyanhydride is to carboxy phenyl propane (p-CPP), content during to carboxy phenyl propane (p-CPP) and the copolymerization of certain herbaceous plants with big flowers diacid is respectively percentage by weight 10-60% and 20-90%, the blend weight ratio is 10-40: 50-90, preferably weight ratio 15-30: 65-85.
Another form of anticancer medicine slow-release preparation containing of the present invention is that anticancer medicine slow-release preparation containing is a sustained-release implant.The effective ingredient of anticancer implant can be packaged in the whole pharmaceutic adjuvant equably, also can be packaged in carrier holder center or its surface; Can effective ingredient be discharged by direct diffusion and/or the mode of degrading through polymer.
The characteristics of sustained-release implant are that used slow-release auxiliary material removes the high molecular polymerization beyond the region of objective existence, also contain above-mentioned any one or multiple other adjuvant.The pharmaceutic adjuvant that adds is referred to as additive.Additive can be divided into filler, porogen, excipient, dispersant, isotonic agent, preservative agent, blocker, solubilizing agent, absorption enhancer, film former, gellant etc. according to its function.
The Main Ingredients and Appearance of sustained-release implant can be made into multiple dosage form.As, but be not limited to capsule, slow releasing agent, implant, slow releasing agent implant etc.; Be multiple shape, as, but be not limited to granule, pill, tablet, powder, sphere, bulk, needle-like, bar-shaped, column and membranaceous.In various dosage forms, serve as preferred slowly to discharge implant in the body.The volume size depends on factors such as the position, size of focus.Can be the bar-shaped of 0.1-5mm (slightly) * 1-10mm (length), also can be other shapes such as lamellar.
The most preferred dosage form of sustained-release implant is that the slow releasing agent that biocompatibility, degradable absorb is implanted, and can make different shape and various dosage form because of the clinical needs of difference.The packing method of its Main Ingredients and Appearance and step in United States Patent (USP) (US5651986) have a detailed description, comprise the some kinds of methods that prepare slow releasing preparation: as, but be not limited to, (i) carrier holder powder and medicament mixed be pressed into implant then, promptly so-called mixing method; (ii) carrier holder fusing, mix solid cooled then, promptly so-called fusion method mutually with medicine to be packaged; (iii) the carrier holder is dissolved in the solvent, medicine dissolution to be packaged or be scattered in the polymer solution, evaporating solvent then, drying, promptly so-called dissolution method; (iv) spray drying method; And (v) freeze-drying etc.
Anticancer effective component and percentage by weight in the sustained-release implant are preferably as follows:
(1) elastoser of 2-40%, trypsin, pepsin, pronase, Bacillus polymyxa Neutral proteinase, bromelain, Chymotrypsin, clostripain, fibrinolysin, cathepsin-G, plasminogen activator, collagenase, streptokinase, glycosidase, hyaluronidase, lysozyme, Cervilaxin, gamma interferon, brinase, gefitinib, Erlotinib, Lapatinib, votaranib, WAY-EKB 569, NSC 609974, thalidomide, LS-2616, angiostatin, Endostatin, the blood vessel endothelium chalone, imatinib mesylate, Sugen 5416, BMS 354825, Avastin, Cl 1033, Sorafenib, Sutent, TLK286, ABX-EGF, Marimastat, SU5416, SU6668, Amebacilin or TNP-470; Or
(2) elastoser of 2-40%, trypsin, pepsin, pronase, Bacillus polymyxa Neutral proteinase, bromelain, Chymotrypsin, clostripain, fibrinolysin, cathepsin-G, plasminogen activator, collagenase, streptokinase, glycosidase, hyaluronidase, lysozyme, Cervilaxin, gamma interferon, brinase, gefitinib, Erlotinib, Lapatinib, votaranib, WAY-EKB 569, NSC 609974, thalidomide, LS-2616, angiostatin, Endostatin, the blood vessel endothelium chalone, imatinib mesylate, Sugen 5416, BMS 354825, Avastin, Cl 1033, Sorafenib, Sutent, TLK286, ABX-EGF, Marimastat, SU5416, SU6668, the cisplatin of Amebacilin or TNP-470 and 1-30%, carboplatin, ring platinum, heptan platinum, DNA-2114, cis-Dichlorobis(cyclopentylamine)platinum, platinum blue, cis-Dichlorobis(cyclopropylamine)platinum, Ethylenediammineplatinum(II) malonate, CL 286558., enloplatin, sulfatodiamino cyclohexane platinum, Spiroplatin, dexormaplatin, iproplatin, lobaplatin, rice platinum, pick up platinum, nedaplatin, ormaplatin, oxaliplatin, sebriplatin, spiroplatin, platinum relaxes, bicycloplatin, according to platinum, picoplatin, citricplatin, the combination of ZD 0473 or zeniplatin.
Slow-release auxiliary material and percentage by weight thereof are most preferably as follows in the sustained-release implant of the present invention:
(1) PLA of 55-90%;
(2) PLGA of 50-90%;
(3) polifeprosan of 50-85%;
(4) bis-fatty acid of 55-90% and decanedioic acid copolymer;
(5) EVAc of 55-90%;
(6) xylitol of 40-95%, oligosaccharide, chrondroitin, chitin, hyaluronic acid, collagen protein, gelatin or albumin glue; Or
(7) poly-dl-lactide of 40-95%, poly-dl-lactide/ethanol copolymer, monomethyl polyethylene glycol, monomethyl polyethylene glycol copolymer, polyethylene glycol, polyethylene glycol copolymer, end carboxyl polylactic acid or end carboxyl polylactic acid/ethanol copolymer.
When the cancer therapy drug in the medicament slow-release microsphere only is platinum-like compounds or its synergist, the application of anti-cancer sustained-released implantation agent and the same slow releasing injection of potentiation mode.
Route of administration depends on multiple factor, for obtain valid density in former or position, metastatic tumour place, medicine can give through number of ways, as in subcutaneous, intracavity (in abdominal cavity, thoracic cavity and canalis spinalis), the tumor, in all injections of tumor or placement, selective arterial injection, the lymph node and injection in the bone marrow.With in selective arterial injection, intracavity, the tumor, tumor week injection or be placed as preferred.
The present invention can be used to prepare the pharmaceutical preparation of the various tumors for the treatment of people and animal, be mainly slow releasing injection or sustained-release implant, the indication tumor comprises former or cancer or sarcoma or the carcinosarcoma that shifts that originates from brain, central nervous system, kidney, liver, gallbladder, incidence, oral cavity, thyroid, skin, mucosa, body of gland, blood vessel, osseous tissue, lymph node, lungs, esophagus, stomach, mammary gland, pancreas, eyes, nasopharynx part, uterus, ovary, endometrium, cervix uteri, prostate, bladder, colon, rectum.
The clinical practice dosage of effective ingredient depends on patient's concrete condition, can be from 0.1 to 3000mg/kg body weight, and 0.5 to 2000mg/kg is preferred, 0.8 to 1000mg/kg for there being most choosing.
Also can add other medicinal ingredient in slow releasing injection that the present invention is made or the sustained-release implant, as, but be not limited to antibiotics, antalgica, anticoagulant medicine, hemorrhage etc.
By following test and embodiment technical method of the present invention is further described:
The local drug concentration that test 1, different modes are used behind the platinum-like compounds (according to platinum) 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 5mg/kg according to platinum.Measure medicament contg (%) in the different time tumor, the result shows, according to the local drug concentration significant difference of platinum after different modes is used, topical can obviously improve and effectively keep the active drug concentration at position, tumor place, and is wherein best with the effect of placing sustained-release implant and intratumor injection slow releasing injection in the tumor.Yet, intratumor injection slow releasing injection operation most convenient, easy.This discovery constitutes key character of the present invention.Following relevant inhibition test has further confirmed this point.
The interior tumor-inhibiting action of body that test 2, different modes are used behind the platinum-like compounds (bicycloplatin) compares
With the rat is subjects, with 2 * 10
5Individual oophoroma 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 bicycloplatin.The treatment back was measured gross tumor volume size, relatively therapeutic effect on the 10th day.The result shows, the tumor-inhibiting action significant difference of bicycloplatin after different modes is used, topical can obviously improve and effectively keep the active drug concentration at position, tumor place, and is wherein best with the effect of placing sustained-release implant and intratumor injection slow releasing injection in the tumor.Yet, intratumor injection slow releasing injection operation most convenient, easy.Good effect not only, toxic and side effects is also little.
Test 3, contain tumor-inhibiting action in the body of platinum-like compounds and mesenchyme hydrolytic agent (slow releasing injection)
With the rat is subjects, with 2 * 10
5Individual pancreatic tumor cell subcutaneous injection is in its hypochondrium, treats that tumor growth after 14 days is divided into it following 10 groups (seeing Table 1).First group is contrast, and the 2nd to 10 group is the treatment group, and medicine is all through intratumor injection.The dosage of mesenchyme hydrolytic agent-vasoinhibitor is 1.5mg/kg, and cancer therapy drug-platinum-like compounds is 7.5mg/kg.The treatment back was measured gross tumor volume size, relatively therapeutic effect (seeing Table 1) on the 21st day.
Table 1
| Test group (n) | Suffered treatment | Gross tumor volume (cm 3) | The P value |
| 1(6) | Contrast | 60±10 | |
| 2(6) | Mesenchyme hydrolytic agent | 50±5.0 | ＜0.05 |
| 3(6) | Cisplatin | 52±2.0 | ＜0.01 |
| 4(6) | Carboplatin | 48±2.4 | ＜0.01 |
| 5(6) | Heptan platinum | 46±5.0 | ＜0.01 |
| 6(6) | DNA-2114 | 48±3.0 | ＜0.01 |
| 7(6) | Mesenchyme hydrolytic agent+cisplatin | 26±2.2 | ＜0.001 |
| 8(6) | Mesenchyme hydrolytic agent+carboplatin | 32±3.6 | ＜0.001 |
| 9(6) | Mesenchyme hydrolytic agent+heptan platinum | 36±3.2 | ＜0.001 |
| 10(6) | Mesenchyme hydrolytic agent+DNA-2114 | 20±2.2 | ＜0.001 |
Above result shows, growth all has the obvious suppression effect to kinds of tumor cells when this concentration is used separately for platinum-like compounds (cisplatin, carboplatin, heptan platinum, DNA-2114) and used mesenchyme hydrolytic agent (collagenase), can show significant potentiation when use in conjunction.
The tumor-inhibiting action of test 4, platinum-like compounds and mesenchyme hydrolytic agent (slow releasing injection)
Used tumor cell comprises CNS-1, C6,9L, gastric gland epithelial cancer (SA), bone tumor (BC), breast carcinoma (BA), pulmonary carcinoma (LH), papillary adenocarcinoma of thyroid (PAT), hepatocarcinoma etc.Medicine is through intratumor injection.Therapeutic effect (seeing Table 2).Neovascularization inhibitor dosage is 2.5mg/kg, and cancer therapy drug is 10mg/kg.The treatment back was measured the gross tumor volume size on the 20th day, made relatively therapeutic effect (seeing Table 2) of index with inhibition rate of tumor growth (%).
Table 2
| Oncocyte | Citricplatin | Lobaplatin | Nedaplatin | Mesenchyme hydrolytic agent | Citricplatin+mesenchyme hydrolytic agent | Lobaplatin+mesenchyme hydrolytic agent | Nedaplatin+mesenchyme hydrolytic agent |
| CNS | 44％ | 50％ | 62％ | 60％ | 88％ | 80％ | 74％ |
| C6 | 34％ | 64％ | 60％ | 64％ | 94％ | 80％ | 94％ |
| SA | 34％ | 60％ | 50％ | 62％ | 86％ | 92％ | 92％ |
| BC | 36％ | 62％ | 54％ | 64％ | 94％ | 82％ | 80％ |
| BA | 38％ | 60％ | 62％ | 60％ | 92％ | 72％ | 92％ |
| LH | 42％ | 56％ | 62％ | 58％ | 90％ | 86％ | 84％ |
| PAT | 40％ | 50％ | 66％ | 52％ | 90％ | 88％ | 78％ |
Above result shows, growth all has the obvious suppression effect to kinds of tumor cells when this concentration is used separately for used platinum-like compounds (lobaplatin, nedaplatin, citricplatin) and mesenchyme hydrolytic agent (hyaluronidase), can show significant potentiation when use in conjunction.
The tumor-inhibiting action of test 5, platinum-like compounds and mesenchyme hydrolytic agent (slow releasing injection)
With the rat is subjects, with 2 * 10
5Individual tumor cell of liver subcutaneous injection is in its hypochondrium, treats that tumor growth after 14 days is divided into it following 10 groups (seeing Table 3).First group is contrast, and the 2nd to 10 group is the treatment group, and sustained-release implant is placed in tumor.Dosage is 5mg/kg.The treatment back was measured gross tumor volume size, relatively therapeutic effect (seeing Table 3) on the 14th day.
Table 3
| Test group (n) | Suffered treatment | Gross tumor volume (cm 3) | The P value |
| 1(6) | Contrast | 62±10 | |
| 2(6) | Mesenchyme hydrolytic agent | 48±5.0 | ＜0.05 |
| 3(6) | Ormaplatin | 52±2.2 | ＜0.01 |
| 4(6) | Spiroplatin | 34±2.6 | ＜0.001 |
| 5(6) | Sebriplatin | 46±3.2 | ＜0.01 |
| 6(6) | Oxaliplatin | 20±3.0 | ＜0.001 |
| 7(6) | Mesenchyme hydrolytic agent+ormaplatin | 32±2.6 | ＜0.01 |
| 8(6) | Mesenchyme hydrolytic agent+spiroplatin | 24±2.4 | ＜0.001 |
| 9(6) | Mesenchyme hydrolytic agent+sebriplatin | 30±3.4 | ＜0.01 |
| 10(6) | Mesenchyme hydrolytic agent+oxaliplatin | 18±2.2 | ＜0.001 |
Above result shows, growth all has the obvious suppression effect to kinds of tumor cells when this concentration is used separately for used platinum-like compounds (ormaplatin, oxaliplatin, sebriplatin, spiroplatin) and mesenchyme hydrolytic agent (pancreatin), can show significant potentiation when use in conjunction.
The tumor-inhibiting action of test 6, platinum-like compounds and mesenchyme hydrolytic agent (slow releasing injection)
With the rat is subjects, with 2 * 10
5Individual pulmonary carcinoma 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 (platinum-like compounds or mesenchyme hydrolytic agent) and therapeutic alliance group (platinum-like compounds and mesenchyme hydrolytic agent).Platinum-like compounds is through intratumor injection, and mesenchyme hydrolytic agent is through lumbar injection.Dosage is 5mg/kg.The treatment back was measured the gross tumor volume size on the 10th day, made relatively therapeutic effect (seeing Table 4) of index with inhibition rate of tumor growth.
Table 4
| Test group (n) | Suffered treatment | Suppression ratio (%) | The P value |
| 1(6) | Contrast | - | |
| 2(6) | Mesenchyme hydrolytic agent | 50 | ＜0.05 |
| 3(6) | Platinum relaxes | 36 | ＜0.01 |
| 4(6) | Bicycloplatin | 38 | ＜0.01 |
| 5(6) | According to platinum | 32 | ＜0.01 |
| 6(6) | Picoplatin | 38 | ＜0.01 |
| 7(6) | Mesenchyme hydrolytic agent+platinum relaxes | 80 | ＜0.001 |
| 8(6) | Mesenchyme hydrolytic agent+bicycloplatin | 74 | ＜0.001 |
| 9(6) | Mesenchyme hydrolytic agent+according to platinum | 70 | ＜0.001 |
| 10(6) | Mesenchyme hydrolytic agent+picoplatin | 78 | ＜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 platinum-like compounds (platinum that relaxes, bicycloplatin, according to platinum, picoplatin) and mesenchyme hydrolytic agent (gefitinib), can show significant potentiation when use in conjunction.
The tumor-inhibiting action of test 7, platinum-like compounds and mesenchyme hydrolytic agent (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.Platinum-like compounds is through lumbar injection, and mesenchyme hydrolytic agent is through the injection of tumor week.Neovascularization inhibitor dosage is 10mg/kg, and cancer therapy drug is 2.5mg/kg.The treatment back was measured the gross tumor volume size on the 20th day, make relatively therapeutic effect of index with inhibition rate of tumor growth, above result shows, mesenchyme hydrolytic agent (Erlotinib) obviously strengthens the inhibitory action to the kinds of tumors growth such as cisplatin, carboplatin, heptan platinum, DNA-2114, enloplatin, dexormaplatin, iproplatin, lobaplatin, rice platinum, pick up platinum, nedaplatin, ormaplatin, oxaliplatin, wherein to the potentiation the most obviously (P＜0.01) of cisplatin, carboplatin, heptan platinum, DNA-2114, lobaplatin, nedaplatin and oxaliplatin.
The tumor-inhibiting action of test 8, platinum-like compounds and mesenchyme hydrolytic agent (sustained-release implant)
With the rat is subjects, with 2 * 10
5Individual pancreatic cancer cell subcutaneous injection is in its hypochondrium, treats that tumor growth after 14 days is divided into it negative control (blank), single therapy group, therapeutic alliance group.Sustained-release implant is all placed in tumor.Dosage is 5mg/kg.The treatment back was measured the gross tumor volume size on the 10th day, made relatively therapeutic effect of index with inhibition rate of tumor growth.Above result shows, mesenchyme hydrolytic agent (hyaluronidase) obviously strengthens the inhibitory action (P＜0.01) to cancer of pancreas such as cisplatin, carboplatin, heptan platinum, DNA-2114, lobaplatin, nedaplatin and oxaliplatin.
The tumor-inhibiting action of test 9, platinum-like compounds and mesenchyme hydrolytic agent (sustained-release implant)
By testing 8 described methods mensuration platinum-like compounds and mesenchyme hydrolytic agent (sustained-release implant) tumor-inhibiting action to colon cancer, above result shows, mesenchyme hydrolytic agent (Cervilaxin) obviously strengthens the tumor-inhibiting action (P＜0.01) of cisplatin, carboplatin, heptan platinum, DNA-2114, lobaplatin, nedaplatin or oxaliplatin etc.
The test 10, the different molecular weight polylactic acid make according to release ratio in the body of platinum sustained-release implant
With the rat is subjects, grouping (3/group) and in the equivalent of subcutaneous polylactic acid (PLA) carrying that contains different molecular weight (MW) according to the platinum sustained-release implant.Survey the surplus of medicine in implant respectively at 1,3,7,14,21,28 and 35 day then, and then draw rate of release (%) in its body.The result shows, molecular weight is 20000 is released to: 1 day (8%), 3 (28%), 7 (56%), 14 (82%), 21 (90), 28 (94) and 35 (98%).What relatively the different molecular weight polylactic acid was made finds according to discharging in the body of platinum sustained-release implant, slack-off with the molecular weight increase, with the 7th day was example, compare with whole body administration group, tumor control rate increases with the polylactic acid molecule amount and improves, and is followed successively by 68% (MW:5000), 66% (MW:15000), 54% (MW:25000), 50% (MW:40000) and 48 (MW:60000).
It is platinum in heptan, DNA-2114, lobaplatin, nedaplatin, oxaliplatin, citricplatin, ZD 0473, easypro platinum, bicycloplatin or mesenchyme hydrolytic agent (fibrinolysin) slow releasing agent that adjuvant is made that same result also sees with polylactic acid.
That pays special attention to is simple to operation, the good reproducibility of slow releasing agent of the present invention, particularly slow releasing injection.Good effect not only, toxic and side effects is little.
Different drug packages is to want characteristic different with different Biodegradable high moleculars.Discover that further the slow-release auxiliary material that is most appropriate to medicament slow release of the present invention is a poly-dl-lactide, poly-dl-lactide/ethanol copolymer, the monomethyl polyethylene glycol, monomethyl polyethylene glycol copolymer, polyethylene glycol, the polyethylene glycol copolymer, end carboxyl polylactic acid, end carboxyl polylactic acid/ethanol copolymer, polifeprosan, bis-fatty acid and decanedioic acid copolymer, poly-(erucic acid dimer-decanedioic acid), poly-(fumaric acid-decanedioic acid), ethylene vinyl acetate copolymer, polylactic acid, the copolymer of polyglycolic acid and hydroxyacetic acid, xylitol, oligosaccharide, chrondroitin, chitin, hyaluronic acid, collagen protein, gelatin, one of albumin glue or its combination; Optimum suspending agent is one of methylcellulose, hydroxy methocel, sodium carboxymethyl cellulose, (iodine) glycerol, simethicone, propylene glycol, carbomer, mannitol, sorbitol, surfactant, soil temperature 20, soil temperature 40, soil temperature 80 or its combination.
In a word, growth all had the obvious suppression effect to kinds of tumor cells when used platinum-like compounds and mesenchyme hydrolytic agent were used separately, can show significant potentiation when use in conjunction.Therefore, effective ingredient of the present invention is the combination of mesenchyme hydrolytic agent or any one (or more than one) platinum-like compounds and mesenchyme hydrolytic agent.The medicine that contains above effective ingredient can be made into sustained-release micro-spheres, and then makes slow releasing injection and implant, serves as preferred with the suspensoid injectio that is combined to form with the special solvent that contains suspending agent wherein.
Slow releasing injection or sustained-release implant also can be further specified by following embodiment.Just the invention will be further described for the foregoing description and following examples, is not its content and use are imposed any restrictions.
(4) specific embodiment
Embodiment 1.
80mg polifeprosan (to carboxy phenyl propane (p-CPP): certain herbaceous plants with big flowers diacid (SA) is 20: 80) copolymer is put into container, add 100 milliliters of dichloromethane, behind the dissolving mixing, add 10mg cisplatin and 10mg gefitinib, shake up the back contains 10% cisplatin and 10% gefitinib with spray drying method for preparation injectable microsphere again.Then microsphere is suspended in the normal saline that contains 15% mannitol, makes corresponding suspension type slow releasing injection.The drug release time of this slow releasing injection in external normal saline is 10-15 days, is about 20-30 days at the subcutaneous drug release time of mice.
Embodiment 2.
The method step that is processed into slow releasing injection is identical with embodiment 1, but different is that contained anticancer effective component and percentage by weight thereof are:
(1) gefitinib of 2-40%, Erlotinib, Lapatinib, votaranib, WAY-EKB 569, NSC 609974, thalidomide, LS-2616, angiostatin, Endostatin, the blood vessel endothelium chalone, imatinib mesylate, Sugen 5416, BMS 354825, Avastin, Cl 1033, Sorafenib, Sutent, TLK286, ABX-EGF, Bacillus polymyxa Neutral proteinase, bromelain, Chymotrypsin, clostripain, fibrinolysin, pancreatin, cathepsin-G, plasminogen activator, collagenase, streptokinase, glycosidase, hyaluronidase, lysozyme, Cervilaxin, interferon or brinase; Or
(2) gefitinib of 2-40%, Erlotinib, plasminogen activator, collagenase, streptokinase, glycosidase, hyaluronidase, lysozyme, Cervilaxin, the cisplatin of interferon or brinase and 1-30%, carboplatin, ring platinum, heptan platinum, DNA-2114, cis-Dichlorobis(cyclopentylamine)platinum, platinum blue, cis-Dichlorobis(cyclopropylamine)platinum, Ethylenediammineplatinum(II) malonate, CL 286558., enloplatin, sulfatodiamino cyclohexane platinum, Spiroplatin, dexormaplatin, iproplatin, lobaplatin, rice platinum, pick up platinum, nedaplatin, ormaplatin, oxaliplatin, sebriplatin, spiroplatin, platinum relaxes, bicycloplatin, according to platinum, picoplatin, citricplatin, the combination of ZD 0473 or zeniplatin.
Used adjuvant is: poly-dl-lactide, poly-dl-lactide/ethanol copolymer, monomethyl polyethylene glycol, monomethyl polyethylene glycol copolymer, polyethylene glycol, polyethylene glycol copolymer, end carboxyl polylactic acid or end carboxyl polylactic acid/ethanol copolymer.
Embodiment 3.
With 70mg molecular weight peak value is that 35000 polylactic acid (PLA) is put into container, adds 100 milliliters of dichloromethane, behind the dissolving mixing, adds 15mg citricplatin and 15mg Erlotinib, shakes up the dry organic solvent of removing of final vacuum again.Dried pastille solid composite freezing and pulverizing is made the micropowder that contains 15% citricplatin and 15% Erlotinib, be suspended in then in the normal saline that contains 1.5% sodium carboxymethyl cellulose, make corresponding suspension type slow releasing injection.The drug release time of this slow releasing injection in external normal saline is 20-35 days, is about 35-50 days at the subcutaneous drug release time of mice.
Embodiment 4
The method step that is processed into slow releasing injection is identical with embodiment 3, but different is that contained anticancer effective component and percentage by weight thereof are: the Erlotinib of 2-40%, plasminogen activator, collagenase, streptokinase, glycosidase, hyaluronidase, lysozyme, Cervilaxin, the cisplatin of interferon or brinase and 1-30%, carboplatin, ring platinum, heptan platinum, DNA-2114, cis-Dichlorobis(cyclopentylamine)platinum, platinum blue, cis-Dichlorobis(cyclopropylamine)platinum, Ethylenediammineplatinum(II) malonate, CL 286558., enloplatin, sulfatodiamino cyclohexane platinum, Spiroplatin, dexormaplatin, iproplatin, lobaplatin, rice platinum, pick up platinum, nedaplatin, ormaplatin, oxaliplatin, sebriplatin, spiroplatin, platinum relaxes, bicycloplatin, according to platinum, picoplatin, citricplatin, the combination of ZD 0473 or zeniplatin.
Embodiment 5.
(EVAc) puts into container with the 70mg ethylene vinyl acetate copolymer, after adding 100 milliliters of dichloromethane dissolving mixings, add 20 milligrams of cisplatin and 10 milligrams of plasminogen activators, shake up the back contains 20% cisplatin and 10% plasminogen activator with spray drying method for preparation injectable microsphere again.Then microsphere is suspended in the injection that contains the 5-15% sorbitol, makes corresponding suspension type slow releasing injection.The drug release time of this slow releasing injection in external normal saline is 10-15 days, is about 20-30 days at the subcutaneous drug release time of mice.
Embodiment 6.
The method step that is processed into slow releasing injection is identical with embodiment 5, but different is that contained anticancer effective component is: the carboplatin of 1-40%, heptan platinum, DNA-2114, lobaplatin, rice platinum, nedaplatin or oxaliplatin and 1-40% the combination of collagenase, streptokinase, glycosidase, hyaluronidase, lysozyme, Cervilaxin, interferon or brinase.
Embodiment 7.
70mg polifeprosan (to carboxy phenyl propane (p-CPP): certain herbaceous plants with big flowers diacid (SA) is 20: 80) copolymer is put into container, add 100 milliliters of dichloromethane, behind the dissolving mixing, add easypro platinum of 20mg and 10mg collagenase, shake up the back contains 20% easypro platinum and 10% collagenase with spray drying method for preparation injectable microsphere again.Microsphere is suspended in the normal saline that contains 1.5% sodium carboxymethyl cellulose and 0.5% Tween 80 then, makes corresponding suspension type slow releasing injection.The drug release time of this slow releasing injection in external normal saline is 10-15 days, is about 20-30 days at the subcutaneous drug release time of mice.
Embodiment 8.
The method step that is processed into slow releasing injection is identical with embodiment 7, but different is that contained anticancer effective component is: the cisplatin of the collagenase of 2-40%, streptokinase, glycosidase, hyaluronidase, lysozyme, Cervilaxin, interferon or brinase and 1-30%, carboplatin, heptan platinum, DNA-2114, enloplatin, lobaplatin, rice platinum, nedaplatin, ormaplatin, oxaliplatin, sebriplatin, spiroplatin, the platinum that relaxes, bicycloplatin, according to the combination of platinum, picoplatin, citricplatin, ZD 0473 or zeniplatin.
Embodiment 9
70mg polifeprosan (to carboxy phenyl propane (p-CPP): certain herbaceous plants with big flowers diacid (SA) is 20: 80) copolymer is put into container, add 100 milliliters of dichloromethane, behind the dissolving mixing, add 20mg bicycloplatin and 10mg streptokinase, shake up the back contains 20% bicycloplatin and 10% streptokinase with spray drying method for preparation injectable microsphere again.Then microsphere is suspended in the normal saline that contains 1.5% sodium carboxymethyl cellulose and 15% sorbitol and 0.2% Tween 80, makes corresponding suspension type slow releasing injection.The drug release time of this slow releasing injection in external normal saline is 10-15 days, is about 20-30 days at the subcutaneous drug release time of mice.
Embodiment 10
The method step that is processed into slow releasing injection is identical with embodiment 9, but different is that contained anticancer effective component is: the cisplatin of the collagenase of 2-40%, streptokinase, glycosidase, hyaluronidase, lysozyme, Cervilaxin, interferon or brinase and 1-30%, carboplatin, heptan platinum, DNA-2114, enloplatin, lobaplatin, rice platinum, nedaplatin, ormaplatin, oxaliplatin, sebriplatin, spiroplatin, the platinum that relaxes, bicycloplatin, according to the combination of platinum, picoplatin, citricplatin, ZD 0473 or zeniplatin.
Embodiment 11
70mg polifeprosan (to carboxy phenyl propane (p-CPP): certain herbaceous plants with big flowers diacid (SA) is 20: 80) copolymer is put into container, add 100 milliliters of dichloromethane, behind the dissolving mixing, add the easypro platinum of 10mg lysozyme and 20mg, shake up the back contains 10% lysozyme and 20% easypro platinum with spray drying method for preparation injectable microsphere again.Then microsphere is made corresponding sustained-release implant through pressed disc method.The drug release time of this sustained-release implant in external normal saline is 10-15 days, is about 30-40 days at the subcutaneous drug release time of mice.
Embodiment 12
The method step that is processed into sustained-release implant is identical with embodiment 11, but different is that contained anticancer effective component is: 10% collagenase, streptokinase, glycosidase, hyaluronidase, lysozyme or Cervilaxin and 10% cisplatin, carboplatin, heptan platinum, DNA-2114, enloplatin, lobaplatin, rice platinum, nedaplatin, ormaplatin, oxaliplatin, sebriplatin, spiroplatin, the platinum that relaxes, bicycloplatin, according to the combination of platinum, picoplatin, citricplatin, ZD 0473 or zeniplatin.
Embodiment 13
With 70mg molecular weight peak value 80000 polylactic acid (PLGA, 50: 50) put into container, add 100 milliliters of dichloromethane, behind the dissolving mixing, add 10mg carboplatin and 10mg collagenase and 10mg hyaluronidase, shake up the back contains 10% carboplatin and 10% collagenase and 10% hyaluronidase with spray drying method for preparation injectable microsphere again.Then microsphere is made corresponding sustained-release implant through pressed disc method.The drug release time of this sustained-release implant in external normal saline is 25-30 days, is about 35-50 days at the subcutaneous drug release time of mice.
Embodiment 14
The method step that is processed into sustained-release implant is identical with embodiment 11,13, but different is that contained anticancer effective component is: the combination of cisplatin, carboplatin or the oxaliplatin of 10% collagenase and 10% hyaluronidase and 15%.
Embodiment 15
The method step that is processed into slow releasing agent is identical with embodiment 1-14, but different is used slow-release auxiliary material is one of following or its combination:
A) the molecular weight peak value is the polylactic acid (PLA) of 5000-10000,10000-30000,30000-60000,60000-100000 or 100000-150000;
B) the molecular weight peak value is the polyglycolic acid of 5000-10000,10000-30000,30000-60000,60000-100000 or 100000-150000 and the copolymer of hydroxyacetic acid (PLGA), wherein, the ratio of polyglycolic acid and hydroxyacetic acid is 50-95: 50-50;
C) ethylene vinyl acetate copolymer (EVAc);
D) 10: 90,20: 80,30: 70,40: 60,50: 50 or 60: 40 to carboxy phenyl propane (p-CPP): certain herbaceous plants with big flowers diacid (SA) copolymer (polifeprosan);
E) bis-fatty acid and decanedioic acid copolymer;
F) poly-(erucic acid dimer-decanedioic acid) copolymer;
G) poly-(fumaric acid-decanedioic acid) copolymer;
H) xylitol, oligosaccharide, chrondroitin, chitin, potassium salt, sodium salt, hyaluronic acid, collagen protein, gelatin or albumin glue;
I) poly-dl-lactide, poly-dl-lactide/ethanol copolymer, monomethyl polyethylene glycol, monomethyl polyethylene glycol copolymer, polyethylene glycol, polyethylene glycol copolymer, end carboxyl polylactic acid or end carboxyl polylactic acid/ethanol copolymer.
Embodiment 16
The method step that is processed into slow releasing injection is identical with embodiment 1-15, but different is used suspending agent is respectively one of following or its combination:
A) 0.5-3.0% carboxymethyl cellulose (sodium);
B) 5-15% mannitol;
C) 5-15% sorbitol;
D) 0.1-1.5% surfactant;
E) 0.1-0.5% polysorbas20.
Embodiment 17
The method step that is processed into slow releasing injection is identical with embodiment 11-15, but different is that contained anticancer effective component is:
(1) collagenase of 2-40%, streptokinase, glycosidase, hyaluronidase, lysozyme or Cervilaxin; Or
(2) cisplatin of the collagenase of 2-40%, streptokinase, glycosidase, hyaluronidase, lysozyme or Cervilaxin and 1-30%, carboplatin, heptan platinum, DNA-2114, nedaplatin, oxaliplatin, the platinum that relaxes, according to the combination of platinum, picoplatin, citricplatin, ZD 0473 or zeniplatin.
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 the embodiment scope that the present invention is not limited to be given an example, this embodiment is intended to illustrate as the present invention is discrete.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.
Above embodiment only is used for explanation, and is not limitation application of the present invention.
The present invention disclosed and the protection the content see claim.
Claims (10)
1. the anticancer pharmaceutical composition of loaded with platinum compound and mesenchyme hydrolytic agent is characterized in that this anticancer pharmaceutical composition is a slow releasing injection, is grouped into by following one-tenth:
(A) sustained-release micro-spheres comprises:
Anticancer effective component 0.5-60%
Slow-release auxiliary material 40-99%
Suspending agent 0.0-30%
More than be weight percentage
With
(B) solvent is for common solvent or contain the special solvent of suspending agent.
Wherein,
Anticancer effective component is the combination of mesenchyme hydrolytic agent or mesenchyme hydrolytic agent and platinum-like compounds, and mesenchyme hydrolytic agent is proteolytic enzyme and vasoinhibitor;
Suspending agent is selected from one of sodium carboxymethyl cellulose, iodine glycerol, simethicone, propylene glycol, carbomer, mannitol, sorbitol, surfactant, soil temperature 20, soil temperature 40 and soil temperature 80 or its combination;
Slow-release auxiliary material range of viscosities IV (dl/g) is 0.1～0.8, is selected from one of following or its combination:
A) polylactic acid;
B) copolymer of polyglycolic acid and hydroxyacetic acid;
C) polifeprosan;
D) ethylene vinyl acetate copolymer;
E) bis-fatty acid and decanedioic acid copolymer;
F) poly-(erucic acid dimer-decanedioic acid) copolymer;
G) poly-(fumaric acid-decanedioic acid) copolymer;
H) xylitol, oligosaccharide, chrondroitin, chitin, hyaluronic acid, collagen protein, gelatin or albumin glue;
I) poly-dl-lactide, poly-dl-lactide/ethanol copolymer, monomethyl polyethylene glycol, monomethyl polyethylene glycol copolymer, polyethylene glycol, polyethylene glycol copolymer, end carboxyl polylactic acid or end carboxyl polylactic acid/ethanol copolymer.
The viscosity of suspending agent is 100cp-3000cp (20 ℃-30 ℃ time), is selected from one of sodium carboxymethyl cellulose, hydroxy methocel, iodine glycerol, simethicone, propylene glycol, carbomer, mannitol, sorbitol, surfactant, soil temperature 20, soil temperature 40 and soil temperature 80 or its combination.
2. the slow-releasing anticarcinogen injection according to claim 1, it is characterized in that platinum-like compounds be selected from cisplatin, carboplatin, ring platinum, heptan platinum, DNA-2114, cis-Dichlorobis(cyclopentylamine)platinum, platinum blue, cis-Dichlorobis(cyclopropylamine)platinum, Ethylenediammineplatinum(II) malonate, CL 286558., enloplatin, sulfatodiamino cyclohexane platinum, Spiroplatin, dexormaplatin, iproplatin, lobaplatin, rice platinum, pick up platinum, nedaplatin, ormaplatin, oxaliplatin, sebriplatin, spiroplatin, the platinum that relaxes, bicycloplatin, according to platinum, picoplatin, citricplatin, ZD 0473 or zeniplatin.
3. the slow-releasing anticarcinogen injection according to claim 1 is characterized in that vasoinhibitor is selected from a kind of or its combination among gefitinib, Erlotinib, Lapatinib, votaranib, WAY-EKB 569, NSC 609974, thalidomide, LS-2616, angiostatin, Endostatin, blood vessel endothelium chalone, imatinib mesylate, Sugen 5416, BMS 354825, Avastin, Cl 1033, Sorafenib, Sutent, TLK286, ABX-EGF, Marimastat, SU5416, SU6668, Amebacilin, the TNP-470.
4. the slow-releasing anticarcinogen injection according to claim 1 is characterized in that proteolytic enzyme is selected from elastoser, pancreatic elastase, metalloproteases, trypsin, chymase, pepsin, pronase, Bacillus polymyxa Neutral proteinase, bromelain, Chymotrypsin, clostripain, thermolysin, subtilisin, carase, papain, chymopapain, fibrinolysin, house thunder sulfo-peptidase, pancreatin, cathepsin-G, cysteine proteinase, thioesterase, amide transferase, the transesterification enzymatic activity, plasminogen activator, collagenase, the polymorphonuclear leukocyte serine protease, nuclease, lipase, esterase, streptokinase, glycosidase, hyaluronidase, neuraminidase, amylase, Cervilaxin, a kind of or its combination in interferon (gamma interferon) and the brinase.
5. the slow-releasing anticarcinogen injection according to claim 1 is characterized in that the anticancer effective component of slow-releasing anticarcinogen injection and percentage by weight are:
(1) collagenase of 2-40%, streptokinase, glycosidase, hyaluronidase, lysozyme or Cervilaxin; Or
(2) cisplatin of the collagenase of 2-40%, streptokinase, glycosidase, hyaluronidase, lysozyme or Cervilaxin and 1-30%, carboplatin, heptan platinum, DNA-2114, dexormaplatin, nedaplatin, oxaliplatin, the platinum that relaxes, according to the combination of platinum or zeniplatin.
6. the slow-releasing anticarcinogen injection according to claim 1 is characterized in that the molecular weight peak value of polylactic acid in the selected slow-release auxiliary material is selected from 5000-10000,10000-30000,300000-60000,60000-100000 or 100000-150000; The ratio of polyglycolic acid and hydroxyacetic acid is 50-95: 50-50; The molecular weight peak value is 5000-10000,10000-30000,300000-60000,60000-100000 or 100000-150000; In the polifeprosan, it is 10: 90,20: 80,30: 70,40: 60,50: 50 or 60: 40 to the composition weight ratio of carboxy phenyl propane and certain herbaceous plants with big flowers diacid.
7. the slow-releasing anticarcinogen injection according to claim 1 is characterized in that used suspending agent is respectively one of following or its combination:
A) 0.5-3.0% carboxymethyl cellulose (sodium);
B) 5-15% mannitol;
C) 5-15% sorbitol;
D) 0.1-1.5% surfactant;
E) 0.1-0.5% polysorbas20;
F) iodine glycerol, simethicone, propylene glycol or carbomer;
G) 0.5-5% sodium carboxymethyl cellulose+0.1-0.5% soil temperature 80;
H) 5-20% mannitol+0.1-0.5% soil temperature 80; Or
I) 0.5-5% sodium carboxymethyl cellulose+5-20% sorbitol+0.1-0.5% soil temperature 80.
8. the slow-releasing anticarcinogen injection according to claim 1, it is characterized in that being used for anticancer effective component is used for preparation treatment and originates from people and animal brain, the central nervous system, kidney, liver, gallbladder, incidence, the oral cavity, thyroid, skin, mucosa, body of gland, blood vessel, osseous tissue, lymph node, lungs, esophagus, stomach, mammary gland, pancreas, eyes, nasopharynx part, the uterus, ovary, endometrium, cervix uteri, prostate, bladder, former or the cancer of secondary of colon or rectum, the suspensoid injectio of sarcoma or carcinosarcoma or sustained-release implant are in tumor or tumor week injection or place administration.
9. described according to Claim 8 anti-cancer sustained-released implantation agent is characterized in that being used for anticancer effective component and is:
(1) collagenase of 2-40%, streptokinase, glycosidase, hyaluronidase, lysozyme or Cervilaxin; Or
(2) cisplatin of the collagenase of 2-40%, streptokinase, glycosidase, hyaluronidase, lysozyme or Cervilaxin and 1-30%, carboplatin, heptan platinum, DNA-2114, dexormaplatin, nedaplatin, oxaliplatin, the platinum that relaxes, according to the combination of platinum or zeniplatin.
10. described according to Claim 8 anti-cancer sustained-released implantation agent is characterized in that being used for slow-release auxiliary material and is one of following or its combination:
A) polylactic acid, molecular weight peak value are 10000-30000,300000-60000,60000-100000 or 100000-150000;
B) copolymer of polyglycolic acid and hydroxyacetic acid, wherein, the ratio of polyglycolic acid and hydroxyacetic acid is 50-95: 50-50, the molecular weight peak value is 10000-30000,300000-60000,60000-100000 or 100000-150000;
C) ethylene vinyl acetate copolymer;
D) polifeprosan, to carboxy phenyl propane: the certain herbaceous plants with big flowers diacid is 10: 90,20: 80,30: 70,40: 60,50: 50 or 60: 40;
E) bis-fatty acid and decanedioic acid copolymer;
F) poly-(erucic acid dimer-decanedioic acid);
G) poly-(fumaric acid-decanedioic acid);
H) xylitol, oligosaccharide, chrondroitin, chitin, hyaluronic acid, collagen protein, gelatin or white tempera;
I) poly-dl-lactide, poly-dl-lactide/ethanol copolymer, monomethyl polyethylene glycol, monomethyl polyethylene glycol copolymer, polyethylene glycol, polyethylene glycol copolymer, end carboxyl polylactic acid or end carboxyl polylactic acid/ethanol copolymer.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA2006102011951A CN1957913A (en) | 2006-12-01 | 2006-12-01 | Composition of anti cancer medication prepared from carried platinum category compound and consubstantial hydrolytic agent |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US8168661B2 (en) | 2006-11-06 | 2012-05-01 | Poniard Pharmaceuticals, Inc. | Use of picoplatin to treat colorectal cancer |
| US8168662B1 (en) | 2006-11-06 | 2012-05-01 | Poniard Pharmaceuticals, Inc. | Use of picoplatin to treat colorectal cancer |
| US8173686B2 (en) | 2006-11-06 | 2012-05-08 | Poniard Pharmaceuticals, Inc. | Use of picoplatin to treat colorectal cancer |
| US8178564B2 (en) | 2006-11-06 | 2012-05-15 | Poniard Pharmaceuticals, Inc. | Use of picoplatin to treat colorectal cancer |
-
2006
- 2006-12-01 CN CNA2006102011951A patent/CN1957913A/en active Pending
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US8168661B2 (en) | 2006-11-06 | 2012-05-01 | Poniard Pharmaceuticals, Inc. | Use of picoplatin to treat colorectal cancer |
| US8168662B1 (en) | 2006-11-06 | 2012-05-01 | Poniard Pharmaceuticals, Inc. | Use of picoplatin to treat colorectal cancer |
| US8173686B2 (en) | 2006-11-06 | 2012-05-08 | Poniard Pharmaceuticals, Inc. | Use of picoplatin to treat colorectal cancer |
| US8178564B2 (en) | 2006-11-06 | 2012-05-15 | Poniard Pharmaceuticals, Inc. | Use of picoplatin to treat colorectal cancer |
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