CN101301470A - Anticancer composition containing neovascularization inhibitor and bortezomib - Google Patents
Anticancer composition containing neovascularization inhibitor and bortezomib Download PDFInfo
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- CN101301470A CN101301470A CNA2008103026953A CN200810302695A CN101301470A CN 101301470 A CN101301470 A CN 101301470A CN A2008103026953 A CNA2008103026953 A CN A2008103026953A CN 200810302695 A CN200810302695 A CN 200810302695A CN 101301470 A CN101301470 A CN 101301470A
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Abstract
The invention provides a sustained-release injection which is an anti-tumor composite containing agiogenesis inhibitors and bortezomib. The sustained-release injection comprises a sustained-release microsphere and a solution medium, wherein the sustained-release microsphere comprises effective anti-tumor ingredient and sustained-release excipient, the solution medium is a common solution medium or a special solution medium containing a suspending drug. The suspending drug has the viscosity between 100cp and 3000cp (under twenty centi degrees to thirty centi degrees) and is selected from sodium carboxymethylcellulose and others; the effective anti-tumor ingredient comprises the agiogenesis inhibitors and/or the combination thereof; the sustained-release excipient is selected from polyphosphonate copolymer like p(LAEG-EOP)or p(DAPG-EOP), PLA, polyphosphonate with PLA, polifeprosan, copolymer of dual fatty acid and sebacic acid, the polymer or blending polymer of ( erucic acid dipolymer-sebacic acid) or poly(boletic acid-sebacic acid); the anti-tumor composite can also be prepared to be a sustained-release implant which can maintain the effective concentration of drug over forty days for intratumor or tumor circumference injection or placement, can also reduce general reaction obviously and enhance the treatment effect of non-operative therapeutics such as chemotherapy and radiotherapy.
Description
(1) technical field
The present invention relates to a kind of anti-cancer composition that contains neovascularization inhibitor and bortezomib, belong to technical field of pharmaceuticals.Particularly, this invention relates to a kind ofly can be released to the partial slow releasing preparation of entity tumor with neovascularization inhibitor and bortezomib are stable, is mainly sustained-release implant and slow releasing injection, can prolong drug release time, and can increase the sensitivity of medicine.
(2) background technology
Up-to-date data show that China had 3,000,000 people to die from cancer in 2006.Cancer morbidity rises year by year and is rejuvenation trend, has data to show that in less than the time in 20 years, China's cancer morbidity has risen 69%, and mortality rate has increased by 29.4%.According to World Health Organization's recent statistics, will increase by 50 percent to the year two thousand twenty whole world cancer morbidity, number of the infected increases to 15,000,000.Estimate that the year two thousand twenty China will have 4,000,000 people to die from cancer therefore every year, inquire into the focus that a kind of effective treatment method for cancer or medicine have become present research.
In recent years, bortezomib is used as one of treatment multiple myeloma choice drug.The effect that is used for the treatment of other tumor separately is unclear.Though unite some tumors may be had certain effect by tool, limited its clinical practice by the caused whole body toxic and side effects of conventional route administration with other anticarcinogen.
Chemotherapeutics topical application, particularly local sustained release have become the research direction and the focus of current entity tumor chemotherapy.Referring to (Chinese patent application numbers 200510042234.3,03148624.X, 200510042236.2,96116041.1,97107078.4,200510042260.6,200510042261.0,200510042262.5,200510042263.X; U.S. Pat 5651986, RE37410).
Yet existing slow-release auxiliary material above-mentioned and that other pharmaceutical preparation is used causes the prominent of medicine to release or unbalanced release when release more or less.The release medicine that has is slow excessively, is not enough to obtain in the part active drug concentration, thereby effective kill tumor cell; The release that has is too fast, often causes prominent releasing, and causes general toxic reaction as conventional injection easily.
Therefore, research and development can discharge in the specific time different pharmaceutical with stable or constant amount and speed just becomes present problem demanding prompt solution.
(3) summary of the invention
The present invention is directed to the deficiencies in the prior art, a kind of anticancer medicine slow-release preparation containing that contains neovascularization inhibitor and bortezomib is provided, particularly, is a kind of slow releasing injection or sustained-release implant that contains neovascularization inhibitor and bortezomib.Neovascularization inhibitor and the stable partial slow releasing preparation of entity tumor that is released to of bortezomib can prolong drug can be able to be kept higher drug level, and can increase the sensitivity of medicine release time.
The present invention also finds to have the composition of active anticancer, is not the slow release effect that all slow-release auxiliary material all can reach effective release.Pharmaceutic adjuvant have hundreds of more than, pharmaceutic adjuvant with slow releasing function, particularly the pharmaceutic adjuvant that different pharmaceutical 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.Discharged and be not enough to obtain active drug concentration slowly, thereby effective kill tumor cell; Cause prominent releasing if discharge too fast meeting, then cause general toxic reaction easily, as polifeprosan (A.J.Domb etc., Biomaterials (1995), 16 (14): 1069-1072; Wenbin Dang etc., Journal of Controlled Release (1996), 42:83-92; Eric P.Sipos etc., Cancer Chemother Pharmacol (1997), 39:383-389; Lawrence K.Fung etc., CancerResearch (1998), 58:672-684).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.
A kind of form of neovascularization inhibitor slow releasing agent of the present invention is a slow releasing injection, is made up of sustained-release micro-spheres and solvent.Particularly, this slow-releasing anticarcinogen injection is grouped into by following one-tenth:
(A) sustained-release micro-spheres comprises:
Anticancer effective component 0.5-70%
Slow-release auxiliary material 30-99%
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 neovascularization inhibitor and bortezomib;
Slow-release auxiliary material range of viscosities IV (dl/g) 0.05～1.8 serves as preferred with 0.1～1.4, with 0.1～1.4 for most preferably.The used slow-release auxiliary material of the present invention is selected from poly-phosphide (polyphosphoesters), poly phosphate (polyphosphate), poly-phosphite ester (polyphosphite), polyphosphonates (polyphosphonate), polyester cyclic phosphate (poly (cycloaliphatic phosphoester)), etherophosphoric acid (EOP), poly-(1,4-two (hydroxyl ethyl ester) terephthalate-co-etherophosphoric acid/terephthalic acids ester hydrochloride ester, 80/20) (p (BHET-EOP/TC, 80/20)), p (BHET-EOP/TC, 50/50), poly-(L-lactide-co-etherophosphoric acid (p (LAEG-EOP)), poly-(L-lactide-co-phosphoric acid propyl ester) (p (DAPG-EOP)), anti-(formula)-1,4-dimethyl cyclohexane (trans-1,4-cyclohexanedimethanil, CHDM), hexyl dichloro-phosphate ester (hexyl phosphorodichloridate, HOP), 4-dimethylamino pyridine (4-dimethylaminopyridine, DMAP), poly-(1,4-two (hydroxyl ethyl ester) terephthalate-co-4-dimethylamino pyridine-co-etherophosphoric acid/terephthalic acids ester hydrochloride, 80/20) (p (BHDPT-EOP/TC, 80/20)), p (BHDPT-EOP/TC, 50/50), poly-(anti-(formula)-1,4-dimethyl cyclohexane-etherophosphoric acid) (p (CHDM-HOP)), poly-(anti-(formula)-1, a kind of or its combination in the 4-dimethyl cyclohexane-hexyl dichloro-phosphate ester (p (CHDM-EOP)).
Serve as preferred with p (BHET-EOP/TC), p (BHET-EOP/TC), p (LAEG-EOP), p (DAPG-EOP), p (BHDPT-EOP/TC), p (BHDPT-EOP/TC), p (CHDM-HOP), p (CHDM-EOP) in the above-mentioned phosphate ester.
The used slow-release auxiliary material of the present invention also is 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 polylactic acid and hydroxyacetic acid (PLGA), PPDO (PDO), PTMC (PTMC), xylitol, oligosaccharide, chrondroitin, chitin, chitosan, poloxamer 188, poloxamer 407, hyaluronic acid, collagen protein, the blend of gelatin or albumin glue or copolymer, or with the combination of above-mentioned phosphate ester.
The used slow-release auxiliary material of the present invention also is selected from the combination of the copolymer (PLGA) of polifeprosan and polylactic acid (PLA) or polylactic acid and hydroxyacetic acid.
The used slow-release auxiliary material of the present invention also is selected from the combination of organosilicon or itself and above-mentioned adjuvant, and organosilicon can be used as the centre of sphere of microsphere or as the carrier of microsphere.
Suspending agent is selected from one of sodium carboxymethyl cellulose, (iodine) glycerol, simethicone, propylene glycol, carbomer, mannitol, sorbitol, surfactant, polysorbas20, polysorbate40 and Tween 80 or its combination.
Vasoinhibitor in the anticancer effective component is selected from one of following or combination: ZD6474, Zarnestra, sirolimus, rapamycin, lenalidomide, Ai Sha is for health, gefitinib, Erlotinib, Lapatinib, votaranib, WAY-EKB 569, NSC 609974, Thalidomide, LS-2616, angiostatin, Endostatin, the blood vessel endothelium chalone, the endothelial growth factor receptor inhibitor, imatinib mesylate, Sugen 5416, BMS 354825, Avastin, Cl 1033, Sorafenib, Sutent, TLK286, ABX-EGF, Marimastat, SU5416, SU6668, Amebacilin, TNP-470.
Above vasoinhibitor 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.
The percentage by weight of medicine in sustained-release micro-spheres is 0.5%-60%, is good with 2%-40%, is best with 5%-30%.Wherein, the content of neovascularization inhibitor in compositions is 0.01%-60%, is good with 1%-40%, is best with 2%-25%, more than all be weight percentage.
The content of bortezomib in compositions is 0.01%-60%, is good with 1%-40%, is best with 5%-20%, more than all be weight percentage.
The weight ratio of neovascularization inhibitor and bortezomib is 1-9: 1 to 1: 1-9.With 1-2: 1 serves as preferred.
Clinical needs are depended in the packing of neovascularization inhibitor and bortezomib and application.Neovascularization inhibitor and bortezomib can be packed alone or in combination.Assembly packaging is mainly used in local potentiation, and separately packing then is mainly used in to the potentiation of different approaches administration or to the potentiation of other therapies.As, local separately placement (or injection) neovascularization inhibitor and bortezomib then can be united with the bortezomib and the neovascularization inhibitor of intravenous applications respectively; The neovascularization inhibitor and the bortezomib of local placement the (or injection) also can be used for radiocurable potentiation.
Therefore, the anticancer effective component percentage by weight in the anticancer slow-release microsphere of the present invention is preferably as follows:
(1) combination of the neovascularization inhibitor of the bortezomib of 0.1-40% and 0.1-20%;
(2) combination of the neovascularization inhibitor of the bortezomib of 2-10% and 2-10%;
(3) combination of the neovascularization inhibitor of the bortezomib of 10-20% and 10-20%.
Wherein neovascularization inhibitor serves as preferred with ZD6474, Zarnestra, sirolimus, rapamycin, lenalidomide, Ai Sha for health, gefitinib, Erlotinib, Lapatinib, votaranib, WAY-EKB 569, Thalidomide, LS-2616, angiostatin, Endostatin, imatinib mesylate, Sugen 5416, BMS 354825, Avastin, Cl 1033, Sorafenib, Sutent.
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 slow-release auxiliary material 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.Be convenient injection, the viscosity of suspending agent is 100cp-3000cp (20 ℃-30 ℃ time), preferred 1000cp-3000cp (20 ℃-30 ℃ time), most preferably 1500cp-3000cp (20 ℃-30 ℃ time).Suspending agent is selected from one of sodium carboxymethyl cellulose, (iodine) glycerol, simethicone, propylene glycol, carbomer, mannitol, sorbitol, surfactant, polysorbas20, polysorbate40 and Tween 80 or its combination.
The content of suspending agent 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% Tween 80; Or
B) 5-20% mannitol+0.1-0.5% Tween 80; Or
C) 0.5-5% sodium carboxymethyl cellulose+5-20% sorbitol+0.1-0.5% Tween 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 Tween 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 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 and emulsion process prepare microsphere, dissolution method is 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) 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 ε 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, the 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 are first-selection, mixture and copolymer can be selected from, but be not limited to PLA, PLGA, the mixture of PLA and PLGA, the mixture or the copolymer of certain herbaceous plants with big flowers diacid and fragrant polyanhydride or aliphatic polyanhydride, 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) and polyglycolic acid the blend ratio be 10/90-90/10 (weight), 25/75-75/25 (weight) preferably.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.
Wherein, the molecular weight peak value of polylactic acid can be, but is not limited to, 5000-200, and 000, but with 20,000-60,000 is preferred, with 30,000-50,000 for most preferably; The molecular weight of the copolymer of polylactic acid and hydroxyacetic acid (PLGA) can be, but be not limited to 5000-200,000, but with 20,000-60,000 is preferred, with 30,000-50,000 for most preferably, and the blend ratio of polylactic acid and hydroxyacetic acid is 10/90-90/10 (weight), is best (weight) with 25/75-75/25.The method of blend is arbitrarily.Content when polylactic acid and hydroxyacetic 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.
Except that above-mentioned original adjuvant, also can select for use other materials to see United States Patent (USP) (4757128; 4857311; 4888176; 4789724) and in " pharmaceutic adjuvant complete works " (the 123rd page, Sichuan science tech publishing house published in 1993, Luo Mingsheng and Gao Tianhui chief editor) have a detailed description.In addition, Chinese patent (application number 96115937.5; 91109723.6; 9710703.3; 01803562.0) and U.S.'s patent of invention (patent No. 5,651,986) also enumerated some pharmaceutic adjuvant, comprise filler, solubilizing agent, absorption enhancer, film former, gellant, system (or causing) hole agent, excipient or blocker etc.
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, chitosan, poloxamer etc., and wherein salt can be, but is not limited to, potassium salt and sodium salt etc.; Also can add other pharmaceutic adjuvant, as but be not limited to filler, solubilizing agent, absorption enhancer, film former, gellant, system (or causing) hole agent, excipient or blocker etc.
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, granule, 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 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.
The route of administration of slow releasing agent 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 tumor of above-mentioned internal organs can be different histological type, and why the tumor of the lymph node of lymph node divides outstanding golden lymphoma and non_hodgkin lymphoma, and pulmonary carcinoma comprises small cell lung cancer and nonsmall-cell lung cancer etc., and the cerebral tumor comprises glioma etc.Yet common tumor comprises entity tumors such as the retinoblastoma, nasopharyngeal carcinoma, ovarian cancer, carcinoma of endometrium, cervical cancer, carcinoma of prostate, bladder cancer, colon cancer, rectal cancer, carcinoma of testis of the cerebral tumor, cerebral glioma, renal carcinoma, hepatocarcinoma, carcinoma of gallbladder, tumor of head and neck, oral cancer, thyroid carcinoma, skin carcinoma, hemangioma, osteosarcoma, lymphoma, pulmonary carcinoma, thymic carcinoma, the esophageal carcinoma, gastric cancer, breast carcinoma, cancer of pancreas, eyes.
The application of sustained-release implant and the same slow-releasing anticarcinogen injection of potentiation mode, the cancer therapy drug that place the associating of the chemical-therapy synergistic agent of the associating of the cancer therapy drug of the promptly local chemical-therapy synergistic agent of placing and other administration, the local cancer therapy drug of placing and other administration, part and the associating of the local chemical-therapy synergistic agent of placing.Wherein the cancer therapy drug of topical application and chemical-therapy synergistic agent can be separately or Joint Production, packing, sale, use.Packing refers to medicine carrying process and pastille slow-release agent the exterior and interior packing for transport and/or store of medicine for adjuvant.The medicine carrying process includes, but not limited to weighing, dissolving, mixing, drying, shaping, coating, spraying, granulation etc.As medicine is mixed and made into the sustained-release micro-spheres that contains different pharmaceutical with different adjuvant, this sustained-release micro-spheres is packing and storing separately, when using simultaneously or successively be injected in the body; This sustained-release micro-spheres also can further be shaped by several different methods, makes the sustained-release implant of different shape.
The same slow-releasing anticarcinogen injection of medicine in the sustained-release implant and weight ratio thereof, but be preferably as follows:
Anticancer effective component in the anticancer slow-release microsphere and percentage by weight are most preferably as follows:
The ZD6474 of 1-20%, Zarnestra, sirolimus, rapamycin, lenalidomide, Ai Sha is for health, gefitinib, Erlotinib, Lapatinib, votaranib, WAY-EKB 569, NSC 609974, Thalidomide, LS-2616, angiostatin, Endostatin, the blood vessel endothelium chalone, the endothelial growth factor receptor inhibitor, imatinib mesylate, Sugen 5416, BMS 354825, Avastin, Cl 1033, Sorafenib, Sutent, TLK286, ABX-EGF, Marimastat, SU5416, SU6668, the combination of the bortezomib of Amebacilin or TNP-470 and 5-20%.
The clinical practice dosage of effective ingredient depends on patient's concrete condition, can be from 0.01 to 1000mg/kg body weight, and 0.1 to 800mg/kg is preferred, 1 to 500mg/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 Erlotinib 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.Measure medicament contg (%) in the different time tumor, the result shows, the local drug concentration significant difference of Erlotinib 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 gefitinib compares
With the rat is subjects, with 2 * 10
5Individual thyroid adenoncus oncocyte subcutaneous injection is in its hypochondrium, treats behind tumor growth to 0.5 cm diameter its grouping.Every group of dosage is 5mg/kg.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 gefitinib 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 neovascularization inhibitor and bortezomib (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 through intratumor injection.Dosage is 2.5mg/kg.The treatment back was measured gross tumor volume size, relatively therapeutic effect (seeing Table 1) on the 30th day.
Table 1
| Test group (n) | Suffered treatment | Gross tumor volume (cm 3) | The P value |
| 1(6) | Contrast | 50±12 | |
| 2(6) | Bortezomib | 40±8.2 | ＜0.05 |
| 3(6) | ZD6474 | 42±6.0 | ＜0.01 |
| 4(6) | Zarnestra | 36±6.2 | ＜0.01 |
| 5(6) | Sirolimus | 38±5.8 | ＜0.01 |
| 6(6) | Rapamycin | 36±6.2 | ＜0.01 |
| 7(6) | Bortezomib+ZD6474 | 24±6.2 | ＜0.001 |
| 8(6) | Bortezomib+Zarnestra | 22±6.8 | ＜0.001 |
| 9(6) | Bortezomib+sirolimus | 18±4.4 | ＜0.001 |
| 10(6) | Bortezomib+rapamycin | 20±4.0 | ＜0.001 |
Above result shows, growth all has the obvious suppression effect to kinds of tumor cells when this concentration is used separately for neovascularization inhibitor (ZD6474, Zarnestra, sirolimus, rapamycin) and used bortezomib, can show significant potentiation when use in conjunction.
The tumor-inhibiting action of test 4, neovascularization inhibitor and bortezomib (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.Neovascularization inhibitor (gefitinib) and bortezomib are added in 24 hours the various tumor cells of In vitro culture by 10 μ g/ml concentration, continue to cultivate counting cells sum after 48 hours.Its growth of tumour cell suppresses effect and is shown in Table 2.
Table 2
| Oncocyte | Bortezomib | Erlotinib | Ai Sha is for health | Gefitinib | Lenalidomide | Erlotinib+bortezomib | Ai Sha is for health+bortezomib | Gefitinib+bortezomib | Lenalidomide+bortezomib |
| CNS | 56％ | 52％ | 64％ | 60％ | 64％ | 80％ | 90％ | 84％ | 84％ |
| C6 | 52％ | 64％ | 64％ | 60％ | 64％ | 82％ | 90％ | 88％ | 92％ |
| SA | 46％ | 62％ | 56％ | 62％ | 56％ | 82％ | 86％ | 90％ | 90％ |
| BC | 44％ | 64％ | 54％ | 64％ | 54％ | 78％ | 88％ | 86％ | 80％ |
| BA | 48％ | 60％ | 62％ | 66％ | 62％ | 82％ | 82％ | 84％ | 90％ |
| LH | 54％ | 58％ | 62％ | 52％ | 62％ | 80％ | 90％ | 88％ | 86％ |
| PAT | 58％ | 50％ | 60％ | 52％ | 60％ | 78％ | 90％ | 88％ | 86％ |
Above result shows, growth all has the obvious suppression effect to kinds of tumor cells when this concentration is used separately for used neovascularization inhibitor (Erlotinib, Ai Sha are for health, gefitinib, lenalidomide) and bortezomib, can show significant potentiation when use in conjunction.
The tumor-inhibiting action of test 5, neovascularization inhibitor and bortezomib (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.Bortezomib dosage is 1.5mg/kg, and neovascularization inhibitor dosage is 10mg/kg.The treatment back was measured gross tumor volume size, relatively therapeutic effect (seeing Table 3) on the 30th day.
Table 3
Above result shows, growth all has the obvious suppression effect to kinds of tumor cells when this concentration is used separately for used neovascularization inhibitor (Lapatinib, votaranib, WAY-EKB 569, Thalidomide) and bortezomib, can show significant potentiation when use in conjunction.
The tumor-inhibiting action of test 6, neovascularization inhibitor and bortezomib (slow releasing injection)
With the rat is subjects, with 2 * 10
5Individual brain 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 (neovascularization inhibitor or bortezomib) and therapeutic alliance group (neovascularization inhibitor and bortezomib).Medicine is through intratumor injection.Bortezomib dosage is 0.5mg/kg, and neovascularization inhibitor dosage is equal 5mg/kg.The treatment back was measured the gross tumor volume size on the 30th 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) | Bortezomib | 50 | ＜0.05 |
| 3(6) | Imatinib mesylate | 30 | ＜0.01 |
| 4(6) | Sugen 5416 | 44 | ＜0.01 |
| 5(6) | Sarmustine SarCNU | 42 | ＜0.01 |
| 6(6) | Avastin | 46 | ＜0.01 |
| 7(6) | Bortezomib+imatinib mesylate | 80 | ＜0.001 |
| 8(6) | Bortezomib+Sugen 5416 | 82 | ＜0.001 |
| 9(6) | Bortezomib+BMS 354825 | 72 | ＜0.001 |
| 10(6) | Bortezomib+Avastin | 76 | ＜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 neovascularization inhibitor (imatinib mesylate, Sugen 5416, BMS 354825, Avastin) and bortezomib, can show significant potentiation when use in conjunction.
The tumor-inhibiting action of test 7, neovascularization inhibitor and bortezomib (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, therapeutic alliance group.Medicine is through intratumor injection.Bortezomib dosage is 2.5mg/kg, and neovascularization inhibitor dosage is 10mg/kg.The treatment back was measured the gross tumor volume size on the 20th day, made relatively therapeutic effect (seeing Table 5) of index with inhibition rate of tumor growth.
Table 5
| Test group (n) | Suffered treatment | Tumor control rate (%) | The P value |
| 1(6) | Contrast | - | |
| 2(6) | Bortezomib | 52 | ＜0.05 |
| 3(6) | Sorafenib | 48 | ＜0.01 |
| 4(6) | Sutent | 50 | ＜0.01 |
| 5(6) | Ranimustine | 48 | ＜0.01 |
| 6(6) | TLK286 | 48 | ＜0.01 |
| 7(6) | Bortezomib+Cl 1033 | 78 | ＜0.001 |
| 8(6) | Bortezomib+Sorafenib | 84 | ＜0.001 |
| 9(6) | Bortezomib+Sutent | 80 | ＜0.001 |
| 10(6) | Bortezomib+TLK286 | 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 neovascularization inhibitor (Cl 1033, Sorafenib, Sutent, TLK286) and bortezomib, can show significant potentiation when use in conjunction.
The tumor-inhibiting action of test 8, neovascularization inhibitor and bortezomib (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.Bortezomib dosage is 2.5mg/kg, and neovascularization inhibitor dosage is 15mg/kg.The treatment back was measured the gross tumor volume size on the 20th day, made relatively therapeutic effect (seeing Table 6) of index with inhibition rate of tumor growth.
Table 6
Above result shows, growth all has the obvious suppression effect to kinds of tumor cells when this concentration is used separately for used neovascularization inhibitor (ABX-EGF, Marimastat, SU5416, SU6668) and bortezomib, can show significant potentiation when use in conjunction.
The tumor-inhibiting action of test 9, neovascularization inhibitor and bortezomib (sustained-release implant)
Measure the tumor-inhibiting action of neovascularization inhibitor and bortezomib (sustained-release implant) by test 8 described methods.
The result shows, growth all has the obvious suppression effect to the rectal neoplasm cell when this concentration is used separately for used neovascularization inhibitor (angiostatin, Endostatin, blood vessel endothelium chalone, endothelial growth factor receptor inhibitor, Amebacilin, TNP-470) and bortezomib, can show significant potentiation when use in conjunction.
The tumor-inhibiting action of test 10, neovascularization inhibitor and bortezomib (sustained-release implant)
Measure the tumor-inhibiting action of neovascularization inhibitor and bortezomib (sustained-release implant) by test 4 described methods.Found that the action effect (P＜0.05) that 25% the bortezomib according to the remarkable enhancing 30% of imatinib is grown to brain tumor cell.
In a word, growth all had the obvious suppression effect to kinds of tumor cells when used neovascularization inhibitor and various bortezomib were used separately, when use in conjunction, can show significant potentiation, growth all had the obvious suppression effect to kinds of tumor cells when various bortezomibs were used separately, also can show significant potentiation when use in conjunction.Therefore, effective ingredient of the present invention is the combination of any one or several neovascularization inhibitor and bortezomib.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.
With 90,90 and 80mg p (BHET-EOP/TC), BHET-EOP: TC is 80: 20) copolymer puts into first, second and the third three containers respectively, add 100 milliliters of dichloromethane then in each, behind the dissolving mixing, add 10mg Erlotinib, 10mg bortezomib, 10mg Erlotinib and 10mg bortezomib respectively, shake up the back again and contain 10% Erlotinib, 10% bortezomib, and the injectable microsphere of 10% Erlotinib and 10% bortezomib with spray drying method for preparation.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 40-50 days, is more than 50 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 used adjuvant is 50: 50 p (BHET-EOP/TC), contains anticancer effective component and percentage by weight thereof and is:
(1) Erlotinib of 5-30% or gefitinib;
(2) bortezomib of 5-30%; Or
(3) combination of the bortezomib of the Erlotinib of 5-30% or gefitinib and 5-30%.
Embodiment 3.
With 70mg molecular weight peak value is that the p (LAEG-EOP) of 10000-25000 puts into first, second and the third three containers respectively, add 100 milliliters of dichloromethane then in each, behind the dissolving mixing, in three containers, add 30mg gefitinib, 30mg bortezomib, 15mg gefitinib and 15mg bortezomib respectively, shake up the back contains 30% gefitinib, 30% bortezomib, 15% gefitinib and 15% bortezomib with spray drying method for preparation injectable microsphere again.Dried microsphere is suspended in the normal saline that contains 1.5% sodium carboxymethyl cellulose, makes corresponding suspension type slow releasing injection.The drug release time of this slow releasing injection in external normal saline is 50-65 days, is about 60 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 the molecular weight peak value of different is p (LAEG-EOP) is 25000-45000, and contained anticancer effective component and percentage by weight thereof are:
(1) bortezomib of 5-30%; Or
(2) 5-30% gefitinib; Or
(3) combination of the bortezomib of the gefitinib of 5-30% and 5-30%, bortezomib, fotemustine, bortezomib, lomustine, Ranimustine or Sarmustine SarCNU.
Embodiment 5.
With 70mg molecular weight peak value is that the p (DAPG-EOP) of 10000-25000 puts into container, after adding 100 milliliters of dichloromethane dissolving mixings, add 20 milligrams of bortezomibs and 10 milligrams of fotemustines, shake up the back contains 20% bortezomib and 10% fotemustine with spray drying method for preparation microsphere.Then microsphere is suspended in the injection that contains 15% sorbitol, makes corresponding suspension type slow releasing injection.The drug release time of this slow releasing injection in external normal saline is 45-55 days, is about 55 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 the molecular weight peak value of different is used adjuvant is 25000-45000, contains anticancer effective component and is:
(1) BMS 354825 of 5-30%; Or
(2) combination of the bortezomib of the BMS 354825 of 5-30% and 5-30%, bortezomib, fotemustine or bortezomib.
Embodiment 7.
With 70mg molecular weight peak value is the p (BHDPT-EOP/TC of 10000-25000,80/20) puts into container, add 100 milliliters of dichloromethane, behind the dissolving mixing, add 20mg Zarnestra and 10mg bortezomib, shake up the back contains 20% Zarnestra and 10% bortezomib 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 40-45 days, is about 50 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 the molecular weight peak value of different is p (BHDPT-EOP/TC) is 40000-65000, BHDPT-EOP: TC position 50: 50, and contained anticancer effective component is:
The Erlotinib of the bortezomib of 10-20%, bortezomib, fotemustine, bortezomib or lomustine and 10-25% or the combination of gefitinib.
Embodiment 9.
With 30mg polifeprosan (to carboxy phenyl propane (p-CPP): certain herbaceous plants with big flowers diacid (SA) is 20: 80) and 40mg molecular weight peak value is that p (DAPG-EOP) copolymer of 30000-45000 is put into container, add 100 milliliters of dichloromethane, behind the dissolving mixing, add 30mg Erlotinib, 30mg bortezomib, 15mg Erlotinib and 15mg bortezomib respectively, shake up the back again and contain 30% Erlotinib, 30% bortezomib, 15% Erlotinib and 15% bortezomib injectable microsphere with spray drying method for preparation.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 40-45 days, is about 45 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 in the polifeprosan to carboxy phenyl propane: the certain herbaceous plants with big flowers diacid is 50: 50, and the molecular weight peak value of p (DAPG-EOP) is 40000-65000, and contained anticancer effective component is:
(1) Erlotinib of 20-40% or gefitinib;
(2) bortezomib of 20-40%;
The combination of the bortezomib of (3) 20% Erlotinib or gefitinib and 20-40%.
Embodiment 11.
With 40mg molecular weight peak value is that (LAEG-EOP) of 20000-45000p and PLA copolymer that 30mg molecular weight peak value is 10000-25000 are put into container, add 100 milliliters of dichloromethane, behind the dissolving mixing, add 10mg fotemustine and 20mg rapamycin, shake up the back contains 10% fotemustine and 20% rapamycin 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 40-45 days, is about 45 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 used adjuvant contains anticancer effective component to be for the molecular weight peak value is that (LAEG-EOP) and the molecular weight peak value of 40000-65000p is the PLA of 25000-45000:
(1) bortezomib of 10-20%; Or
(2) combination of the bortezomib of the ZD6474 of 10-20%, Erlotinib, Zarnestra, sirolimus or rapamycin and 10-20%.
Embodiment 13.
With 40mg molecular weight peak value is the polylactic acid (PLGA of 15000-35000,50: 50) and 30 molecular weight peak values be that (LAEG-EOP) of 20000-45000p puts into container, add 100 milliliters of dichloromethane, behind the dissolving mixing, add 10mg rapamycin and 20mg bortezomib, shake up the back contains 10% rapamycin and 20% bortezomib 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 50-60 days, is about 60 days at the subcutaneous drug release time of mice.
Embodiment 14.
The method step of processing sustained-release implant is identical with embodiment 11,13, but different is that contained anticancer effective component is:
(1) bortezomib of 10-20%; Or
(2) lenalidomide of 10-20%, Ai Sha are for health, gefitinib, Erlotinib, Lapatinib, votaranib or WAY-EKB 569; Or
(3) lenalidomide of 10-20%, Ai Sha replace the combination of the bortezomib of health, gefitinib, Erlotinib, Lapatinib, votaranib or WAY-EKB 569 and 10-20%.
Embodiment 15.
With 70mg molecular weight peak value is polylactic acid and the co-glycolic acid (PLGA of 15000-35000,50: 50) put into container, add 100 milliliters of dichloromethane, behind the dissolving mixing, add 10mg rapamycin and 20mg bortezomib, shake up the back contains 10% rapamycin and 20% bortezomib 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 50-60 days, is about 60 days at the subcutaneous drug release time of mice.
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 of processing sustained-release implant is identical with embodiment 11,13, but different is that contained anticancer effective component is:
(1) ZD6474 of 1-40%, Zarnestra, sirolimus, rapamycin, lenalidomide, Ai Sha is for health, gefitinib, Erlotinib, Lapatinib, votaranib, WAY-EKB 569, NSC 609974, Thalidomide, LS-2616, angiostatin, Endostatin, the blood vessel endothelium chalone, the endothelial growth factor receptor inhibitor, imatinib mesylate, Sugen 5416, BMS 354825, Avastin, Cl 1033, Sorafenib, Sutent, TLK286, ABX-EGF, Marimastat, SU5416, SU6668, Amebacilin or TNP-470;
(2) bortezomib of 1-40%; Or
(3) ZD6474 of 1-40%, Zarnestra, sirolimus, rapamycin, lenalidomide, Ai Sha is for health, gefitinib, Erlotinib, Lapatinib, votaranib, WAY-EKB 569, NSC 609974, Thalidomide, LS-2616, angiostatin, Endostatin, the blood vessel endothelium chalone, the endothelial growth factor receptor inhibitor, imatinib mesylate, Sugen 5416, BMS 354825, Avastin, Cl 1033, Sorafenib, Sutent, TLK286, ABX-EGF, Marimastat, SU5416, SU6668, the combination of the bortezomib of Amebacilin or TNP-470 and 1-40%.
Drug release characteristic (table 7) after embodiment 18. more different slow-release auxiliary material and the combination thereof
The method step of processing sustained-release implant is identical with embodiment 11, the drug release characteristic after more different slow-release auxiliary material and the combination thereof.First day release amount of medicine (external) surpass 20% of total amount and release for prominent.
Table 7
Data show in the table, and when PLA, PLGA (50/50) and polifeprosan sugared acid anhydride family macromolecule polymer such as (20/80) were used separately, drug release was very fast, and wherein the drug release time of polifeprosan is 8-10 days and obviously prominent releasing arranged.P (LAEG-EOP) and p poly phosphate high molecular polymer releases such as (DAPG-EOP) are slow and steady, can alleviate caused prominent the releasing of the latter when share with sugared acid anhydride family macromolecule polymer such as PLA, PLGA, polifeprosans, but its steadily slowly drug release feature be not subjected to too big influence
Drug release characteristic (table 8) after embodiment 19. more different slow-release auxiliary material and the combination thereof
The method step of processing sustained-release implant is identical with embodiment 11, the drug release characteristic after more different slow-release auxiliary material and the combination thereof.First day release amount of medicine (external) surpass 20% of total amount and release for prominent.
Table 8
Data show in the table, and when PLA, PLGA (50/50) and polifeprosan sugared acid anhydride family macromolecule polymer such as (20/80) were used separately, drug release was very fast, and wherein the drug release time of polifeprosan is 10-13 days and obviously prominent releasing arranged.P (LAEG-EOP) and p poly phosphate high molecular polymer releases such as (DAPG-EOP) are slow and steady, can alleviate caused prominent the releasing of the latter when share with sugared acid anhydride family macromolecule polymer such as PLA, PLGA, polifeprosans, but its steadily slowly drug release feature be not subjected to too big influence.This beyond thought discovery constitutes another major technique feature of the present invention.Because the poly phosphate high molecular polymer costs an arm and a leg, this will help reducing the cost of slow releasing preparation, and improve its drug release feature.
Above embodiment only is used for explanation, and is not limitation application of the present invention.
The present invention disclosed and the protection the content see claim.
Claims (10)
1. anti-cancer composition that contains neovascularization inhibitor and bortezomib is characterized in that anti-cancer composition is a slow releasing injection, is grouped into by following one-tenth:
(A) sustained-release micro-spheres comprises:
Anticancer effective component 0.5-70%
Slow-release auxiliary material 30-99%
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 neovascularization inhibitor and bortezomib;
The viscosity of suspending agent is 100cp-3000cp (20 ℃-30 ℃ time), is selected from one of sodium carboxymethyl cellulose, iodine glycerol, simethicone, propylene glycol, carbomer, mannitol, sorbitol, surfactant, polysorbas20, polysorbate40 and Tween 80 or its combination;
Cancer is for coming from 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, colon, former or cancer or sarcoma or the carcinosarcoma that shifts of rectum, be selected from the cerebral tumor, cerebral glioma, renal carcinoma, hepatocarcinoma, carcinoma of gallbladder, tumor of head and neck, oral cancer, thyroid carcinoma, skin carcinoma, hemangioma, osteosarcoma, lymphoma, pulmonary carcinoma, thymic carcinoma, the esophageal carcinoma, gastric cancer, breast carcinoma, cancer of pancreas, the retinoblastoma of eyes, nasopharyngeal carcinoma, ovarian cancer, carcinoma of endometrium, cervical cancer, carcinoma of prostate, bladder cancer, colon cancer, rectal cancer, carcinoma of testis, the He Jiejin lymphoma, non_hodgkin lymphoma, small cell lung cancer, nonsmall-cell lung cancer.
2. the slow-releasing anticarcinogen injection according to claim 1 is characterized in that neovascularization inhibitor mainly is selected from ZD6474, Zarnestra, sirolimus, rapamycin, lenalidomide, Ai Sha is for health, gefitinib, Erlotinib, Lapatinib, votaranib, WAY-EKB 569, NSC 609974, Thalidomide, LS-2616, angiostatin, Endostatin, the blood vessel endothelium chalone, the endothelial growth factor receptor inhibitor, imatinib mesylate, Sugen 5416, BMS 354825, Avastin, Cl 1033, Sorafenib, Sutent, TLK286, ABX-EGF, Marimastat, SU5416, SU6668, Amebacilin, one of TNP-470 or its combination.
3. the slow-releasing anticarcinogen injection according to claim 1 is characterized in that bortezomib is selected from alestramustine; atrimustine; ambamustine; bortezomib; bortezomib; ditiomustine; bofumustine; bortezomib; elmustine; ecomustine; galamustine; fotemustine; estramustine; hemustine heCNU He; pentamustine; mannomustine; lomustine; methyl lomustine; semustine; Ranimustine; sprinkle bortezomib; uracil mustard; Sarmustine SarCNU; tauromustine; tallimustine; one of spiromustine or its combination.
4. the slow-releasing anticarcinogen injection according to claim 1, the weight ratio that it is characterized in that neovascularization inhibitor and bortezomib is 1-9: 1 to 1: 1-9.
5. the slow-releasing anticarcinogen injection according to claim 1 is characterized in that the anticancer effective component of slow-releasing anticarcinogen injection is:
The ZD6474 of 1-40%, Zarnestra, sirolimus, rapamycin, lenalidomide, Ai Sha is for health, gefitinib, Erlotinib, Lapatinib, votaranib, WAY-EKB 569, NSC 609974, Thalidomide, LS-2616, angiostatin, Endostatin, the blood vessel endothelium chalone, the endothelial growth factor receptor inhibitor, imatinib mesylate, Sugen 5416, BMS 354825, Avastin, Cl 1033, Sorafenib, Sutent, TLK286, ABX-EGF, Marimastat, SU5416, SU6668, the combination of the bortezomib of Amebacilin or TNP-470 and 1-40%;
Below all be weight percentage;
Slow-release auxiliary material is one of following or its combination:
A) poly-(1,4-two (hydroxyl ethyl ester) terephthalate-co-etherophosphoric acid/terephthalic acids ester hydrochloride ester), poly-(L-lactide-co-etherophosphoric acid, poly-(L-lactide-co-phosphoric acid propyl ester), poly-(1,4-two (hydroxyl ethyl ester) terephthalate-co-4-dimethylamino pyridine-co-etherophosphoric acid/terephthalic acids ester hydrochloride), poly-(anti-(formula)-1,4-dimethyl cyclohexane-etherophosphoric acid) or poly-(anti-(formula)-1,4-dimethyl cyclohexane-hexyl dichloro-phosphate ester (p (CHDM-EOP));
B) poly-(1,4-two (hydroxyl ethyl ester) terephthalate-co-etherophosphoric acid/terephthalic acids ester hydrochloride ester), poly-(L-lactide-co-etherophosphoric acid, poly-(L-lactide-co-phosphoric acid propyl ester), poly-(1,4-two (hydroxyl ethyl ester) terephthalate-co-4-dimethylamino pyridine-co-etherophosphoric acid/terephthalic acids ester hydrochloride), poly-(anti-(formula)-1,4-dimethyl cyclohexane-etherophosphoric acid) or poly-(anti-(formula)-1, the combination of the copolymer of 4 dimethyl cyclohexanes-hexyl dichloro-phosphate ester (p (CHDM-EOP)) and polylactic acid and hydroxyacetic acid, wherein, the ratio of polylactic acid and hydroxyacetic acid is 50-95: 50-50;
C) poly-(1,4-two (hydroxyl ethyl ester) terephthalate-co-etherophosphoric acid/terephthalic acids ester hydrochloride ester), poly-(L-lactide-co-etherophosphoric acid, poly-(L lactide-co-phosphoric acid propyl ester), poly-(1,4-two (hydroxyl ethyl ester) terephthalate-co-4-dimethylamino pyridine-co-etherophosphoric acid/terephthalic acids ester hydrochloride), poly-(anti-(formula)-1,4-dimethyl cyclohexane-etherophosphoric acid) or poly-(anti-(formula)-1, the combination of 4-dimethyl cyclohexane-hexyl dichloro-phosphate ester (p (CHDM-EOP)) and polylactic acid;
D) poly-(1,4-two (hydroxyl ethyl ester) terephthalate-co-etherophosphoric acid/terephthalic acids ester hydrochloride ester), poly-(L-lactide-co-etherophosphoric acid, poly-(L-lactide-co-phosphoric acid propyl ester), poly-(1,4-two (hydroxyl ethyl ester) terephthalate-co-4-dimethylamino pyridine-co-etherophosphoric acid/terephthalic acids ester hydrochloride), poly-(anti-(formula)-1,4-dimethyl cyclohexane-etherophosphoric acid) or poly-(anti-(formula)-1, the combination of 4-dimethyl cyclohexane-hexyl dichloro-phosphate ester (p (CHDM-EOP)) and polifeprosan, wherein in the polifeprosan to carboxy phenyl propane: the certain herbaceous plants with big flowers diacid is 10: 90,20: 80,30: 70,40: 60,50: 50 or 60: 40; Or
E) poly-(1,4-two (hydroxyl ethyl ester) terephthalate-co-etherophosphoric acid/terephthalic acids ester hydrochloride ester), poly-(L-lactide-co-etherophosphoric acid, poly-(L-lactide-co-phosphoric acid propyl ester), poly-(1,4-two (hydroxyl ethyl ester) terephthalate-co-4-dimethylamino pyridine-co-etherophosphoric acid/terephthalic acids ester hydrochloride), poly-(anti-(formula)-1,4-dimethyl cyclohexane-etherophosphoric acid) or poly-(anti-(formula)-1,4-dimethyl cyclohexane-hexyl dichloro-phosphate ester (p (CHDM-EOP)) and bis-fatty acid and decanedioic acid copolymer, poly-(erucic acid dimer-decanedioic acid), poly-(fumaric acid-decanedioic acid), xylitol, oligosaccharide, chrondroitin, chitin, chitosan, poloxamer, hyaluronic acid, collagen protein, the combination of gelatin or white tempera; Or
F) copolymer of polylactic acid, lactic acid and hydroxyacetic acid or polifeprosan.
6. according to claim 1 or 5 described slow-releasing anticarcinogen injections, it is characterized in that used suspending agent is respectively 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; Or
F) glycerol, simethicone, propylene glycol or carbomer.
7. the slow-releasing anticarcinogen injection according to claim 1 is characterized in that used suspending agent is one of following:
A) 0.5-5% sodium carboxymethyl cellulose+0.1-0.5% Tween 80;
B) 5-20% mannitol+0.1-0.5% Tween 80; Or
C) 0.5-5% sodium carboxymethyl cellulose+5-20% sorbitol+0.1-0.5% Tween 80.
8. be used to prepare sustained-release implant according to the described anticancer slow-release microsphere of claim 1.
9. described according to Claim 8 anti-cancer sustained-released implantation agent is characterized in that anticancer effective component is:
The ZD6474 of 1-40%, Zarnestra, sirolimus, rapamycin, lenalidomide, Ai Sha is for health, gefitinib, Erlotinib, Lapatinib, votaranib, WAY-EKB 569, NSC 609974, Thalidomide, LS-2616, angiostatin, Endostatin, the blood vessel endothelium chalone, the endothelial growth factor receptor inhibitor, imatinib mesylate, Sugen 5416, BMS 354825, Avastin, Cl 1033, Sorafenib, Sutent, TLK286, ABX-EGF, Marimastat, SU5416, SU6668, the combination of the bortezomib of Amebacilin or TNP-470 and 1-40%.
10. described according to Claim 8 anti-cancer sustained-released implantation agent, it is one of following to it is characterized in that slow-release auxiliary material is selected from:
A) poly-(1,4-two (hydroxyl ethyl ester) terephthalate-co-etherophosphoric acid/terephthalic acids ester hydrochloride ester), poly-(L-lactide-co-etherophosphoric acid, poly-(L-lactide-co-phosphoric acid propyl ester), poly-(1,4-two (hydroxyl ethyl ester) terephthalate-co-4-dimethylamino pyridine-co-etherophosphoric acid/terephthalic acids ester hydrochloride), poly-(anti-(formula)-1,4-dimethyl cyclohexane-etherophosphoric acid) or poly-(anti-(formula)-1,4-dimethyl cyclohexane-hexyl dichloro-phosphate ester (p (CHDM-EOP));
B) poly-(1,4-two (hydroxyl ethyl ester) terephthalate-co-etherophosphoric acid/terephthalic acids ester hydrochloride ester), poly-(L-lactide-co-etherophosphoric acid, poly-(L-lactide-co-phosphoric acid propyl ester), poly-(1,4-two (hydroxyl ethyl ester) terephthalate-co-4-dimethylamino pyridine-co-etherophosphoric acid/terephthalic acids ester hydrochloride), poly-(anti-(formula)-1,4-dimethyl cyclohexane-etherophosphoric acid) or poly-(anti-(formula)-1, the combination of the copolymer of 4-dimethyl cyclohexane-hexyl dichloro-phosphate ester (p (CHDM-EOP)) and polyglycolic acid and hydroxyacetic acid, wherein, the ratio of polyglycolic acid and hydroxyacetic acid is 50-95: 50-50;
C) poly-(1,4-two (hydroxyl ethyl ester) terephthalate-co-etherophosphoric acid/terephthalic acids ester hydrochloride ester), poly-(L-lactide-co-etherophosphoric acid, poly-(L-lactide-co-phosphoric acid propyl ester), poly-(1,4-two (hydroxyl ethyl ester) terephthalate-co-4-dimethylamino pyridine-co-etherophosphoric acid/terephthalic acids ester hydrochloride), poly-(anti-(formula)-1,4-dimethyl cyclohexane-etherophosphoric acid) or poly-(anti-(formula)-1, the combination of 4-dimethyl cyclohexane-hexyl dichloro-phosphate ester (p (CHDM-EOP)) and polylactic acid;
D) poly-(1,4-two (hydroxyl ethyl ester) terephthalate-co-etherophosphoric acid/terephthalic acids ester hydrochloride ester), poly-(L-lactide-co-etherophosphoric acid, poly-(L-lactide-co-phosphoric acid propyl ester), poly-(1,4-two (hydroxyl ethyl ester) terephthalate-co-4-dimethylamino pyridine-co-etherophosphoric acid/terephthalic acids ester hydrochloride), poly-(anti-(formula)-1,4-dimethyl cyclohexane-etherophosphoric acid) or poly-(anti-(formula)-1, the combination of 4-dimethyl cyclohexane-hexyl dichloro-phosphate ester (p (CHDM-EOP)) and polifeprosan, wherein in the polifeprosan to carboxy phenyl propane: the certain herbaceous plants with big flowers diacid is 10: 90,20: 80,30: 70,40: 60,50: 50 or 60: 40; Or
E) poly-(1,4-two (hydroxyl ethyl ester) terephthalate-co-etherophosphoric acid/terephthalic acids ester hydrochloride ester), poly-(L-lactide-co-etherophosphoric acid, poly-(L-lactide-co-phosphoric acid propyl ester), poly-(1,4-two (hydroxyl ethyl ester) terephthalate-co-4-dimethylamino pyridine-co-etherophosphoric acid/terephthalic acids ester hydrochloride), poly-(anti-(formula)-1,4-dimethyl cyclohexane-etherophosphoric acid) or poly-(anti-(formula)-1,4-dimethyl cyclohexane-hexyl dichloro-phosphate ester (p (CHDM-EOP)) and bis-fatty acid and decanedioic acid copolymer, poly-(erucic acid dimer-decanedioic acid), poly-(fumaric acid-decanedioic acid), xylitol, oligosaccharide, chrondroitin, chitin, chitosan, poloxamer, hyaluronic acid, collagen protein, the combination of gelatin or white tempera; Or
F) copolymer of polylactic acid, lactic acid and hydroxyacetic acid or polifeprosan.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2010118683A1 (en) * | 2009-04-16 | 2010-10-21 | 北京圣医耀科技发展有限责任公司 | Targeted sustained-release microsphere of vascular occlusive agent containing sodium alginate and sorafenib, production method and use thereof |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2010118683A1 (en) * | 2009-04-16 | 2010-10-21 | 北京圣医耀科技发展有限责任公司 | Targeted sustained-release microsphere of vascular occlusive agent containing sodium alginate and sorafenib, production method and use thereof |
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