CN101264052A - Compound anticancer sustained-release agent containing clofarabine - Google Patents
Compound anticancer sustained-release agent containing clofarabine Download PDFInfo
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Abstract
The invention discloses an anticancer compound sustained release injection containing clofarabine, which comprises sustained release microspheres and solvent, wherein, the sustained release microsphere comprises active anti-cancer ingredient and sustained release accessories; the active anti-cancer ingredient is the combination of clofarabine and the potentiating agent of clofarabine selected from anti-tumor antibiotic and / or anti-metabolism drug; the solvent is special solvent comprising suspending agent; the sustained release accessories are selected from polylactic acid / glycollic acid copolymer, monomethy polyethylene glycol / polylactic acid, polyethylene glycol / polylactic acid, carboxyl end group polylactic acid, carboxyl end group polylactic acid / glycollic acid copolymer, EVAc, fatty acid and sebacic acid copolymer; the viscosity of suspending agent is 80cp-3000cp (when temperature is 20 DEG C to 30 DEG C) and selected from carboxymethyl cellulose and other substances; the sustained release microspheres also can be produced into sustained-release implant, which can be injected in tumor or around tumor, or the substained-release agent can be arranged and released about 30 to 50 days at partial part. The anticancer compound sustained release injection has the advantages of effectively inhibiting growth of tumor if the sustained release injection and the sustained-release implant can be singly applied and obviously enhancing therapeutic effect if joint applied with chemotherapeutic drug and / or radiotherapy and other non operative treatment.
Description
(1) technical field
The present invention relates to the compound anticancer sustained releasing agent of a kind of chloride farad shore, belong to technical field of pharmaceuticals.Particularly, be the slow releasing agent of anti entity tumour, comprise slow releasing injection and sustained-release implant.
(2) background technology
Clofarabine (Clofarabine) has been widely used in treating children acute myelocytic leukemia (ALL), recurrence or repellence acute myeloid leukemia (AML), has become multiple malignant tumor such as human leukemia and entity tumor as the new chemotherapeutics of a class, and action effect is comparatively obvious.Yet its tangible general toxicity has greatly limited the application of this medicine.
Moreover, blood vessel in the mesenchyma stroma of tumors, connective tissue, stromatin, fibrin and collagen protein etc. not only provide support and requisite nutrient substance for the growth of tumor cell, also influenced chemotherapeutics around tumor and the infiltration in the tumor tissues and diffusion (carry and to wait " situation of extracellular matrix to entity tumor in the medicine influence of turning round " " cancer research " 60 phase 2497-503 page or leaf (2000) (Netti PA referring to the Buddhist nun, Cancer Res.2000,60 (9): 2497-503)).Because entity tumor excessive expansion hypertrophy, the viscosity of matter was high than its normal surrounding tissue all between matter pressure, tissue elasticity pressure, fluid pressure reached therebetween, therefore, conventional chemotherapy, be difficult to tumor by local and form effective drug level, referring to " placing cisplatin adding system carmustine treatment rat brain tumor in the tumor " " surgery tumor magazine " 69 phase 76-82 pages or leaves (1998) (Kong Q et al., J Surg Oncol.1998 Oct such as Kong Qingzhongs; 69 (2): 76-82), improve the restriction that dosage is subjected to general reaction again merely.Pharmaceutical topical application may solve the problem (Chinese patent) of drug level to a certain extent, yet operation techniques such as medicine implantation are complicated, traumatic big, the various complication such as, infection hemorrhage, immunity reduction, also can cause or quicken the diffusion and the transfer of tumor except that easily causing.In addition, the preparation of perioperatively itself and expensive expense usually influence its effective enforcement.
In addition, the cancer drug therapy of low dosage not only can increase the Drug tolerance of cancerous cell, but also can promote its infiltrative growth " (referring to beam etc. " increased the Drug tolerance of human lung carcinoma cell and external wetting capacity after the cancer therapy drug pulse screening and with the change of gene expression " " international journal of cancer " 111 phase 484-93 page or leaf (2004) (Liang Y; etal., Int J Cancer.2004; 111 (4): 484-93)).
Therefore, be convenient to keep high drug level and increase tumor cell the preparation and the method for the sensitivity of medicine just become an important subject at tumor by local.
(3) summary of the invention
The present invention is directed to the deficiencies in the prior art, the compound anticancer sustained releasing agent of a kind of chloride farad shore is provided, more specifically, is the slow releasing agent of anti entity tumour, comprises slow releasing injection and sustained-release implant.
Anti-cancer medicine sustained-release injection of the present invention is made up of sustained-release micro-spheres and solvent.Particularly, this slow-releasing anticarcinogen injection is grouped into by following one-tenth:
Sustained-release microparticle, the one-tenth following by percentage by weight is grouped into:
Anticancer effective component 0.5-60%
Slow-release auxiliary material 41-99.9%
Suspending agent 0.0-30%
Solvent is divided into common solvent and special solvent.
Anticancer effective component is clofarabine and clofarabine synergist, and the clofarabine synergist is to have the medicine that suppresses growth of tumour cell, is selected from antitumor antibiotics and antimetabolitas.The decapacitation of clofarabine synergist suppresses can also increase the sensitivity of tumor cell to clofarabine outside the tumor growth.
The drug main that clofarabine is made is wanted conventional route administrations such as oral administration or intravenous injection, and administering mode of the present invention is the local sustained release administration, obviously reduces the toxic action of its whole body in the therapeutic effect that significantly strengthens medicine.With regard to clofarabine, be not the slow release effect that all slow-release auxiliary material all can reach effective release with active anticancer.Pharmaceutic adjuvant have hundreds of more than, pharmaceutic adjuvant with slow releasing function, particularly the pharmaceutic adjuvant that selected clofarabine among the present invention slowly can be discharged in the regular hour in human body or animal body must could obtain through a large amount of creationary experiments, specific slow-release auxiliary material and can need be passed through a large amount of creative works by the selection of the combination of slow releasing pharmaceutical and could determine.The data of release characteristics need could obtain through a large amount of creationary experiments in inside and outside in the related data, particularly animal body, are not just can determine to have unobviousness through limited experiment.
The above unexpected main contents of the present invention of finding to constitute.
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), PPDO (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.
Clofarabine 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.Above clofarabine 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.
Antitumor antibiotics mainly be selected from doxorubicin hydrochloride (adriamycin), triferricdoxorubicin, epirubicin (epiadriamycin), 7-O-methyl Nuo Jia-4 '-epirubicin (7-o-methylnogallol-4 '-epiadriamycin), diethoxy acetyl amycin, mitomycin (Mitomycin), ametycin (mitomycin C), NSC-69529, actinomycin D (Dactinomycin), actinomycin C, cyclosporin A.Serve as preferred wherein with amycin, epirubicin, ametycin, actinomycin D, dactinomycin.Above antitumor antibiotics medicine also comprises its salt, as, but be not limited to sulfate, phosphate, hydrochlorate, Lactobionate, acetate, aspat, nitrate, citrate, purine or pyrimidine salt, succinate or maleate.
Above-mentioned antitumor antibiotic shared ratio in slow releasing injection is decided because of concrete condition, can be 0.1%-50%, is good with 1%-40%, and 2%-30% is best.
Antimetabolitas can stop the synthetic of DNA in different links respectively, suppresses cell division propagation, and cell cycle and DNA are synthetic to play a role by influencing.
Antimetabolitas is selected from one of following or combination: floxuridine (fluridine), doxifluridine (Doxifloridine, fortulon), the 5-doxifluridine, propylthiouracil, fluorouracil (Fluoracil, Fluracil), the fluorobutane uracil, tegadifurum, the 5-fluoxydin, sulfomercaprine sodium, mercaptopurine (Mercaptopurine, happy disease is peaceful, 6-MP), mercapto miaow purine, Ismipur, the adenine hydrochlorate, Benin, thioguanine (thioguanine, 6-TG), methotrexate (methotrexate, MTX), fluoromethotrexate, the dioxy methotrexate, folic acid, 10-ethyl denitrification aminopterin (deaza-aminopterin), fluoromethotrexate, the dioxy methotrexate, 5, the 10-lonetrexol, N5-Methyltetrahydrohmofotic Acid, carmofur (Carmofur), ftorafur (Tegafur, tegafur, FT-207), UFT (Tegafur-Uracil, UFT), Tegafur-uracil mixt., 8-azaguanine (8-azaguanine), uracil, 5-mercaptomethyluracil, calcium levofolinate, calcium folinate (Calcium Levofolinate, calcium leucovorin), hycamtin, topotecan hydrochloride, cytosine arabinoside (cytosine arabinoside, Cytarabine (Ara-C)), ancitabine (cyclotidine, Cyclocytidine), ancitabine (cyclotidine, Cyclocytidine), hydroxyurea (Hydroxycarbamide, hydroxyurea), the hydroxyl guanidine.
In the above antimetabolite with floxuridine, doxifluridine, the 5-doxifluridine, propylthiouracil, fluorouracil, the fluorobutane uracil, tegadifurum, the 5-fluoxydin, sulfomercaprine sodium, mercaptopurine, mercapto miaow purine, Ismipur, the adenine hydrochlorate, Benin, thioguanine, methotrexate, fluoromethotrexate, the dioxy methotrexate, 10-ethyl denitrification aminopterin, the dioxy methotrexate, N5-Methyltetrahydrohmofotic Acid, folic acid, 5, the 10-lonetrexol, calcium levofolinate, calcium folinate, carmofur, ftorafur, UFT, Tegafur-uracil mixt., the 8-azaguanine, uracil, 5-mercaptomethyluracil, hycamtin, topotecan hydrochloride, cytosine arabinoside, ancitabine, hydroxyurea, the hydroxyl guanidine is preferred.
The percentage by weight of above-mentioned antimetabolitas in slow releasing injection is 0.1%-50%, is good with 1%-40%, and 2%-30% is best.
When the anticancer effective component in the medicament slow-release microsphere only is clofarabine or clofarabine synergist, slow-releasing anticarcinogen injection is mainly used in the clofarabine of other approach application of increase or the action effect of clofarabine synergist, or is used for the potentiation to radiotherapy or other therapies.When the cancer therapy drug in the medicament slow-release microsphere only was clofarabine or its synergist, the application of slow-releasing anticarcinogen injection and potentiation mode were:
(1) the slow releasing injection local injection of chloride farad of shore, and the clofarabine synergist is used through other approach;
(2) slow releasing injection of the chloride farad of local injection shore synergist, other approach are used clofarabine;
(3) slow releasing injection of the slow releasing injection of the chloride farad of local injection shore and chloride farad shore synergist; Or
(4) slow releasing injection of local injection chloride farad shore 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, be not limited to tremulous pulse, vein, abdominal cavity, subcutaneous, intracavitary administration.
Anticancer effective component clofarabine and/or the percentage by weight of clofarabine synergist in medicament slow-release microsphere are 0.1%-50%, are good with 1%-40%, and 2%-30% is best.The weight ratio of clofarabine and clofarabine synergist is 1-9: 1 to 1: 1-9, with 1-2: 1 serves as preferred.
Anticancer effective component is a kind of or the combination of several clofarabines and/or a kind of or several anticarcinogens in the anticancer pharmaceutical composition of the present invention, and the anticancer effective component preferred compositions is as follows:
(1) combination of the amycin of the clofarabine of 1-40% and 1-40%, epirubicin, ametycin, actinomycin D or dactinomycin; Or
(2) floxuridine of the clofarabine of 1-40% and 1-40%, doxifluridine, the 5-doxifluridine, propylthiouracil, fluorouracil, the fluorobutane uracil, tegadifurum, the 5-fluoxydin, sulfomercaprine sodium, mercaptopurine, mercapto miaow purine, Ismipur, the adenine hydrochlorate, Benin, thioguanine, methotrexate, fluoromethotrexate, the dioxy methotrexate, 10-ethyl denitrification aminopterin, N5-Methyltetrahydrohmofotic Acid, folic acid, 5, the 10-lonetrexol, calcium levofolinate, calcium folinate, carmofur, ftorafur, UFT, Tegafur-uracil mixt., the 8-azaguanine, uracil, 5-mercaptomethyluracil, hycamtin, topotecan hydrochloride, cytosine arabinoside, ancitabine, hydroxyurea, the combination of hydroxyl guanidine.
Slow-release auxiliary material of the present invention can be through enzyme, soda acid or tissue fluid hydrolysis or degraded, comprises one of following or its combination:
(1) biocompatibility polymer comprises biodegradable or biological nondegradable polymer and composition thereof or copolymer;
(2) water-soluble low-molecular chemical compound; Or/and
(3) be used to realize the suitable additive and the excipient of pharmaceutical dosage forms such as injection and slow releasing agent.
Slow-release auxiliary material can be various water solublity or water-insoluble macromolecule polymer, and 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 dimerization-body 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 slow-release auxiliary material, 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.; 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.
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, 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 Tween 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).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 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, 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.
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.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.
The anticancer effective component of sustained-release implant is preferably as follows, and all is weight percentage:
(1) combination of the amycin of the clofarabine of 1-40% and 1-40%, epirubicin, ametycin, actinomycin D or dactinomycin; Or
(2) floxuridine of the clofarabine of 1-40% and 1-40%, doxifluridine, the 5-doxifluridine, propylthiouracil, fluorouracil, the fluorobutane uracil, tegadifurum, the 5-fluoxydin, sulfomercaprine sodium, mercaptopurine, mercapto miaow purine, Ismipur, the adenine hydrochlorate, Benin, thioguanine, methotrexate, fluoromethotrexate, the dioxy methotrexate, 10-ethyl denitrification aminopterin, N5-Methyltetrahydrohmofotic Acid, folic acid, 5, the 10-lonetrexol, calcium levofolinate, calcium folinate, carmofur, ftorafur, UFT, Tegafur-uracil mixt., the 8-azaguanine, uracil, 5-mercaptomethyluracil, hycamtin, topotecan hydrochloride, cytosine arabinoside, ancitabine, hydroxyurea, the combination of hydroxyl guanidine.
Sustained-release micro-spheres also can be used for preparing sustained-release implant, and used slow-release auxiliary material can be any or multiple material in the above-mentioned pharmaceutic adjuvant, is main separation with the high molecular weight water soluble polymer in various high molecular polymers.
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.
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 application of sustained-release implant and the same slow-releasing anticarcinogen injection of potentiation mode, the clofarabine synergist that place the associating of the clofarabine of the associating of the synergist of the promptly local clofarabine of placing and other administration, the local clofarabine synergist of placing and other administration, part and the associating of the local clofarabine of placing.Wherein the clofarabine synergist of topical application and clofarabine 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 present invention can be used to prepare the pharmaceutical preparation of the various tumors for the treatment of people and animal, be mainly slow releasing injection or sustained-release implant, the indication tumor comprises former or cancer or sarcoma or the carcinosarcoma that shifts that originates from brain, central nervous system, kidney, liver, gallbladder, incidence, oral cavity, thyroid, skin, mucosa, body of gland, blood vessel, osseous tissue, lymph node, lungs, esophagus, stomach, mammary gland, pancreas, eyes, nasopharynx part, uterus, ovary, endometrium, cervix uteri, prostate, bladder, colon, rectum.
Also can add other medicinal ingredient in slow releasing injection that the present invention is made or the sustained-release implant, as, but be not limited to antibiotics, antalgica, anticoagulant medicine, hemorrhage etc.
By following test and embodiment the technology of composition for treating solid tumor of the present invention is further described:
Tumor-inhibiting action in the body of test one, clofarabine and clofarabine synergist.
With the rat is subjects, with 2 * 10
5Individual colon cancer 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 wherein, the 2nd group is clofarabine, and the 3rd to 6 group is respectively amycin, epirubicin, ametycin, actinomycin D.The the 7th to 10 group of associating that is respectively clofarabine and amycin, epirubicin, ametycin, actinomycin D.Outside placed in tumor dechlorination farad shore, amycin, epirubicin, ametycin, actinomycin D were intraperitoneal administration.Dosage measuring dechlorination farad shore is that 10mg/kg is 5mg/kg outward.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 | 68±16 | |
| 2(6) | Clofarabine | 28±6 | ＜0.05 |
| 3(6) | Amycin | 52±12 | ＜0.05 |
| 4(6) | Epirubicin | 54±12 | ＜0.05 |
| 5(6) | Ametycin | 54±10 | ＜0.01 |
| 6(6) | Actinomycin D | 44±8 | ＜0.01 |
| 7(6) | Clofarabine+amycin | 22±4 | ＜0.001 |
| 8(6) | Clofarabine+epirubicin | 24±6 | ＜0.001 |
| 9(6) | Clofarabine+ametycin | 16±4 | ＜0.001 |
| 10(6) | Clofarabine+actinomycin D | 18±4 | ＜0.001 |
Annotate: amycin, epirubicin, ametycin, actinomycin D are antitumor antibiotic.The result shows, compares with matched group, and clofarabine (the 2nd group) and antitumor antibiotic (the 3rd to 6 group) application separately all have certain tumor-inhibiting action (P＜0.05), particularly topical.And use in conjunction (the 7th to 10 group) has obvious synergistic effect (P＜0.001).
Tumor-inhibiting action in the body of test two, clofarabine and clofarabine synergist.
Measure tumor-inhibiting action in the body of clofarabine and clofarabine synergist according to testing a described method, the result shows that clofarabine synergists such as amycin, epirubicin, ametycin, actinomycin D or dactinomycin can obviously strengthen the tumor-inhibiting action (P＜0.05) of clofarabine.The two uses separately particularly that topical all has certain tumor-inhibiting action (P＜0.05), and use in conjunction has obvious synergistic effect (P＜0.001).
Test three, topical application anti-metabolism cancer therapy drug are to the potentiation of clofarabine.
With the rat is subjects, with 2 * 10
5Individual tumor cell subcutaneous injection is in its hypochondrium, treats that tumor growth after 14 days is divided into it following 10 groups (seeing Table 2).First group is contrast, and the 2nd to 10 group is the treatment group, and wherein, the 2nd group is clofarabine, and the 3rd to 6 group is respectively 5-fluorouracil, Ismipur, methotrexate and hycamtin.The the 7th to 10 group of associating that is respectively clofarabine and 5-fluorouracil, Ismipur, methotrexate and hycamtin.All medicines are placed in being tumor, and dechlorination farad shore is that 10mg/kg is equal outward, and the anti-metabolism cancer therapy drug is 5mg/kg.The treatment back was measured gross tumor volume size, relatively therapeutic effect (seeing Table 2) on the 30th day.
Table 2
| Test group (n) | Suffered treatment | Gross tumor volume (cm 3) | The P value |
| 1(6) | Contrast | 58±12 | |
| 2(6) | Clofarabine | 38±10 | ＜0.05 |
| 3(6) | 5-fluorouracil | 34±10 | ＜0.01 |
| 4(6) | Ismipur | 38±8 | ＜0.01 |
| 5(6) | Methotrexate | 36±8 | ＜0.01 |
| 6(6) | Hycamtin | 38±8 | ＜0.01 |
| 7(6) | Clofarabine+5-fluorouracil | 24±4.6 | ＜0.001 |
| 8(6) | Clofarabine+Ismipur | 20±4.4 | ＜0.001 |
| 9(6) | Clofarabine+methotrexate | 18±4 | ＜0.001 |
| 10(6) | Clofarabine+hycamtin | 16±3 | ＜0.001 |
Annotate: 5-fluorouracil, Ismipur, methotrexate and hycamtin are the anti-metabolism cancer therapy drug.The result shows, compares with matched group, and clofarabine (the 2nd group) and anti-metabolism cancer therapy drug (the 3rd to 6 group) application separately all have certain tumor-inhibiting action (P＜0.05).Yet use in conjunction (the 7th to 10 group) has obvious synergistic effect (P＜0.001).
Tumor-inhibiting action in the body of test four, clofarabine and anti-metabolism cancer therapy drug.
Detected tumor-inhibiting action in the body of clofarabine and anti-metabolism cancer therapy drug according to test three method.The result shows clofarabine and is selected from floxuridine, doxifluridine, the 5-doxifluridine, propylthiouracil, fluorouracil, the fluorobutane uracil, tegadifurum, the 5-fluoxydin, sulfomercaprine sodium, mercaptopurine, mercapto miaow purine, Ismipur, the adenine hydrochlorate, Benin, thioguanine, methotrexate, fluoromethotrexate, the dioxy methotrexate, 10-ethyl denitrification aminopterin, N5-Methyltetrahydrohmofotic Acid, folic acid, 5, the 10-lonetrexol, calcium levofolinate, calcium folinate, carmofur, ftorafur, UFT, Tegafur-uracil mixt., the 8-azaguanine, uracil, 5-mercaptomethyluracil, hycamtin, topotecan hydrochloride, cytosine arabinoside, ancitabine, ancitabine, hydroxyurea, the independent application of anti-metabolism cancer therapy drug of hydroxyl guanidine all has obvious tumor-inhibiting action (P＜0.05).And use in conjunction has obvious synergistic effect (P＜0.001).
Tumor-inhibiting action in the body of test five, clofarabine and anti-metabolism cancer therapy drug.
With the rat is subjects, with 2 * 10
5Individual tumor cell subcutaneous injection is in its hypochondrium, treats that tumor growth after 14 days is divided into it following 10 groups (seeing Table 3).The 1st group is contrast, and the 2nd to 10 group is the treatment group, and wherein, the 2nd group is clofarabine; The the 3rd to 6 group is respectively the antimetabolic anticarcinoma agent thing.The the 7th to 10 group of associating that is respectively clofarabine and different antimetabolic anticarcinoma agent things.Outside placed in tumor dechlorination farad shore, carmofur, ftorafur, UFT and topotecan hydrochloride were intraperitoneal administration.The dosage measuring clofarabine is that 10mg/kg is 10mg/kg outward.The treatment back was measured gross tumor volume size, relatively therapeutic effect (seeing Table 3) on the 30th day.
Table 3
| Test group (n) | Suffered treatment | Gross tumor volume (cm 3) | The P value |
| 1(6) | Contrast | 60±10 | |
| 2(6) | Clofarabine | 24±5 | ＜0.05 |
| 3(6) | Carmofur | 54±8 | ＜0.01 |
| 4(6) | Ftorafur | 62±8 | ＜0.01 |
| 5(6) | UFT | 62±9 | ＜0.01 |
| 6(6) | Topotecan hydrochloride | 52±6 | ＜0.01 |
| 7(6) | Clofarabine+carmofur | 24±3.2 | ＜0.001 |
| 8(6) | Clofarabine+ftorafur | 20±3.2 | ＜0.001 |
| 9(6) | Clofarabine+UFT | 22±3.0 | ＜0.001 |
| 10(6) | Clofarabine+topotecan hydrochloride | 16±3.0 | ＜0.001 |
Annotate: carmofur, ftorafur, UFT and topotecan hydrochloride are the anti-metabolism cancer therapy drug.
Tumor-inhibiting action in the body of test six, clofarabine and anti-metabolism cancer therapy drug.
With the rat is subjects, with 2 * 10
5Individual tumor cell subcutaneous injection is in its hypochondrium, treats that tumor growth after 14 days is divided into it following 10 groups (seeing Table 4).The 1st group is contrast, and the 2nd to 10 group is the treatment group, and wherein, the 2nd group is clofarabine; The the 3rd to 6 group is respectively the anti-metabolism cancer therapy drug.The the 7th to 10 group of associating that is respectively clofarabine and different anti-metabolism cancer therapy drugs.Outside placed in tumor dechlorination farad shore, carmofur, ftorafur, 8-azaguanine and cytosine arabinoside were intraperitoneal administration.Dechlorination farad shore is that 10mg/kg is 5mg/kg outward.The treatment back was measured gross tumor volume size, relatively therapeutic effect (seeing Table 4) on the 30th day.
Table 4
| Test group (n) | Suffered treatment | Gross tumor volume (cm 3) | The P value |
| 1(6) | Contrast | 62±14 | |
| 2(6) | Clofarabine | 26±10 | ＜0.05 |
| 3(6) | Carmofur | 46±6.3 | ＜0.05 |
| 4(6) | Ftorafur | 48±6.6 | ＜0.05 |
| 5(6) | The 8-azaguanine | 42±6.4 | ＜0.05 |
| 6(6) | Cytosine arabinoside | 40±4.8 | ＜0.05 |
| 7(6) | Clofarabine+carmofur | 18±2.8 | ＜0.001 |
| 8(6) | Clofarabine+ftorafur | 20±3.6 | ＜0.001 |
| 9(6) | Clofarabine+8-azaguanine | 14±2.0 | ＜0.001 |
| 10(6) | Clofarabine+cytosine arabinoside | 18±2.4 | ＜0.001 |
Annotate: carmofur, ftorafur, 8-azaguanine and cytosine arabinoside are the anti-metabolism cancer therapy drug.
Similar potentiation also sees the associating of other clofarabine and other anti-metabolism cancer therapy drug, as: floxuridine, doxifluridine, the 5-doxifluridine, propylthiouracil, fluorouracil, the fluorobutane uracil, tegadifurum, the 5-fluoxydin, sulfomercaprine sodium, mercaptopurine, mercapto miaow purine, Ismipur, the adenine hydrochlorate, Benin, thioguanine, methotrexate, fluoromethotrexate, the dioxy methotrexate, 10-ethyl denitrification aminopterin, N5-Methyltetrahydrohmofotic Acid, folic acid, 5, the 10-lonetrexol, calcium levofolinate, calcium folinate, carmofur, ftorafur, UFT, Tegafur-uracil mixt., the 8-azaguanine, uracil, 5-mercaptomethyluracil, hycamtin, topotecan hydrochloride, cytosine arabinoside, ancitabine, ancitabine, the combination of anti-metabolism cancer therapy drugs such as hydroxyurea or hydroxyl guanidine and clofarabine, and amycin, epirubicin, ametycin, the combination of antibiotics such as actinomycin D or dactinomycin cancer therapy drug and clofarabine.
With multiple other tumor cell (comprising the cerebral tumor (CNS-1, C6,9L), gastric gland epithelial cancer (SA), bone tumor (BC), breast carcinoma (BA), papillary adenocarcinoma of thyroid (PAT), hepatocarcinoma, cancer of pancreas, renal carcinoma and the esophageal carcinoma etc.) is that subjects draws similar results.
Release ratio in the body of the clofarabine sustained-release implant that test 7, different molecular weight polylactic acid are made
With the rat is subjects, grouping (3/group) and the equivalent clofarabine sustained-release implant that carries in the subcutaneous polylactic acid (PLA) that contains different molecular weight (MW).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%).Discharge in the body of the clofarabine sustained-release implant that comparison different molecular weight polylactic acid is made and find, 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 the slow releasing agent that adjuvant is made that same result also sees with polylactic acid, comprise the combination of anti-metabolism cancer therapy drugs such as fluorouracil, mercaptopurine, Ismipur, methotrexate, folic acid, calcium folinate, carmofur, ftorafur, UFT, Tegafur-uracil mixt., 8-azaguanine, hycamtin, topotecan hydrochloride, cytosine arabinoside, hydroxyurea or hydroxyl guanidine and clofarabine, and the combination of antibiotics cancer therapy drug such as amycin, epirubicin, ametycin, actinomycin D or dactinomycin and clofarabine.
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, experimental result shows that clofarabine among the present invention is to the potentiation of listed anti-metabolism cancer therapy drug or antibiotics cancer therapy drug.Therefore, the effective ingredient of anticancer compound of the present invention is the associating of clofarabine and any one (or multiple) anti-metabolism cancer therapy drug or antibiotics cancer therapy drug or packs separately.Above effective ingredient can be made into any dosage form or shape, but serves as preferred with the agent for slow releasing type, is mainly slow releasing injection or sustained-release implant.
(4) specific embodiment
Embodiment 1.
With 80mg molecular weight peak value is that 35000 polylactic acid (PLGA) is put into container, adds 100 milliliters of dichloromethane, behind the dissolving mixing, adds 10mg clofarabine and 10mg methotrexate, shakes up the dry organic solvent of removing of final vacuum again.Dried solid composite is shaped immediately, and ray sterilizing after the packing must contain the anticancer slow-release of 10% clofarabine and 10% methotrexate.All be weight percentage.The drug release time of this entity-tumor-resistant medicine composition in external normal saline is 15-25 days, is 25-50 days at the subcutaneous drug release time of mice.
Embodiment 2.
As described in embodiment 1, different is anticancer effective component and percentage by weight is one of following:
(1) combination of the amycin of the clofarabine of 1-40% and 1-40%, epirubicin, ametycin, actinomycin D or dactinomycin; Or
(2) floxuridine of the clofarabine of 1-40% and 1-40%, doxifluridine, the 5-doxifluridine, propylthiouracil, fluorouracil, the fluorobutane uracil, tegadifurum, the 5-fluoxydin, sulfomercaprine sodium, mercaptopurine, mercapto miaow purine, Ismipur, the adenine hydrochlorate, Benin, thioguanine, methotrexate, fluoromethotrexate, the dioxy methotrexate, 10-ethyl denitrification aminopterin, N5-Methyltetrahydrohmofotic Acid, folic acid, 5, the 10-lonetrexol, calcium levofolinate, calcium folinate, carmofur, ftorafur, UFT, Tegafur-uracil mixt., the 8-azaguanine, uracil, 5-mercaptomethyluracil, hycamtin, topotecan hydrochloride, cytosine arabinoside, ancitabine, hydroxyurea, the combination of hydroxyl guanidine.
Used slow-release auxiliary material 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.
80mg polifeprosan (to carboxy phenyl propane (p-CPP): decanedioic acid (SA) is 20: 80) copolymer is put into container, add the 100ml dichloromethane, behind the dissolving mixing, add 10mg clofarabine and 10mg fluorouracil, shake up the back contains 10% clofarabine and 10% fluorouracil with spray drying method for preparation injectable microsphere again.Then microsphere is suspended in the normal saline that contains 15% mannitol, makes corresponding suspension type slow releasing injection, viscosity is 20cp-300cp (20 ℃-30 ℃ time).The drug release time of this slow releasing injection in external normal saline is 15-25 days, is about 30-40 days at the subcutaneous drug release time of mice.
Embodiment 4.
The method step that is processed into slow releasing injection is identical with embodiment 3, but different is that contained anticancer effective component and percentage by weight thereof are: the clofarabine of 2-30% and the floxuridine of 2-30%, doxifluridine, the 5-doxifluridine, propylthiouracil, fluorouracil, the fluorobutane uracil, tegadifurum, the 5-fluoxydin, sulfomercaprine sodium, mercaptopurine, mercapto miaow purine, Ismipur, the adenine hydrochlorate, Benin, thioguanine, methotrexate, fluoromethotrexate, the dioxy methotrexate, 10-ethyl denitrification aminopterin, N5-Methyltetrahydrohmofotic Acid, folic acid, 5, the 10-lonetrexol, calcium levofolinate, calcium folinate, carmofur, ftorafur, UFT, Tegafur-uracil mixt., the 8-azaguanine, uracil, 5-mercaptomethyluracil, hycamtin, topotecan hydrochloride, cytosine arabinoside, ancitabine, hydroxyurea, the combination of hydroxyl guanidine.The viscosity of slow releasing injection is 200cp-600cp (20 ℃-30 ℃ time).
Embodiment 5.
With 70mg molecular weight peak value is that 25000 polylactic acid (PLGA, 75: 25) is put into container, adds 100 milliliters of dichloromethane, behind the dissolving mixing, adds 15mg amycin and 15mg clofarabine, 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% amycin and 15% clofarabine, be suspended in then in the normal saline that contains 1.5% sodium carboxymethyl cellulose, make corresponding suspension type slow releasing injection, viscosity is 220cp-340cp (20 ℃-30 ℃ time).The drug release time of this slow releasing injection in external normal saline is 10-15 days, is about 20-30 days at the subcutaneous drug release time of mice.
Embodiment 6
The method step that is processed into slow releasing injection is identical with embodiment 5, but different is that contained anticancer effective component and percentage by weight thereof are: the combination of the clofarabine of 2-30% and the amycin of 1-40%, epirubicin, ametycin, actinomycin D or dactinomycin; The viscosity of injection is 10cp-650cp (20 ℃-30 ℃ time).
Embodiment 7.
70mg polifeprosan (to carboxy phenyl propane (p-CPP): decanedioic acid (SA) is 20: 80) copolymer is put into container, add 100 milliliters of dichloromethane, behind the dissolving mixing, add 20mg epirubicin and 10mg clofarabine, shake up the back contains 20% epirubicin and 10% clofarabine with spray drying method for preparation injectable microsphere again.Microsphere is suspended in the normal saline that contains 1.5% sodium carboxymethyl cellulose and 0.5% Tween 80 then, makes corresponding suspension type slow releasing injection, viscosity is 180cp-260cp (25 ℃-30 ℃ time).The drug release time of this slow releasing injection in external normal saline is 14-25 days, is about 30-50 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 different is that contained anticancer effective component is: the combination of the clofarabine of 5-25% and the amycin of 5-25%, epirubicin, ametycin, actinomycin D or dactinomycin; Viscosity is 440cp-650cp (25 ℃-30 ℃ time).
Embodiment 9
70mg polifeprosan (to carboxy phenyl propane (p-CPP): decanedioic acid (SA) is 20: 80) copolymer is put into container, add 100 milliliters of dichloromethane, behind the dissolving mixing, add 20mg actinomycin D and 10mg clofarabine, shake up the back contains 20% actinomycin D and 10% clofarabine with spray drying method for preparation injectable microsphere again.Then microsphere is suspended in the normal saline that contains 1.5% sodium carboxymethyl cellulose and 15% sorbitol and 0.2% Tween 80, makes corresponding suspension type slow releasing injection, viscosity is 100cp-160cp (25 ℃-30 ℃ time).The drug release time of this slow releasing injection in external normal saline is 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 combination of 15% amycin, epirubicin, ametycin, actinomycin D or dactinomycin and 15% clofarabine; Viscosity is 560cp-640cp (25 ℃-30 ℃ time).
Embodiment 11
70mg polifeprosan (to carboxy phenyl propane (p-CPP): decanedioic acid (SA) is 20: 80) copolymer is put into container, add 100 milliliters of dichloromethane, behind the dissolving mixing, add 10mg amycin and 20mg clofarabine, shake up the back contains 10% amycin and 20% clofarabine 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 15-25 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 used slow-release auxiliary material is: the poly-dl-lactide of 60-95%, 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, bis-fatty acid and decanedioic acid copolymer (PFAD-SA), poly-(erucic acid dimer-decanedioic acid) [P (EAD-SA)] or poly-(fumaric acid-decanedioic acid) [P (FA-SA)].
Embodiment 13
With 70mg molecular weight peak value 35000 polylactic acid (PLGA, 50: 50) put into container, add 100 milliliters of dichloromethane, behind the dissolving mixing, add 10mg epirubicin and 20mg clofarabine, shake up the back contains 10% epirubicin and 20% clofarabine 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 15-20 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 and percentage by weight are:
(1) combination of the amycin of the clofarabine of 1-40% and 1-40%, epirubicin, ametycin, actinomycin D or dactinomycin; Or
(2) floxuridine of the clofarabine of 1-40% and 1-40%, doxifluridine, the 5-doxifluridine, propylthiouracil, fluorouracil, the fluorobutane uracil, tegadifurum, the 5-fluoxydin, sulfomercaprine sodium, mercaptopurine, mercapto miaow purine, Ismipur, the adenine hydrochlorate, Benin, thioguanine, methotrexate, fluoromethotrexate, the dioxy methotrexate, 10-ethyl denitrification aminopterin, N5-Methyltetrahydrohmofotic Acid, folic acid, 5, the 10-lonetrexol, calcium levofolinate, calcium folinate, carmofur, ftorafur, UFT, Tegafur-uracil mixt., the 8-azaguanine, uracil, 5-mercaptomethyluracil, hycamtin, topotecan hydrochloride, cytosine arabinoside, ancitabine, hydroxyurea, the combination of hydroxyl guanidine.
Embodiment 15
The method step that is processed into slow releasing agent is identical with embodiment 1-14, but different is used slow-release auxiliary material is one of following or its combination:
A) polylactic acid (PLA), the molecular weight peak value is 10000-30000,300000-60000,60000-100000 or 100000-150000;
B) copolymer of polyglycolic acid and hydroxyacetic acid (PLGA), wherein, the ratio of polyglycolic acid and hydroxyacetic acid is 50-95: 50-50, the molecular weight peak value is 10000-30000,300000-60000,60000-100000 or 100000-150000;
C) ethylene vinyl acetate copolymer (EVAc);
D) polifeprosan, to carboxy phenyl propane (p-CPP): decanedioic acid (SA) is 10: 90,20: 80,30: 70,40: 60,50: 50 or 60: 40;
E) bis-fatty acid and decanedioic acid copolymer (PFAD-SA);
F) poly-(erucic acid dimer-decanedioic acid) [P (EAD-SA)];
G) poly-(fumaric acid-decanedioic acid) [P (FA-SA)];
H) xylitol, oligosaccharide, chrondroitin, chitin, hyaluronic acid, collagen protein, gelatin or white tempera;
I) poly-dl-lactide, poly-dl-lactide/ethanol copolymer, monomethyl polyethylene glycol, monomethyl polyethylene glycol copolymer, polyethylene glycol, polyethylene glycol copolymer, end carboxyl polylactic acid or end carboxyl polylactic acid/ethanol copolymer.
Embodiment 16
The method step that is processed into slow releasing injection is identical with embodiment 1-10, but different is used suspending agent is respectively one of following or its combination:
A) 0.5-3.0% carboxymethyl cellulose (sodium);
B) 5-15% mannitol;
C) 5-15% sorbitol;
D) 0.1-1.5% surfactant;
E) 0.1-0.5% polysorbas20.
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.
Above result shows that the clofarabine that the present invention is used and the combination and the consequent anticancer synergia effect of its synergist are of universal significance.Dosage when therefore, clofarabine and its synergist are united is selected and can be released according to relevant data of the present invention.Above embodiment only is used for explanation, and also unrestricted application of the present invention.
Claims (3)
1. chloride farad the compound anti-cancer slow-release injected of shore is slow-releasing anticarcinogen injection, is grouped into by following one-tenth:
(A) sustained-release micro-spheres comprises:
Anticancer effective component
Slow-release auxiliary material
With
(B) solvent is for common solvent or contain the special solvent of suspending agent;
Wherein,
Anticancer effective component is the combination of clofarabine and antitumor antibiotics;
The component of described slow-releasing anticarcinogen injection is one of following combination:
(1) anticancer effective component is 15% amycin and 15% clofarabine, and slow-release auxiliary material is that 70% molecular weight is 25000 polylactic acid, and solvent is the normal saline that contains 1.5% sodium carboxymethyl cellulose, and its viscosity is 220cp-340cp in the time of 20 ℃-30 ℃;
(2) anticancer effective component is 20% epirubicin and 10% clofarabine, slow-release auxiliary material is 70% a pair of carboxy phenyl propane: decanedioic acid is 20: 80 a polifeprosan, solvent is the normal saline that contains 1.5% sodium carboxymethyl cellulose and 0.5% Tween 80, and its viscosity is 180cp-260cp in the time of 25 ℃-30 ℃;
Below all be weight percentage.
2. the slow-releasing anticarcinogen injection according to claim 1 is characterized in that described pharmaceutical preparation is the sustained-release implant that sustained-release micro-spheres is made, in tumor or tumor week injection or place administration.
3. the anti-cancer sustained-released implantation agent according to claim 2, the component that it is characterized in that anti-cancer sustained-released implantation agent is following combination:
(1) anticancer effective component is 10% amycin and 20% clofarabine, and slow-release auxiliary material is 70% a pair of carboxy phenyl propane: decanedioic acid is 20: 80 a polifeprosan;
(2) anticancer effective component is 10% epirubicin and 20% clofarabine, and slow-release auxiliary material is that 70% molecular weight is 35000 polylactic acid;
Below all be weight percentage.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA2008103003190A CN101264052A (en) | 2006-07-18 | 2006-07-18 | Compound anticancer sustained-release agent containing clofarabine |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA2008103003190A CN101264052A (en) | 2006-07-18 | 2006-07-18 | Compound anticancer sustained-release agent containing clofarabine |
Related Parent Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA2006102006987A Division CN1887259A (en) | 2006-07-18 | 2006-07-18 | Slow released compound anticancer prepn containing clorfarabine |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN101264052A true CN101264052A (en) | 2008-09-17 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA2008103003190A Pending CN101264052A (en) | 2006-07-18 | 2006-07-18 | Compound anticancer sustained-release agent containing clofarabine |
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| Country | Link |
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| CN (1) | CN101264052A (en) |
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2006
- 2006-07-18 CN CNA2008103003190A patent/CN101264052A/en active Pending
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Open date: 20080917 |