CN1969825A - Sustained release agent containing fluorouracil and synergist thereof - Google Patents
Sustained release agent containing fluorouracil and synergist thereof Download PDFInfo
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- CN1969825A CN1969825A CNA2006102009453A CN200610200945A CN1969825A CN 1969825 A CN1969825 A CN 1969825A CN A2006102009453 A CNA2006102009453 A CN A2006102009453A CN 200610200945 A CN200610200945 A CN 200610200945A CN 1969825 A CN1969825 A CN 1969825A
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Abstract
Disclosed is an anticancer slow release injection containing fluorouracil and synergistic agents, which comprises slow release micro-balloons and dissolvent, wherein the slow release microballoons comprise anti-cancer active constituents and slow release auxiliary materials, the dissolvent being specific dissolvent containing suspension adjuvant. The suspending agent is selected from sodium carboxymethylcellulose, mannitol, sorbitol, Tween-80 or their combination. The anticancer active constituents are the combination of 5-FU anddocetaxel, monohydric camptothecine, Etoposide as 5-FU synergistic agent. The slow release auxiliary materials are selected from polylactic acid, ethylene-vinylacetate copolymer, Polifeprosan, FAD, sebacic acid copolymer, polyglycolic acid and glycolic acid copolymer or their combination. The viscosity of the injection is 50-1000cp (at 20-30 deg C), The slow release microspheres can also be prepared into slow release implanting agent, when in-tumor or around-tumor injected or placed, the slow release agent can not only lower down the whole body toxicity reaction of the anti-cancer medicament, but also can selectively increase the tumor local medicinal concentration, and improve the treatment effect of the non-operative treatment methods such as chemotherapy, medicament and radiation.
Description
(1) technical field
The present invention relates to slow releasing agent of a kind of fluorouracil (5-FU) and synergist thereof and preparation method thereof, belong to technical field of pharmaceuticals.Slow releasing agent is mainly slow releasing injection and sustained-release implant.
(2) background technology
As a kind of chemotherapeutics commonly used, 5-fluorouracil (5-FU) has been widely used in the treatment of multiple malignant tumor, and action effect is comparatively obvious.Yet its beat all neurotoxicity has greatly limited the application of this medicine.Blood vessel in the mesenchyma stroma of tumors, connective tissue, stromatin, 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 SurgOncol.1998 Oct such as Kong Qingzhongs; 69 (2): 76-82), improve the restriction that dosage is subjected to general reaction again merely.Pharmaceutical topical application may solve the problem (Chinese patent) of drug level to a certain extent, yet operation techniques such as medicine implantation are complicated, traumatic big, the various complication such as, infection hemorrhage, immunity reduction, also can cause or quicken the diffusion and the transfer of tumor except that easily causing.In addition, the preparation of perioperatively itself and expensive expense usually influence its effective enforcement.
In addition, the DNA repair function in many tumor cells obviously increases after chemotherapy.The latter often causes the enhancing of tumor cell to the toleration of cancer therapy drug, consequently treatment failure.
In addition, the cancer drug therapy of low dosage not only can increase the Drug tolerance of cancerous cell, but also can promote its infiltrative growth " (referring to beam etc. " increased the Drug tolerance of human lung carcinoma cell and external wetting capacity after the cancer therapy drug pulse screening and with the change of gene expression " " international journal of cancer " 111 phase 484-93 page or leaf (2004) (Liang Y; etal., Int J Cancer.2004; 111 (4): 484-93)).
Therefore, be convenient to keep high drug level and increase tumor cell the preparation and the method for the sensitivity of medicine just become an important subject at tumor by local.
(3) summary of the invention
5-fluorouracil has been widely used in the treatment kinds of tumors as a kind of cancer therapy drug commonly used, as straight colon cancer etc.Yet in application process, its tangible general toxicity has greatly limited the application of this medicine.
Be effectively to improve tumor by local drug level, reduce the drug level of medicine in blood circulation, people have studied the drug sustained release system that contains 5-fluorouracil, comprise that sustained-release micro-spheres (capsule) (sees: (China Patent No. ZL00809160.9; Application number 91109723.6), Ciftci K etc. " with the polylactic acid microsphere treatment entity tumor that contains fluorouracil and the research of drug release " " drug development technology " (Pharm Dev Technol.) 2 (2): 151-60,1997), sustained-release implant (sees: China Patent No. ZL96115937.5; ZL97107076.8) etc.Yet, solid sustained-release implant (China Patent No. ZL96115937.5; ZL97107076.8) and existing as be used for the treatment of the cerebral tumor (ZL00809160.9) sustained-release micro-spheres or United States Patent (USP) (US5,651,986) and all have problem such as be not easy more than operation, weak curative effect, the complication.In addition, the sensitivity that many entity tumors are drawn together 5 fluorouracil to anticancer medicated bag is relatively poor, and is easy to generate drug resistance in therapeutic process.The present invention finds that medicine of mentioning among the present invention and 5-FU share and can make its antitumaous effect strengthen (the following medicine that the 5-FU antitumaous effect will be increased mutually is referred to as the 5-FU synergist) mutually.
In addition, with the assembly packaging of 5-FU and its synergist in specific slow-release auxiliary material and be equipped with special solvent and make drug level that anti-cancer medicine sustained-release injection not only can greatly improve tumor by local, reduce the drug level of medicine in blood circulation, reduce the toxicity of medicine to normal structure, can also greatly make things convenient for the medicine injection, reduce operation technique complication, reduce patient's expense.The decapacitation of 5-FU synergist suppresses can also increase the sensitivity of tumor cell to cancer therapy drug outside the tumor growth.
The present invention finds, is not that all adjuvants can both effectively discharge 5-FU.Pharmaceutic adjuvant have hundreds of more than, pharmaceutic adjuvant with slow releasing function, particularly the pharmaceutic adjuvant that selected 5-FU 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.
Topical remedy's slow release in the stable lastingly and drug level, has obviously reduced systemic drug concentration in having guaranteed local application's scope, alleviated toxic and side effects.
The present invention is directed to the deficiencies in the prior art, invented the slow releasing agent that contains 5-FU and synergist thereof.This slow releasing agent comprises anticancer effective component and medicinal slow-release auxiliary material.Be mainly slow releasing injection and sustained-release implant
The present invention is directed to the deficiencies in the prior art, a kind of new slow releasing injection that contains fluorouracil and 5-fluorouracil synergist is provided.
A kind of form of the present invention is a slow releasing injection, is made up of sustained-release micro-spheres and solvent.Particularly, this slow-releasing anticarcinogen injection is grouped into by following one-tenth:
(A) sustained-release micro-spheres comprises:
Anticancer effective component 0.5-60%
Slow-release auxiliary material 40-99%
Suspending agent 0.0-30%
More than be weight percentage
With
(B) solvent is for common solvent or contain the special solvent of suspending agent.
Wherein,
Anticancer effective component is 5-FU and 5-FU synergist, and the 5-FU synergist is selected from docetaxel, hydroxy camptothecin, Etoposide; Slow-release auxiliary material comprises one of following or its combination: 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.
In various high molecular polymers, with polylactic acid, decanedioic acid, the mixture or the copolymer that contain the macromolecule polymer of polylactic acid or certain herbaceous plants with big flowers diacid is first-selection, mixture and copolymer can be selected from, but be not limited to the mixture or the copolymer of the mixture of PLA, PLGA, glycolic and hydroxy carboxylic acid, certain herbaceous plants with big flowers diacid and fragrant polyanhydride or aliphatic polyanhydride.The blend ratio of glycolic and hydroxy carboxylic acid is 10/90-90/10 (weight), preferably 25/75-75/25 (weight).The method of blend is arbitrarily.Content when glycolic and hydroxy carboxylic acid copolymerization is respectively percentage by weight 10-90% and 90-10%.The representative of fragrance polyanhydride is polifeprosan [poly-(1,3-two (to the carboxyl phenoxy group) propane-decanedioic acid) (p (CPP-SA)), bis-fatty acid-decanedioic acid copolymer (PFAD-SA)], poly-(erucic acid dimer-decanedioic acid) [P (EAD-SA)] and poly-(fumaric acid-decanedioic acid) [P (FA-SA)] etc.Content during to carboxylic phenoxypropane (p-CPP) and decanedioic acid copolymerization is respectively percentage by weight 10-60% and 20-90%, and the blend weight ratio is 10-40: 50-90, preferably weight ratio 15-30: 65-85.
The molecular weight peak value of polylactic acid can be, but is not limited to, 5000-100, and 000, but with 20,000-60,000 is preferred, with 5,000-30,000 for most preferably; The molecular weight of polyglycolic acid can be, but is not limited to, 5000-100, and 000, but with 5,000-50,000 is preferred, with 10,000-30,000 for most preferably; Above polyhydroxy acid can singly select or multiselect.When singly selecting, serve as preferred with the copolymer (PLGA) of polylactic acid (PLA) or hydroxy carboxylic acid and glycolic, the molecular weight of copolymer can be, but is not limited to, 5000-100,000, but with 20,000-60,000 be preferably, with 30,000-50,000 for most preferably; When multiselect, compound polymer or the copolymer formed with macromolecule polymer or different macromolecule polymer serve as preferred, with the compound polymer that contains different molecular weight polylactic acid or decanedioic acid or copolymer for most preferably, as, but be not limited to, molecular weight is 1000 to 30000 polylactic acid with molecular weight is that 20000 to 50000 polylactic acid mixes, molecular weight is 10000 to 30000 polylactic acid with molecular weight is that 30000 to 80000 PLGA mixes, molecular weight is that 20000 to 30000 polylactic acid mixes with decanedioic acid, molecular weight is that 30000 to 80000 PLGA mixes with decanedioic acid.Used polylactic acid serves as preferred with Poly-L-lactic acid (L-PLA).Poly-L-lactic acid (L-PLA) range of viscosities IV (dl/g) is 0.2～0.8, and glass transition temperature range is 55～65 ℃, 175～185 ℃ of fusing points.
Except that above-mentioned 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.
The percentage by weight of synergist (docetaxel, hydroxy camptothecin, Etoposide) in slow releasing agent is good from 0.1%-60% with 1%-50%, is best with 5%-30%.
Anticancer effective component is the combination of 5-FU and its synergist.When the cancer therapy drug in the medicament slow-release microsphere only was the 5-FU synergist, slow-releasing anticarcinogen injection was mainly used in the action effect that increases the 5-FU that other approach use or is used for potentiation to radiotherapy or other therapies.When being used to increase the action effect of the 5-FU that other approach use, 5-FU can be through tremulous pulse, vein or local injection, placement administration.
The percentage by weight of anticancer effective component in sustained-release micro-spheres is 0.5%-60%, is good with 2%-40%, is best with 5%-30%.The weight ratio of 5-FU and 5-FU synergist is 1-9: 1 to 1: 1-9.With 1-2: 1 serves as preferred.
Anticancer effective component percentage by weight in the anticancer slow-release microsphere of the present invention is preferably as follows:
The combination of the 5-FU of 5-30% and the docetaxel of 5-30%, hydroxy camptothecin or Etoposide.
Anticancer effective component percentage by weight in the anticancer slow-release microsphere is most preferably as follows:
(a) docetaxel of the 5-FU of 5-30% and 5-30%;
(b) hydroxy camptothecin of the 5-FU of 5-30% and 5-30%;
(c) Etoposide of the 5-FU of 5-30% and 5-30%.
One of the copolymer (PLGA) of the preferred polylactic acid of slow-release auxiliary material (PLA), polyglycolic acid and hydroxyacetic acid, ethylene vinyl acetate copolymer (EVAc), FAD:SA copolymer and polifeprosan or its combination.
When selecting the copolymer (PLGA) of polylactic acid (PLA), polyglycolic acid (PGA), polylactic acid (PLA) and mixture, glycolic and the hydroxy carboxylic acid of polyglycolic acid for use, PLA and PLGA content percentage by weight are respectively 0.1-99.9% and 99.9-0.1%.The molecular weight peak value of polylactic acid can be, but is not limited to, 5000-200, and 000, with 20,000-60,000 is preferred, with 30,000-50,000 for most preferably; The molecular weight of polyglycolic acid can be, but is not limited to, 5000-200, and 000, with 20,000-60,000 is preferred, with 30,000-50,000 for most preferably; Above polyhydroxy acid can singly select or multiselect.When singly selecting, serve as preferred with the copolymer (PLGA) of polylactic acid (PLA) or hydroxy carboxylic acid and glycolic, the molecular weight of copolymer can be, but is not limited to, 5000-200,000, 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.
In various high molecular polymers, with polylactic acid, decanedioic acid, the mixture or the copolymer that contain the macromolecule polymer of polylactic acid or certain herbaceous plants with big flowers diacid is first-selection, mixture and copolymer can be selected from, but be not limited to the mixture or the copolymer of the mixture of PLA, PLGA, glycolic and hydroxy carboxylic acid, certain herbaceous plants with big flowers diacid and fragrant polyanhydride or aliphatic polyanhydride.The blend ratio of glycolic and hydroxy carboxylic acid is 10/90-90/10 (weight), preferably 25/75-75/25 (weight).The method of blend is arbitrarily.Content when glycolic and hydroxy carboxylic acid copolymerization is respectively percentage by weight 10-90% and 90-10%.The representative of fragrance polyanhydride is polifeprosan [poly-(1,3-two (to the carboxyl phenoxy group) propane-decanedioic acid) (p (CPP-SA)), bis-fatty acid-decanedioic acid copolymer (PFAD-SA)], poly-(erucic acid dimer-decanedioic acid) [P (EAD-SA)] and poly-(fumaric acid-decanedioic acid) [P (FA-SA)] etc.Content during to carboxylic phenoxypropane (p-CPP) and decanedioic acid copolymerization is respectively percentage by weight 10-60% and 20-90%, and the blend weight ratio is 10-40: 50-90, preferably weight ratio 15-30: 65-85.
Except that above-mentioned adjuvant, also can select for use other materials to see United States Patent (USP) (4757128; 4857311; 4888176; 4789724 and " pharmaceutic adjuvant complete works " (the 123rd page, Sichuan science tech publishing house 1993 publishes, Luo Mingsheng and Gao Tianhui chief editor) in have a detailed description.In addition, Chinese patent (application number 96115937.5; 91109723.6; 9710703.3; 01803562.0) and U.S.'s patent of invention (patent No. 5,651,986) also enumerated some pharmaceutic adjuvant, comprise filler, solubilizing agent, absorption enhancer, film former, gellant, system (or causing) hole agent, excipient or blocker etc.).
For regulating drug releasing rate or changing other characteristic of the present invention, can change the composition and the proportioning of monomer component or molecular weight, interpolation or the adjusting pharmaceutic adjuvant of polymer, add the water-soluble low-molecular chemical compound, as, but be not limited to various sugar or salt etc.Wherein sugar can be, but is not limited to, xylitol, oligosaccharide, (sulphuric acid) chrondroitin and chitin etc., and wherein salt can be, but is not limited to, potassium salt and sodium salt etc.
In the slow releasing injection, drug sustained release system can be made into microsphere, sub-micro ball, microemulsion, nanosphere, granule or spherical piller, makes the injection use then with after the injection solvent mixes.In various slow releasing injection, serve as preferred with the suspension type slow releasing injection, the suspension type slow releasing injection is the preparation that the drug sustained release system that will contain anticancer component is suspended in gained in the injection, used adjuvant is a kind of or its combination in the above-mentioned slow-release auxiliary material, and used solvent is common solvent or the special solvent that contains suspending agent.Common solvent is, but is not limited to the buffer that distilled water, water for injection, physiology are prepared towards liquid, dehydrated alcohol or various salt.The purpose of suspending agent is the pastille microsphere that effectively suspends, thereby is beneficial to injection.
Suspending agent is selected from one of sodium carboxymethyl cellulose, (iodine) glycerol, simethicone, propylene glycol, carbomer, mannitol, sorbitol, surfactant, soil temperature 20, soil temperature 40 and soil temperature 80 or its combination.
The content of suspending agent in common solvent is decided because of its characteristic, can be 0.1-30% and decides because of concrete condition.Consisting of of preferred suspending agent:
(a) 0.5-5% sodium carboxymethyl cellulose+0.1-0.5% soil temperature 80; Or
(b) 5-20% mannitol+0.1-0.5% soil temperature 80; Or
(c) 0.5-5% sodium carboxymethyl cellulose+5-20% sorbitol+0.1-0.5% soil temperature 80.
The kind of solvent is then depended in the preparation of solvent, and common solvent has commercially available, also can make by oneself, and as distilled water, water for injection, physiology buffer towards liquid, dehydrated alcohol or the preparation of various salt, but must be in strict accordance with related standards.Special solvent need be considered the kind of suspending agent and the medicine that composition, solvent suspended, composition, character and the requirement thereof of sustained-release micro-spheres (or microcapsule) and the preparation method of injection, as sodium carboxymethyl cellulose (1.5%)+mannitol and/or sorbitol (15%) and/or 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 methods 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 because of specifically deciding, can be, but is not limited to, 10-400mg/ml is preferred 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, certain herbaceous plants with big flowers diacid, the mixture or the copolymer that contain the macromolecule polymer of polylactic acid or certain herbaceous plants with big flowers diacid is first-selection, mixture and copolymer can be selected from, but be not limited to the mixture or the copolymer of the mixture of PLA, PLGA, PLA and PLGA, certain herbaceous plants with big flowers diacid and fragrant polyanhydride or aliphatic polyanhydride.Polylactic acid (PLA) is 10/90-90/10 (weight) with the blend ratio of polyglycolic acid, preferably 25/75-75/25 (weight).The method of blend is arbitrarily.Content when glycolic and lactic acid copolymerization is respectively percentage by weight 10-90% and 90-10%.The representative of fragrance polyanhydride is to carboxy phenyl propane (p-CPP), content during to carboxy phenyl propane (p-CPP) and the copolymerization of certain herbaceous plants with big flowers diacid is respectively percentage by weight 10-60% and 20-90%, the blend weight ratio is 10-40: 50-90, preferably weight ratio 15-30: 65-85.
The another kind of form of anticancer medicine slow-release preparation containing of the present invention is that anticancer medicine slow-release preparation containing is a sustained-release implant.The effective ingredient of anticancer implant can be packaged in the whole pharmaceutic adjuvant equably, also can be packaged in carrier holder center or its surface; Can effective ingredient be discharged by direct diffusion and/or the mode of degrading through polymer.
The characteristics of sustained-release implant are that used slow-release auxiliary material removes the high molecular polymerization beyond the region of objective existence, also contain above-mentioned any one or multiple other adjuvant.The pharmaceutic adjuvant that adds is referred to as additive.Additive can be divided into filler, porogen, excipient, dispersant, isotonic agent, preservative agent, blocker, solubilizing agent, absorption enhancer, film former, gellant etc. according to its function.
The Main Ingredients and Appearance of sustained-release implant can be made into multiple dosage form.As, but be not limited to capsule, slow releasing agent, implant, slow releasing agent implant etc.; Be multiple shape, as, but be not limited to granule, pill, tablet, powder, sphere, bulk, needle-like, bar-shaped, column and membranaceous.In various dosage forms, serve as preferred slowly to discharge implant in the body.
The most preferred dosage form of sustained-release implant is the sustained-release implant that biocompatibility, degradable absorb, and can make different shape and various dosage form because of the clinical needs of difference.The packing method of its Main Ingredients and Appearance and step in United States Patent (USP) (US5651986) have a detailed description, comprise the some kinds of methods that prepare slow releasing preparation: as, but be not limited to, (i) carrier holder powder and medicament mixed be pressed into implant then, promptly so-called mixing method; (ii) carrier holder fusing, mix solid cooled then, promptly so-called fusion method mutually with medicine to be packaged; (iii) the carrier holder is dissolved in the solvent, medicine dissolution to be packaged or be scattered in the polymer solution, evaporating solvent then, drying, promptly so-called dissolution method; (iv) spray drying method; And (v) freeze-drying etc.
Anticancer effective component percentage by weight in the sustained-release implant is as follows, the combination of the 5-FU of 5-30% and the docetaxel of 5-30%, hydroxy camptothecin, Etoposide.
Anticancer effective component percentage by weight in the sustained-release implant is most preferably as follows:
(a) docetaxel of the 5-FU of 5-30% and 5-30%;
(b) hydroxy camptothecin of the 5-FU of 5-30% and 5-30%;
(c) Etoposide of the 5-FU of 5-30% and 5-30%.
One of the copolymer (PLGA) of the preferred polylactic acid of slow-release auxiliary material (PLA), polyglycolic acid and hydroxyacetic acid, ethylene vinyl acetate copolymer (EVAc), FAD:SA copolymer and polifeprosan or its combination.
The present invention can be used to prepare the pharmaceutical preparation of the various tumors for the treatment of people and animal, is mainly slow releasing injection or sustained-release implant.Prepared tumor comprises various entity tumors.Comprise former of originating from brain and central nervous system or shift, and originate from the outer various entity tumors of cranium, as 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 are wherein with the cerebral tumor, renal carcinoma, tumor of head and neck, thyroid carcinoma, pulmonary carcinoma, the esophageal carcinoma, gastric cancer, breast carcinoma, cancer of pancreas, cervical cancer, ovarian cancer, carcinoma of prostate, bladder cancer, colorectal former or metastatic carcinoma are preferred.
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.Can in when operation or perioperatively in tumor, tumor week injection or place; Can with radiation and systemic chemotherapy simultaneously or front and back separate applications, but sustained-release implant with in the tumor, tumor week inject or be placed as preferably.
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 5-FU compares
(Fisher344) is subjects with rat, with 2 * 10
5Individual prostate tumor cells subcutaneous injection is treated behind tumor growth to 1 cm diameter it to be divided into following 8 groups (seeing Table 1) in its hypochondrium.Every group of dosage is 5mg/kg.Measure medicament contg (%) in the different time tumor.
Table 1
| Test group (n) | Administering mode | Medication amount in first day tumor | Medicament contg in the 3rd day tumor | Medicament contg in the 7th day tumor |
| 1(3) | The agent of tail vein injection normal injection | 0.60 | 0.32 | 0.12 |
| 2(3) | The agent of lumbar injection normal injection | 0.56 | 0.3 | 0.08 |
| 3(3) | The agent of tumor week injection normal injection | 2.6 | 1.2 | 0.3 |
| 4(3) | Tumor week injection slow releasing injection | 10 | 18 | 20 |
| 5(3) | Tumor week is placed sustained-release implant | 18 | 30 | 32 |
| 6(3) | The agent of intratumor injection normal injection | 4 | 2 | 1 |
| 7(3) | The intratumor injection slow releasing injection | 92 | 80 | 60 |
| 8(3) | Place sustained-release implant in the tumor | 94 | 92 | 86 |
Above result shows, the local drug concentration significant difference of 5-FU after different modes is used, topical can obviously improve and effectively keep the active drug concentration at position, tumor place, and is wherein best with the effect of placing sustained-release implant and intratumor injection slow releasing injection in the tumor.Yet, intratumor injection slow releasing injection operation most convenient, 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 5-FU compares
(Fisher344) is subjects with rat, with 2 * 10
5Individual prostate tumor cells subcutaneous injection is treated behind tumor growth to 0.5 cm diameter it to be divided into following 9 groups (seeing Table 2) in its hypochondrium.Every group of dosage is 5mg/kg.The treatment back was measured gross tumor volume size, relatively therapeutic effect on the 30th day.
Table 2
| Test group (n) | Administering mode | Gross tumor volume (cm 3) | The P value |
| 1(6) | - | 60 | |
| 2(6) | The agent of tail vein injection normal injection | 58 | 0.05 |
| 3(6) | The agent of lumbar injection normal injection | 56 | 0.05 |
| 4(6) | The agent of tumor week injection normal injection | 46 | 0.04 |
| 5(6) | Tumor week injection slow releasing injection | 24 | ＜0.01 |
| 6(6) | Tumor week is placed sustained-release implant | 16 | ＜0.01 |
| 7(6) | The agent of intratumor injection normal injection | 42 | 0.03 |
| 8(6) | The intratumor injection slow releasing injection | 18 | ＜0.001 |
| 9(6) | Place sustained-release implant in the tumor | 16 | ＜0.001 |
Above result shows, the tumor-inhibiting action significant difference of 5-FU after different modes is used, topical can obviously improve and effectively keep the active drug concentration at position, tumor place, and is wherein best with the effect of placing sustained-release implant and intratumor injection slow releasing injection in the tumor.Yet, intratumor injection slow releasing injection operation most convenient, easy.Good effect not only, toxic and side effects is also little.
Test 3, contain tumor-inhibiting action in the body of 5-FU and 5-FU synergist (slow releasing injection)
(Fisher344) is subjects with rat, with 2 * 10
5Individual pancreatic tumor cell subcutaneous injection is in its hypochondrium, treats that tumor growth after 14 days is divided into it following 10 groups (seeing Table 3).First group is contrast, and the 2nd to 10 group is the treatment group, and medicine is through intratumor injection.Dosage sees Table.The treatment back was measured gross tumor volume size, relatively therapeutic effect (seeing Table 3) on the 20th day.
Table 3
| Test group (n) | Suffered treatment (mg/kg) | Gross tumor volume (cm 3) | The P value |
| 1(6) | Contrast | 54±12 | |
| 2(6) | 5-FU(1) | 46±10.4 | ＜0.05 |
| 3(6) | 5-FU(2) | 34±8.0 | ＜0.01 |
| 4(6) | 5-FU(4) | 30±6.2 | ＜0.01 |
| 5(6) | 5-FU(8) | 26±6.0 | ＜0.01 |
| 6(6) | Docetaxel (4) | 38±6.0 | ＜0.01 |
| 7(6) | 5-FU (1)+docetaxel | 36±6.2 | ＜0.001 |
| 8(6) | 5-FU (2)+docetaxel | 28±4.6 | ＜0.001 |
| 9(6) | 5-FU (4)+docetaxel | 20±3.6 | ＜0.001 |
| 10(6) | 5-FU (8)+docetaxel | 12±2.0 | ＜0.001 |
Above result shows that 5-FU and used 5-FU synergist (docetaxel) all have the obvious suppression effect to tumor growth when this concentration is used separately, can show significant potentiation when use in conjunction.Wherein, 5-FU is relevant with dosage to the inhibitory action of tumor growth.
The tumor-inhibiting action of test 4,5-FU and 5-FU synergist (slow releasing injection)
Used tumor cell comprises CNS-1, C6,9L, gastric gland epithelial cancer (SA), bone tumor (BC), breast carcinoma (BA), pulmonary carcinoma (LH), papillary adenocarcinoma of thyroid (PAT), hepatocarcinoma etc.5-FU and 5-FU synergist are added in 24 hours the various tumor cells of In vitro culture by 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 4.
Table 4
| Oncocyte | 5-FU | Hydroxy camptothecin | Etoposide | Docetaxel | The 5-FU+ hydroxy camptothecin | The 5-FU+ Etoposide | The 5-FU+ docetaxel |
| CNS | 56％ | 54％ | 62％ | 44％ | 90％ | 84％ | 94％ |
| C6 | 54％ | 64％ | 64％ | 44％ | 94％ | 84％ | 90％ |
| SA | 48％ | 62％ | 56％ | 42％ | 88％ | 90％ | 90％ |
| BC | 44％ | 64％ | 54％ | 34％ | 94％ | 84％ | 82％ |
| BA | 48％ | 60％ | 62％ | 50％ | 90％ | 90％ | 90％ |
| LH | 50％ | 58％ | 62％ | 48％ | 92％ | 88％ | 84％ |
| PAT | 54％ | 54％ | 52％ | 34％ | 94％ | 88％ | 96％ |
Above result shows that growth all has the obvious suppression effect to kinds of tumor cells when this concentration is used separately for used 5-FU and 5-FU synergist (hydroxy camptothecin, Etoposide, docetaxel), can show significant potentiation when use in conjunction.
The tumor-inhibiting action of test 5,5-FU and 5-FU synergist (slow releasing injection)
(Fisher344) is subjects with rat, 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 8 groups (seeing Table 5).First group is contrast, and the 2nd to 8 group is the treatment group, and sustained-release implant is placed in tumor.The equal 5mg/kg of 5-FU dosage, the dosage of synergist is 2.5mg/kg.The treatment back was measured gross tumor volume size, relatively therapeutic effect (seeing Table 5) on the 20th day.
Table 5
| Test group (n) | Suffered treatment | Gross tumor volume (cm 3) | The P value |
| 1(6) | Contrast | 52±10 | |
| 2(6) | Docetaxel | 44±8.6 | ＜0.05 |
| 3(6) | 5-FU | 36±6.8 | ＜0.01 |
| 4(6) | Docetaxel+5-FU | 30±6.4 | ＜0.001 |
| 5(6) | Hydroxy camptothecin | 46±6.0 | ＜0.01 |
| 6(6) | Hydroxy camptothecin+5-FU | 26±4.0 | ＜0.001 |
| 7(6) | Etoposide | 38±6.8 | ＜0.01 |
| 8(6) | Etoposide+5-FU | 22±4.6 | ＜0.001 |
Above result shows that growth all has the obvious suppression effect to kinds of tumor cells when this concentration is used separately for used 5-FU and 5-FU thing synergist (docetaxel, hydroxy camptothecin, Etoposide), can show significant potentiation when use in conjunction.
The tumor-inhibiting action of test 6,5-FU and 5-FU synergist (slow releasing injection)
(Fisher344) is subjects with rat, with 2 * 10
5Individual prostate tumor cells subcutaneous injection is in its hypochondrium, treats that tumor growth after 14 days is divided into it negative control (blank), single therapy group (5-FU or 5-FU synergist) and therapeutic alliance group (5-FU and 5-FU synergist).Medicine is through intratumor injection.The dosage of 5-FU and synergist sees Table 6.The treatment back was measured the gross tumor volume size on the 30th day, made relatively therapeutic effect (seeing Table 6) of index with inhibition rate of tumor growth.
Table 6
| Test group (n) | Suffered treatment (mg/kg) | Tumor control rate (%) | The P value |
| 1(6) | Contrast | - | |
| 2(6) | 5-FU(4) | 52 | ＜0.05 |
| 3(6) | Docetaxel (1) | 48 | ＜0.01 |
| 4(6) | Docetaxel (2) | 52 | ＜0.01 |
| 5(6) | Docetaxel (4) | 58 | ＜0.01 |
| 6(6) | Docetaxel (8) | 62 | ＜0.01 |
| 7(6) | 5-FU+ docetaxel (1) | 78 | ＜0.001 |
| 8(6) | 5-FU+ docetaxel (2) | 84 | ＜0.001 |
| 9(6) | 5-FU+ docetaxel (4) | 88 | ＜0.001 |
| 10(6) | 5-FU+ docetaxel (8) | 94 | ＜0.001 |
Above result shows that used 5-FU and 5-FU synergist (docetaxel) growth of tumour cell when this concentration is used separately all has the obvious suppression effect, can show significant potentiation when use in conjunction.
The tumor-inhibiting action of test 7,5-FU and 5-FU synergist (slow releasing injection)
(Fisher344) is subjects with rat, with 2 * 10
5Individual breast tumor cell subcutaneous injection is in its hypochondrium, treats that tumor growth after 14 days is divided into it negative control (blank), single therapy group, therapeutic alliance group.Medicine is through intratumor injection.The dosage of 5-FU and synergist sees Table 7.The treatment back was measured the gross tumor volume size on the 30th day, made relatively therapeutic effect (seeing Table 7) of index with inhibition rate of tumor growth.
Table 7
| Test group (n) | Suffered treatment (mg/kg) | Tumor control rate (%) | The P value |
| 1(6) | Contrast | - | |
| 2(6) | 5-FU(5) | 56 | ＜0.05 |
| 3(6) | Hydroxy camptothecin (1) | 42 | ＜0.01 |
| 4(6) | Hydroxy camptothecin (2) | 4 | ＜0.01 |
| 5(6) | Hydroxy camptothecin (4) | 54 | ＜0.01 |
| 6(6) | Hydroxy camptothecin (8) | 66 | ＜0.01 |
| 7(6) | 5-FU+ hydroxy camptothecin (1) | 68 | ＜0.001 |
| 8(6) | 5-FU+ hydroxy camptothecin (2) | 82 | ＜0.001 |
| 9(6) | 5-FU+ hydroxy camptothecin (4) | 86 | ＜0.001 |
| 10(6) | 5-FU+ hydroxy camptothecin (8) | 92 | ＜0.001 |
Above result shows that used 5-FU and 5-FU synergist (hydroxy camptothecin) all have the obvious suppression effect to growth of tumour cell when this concentration is used separately, can show significant potentiation when use in conjunction.
The tumor-inhibiting action of test 8,5-FU and 5-FU synergist (sustained-release implant)
(Fisher344) is subjects with rat, 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.The treatment back was measured the gross tumor volume size on the 20th day, made relatively therapeutic effect (seeing Table 8) of index with inhibition rate of tumor growth
Table 8
| Test group (n) | Suffered treatment (mg/kg) | Tumor control rate (%) | The P value |
| 1(6) | Contrast | - | |
| 2(6) | 5-FU(10) | 68 | ＜0.05 |
| 3(6) | Docetaxel (2) | 34 | ＜0.05 |
| 4(6) | Docetaxel (4) | 46 | ＜0.05 |
| 5(6) | Docetaxel (8) | 58 | ＜0.05 |
| 6(6) | Docetaxel (16) | 64 | ＜0.01 |
| 7(6) | 5-FU+ docetaxel (2) | 82 | ＜0.01 |
| 8(6) | 5-FU+ docetaxel (4) | 88 | ＜0.01 |
| 9(6) | 5-FU+ docetaxel (8) | 92 | ＜0.01 |
| 10(6) | 5-FU+ docetaxel (16) | 96 | ＜0.001 |
Above result shows that used 5-FU and 5-FU synergist (docetaxel) all have the obvious suppression effect to growth of tumour cell when this concentration is used separately, can show significant potentiation when use in conjunction, and be dose-effect relationship.
The tumor-inhibiting action of test 9,5-FU and 5-FU synergist (sustained-release implant)
By the tumor-inhibiting action of test 8 described methods mensuration 5-FU and 5-FU synergist (sustained-release implant), its inhibition rate of tumor growth sees Table 9.
Table 9
| Test group (n) | Suffered treatment (mg/kg) | Tumor control rate (%) | The P value |
| 1(6) | Contrast | - | |
| 2(6) | 5-FU(8) | 52 | ＜0.05 |
| 3(6) | Etoposide (2) | 36 | ＜0.05 |
| 4(6) | Etoposide (4) | 44 | ＜0.05 |
| 5(6) | Etoposide (8) | 52 | ＜0.05 |
| 6(6) | Etoposide (16) | 62 | ＜0.01 |
| 7(6) | 5-FU+ Etoposide (2) | 80 | ＜0.01 |
| 8(6) | 5-FU+ Etoposide (4) | 84 | ＜0.01 |
| 9(6) | 5-FU+ Etoposide (8) | 90 | ＜0.01 |
| 10(6) | 5-FU+ Etoposide (16) | 94 | ＜0.001 |
Above result shows that growth all has the obvious suppression effect to kinds of tumor cells when this concentration is used separately for used 5-FU and 5-FU synergist (Etoposide), can show significant potentiation when use in conjunction.
In a word, growth all had the obvious suppression effect to kinds of tumor cells when used 5-FU and various 5-FU synergist were used separately, can show significant potentiation when use in conjunction.Therefore, effective ingredient of the present invention is the combination of 5-FU and any one 5-FU synergist.The medicine that contains above effective ingredient can be made into sustained-release micro-spheres, and then makes slow releasing injection and implant, serves as preferred with the suspensoid injectio that is combined to form with the special solvent that contains suspending agent wherein.
Slow releasing injection or sustained-release implant also can be further specified by following embodiment.Just the invention will be further described for the foregoing description and following examples, is not its content and use are imposed any restrictions.
(4) specific embodiment
Embodiment 1.
70mg polifeprosan (to carboxy phenyl propane (p-CPP): certain herbaceous plants with big flowers diacid (SA) is 20: 80) copolymer is put into container respectively, add 100 milliliters of dichloromethane then, add 15mg5-FU and 15mg docetaxel behind the dissolving mixing, shake up the back contains 15%5-FU and 15% docetaxel 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 360cp-480cp (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 2.
80mg polifeprosan (to carboxy phenyl propane (p-CPP): certain herbaceous plants with big flowers diacid (SA) is 50: 50) copolymer is put into container respectively, add 100 milliliters of dichloromethane then, add 5mg5-FU and 15mg docetaxel behind the dissolving mixing, shake up the back contains 5%5-FU and 15% docetaxel with spray drying method for preparation injectable microsphere again.Then microsphere is suspended in the normal saline that contains 1.5% sodium carboxymethyl cellulose, makes corresponding suspension type slow releasing injection, viscosity is 380cp-460cp (25 ℃-30 ℃ time).The drug release time of this slow releasing injection in external normal saline is 14-20 days, is about 25-35 days at the subcutaneous drug release time of mice.
Embodiment 3
The method step that is processed into slow releasing injection is identical with embodiment 2, but different is that contained anticancer effective component and percentage by weight thereof are: 15% 5-FU and 5% docetaxel, the viscosity of suspension type slow releasing injection are 420cp-520cp (25 ℃-30 ℃ time).The drug release time of this slow releasing injection in external normal saline is 15-25 days, is about 25-35 days at the subcutaneous drug release time of mice.
Embodiment 4.
With 80mg molecular weight peak value is that PLGA (50: the 50) copolymer of 25000-50000 is put into container respectively, add 100 milliliters of dichloromethane then, add 10mg5-FU and 10mg docetaxel behind the dissolving mixing, shake up the back contains 10%5-FU and 10% docetaxel with spray drying method for preparation injectable microsphere again.Then microsphere is suspended in the normal saline that contains 1.5% sodium carboxymethyl cellulose, makes corresponding suspension type slow releasing injection, viscosity is 360cp-420cp (25 ℃-30 ℃ time).The drug release time of this slow releasing injection in external normal saline is 15-20 days, is about 20-25 days at the subcutaneous drug release time of mice.
Embodiment 5.
With 70mg molecular weight peak value is that the PLGA (75: 25) of 40000-60000 puts into container respectively, add 100 milliliters of dichloromethane then, add 10mg5-FU and 20mg docetaxel behind the dissolving mixing, shake up the back contains 10%5-FU and 20% docetaxel 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 10-15 days, is about 20-30 days at the subcutaneous drug release time of mice.
Embodiment 6
With 80mg molecular weight peak value is that the PLGA (50: 50) of 20000-40000 puts into container respectively, add 100 milliliters of dichloromethane then, add 15mg5-FU and 5mg docetaxel behind the dissolving mixing, shake up the back contains 15%5-FU and 5%mg docetaxel 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 14-20 days, is about 20-25 days at the subcutaneous drug release time of mice.
Embodiment 7
The method step that is processed into slow releasing injection is identical with embodiment 6, but different is that contained anticancer effective component and percentage by weight thereof are: the combination of the 5-FU of 5-30% and the docetaxel of 5-30%, hydroxy camptothecin or Etoposide.
Embodiment 8.
(EVAc) puts into container with the 70mg ethylene vinyl acetate copolymer, after adding 100 milliliters of dichloromethane dissolving mixings, add 20 milligrams of 5-FU and 10 milligrams of hydroxy camptothecins, shake up the back contains 20%5-FU and 10% hydroxy camptothecin with spray drying method for preparation injectable microsphere again.Then microsphere is suspended in the injection that contains the 5-15% sorbitol, makes corresponding suspension type slow releasing injection.The drug release time of this slow releasing injection in external normal saline is 15-20 days, is about 20-25 days at the subcutaneous drug release time of mice.
Embodiment 9.
The method step that is processed into slow releasing injection is identical with embodiment 8, but different is that contained anticancer effective component is:
The combination of the 5-FU of 10-20% and the docetaxel of 10-20%, hydroxy camptothecin, Etoposide.
Embodiment 10.
70mg polifeprosan (to carboxy phenyl propane (p-CPP): certain herbaceous plants with big flowers diacid (SA) is 50: 50) copolymer is put into container, add 100 milliliters of dichloromethane, behind the dissolving mixing, add 10mg5-FU and 20mg hydroxy camptothecin, shake up the back contains 10%5-FU and 20% hydroxy camptothecin with spray drying method for preparation injectable microsphere again.Microsphere is suspended in the normal saline that contains 1.5% sodium carboxymethyl cellulose and 0.5% Tween 80 then, makes corresponding suspension type slow releasing injection.The drug release time of this slow releasing injection in external normal saline is 10-15 days, is about 20-30 days at the subcutaneous drug release time of mice.
Embodiment 11.
The method step that is processed into slow releasing injection is identical with embodiment 10, but different is that contained anticancer effective component is:
The combination of 10% 5-FU and 20% docetaxel, hydroxy camptothecin or Etoposide.
Embodiment 12.
70mg polifeprosan (to carboxy phenyl propane (p-CPP): certain herbaceous plants with big flowers diacid (SA) is 20: 80) copolymer is put into container, add 100 milliliters of dichloromethane, behind the dissolving mixing, add 15mg5-FU and 15mg docetaxel, shake up the back contains 15%5-FU and 15% with spray drying method for preparation docetaxel injectable microsphere again.Then microsphere is suspended in the normal saline that contains 1.5% sodium carboxymethyl cellulose and 15% sorbitol and 0.2% Tween 80, makes corresponding suspension type slow releasing injection.The drug release time of this slow releasing injection in external normal saline is 10-15 days, is about 20-30 days at the subcutaneous drug release time of mice.
Embodiment 13.
The method step that is processed into slow releasing injection is identical with embodiment 12, but different is that contained anticancer effective component is:
The combination of 15% 5-FU and 15% docetaxel, hydroxy camptothecin or Etoposide.
Embodiment 14
80mg polifeprosan (to carboxy phenyl propane (p-CPP): certain herbaceous plants with big flowers diacid (SA) is 20: 80) copolymer is put into container, add 100 milliliters of dichloromethane, behind the dissolving mixing, add 7.5mg Etoposide and 12.5mg5-FU, shake up the back contains 7.5% Etoposide and 12.5%5-FU with spray drying method for preparation injectable microsphere again.Then microsphere is made corresponding sustained-release implant through pressed disc method.The drug release time of this sustained-release implant in external normal saline is 10-15 days, is about 30-40 days at the subcutaneous drug release time of mice.
Embodiment 15
The method step that is processed into sustained-release implant is identical with embodiment 14, but different is that contained anticancer effective component is:
The combination of 12.5% 5-FU and 7.5% docetaxel, hydroxy camptothecin or Etoposide.
Embodiment 16
With 70mg molecular weight peak value is that the PLGA (50: 50) of 20000-40000 puts into container, add 100 milliliters of dichloromethane, behind the dissolving mixing, add 10mg5-FU and 20mg docetaxel, shake up the back contains 10%5-FU and 20% docetaxel 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 35-50 days at the subcutaneous drug release time of mice.
Embodiment 17
With 70mg molecular weight peak value is that the PLA of 20000-40000 puts into container, add 100 milliliters of dichloromethane, behind the dissolving mixing, add 10mg5-FU and 20mg Etoposide, shake up the back contains 10%5-FU and 20% Etoposide 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 20-25 days, is about 30-40 days at the subcutaneous drug release time of mice.
Embodiment 18
With 70mg molecular weight peak value is that the PLGA (50: 50) of 40000-60000 puts into container, add 100 milliliters of dichloromethane, behind the dissolving mixing, add 20mg5-FU and 10mg Etoposide, shake up the back contains 20%5-FU and 10% Etoposide with spray drying method for preparation injectable microsphere again.Then microsphere is made corresponding sustained-release implant through pressed disc method.The drug release time of this sustained-release implant in external normal saline is 20-25 days, is about 35-40 days at the subcutaneous drug release time of mice.
Embodiment 19
The method step of processing sustained-release implant is identical with embodiment 17 and 18, but different is that contained anticancer effective component is:
The combination of (1) 15% 5-FU and 5% docetaxel, hydroxy camptothecin or Etoposide; Or
The combination of (2) 10% 5-FU and 10% docetaxel, hydroxy camptothecin or Etoposide; Or
The combination of (3) 5% 5-FU and 15% docetaxel, hydroxy camptothecin or Etoposide.
Embodiment 20
With 70mg molecular weight peak value is that the PLGA (50: 50) of 25000-40000 puts into container, add 100 milliliters of dichloromethane, behind the dissolving mixing, add 20mg5-FU and 10mg hydroxy camptothecin, shake up the back contains 20%5-FU and 10% hydroxy camptothecin 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 20-25 days, is about 35-40 days at the subcutaneous drug release time of mice.
Embodiment 21
With 70mg molecular weight peak value is that the PLA of 25000-40000 puts into container, add 100 milliliters of dichloromethane, behind the dissolving mixing, add 10mg5-FU and 20mg hydroxy camptothecin, shake up the back contains 10%5-FU and 20% hydroxy camptothecin 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 20-25 days, is about 30-35 days at the subcutaneous drug release time of mice.
Embodiment 22
The method step that is processed into slow releasing agent is identical with embodiment 1-21, but different is used slow-release auxiliary material is one of following or its combination:
A) the molecular weight peak value is the polylactic acid (PLA) of 10000-30000,30000-60000,60000-100000 or 100000-150000;
B) the molecular weight peak value is the polyglycolic acid of 10000-30000,30000-60000,60000-100000 or 100000-150000 and the copolymer of hydroxyacetic acid (PLGA), and wherein, the ratio of polyglycolic acid and hydroxyacetic acid is 50-95: 50-50;
C) ethylene vinyl acetate copolymer (EVAc);
D) 10: 90,20: 80,30: 70,40: 60,50: 50 or 60: 40 to carboxy phenyl propane (p-CPP): certain herbaceous plants with big flowers diacid (SA) copolymer (polifeprosan);
E) FAD and certain herbaceous plants with big flowers diacid (SA) copolymer;
F) xylitol, oligosaccharide, chrondroitin, chitin, hyaluronic acid, collagen protein, gelatin or white tempera.
Embodiment 23.
The method step that is processed into slow releasing injection is identical with embodiment 1-21, 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.
Claims (10)
1. the slow releasing injection of fluorouracil and synergist thereof is grouped into by following one-tenth:
(A) sustained-release micro-spheres comprises:
Anticancer effective component 0.5-60%
Slow-release auxiliary material 40-99%
Suspending agent 0.0-30%
More than be weight percentage
With
(B) solvent is for common solvent or contain the special solvent of suspending agent.
Wherein,
Anticancer effective component is 5-FU and 5-FU synergist;
Suspending agent is selected from one of sodium carboxymethyl cellulose, iodine glycerol, simethicone, propylene glycol, carbomer, mannitol, sorbitol, surfactant, soil temperature 20, soil temperature 40 and soil temperature 80 or its combination,
The viscosity of injection is 50cp-1000cp (20 ℃-30 ℃ time)
2. the slow-releasing anticarcinogen injection according to claim 1 is characterized in that synergist is selected from one of docetaxel, hydroxy camptothecin, Etoposide or its combination.
3. the slow-releasing anticarcinogen injection according to claim 1 is characterized in that the anticancer effective component of slow-releasing anticarcinogen injection is: the combination of the 5-FU of 5-30% and the docetaxel of 5-30%, hydroxy camptothecin or Etoposide.
Below all be weight percentage.
4. the slow-releasing anticarcinogen injection according to claim 1 is characterized in that the anticancer effective component of slow-releasing anticarcinogen injection is:
The combination of (1) 15% 5-FU and 5% docetaxel, hydroxy camptothecin or Etoposide; Or
The combination of (2) 10% 5-FU and 10% docetaxel, hydroxy camptothecin or Etoposide; Or
The combination of (3) 5% 5-FU and 15% docetaxel, hydroxy camptothecin or Etoposide; Or
The combination of (4) 25% 5-FU and 5% docetaxel, hydroxy camptothecin or Etoposide.
5. the slow-releasing anticarcinogen injection according to claim 1 is characterized in that slow-release auxiliary material is selected from one of following or its combination:
A) polylactic acid;
B) copolymer of polyglycolic acid and hydroxyacetic acid;
C) polifeprosan;
D) ethylene vinyl acetate copolymer;
E) FAD and certain herbaceous plants with big flowers diacid copolymer.
6. the slow-releasing anticarcinogen injection according to claim 1 is characterized in that used suspending agent is respectively one of following or its combination:
A) 0.5-3.0% carboxymethyl cellulose (sodium);
B) 5-15% mannitol;
C) 5-15% sorbitol;
D) 0.1-1.5% surfactant;
E) 0.1-0.5% polysorbas20, or
F) (iodine) 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% soil temperature 80;
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.
8. be used to prepare the sustained-release implant that treatment originates from people and the outer entity tumor of animal cranium or the cerebral tumor 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 combination of (1) 15% 5-FU and 5% docetaxel, hydroxy camptothecin or Etoposide; Or
The combination of (2) 10% 5-FU and 10% docetaxel, hydroxy camptothecin or Etoposide; Or
The combination of (3) 5% 5-FU and 15% docetaxel, hydroxy camptothecin or Etoposide; Or
The combination of (4) 25% 5-FU and 5% docetaxel, hydroxy camptothecin or Etoposide.
Slow-release auxiliary material is selected from one of following or its combination:
A) polylactic acid;
B) copolymer of polyglycolic acid and hydroxyacetic acid;
C) polifeprosan;
D) ethylene vinyl acetate copolymer;
E) FAD and certain herbaceous plants with big flowers diacid copolymer.
10. described according to Claim 8 described anti-cancer sustained-released implantation agent is characterized in that the outer entity tumor of cranium is to originate from people and animal origin in former or cancer, sarcoma or the carcinosarcoma of secondary of people and animal kidney, liver, gallbladder, incidence, oral cavity, thyroid, skin, mucosa, body of gland, blood vessel, osseous tissue, lymph node, lungs, esophagus, stomach, mammary gland, pancreas, eyes, nasopharynx part, uterus, ovary, endometrium, cervix uteri, prostate, bladder, colon or rectum.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA2006102009453A CN1969825A (en) | 2006-09-28 | 2006-09-28 | Sustained release agent containing fluorouracil and synergist thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA2006102009453A CN1969825A (en) | 2006-09-28 | 2006-09-28 | Sustained release agent containing fluorouracil and synergist thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1969825A true CN1969825A (en) | 2007-05-30 |
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA2006102009453A Pending CN1969825A (en) | 2006-09-28 | 2006-09-28 | Sustained release agent containing fluorouracil and synergist thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN1969825A (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1957920B (en) * | 2006-09-28 | 2010-05-19 | 山东蓝金生物工程有限公司 | Anti cancer slow release agent carrying fluorouracil and synergist |
| CN104267188A (en) * | 2014-08-28 | 2015-01-07 | 汪建平 | Applications of related preparations aiming at MSK1 gene in preparation of 5-FU drug resistance detection reagent and 5-FU drug resistance reversal agent |
| CN112704683A (en) * | 2020-12-30 | 2021-04-27 | 烟台大学 | Novel camptothecin derivative and application thereof in preparing antitumor drugs |
-
2006
- 2006-09-28 CN CNA2006102009453A patent/CN1969825A/en active Pending
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1957920B (en) * | 2006-09-28 | 2010-05-19 | 山东蓝金生物工程有限公司 | Anti cancer slow release agent carrying fluorouracil and synergist |
| CN104267188A (en) * | 2014-08-28 | 2015-01-07 | 汪建平 | Applications of related preparations aiming at MSK1 gene in preparation of 5-FU drug resistance detection reagent and 5-FU drug resistance reversal agent |
| CN112704683A (en) * | 2020-12-30 | 2021-04-27 | 烟台大学 | Novel camptothecin derivative and application thereof in preparing antitumor drugs |
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