CN101023921A - Anti-cancer composition containing glucocorticoid hormone - Google Patents
Anti-cancer composition containing glucocorticoid hormone Download PDFInfo
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Abstract
The present invention relates to an anti-cancer medicine composition containing glucocorticoid. Said anti-cancer medicine composition is a slow-release injection formed from slow-release microsphere and solvent. Said slow-release microsphere includes anti-cancer medicine of taxane, alkylation agent and/or plant alkaloid, glucocorticoid and slow-release auxiliary material, and the solvent is a special solvent containing suspension adjuvant. The glucocorticoid is selected from prednisone, dexamethasone, betamethasone, triamcinolone and triamcinolone acetonide, etc. The slow-release auxiliary material is selected from racemic polylactic acid and its glycolic acid copolymer, polyethylene glycol and its polylactic acid copolymer, carboxyl-terminated polylactic acid copolymer and fatty acid and sebacic acid copolymer or mixture. The suspension adjuvant is selected from carboxymethylcellulose sodium, etc. Said medicine composition also can be made into slow-release implantation preparation.
Description
(1) technical field
The present invention relates to a kind of anti-cancer composition that contains glucocorticoid, belong to technical field of pharmaceuticals.Particularly, the invention provides a kind of slow releasing injection and sustained-release implant that contains glucocorticoid.This anticancer sustained-release agent can suppress or alleviate the formation of edema effectively, helps medicine and enters entity tumor and the effective diffusion in tumor.
(2) background technology
Traditional chemotherapy is not had a selectivity, and be difficult to tumor by local and form effective drug level or therapeutic dose, weak effect, toxicity is big, improves the restriction that medicine or radiological dose are subjected to general toxic reaction again merely.Referring to " placing cisplatin adding system carmustine treatment rat brain tumor in the tumor " " surgery tumor magazine " 69 phase 76-82 pages or leaves such as hole, (Kong Q et al., J SurgOncol.1998 Oct in 1998; 69 (2): 76-82).The cancer drug therapy of low dosage not only can increase the Drug tolerance of cancerous cell, but also can promote its infiltrative growth "; referring to beam etc. " increased the Drug tolerance of human lung carcinoma cell and external wetting capacity after the cancer therapy drug pulse screening and with the change of gene expression " " international journal of cancer " 111 phase 484-93 page or leaf; 2004 (Liang Y; et al., Int J Cancer.2004; 111 (4): 484-93).
The antitumor drug local sustained release can overcome above defective preferably, not only can obviously improve the drug level of tumor by local, and can significantly reduce general toxic reaction.A large amount of internal and external tests have demonstrated the therapeutic effect to entity tumor, referring to " placing cisplatin adding system carmustine treatment rat brain tumor in the tumor " " surgery tumor magazine " 69 phase 76-82 pages or leaves such as Kong Qingzhongs, (Kong Q et al., J Surg Oncol.1998 Oct in 1998; 69 (2): 76-82) and Kong Qingzhong etc. " place cisplatin in the tumor and cure the former carbuncle in the occipital region tumor of rat " " surgery tumor magazine " 64 phase 268-273 pages or leaves (1997) (Kong Q et al., JSurg Oncol.1997 Oct; 64:268-273).Also can be referring to Chinese patent (ZL00111093.4; ZL96115937.5; Application number 001111264,001111272) and U.S.'s patent of invention (patent No. 6,376,525B1; 5,651,986; 5,626,862).
Yet, entity tumor is made up of tumor cell and mesenchyma stroma of tumors, wherein the blood vessel in the mesenchyma stroma of tumors not only provides support and requisite nutrient substance for the growth of tumor cell, also influenced chemotherapeutics around tumor and infiltration and diffusion in the tumor tissues, " situation of extracellular matrix is to the influence of medicine running in the entity tumor " " cancer research " 60 phase 2497-503 page or leaf such as carry referring to the Buddhist nun, (Netti PA, Cancer Res.2000,60 (9): 2497-503) in 2000.
Yet, the tumor cell of composition such as the blood vessel in the mesenchyma stroma of tumors and fibrin in the connective tissue and collagen protein and hyperplasia cause entity tumor between matter pressure (interstitial presure) height, the local placement of antitumor drug often causes the local organization edema.The local organization edema can influence wound healing, increases post-operative complication.The increasing of local pressure also can quicken medicine prominent release and tumor in removing, be unfavorable for keeping of active drug concentration in the tumor.Occur in significant points, as brain, edema also can cause severe complications such as cerebral hernia, therefore constitute the major obstacle that tumor is implanted chemotherapy, cause the treatment failure.
(3) summary of the invention
The present invention is directed to the deficiencies in the prior art, a kind of new anticancer pharmaceutical composition is provided, contain glucocorticoid and/or cancer therapy drug.More specifically, be the slow releasing agent of anti entity tumour, be mainly sustained-release implant and slow releasing injection.Topical application can suppress or alleviate local edema effectively; Decapacitation suppresses can also increase the sensitivity of tumor cell to cancer therapy drug outside the tumor growth; Help medicine and enter entity tumor and the effective diffusion in tumor.
In addition, glucocorticoid and/or cancer therapy drug are made drug level that slow releasing agent (being mainly slow releasing injection and sustained-release implant) not only can greatly improve tumor by local, reduce the drug level of medicine in blood circulation, are reduced the toxicity of medicine to normal structure, can also greatly make things convenient for the medicine injection, reduce operation technique complication, reduce patient's expense.The cancer therapy drug decapacitation suppresses can also increase the sensitivity of tumor cell to cancer therapy drug outside the tumor growth.The above unexpected main contents of the present invention of finding to constitute.
Anti-cancer composition of the present invention comprises anticancer effective component and pharmaceutic adjuvant, and anticancer effective component is selected from taxane, alkylating agent and/or plant alkaloid and glucocorticoid.Glucocorticoid can suppress or alleviate local edema effectively except that having the effect that suppresses growth of tumour cell, therefore can obviously promote chemotherapeutics to enter tumor and reach around tumor and infiltration and diffusion in the tumor tissues.
Compound medicament composition of the present invention can be made into any dosage form, as, but be not limited to capsule, slow releasing agent, granule, pill, tablet, powder, injection, ointment, patch, implant, slow releasing agent implant, slow releasing agent injection etc.Wherein be preferred with the slow releasing agent, with slow releasing agent implant and slow releasing agent injection for most preferably.
The present invention is directed to the deficiencies in the prior art, a kind of new slow releasing injection that contains glucocorticoid and cancer therapy drug is provided.
Glucocorticoid slow releasing injection of the present invention is made up of sustained-release micro-spheres and solvent.Particularly, this slow-releasing anticarcinogen injection is grouped into by following one-tenth:
(A) sustained-release micro-spheres comprises:
Anticancer effective component 0.01-60%
Slow-release auxiliary material 40-99.99%
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 glucocorticoid and cancer therapy drug, and cancer therapy drug is selected from taxane, alkylating agent and/or plant alkaloid; 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)], 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, chitosan, poloxamer, one of albumin glue or its combination; Suspending agent is selected from one of sodium carboxymethyl cellulose, (iodine) glycerol, simethicone, propylene glycol, carbomer, mannitol, sorbitol, surfactant, soil temperature 20, soil temperature 40 and soil temperature 80 or its combination.
Glucocorticoid is vasoinhibitor and/or proteolytic enzyme, vasoinhibitor is except that having the effect that suppresses growth of tumour cell, the blood vessel that can suppress or destroy tumor effectively also can suppress the formation of the new vessels of tumor, and then not only make tumor cell lose the required support of growth and the source of nutrient substance, also can obviously promote chemotherapeutics to enter tumor and reach around tumor and infiltration and diffusion in the tumor tissues.
Pharmaceutic adjuvant have hundreds of more than, pharmaceutic adjuvant with slow releasing function, it is not apparent particularly selected platinum-like compounds among the present invention slowly being discharged in the regular hour in human body or animal body, but specific slow-release auxiliary material need could be determined through a large amount of creative works with the selection of slow releasing pharmaceutical combination.Discharged and be not enough to obtain active drug concentration slowly, thereby effective kill tumor cell; Cause prominent releasing if discharge too fast meeting, then cause general toxic reaction as conventional injection easily.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.
Available glucocorticoid medicine comprises, but be not limited to, cortisone (cortisone), hydrocortisone (hydrocortisone), hydrocortisone acetate (hydrocortisone acetate), hydrocortisone butyrate (hydrocortisone butyrate), prednisone (Prednisone), meticortelone (prednisolone), methyl meticortelone (Methylprednisolone), omcilon (triamcinolone acetonide, triamcinolone Triamcinolone, Triamcinolone, triamcinolone, Fluoxyprednisolone, Triamcortisone), dexamethasone (dexamethasone), betamethasone (Betemethasone), clobetasone butyrate (clobetasone butyrate), clobetasol propionate (clobetasol propionate, chlorine times Mi Song, dermovate), beclometasone (Beclomethasone, the Beclomethasone, beclomethasone dipropionate, Beclomethasone, Beclomethasone Dipropionate), triamcinolone acetonide (Triamcinolone Acetonide, triamcinolone acetonide, Triamcinolone Acetonide, Triamcinolone Acetonide, Adcortyl A), pivalic acid dexamethasone (flumethasone pivalate), momestasone furoate (mometasone furoate), valeric acid Tuo Tamisong (betamethasone valerate), betamethasone dipropionate (betamethasone dipropionate), fluocinonide (flucinonode), halcinonidedcorten (halcinonide, halcinonide Halcinonide, halcinonide)), sicorten see halometasone (halmetasone), beclomethasone (BDP), budesonide (BDU) and fluticasone.
Glucocorticoids also comprises available salt and ester, as, but be not limited to acetic acid, butanoic acid, sodium succinate, diacetate, phosphoric acid, propanoic acid, hydrochlorate or ester, sulfate, phosphate, hydrochlorate, Lactobionate, aspat, nitrate, citrate, purine or pyrimidine salt and maleate etc.
Above-mentioned glucocorticoid medicine is divided into basic, normal, high effect according to its effect power, it is generally acknowledged, poor efficiency is mainly cortisone and hydrocortisone, and consumption per day is about 1-50mg; The middle effect is mainly prednisone, meticortelone, methyl meticortelone and omcilon, and consumption per day is 0.1-10mg; Efficiently be mainly betamethasone and dexamethasone, consumption per day is 0.01-5mg.
The present invention selects according to its clinical consumption, it is divided into following a few class, (1) poor efficiency class: include, but not limited to cortisone, hydrocortisone, hydrocortisone acetate, prednisone; (2) imitate class in: include, but not limited to meticortelone, methyl meticortelone, clobetasone butyrate, hydrocortisone butyrate, dexamethasone, betamethasone, omcilon, triamcinolone acetonide, momestasone furoate, fluocinonide; (3) efficient class: include, but not limited to pivalic acid dexamethasone, valeric acid Tuo Tamisong, betamethasone dipropionate, halcinonidedcorten, chlorine times Mi Song, Beclomethasone, sicorten see halometasone, beclomethasone, budesonide, fluticasone.
The application dose of above-mentioned glucocorticoid medicine is decided as the case may be, and when it is generally acknowledged the clinical system consumption, the consumption per day of poor efficiency class is about 1-50mg; Middle effect consumption per day is 0.1-10mg; Efficient consumption per day is 0.01-5mg.Consumption of the present invention can be, but is not limited to, and 0.1 to 10 times of above-mentioned consumption per day serves as preferred with 0.1 to 5 times.
Above-mentioned glucocorticoid shared ratio in slow releasing agent is decided because of concrete condition, can be 0.01%-50%, is good with 0.1%-30%, and 1%-20% is best.
Taxane in the anticancer effective component (Taxanes) kind anti-cancer drugs owner will be selected from paclitaxel (Taxol), Docetaxel (Docetaxel, taxotere, docetaxel), 2 ' hydroxyl paclitaxel (paclitaxel-2 ' hydroxy), 10-removes acetyl paclitaxel (10-deacetyl taxol), 7 Epitaxols (7-epi-taxol).With paclitaxel and docetaxel serves as preferred.
Alkylating agent comprises and selects alestramustine; atrimustine; ambamustine; carmustine; nimustine; ditiomustine; bofumustine; bendamustine; galamustine; Ranimustine; fotemustine; elmustine; ecomustine; estramustine; hemustine heCNU He; pentamustine; mannomustine; lomustine; methyl lomustine; prednimustine; uracil mustard; tauromustine; tallimustine; spiromustine; streptozocin; Sarmustine SarCNU; semustine; methyl lomustine; streptozocin; a kind of or its combination in the appropriate azoles amine of miaow.Above alkylating agent also comprises their salt, as, but be not limited to sulfate, phosphate, hydrochlorate, Lactobionate, acetate, aspat, nitrate, citrate, purine or pyrimidine salt, succinate and maleate etc.
The percentage by weight of above-mentioned alkylating agent in slow releasing agent is good from 1%-60% with 2%-40%, is best with 5%-30%.
Plant alkaloid mainly is selected from vincristine, vincaleucoblastine, vinorelbine, vindesine, Vinmegallate, vinleurosine, vinleucinol, vinglycinate, vinfosiltine, vinformide, vinflunine, vinepidine, vinzolidine, vintriptol, vinrosidine, monocrotaline or cephalotaxin.
Plant alkaloid shared ratio in compositions is decided because of concrete condition, and generally speaking, percentage by weight can be good with 2%-40% from 1%-60%, is best with 5%-30%.
When the cancer therapy drug in the medicament slow-release microsphere only was glucocorticoid or cancer therapy drug, slow-releasing anticarcinogen injection was mainly used in the glucocorticoid of other approach application of increase or the action effect of cancer therapy drug, or was used for the potentiation to radiotherapy or other therapies.When the cancer therapy drug in the medicament slow-release microsphere only was glucocorticoid or cancer therapy drug, the application of slow-releasing anticarcinogen injection and potentiation mode were:
(1) contain the slow releasing injection local injection of glucocorticoid, and cancer therapy drug is used through other approach;
(2) local injection contains the slow releasing injection of cancer therapy drug, and other approach are used glucocorticoid;
(3) local injection contains the slow releasing injection and the slow releasing injection that contains cancer therapy drug of glucocorticoid; Or
(4) local injection contains the slow releasing injection of glucocorticoid and cancer therapy drug.
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 glucocorticoid and/or the cancer therapy drug percentage by weight in medicament slow-release microsphere is 0.5%-60%, is good with 2%-40%, is best with 5%-30%.The weight ratio of glucocorticoid and cancer therapy drug is 1-99: 1 and 1: 1-99, and with 1-49: 1 to 1: 1-49 serves as preferred, with 1-19: 1 to 1: 1-19 serves as preferred.
Anticancer effective component in the slow-releasing anticarcinogen injection microsphere of the present invention is preferably as follows, and all is weight percentage:
(a) cortisone of 0.01-20%, hydrocortisone, hydrocortisone acetate, prednisone, meticortelone, methyl meticortelone, clobetasone butyrate, hydrocortisone butyrate, dexamethasone, betamethasone, omcilon, triamcinolone acetonide, momestasone furoate, fluocinonide, the pivalic acid dexamethasone, valeric acid Tuo Tamisong, betamethasone dipropionate, halcinonidedcorten, chlorine times Mi Song, the Beclomethasone, sicorten see halometasone, beclomethasone, the paclitaxel of budesonide or fluticasone and 2-40%, Docetaxel, 2 '-hydroxyl paclitaxel, 10-goes the combination of acetyl paclitaxel or 7-table-paclitaxel;
(b) cortisone of 0.01-20%, hydrocortisone, hydrocortisone acetate, prednisone, meticortelone, methyl meticortelone, clobetasone butyrate, hydrocortisone butyrate, dexamethasone, betamethasone, omcilon, triamcinolone acetonide, momestasone furoate, fluocinonide, the pivalic acid dexamethasone, valeric acid Tuo Tamisong, betamethasone dipropionate, halcinonidedcorten, chlorine times Mi Song, the Beclomethasone, sicorten see halometasone, beclomethasone, the carmustine of budesonide or fluticasone and 2-40%, nimustine, bendamustine, galamustine, Ranimustine, fotemustine, lomustine, uracil mustard, tauromustine, tallimustine, spiromustine, streptozocin, Sarmustine SarCNU, semustine, methyl lomustine, the combination of the appropriate azoles amine of streptozocin or miaow; Or
(c) cortisone of 0.01-20%, hydrocortisone, hydrocortisone acetate, prednisone, meticortelone, methyl meticortelone, clobetasone butyrate, hydrocortisone butyrate, dexamethasone, betamethasone, omcilon, triamcinolone acetonide, momestasone furoate, fluocinonide, the pivalic acid dexamethasone, valeric acid Tuo Tamisong, betamethasone dipropionate, halcinonidedcorten, chlorine times Mi Song, the Beclomethasone, sicorten see halometasone, beclomethasone, the vincristine of budesonide or fluticasone and 2-40%, vincaleucoblastine, vinorelbine, vindesine, Vinmegallate, vinleurosine, vinleucinol, vinglycinate, vinfosiltine, vinformide, vinflunine, vinepidine, vinzolidine, vintriptol, vinrosidine, the combination of monocrotaline or cephalotaxin.
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), polylactic acid, the copolymer of polyglycolic acid and hydroxyacetic acid, xylitol, oligosaccharide, chrondroitin, chitin, hyaluronic acid, collagen protein, gelatin, chitosan, one of poloxamer 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 55-95%;
(2) PLGA of 50-95%;
(3) polifeprosan of 50-95%;
(4) bis-fatty acid of 55-95% and decanedioic acid copolymer;
(5) combination of the PLGA of the PLA of the polifeprosan of 30-60% and 30-60% or 30-60%;
(6) xylitol of 40-95%, oligosaccharide, chrondroitin, chitin, hyaluronic acid, collagen protein, gelatin, chitosan, poloxamer 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 decanedioic acid 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, decanedioic acid 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.
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, decanedioic acid, the mixture or the copolymer that contain the macromolecule polymer of polylactic acid or decanedioic acid 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 decanedioic acid 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 decanedioic acid copolymerization 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 can be with reference to slow releasing injection, but is preferably as follows, and all is weight percentage:
(a) cortisone of 0.01-20%, hydrocortisone, hydrocortisone acetate, prednisone, meticortelone, methyl meticortelone, clobetasone butyrate, hydrocortisone butyrate, dexamethasone, betamethasone, omcilon, triamcinolone acetonide, momestasone furoate, fluocinonide, the pivalic acid dexamethasone, valeric acid Tuo Tamisong, betamethasone dipropionate, halcinonidedcorten, chlorine times Mi Song, the Beclomethasone, sicorten see halometasone, beclomethasone, the paclitaxel of budesonide or fluticasone and 2-40%, Docetaxel, 2 '-hydroxyl paclitaxel, 10-goes the combination of acetyl paclitaxel or 7-table-paclitaxel;
(b) cortisone of 0.01-20%, hydrocortisone, hydrocortisone acetate, prednisone, meticortelone, methyl meticortelone, clobetasone butyrate, hydrocortisone butyrate, dexamethasone, betamethasone, omcilon, triamcinolone acetonide, momestasone furoate, fluocinonide, the pivalic acid dexamethasone, valeric acid Tuo Tamisong, betamethasone dipropionate, halcinonidedcorten, chlorine times Mi Song, the Beclomethasone, sicorten see halometasone, beclomethasone, the carmustine of budesonide or fluticasone and 2-40%, nimustine, bendamustine, galamustine, Ranimustine, fotemustine, lomustine, uracil mustard, tauromustine, tallimustine, spiromustine, streptozocin, Sarmustine SarCNU, semustine, methyl lomustine, the combination of the appropriate azoles amine of streptozocin or miaow; Or
(c) cortisone of 0.01-20%, hydrocortisone, hydrocortisone acetate, prednisone, meticortelone, methyl meticortelone, clobetasone butyrate, hydrocortisone butyrate, dexamethasone, betamethasone, omcilon, triamcinolone acetonide, momestasone furoate, fluocinonide, the pivalic acid dexamethasone, valeric acid Tuo Tamisong, betamethasone dipropionate, halcinonidedcorten, chlorine times Mi Song, the Beclomethasone, sicorten see halometasone, beclomethasone, the vincristine of budesonide or fluticasone and 2-40%, vincaleucoblastine, vinorelbine, vindesine, Vinmegallate, vinleurosine, vinleucinol, vinglycinate, vinfosiltine, vinformide, vinflunine, vinepidine, vinzolidine, vintriptol, vinrosidine, the combination of monocrotaline or cephalotaxin.
Slow-release auxiliary material can be various water solublity or water-insoluble macromolecule polymer.Slow-release auxiliary material and percentage by weight thereof are most preferably as follows in the sustained-release implant of the present invention:
(1) PLA of 55-95%;
(2) PLGA of 50-95%;
(3) polifeprosan of 50-95%;
(4) bis-fatty acid of 55-195% and decanedioic acid copolymer;
(5) combination of the PLGA of the PLA of the polifeprosan of 30-60% and 30-60% or 30-60%;
(6) xylitol of 40-95%, oligosaccharide, chrondroitin, chitin, hyaluronic acid, collagen protein, gelatin, chitosan, poloxamer 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.
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 cancer therapy drug that place the associating of the chemical-therapy synergistic agent of the associating of the cancer therapy drug of the promptly local chemical-therapy synergistic agent of placing and other administration, the local cancer therapy drug of placing and other administration, part and the associating of the local chemical-therapy synergistic agent of placing.Wherein the cancer therapy drug of topical application and chemical-therapy synergistic agent can be separately or Joint Production, packing, sale, use.Packing refers to medicine carrying process and pastille slow-release agent the exterior and interior packing for transport and/or store of medicine for adjuvant.The medicine carrying process includes, but not limited to weighing, dissolving, mixing, drying, shaping, coating, spraying, granulation etc.
The clinical practice dosage of cancer therapy drug depends on patient's concrete condition, can be from 0.1 to 300mg/kg body weight, and 1 to 200mg/kg is preferred, 10 to 100mg/kg for there being most choosing.And one of percentage that the consumption of hormone is only measured for this reason is to 1/10th.
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.Be particularly suitable for treating brain and central nervous system's tumor, especially cerebral glioma.
Preferred example application as, the compositions that contains dexamethasone and carmustine, nimustine or paclitaxel is used for the treatment of the cerebral tumor, particularly cerebral glioma.
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 glucocorticoid compares
With the rat is subjects, with 2 * 10
5Individual prostate tumor cells subcutaneous injection is in its hypochondrium, treats behind tumor growth to 1 cm diameter its grouping.Every group of dosage is the 0.5mg/kg dexamethasone.Measure medicament contg (%) in the different time tumor, the result shows, the local drug concentration significant difference of dexamethasone 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 glucocorticoid compares
With the rat is subjects, with 2 * 10
5Individual pancreatic tumor cell subcutaneous injection is in its hypochondrium, treats behind tumor growth to 0.5 cm diameter its grouping.Every group of dosage is the 5mg/kg betamethasone.The treatment back was measured gross tumor volume size, relatively therapeutic effect on the 20th day.The result shows, the tumor-inhibiting action significant difference of glucocorticoid 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.
Tumor-inhibiting action in the body of test 3, glucocorticoid and cancer therapy drug (slow releasing injection)
With the rat is subjects, with 2 * 10
5Individual breast tumor cell subcutaneous injection is in its hypochondrium, treats that tumor growth after 14 days is divided into it following 10 groups (seeing Table 1).First group is contrast, and the 2nd to 10 group is the treatment group, and medicine is through intratumor injection.Glucocorticoid is 1.5mg/kg, and cancer therapy drug is 7.5mg/kg.The treatment back was measured gross tumor volume size, relatively therapeutic effect (seeing Table 1) on the 21st day.
Table 1
| Test group (n) | Suffered treatment | Gross tumor volume (cm 3) | The P value |
| 1(6) | Contrast | 60±10 | |
| 2(6) | Glucocorticoid | 52±8.2 | ＜0.05 |
| 3(6) | Paclitaxel | 30±4.0 | ＜0.01 |
| 4(6) | Docetaxel | 30±4.0 | ＜0.01 |
| 5(6) | The hydroxyl paclitaxel | 34±3.8 | ＜0.01 |
| 6(6) | 7-table-paclitaxel | 36±4.2 | ＜0.01 |
| 7(6) | Paclitaxel+glucocorticoid | 18±2.2 | ＜0.001 |
| 8(6) | Docetaxel+glucocorticoid | 24±2.4 | ＜0.001 |
| 9(6) | Hydroxyl paclitaxel+glucocorticoid | 18±2.0 | ＜0.001 |
| 10(6) | 7-table-paclitaxel+glucocorticoid | 14±1.6 | ＜0.001 |
Above result shows, growth all has the obvious suppression effect to kinds of tumor cells when this concentration is used separately for glucocorticoid (betamethasone) and its synergist-taxanes cancer therapy drug (paclitaxel, Docetaxel, 2 '-hydroxyl paclitaxel, 7-table-paclitaxel), can show significant potentiation when use in conjunction.This discovery constitutes the another key character of the present invention.
The tumor-inhibiting action of test 4, glucocorticoid and cancer therapy drug (slow releasing injection)
Used tumor cell comprises the cerebral tumor (CNS-1, C6), gastric gland epithelial cancer (SA), bone tumor (BC), breast carcinoma (BA), pulmonary carcinoma (LH), papillary adenocarcinoma of thyroid (PAT) etc.Glucocorticoid is 1.5mg/kg, and cancer therapy drug is 7.5mg/kg.The gross tumor volume size was measured on the 21st day in the treatment back, and its growth of tumour cell suppression ratio (%) is shown in Table 2.
Table 2
| Oncocyte | Carmustine | Nimustine | Fotemustine | Glucocorticoid | Carmustine+glucocorticoid | Nimustine+glucocorticoid | Fotemustine+glucocorticoid |
| CNS | 50％ | 48％ | 42％ | 26％ | 82％ | 78％ | 80％ |
| C6 | 60％ | 52％ | 40％ | 24％ | 74％ | 76％ | 78％ |
| SA | 48％ | 40％ | 26％ | 22％ | 78％ | 82％ | 60％ |
| BC | 52％ | 48％ | 34％ | 24％ | 74％ | 76％ | 80％ |
| BA | 54％ | 52％ | 52％ | 22％ | 68％ | 82％ | 78％ |
| LH | 52％ | 50％ | 22％ | 18％ | 90％ | 82％ | 82％ |
| PAT | 58％ | 50％ | 40％ | 18％ | 82％ | 84％ | 80％ |
Above result shows, growth all has the obvious suppression effect to kinds of tumor cells when this concentration is used separately for used cancer therapy drug (carmustine, nimustine, fotemustine) and glucocorticoid (dexamethasone), can show significant potentiation when use in conjunction.Same effect also sees the other types tumor, as esophageal carcinoma, ovarian cancer, cancer of pancreas, hepatocarcinoma, intestinal cancer etc.
The tumor-inhibiting action of test 5, glucocorticoid and cancer therapy drug (slow releasing injection)
With the rat is subjects, with 2 * 10
5Individual prostate tumor cells subcutaneous injection is in its hypochondrium, treats that tumor growth after 14 days is divided into it following 10 groups (seeing Table 3).First group is contrast, and the 2nd to 10 group is the treatment group, and sustained-release implant is placed in tumor.Glucocorticoid is 0.5mg/kg, and cancer therapy drug is 15mg/kg.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 | Gross tumor volume (cm 3) | The P value |
| 1(6) | Contrast | 60±10 | |
| 2(6) | Glucocorticoid | 52±8.0 | ＜0.05 |
| 3(6) | Nimustine | 40±6.0 | ＜0.01 |
| 4(6) | Glucocorticoid+nimustine | 30±4.2 | ＜0.001 |
| 5(6) | Carmustine | 38±5.2 | ＜0.01 |
| 6(6) | Glucocorticoid+carmustine | 24±4.8 | ＜0.001 |
| 7(6) | Fotemustine | 48±4.8 | ＜0.01 |
| 8(6) | Glucocorticoid+fotemustine | 30±4.6 | ＜0.001 |
| 9(6) | Sarmustine SarCNU | 32±4.0 | ＜0.01 |
| 10(6) | Glucocorticoid+Sarmustine SarCNU | 22±3.2 | ＜0.001 |
Above result shows, growth all has the obvious suppression effect to kinds of tumor cells when this concentration is used separately for used glucocorticoid (triamcinolone acetonide) and cancer therapy drug alkylating agent (nimustine, carmustine, fotemustine, Sarmustine SarCNU), can show significant potentiation when use in conjunction.This discovery constitutes the another key character of the present invention.
The tumor-inhibiting action of test 6, glucocorticoid and cancer therapy drug (slow releasing injection)
With the rat is subjects, with 2 * 10
5Individual pancreatic tumor cell subcutaneous injection is in its hypochondrium, treats that tumor growth after 14 days is divided into it negative control (blank), single therapy group (glucocorticoid or cancer therapy drug) and therapeutic alliance group (glucocorticoid and cancer therapy drug).Medicine is through intratumor injection.Glucocorticoid is 0.05mg/kg, and cancer therapy drug is 5mg/kg.The treatment back was measured gross tumor volume size, relatively therapeutic effect (seeing Table 3) on the 20th day.The treatment back was measured the gross tumor volume size on the 20th day, made relatively therapeutic effect (seeing Table 4) of index with inhibition rate of tumor growth.
Table 4
| Test group (n) | Suffered treatment | Tumor control rate (%) | The P value |
| 1(6) | Contrast | - | |
| 2(6) | Glucocorticoid | 26 | ＜0.05 |
| 3(6) | Semustine | 46 | ＜0.01 |
| 4(6) | Lomustine | 42 | ＜0.01 |
| 5(6) | Estramustine | 50 | ＜0.01 |
| 6(6) | Streptozocin | 42 | ＜0.01 |
| 7(6) | Glucocorticoid+semustine | 66 | ＜0.001 |
| 8(6) | Glucocorticoid+lomustine | 64 | ＜0.001 |
| 9(6) | Glucocorticoid+estramustine | 72 | ＜0.001 |
| 10(6) | Glucocorticoid+streptozocin | 70 | ＜0.001 |
Above result shows, growth all has the obvious suppression effect to kinds of tumor cells when this concentration is used separately for used glucocorticoid (omcilon) and cancer therapy drug-alkylating agent (semustine, lomustine, estramustine, streptozocin), can show significant potentiation when use in conjunction.
The tumor-inhibiting action of test 7, glucocorticoid and cancer therapy drug (slow releasing injection)
With the rat is subjects, with 2 * 10
5Individual breast tumor cell subcutaneous injection is in its hypochondrium, treats that tumor growth after 14 days is divided into it negative control (blank), single therapy group, therapeutic alliance group.Medicine is through intratumor injection.Dosage is 0.5mg/kg.The treatment back was measured the gross tumor volume size on the 20th day, made relatively therapeutic effect (seeing Table 5) of index with inhibition rate of tumor growth.
Table 5
| Test group (n) | Suffered treatment | Tumor control rate (%) | The P value |
| 1(6) | Contrast | ||
| 2(6) | Glucocorticoid | 38 | ＜0.05 |
| 3(6) | Galamustine | 24 | ＜0.01 |
| 4(6) | Ranimustine | 36 | ＜0.01 |
| 5(6) | Fotemustine | 30 | ＜0.01 |
| 6(6) | Tallimustine | 34 | ＜0.01 |
| 7(6) | Glucocorticoid+galamustine | 54 | ＜0.001 |
| 8(6) | Glucocorticoid+Ranimustine | 72 | ＜0.001 |
| 9(6) | Glucocorticoid+fotemustine | 64 | ＜0.001 |
| 10(6) | Glucocorticoid+tallimustine | 72 | ＜0.001 |
Above result shows, growth all has the obvious suppression effect to kinds of tumor cells when this concentration is used separately for used glucocorticoid (betamethasone) and cancer therapy drug-alkylating agent (galamustine, Ranimustine, fotemustine, tallimustine), can show significant potentiation when use in conjunction.This discovery constitutes the another key character of the present invention.
The tumor-inhibiting action of test 8, glucocorticoid and cancer therapy drug (slow releasing injection)
With the rat is subjects, with 2 * 10
5Individual breast tumor cell subcutaneous injection is in its hypochondrium, treats that tumor growth after 14 days is divided into it negative control (blank), single therapy group, therapeutic alliance group.Sustained-release implant is placed in tumor.Glucocorticoid is 0.5mg/kg, and cancer therapy drug is 15mg/kg.The treatment back was measured the gross tumor volume size on the 20th day, made relatively therapeutic effect (seeing Table 6) of index with inhibition rate of tumor growth.
Table 6
| Test group (n) | Suffered treatment | Tumor control rate (%) | The P value |
| 1(6) | Contrast | ||
| 2(6) | Glucocorticoid | 38 | ＜0.05 |
| 3(6) | Vincristine | 62 | ＜0.01 |
| 4(6) | Vincaleucoblastine | 58 | ＜0.01 |
| 5(6) | Vinorelbine | 60 | ＜0.01 |
| 6(6) | Vindesine | 56 | ＜0.01 |
| 7(6) | Glucocorticoid+vincristine | 82 | ＜0.001 |
| 8(6) | Glucocorticoid+vincaleucoblastine | 78 | ＜0.001 |
| 9(6) | Glucocorticoid+vinorelbine | 82 | ＜0.001 |
| 10(6) | Glucocorticoid+vindesine | 84 | ＜0.001 |
Above result shows, growth all has the obvious suppression effect to kinds of tumor cells when this concentration is used separately for used glucocorticoid (methyl meticortelone) and cancer therapy drug-plant alkaloid (vincristine, vincaleucoblastine, vinorelbine, vindesine), can show significant potentiation when use in conjunction.This discovery constitutes the another key character of the present invention.
The tumor-inhibiting action of test 9, glucocorticoid and cancer therapy drug (slow releasing injection)
Measure the tumor-inhibiting action of glucocorticoid and cancer therapy drug (slow releasing injection) by test 7 described methods; the result shows that chlorine times rice pine or Beclomethasone can significantly strengthen alestramustine; atrimustine; ambamustine; ditiomustine; bofumustine; ecomustine; methyl lomustine; prednimustine; uracil mustard; tauromustine; tallimustine; spiromustine; streptozocin; Sarmustine SarCNU; semustine; methyl lomustine; alkylating agents such as the appropriate azoles amine of streptozocin or miaow are to the tumor killing effect of breast carcinoma and carcinoma of prostate, and potentiation is in 38-70% (P＜0.01).
The tumor-inhibiting action of test 10, glucocorticoid and cancer therapy drug (slow releasing injection)
Measure the tumor-inhibiting action of glucocorticoid and cancer therapy drug (slow releasing injection) by test 7 described methods, the result shows that budesonide or fluticasone can significantly strengthen paclitaxel, Docetaxel, 2 '-hydroxyl paclitaxel, 10-and remove the tumor killing effect of taxanes anticarcinogens such as acetyl paclitaxel or 7-table-paclitaxel to pulmonary carcinoma and cancer of pancreas, and potentiation is in 40-80% (P＜0.01).
The tumor-inhibiting action of test 11, cancer therapy drug (slow releasing injection)
Measure the tumor-inhibiting action of glucocorticoid and cancer therapy drug (slow releasing injection) by test 7 described methods, the result shows that sicorten see halometasone, beclomethasone can significantly strengthen vincristine, vincaleucoblastine, vinorelbine, vindesine or the cephalotaxin tumor killing effect to gastric cancer and colon cancer, and potentiation is in 60-80% (P＜0.01).
Release ratio in the body of the glucocorticoid sustained-release implant that test 12, different molecular weight polylactic acid are made
With the rat is subjects, and grouping (3/group) and the Mi Songhuan of plug equally that carries in the subcutaneous polylactic acid (PLA) that contains different molecular weight (MW) release implant.Survey the surplus of medicine in implant respectively at 1,3,7,14,21,28 and 35 day then, and then draw rate of release (%) in its body.The result shows, molecular weight is 20000 is released to: 1 day (8%), 3 (28%), 7 (56%), 14 (82%), 21 (90), 28 (94) and 35 (98%).Discharge in the body of the dexamethasone 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).
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), polylactic acid, the copolymer of polyglycolic acid and hydroxyacetic acid, xylitol, oligosaccharide, chrondroitin, chitin, hyaluronic acid, collagen protein, gelatin, chitosan, poloxamer, one of albumin glue or its combination.The slow releasing preparation that above-mentioned slow-release auxiliary material is made does not have the prominent phenomenon of releasing of tangible medicine; Optimum suspending agent is one of methylcellulose, hydroxy methocel, sodium carboxymethyl cellulose, (iodine) glycerol, simethicone, propylene glycol, carbomer, mannitol, sorbitol, surfactant, soil temperature 20, soil temperature 40, soil temperature 80 or its combination.
In a word, growth all had the obvious suppression effect to kinds of tumor cells when used glucocorticoid and various cancer therapy drug were used separately, can show significant potentiation when use in conjunction.Therefore, effective ingredient of the present invention is glucocorticoid and any one cancer therapy drug.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.
80 parts of polifeprosans (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 10 parts of paclitaxels and 10 parts of dexamethasone, shake up the back contains 10% paclitaxel and 10% dexamethasone 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 220cp-460cp (20 ℃-30 ℃ time).The drug release time of this slow releasing injection in external normal saline is 20-25 days, is about 20-30 days at the subcutaneous drug release time of mice.
Embodiment 2.
The method step that is processed into slow releasing injection is identical with embodiment 1, but different is that polifeprosan is 50: 50, and contained anticancer effective component and percentage by weight thereof are: the combination that the paclitaxel of the cortisone of 1-20%, prednisone, meticortelone, methyl meticortelone, clobetasone butyrate, hydrocortisone butyrate, dexamethasone, betamethasone or omcilon and 2-40%, Docetaxel, 2 '-hydroxyl paclitaxel, 10-remove acetyl paclitaxel or 7-table-paclitaxel;
The viscosity of slow releasing injection is 200cp-650cp (20 ℃-30 ℃ time).
Embodiment 3.
The polylactic acid (PLGA, 75: 25) that 75 parts of molecular weight peak values are 20000-45000 is put into container, add an amount of dichloromethane, behind the dissolving mixing, add 15mg betamethasone and 10mg nimustine, shake 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% betamethasone and 10% nimustine, be suspended in then in the normal saline that contains 1.5% sodium carboxymethyl cellulose, make corresponding suspension type slow releasing injection, viscosity is 300cp-400cp (20 ℃-30 ℃ time).The drug release time of this slow releasing injection in external normal saline is 25-30 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 used adjuvant is the polylactic acid (PLGA of 10000-25000 for the molecular weight peak value; 50: 50), contained anticancer effective component and percentage by weight thereof are: the dexamethasone of 0.1-10%; betamethasone; omcilon; triamcinolone acetonide; the carmustine of momestasone furoate or fluocinonide and 2-40%; nimustine; bendamustine; galamustine; Ranimustine; fotemustine; lomustine; uracil mustard; tauromustine; tallimustine; spiromustine; streptozocin; Sarmustine SarCNU; semustine; methyl lomustine; the combination of the appropriate azoles amine of streptozocin or miaow
Embodiment 5.
The polylactic acid (PLA) that 80 parts of molecular weight peak values are 15000-25000 is put into container, after adding an amount of dichloromethane dissolving mixing, add 19 milligrams of vincristine and 1 milligram of triamcinolone acetonide, shake up the back contains 19% vincristine and 1% triamcinolone acetonide with spray drying method for preparation injectable microsphere again.Then microsphere is suspended in the injection that contains the 5-15% sorbitol, makes corresponding suspension type slow releasing injection, viscosity is 100cp-300cp (20 ℃-30 ℃ time).The drug release time of this slow releasing injection in external normal saline is 30-35 days, is about 35-40 days at the subcutaneous drug release time of mice.
Embodiment 6.
The method step that is processed into slow releasing injection is identical with embodiment 5, but the molecular weight peak value of different is polylactic acid is 25000-45000, and contained anticancer effective component is: the combination of vincristine, vincaleucoblastine, vinorelbine or the vindesine of the triamcinolone acetonide of 0.01-5%, momestasone furoate, fluocinonide, pivalic acid dexamethasone, valeric acid Tuo Tamisong, betamethasone dipropionate, halcinonidedcorten, chlorine times Mi Song, Beclomethasone, sicorten see halometasone, beclomethasone, budesonide or fluticasone and 2-40%.
Embodiment 7.
The polylactic acid (PLA) that 30 parts of polifeprosans (20: 80) and 50 parts of molecular weight peak values are 15000-25000 is put into container, add an amount of dichloromethane, add 15 parts of paclitaxels and 5 parts of chlorine times Mi Song behind the dissolving mixing, shake up the back contains 15% paclitaxel and 5% chlorine times Mi Song 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 80cp-150cp (20 ℃-25 ℃ time).The drug release time of this slow releasing injection in external normal saline is 20-25 days, is about 20-30 days at the subcutaneous drug release time of mice.
Embodiment 8.
The method step that is processed into slow releasing injection is identical with embodiment 7, but different is that used adjuvant is 30 parts of polifeprosans (40: 60) and 50 parts of polylactic acid (PLA) that the molecular weight peak value is 25000-45000, and contained anticancer effective component is: the combination of the triamcinolone acetonide of the paclitaxel of 10-20% or docetaxel and 1-10%, momestasone furoate, fluocinonide, pivalic acid dexamethasone, valeric acid Tuo Tamisong, betamethasone dipropionate, halcinonidedcorten, chlorine times Mi Song, Beclomethasone, sicorten see halometasone, beclomethasone or budesonide.
Embodiment 9
With 40 parts of polifeprosans (20: 80) and 30 parts of polylactic acid (PLGA that the molecular weight peak value is 15000-25000,50: 50) put into container, add an amount of dichloromethane, add 25 parts of Docetaxels and 5 fluocinonide, shake up the back again and contain 25% Docetaxel and 5% fluocinonide injectable microsphere with spray drying method for preparation.Then microsphere is suspended in the normal saline that contains 1.5% sodium carboxymethyl cellulose and 15% sorbitol and 0.2% Tween 80, makes corresponding suspension type slow releasing injection, viscosity is 460cp-600cp (20 ℃-30 ℃ time).The drug release time of this slow releasing injection in external normal saline is 30-35 days, is about 35-40 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 used adjuvant is 50 parts of polifeprosans (50: 50) and 30 parts of polylactic acid (PLGA that the molecular weight peak value is 10000-25000,73: 25), contained anticancer effective component is: the combination of the halcinonidedcorten of 5-25% paclitaxel or Docetaxel and 1-10%, chlorine times Mi Song, Beclomethasone, sicorten see halometasone, beclomethasone or budesonide.
Embodiment 11
70mg bis-fatty acid and decanedioic acid copolymer (PFAD-SA) are put into container, add 100 milliliters of dichloromethane, behind the dissolving mixing, add 15mg carmustine and 15mg dexamethasone, shake up the back contains 15% carmustine and 15% dexamethasone 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 30-35 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 slow-release auxiliary material is poly-(erucic acid dimer decanedioic acid) [P (EAD-SA)], and contained anticancer effective component is the combination of the appropriate azoles amine of nimustine, bendamustine, carmustine or miaow of prednisone, meticortelone, methyl meticortelone, clobetasone butyrate, hydrocortisone butyrate, dexamethasone, betamethasone or the omcilon of 1-20% and 10-20%.
Embodiment 13
With 70mg molecular weight peak value is that poly-(fumaric acid decanedioic acid) [P (FA-SA)] of 15000-35000 puts into container, add 100 milliliters of dichloromethane, behind the dissolving mixing, add 5mg betamethasone and 25mg vinorelbine, shake up the back contains 5% betamethasone and 25% vinorelbine 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 30-35 days, is about 35-50 days at the subcutaneous drug release time of mice.
Embodiment 14
The method step that is processed into sustained-release implant is identical with embodiment 11,13, but different is that contained anticancer effective component is:
(a) combination of the paclitaxel of the prednisone of 1-10%, meticortelone, methyl meticortelone, clobetasone butyrate, hydrocortisone butyrate, dexamethasone, betamethasone or omcilon and 10-40% or docetaxel;
(b) combination of the appropriate azoles amine of the nimustine of the prednisone of 0.1-5%, meticortelone, methyl meticortelone, clobetasone butyrate, hydrocortisone butyrate, dexamethasone, betamethasone or omcilon and 5-20%, carmustine or miaow; Or
(c) combination of the vincristine of the prednisone of 0.5-15%, meticortelone, methyl meticortelone, dexamethasone, betamethasone or omcilon and 5-30%, vincaleucoblastine, vinorelbine or vindesine.
Embodiment 15.
With 35mg molecular weight peak value is that the polylactic acid (PLA) of 20000-35000 and PLGA (50: 50) that 35mg molecular weight peak value is 30000-45000 put into container, add 100 milliliters of dichloromethane, behind the dissolving mixing, add 5mg methyl meticortelone and 25mg vincaleucoblastine, shake up the dry organic solvent of removing of final vacuum again.Dried pastille solid composite freezing and pulverizing is made the micropowder that contains 5% methyl meticortelone and 25% vincaleucoblastine, 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-260cp (25 ℃-30 ℃ time).The drug release time of this slow releasing injection in external normal saline is 30-35 days, is about 35-50 days at the subcutaneous drug release time of mice.
Embodiment 16
The method step that is processed into slow releasing injection is identical with embodiment 15, but different is that contained anticancer effective component and percentage by weight thereof are:
The combination of the vincristine of the dexamethasone of 1-5% or betamethasone and 10-30%, vincaleucoblastine, vinorelbine or vindesine.
Embodiment 17.
With 80mg molecular weight peak value is that bis-fatty acid and decanedioic acid (SA) copolymer (bis-fatty acid: decanedioic acid is 20: 80) of 10000-30000 put into container, add 100 milliliters of dichloromethane, behind the dissolving mixing, add 10mg prednisone and 10mg vincristine, shake up the dry organic solvent of removing of final vacuum again.Dried pastille solid composite freezing and pulverizing is made the micropowder that contains 10% prednisone and 10% vincristine, be suspended in then in the normal saline that contains 1.5% sodium carboxymethyl cellulose, make corresponding suspension type slow releasing injection, viscosity is 380cp-1440cp (25 ℃-30 ℃ time).The drug release time of this slow releasing injection in external normal saline is 30-35 days, is about 40-45 days at the subcutaneous drug release time of mice.
Embodiment 18.
The method step that is processed into slow releasing injection is identical with embodiment 17, but the molecular weight peak value of different is bis-fatty acid and decanedioic acid copolymer is 30000-50000 (bis-fatty acid: decanedioic acid is 40: 60), and contained anticancer effective component and percentage by weight thereof are: the combination of the vincristine of the meticortelone of 0.5-5%, methyl meticortelone or omcilon and 10-30%, vincaleucoblastine, vinorelbine, vindesine or vinleurosine.
Embodiment 19
The method step that is processed into slow releasing agent is identical with embodiment 1-18, 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, the molecular weight peak value is 10000-30000,300000-60000,60000-100000 or 100000-150000;
C) combination of the copolymer of polifeprosan and polylactic acid or polyglycolic acid and hydroxyacetic acid;
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, chitosan, poloxamer 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 20
The method step that is processed into slow releasing injection is identical with embodiment 1-19, but different is used suspending agent is respectively one of following or its combination:
A) 0.5-3.0% carboxymethyl cellulose (sodium);
B) 5-15% mannitol;
C) 5-15% sorbitol;
D) 0.1-1.5% surfactant;
E) 0.1-0.5% polysorbas20.
Embodiment 21
The method step that is processed into slow releasing injection is identical with embodiment 1-20, but different is that contained anticancer effective component is: the combination of the paclitaxel of 0.5% dexamethasone or betamethasone and 5-25%, docetaxel, nimustine, carmustine, the appropriate azoles amine of miaow, vincristine, vincaleucoblastine or vinorelbine.
Embodiment 22
The method step that is processed into slow releasing injection is identical with embodiment 1-20, but different is that contained anticancer effective component is:
(a) combination of the paclitaxel of the prednisone of 1-20%, meticortelone, methyl meticortelone, clobetasone butyrate, hydrocortisone butyrate, dexamethasone, betamethasone or omcilon and 10-40% or docetaxel;
(b) combination of the appropriate azoles amine of the nimustine of the prednisone of 0.1-10%, meticortelone, methyl meticortelone, clobetasone butyrate, hydrocortisone butyrate, dexamethasone, betamethasone or omcilon and 5-30%, carmustine or miaow; Or
(c) combination of the vincristine of the prednisone of 0.05-5%, meticortelone, methyl meticortelone, dexamethasone, betamethasone or omcilon and 5-30%, vincaleucoblastine, vinorelbine or vindesine.
The foregoing description is to illustrate for example rather than will limit scope of the present invention.In fact, except that shown in this paper and the of the present invention various changes described, to those skilled in the art all can be from description and chart apparent.Certainly these changes should be in the scope of appended claim.Therefore, to disclose some specific implementations of the present invention emphatically and its being equal to of making is changed or replaces all be in described design of appended claims and scope to the description that should be realized that the front.
Claims (10)
1. an anti-cancer composition that contains glucocorticoid is characterized in that the effective ingredient in the said composition also comprises the cancer therapy drug that is selected from taxane, alkylating agent and/or plant alkaloid.
2. the anti-cancer composition according to claim 1 is characterized in that the anticancer effective component of anti-cancer composition is used to prepare anticancer sustained-release agent, is selected from slow releasing injection or sustained-release implant.
3. the anti-cancer composition according to claim 2 is characterized in that slow releasing injection is grouped into by following one-tenth:
(A) sustained-release micro-spheres comprises:
Anticancer effective component 0.01-60%
Slow-release auxiliary material 40-99.99%
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 glucocorticoid and the combination that is selected from the cancer therapy drug of taxane, alkylating agent and/or plant alkaloid;
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) polyethylene glycol or polyethylene glycol copolymer,
E) bis-fatty acid and decanedioic acid copolymer;
F) poly-(erucic acid dimer-decanedioic acid) copolymer;
G) poly-(fumaric acid-decanedioic acid) copolymer;
H) poly-dl-lactide, poly-dl-lactide/ethanol copolymer, monomethyl polyethylene glycol, monomethyl polyethylene glycol copolymer, end carboxyl polylactic acid or end carboxyl polylactic acid/ethanol copolymer.
Suspending agent is selected from one of sodium carboxymethyl cellulose, iodine glycerol, simethicone, propylene glycol, carbomer, mannitol, sorbitol, surfactant, soil temperature 20, soil temperature 40 and soil temperature 80 or its combination,
The viscosity of suspending agent is 100cp-3000cp (20 ℃ 30 ℃ time).
4. the slow-releasing anticarcinogen injection according to claim 3 is characterized in that used suspending agent is one of following or its combination:
A) 0.5-3.0% carboxymethyl cellulose (sodium);
B) 5-15% mannitol;
C) 5-15% sorbitol;
D) 0.1-1.5% surfactant;
E) 0.1-0.5% polysorbas20;
F) (iodine) glycerol, simethicone, propylene glycol or carbomer;
G) 0.5-5% sodium carboxymethyl cellulose+0.1-0.5% soil temperature 80;
H) 5-20% mannitol+0.1-0.5% soil temperature 80; Or
I) 0.5-5% sodium carboxymethyl cellulose+5-20% sorbitol+0.1-0.5% soil temperature 80.
5. the anti-cancer composition according to claim 1 is characterized in that taxane is selected from paclitaxel, Docetaxel, 2 '-hydroxyl paclitaxel, 10-and removes acetyl paclitaxel or 7-table-paclitaxel.
6. the anticancer anti-cancer composition according to claim 1 is characterized in that alkylating agent is selected from alestramustine; atrimustine; ambamustine; nimustine; bendamustine; ditiomustine; bofumustine; carmustine; elmustine; ecomustine; CNCC; galamustine; fotemustine; estramustine; hemustine heCNU He; pentamustine; mannomustine; lomustine; methyl lomustine; semustine; Ranimustine; prednimustine; uracil mustard; Sarmustine SarCNU; tauromustine; streptozocin; tallimustine; spiromustine; one of appropriate azoles amine of miaow or its combination.
7. the anti-cancer composition according to claim 1 is characterized in that plant alkaloid is selected from vincristine, vincaleucoblastine, vinorelbine, vindesine, Vinmegallate, vinleurosine, vinleucinol, vinglycinate, vinfosiltine, vinformide, vinflunine, vinepidine, vinzolidine, vintriptol, vinrosidine, monocrotaline or cephalotaxin.
8. the anti-cancer composition according to claim 1 is characterized in that glucocorticoid is selected from a kind of or its combination in cortisone, hydrocortisone, hydrocortisone acetate, prednisone, meticortelone, methyl meticortelone, clobetasone butyrate, hydrocortisone butyrate, dexamethasone, betamethasone, omcilon, triamcinolone acetonide, momestasone furoate, fluocinonide, pivalic acid dexamethasone, valeric acid Tuo Tamisong, betamethasone dipropionate, halcinonidedcorten, chlorine times Mi Song, Beclomethasone, sicorten see halometasone, beclomethasone, budesonide, the fluticasone.
9. the anticancer sustained-release agent according to claim 2 is characterized in that slow-release auxiliary material used in the anticancer sustained-release agent 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, the molecular weight peak value is 10000-30000,300000-60000,60000-100000 or 100000-150000;
C) combination of the copolymer of polifeprosan and polylactic acid or polyglycolic acid and hydroxyacetic acid;
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.
10. the anti-cancer composition according to claim 1 is characterized in that its anticancer effective component is:
(a) cortisone of 0.01-20%, hydrocortisone, hydrocortisone acetate, prednisone, meticortelone, methyl meticortelone, clobetasone butyrate, hydrocortisone butyrate, dexamethasone, betamethasone, omcilon, triamcinolone acetonide, momestasone furoate, fluocinonide, the pivalic acid dexamethasone, valeric acid Tuo Tamisong, betamethasone dipropionate, halcinonidedcorten, chlorine times Mi Song, the Beclomethasone, sicorten see halometasone, beclomethasone, the paclitaxel of budesonide or fluticasone and 2-40%, Docetaxel, 2 '-hydroxyl paclitaxel, 10-goes the combination of acetyl paclitaxel or 7-table-paclitaxel;
(b) cortisone of 0.01-20%, hydrocortisone, hydrocortisone acetate, prednisone, meticortelone, methyl meticortelone, clobetasone butyrate, hydrocortisone butyrate, dexamethasone, betamethasone, omcilon, triamcinolone acetonide, momestasone furoate, fluocinonide, the pivalic acid dexamethasone, valeric acid Tuo Tamisong, betamethasone dipropionate, halcinonidedcorten, chlorine times Mi Song, the Beclomethasone, sicorten see halometasone, beclomethasone, the carmustine of budesonide or fluticasone and 2-40%, nimustine, bendamustine, galamustine, Ranimustine, fotemustine, lomustine, uracil mustard, tauromustine, tallimustine, spiromustine, streptozocin, Sarmustine SarCNU, semustine, methyl lomustine, the combination of the appropriate azoles amine of streptozocin or miaow; Or
(c) cortisone of 0.01-20%, hydrocortisone, hydrocortisone acetate, prednisone, meticortelone, methyl meticortelone, clobetasone butyrate, hydrocortisone butyrate, dexamethasone, betamethasone, omcilon, triamcinolone acetonide, momestasone furoate, fluocinonide, the pivalic acid dexamethasone, valeric acid Tuo Tamisong, betamethasone dipropionate, halcinonidedcorten, chlorine times Mi Song, the Beclomethasone, sicorten see halometasone, beclomethasone, the vincristine of budesonide or fluticasone and 2-40%, vincaleucoblastine, vinorelbine, vindesine, Vinmegallate, vinleurosine, vinleucinol, vinglycinate, vinfosiltine, vinformide, vinflunine, vinepidine, vinzolidine, vintriptol, vinrosidine, the combination of monocrotaline or cephalotaxin.
The glucocorticoid wherein and the percentage by weight of cancer therapy drug are 1-99: 1 and 1: 1-99.
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