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CN101244029A - Anticancer sustained-release injection containing estrogen receptor antagon - Google Patents

Anticancer sustained-release injection containing estrogen receptor antagon Download PDF

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Publication number
CN101244029A
CN101244029A CNA2008103005020A CN200810300502A CN101244029A CN 101244029 A CN101244029 A CN 101244029A CN A2008103005020 A CNA2008103005020 A CN A2008103005020A CN 200810300502 A CN200810300502 A CN 200810300502A CN 101244029 A CN101244029 A CN 101244029A
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Prior art keywords
estrogen receptor
acid
slow
fulvestrant
receptor antagon
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孙娟
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Jinan Kangquan Medicine Science and Technology Co Ltd
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Jinan Kangquan Medicine Science and Technology Co Ltd
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Abstract

The invention relates to an anticancer slow release agent with estrogen receptor antagonist, which comprises a slow release microsphere and a menstruum; wherein, the slow release microsphere comprises anticancer effective constituents and slow release adjuvant, and the menstruum comprises a suspending agent. The anticancer effective constituents are the estrogen receptor antagonists chosen from fulvestrant, anastrozole, Exemestane, and Tamoxifen or the combination of the estrogen receptor antagonists and the synergists, which are selected from anti-taxane, alkylating agent and plant alkaloid; the slow release adjuvant is selected from Polifeprosan, double fatty acids, sebacic acid copolymer, poly (erucic acid dimmer-sebacic acid), poly (fumaric acid-sebacic acid), EVAc, and polylactic acid. The suspending agent has a viscosity of 100cp-3000cp (at 25-30 DEG C), and is selected from carboxymethyl cellulose sodium. The slow release microsphere also can be made into slow release implants; by injecting or placing the slow release agent into or around the tumors, the slow release agent has the advantages of lessening the toxic reaction of a medicine all over the body, selectively elevating the local drug concentration of the tumors, and strengthening the therapeutic effects of non-operative treatments like radiotherapy and chemotherapy.

Description

The slow-releasing anticarcinogen injection that contains estrogen receptor antagon
(1) technical field
The present invention relates to a kind of slow-releasing anticarcinogen injection and preparation method thereof, belong to technical field of pharmaceuticals.Particularly, the invention provides a kind of anticancer medicine slow-release preparation containing that contains estrogen receptor antagon and/or estrogen receptor antagon synergist, be mainly slow releasing injection and sustained-release implant.
(2) background technology
The generation of a lot of tumors is relevant unusually with estrogen metabolism.Wherein, most typical is breast carcinoma, ovarian cancer, pulmonary carcinoma, digestive tract tumor etc.Therefore, utilize estrogen receptor antagon or arimedex that above-mentioned tumor is had the obvious suppression effect.As, fulvestrant (fulvestrant, commodity are called Faslodex) is the new estrogen receptor antagon of a class, it is used for the treatment of the hormone receptor positive metastatic breast cancer in JIUYUE, 2002 U.S. FDA approved.Fulvestrant is the estrogen receptor antagon of no agonist effect, the estrogen receptor in its combination, retardance and the degraded breast cancer cell.Aromatase inhibitor then reduces body inner estrogen quantity.Postmenopausal women's body inner estrogen derives from the androgen that the adrenal gland produces, androgen is only organized around and is just changed estrogen under the aromatase effect into, arimedex makes aromatase ineffective, androgen can't be converted into estrogen, thereby has blocked the growth of tumour cell under the estrogen action.The representative of this type of medicine is A Naluo azoles (anastrozole, commodity are called Arimidex) and exemestane (exemestane, commodity are called Aromasin).In addition, tamoxifen also has some estrogen actions except that the retardance estrogen receptor.The binding mode of this uniqueness has determined the form of therapy that it is unique.
As class chemotherapeutics commonly used, estrogen receptor antagon has been widely used in the treatment of multiple malignant tumor, and action effect is comparatively obvious.Yet its tangible general toxicity has greatly limited the application of this medicine.Moreover, blood vessel in the mesenchyma stroma of tumors, connective tissue, stromatin, fibrin and collagen protein etc. not only provide support and requisite nutrient substance for the growth of tumor cell, also influenced chemotherapeutics around tumor and the infiltration in the tumor tissues and diffusion (carry and to wait " situation of extracellular matrix to entity tumor in the medicine influence of turning round " " cancer research " 60 phase 2497-503 page or leaf (2000) (Netti PA referring to the Buddhist nun, Cancer Res.2000,60 (9): 2497-503)).Because entity tumor excessive expansion hypertrophy, the viscosity of matter was high than its normal surrounding tissue all between matter pressure, tissue elasticity pressure, fluid pressure reached therebetween, therefore, conventional chemotherapy, be difficult to tumor by local and form effective drug level, referring to " placing cisplatin adding system carmustine treatment rat brain tumor in the tumor " " surgery tumor magazine " 69 phase 76-82 pages or leaves (1998) (Kong Q et al., J 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 of drug level to a certain extent, yet operation techniques such as medicine implantation are complicated, traumatic big, the various complication such as, infection hemorrhage, immunity reduction, also can cause or quicken the diffusion and the transfer of tumor except that easily causing.In addition, the preparation of perioperatively itself and expensive expense usually influence its effective enforcement.
In addition, the cancer drug therapy of low dosage not only can increase the Drug tolerance of cancerous cell, but also can promote its infiltrative growth " (referring to beam etc. " increased the Drug tolerance of human lung carcinoma cell and external wetting capacity after the cancer therapy drug pulse screening and with the change of gene expression " " international journal of cancer " 111 phase 484-93 page or leaf (2004) (Liang Y; etal., Int J Cancer.2004; 111 (4): 484-93)).
Therefore, be convenient to keep high drug level and increase tumor cell the preparation and the method for the sensitivity of medicine just become an important subject at tumor by local.
(3) summary of the invention
Estrogen receptor antagon has been widely used in the treatment kinds of tumors as the new cancer therapy drug of a class.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 slow-released system that contains cancer therapy drug, 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 estrogen receptor antagon 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 estrogen receptor antagon share and can make its antitumaous effect strengthen (the following medicine that the estrogen receptor antagon antitumaous effect will be increased mutually is referred to as the estrogen receptor antagon synergist) mutually.In addition, with the assembly packaging of estrogen receptor antagon or estrogen receptor antagon 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 above unexpected main contents of the present invention of finding to constitute.
The present invention is directed to the deficiencies in the prior art, a kind of new slow releasing injection that contains estrogen receptor antagon and/or estrogen receptor antagon synergist is provided.
Estrogen receptor antagon 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 0.5-60%
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 estrogen receptor antagon and estrogen receptor antagon synergist, and the estrogen receptor antagon synergist is selected from taxane, alkylating agent and/or plant alkaloid; Slow-release auxiliary material is selected from one of copolymer (PLGA), xylitol, oligosaccharide, chrondroitin, chitin, hyaluronic acid, collagen protein, gelatin and white tempera of polifeprosan, bis-fatty acid and decanedioic acid copolymer (PFAD-SA), poly-(erucic acid dimer-decanedioic acid) [P (EAD-SA)], poly-(fumaric acid-decanedioic acid) [P (FA-SA)], ethylene vinyl acetate copolymer (EVAc), polylactic acid (PLA), polyglycolic acid and hydroxyacetic acid 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.
Estrogen receptor antagon is that the medicine such as the fulvestrant (fulvestrant, commodity are called Faslodex) that act on estrogen receptor are the new estrogen receptor antagons of a class, is used for the treatment of the hormone receptor positive metastatic breast cancer.Fulvestrant is the estrogen receptor antagon of no agonist effect, the estrogen receptor in its combination, retardance and the degraded breast cancer cell.Estrogen receptor antagon also comprises aromatase inhibitor, and its effect is to reduce body inner estrogen quantity.Postmenopausal women's body inner estrogen derives from the androgen that the adrenal gland produces, androgen is only organized around and is just changed estrogen under the aromatase effect into, arimedex makes aromatase ineffective, androgen can't be converted into estrogen, thereby has blocked the growth of tumour cell under the estrogen action.The representative of this type of medicine is A Naluo azoles (anastrozole, commodity are called Arimidex) and exemestane (exemestane, commodity are called Aromasin).In addition, tamoxifen can suppress tumor growth by number of ways.Therefore, used estrogen receptor antagon comprises the various materials that variously reduce estrogenic generation, antagonism and receptors bind, quicken estrogen drainage etc., but serves as preferred with fulvestrant, A Naluo azoles, exemestane and tamoxifen.Most preferably act on the combination of the medicine of the different links of estrogen metabolism, as the combination of fulvestrant and A Naluo azoles and/or exemestane and/or tamoxifen.
Above estrogen receptor antagon also comprises its salt, as, but be not limited to sulfate, phosphate, hydrochlorate, Lactobionate, acetate, aspat, nitrate, citrate, purine or pyrimidine salt, succinate or maleate.
Following estrogen receptor antagon synergist can make the anticancer effect of estrogen receptor antagon obviously strengthen.This discovery has constituted another major technique feature of the present invention.
Wherein, taxane (Taxanes) kind anti-cancer drugs owner to be selected from paclitaxel (Taxol), Docetaxel (Docetaxel, taxotere, docetaxel), 2 '-hydroxyl paclitaxel (paclitaxel-2 '-hydroxy), 10-removes acetyl paclitaxel (10-deacetyl taxol), 7-table-paclitaxel (7-epi-taxol).With paclitaxel and docetaxel serves as preferred.
Alkylating agent comprises alestramustine (Alestramustine); atrimustine (Atrimustine); ambamustine (Ambamustine); nimustine (ACNU; Nimustine); bendamustine (Bendamustine); ditiomustine (Ditiomustine); bofumustine (Bofumustine); carmustine (carmustine; BCNU; carmustine); elmustine (Elmustine); ecomustine (Ecomustine); galamustine (Galamustine; GCNU); fotemustine (Fotemustine); estramustine (Estramustine); hemustine heCNU He (hemustine; heCNU); pentamustine (Pentamustine; Neptamustine); mannomustine (Mannomustine; MCNU); lomustine (lomustine; CCNU; lomustine; chlorethyl cyclohexyl nitrosourea); methyl lomustine (methyl-CCNU); semustine (Semustine; CH3-CCNU; Me-CCNU); Ranimustine (Ranimustine); prednimustine (Prednimustine); uracil mustard (Uramustine; UracilMustard); Sarmustine SarCNU (SarCNU); tauromustine (Tauromustine); tallimustine (Tallimustine); spiromustine (Spiromustine); streptozocin (streptozotocin; STZ); the appropriate azoles amine of miaow (mitozolomide, MTZ); a kind of or its combination in cyclophosphamide and the melphalan (melphalan).
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 preferred alestramustine of above-mentioned alkylating agent; 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; the appropriate azoles amine of miaow; cyclophosphamide; melphalan.
The percentage by weight of above-mentioned alkylating agent in slow releasing agent is good from 0.01%-99.99% with 1%-50%, 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 1%-50% from 0.01%-99.99%, is best with 5%-30%.
When the cancer therapy drug in the medicament slow-release microsphere only is estrogen receptor antagon or estrogen receptor antagon synergist, slow-releasing anticarcinogen injection is mainly used in the estrogen receptor antagon of other approach application of increase or the action effect of estrogen receptor antagon synergist, or is used for the potentiation to radiotherapy or other therapies.When the cancer therapy drug in the medicament slow-release microsphere only was estrogen receptor antagon or its synergist, the application of slow-releasing anticarcinogen injection and potentiation mode were:
(1) contain the slow releasing injection local injection of estrogen receptor antagon, other approach of estrogen receptor antagon synergist are used;
(2) local injection contains the slow releasing injection of estrogen receptor antagon synergist, and other approach are used estrogen receptor antagon;
(3) local injection contains the slow releasing injection and the slow releasing injection that contains the estrogen receptor antagon synergist of estrogen receptor antagon; Or
(4) local injection contains the slow releasing injection of estrogen receptor antagon and synergist.
The slow-releasing anticarcinogen injection of topical application also is used for the potentiation to radiotherapy or other therapies.Other approach refer to, but, be not limited to tremulous pulse, vein, abdominal cavity, subcutaneous, intracavitary administration.
Anticancer effective component estrogen receptor antagon and/or the percentage by weight of estrogen receptor antagon synergist in medicament slow-release microsphere are 0.5%-60%, are good with 2%-40%, are best with 5%-30%.The weight ratio of estrogen receptor antagon and estrogen receptor antagon synergist is 1-9: 1 to 1: 1-9, with 1-2: 1 serves as preferred.
Anticancer effective component in the slow-releasing anticarcinogen injection microsphere of the present invention is preferably as follows, and all is weight percentage:
(a) fulvestrant of 2-40%, A Naluo azoles, exemestane or tamoxifen;
(b) paclitaxel of the fulvestrant of 2-40%, A Naluo azoles, exemestane or tamoxifen and 2-40%, Docetaxel, 2 '-hydroxyl paclitaxel, the 10-combination of removing acetyl paclitaxel or 7-table-paclitaxel;
(c) fulvestrant of 2-40%, the A Naluo azoles, the alestramustine of exemestane or tamoxifen and 2-40%, 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, the appropriate azoles amine of miaow, the combination of cyclophosphamide or melphalan;
(d) combination of vincristine, vincaleucoblastine, vinorelbine, vindesine, Vinmegallate, vinleurosine, vinleucinol, vinglycinate, vinfosiltine, vinformide, vinflunine, vinepidine, vinzolidine, vintriptol, vinrosidine, monocrotaline or the cephalotaxin of the fulvestrant of 2-40%, A Naluo azoles, exemestane or tamoxifen and 2-40%;
(e) combination of the fulvestrant of 2-40% and A Naluo azoles and/or exemestane; Or
(f) combination of the fulvestrant of 2-40%, A Naluo azoles and/or exemestane and/or tamoxifen.
Slow-release auxiliary material can be various water solublity or water-insoluble macromolecule polymer, copolymer (PLGA), ethylene vinyl acetate copolymer (EVAc), polifeprosan, bis-fatty acid and the decanedioic acid copolymer (PFAD-SA) of preferred polylactic acid (PLA), polyglycolic acid and hydroxyacetic acid, one of poly-(erucic acid dimer-decanedioic acid) [P (EAD-SA)], poly-(fumaric acid-decanedioic acid) [P (FA-SA)] or its combination in multiple slow-release auxiliary material.
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 be for arbitrarily, but preferably 1-99% and 99-1%.The molecular weight peak value of polylactic acid can be, but is not limited to, 5000-200, and 000, but with 20,000-60,000 is preferred, with 30,000-50,000 for most preferably; The molecular weight of polyglycolic acid can be, but is not limited to, 5000-200, and 000, but with 20,000-60,000 is preferred, with 30,000-50,000 for most preferably; 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, 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 10000 to 100000 polylactic acid with molecular weight is that 20000 to 150000 polylactic acid mixes, molecular weight is 10000 to 100000 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 slow beginning adjuvant, also can select for use other materials to see the United States Patent (USP) (patent No.: 4757128; 4857311; 4888176; 4789724) and in " pharmaceutic adjuvant complete works " (the 123rd page, Sichuan science tech publishing house published in 1993, Luo Mingsheng and Gao Tianhui chief editor) have a detailed description.In addition, Chinese patent (application number 96115937.5; 91109723.6; 9710703.3; 01803562.0) and U.S.'s patent of invention (patent No. 5,651,986) also enumerated some pharmaceutic adjuvant, comprise filler, solubilizing agent, absorption enhancer, film former, gellant, system (or causing) hole agent, excipient or blocker etc.
For regulating drug releasing rate or changing other characteristic of the present invention, can change the composition and the proportioning of monomer component or molecular weight, interpolation or the adjusting pharmaceutic adjuvant of polymer, add the water-soluble low-molecular chemical compound, as, but be not limited to various sugar or salt etc.Wherein sugar can be, but is not limited to, xylitol, oligosaccharide, (sulphuric acid) chrondroitin and chitin etc., and wherein salt can be, but is not limited to, potassium salt and sodium salt etc.; Also can add other pharmaceutic adjuvant, as but be not limited to filler, solubilizing agent, absorption enhancer, film former, gellant, system (or causing) hole agent, excipient or blocker etc.
In the slow releasing injection, drug sustained release system can be made into microsphere, sub-micro ball, microemulsion, nanosphere, granule or spherical piller, makes the injection use then with after the injection solvent mixes.In various slow releasing injection, serve as preferred with the suspension type slow releasing injection, the suspension type slow releasing injection is the preparation that the drug sustained release system that will contain anticancer component is suspended in gained in the injection, used slow-release auxiliary material is a kind of or its combination in the above-mentioned slow-release auxiliary material, and used solvent is common solvent or the special solvent that contains suspending agent.Common solvent is, but is not limited to the buffer that distilled water, water for injection, physiology are prepared towards liquid, dehydrated alcohol or various salt.The purpose of suspending agent is the pastille microsphere that effectively suspends, thereby is beneficial to the usefulness of injection.Be convenient injection, the viscosity of suspending agent is 100cp-3000cp (20 ℃-30 ℃ time), preferred 1000cp-3000cp (20 ℃-30 ℃ time), most preferably 1500cp-3000cp (20 ℃-30 ℃ time).Suspending agent is selected from one of sodium carboxymethyl cellulose, (iodine) glycerol, simethicone, propylene glycol, carbomer, mannitol, sorbitol, surfactant, soil temperature 20, soil temperature 40 and soil temperature 80 or its combination.
The content of suspending agent in common solvent is decided because of its characteristic, can be 0.1-30% and decides because of concrete condition.Consisting of of preferred suspending agent:
A) 0.5-5% sodium carboxymethyl cellulose+0.1-0.5% soil temperature 80; Or
B) 5-20% mannitol+0.1-0.5% soil temperature 80; Or
C) 0.5-5% sodium carboxymethyl cellulose+5-20% sorbitol+0.1-0.5% soil temperature 80.
The kind of solvent is then depended in the preparation of solvent, and common solvent has commercially available, also can make by oneself, and as distilled water, water for injection, physiology buffer towards liquid, dehydrated alcohol or the preparation of various salt, but must be in strict accordance with related standards.Special solvent need be considered the kind of suspending agent and the medicine that composition, solvent suspended, composition, character and the requirement thereof of sustained-release micro-spheres (or microcapsule) and the preparation method of injection, as sodium carboxymethyl cellulose (1.5%)+mannitol and/or sorbitol (15%) and/or Tween 80 (0.1%) are dissolved in the normal saline corresponding solvent, viscosity is at 10cp-650cp (20 ℃-30 ℃ time).
The present invention finds to influence medicine and/or sustained-release micro-spheres suspends and/or the key factor of injection is the viscosity of solvent, and viscosity is big more, and suspension effect is good more, and syringeability is strong more.This unexpected one of main index characteristic of the present invention of finding to have constituted.The viscosity of solvent depends on the viscosity of suspending agent, and the viscosity of suspending agent is 100cp-3000cp (20 ℃-30 ℃ time), preferred 1000cp-3000cp (20 ℃-30 ℃ time), most preferably 1500cp-3000cp (20 ℃-30 ℃ time).According to the viscosity of the prepared solvent of this condition is 10cp-650cp (20 ℃-30 ℃ time), preferred 20cp-650cp (20 ℃-30 ℃ time), most preferably 60cp-650cp (20 ℃-30 ℃ time).
The preparation of injection has several different methods, and a kind of is that the sustained-release microparticle (A) of suspending agent for " 0 " directly mixed in special solvent, obtains corresponding sustained-release microparticle injection; Another kind is that suspending agent is not mixed in special solvent or common solvent for the sustained-release microparticle (A) of " 0 ", obtains corresponding sustained-release microparticle injection; Another is that sustained-release microparticle (A) is mixed in common solvent, adds the suspending agent mixing then, obtains corresponding sustained-release microparticle injection.Except, also can earlier sustained-release microparticle (A) be mixed and in special solvent, make corresponding suspension, with the moisture in ways such as the vacuum drying removal suspension, special solvent of reuse or common solvent suspendible obtain corresponding sustained-release microparticle injection afterwards then.Above method just is illustrative rather than definitive thereof the present invention.It should be noted that suspended drug or sustained-release micro-spheres (or microcapsule) concentration in injection decide because of specifically needing, can be, but be not limited to, 10-400mg/ml, but be preferably with 30-300mg/ml, with 50-200mg/ml most preferably.The viscosity of injection is 50cp-1000cp (20 ℃-30 ℃ time), preferred 100cp-1000cp (20 ℃-30 ℃ time), most preferably 200cp-650cp (20 ℃-30 ℃ time).This viscosity is applicable to 18-22 injection needle and special bigger (to 3 millimeters) injection needle of internal diameter.
The preparation method of slow releasing injection is arbitrarily, available some kinds of methods preparation: as, but be not limited to, mixing method, fusion method, dissolution method, spray drying method for preparation microsphere, dissolution method are made micropowder, liposome bag medicine method and emulsion process etc. in conjunction with freezing (drying) comminuting method.Serve as preferred wherein with dissolution method (being the solvent volatility process), seasoning, spray drying method and emulsion process.Microsphere then can be used for preparing above-mentioned various slow releasing injection, and its method is arbitrarily.The particle size range of used microsphere can be between 5-400um, serving as preferred between the 10-300um, with between the 20-200um for most preferably.
Microsphere also can be used for preparing other slow releasing injection, as gel injection, block copolymer micelle injection.Wherein, block copolymer micelle is formed in aqueous solution by hydrophobic-hydrophilic block copolymers, has spherical inner core-shell mechanism, and hydrophobic block forms kernel, and hydrophilic block forms shell.The carrier micelle injection enters the purpose that reaches control drug release or targeted therapy in the body.Used pharmaceutical carrier is above-mentioned any one or its combination.Wherein preferred molecular weight is the hydrophilic block of the Polyethylene Glycol (PEG) of 1000-15000 as the micelle copolymer, and preferred biological degradation polyalcohol (as PLA, polylactide, polycaprolactone and copolymer thereof (molecular weight 1500-25000)) is as the hydrophobic block of micelle copolymer.The particle size range of block copolymer micelle can be between 10-300um, between the 20-200um serving as preferred.Gel injection system is dissolved in some amphipathic solvent with biological degradation polyalcohol (as PLA, PLGA or DL-LA and epsilon-caprolactone copolymer), adds medicine miscible with it (or suspendible) back again and forms flowability gel preferably, can be through tumor week or intratumor injection.In case inject, amphipathic solvent diffuses to body fluid very soon, the moisture in the body fluid then infiltrates gel, makes polymer cure, slowly discharges medicine.
Sustained-release micro-spheres also can be used for preparing sustained-release implant, used pharmaceutic adjuvant can be any or multiple material in the above-mentioned pharmaceutic adjuvant, but with the high molecular weight water soluble polymer is main separation, in various high molecular polymers, with polylactic acid, the certain herbaceous plants with big flowers diacid, the mixture or the copolymer that contain the macromolecule polymer of polylactic acid or certain herbaceous plants with big flowers diacid are first-selection, mixture and copolymer can be selected from, but be not limited to PLA, PLGA, the mixture of PLA and PLGA, the mixture or the copolymer of certain herbaceous plants with big flowers diacid and fragrant polyanhydride or aliphatic polyanhydride, bis-fatty acid and decanedioic acid copolymer (PFAD-SA), poly-(erucic acid dimer-decanedioic acid) [P (EAD-SA)], poly-(fumaric acid decanedioic acid) [P (FA-SA)].Polylactic acid (PLA) is 10/90-90/10 (weight) with the blend ratio of polyglycolic acid, preferably 25/75-75/25 (weight).The method of blend is arbitrarily.Content when glycolic and lactic acid copolymerization is respectively percentage by weight 10-90% and 90-10%.The representative of fragrance polyanhydride is to carboxy phenyl propane (p-CPP), content during to carboxy phenyl propane (p-CPP) and the copolymerization of certain herbaceous plants with big flowers diacid is respectively percentage by weight 10-60% and 20-90%, the blend weight ratio is 10-40: 50-90, preferably weight ratio 15-30: 65-85.
Another form of anticancer medicine slow-release preparation containing of the present invention is that anticancer medicine slow-release preparation containing is a sustained-release implant.The effective ingredient of anticancer implant can be packaged in the whole pharmaceutic adjuvant equably, also can be packaged in carrier holder center or its surface; Can effective ingredient be discharged by direct diffusion and/or the mode of degrading through polymer.
The characteristics of sustained-release implant are that used slow-release auxiliary material removes the high molecular polymerization beyond the region of objective existence, also contain above-mentioned any one or multiple other adjuvant.The pharmaceutic adjuvant that adds is referred to as additive.Additive can be divided into filler, porogen, excipient, dispersant, isotonic agent, preservative agent, blocker, solubilizing agent, absorption enhancer, film former, gellant etc. according to its function.
The Main Ingredients and Appearance of sustained-release implant can be made into multiple dosage form.As, but be not limited to capsule, slow releasing agent, implant, slow releasing agent implant etc.; Be multiple shape, as, but be not limited to granule, pill, tablet, powder, sphere, bulk, needle-like, bar-shaped, column and membranaceous.In various dosage forms, serve as preferred slowly to discharge implant in the body.
The most preferred dosage form of sustained-release implant is that the slow releasing agent that biocompatibility, degradable absorb is implanted, and can make different shape and various dosage form because of the clinical needs of difference.The packing method of its Main Ingredients and Appearance and step in United States Patent (USP) (US5651986) have a detailed description, comprise the some kinds of methods that prepare slow releasing preparation: as, but be not limited to, (i) carrier holder powder and medicament mixed be pressed into implant then, promptly so-called mixing method; (ii) carrier holder fusing, mix solid cooled then, promptly so-called fusion method mutually with medicine to be packaged; (iii) the carrier holder is dissolved in the solvent, medicine dissolution to be packaged or be scattered in the polymer solution, evaporating solvent then, drying, promptly so-called dissolution method; (iv) spray drying method; And (v) freeze-drying etc.
The anticancer effective component of sustained-release implant is preferably as follows, and all is weight percentage:
(a) fulvestrant of 2-40%, A Naluo azoles, exemestane or tamoxifen;
(b) paclitaxel of the fulvestrant of 2-40%, A Naluo azoles, exemestane or tamoxifen and 2-40%, Docetaxel, 2 '-hydroxyl paclitaxel, the 10-combination of removing acetyl paclitaxel or 7-table-paclitaxel;
(c) fulvestrant of 2-40%, the A Naluo azoles, the alestramustine of exemestane or tamoxifen and 2-40%, 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, the appropriate azoles amine of miaow, the combination of cyclophosphamide or melphalan;
(d) combination of vincristine, vincaleucoblastine, vinorelbine, vindesine, Vinmegallate, vinleurosine, vinleucinol, vinglycinate, vinfosiltine, vinformide, vinflunine, vinepidine, vinzolidine, vintriptol, vinrosidine, monocrotaline or the cephalotaxin of the fulvestrant of 2-40%, A Naluo azoles, exemestane or tamoxifen and 2-40%;
(e) combination of the fulvestrant of 2-40% and A Naluo azoles and/or exemestane; Or
(f) combination of the fulvestrant of 2-40% and/or A Naluo azoles and exemestane and/or tamoxifen.
Slow-release auxiliary material can be various water solublity or water-insoluble macromolecule polymer, copolymer (PLGA), ethylene vinyl acetate copolymer (EVAc), polifeprosan, bis-fatty acid and the decanedioic acid copolymer (PFAD-SA) of preferred polylactic acid (PLA), polyglycolic acid and hydroxyacetic acid, one of poly-(erucic acid dimer-decanedioic acid) [P (EAD-SA)], poly-(fumaric acid-decanedioic acid) [P (FA-SA)] or its combination in multiple slow-release auxiliary material.
Route of administration depends on multiple factor, for obtain valid density in former or position, metastatic tumour place, medicine can give through number of ways, as in subcutaneous, intracavity (in abdominal cavity, thoracic cavity and canalis spinalis), the tumor, in all injections of tumor or placement, selective arterial injection, the lymph node and injection in the bone marrow.With in selective arterial injection, intracavity, the tumor, tumor week injection or be placed as preferred.
The present invention can be used to prepare the pharmaceutical preparation of the various tumors for the treatment of people and animal, be mainly slow releasing injection or sustained-release implant, the indication tumor comprises former or cancer or sarcoma or the carcinosarcoma that shifts that originates from brain, central nervous system, kidney, liver, gallbladder, incidence, oral cavity, thyroid, skin, mucosa, body of gland, blood vessel, osseous tissue, lymph node, lungs, esophagus, stomach, mammary gland, pancreas, eyes, nasopharynx part, uterus, ovary, endometrium, cervix uteri, prostate, bladder, colon, rectum.
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 estrogen receptor antagon (A Naluo azoles) 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 25mg/kg A Naluo azoles.Measure medicament contg (%) in the different time tumor, the result shows, the local drug concentration significant difference of A Naluo azoles 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 estrogen receptor antagon (fulvestrant) compares
With the rat is subjects, with 2 * 10 5Individual prostate tumor cells subcutaneous injection is in its hypochondrium, treats behind tumor growth to 0.5 cm diameter its grouping.Every group of dosage is the 20mg/kg fulvestrant.The treatment back was measured gross tumor volume size, relatively therapeutic effect on the 10th day.The result shows, the tumor-inhibiting action significant difference of fulvestrant 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, estrogen receptor antagon and estrogen receptor antagon synergist (slow releasing injection)
With the rat is subjects, with 2 * 10 5Individual pancreatic tumor cell subcutaneous injection is in its hypochondrium, treats that tumor growth after 14 days is divided into it following 10 groups (seeing Table 1).First group is contrast, and the 2nd to 10 group is the treatment group, and medicine is through intratumor injection.Dosage is 5mg/kg.The treatment back was measured gross tumor volume size, relatively therapeutic effect (seeing Table 1) on the 10th day.
Table 1
Test group (n) Suffered treatment Gross tumor volume (cm 3) The P value
1(6) Contrast 70±10
2(6) Paclitaxel 46±5.4 ＜0.05
3(6) Fulvestrant 54±6.0 ＜0.01
4(6) The A Naluo azoles 54±5.2 ＜0.01
5(6) Exemestane 62±6.2 ＜0.01
6(6) Tamoxifen 60±5.0 ＜0.01
7(6) Paclitaxel+fulvestrant 22±2.2 ＜0.001
8(6) Paclitaxel+A Naluo azoles 30±3.4 ＜0.001
9(6) Paclitaxel+exemestane 24±3.0 ＜0.001
10(6) Paclitaxel+tamoxifen 18±2.0 ＜0.001
Above result shows, growth all has the obvious suppression effect to kinds of tumor cells when this concentration is used separately for estrogen receptor antagon (fulvestrant, A Naluo azoles, exemestane, tamoxifen) and its synergist (paclitaxel), can show significant potentiation when use in conjunction.This discovery constitutes the another key character of the present invention.
Tumor-inhibiting action in the body of test 4, estrogen receptor antagon and estrogen receptor antagon 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.Paclitaxel and paclitaxel synergist are added in 24 hours the various tumor cells of In vitro culture by 10ug/ml concentration, continue to cultivate counting cells sum after 48 hours.Its growth of tumour cell suppresses effect and is shown in Table 2.
Table 2
Oncocyte Docetaxel Fulvestrant The A Naluo azoles Exemestane Docetaxel+fulvestrant Docetaxel+A Naluo azoles Docetaxel+exemestane
CNS 62％ 56％ 38％ 60％ 90％ 84％ 80％
C6 66％ 50％ 30％ 64％ 94％ 80％ 94％
SA 56％ 42％ 46％ 60％ 88％ 92％ 90％
BC 56％ 44％ 24％ 64％ 94％ 84％ 82％
BA 52％ 52％ 42％ 60％ 98％ 90％ 92％
LH 62％ 28％ 50％ 58％ 90％ 88％ 84％
PAT 64％ 46％ 40％ 52％ 92％ 82％ 90％
Above result shows, growth all has the obvious suppression effect to kinds of tumor cells when this concentration is used separately for used estrogen receptor antagon (fulvestrant, A Naluo azoles, exemestane) and estrogen receptor antagon synergist (docetaxel), can show significant potentiation when use in conjunction.
Tumor-inhibiting action in the body of test 5, estrogen receptor antagon and estrogen receptor antagon synergist (slow releasing injection)
With the rat is subjects, with 2 * 10 5Individual tumor cell of liver subcutaneous injection is in its hypochondrium, treats that tumor growth after 14 days is divided into it following 10 groups (seeing Table 3).First group is contrast, and the 2nd to 10 group is the treatment group, and sustained-release implant is placed in tumor.Dosage is 5mg/kg.The treatment back was measured gross tumor volume size, relatively therapeutic effect (seeing Table 3) on the 10th day.
Table 3
Test group (n) Suffered treatment Gross tumor volume (cm 3) The P value
1(6) Contrast 60±10
2(6) Fulvestrant 32±4.0 ＜0.05
3(6) Nimustine 30±2.0 ＜0.01
4(6) Fulvestrant+nimustine 20±2.2 ＜0.001
5(6) Carmustine 38±3.2 ＜0.01
6(6) Fulvestrant+carmustine 18±1.8 ＜0.001
7(6) Fotemustine 30±2.6 ＜0.01
8(6) Fulvestrant+fotemustine 20±2.8 ＜0.001
9(6) Sarmustine SarCNU 42±4.4 ＜0.01
10(6) Fulvestrant+Sarmustine SarCNU 14±2.0 ＜0.001
Above result shows, growth all has the obvious suppression effect to kinds of tumor cells when this concentration is used separately for used estrogen receptor antagon (fulvestrant) and estrogen receptor antagon synergist-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.
Tumor-inhibiting action in the body of test 6, estrogen receptor antagon and estrogen receptor antagon synergist (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 negative control (blank), single therapy group (estrogen receptor antagon or estrogen receptor antagon synergist) and therapeutic alliance group (estrogen receptor antagon and estrogen receptor antagon synergist).Medicine is through intratumor injection.Dosage is 5mg/kg.The treatment back was measured the gross tumor volume size on the 10th day, made relatively therapeutic effect (seeing Table 4) of index with inhibition rate of tumor growth.
Table 4
Test group (n) Suffered treatment Tumor control rate (%) The P value
1(6) Contrast -
2(6) The A Naluo azoles 46 ＜0.05
3(6) Semustine 48 ＜0.01
4(6) Lomustine 42 ＜0.01
5(6) Methyl lomustine 52 ＜0.01
6(6) Streptozocin 40 ＜0.01
7(6) A Naluo azoles+semustine 88 ＜0.001
8(6) A Naluo azoles+lomustine 90 ＜0.001
9(6) A Naluo azoles+methyl lomustine 86 ＜0.001
10(6) A Naluo azoles+streptozocin 90 ＜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 estrogen receptor antagon (A Naluo azoles) and estrogen receptor antagon synergist-alkylating agent (semustine, lomustine, methyl lomustine, streptozocin), can show significant potentiation when use in conjunction.
Tumor-inhibiting action in the body of test 7, estrogen receptor antagon and estrogen receptor antagon synergist (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 5mg/kg.The treatment back was measured the gross tumor volume size on the 10th 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) Tamoxifen 36 ＜0.05
3(6) Galamustine 54 ＜0.01
4(6) Ranimustine 46 ＜0.01
5(6) Cyclophosphamide 48 ＜0.01
6(6) Melphalan 46 ＜0.01
7(6) Tamoxifen+galamustine 76 ＜0.001
8(6) Tamoxifen+Ranimustine 82 ＜0.001
9(6) Tamoxifen+cyclophosphamide 90 ＜0.001
10(6) Tamoxifen+melphalan 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 estrogen receptor antagon (tamoxifen) and estrogen receptor antagon synergist-alkylating agent (galamustine, Ranimustine, cyclophosphamide, melphalan), 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, estrogen receptor antagon and estrogen receptor antagon synergist (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.Dosage is 5mg/kg.The treatment back was measured the gross tumor volume size on the 10th 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) Fulvestrant 44 ＜0.05
3(6) Vincristine 48 ＜0.01
4(6) Vincaleucoblastine 56 ＜0.01
5(6) Vinorelbine 48 ＜0.01
6(6) Vindesine 48 ＜0.01
7(6) Fulvestrant+vincristine 86 ＜0.001
8(6) Fulvestrant+vincaleucoblastine 82 ＜0.001
9(6) Fulvestrant+vinorelbine 90 ＜0.001
10(6) Fulvestrant+vindesine 92 ＜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 estrogen receptor antagon (fulvestrant) and estrogen receptor antagon synergist-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, estrogen receptor antagon and estrogen receptor antagon synergist (slow releasing injection)
Measure the tumor-inhibiting action of estrogen receptor antagon (slow releasing injection) by test 7 described methods, the result shows that the estrogen receptor antagon that is selected from fulvestrant, A Naluo azoles, exemestane or tamoxifen can significantly strengthen the tumor killing effect that paclitaxel, Docetaxel, 2 '-hydroxyl paclitaxel, 10-remove acetyl paclitaxel or 7-table-paclitaxel, and potentiation is in 48-70% (P＜0.01).
The tumor-inhibiting action of test 10, estrogen receptor antagon and estrogen receptor antagon synergist (slow releasing injection)
Measure the tumor-inhibiting action of estrogen receptor (slow releasing injection) short of money by test 7 described methods; the result shows and is selected from fulvestrant; the A Naluo azoles; the estrogen receptor antagon of exemestane or tamoxifen can significantly strengthen 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; the appropriate azoles amine of miaow; cyclophosphamide; melphalan; vincristine; vincaleucoblastine; vinorelbine; vindesine; Vinmegallate; vinleurosine; vinleucinol; vinglycinate; vinfosiltine; vinformide; vinflunine; vinepidine; vinzolidine; vintriptol; vinrosidine; the tumor killing effect of monocrotaline or cephalotaxin, potentiation is in 58-80% (P＜0.01).
The tumor-inhibiting action of test 11, estrogen receptor antagon (slow releasing injection)
Measure the tumor-inhibiting action of estrogen receptor antagons (slow releasing injection) by test 7 described methods, the result shows and is selected from
The estrogen receptor antagon of fulvestrant, A Naluo azoles, exemestane or tamoxifen can significantly strengthen the tumor killing effect of vincristine, vincaleucoblastine, vinorelbine, vindesine, Vinmegallate, vinleurosine, vinleucinol, vinglycinate, vinfosiltine, vinformide, vinflunine, vinepidine, vinzolidine, vintriptol, vinrosidine, monocrotaline or cephalotaxin, and potentiation is in 50-88% (P＜0.01).
The tumor-inhibiting action of test 12, estrogen receptor antagon (slow releasing injection)
Measure the tumor-inhibiting action of estrogen receptor antagons (slow releasing injection) by test 7 described methods, the result shows and is selected from
The estrogen receptor antagon of fulvestrant or tamoxifen can significantly strengthen the tumor killing effect of A Naluo azoles or exemestane, and potentiation is in 60-80% (P＜0.01).
In a word, growth all had the obvious suppression effect to kinds of tumor cells when used estrogen receptor antagon and various estrogen receptor antagon synergist were used separately, can show significant potentiation when use in conjunction.Therefore, the combination of effective ingredient of the present invention (or the more than one) estrogen receptor antagon that is any one or any one (or more than one) estrogen receptor antagon and any one (or more than one) estrogen receptor antagon 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.
80mg polifeprosan (to carboxy phenyl propane (p-CPP): certain herbaceous plants with big flowers diacid (SA) is 20: 80) copolymer is put into container, add 100 milliliters of dichloromethane, behind the dissolving mixing, add 10mg paclitaxel and 10mg fulvestrant, shake up the back contains 10% paclitaxel and 10% fulvestrant 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 10-15 days, is about 20-30 days at the subcutaneous drug release time of mice.
Embodiment 2.
The method step that is processed into slow releasing injection is identical with embodiment 1, but different is that contained anticancer effective component and percentage by weight thereof are:
(a) fulvestrant of 2-40%, A Naluo azoles, exemestane or tamoxifen; Or
(b) paclitaxel of the fulvestrant of 2-40%, A Naluo azoles, exemestane or tamoxifen and 2-40%, Docetaxel, 2 '-hydroxyl paclitaxel, the 10-combination of removing acetyl paclitaxel or 7-table-paclitaxel.
Embodiment 3.
With 70mg molecular weight peak value is that 65000 polylactic acid (PLGA, 75: 25) is put into container, adds 100 milliliters of dichloromethane, behind the dissolving mixing, adds 15mg fulvestrant and 15mg nimustine, shakes up the dry organic solvent of removing of final vacuum again.Dried pastille solid composite freezing and pulverizing is made the micropowder that contains 15% fulvestrant and 15% 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 10-15 days, is about 20-30 days at the subcutaneous drug release time of mice.
Embodiment 4
The method step that is processed into slow releasing injection is identical with embodiment 3, but different is that contained anticancer effective component and percentage by weight thereof are:
The fulvestrant of 2-40%; the A Naluo azoles; the alestramustine of exemestane or tamoxifen and 2-40%; 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; the appropriate azoles amine of miaow; the combination of cyclophosphamide or melphalan.
Embodiment 5.
(EVAc) puts into container with the 70mg ethylene vinyl acetate copolymer, after adding 100 milliliters of dichloromethane dissolving mixings, add 20 milligrams of vincristine and 10 milligrams of fulvestrants, shake up the back contains 20% vincristine and 10% fulvestrant 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-200cp (20 ℃-30 ℃ time).The drug release time of this slow releasing injection in external normal saline is 10-15 days, is about 20-30 days at the subcutaneous drug release time of mice.
Embodiment 6.
The method step that is processed into slow releasing injection is identical with embodiment 5, but different is that contained anticancer effective component is: the combination of vincristine, vincaleucoblastine, vinorelbine, vindesine, Vinmegallate, vinleurosine, vinleucinol, vinglycinate, vinfosiltine, vinformide, vinflunine, vinepidine, vinzolidine, vintriptol, vinrosidine, monocrotaline or the cephalotaxin of the fulvestrant of 2-40%, A Naluo azoles, exemestane or tamoxifen and 2-40%.
Embodiment 7.
70mg polifeprosan (to carboxy phenyl propane (p-CPP): certain herbaceous plants with big flowers diacid (SA) is 20: 80) copolymer is put into container, add 100 milliliters of dichloromethane, behind the dissolving mixing, add 20mg fulvestrant and 10mg exemestane, shake up the back contains 20% fulvestrant and 10% exemestane 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 10-15 days, is about 20-30 days at the subcutaneous drug release time of mice.
Embodiment 8.
The method step that is processed into slow releasing injection is identical with embodiment 7, but different is that contained anticancer effective component is: the combination of A Naluo azoles, exemestane and/or the tamoxifen of the fulvestrant of 2-40% and 2-40%.
Embodiment 9
70mg polifeprosan (to carboxy phenyl propane (p-CPP): certain herbaceous plants with big flowers diacid (SA) is 20: 80) copolymer is put into container, add 100 milliliters of dichloromethane, behind the dissolving mixing, add 20mg Docetaxel and 10mg A Naluo azoles, shake up the back contains 20% Docetaxel and 10% with spray drying method for preparation A Naluo azoles injectable microsphere again.Then microsphere is suspended in the normal saline that contains 1.5% sodium carboxymethyl cellulose and 15% sorbitol and 0.2% Tween 80, makes corresponding suspension type slow releasing injection, viscosity is 560cp-640cp (20 ℃-30 ℃ time).The drug release time of this slow releasing injection in external normal saline is 10-15 days, is about 20-30 days at the subcutaneous drug release time of mice.
Embodiment 10
The method step that is processed into slow releasing injection is identical with embodiment 9, but different is that contained anticancer effective component is:
The combination that the paclitaxel of the fulvestrant of 2-40%, A Naluo azoles, exemestane or tamoxifen and 2-40%, Docetaxel, 2 ' hydroxyl paclitaxel, 10-remove acetyl paclitaxel or 7-table-paclitaxel.
Embodiment 11
70mg polifeprosan (to carboxy phenyl propane (p-CPP): certain herbaceous plants with big flowers diacid (SA) is 20: 80) copolymer is put into container, add 100 milliliters of dichloromethane, behind the dissolving mixing, add 10mg carmustine and 20mg fulvestrant, shake up the back contains 10% carmustine and 20% fulvestrant with spray drying method for preparation injectable microsphere again.Then microsphere is made corresponding sustained-release implant through pressed disc method.The drug release time of this sustained-release implant in external normal saline is 10-15 days, is about 30-40 days at the subcutaneous drug release time of mice.
Embodiment 12
The method step that is processed into sustained-release implant is identical with embodiment 11, but different is that contained anticancer effective component is: 20% fulvestrant; the A Naluo azoles; exemestane or tamoxifen and 10% 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; the appropriate azoles amine of miaow; the combination of cyclophosphamide or melphalan.
Embodiment 13
With 70mg molecular weight peak value 35000 polylactic acid (PLGA, 50: 50) put into container, add 100 milliliters of dichloromethane, behind the dissolving mixing, add 10mg vinorelbine and 20mg fulvestrant, shake up the back contains 10% vinorelbine and 20% fulvestrant 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 35-50 days at the subcutaneous drug release time of mice.
Embodiment 14
The method step that is processed into sustained-release implant is identical with embodiment 11,13, but different is that contained anticancer effective component is: the combination of vincristine, vincaleucoblastine, vinorelbine, vindesine, Vinmegallate, vinleurosine, vinleucinol, vinglycinate, vinfosiltine, vinformide, vinflunine, vinepidine, vinzolidine, vintriptol, vinrosidine, monocrotaline or the cephalotaxin of 20% fulvestrant, A Naluo azoles, exemestane or tamoxifen and 2-40%.
Embodiment 15.
With 70mg molecular weight peak value is that 35000 polylactic acid (PLA) is put into container, adds 100 milliliters of dichloromethane, behind the dissolving mixing, adds 15mg paclitaxel and 15mg vincaleucoblastine, shakes up the dry organic solvent of removing of final vacuum again.Dried pastille solid composite freezing and pulverizing is made the micropowder that contains 15% paclitaxel and 15% 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 10-15 days, is about 20-30 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 15% paclitaxel or docetaxel and 15% vincristine, vincaleucoblastine, vinorelbine, vindesine, Vinmegallate, vinleurosine, vinleucinol, vinglycinate, vinfosiltine, vinformide, vinflunine, vinepidine, vinzolidine, vintriptol, vinrosidine, monocrotaline or cephalotaxin.
Embodiment 17.
With 70mg molecular weight peak value is that 30000 bis-fatty acid and certain herbaceous plants with big flowers diacid (SA) copolymer (bis-fatty acid: the certain herbaceous plants with big flowers diacid is 20: 80) are put into container, add 100 milliliters of dichloromethane, behind the dissolving mixing, add 15mg nimustine and 15mg vinorelbine, 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% nimustine and 15% vinorelbine, 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-460cp (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 18.
The method step that is processed into slow releasing injection is identical with embodiment 17, but different is that contained anticancer effective component and percentage by weight thereof are:
15% 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; the appropriate azoles amine of miaow; the new alkali of spring of cyclophosphamide or melphalan length and 15%; vincaleucoblastine; vinorelbine; vindesine; Vinmegallate; vinleurosine; vinleucinol; vinglycinate; vinfosiltine; vinformide; vinflunine; vinepidine; vinzolidine; vintriptol; vinrosidine; the combination of monocrotaline or cephalotaxin.
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: 50-50, the molecular weight peak value is 10000-30000,300000-60000,60000-100000 or 100000-150000;
C) ethylene vinyl acetate copolymer (EVAc);
D) polifeprosan, to carboxy phenyl propane (p-CPP): certain herbaceous plants with big flowers diacid (SA) is 10: 90,20: 80,30: 70,40: 60,50: 50 or 60: 40;
D) bis-fatty acid and decanedioic acid copolymer (PFAD-SA);
E) poly-(erucic acid dimer-decanedioic acid) [P (EAD-SA)];
F) poly-(fumaric acid-decanedioic acid) [P (FA-SA)];
G) xylitol, oligosaccharide, chrondroitin, chitin, hyaluronic acid, collagen protein, gelatin or white tempera.
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: 15% fulvestrant; the A Naluo azoles; exemestane; tamoxifen; paclitaxel; Docetaxel (docetaxel); 2 '-hydroxyl taxol; 10-removes the acetyl taxol; 7-table-taxol; 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; the appropriate azoles amine of miaow; cyclophosphamide; melphalan; vincristine; vincaleucoblastine; vinorelbine; vindesine; Vinmegallate; vinleurosine; vinleucinol; vinglycinate; vinfosiltine; vinformide; vinflunine; vinepidine; vinzolidine; vintriptol; vinrosidine; monocrotaline or cephalotaxin.
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) fulvestrant of 5-30%, A Naluo azoles, exemestane or tamoxifen;
(b) paclitaxel of the fulvestrant of 5-30%, A Naluo azoles, exemestane or tamoxifen and 2-40%, Docetaxel, 2 '-hydroxyl paclitaxel, the 10-combination of removing acetyl paclitaxel or 7-table-paclitaxel;
(c) fulvestrant of 5-30%, the A Naluo azoles, the alestramustine of exemestane or tamoxifen and 5-30%, 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, the appropriate azoles amine of miaow, the combination of cyclophosphamide or melphalan;
(d) combination of vincristine, vincaleucoblastine, vinorelbine, vindesine, Vinmegallate, vinleurosine, vinleucinol, vinglycinate, vinfosiltine, vinformide, vinflunine, vinepidine, vinzolidine, vintriptol, vinrosidine, monocrotaline or the cephalotaxin of the fulvestrant of 5-30%, A Naluo azoles, exemestane or tamoxifen and 2-40%;
(e) combination of the fulvestrant of 5-30% and A Naluo azoles and/or exemestane; Or
(f) combination of the fulvestrant of 5-30%, A Naluo azoles and/or exemestane and/or tamoxifen.
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 (3)

1. the slow-releasing anticarcinogen injection that contains estrogen receptor antagon 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 estrogen receptor antagon and the combination that is selected from the estrogen receptor antagon synergist of alkylating agent;
Described estrogen receptor antagon is selected from one of fulvestrant, A Naluo azoles, exemestane, tamoxifen or its combination;
Described 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, the appropriate azoles amine of miaow, one of cyclophosphamide and melphalan or its combination;
Slow-release auxiliary material is selected from one of following or its combination:
A) polylactic acid, its molecular weight peak value is 10000-30000,30000-60000,60000-100000 or 100000-150000;
B) copolymer of polylactic acid and hydroxyacetic acid, wherein, the ratio of polylactic acid and hydroxyacetic acid is 10/90-90/10, the molecular weight peak value is 10000-30000,30000-60000,60000-100000 or 100000-150000;
C) polifeprosan, wherein, to carboxy phenyl propane: decanedioic acid is 10: 90,20: 80,30: 70,40: 60,50: 50 or 60: 40;
D) ethylene vinyl acetate copolymer;
E) bis-fatty acid and decanedioic acid copolymer;
F) poly-(erucic acid dimer-decanedioic acid) copolymer;
G) poly-(fumaric acid-decanedioic acid) copolymer;
The viscosity of suspending agent is 100cp-3000cp (20 ℃-30 ℃ time), is selected from one of following or its combination:
A) 0.5-3.0% sodium carboxymethyl cellulose;
B) 5-15% mannitol;
C) 5-15% sorbitol;
D) 0.1-1.5% surfactant;
E) 0.1-0.5% polysorbas20;
F) iodine glycerol, simethicone, propylene glycol or carbomer;
G) 0.5-5% sodium carboxymethyl cellulose+0.1-0.5% Tween 80;
H) 5-20% mannitol+0.1-0.5% Tween 80; Or
I) 0.5-5% sodium carboxymethyl cellulose+5-20% sorbitol+0.1-0.5% Tween 80.
2. the slow-releasing anticarcinogen injection according to claim 1 is characterized in that the anticancer effective component in the slow-releasing anticarcinogen injection microsphere is:
The fulvestrant of 2-40%, the A Naluo azoles, the alestramustine of exemestane or tamoxifen and 2-40%, 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, the appropriate azoles amine of miaow, the combination of cyclophosphamide or melphalan;
Below all be weight percentage.
3. the slow-releasing anticarcinogen injection according to claim 1, the component that it is characterized in that slow-releasing anticarcinogen injection is one of following combination:
Anticancer effective component is 15% fulvestrant and 15% nimustine, and slow-release auxiliary material is 65000 polylactic acid for the molecular weight peak value, and solvent is the normal saline that contains 1.5% sodium carboxymethyl cellulose;
Below all be weight percentage.
CNA2008103005020A 2006-03-28 2006-03-28 Anticancer sustained-release injection containing estrogen receptor antagon Pending CN101244029A (en)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3706719A1 (en) * 2017-11-08 2020-09-16 Eagle Pharmaceuticals, Inc. Fulvestrant formulations and methods of their use

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3706719A1 (en) * 2017-11-08 2020-09-16 Eagle Pharmaceuticals, Inc. Fulvestrant formulations and methods of their use
US12186427B2 (en) 2017-11-08 2025-01-07 Eagle Pharmaceuticals, Inc. Fulvestrant formulations and methods of their use

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