CN101219113A - Compound anticancer sustained-release injection containing bendamustine - Google Patents
Compound anticancer sustained-release injection containing bendamustine Download PDFInfo
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- CN101219113A CN101219113A CNA2008103002395A CN200810300239A CN101219113A CN 101219113 A CN101219113 A CN 101219113A CN A2008103002395 A CNA2008103002395 A CN A2008103002395A CN 200810300239 A CN200810300239 A CN 200810300239A CN 101219113 A CN101219113 A CN 101219113A
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Abstract
The invention provides a compound anticancer drug sustained release agent containing bendamustine, which is a sustained release injection consisting of sustained release microspheres and solvent, wherein, the sustained release microspheres comprise effective anticancer components and sustained-release excipient, and the solvent is a special solvent containing a suspending agent. The effective anticancer components are bendamustine and the combination of bendamustine synergist chosen from alkylating agent and/or hormone anticarcinogen. The sustained-release excipient is chosen from one of or the combination of polylactic acid, copolymer thereof, monomethyl polyethylene glycol, polyethylene glycol, carboxyl end polylactide copolymer, dual fatty acid, sebacie acid copolymer, poly (erucic dimer- sebacie acid), poly (fumarate- sebacie acid), Polifeprosan, polylactide copolymer or mixture and EVAc. The suspending agent is chosen from carboxymethyl cellulose, etc., and the viscosity of the suspending agent is 80cp-3000cp (in the temperature of 20 DEG C-30 DEG C). The sustained release microspheres can also be produced into a sustained-release implant. The sustained-release implant and the sustained release injection is arranged around the tumor or injected in the tumor, which can obviously improve the curative effect if being applied independently or combined with chemotherapeutics and/or radiotherapeutics and other non-operative treatment.
Description
(1) technical field
The present invention relates to a kind of the compound anti-cancer slow-release injected of bendamustine that contain, belong to technical field of pharmaceuticals.Particularly, the invention provides a kind of slow releasing injection or sustained-release implant with carrying bendamustine spit of fland and its synergist, bendamustine synergist wherein is alkylating agent and/or hormone anti-cancer medicine.
(2) background technology
Treatment for cancer still mainly comprises methods such as operation, radiotherapy and chemotherapy at present.Therefore wherein operative treatment can not be removed the oncocyte that is dispersed in, and often recurs or causes tumor cell to stimulate diffusion transfer because of operation; Radiotherapy and traditional chemotherapy are 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 (1998) (Kong Q et al., J Surg Oncol.1998 Oct such as Kong Qingzhongs; 69 (2): 76-82).
The local placement of chemotherapeutics 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 (1998) (Kong Q et al., J Surg Oncol.1998 Oct such as Kong Qingzhongs; 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 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 phases 2497503 pages of (2000) (Netti PA referring to the Buddhist nun, Cancer Res.2000,60 (9): 2497-503)).Moreover, the blood vessel in the mesenchyma stroma of tumors often causes the enhancing of tumor cell to the toleration of cancer therapy drug to conventional chemotherapy medicine and insensitive, consequently treatment failure.
In addition, the cancer drug therapy of low dosage not only can increase the Drug tolerance of cancerous cell, but also can promote its infiltrative growth "; referring to beam etc. " increased the Drug tolerance of human lung carcinoma cell and external wetting capacity after the cancer therapy drug pulse screening and with the change of gene expression " " international journal of cancer " 111 phase 48-493 page or leaf (2004) (Liang Y; etal., Int J Cancer.2004; 111 (4): 48493).
Therefore, develop a kind of effective cancer therapy drug or Therapeutic Method and just become a current important topic.The present invention provides a kind of new anticancer pharmaceutical composition just at the deficiencies in the prior art, can suppress growth of tumour cell effectively, and can strengthen the treatment tumor effect of other medicines, reduces recurrence.
(3) summary of the invention
The present invention is directed to the deficiencies in the prior art, a kind of slow-releasing anticarcinogen injection that contains bendamustine is provided, belong to technical field of pharmaceuticals.Particularly, the invention provides a kind of slow releasing injection or sustained-release implant with carrying bendamustine spit of fland and its synergist, bendamustine synergist wherein is alkylating agent, purine derivative and/or hormone anti-cancer medicine.
All tumor growth can be suppressed when bendamustine and alkylating agent and/or hormone anti-cancer medicine are used separately, tumor cell can also be increased during use in conjunction mutual sensitivity.Be widely used in the multiple entity tumor of treatment both at home and abroad.Yet in application process, its tangible general toxicity has greatly limited the application of this medicine.
The present invention finds that many bendamustine synergists and bendamustine share its antitumaous effect is strengthened mutually; In addition, the compositions of alkylating agent and/or steroids anti-cancer drugs and bendamustine is made drug level that anticancer medicine slow-release preparation containing (being mainly slow releasing injection and sustained-release implant) not only can greatly improve tumor by local, reduces the drug level of medicine in blood circulation, is 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 above unexpected main contents of the present invention of finding to constitute.
A kind of form of the present invention is a slow releasing injection, is made up of sustained-release micro-spheres and solvent.Particularly, this slow-releasing anticarcinogen injection is grouped into by following one-tenth:
(A) sustained-release microparticle, the one-tenth following by percentage by weight is grouped into:
Biological effective components 0.5-60%
Slow-release auxiliary material 41-99.9%
Suspending agent 0.0-30%
(B) solvent is divided into common solvent and special solvent.
Wherein, common solvent comprises the buffer that distilled water, water for injection, physiology are prepared towards liquid, dehydrated alcohol or various salt; Special solvent is the common solvent that contains suspending agent, and 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.When the suspending agent in the sustained-release microparticle (A) was " 0 ", solvent (B) was special solvent.
Sustained-release microparticle of the present invention is made up of effective medicinal components and slow-release auxiliary material and/or suspending agent, and wherein, effective ingredient can be bendamustine and alkylating agent and/or steroids anti-cancer drugs.
The percentage by weight of effective ingredient in medicament slow-release microsphere is 0.5%-60%, is good with 2%-40%, is best with 5%-30%.
Selected bendamustine shared ratio in compositions is decided because of concrete condition among the present invention, can be 0.1%-50%, is good with 1%-30%, and 5%-20% is best.
Alkylating agent is selected from one of following or combination: cyclophosphamide (CTX), melphalan (Melphalan), Chlorambucil (chlorambucil), 4H-peroxide cyclophosphamide (4H-CTX), ifosfamide (Ifosfamide, Isophosphamide), three mustard cyclophosphamide, sufosfamide (Sufosfamide), defosfamide (Defosfamide), Mafosfamide (Mafosfamide), perfosfamide (Perfosfamide), trofosfamide (Trofosfamide), thiocarzolamide, metamelfalan (Metamelfalan), formylmerphalan (Formylmerphalan), hexamethylmelamine (hexamethylmelamine), Ametantrone, Thymopentin, clomifene, letrozole, disodium cantharidinate, cantharidin (cantharidine), sodium cantharidinate, N-methylcantharidimide, N-hydroxycantharidin, norcantharidin (Norcantharidin), mannomustine (Mannosulfan), treosulfan (Treosulfan), ritrosulfan (Ritrosulfan), an improsulfan (Improsulfan), etoglucid (etoglucid, Ethoglucid, Etoglucid), pipobroman (pipobroman, Pipobroman), piposulfan (A-20968, Piposulfan), triethylenemelaine (triethylenemelamine), epoxypiperazine (epoxypiperazine), benzene assistant TEPA (Benzodepa), Phopurine (Pumitepa), meturedepa (Meturedepa), Ah bundle's TEPA (Aza-TEPA), the salt of urethimine (Uredepa) or said medicine.
Above-mentioned alkylating agent serves as preferred with cyclophosphamide, melphalan, Chlorambucil, ifosfamide, 4H-peroxide cyclophosphamide, defosfamide, Mafosfamide, perfosfamide, hexamethylmelamine, cantharidin, norcantharidin, mannomustine, treosulfan, ritrosulfan, an improsulfan, etoglucid, pipobroman, piposulfan, triethylenemelaine, epoxypiperazine, benzene assistant TEPA, Phopurine, meturedepa, urethimine or Ah bundle's TEPA.
The salt of above-mentioned alkylating agent comprises: sulfate, phosphate, hydrochlorate, Lactobionate, acetate, aspat, nitrate, citrate, purine or pyrimidine salt, succinate or maleate.
The percentage by weight of alkylating agent in slow releasing agent is good from 0.01%-90% with 1%-50%, is best with 5%-30%.
Conventional route administrations such as main oral administration of cancer therapy drug or intravenous injection, administering mode of the present invention is the local sustained release administration, obviously reduces the toxic action of its whole body in the therapeutic effect that significantly strengthens medicine.That has reported has cisplatin and a carboplatin etc. through what the slow release approach was used, yet is not all slow release effects that all can reach effective release in slow-release auxiliary material of the present invention in numerous chemical compounds with active anticancer.Pharmaceutic adjuvant have hundreds of more than, pharmaceutic adjuvant with slow releasing function, particularly can slowly release ratio be non-apparent in the regular hour in human body or animal body with selected bendamustine among the present invention, 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.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.
Steroids anti-cancer drugs is mainly steroid hormone and hormone antagonist; comprise; but be not limited to; Anastrozole (anastrozole); idoxifene (idoxifene); Miproxifene (Miproxifene); tamoxifen (tamoxifen; tamoxifen); 4-monohydroxy tamoxifen (trans-4-monohydroxytamoxifen; OH-TAM); former times sweet smell (keoxifene not; LY156758); ICI-M 164384 (ICI164384; the 7-alpha-alkyl amide analogue of estradiol); 7-α-[9-(4; 4; 5; 5; 5-five fluorine amyl group sulfinyls) nonyl] female steroid-1; 3; 5 (10) triolefins-3; 17 β diphenol (anticancer steroid alkene phenol; fulvestrant; 7 alpha-[9-(4; 4; 5; 5; 5-pentafluoropentylsulfinyl) nonyl] estra-1; 3; 5 (10)-triene-3; 17 beta-diol; ICI 182780); 4-trans-Hydroxytamoxifen (4-hydroxytamoxifen); γ-linoleic acid (gamma-linolenic acid); 2-methoxyestradiol (2-methoxyestradiol); moxestrol (moxestrol); 4-trans-Hydroxytamoxifen (4-hydroxytamoxifen); benzene hexachloride (benzene hexachloride; Gamma Hexaochlorocyclohexane; beta-hexachlorocyclohexane; beta-HCH); raloxifene (raloxifene); diethylstilbestrol (diethylstilbestrol); estradiol (estradiol); 6-(10-hydroxy-6-oxo-trans-1-undecenyl)-.beta.-resorcylic acid lactone (zearalenone); estrone (estrone); 17 alpha-estradiols (17alpha-estradiol); estradiol (estriol); 2-hydroxyestrone (2-hydroxyestrone); 5; 7; 4 trihydroxy-isoflavones (genistein); Progesterone; mepitiostane (Mepitiostane); androgen; (.+-.)-Pyridoglutethimide; rubitecan; Acapodene; Drogenil (Flutamide; flutamide); overstate single silicon indigo plant; bicalutamide (Casodex); aminoglutethimide (Aminoglutethimide, aminoglutethimidium); betamethasone benzoate; calusterone; triptorelin; goserelin; leuprorelin; megestrol; medroxyprogesterone; datiscoside; epitiostanol; the female sweet smell of bromine vinegar ethane; hisphen; clomifene; toremifene; letrozole; Anastrozole; exemestane or testolactone.
Above steroids anti-cancer drugs can singly select or multiselect, with triptorelin, goserelin, leuprorelin, Anastrozole, idoxifene, Miproxifene, tamoxifen, 4-monohydroxy tamoxifen (OH-TAM), not former times sweet smell, raloxifene, ICI-M 164384, anticancer steroid alkene phenol, 4-trans-Hydroxytamoxifen, Drogenil, aminoglutethimide, (.+-.)-Pyridoglutethimide, megestrol, medroxyprogesterone, clomifene, toremifene, letrozole, Anastrozole, exemestane or bicalutamide serve as preferred.
Above steroids anti-cancer drugs can be used for the tumor that various hormones rely on, but different pharmaceutical has relative tumor-selective, as, tamoxifen, (.+-.)-Pyridoglutethimide, rubitecan, Acapodene etc. mainly rely on estrogenic tumor in order to treatment, as breast carcinoma and carcinoma of endometrium; Drogenil, overstate that single silicon indigo plant and bicalutamide mainly rely on androgenic tumor in order to treatment, as carcinoma of prostate; Triptorelin, goserelin, leuprorelin, tamoxifen, raloxifene, aminoglutethimide, clomifene, toremifene, letrozole, Anastrozole and exemestane are then in order to treatment breast carcinoma, carcinoma of prostate and carcinoma of endometrium.
The content of steroids anti-cancer drugs in compositions is 0.01%-60%, is good with 1%-40%, is best with 5%-30%, more than all be weight percentage.
The percentage by weight of bendamustine and bendamustine synergist is 1-9: 1 to 1: 1-9.
Pharmaceutic adjuvant is a lot, the present invention is several slow-release auxiliary material of screening from hundreds of adjuvants, selected slow-release auxiliary material can discharge the selected medicine of the present invention tens of days in people and animal body, discharge since a few hours, continues 30-50 days (seeing the embodiment in the description).Resulting product is an anticancer sustained-release agent.The selection of slow-release auxiliary material particularly need could be determined through a large amount of creative works with the combination of different pharmaceutical, is not just can determine through limited experiment, thereby has unobviousness.
Slow-release auxiliary material range of viscosities IV (dl/g) is 0.1～1.0, be selected from poly-dl-lactide (D, L-PLA), poly-dl-lactide/ethanol copolymer (D, L-PLGA), monomethyl polyethylene glycol (MPEG-PLA), monomethyl polyethylene glycol copolymer (MPEG-PLGA), polyethylene glycol (PLA-PEG-PLA), polyethylene glycol copolymer (PLGA-PEG-PLGA), end carboxyl polylactic acid (PLA-COOH), end carboxyl polylactic acid/ethanol copolymer (PLGA-COOH), polifeprosan, bis-fatty acid and decanedioic acid copolymer (PFAD-SA), poly-(erucic acid dimer-decanedioic acid) [P (EAD-SA)], poly-(fumaric acid-decanedioic acid) [P (FA-SA)], ethylene vinyl acetate copolymer (EVAc), polylactic acid (PLA), the copolymer of polyglycolic acid and hydroxyacetic acid (PLGA), PPDO (PDO), PTMC (PTMC), xylitol, oligosaccharide, chrondroitin, chitin, hyaluronic acid, collagen protein, gelatin, one of albumin glue or its combination; Suspending agent is selected from one of sodium carboxymethyl cellulose, (iodine) glycerol, simethicone, propylene glycol, carbomer, mannitol, sorbitol, surfactant, soil temperature 20, soil temperature 40 and soil temperature 80 or its combination.
Anticancer effective component in the slow-releasing anticarcinogen injection microsphere of the present invention is preferably as follows, and all is weight percentage:
(1) combination of the cyclophosphamide of the bendamustine of 1-40% and 1-40%, melphalan, Chlorambucil, ifosfamide, 4H-peroxide cyclophosphamide, defosfamide, Mafosfamide, perfosfamide, hexamethylmelamine, cantharidin, norcantharidin, mannomustine, treosulfan, ritrosulfan, an improsulfan, etoglucid, pipobroman, piposulfan, triethylenemelaine, epoxypiperazine, benzene assistant TEPA, Phopurine, meturedepa, urethimine or Ah bundle's TEPA; Or
(2) triptorelin of the bendamustine of 1-40% and 1-40%, goserelin, leuprorelin, Anastrozole, idoxifene, Miproxifene, tamoxifen, 4-monohydroxy tamoxifen, not former times sweet smell, raloxifene, ICI-M 164384, anticancer steroid alkene phenol, 4-trans-Hydroxytamoxifen, Drogenil, aminoglutethimide, (.+-.)-Pyridoglutethimide, megestrol, medroxyprogesterone, clomifene, toremifene, letrozole, Anastrozole, exemestane or the combination of bicalutamide.
Slow-release auxiliary material is a bio-capacitivity, can (or non-) degraded and absorbed polymer, preferred silicone rubber, poly-dl-lactide, poly-dl-lactide/ethanol copolymer, the monomethyl polyethylene glycol, monomethyl polyethylene glycol copolymer, polyethylene glycol, the polyethylene glycol copolymer, end carboxyl polylactic acid, end carboxyl polylactic acid/ethanol copolymer, polifeprosan, bis-fatty acid and decanedioic acid copolymer, poly-(erucic acid dimer-decanedioic acid), poly-(fumaric acid-decanedioic acid), ethylene vinyl acetate copolymer, polylactic acid, the copolymer of polyglycolic acid and hydroxyacetic acid, xylitol, oligosaccharide, chrondroitin, chitin, hyaluronic acid, collagen protein, one of gelatin and albumin glue or its combination.
Slow-release auxiliary material and percentage by weight thereof are most preferably as follows in the sustained-release micro-spheres of the present invention:
(1) PLA of 55-90%;
(2) PLGA of 50-90%;
(3) polifeprosan of 50-85%;
(4) bis-fatty acid of 55-90% and decanedioic acid copolymer;
(5) EVAc of 55-90%;
(6) xylitol of 40-95%, oligosaccharide, chrondroitin, chitin, hyaluronic acid, collagen protein, gelatin or white tempera; Or
(7) poly-dl-lactide of 40-95%, poly-dl-lactide/ethanol copolymer, monomethyl polyethylene glycol, monomethyl polyethylene glycol copolymer, polyethylene glycol, polyethylene glycol copolymer, end carboxyl polylactic acid or end carboxyl polylactic acid/ethanol copolymer.
In various high molecular polymers, with polylactic acid, decanedioic acid, the mixture or the copolymer that contain the macromolecule polymer of polylactic acid or certain herbaceous plants with big flowers diacid is first-selection, mixture and copolymer can be selected from, but be not limited to the mixture or the copolymer of the mixture of PLA, PLGA, glycolic and hydroxy carboxylic acid, certain herbaceous plants with big flowers diacid and fragrant polyanhydride or aliphatic polyanhydride.The blend ratio of glycolic and hydroxy carboxylic acid is 10/90-90/10 (weight), preferably 25/75-75/25 (weight).The method of blend is arbitrarily.Content when glycolic and hydroxy carboxylic acid copolymerization is respectively percentage by weight 10-90% and 90-10%.The representative of fragrance polyanhydride is polifeprosan [poly-(1,3-two (to the carboxyl phenoxy group) propane-decanedioic acid) (p (CPP-SA)), bis-fatty acid-decanedioic acid copolymer (PFAD-SA)], poly-(erucic acid 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: 5090, and weight ratio 15-30: 65-85 preferably.
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 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.
Suspending agent be used for preparation and/or effectively suspend, stable and/or protect various medicines or sustained-release micro-spheres (or microcapsule), thereby make prepared injection injectivity good, be not easy obstruction, good stability, be difficult for layering, the viscosity height.
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), preferred 1000cp-3000cp (20 ℃-30 ℃ time), most preferably 1500cp-3000cp (20 ℃-30 ℃ time).
The application of solvent refers to that mainly the application of special solvent is effective suspension, stablizes and/or protects various medicines or sustained-release micro-spheres (or microcapsule), thereby prepares corresponding injection.The application of special solvent can make prepared injection have better injectivity, good stability and higher viscosity.
Common solvent can be, but is not limited to, the buffer that distilled water, water for injection, physiology are prepared towards liquid, dehydrated alcohol or various salt, and pharmacopeia has respective specified; The special solvent of indication of the present invention is the common solvent that contains suspending agent, suspending agent can be, but be not limited to 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 is 0.1-30% volume weight percentage ratio in the special solvent, is preferably as follows:
A) 0.5-5% sodium carboxymethyl cellulose; Or
B) 0.5-5% sodium carboxymethyl cellulose and 0.1-0.5% Tween 80; Or
C) 5-20% mannitol; Or
D) 5-20% mannitol and 0.1-0.5% Tween 80; Or
E) 0.5-5% sodium carboxymethyl cellulose, 5-20% sorbitol and 0.1-0.5% Tween 80.
The above-mentioned volume weight percentage ratio that is contains the weight of suspending agent in the common solvent of unit volume, as g/ml, and kg/l.Down together.
The content of suspending agent is decided because of the medicine that solvent suspended, composition, character and the requirement thereof of sustained-release micro-spheres (or microcapsule), the preparation method of injection and the kind and the composition thereof of suspending agent, as, sodium carboxymethyl cellulose can be 0.5-5%, but with 1-3% is preferred, mannitol and/or sorbitol are 5-30%, but is preferred with 10-20%, and soil temperature 20, soil temperature 40 or soil temperature 80 are 0.05-2%, but are preferred with 0.10-0.5%.In most cases, sustained-release microparticle is made up of effective ingredient and slow-release auxiliary material, and solvent is special solvent.When solvent was common solvent, medicine that is suspended or sustained-release micro-spheres (or microcapsule) then were made up of effective ingredient, slow-release auxiliary material and/or suspending agent.In other words, when the suspending agent in the sustained-release microparticle (A) was " 0 ", solvent (B) was special solvent, and when the suspending agent in the sustained-release microparticle (A) was not " 0 ", solvent (B) can be common solvent or special solvent.The viscosity of suspending agent is 100cp-3000cp (20 ℃-30 ℃ time), preferred 1000cp-3000cp (20 ℃-30 ℃ time), most preferably 1500cp-3000cp (20 ℃-30 ℃ time).
The preparation of injection comprises that the preparation of preparation, solvent of sustained-release micro-spheres or drug microparticles and sustained-release micro-spheres or drug microparticles suspend, and make injection at last in solvent.
Wherein, sustained-release micro-spheres or drug microparticles can prepare with some kinds of methods: as, but be not limited to, mixing method, fusion method, dissolution method, spray drying method for preparation microsphere, dissolution method are in conjunction with freezing (drying) comminuting method, liposome bag medicine method and emulsion process etc.Serve as preferred wherein with dissolution method (being the solvent volatility process), freezing (drying) comminuting method, seasoning, spray drying method and emulsion process.Microsphere then can be used for preparing above-mentioned various slow releasing injection.The particle diameter of suspended drug or sustained-release micro-spheres (or microcapsule) decide because of specifically needing, and can be, but be not limited to, 1-300um, but be that preferably 30-150um most preferably with 20-200um.Medicine or sustained-release micro-spheres can be made into microsphere, sub-micro ball, microemulsion, nanosphere, granule or spherical piller.Slow-release auxiliary material is above-mentioned bio-capacitivity, biodegradable or non-biodegradation polymer.
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 soil temperature 80 (0.1%) are dissolved in the normal saline mutually deserved solvent, viscosity is at 10cp-650cp (20 ℃-30 ℃ time).
The present invention finds to influence medicine and/or sustained-release micro-spheres suspends and/or the key factor of injection is the viscosity of solvent, and viscosity is big more, and suspension effect is good more, and syringeability is strong more.This unexpected one of main index characteristic of the present invention of finding to have constituted.The viscosity of solvent depends on the viscosity of suspending agent, and the viscosity of suspending agent is 100cp-3000cp (20 ℃-30 ℃ time), preferred 1000cp-3000cp (20 ℃-30 ℃ time), most preferably 1500cp-3000cp (20 ℃-30 ℃ time).According to the viscosity of the prepared solvent of this condition is 10cp-650cp (20 ℃-30 ℃ time), preferred 20cp-650cp (20 ℃-30 ℃ time), most preferably 60cp-650cp (20 ℃-30 ℃ time).
The preparation of injection has several different methods, and a kind of is that the sustained-release microparticle (A) of suspending agent for " 0 " directly mixed in special solvent, obtains corresponding sustained-release microparticle injection; Another kind is that suspending agent is not mixed in special solvent or common solvent for the sustained-release microparticle (A) of " 0 ", obtains corresponding sustained-release microparticle injection; Another is that sustained-release microparticle (A) is mixed in common solvent, adds the suspending agent mixing then, obtains corresponding sustained-release microparticle injection.Except, also can earlier sustained-release microparticle (A) be mixed and in special solvent, make corresponding suspension, with the moisture in ways such as the vacuum drying removal suspension, special solvent of reuse or common solvent suspendible obtain corresponding sustained-release microparticle injection afterwards then.Above method just is illustrative rather than definitive thereof the present invention.It should be noted that suspended drug or sustained-release micro-spheres (or microcapsule) concentration in injection decide because of specifically needing, can be, but be not limited to, 10-400mg/ml, but be preferably with 30-300mg/ml, with 50-200mg/ml most preferably.The viscosity of injection is 50cp-1000cp (20 ℃-30 ℃ time), preferred 100cp-1000cp (20 ℃-30 ℃ time), most preferably 200cp-650cp (20 ℃-30 ℃ time).This viscosity is applicable to 18-22 injection needle and special bigger (to 3 millimeters) injection needle of internal diameter.
The route of administration of injection depends on multiple factor.Can be in vein, lymphatic vessel, subcutaneous, muscle, intracavity (in as abdominal cavity, thoracic cavity, articular cavity and in the canalis spinalis), tissue, tumor in, reach in the bone marrow in all, the selective arterial injection of tumor, lymph node and inject.For entity tumor, though can be through above-mentioned administration, with in selective arterial, intracavity, the tumor, the injection of tumor week serves as preferred.For obtaining valid density in former or position, metastatic tumour place, also can unite and give through number of ways, in the time of as vein, lymphatic vessel, subcutaneous, muscle, intracavity (as in abdominal cavity, thoracic cavity, the articular cavity and in the canalis spinalis) or selective arterial injection in conjunction with local injection.So administering drug combinations is specially adapted to entity tumor.As in the tumor, tumor week injection time is in conjunction with systemic injection.
The application of injection is to utilize full-bodied special solvent with pastille microgranule (ball), particularly sustained-release microparticle, makes corresponding slow releasing injection, thereby corresponding medicine can be imported in the patient or mammalian body of required medicine in the mode of injection.The medicine that is injected can be, but is not limited to, said medicine micropowder or medicament slow release microgranule.
The application of injection comprises the application of the injection of making after the application of application, solvent of sustained-release micro-spheres or drug microparticles and sustained-release micro-spheres or drug microparticles suspend in solvent.
In the slow releasing injection, drug sustained release system can be made into microsphere, sub-micro ball, microemulsion, nanosphere, granule or spherical piller, makes the injection use then with after the injection solvent mixes.In various slow releasing injection, serve as preferred with the suspension type slow releasing injection, the suspension type slow releasing injection is the preparation that the drug sustained release system that will contain anticancer component is suspended in gained in the injection, used adjuvant is a kind of or its combination in the above-mentioned slow-release auxiliary material, and used solvent is common solvent or the special solvent that contains suspending agent.Common solvent is, but is not limited to the buffer that distilled water, water for injection, physiology are prepared towards liquid, dehydrated alcohol or various salt.The purpose of suspending agent is the pastille microsphere that effectively suspends, thereby is beneficial to the usefulness of injection.
Anticancer effective component is mainly bendamustine and its synergist.When the cancer therapy drug in the medicament slow-release microsphere only is bendamustine or bendamustine synergist, slow-releasing anticarcinogen injection is mainly used in the bendamustine synergist of other approach application of increase or the action effect of bendamustine, or is used for the potentiation to radiotherapy or other therapies.When the cancer therapy drug in the medicament slow-release microsphere only was bendamustine or its synergist, the application of slow-releasing anticarcinogen injection and potentiation mode were:
(1) local injection contains the slow releasing injection of bendamustine and the bendamustine synergist associating that other approach are used;
(2) local injection contains the slow releasing injection of bendamustine synergist and the bendamustine associating that other approach are used; Or
(3) local injection contains the associating of the slow releasing injection that contains bendamustine of the slow releasing injection of bendamustine synergist and topical application.
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.
The percentage by weight of cancer therapy drug in sustained-release micro-spheres is 0.5%-60%, is good with 2%-40%, is best with 5%-30%.During bendamustine and its synergist (steroids anti-cancer drugs and/or alkylating agent) use in conjunction, the weight ratio of bendamustine and alkylating agent and/or steroids anti-cancer drugs is for for 1-9: 1 to 1: 1-9, with 1-2: 1 serves as preferred.
Microsphere is used to prepare slow releasing injection, as suspension type slow releasing injection, gel injection, block copolymer micelle injection.In various injections, serve as preferred with the suspension type slow releasing injection.The suspension type slow releasing injection is to contain the medicament slow-release microsphere of effective composition or the preparation that drug microparticles is suspended in gained in the solvent, and used adjuvant is a kind of or its combination in the above-mentioned slow-release auxiliary material, and used solvent is common solvent or the special solvent that contains suspending agent.Common solvent is, but is not limited to the buffer that distilled water, water for injection, physiology are prepared towards liquid, dehydrated alcohol or various salt; 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 at 1-300um, but is preferred with 20-200um, and 30-150um most preferably; 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, in various high molecular polymers, be main separation, as polifeprosan with the high molecular weight water soluble polymer, bis-fatty acid and decanedioic acid copolymer (PFAD-SA), poly-(erucic acid dimer-decanedioic acid) [P (EAD-SA)], poly-(fumaric acid-decanedioic acid) [P (FA-SA)], ethylene vinyl acetate copolymer (EVAc), polylactic acid (PLA), the copolymer of polyglycolic acid and hydroxyacetic acid (PLGA), xylitol, oligosaccharide, chrondroitin, chitin, hyaluronic acid, collagen protein, one of gelatin and white tempera or its combination.
Preferred 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 55-90%;
(2) PLGA of 50-90%;
(3) polifeprosan of 50-85%;
(4) bis-fatty acid of 55-90% and decanedioic acid copolymer;
(5) EVAc of 55-90%;
(6) xylitol of 40-95%, oligosaccharide, chrondroitin, chitin, hyaluronic acid, collagen protein, gelatin or albumin glue; Or
(7) poly-dl-lactide of 40-95%, poly-dl-lactide/ethanol copolymer, monomethyl polyethylene glycol, monomethyl polyethylene glycol copolymer, polyethylene glycol, polyethylene glycol copolymer, end carboxyl polylactic acid or end carboxyl polylactic acid/ethanol copolymer.
Therefore, 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, as, but be not limited to capsule, slow releasing agent, implant, slow releasing agent implant etc.; Be multiple shape, as, but be not limited to granule, pill, tablet, powder, sphere, bulk, needle-like, bar-shaped, column and membranaceous.In various dosage forms, serve as preferred slowly to discharge implant in the body.
The most preferred dosage form of sustained-release implant is the slow releasing agent implant that biocompatibility, degradable absorb, and can make different shape and various dosage form because of the clinical needs of difference.The packing method of its Main Ingredients and Appearance and step in United States Patent (USP) (US5651986) have a detailed description, comprise the some kinds of methods that prepare slow releasing preparation: as, but be not limited to, (i) carrier holder powder and medicament mixed be pressed into implant then, promptly so-called mixing method; (ii) carrier holder fusing, mix solid cooled then, promptly so-called fusion method mutually with medicine to be packaged; (iii) the carrier holder is dissolved in the solvent, medicine dissolution to be packaged or be scattered in the polymer solution, evaporating solvent then, drying, promptly so-called dissolution method; (iv) spray drying method; And (v) freeze-drying etc.
The application of anti-cancer sustained-released implantation agent and the same slow releasing injection of potentiation mode, the same slow releasing injection of the anticancer effective component of sustained-release implant and percentage by weight thereof, but be preferably:
(1) combination of the cyclophosphamide of the bendamustine of 1-40% and 1-40%, melphalan, Chlorambucil, ifosfamide, 4H-peroxide cyclophosphamide, defosfamide, Mafosfamide, perfosfamide, hexamethylmelamine, cantharidin, norcantharidin, mannomustine, treosulfan, ritrosulfan, an improsulfan, etoglucid, pipobroman, piposulfan, triethylenemelaine, epoxypiperazine, benzene assistant TEPA, Phopurine, meturedepa, urethimine or Ah bundle's TEPA; Or
(2) triptorelin of the bendamustine of 1-40% and 1-40%, goserelin, leuprorelin, Anastrozole, idoxifene, Miproxifene, tamoxifen, 4-monohydroxy tamoxifen, not former times sweet smell, raloxifene, ICI-M 164384, anticancer steroid alkene phenol, 4-trans-Hydroxytamoxifen, Drogenil, aminoglutethimide, (.+-.)-Pyridoglutethimide, megestrol, medroxyprogesterone, clomifene, toremifene, letrozole, Anastrozole, exemestane or the combination of bicalutamide.
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.In addition, the effective ingredient of anti-cancer sustained-released implantation agent also can be packaged in the liposome equably, or makes microsphere with art methods.
Anticancer implant is multiple shape, as, but be not limited to granule, tablet, powder, sphere, bulk, needle-like, bar-shaped, column and membranaceous.Its most preferred dosage form is the implantation slow release agent that biocompatibility, degradable absorb, and can make different shape and various dosage form because of the clinical needs of difference, as, but be not limited to slow releasing agent implant, granule, capsule, ball, ball, diffusing, excellent.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 anti-cancer sustained-released implantation agent of the present invention and percentage by weight are preferably as slow releasing injection.When the cancer therapy drug in the medicament slow-release microsphere only is bendamustine or its synergist, the application of anti-cancer sustained-released implantation agent and the same slow releasing injection of potentiation mode.
Anti-cancer sustained-released implantation agent of the present invention can give through number of ways, in number of ways, with topical, as with in selective arterial, intracavity, the tumor, tumor week be placed as the master, with in the tumor, the form that slowly discharges of tumor week or tumor chamber serve as preferably, directly to be placed as the best in the tumor body.
The consumption of cancer therapy drug depends on several factors, as, but be not limited to gross tumor volume, patient body weight, administering mode, disease progression situation and therapeutic response.Generally speaking, bendamustine and synergist thereof can be 0.01-1000 milligram/kg body weight, with 1-800 milligram/kg body weight is ideal, with 5-80 milligram/kg body weight for the most desirable, hormone anti-cancer medicine can be 0.01-500 milligram/kg body weight, with 1-100 milligram/kg body weight is ideal, with 5-50 milligram/kg body weight for the most desirable.
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.
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.When the cancer therapy drug in the medicament slow-release microsphere only is bendamustine or its synergist, the application of anti-cancer sustained-released implantation agent and the same slow releasing injection of potentiation mode.
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 alkylating agent (melphalan) 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 5mg/kg melphalan.Measure medicament contg (%) in the different time tumor, the result shows, the local drug concentration significant difference of melphalan 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.
Tumor-inhibiting action relatively in the body of the medicine (bendamustine) that test 2, different modes are used
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 5mg/kg bendamustine.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 bendamustine 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.Make repeated experiments with bendamustine, get same experimental result.
The tumor-inhibiting action of test 3, bendamustine and its synergist
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 matched group and treatment group (1-11).The treatment component is bendamustine and bendamustine synergist group.Drug dose is 5mg/kg, and bendamustine is through intratumor injection, and the bendamustine synergist is through lumbar injection.The treatment back was measured gross tumor volume size, relatively therapeutic effect (seeing Table 1) on the 10th day.
Table 1
| Group | Bendamustine | Synergist | Tumor control rate (%) | The P value |
| 1 | + | - | 40 | * |
| 2 | - | Triptorelin | 42 | * |
| 3 | - | Goserelin | 38 | * |
| 4 | - | Leuprorelin | 40 | * |
| 5 | - | Anastrozole | 42 | * |
| 6 | - | Idoxifene | 32 | * |
| 7 | + | Triptorelin | 68 | ** |
| 8 | + | Goserelin | 80 | ** |
| 9 | + | Leuprorelin | 80 | ** |
| 10 | + | Anastrozole | 76 | ** |
| 11 | + | Idoxifene | 82 | ** |
Above result shows, bendamustine and used bendamustine synergist (triptorelin, goserelin, leuprorelin, Anastrozole, idoxifene) all have significant inhibitory effect (*: the P value is less than 0.05) to tumor growth when this concentration is used separately, can show the potentiation (* *: the P value is less than 0.001) of highly significant when use in conjunction.
The tumor-inhibiting action of test 4, bendamustine and bendamustine 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.Bendamustine and 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 | Bendamustine | A | B | C | D | E | Bendamustine+A | Bendamustine+B | Bendamustine+C | Bendamustine+D | Bendamustine+E |
| CNS | 30 | 50 | 56 | 38 | 52 | 42 | 82 | 70 | 86 | 88 | 88 |
| C6 | 22 | 52 | 46 | 36 | 64 | 40 | 90 | 84 | 84 | 84 | 90 |
| SA | 26 | 52 | 58 | 42 | 62 | 42 | 84 | 84 | 80 | 82 | 86 |
| BC | 36 | 58 | 40 | 44 | 50 | 54 | 88 | 82 | 78 | 76 | 84 |
| BA | 18 | 48 | 38 | 48 | 60 | 56 | 82 | 80 | 90 | 90 | 82 |
| LH | 26 | 56 | 44 | 54 | 58 | 60 | 92 | 80 | 94 | 76 | 84 |
| PAT | 30 | 54 | 50 | 52 | 50 | 62 | 80 | 78 | 82 | 88 | 84 |
Above result shows, used bendamustine and bendamustine synergist (A wherein: Miproxifene, B: tamoxifen, C: not former times sweet smell, D: raloxifene, E: ICI-M 164384) growth all has the obvious suppression effect to kinds of tumor cells when this concentration is used separately, can show significant potentiation when use in conjunction.
The tumor-inhibiting action of test 5, bendamustine and bendamustine 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.Bendamustine and bendamustine 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.The result shows, growth all has obvious suppression effect (P＜0.05) to kinds of tumor cells when using separately for used bendamustine and bendamustine synergist (cyclophosphamide, melphalan, Chlorambucil, ifosfamide, 4H-peroxide cyclophosphamide), can show significant potentiation (P＜0.01) when use in conjunction.Further test shows, so obvious synergistic effect also sees the combination of bendamustine and defosfamide, Mafosfamide, perfosfamide, hexamethylmelamine, cantharidin, norcantharidin, mannomustine, treosulfan, ritrosulfan, an improsulfan, etoglucid, pipobroman, piposulfan, triethylenemelaine, epoxypiperazine, benzene assistant TEPA, Phopurine, meturedepa, urethimine or Ah bundle's TEPA.
The tumor-inhibiting action of test 6, bendamustine and bendamustine 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 negative control (blank), single therapy group (bendamustine or bendamustine synergist) and therapeutic alliance group (bendamustine and bendamustine 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 of index with inhibition rate of tumor growth.The result shows, growth all has obvious suppression effect (P＜0.05) to kinds of tumor cells when using separately for used bendamustine and bendamustine synergist (hexamethylmelamine, cantharidin, norcantharidin, mannomustine), can show significant potentiation (P＜0.01) when use in conjunction.Further test shows, so obvious synergistic effect also sees the combination of bendamustine and mannomustine, treosulfan, ritrosulfan, an improsulfan, etoglucid, pipobroman, piposulfan, triethylenemelaine, epoxypiperazine, benzene assistant TEPA, Phopurine, meturedepa, urethimine or Ah bundle's TEPA.
The tumor-inhibiting action of test 7, bendamustine and bendamustine synergist (sustained-release implant)
With the rat is subjects, with 2 * 10
5Individual breast tumor cell subcutaneous injection is in its hypochondrium, treats that tumor growth after 14 days is divided into it negative control (blank), single therapy group, therapeutic alliance group.Sustained-release implant is placed in tumor.Dosage is 5mg/kg.The treatment back was measured the gross tumor volume size on the 10th day, made relatively therapeutic effect (seeing Table 3) of index with inhibition rate of tumor growth.
Table 3
| Test group (n) | Suffered treatment | Tumor control rate (%) | The P value |
| 1(6) | Contrast | - | |
| 2(6) | Bendamustine | 52 | ＜0.05 |
| 3(6) | Defosfamide | 46 | ＜0.05 |
| 4(6) | Mafosfamide | 38 | ＜0.05 |
| 5(6) | Perfosfamide | 42 | ＜0.05 |
| 6(6) | Hexamethylmelamine | 38 | ＜0.01 |
| 7(6) | Bendamustine+defosfamide | 70 | ＜0.01 |
| 8(6) | Bendamustine+Mafosfamide | 84 | ＜0.01 |
| 9(6) | Bendamustine+perfosfamide | 84 | ＜0.01 |
| 10(6) | Bendamustine+hexamethylmelamine | 82 | ＜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 bendamustine and bendamustine synergist (defosfamide, Mafosfamide, perfosfamide, hexamethylmelamine), can show significant potentiation when use in conjunction.
The tumor-inhibiting action of test 8, bendamustine and bendamustine synergist (sustained-release implant)
By test 7 described methods, with the tumor-inhibiting action of pancreatic cancer cell mensuration bendamustine and bendamustine synergist (sustained-release implant), its inhibition rate of tumor growth sees Table 4.
Table 4
| Test group (n) | Suffered treatment | Tumor control rate (%) | The P value |
| 1(6) | Contrast | - | |
| 2(6) | Bendamustine | 50 | ＜0.05 |
| 3(6) | Triptorelin | 52 | ＜0.01 |
| 4(6) | Goserelin | 54 | ＜0.01 |
| 5(6) | Leuprorelin | 60 | ＜0.01 |
| 6(6) | Anastrozole | 52 | ＜0.01 |
| 7(6) | Bendamustine+triptorelin | 80 | ＜0.001 |
| 8(6) | Bendamustine+goserelin | 82 | ＜0.001 |
| 9(6) | Bendamustine+leuprorelin | 72 | ＜0.001 |
| 10(6) | Bendamustine+Anastrozole | 80 | ＜0.001 |
Above result shows, growth all has the obvious suppression effect to kinds of tumor cells when this concentration is used separately for used bendamustine and bendamustine synergist (triptorelin, goserelin, leuprorelin, Anastrozole), can show significant potentiation when use in conjunction.
The tumor-inhibiting action of test 9, bendamustine and bendamustine synergist (sustained-release implant)
By test 7 described methods, with the tumor-inhibiting action of colon cancer cell mensuration bendamustine and bendamustine synergist (sustained-release implant), its inhibition rate of tumor growth sees Table 5.
Table 5
| Test group (n) | Suffered treatment | Tumor control rate (%) | The P value |
| 1(6) | Contrast | - | |
| 2(6) | Bendamustine | 50 | ＜0.05 |
| 3(6) | Idoxifene | 48 | ＜0.01 |
| 4(6) | Miproxifene | 34 | ＜0.01 |
| 5(6) | Tamoxifen | 42 | ＜0.01 |
| 6(6) | Sutent | 50 | ＜0.01 |
| 7(6) | Bendamustine+idoxifene | 78 | ＜0.01 |
| 8(6) | Bendamustine+Miproxifene | 82 | ＜0.001 |
| 9(6) | Bendamustine+tamoxifen | 82 | ＜0.001 |
| 10(6) | Bendamustine+Sutent | 78 | ＜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 bendamustine and bendamustine synergist (idoxifene, Miproxifene, tamoxifen, Sutent), can show significant potentiation when use in conjunction.
The tumor-inhibiting action of test 10, bendamustine and bendamustine synergist (slow releasing injection)
By test 6 described methods, measure the tumor-inhibiting action of bendamustine and bendamustine synergist (slow releasing injection) with lung carcinoma cell, the result shows that bendamustine can significantly strengthen triptorelin, goserelin, leuprorelin, Anastrozole, idoxifene, Miproxifene, tamoxifen, 4-monohydroxy tamoxifen, not former times sweet smell, raloxifene, ICI-M 164384, anticancer steroid alkene phenol, the 4-trans-Hydroxytamoxifen, Drogenil, aminoglutethimide, (.+-.)-Pyridoglutethimide, megestrol, medroxyprogesterone, clomifene, toremifene, letrozole, the tumor killing effect of bendamustine such as exemestane or bicalutamide synergist, potentiation is in 50-88% (P＜0.01).
In a word, growth all had the obvious suppression effect to kinds of tumor cells when used bendamustine and various bendamustine synergist were used separately, can show significant potentiation when use in conjunction.Therefore, effective ingredient of the present invention is the combination of bendamustine and/or any one bendamustine synergist.The medicine that contains above effective ingredient can be made into sustained-release micro-spheres, and then make slow releasing injection and implant, serve as preferred wherein with the suspensoid injectio that is combined to form with the special solvent that contains suspending agent, the viscosity of the solvent of suspensoid injectio is 10cp-650cp (20 ℃-30 ℃ time), preferred 20cp-650cp (20 ℃-30 ℃ time), most preferably 60cp-650cp (20 ℃-30 ℃ time).
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): decanedioic acid (SA) is 20: 80) copolymer is put into container, add the 100ml dichloromethane, behind the dissolving mixing, add 10mg bendamustine and 10mg melphalan, shake up the back contains 10% bendamustine and 10% melphalan with spray drying method for preparation injectable microsphere again.Then microsphere is suspended in the normal saline that contains 15% mannitol, makes corresponding suspension type slow releasing injection, viscosity is 20cp-300cp (20 ℃-30 ℃ time).The drug release time of this slow releasing injection in external normal saline is 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: the bendamustine of 1-40% and the cyclophosphamide of 1-40%, melphalan, Chlorambucil, ifosfamide, 4H-peroxide cyclophosphamide, defosfamide, Mafosfamide, perfosfamide, hexamethylmelamine, cantharidin, norcantharidin, mannomustine, treosulfan, ritrosulfan, an improsulfan, etoglucid, pipobroman, piposulfan, triethylenemelaine, epoxypiperazine, benzene assistant TEPA, Phopurine, meturedepa, the combination of urethimine or Ah bundle's TEPA;
Used adjuvant is: poly-dl-lactide, poly-dl-lactide/ethanol copolymer, monomethyl polyethylene glycol, monomethyl polyethylene glycol copolymer, polyethylene glycol, polyethylene glycol copolymer, end carboxyl polylactic acid or end carboxyl polylactic acid/ethanol copolymer; The viscosity of slow releasing injection is 10cp-650cp (20 ℃-30 ℃ time).
Embodiment 3.
With 70mg molecular weight peak value is that 25000 polylactic acid (PLGA, 75: 25) is put into container, adds 100 milliliters of dichloromethane, behind the dissolving mixing, adds 15mg bendamustine and 15mg cyclophosphamide, 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% bendamustine and 15% cyclophosphamide, be suspended in then in the normal saline that contains 1.5% sodium carboxymethyl cellulose, make corresponding suspension type slow releasing injection, viscosity is 220cp-340cp (20 ℃-30 ℃ time).The drug release time of this slow releasing injection in external normal saline is 10-15 days, is about 20-30 days at the subcutaneous drug release time of mice.
Embodiment 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 combination of the bendamustine of 1-40% and the cyclophosphamide of 1-40%, melphalan, Chlorambucil, ifosfamide, 4H-peroxide cyclophosphamide, defosfamide, Mafosfamide, perfosfamide, hexamethylmelamine, cantharidin, norcantharidin, mannomustine, treosulfan, ritrosulfan, an improsulfan, etoglucid, pipobroman, piposulfan, triethylenemelaine, epoxypiperazine, benzene assistant TEPA, Phopurine, meturedepa, urethimine or Ah bundle's TEPA;
Used adjuvant is: poly-dl-lactide, poly-dl-lactide/ethanol copolymer, monomethyl polyethylene glycol, monomethyl polyethylene glycol copolymer, polyethylene glycol, polyethylene glycol copolymer, end carboxyl polylactic acid or end carboxyl polylactic acid/ethanol copolymer; The viscosity of slow releasing injection is 100cp-690cp (20 ℃-30 ℃ time).
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 bendamustines and 10 milligrams of tamoxifens, shake up the back contains 20% bendamustine and 10% tamoxifen 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-160cp (25 ℃-30 ℃ time).The drug release time of this slow releasing injection in external normal saline is 10-15 days, is about 20-30 days at the subcutaneous drug release time of mice.
Embodiment 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 bendamustine of 1-40% and the triptorelin of 1-40%, goserelin, leuprorelin, Anastrozole, idoxifene, Miproxifene, tamoxifen, 4-monohydroxy tamoxifen, not former times sweet smell, raloxifene, ICI-M 164384, anticancer steroid alkene phenol, the 4-trans-Hydroxytamoxifen, Drogenil, aminoglutethimide, (.+-.)-Pyridoglutethimide, megestrol, medroxyprogesterone, clomifene, toremifene, letrozole, Anastrozole, the combination of exemestane or bicalutamide; The viscosity of slow releasing injection is 10cp-650cp (20 ℃-30 ℃ time).
Embodiment 7.
70mg polifeprosan (to carboxy phenyl propane (p-CPP): decanedioic acid (SA) is 20: 80) copolymer is put into container, add 100 milliliters of dichloromethane, behind the dissolving mixing, add 20mg bendamustine and 10mg letrozole, shake up the back contains 20% bendamustine and 10% letrozole with spray drying method for preparation injectable microsphere again.Microsphere is suspended in the normal saline that contains 1.5% sodium carboxymethyl cellulose and 0.5% Tween 80 then, makes corresponding suspension type slow releasing injection, viscosity is 180cp-260cp (25 ℃-30 ℃ time).The drug release time of this slow releasing injection in external normal saline is 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 bendamustine of 5-30% and the triptorelin of 10-20%, goserelin, leuprorelin, Anastrozole, idoxifene, Miproxifene, tamoxifen, not former times sweet smell, raloxifene, ICI-M 164384, anticancer steroid alkene phenol, 4-trans-Hydroxytamoxifen, Drogenil, aminoglutethimide, (.+-.)-Pyridoglutethimide, megestrol, medroxyprogesterone, clomifene, toremifene, letrozole, Anastrozole, exemestane or the combination of bicalutamide; Viscosity is 400cp-560cp (25 ℃-30 ℃ time).
Embodiment 9
70mg polifeprosan (to carboxy phenyl propane (p-CPP): decanedioic acid (SA) is 20: 80) copolymer is put into container, add 100 milliliters of dichloromethane, behind the dissolving mixing, add 20mg bendamustine and 10mg goserelin, shake up the back contains 20% bendamustine and 10% goserelin with spray drying method for preparation injectable microsphere again.Then microsphere is suspended in the normal saline that contains 1.5% sodium carboxymethyl cellulose and 15% sorbitol and 0.2% Tween 80, makes corresponding suspension type slow releasing injection, viscosity is 100cp-160cp (25 ℃-30 ℃ time).The drug release time of this slow releasing injection in external normal saline is 10-15 days, is about 20-30 days at the subcutaneous drug release time of mice.
Embodiment 10
The method step that is processed into slow releasing injection is identical with embodiment 9, but different is that contained anticancer effective component is: 20% bendamustine and 10% triptorelin, goserelin, leuprorelin, Anastrozole, idoxifene, Miproxifene, tamoxifen, not former times sweet smell, raloxifene, ICI-M 164384, anticancer steroid alkene phenol, 4-trans-Hydroxytamoxifen, Drogenil, aminoglutethimide, (.+-.)-Pyridoglutethimide, megestrol, medroxyprogesterone, clomifene, toremifene, letrozole, Anastrozole, exemestane or the combination of bicalutamide; Viscosity is 560cp-640cp (25 ℃-30 ℃ time).
Embodiment 11
70mg polifeprosan (to carboxy phenyl propane (p-CPP): decanedioic acid (SA) is 20: 80) copolymer is put into container, add 100 milliliters of dichloromethane, behind the dissolving mixing, add 10mg bendamustine and 20mg leuprorelin, shake up the back contains 10% bendamustine and 20% leuprorelin 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 used slow-release auxiliary material is: the bis-fatty acid of 60-95% and decanedioic acid copolymer (PFAD-SA), poly-(erucic acid dimer-decanedioic acid) [P (EAD-SA)] or poly-(fumaric acid-decanedioic acid) [P (FA-SA)].
Embodiment 13
With 70mg molecular weight peak value 35000 polylactic acid (PLGA, 50: 50) put into container, add 100 milliliters of dichloromethane, behind the dissolving mixing, add 10mg bendamustine and 20mg melphalan, shake up the back contains 10% bendamustine and 20% melphalan 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 and percentage by weight are:
(1) combination of the cyclophosphamide of the bendamustine of 1-40% and 1-40%, melphalan, Chlorambucil, ifosfamide, 4H-peroxide cyclophosphamide, defosfamide, Mafosfamide, perfosfamide, hexamethylmelamine, cantharidin, norcantharidin, mannomustine, treosulfan, ritrosulfan, an improsulfan, etoglucid, pipobroman, piposulfan, triethylenemelaine, epoxypiperazine, benzene assistant TEPA, Phopurine, meturedepa, urethimine or Ah bundle's TEPA; Or
(2) triptorelin of the bendamustine of 1-40% and 1-40%, goserelin, leuprorelin, Anastrozole, idoxifene, Miproxifene, tamoxifen, 4-monohydroxy tamoxifen, not former times sweet smell, raloxifene, ICI-M 164384, anticancer steroid alkene phenol, 4-trans-Hydroxytamoxifen, Drogenil, aminoglutethimide, (.+-.)-Pyridoglutethimide, megestrol, medroxyprogesterone, clomifene, toremifene, letrozole, Anastrozole, exemestane or the combination of bicalutamide.
Embodiment 15
The method step that is processed into slow releasing agent is identical with embodiment 1-14, but different is used slow-release auxiliary material is one of following or its combination:
A) polylactic acid (PLA), the molecular weight peak value is 10000-30000,300000-60000,60000-100000 or 100000-150000;
B) copolymer of polyglycolic acid and hydroxyacetic acid (PLGA), wherein, the ratio of polyglycolic acid and hydroxyacetic acid is 50-95: 5050, the molecular weight peak value is 10000-30000,300000-60000,60000-100000 or 100000-150000;
C) ethylene vinyl acetate copolymer (EVAc);
D) polifeprosan, to carboxy phenyl propane (p-CPP): decanedioic acid (SA) is 10: 90,20: 80,30: 70,40: 60,50: 50 or 60: 40;
E) bis-fatty acid and decanedioic acid copolymer (PFAD-SA);
F) poly-(erucic acid dimer-decanedioic acid) [P (EAD-SA)];
G) poly-(fumaric acid-decanedioic acid) [P (FA-SA)];
H) xylitol, oligosaccharide, chrondroitin, chitin, hyaluronic acid, collagen protein, gelatin or white tempera;
I) poly-dl-lactide, poly-dl-lactide/ethanol copolymer, monomethyl polyethylene glycol, monomethyl polyethylene glycol copolymer, polyethylene glycol, polyethylene glycol copolymer, end carboxyl polylactic acid or end carboxyl polylactic acid/ethanol copolymer.
Embodiment 16
The method step that is processed into slow releasing injection is identical with embodiment 1-10, but different is used suspending agent is respectively one of following or its combination:
A) 0.5-3.0% carboxymethyl cellulose (sodium):
B) 5-15% mannitol;
C) 5-15% sorbitol;
D) 0.1-1.5% surfactant;
E) 0.1-0.5% polysorbas20.
Above embodiment only is used for explanation, and is not limitation application of the present invention.
The present invention disclosed and the protection the content see claim.
Claims (6)
1. one kind contains the compound anti-cancer slow-release injected of bendamustine, is grouped into by following one-tenth:
(A) sustained-release micro-spheres comprises:
Anticancer effective component 0.5-60%
Slow-release auxiliary material 41-99.9%
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 the combination of bendamustine and bendamustine synergist, and the bendamustine synergist is a steroids anti-cancer drugs;
Described steroids anti-cancer drugs is selected from one of aminoglutethimide, letrozole, Anastrozole or exemestane 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;
H) xylitol, oligosaccharide, chrondroitin, chitin, hyaluronic acid, collagen protein, gelatin or white tempera;
I) poly-dl-lactide, poly-dl-lactide/ethanol copolymer, monomethyl polyethylene glycol, monomethyl polyethylene glycol copolymer, polyethylene glycol, polyethylene glycol copolymer, end carboxyl polylactic acid or end carboxyl polylactic acid/ethanol copolymer;
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, the percentage by weight that it is characterized in that bendamustine and bendamustine synergist is 1-9: 1 to 1: 1-9.
3. the slow-releasing anticarcinogen injection according to claim 1 is characterized in that the anticancer effective component of slow-releasing anticarcinogen injection is:
The combination of the bendamustine of 1-40% and the aminoglutethimide of 1-40%, letrozole, Anastrozole or exemestane.
4. 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 20% bendamustine and 10% letrozole, and slow-release auxiliary material is to carboxy phenyl propane: decanedioic acid is 20: 80 a polifeprosan, and solvent is the normal saline that contains 1.5% sodium carboxymethyl cellulose and 0.5% Tween 80;
Below all be weight percentage.
5. the slow-releasing anticarcinogen injection according to claim 1 is characterized in that described pharmaceutical preparation is the sustained-release implant that sustained-release micro-spheres is made, in tumor or tumor week injection or place administration.
6. the anti-cancer sustained-released implantation agent according to claim 5 is characterized in that anticancer effective component and percentage by weight thereof that described sustained-release implant is used are:
The combination of the bendamustine of 1-40% and the aminoglutethimide of 1-40%, letrozole, Anastrozole or exemestane.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2010126676A1 (en) * | 2009-04-28 | 2010-11-04 | Cephalon, Inc. | Oral formulations of bendamustine |
| US8383663B2 (en) | 2010-07-19 | 2013-02-26 | Supratek Pharma Inc. | Bendamustine anionic-catioinic cyclopolysaccharide compositions |
| US8389558B2 (en) | 2009-07-20 | 2013-03-05 | Supratek Pharma Inc. | Bendamustine amphiphilic anionic compositions |
| US8436032B2 (en) | 2009-02-25 | 2013-05-07 | Supratek Pharma Inc. | Bendamustine cyclopolysaccharide compositions |
-
2008
- 2008-01-28 CN CNA2008103002395A patent/CN101219113A/en active Pending
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US8436032B2 (en) | 2009-02-25 | 2013-05-07 | Supratek Pharma Inc. | Bendamustine cyclopolysaccharide compositions |
| US8703964B2 (en) | 2009-02-25 | 2014-04-22 | Supratek Pharma Inc. | Bendamustine cyclopolysaccharide compositions |
| WO2010126676A1 (en) * | 2009-04-28 | 2010-11-04 | Cephalon, Inc. | Oral formulations of bendamustine |
| US8389558B2 (en) | 2009-07-20 | 2013-03-05 | Supratek Pharma Inc. | Bendamustine amphiphilic anionic compositions |
| US8383663B2 (en) | 2010-07-19 | 2013-02-26 | Supratek Pharma Inc. | Bendamustine anionic-catioinic cyclopolysaccharide compositions |
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