CN101390833A - Anti-cancer slow-release formulation loaded with carmustine and synergist thereof - Google Patents
Anti-cancer slow-release formulation loaded with carmustine and synergist thereof Download PDFInfo
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Abstract
Disclosed is an anticancer sustainable-release agent, which contains the combination of carmustine and carmustine synergist. The anticancer sustainable-release agent is injection and implantation agent; the sustainable-release injection contains sustainable-release microspheres which contain effective anticancer ingredients and sustainable-release auxiliary material, and special solvent which contains suspending agent; the viscosity of injection is 50cp-1000cp(20 DEG C-30 DEG C); the suspending agent is selected from one or the combination of the followings, sodium carboxymethyl cellulose, mannitol, sorbitol, tween 80. The sustained-release auxiliary material is selected from copolymer of the combination of the followings, polylactic acid, ethylene vinyl acetate copolymer, polifeprosan, FAD: sebacic acid copolymer, polyglycolic acid and glycolic acid; the sustained-release auxiliary material is high-molecular polymer with biological capability and degradable absorption; the effective anticancer ingredients can be sustainably released on the local part of tumor during the degradable absorption process of the sustained-release auxiliary material so that the systemic toxic reaction caused by the sustained-release agent is obviously reduced; meanwhile, the effective medicine concentration is maintained in local part of the tumor.
Description
(1) technical field
The present invention relates to belong to technical field of pharmaceuticals with the anticancer sustained-release agent that carries carmustine and fluorouracil.Be mainly slow releasing injection and sustained-release implant.
(2) background technology
Though the research about cancer has obtained bigger progress, its mortality rate still occupies the prostatitis of the various common causes of the death.In China 1,600,000 people's cancer strickens are arranged approximately every year, nearly 1,300,000 people die from cancer, account for 1/5th of total death toll.Cancer morbidity rises year by year and is rejuvenation trend, has data to show that in less than the time in 20 years, China's cancer morbidity has risen 69%, and mortality rate has increased by 29.4%.According to World Health Organization's recent statistics, will increase by 50 percent to the year two thousand twenty whole world cancer morbidity, number of the infected increases to 15,000,000.Therefore, inquire into the focus that a kind of effective treatment method for cancer or medicine have become present research.
Carmustine (BCNU) is as one of choice drug of the new treatment cerebral tumor, and more show with the experience of the BCNU local sustained release treatment cerebral tumor, topical remedy's slow release has guaranteed stable lastingly and drug level in local application's scope, reduced systemic drug concentration, alleviate toxic and side effects, brought hope for the glioma chemotherapy.Why use BCNU, particularly local sustained release BCNU treats the cerebral tumor, its rationale is: (1) is owing to be subjected to the restriction of blood brain barrier, many chemotherapeutics can not enter in the brain when conventional intravenous chemotherapy or drug level is difficult to reach or keeps long-time valid density, by contrast, it is less that BCNU is subjected to the restriction of blood brain barrier; (2) 90% patient is in operation inherent local (in the 2cm) recurrence in back 1 year; (3) BCNU has high relatively selectivity as the medicine of the most frequently used treatment cerebral tumor to the cerebral tumor.
Yet BCNU it be unclear that the effect of other tumor.
(3) summary of the invention
Based on above examination to prior art, the present invention compares the cerebral tumor and the outer tumor of some cranium, found that carmustine has comparatively significantly action effect to entity tumors such as bone tumor, thymic carcinoma, lymphoma, hepatocarcinoma, pulmonary carcinoma, the esophageal carcinoma, gastric cancer, breast carcinoma, cancer of pancreas, bladder cancer, carcinoma of testis, colon cancer and rectal cancer.Discover that further the BCNU local sustained release also has good therapeutical effect to other entity tumors such as thyroid carcinoma, nasopharyngeal carcinoma, ovarian cancer, carcinoma of endometrium, cervical cancer, renal carcinoma and carcinoma of prostate.
Though many entity tumors are not poor to the sensitivity of carmustine, are easy to generate drug resistance in therapeutic process.Its main cause is to be difficult to tumor by local to obtain and keep active drug concentration.Simple raising whole body dosage is subjected to the restriction of general toxic reaction again.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.
The present invention finds that medicine of mentioning among the present invention and carmustine share and can make its antitumaous effect strengthen (the following medicine that the carmustine antitumaous effect will be increased mutually is referred to as the carmustine synergist) mutually.In addition, with the assembly packaging of carmustine or carmustine and its synergist in specific slow-release auxiliary material and be equipped with special solvent and make drug level that anti-cancer medicine sustained-release injection not only can greatly improve tumor by local, reduce the drug level of medicine in blood circulation, reduce the toxicity of medicine to normal structure, can also greatly make things convenient for the medicine injection, reduce operation technique complication, reduce patient's expense.The decapacitation of carmustine synergist suppresses can also increase the sensitivity of tumor cell to cancer therapy drug outside the tumor growth.
The present invention finds, is not that all adjuvants can both effectively discharge BCNU.Pharmaceutic adjuvant have hundreds of more than, pharmaceutic adjuvant with slow releasing function, particularly the pharmaceutic adjuvant that selected carmustine among the present invention slowly can be discharged in the regular hour in human body or animal body must could obtain through a large amount of creationary experiments, specific slow-release auxiliary material and can need be passed through a large amount of creative works by the selection of the combination of slow releasing pharmaceutical and could determine.The data of release characteristics need could obtain through a large amount of creationary experiments in inside and outside in the related data, particularly animal body, are not just can determine to have unobviousness through limited experiment.
Topical remedy's slow release in the stable lastingly and drug level, has obviously reduced systemic drug concentration in having guaranteed local application's scope, alleviated toxic and side effects.
The present invention treats the slow releasing agent of entity tumor, comprise anticancer effective component and medicinal slow-release auxiliary material, wherein anticancer effective component be carmustine (BCNU, Carmustine) or carmustine and be selected from the combination of the carmustine synergist of cisplatin, fluorouracil or O6-benzyl guanine (O6-BG).
Medicinal slow-release auxiliary material comprises one of following or its combination: poly-dl-lactide, poly-dl-lactide/ethanol copolymer, the monomethyl polyethylene glycol, monomethyl polyethylene glycol copolymer, polyethylene glycol, the polyethylene glycol copolymer, end carboxyl polylactic acid, end carboxyl polylactic acid/ethanol copolymer, polifeprosan, bis-fatty acid and decanedioic acid copolymer, poly-(erucic acid dimer-decanedioic acid), poly-(fumaric acid-decanedioic acid), ethylene vinyl acetate copolymer, polylactic acid, the copolymer of polyglycolic acid and hydroxyacetic acid, xylitol, oligosaccharide, chrondroitin, chitin, hyaluronic acid, collagen protein, one of gelatin and albumin glue or its combination.
In various high molecular polymers, with polylactic acid, decanedioic acid, the mixture or the copolymer that contain the macromolecule polymer of polylactic acid or certain herbaceous plants with big flowers diacid is first-selection, mixture and copolymer can be selected from, but be not limited to the mixture or the copolymer of the mixture of PLA, PLGA, glycolic and hydroxy carboxylic acid, certain herbaceous plants with big flowers diacid and fragrant polyanhydride or aliphatic polyanhydride.The blend ratio of glycolic and hydroxy carboxylic acid is 10/90-90/10 (weight), preferably 25/75-75/25 (weight).The method of blend is arbitrarily.Content when glycolic and hydroxy carboxylic acid copolymerization is respectively percentage by weight 10-90% and 90-10%.The representative of fragrance polyanhydride is polifeprosan [poly-(1,3-two (to the carboxyl phenoxy group) propane-decanedioic acid) (p (CPP-SA)), bis-fatty acid-decanedioic acid copolymer (PFAD-SA)], poly-(erucic acid dimer-decanedioic acid) [P (EAD-SA)] and poly-(fumaric acid-decanedioic acid) [P (FA-SA)] etc.Content during to carboxylic phenoxypropane (p-CPP) and decanedioic acid copolymerization is respectively percentage by weight 10-60% and 20-90%, and the blend weight ratio is 10-40:50-90, preferably weight ratio 15-30:65-85.
The molecular weight peak value of polylactic acid can be, but is not limited to, 5000-100, and 000, but with 20,000-60,000 is preferred, with 5,000-30,000 for most preferably; The molecular weight of polyglycolic acid can be, but is not limited to, 5000-100, and 000, but with 5,000-50,000 is preferred, with 10,000-30,000 for most preferably; Above polyhydroxy acid can singly select or multiselect.When singly selecting, serve as preferred with the copolymer (PLGA) of polylactic acid (PLA) or hydroxy carboxylic acid and glycolic, the molecular weight of copolymer can be, but is not limited to, 5000-100,000, but with 20,000-60,000 be preferably, with 30,000-50,000 for most preferably; When multiselect, compound polymer or the copolymer formed with macromolecule polymer or different macromolecule polymer serve as preferred, with the compound polymer that contains different molecular weight polylactic acid or decanedioic acid or copolymer for most preferably, as, but be not limited to, molecular weight is 1000 to 30000 polylactic acid with molecular weight is that 20000 to 50000 polylactic acid mixes, molecular weight is 10000 to 30000 polylactic acid with molecular weight is that 30000 to 80000 PLGA mixes, molecular weight is that 20000 to 30000 polylactic acid mixes with decanedioic acid, molecular weight is that 30000 to 80000 PLGA mixes with decanedioic acid.Used polylactic acid serves as preferred with Poly-L-lactic acid (L-PLA).Poly-L-lactic acid (L-PLA) range of viscosities IV (dl/g) is 0.2～0.8, and glass transition temperature range is 55～65 ℃, 175～185 ℃ of fusing points.
Except that above-mentioned slow-release auxiliary material, also can select for use other materials to see the United States Patent (USP) (patent No. 4757128; 4857311; 4888176; 4789724) and in " pharmaceutic adjuvant complete works " (the 123rd page, Sichuan science tech publishing house published in 1993, Luo Mingsheng and Gao Tianhui chief editor) have a detailed description.In addition, Chinese patent (application number 96115937.5; 91109723.6; 9710703.3; 01803562.0) and U.S.'s patent of invention (patent No. 5,651,986) also enumerated some pharmaceutic adjuvant, comprise filler, solubilizing agent, absorption enhancer, film former, gellant, system (or causing) hole agent, excipient or blocker etc.
For regulating drug releasing rate or changing other characteristic of the present invention, can change the composition and the proportioning of monomer component or molecular weight, interpolation or the adjusting pharmaceutic adjuvant of polymer, add the water-soluble low-molecular chemical compound, as, but be not limited to various sugar or salt etc.Wherein sugar can be, but is not limited to, xylitol, oligosaccharide, (sulphuric acid) chrondroitin and chitin etc., and wherein salt can be, but is not limited to, potassium salt and sodium salt etc.; Also can add other pharmaceutic adjuvant, as but be not limited to filler, solubilizing agent, absorption enhancer, film former, gellant, system (or causing) hole agent, excipient or blocker etc.
A kind of form of slow releasing agent is a slow releasing injection, the consisting of of slow releasing injection:
(A) sustained-release microparticle is grouped into percentage by weight by following one-tenth:
Anticancer effective component 0.5-60%
Slow-release auxiliary material 40-99.5%
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, polysorbas20, polysorbate40 and Tween 80 or its combination.When the suspending agent in the sustained-release microparticle (A) was " 0 ", solvent (B) was special solvent.
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.
The percentage by weight of anticancer effective component in slow releasing agent is 1-50%, and 5-30% is preferred, and 10-25% is for most preferably.One of the anticancer effective component of slow releasing injection is preferred following, all is weight percentage:
(A) copolymer of the polyglycolic acid of the anticancer effective component of 5-15% and 85-95% and hydroxyacetic acid;
(B) copolymer of the polyglycolic acid of the anticancer effective component of 15-35% and 65-85% and hydroxyacetic acid;
(C) polylactic acid of the anticancer effective component of 5-15% and 85-95%;
(D) polylactic acid of the anticancer effective component of 15-35% and 65-85%;
(E) polifeprosan of the anticancer effective component of 5-15% and 85-95%;
(F) polifeprosan of the anticancer effective component of 15-35% and 65-85%;
(G) polifeprosan of the copolymer of the polyglycolic acid of the anticancer effective component of 5-35% and 1-95% and hydroxyacetic acid and 1-95%;
(H) polifeprosan of the polylactic acid of the anticancer effective component of 5-35% and 1-95% and 1-95%;
(I) copolymer of the polyglycolic acid of the polylactic acid of the anticancer effective component of 5-35% and 1-95% and 1-95% and hydroxyacetic acid;
(J) polifeprosan of the copolymer of the polyglycolic acid of the polylactic acid of the anticancer effective component of 5-35% and 1-95% and 1-95% and hydroxyacetic acid and 1-95%.
Anticancer effective component be carmustine (BCNU, Carmustine) or carmustine and be selected from the combination of the carmustine synergist of cisplatin, fluorouracil or O6-benzyl guanine (O6-BG); Anticancer effective component is the combination of carmustine and carmustine synergist, and the weight ratio of the two is 1-9:1-5.
Anticancer effective component is preferably as follows:
(1) O6-BG of the carmustine of 5-25% and 5-35%;
(2) cisplatin of the carmustine of 5-25% and 5-35%;
(3) 5-FU of the carmustine of 5-25% and 5-35%.
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.Can be the bar-shaped of 0.1-5mm (slightly) * 1-10mm (length), also can be other shapes such as lamellar.
The most preferred dosage form of sustained-release implant is that the slow releasing agent that biocompatibility, degradable absorb is implanted, and can make different shape and various dosage form because of the clinical needs of difference.The packing method of its Main Ingredients and Appearance and step in United States Patent (USP) (US5651986) have a detailed description, comprise the some kinds of methods that prepare slow releasing preparation: as, but be not limited to, (i) carrier holder powder and medicament mixed be pressed into implant then, promptly so-called mixing method; (ii) carrier holder fusing, mix solid cooled then, promptly so-called fusion method mutually with medicine to be packaged; (iii) the carrier holder is dissolved in the solvent, medicine dissolution to be packaged or be scattered in the polymer solution, evaporating solvent then, drying, promptly so-called dissolution method; (iv) spray drying method; And (v) freeze-drying etc.
The percentage by weight of anticancer effective component in slow releasing agent is 1-50%, and 5-30% is preferred, and 10-25% is for most preferably.One of the anticancer effective component of slow releasing injection is preferred following, all is weight percentage:
(A) copolymer of the polyglycolic acid of the anticancer effective component of 5-15% and 85-95% and hydroxyacetic acid;
(B) copolymer of the polyglycolic acid of the anticancer effective component of 15-35% and 65-85% and hydroxyacetic acid;
(C) polylactic acid of the anticancer effective component of 5-15% and 85-95%;
(D) polylactic acid of the anticancer effective component of 15-35% and 65-85%;
(E) polifeprosan of the anticancer effective component of 5-15% and 85-95%;
(F) polifeprosan of the anticancer effective component of 15-35% and 65-85%;
(G) polifeprosan of the copolymer of the polyglycolic acid of the anticancer effective component of 5-35% and 1-95% and hydroxyacetic acid and 1-95%;
(H) polifeprosan of the polylactic acid of the anticancer effective component of 5-35% and 1-95% and 1-95%;
(I) copolymer of the polyglycolic acid of the polylactic acid of the anticancer effective component of 5-35% and 1-95% and 1-95% and hydroxyacetic acid;
(J) polifeprosan of the copolymer of the polyglycolic acid of the polylactic acid of the anticancer effective component of 5-35% and 1-95% and 1-95% and hydroxyacetic acid and 1-95%.
Anticancer effective component be carmustine (BCNU, Carmustine) or carmustine and be selected from the combination of the carmustine synergist of cisplatin, fluorouracil or O6-benzyl guanine (O6-BG); Anticancer effective component is the combination of carmustine and carmustine synergist, and the weight ratio of the two is 1-9:1-5.
Anticancer effective component is preferably as follows:
(1) O6-BG of the carmustine of 5-25% and 5-35%;
(2) cisplatin of the carmustine of 5-25% and 5-35%;
(3) 5-FU of the carmustine of 5-25% and 5-35%.
Pharmaceutical composition of the present invention is used for the treatment of entity tumor, and entity tumor comprises former or cancer, sarcoma or the carcinosarcoma of secondary of the cerebral tumor, glioma, osteosarcoma, lymphoma, digestive system, respiratory system, genitourinary system.As: hepatocarcinoma, pulmonary carcinoma, the esophageal carcinoma, gastric cancer, breast carcinoma, cancer of pancreas, thyroid carcinoma, nasopharyngeal carcinoma, ovarian cancer, carcinoma of endometrium, cervical cancer, renal carcinoma, carcinoma of prostate, bladder cancer, colon cancer, rectal cancer, carcinoma of testis, skin carcinoma, tumor of head and neck and come from gallbladder, oral cavity, peripheral nervous system, mucosa, body of gland, blood vessel, osseous tissue, lymph node, eyes, former or cancer, sarcoma or the carcinosarcoma of secondary.Therefore, application of the present invention is the above-mentioned various pharmaceutical preparatioies that are used to make the above-mentioned tumor of treatment, serve as preferred wherein with injection, muddy suspension, ointment, capsule, implant, slow releasing agent and sustained-release implant, with slow releasing injection, sustained-release implant, controlled release implant or slowbreak implant for most preferably.
The present invention treats in the pharmaceutical composition of entity tumor also can add other medicinal ingredient, as, but be not limited to antibiotics, antalgica, anticoagulant medicine, hemorrhage etc.Because anticancer pharmaceutical composition of the present invention can make the action effect of methods such as conventional chemotherapy, immunization therapy, high thermal therapeutical, photochemical therapy, electrotherapy, Biotherapeutics, hormone therapy, magnetic therapy, ultrasonic therapeutic, radiotherapy and gene therapy strengthen.Therefore when local slow discharges, can share, thereby its anticancer effect is further strengthened with above-mentioned non-operative treatment.When share with above-mentioned non-operative treatment, anticancer pharmaceutical composition of the present invention can be used simultaneously with non-operative treatment, also can in implementing a few days ago, non-operative treatment use, its purpose is to strengthen as far as possible the sensitivity of tumor, thereby provide a kind of more effective new method for effecting a radical cure former of various human bodies and animal and shifting entity tumor, have very high clinical value and remarkable economical and social benefit.
When used the part, said composition can directly place around former or the entity tumor that shifts or in the tumor body, also can directly place former or all or part of excision of entity tumor shifted formed intracavity afterwards.
The present invention treats that Main Ingredients and Appearance is a holder with the bio-capacitivity material in the pharmaceutical composition of entity tumor, so do not cause foreign body reaction.Support to place in the object back degradable and absorb, so no longer operation is taken out.Cause discharges contained drug at tumor by local, thereby optionally improves and prolong local drug concentration, can reduce the general toxic reaction that is caused by the conventional route administration simultaneously.Entity tumor had the obvious treatment effect.
The present invention treats in the pharmaceutical composition of entity tumor and can be implemented by many schemes, and its purpose is just in order to further specify, and is not in addition any restriction of enforcement of the present invention.
By following test and embodiment technical method of the present invention is further described:
Test one, carmustine are to the inhibitory action of growth of tumour cell.
Be the inhibitory action of checking carmustine to growth of tumour cell, this test is added to carmustine (10ug/ml) in 24 hours the various tumor cells of In vitro culture (table 1), continue to cultivate after 48 hours the counting cells sum and calculates its suppression ratio to growth of tumour cell (%).
The suppression ratio of growth of tumour cell (%)=((cellular control unit number-test group cell number)/cellular control unit number) * 100%
Table 1
| Tumor cell | Suppression ratio (%) |
| Hepatocarcinoma pulmonary carcinoma esophageal carcinoma gastric cancer breast carcinoma cancer of pancreas thyroid carcinoma nasopharyngeal carcinoma ovarian cancer carcinoma of endometrium cervical cancer renal carcinoma carcinoma of prostate bladder cancer colon cancer rectal cancer skin carcinoma carcinoma of testis | 80 82 70 76 82 90 92 82 68 82 80 66 72 80 88 80 88 84 |
The result of test one shows that carmustine all has obvious inhibitory action (P＜0.05) to the examination growth of tumor.This is unexpected finds to constitute major technique feature of the present invention, for the treatment of entity tumor provides new selection.
The pharmaceutical composition that the present invention treats entity tumor can be made into any dosage form or shape, but serves as preferred with the agent for slow releasing of implanting.
The local drug concentration that test two, different modes are used behind the carmustine compares
(Fisher344) is subjects with rat, 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 carmustine.Measure medicament contg (%) in the different time tumor, the result shows, the local drug concentration significant difference of carmustine 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 (molecular weight is that the PLA of 15000-25000 is an adjuvant) 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 three, different modes are used behind the carmustine compares
(Fisher344) is subjects with rat, with 2 * 10
5Individual prostate tumor cells subcutaneous injection is in its hypochondrium, treats behind tumor growth to 0.8 cm diameter its grouping.Every group of dosage is the 5mg/kg carmustine.The treatment back was measured gross tumor volume size, relatively therapeutic effect on the 20th day.The result shows, the tumor-inhibiting action significant difference of carmustine 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 (molecular weight is that the PLGA (75:25) of 30000-50000 is an adjuvant) 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 four, carmustine and carmustine synergist (slow releasing injection)
(Fisher344) is subjects with rat, with 2 * 10
5Individual pancreatic tumor cell subcutaneous injection is in its hypochondrium, treats that tumor growth after 14 days is divided into it following 7 groups (seeing Table 2).First group is contrast, and the 2nd to 7 group is the treatment group, and slow releasing injection (contain 1-32%BCNU, molecular weight is that the PLA of 40000-60000 is an adjuvant) is through intratumor injection.The treatment back was measured gross tumor volume size, relatively therapeutic effect (seeing Table 2) on the 20th day.
Table 2
| Test group (n) | BCNU therapeutic dose (mg/kg) | Gross tumor volume (cm 3) | The P value |
| 1(6) | Contrast | 60±10 | |
| 2(6) | 0.5 | 56±8.0 | >0.05 |
| 3(6) | 1.0 | 50±6.2 | <0.01 |
| 4(6) | 2.0 | 44±5.4 | <0.01 |
| 5(6) | 4.0 | 30±4.8 | <0.01 |
| 6(6) | 8.0 | 16±2.6 | <0.01 |
| 7(6) | 16.0 | 10±2.0 | <0.001 |
Above result shows that the carmustine sustained-release injection has the obvious suppression effect to entity tumor, and its effect is relevant with dosage.
The tumor-inhibiting action of test five, carmustine and carmustine synergist (slow releasing injection)
Used tumor cell comprises cancer of pancreas, esophageal carcinoma, gastric gland epithelial cancer (SA), bone tumor (BC), breast carcinoma (BA), pulmonary carcinoma (LH), papillary adenocarcinoma of thyroid (PAT), hepatocarcinoma etc.Carmustine and carmustine synergist are added in 24 hours the various tumor cells of In vitro culture by the 1:1 concentration ratio, continue to cultivate counting cells sum after 48 hours.Its growth of tumour cell suppresses effect and is shown in Table 3.
Table 3
| Oncocyte | Carmustine | The benzyl guanine | Cisplatin | 5-FU | Carmustine+benzyl guanine | Carmustine+cisplatin | Carmustine+5-FU |
| Cancer of pancreas | 68％ | 54％ | 52％ | 44％ | 82％ | 86％ | 88％ |
| Esophageal carcinoma | 60％ | 52％ | 50％ | 34％ | 84％ | 86％ | 78％ |
| SA | 48％ | 60％ | 26％ | 32％ | 68％ | 82％ | 82％ |
| BC | 52％ | 48％ | 44％ | 24％ | 66％ | 86％ | 80％ |
| BA | 54％ | 52％ | 32％ | 32％ | 68％ | 72％ | 78％ |
| LH | 52％ | 50％ | 22％ | 28％ | 60％ | 82％ | 80％ |
| PAT | 46％ | 50％ | 42％ | 38％ | 76％ | 80％ | 82％ |
Above result shows that growth all has the obvious suppression effect to kinds of tumor cells when this concentration is used separately for used carmustine synergist (benzyl guanine, cisplatin, 5-FU) and carmustine, can show significant potentiation when use in conjunction.Same effect also sees the other types tumor, as esophageal carcinoma, ovarian cancer, cancer of pancreas, intestinal cancer etc.
The tumor-inhibiting action of test six, carmustine and carmustine synergist (slow releasing injection)
(Fisher344) is subjects with rat, with 2 * 10
5Individual tumor cell of liver subcutaneous injection is in its hypochondrium, treats that tumor growth after 14 days is divided into it following 10 groups (seeing Table 4).First group is contrast, and the 2nd to 10 group is the treatment group, and sustained-release implant is placed (contain 5-30%BCNU, molecular weight is that the PLGA (50:50) of 20000-40000 is an adjuvant) in tumor.The treatment back was measured gross tumor volume size, relatively therapeutic effect (seeing Table 4) on the 20th day.
Table 4
| Test group (n) | Therapeutic dose | Gross tumor volume (cm 3) | The P value |
| 1(6) | Contrast | 54±12 | |
| 2(6) | Carmustine (5%) | 44±8.0 | <0.05 |
| 3(6) | Carmustine (10%) | 36±6.0 | <0.01 |
| 4(6) | Carmustine (15%) | 26±4.4 | <0.001 |
| 5(6) | Carmustine (30) | 16±3.2 | <0.01 |
| 6(6) | O6-BG(10％) | 46±8.4 | <0.001 |
| 7(6) | Carmustine (5%)+O6-BG | 34±6.2 | <0.01 |
| 8(6) | Carmustine (10%)+O6-BG | 26±4.6 | <0.001 |
| 9(6) | Carmustine (15%)+O6-GB | 16±2.0 | <0.01 |
| 10(6) | Carmustine (30%)+O6-BG | 6±1.0 | <0.001 |
Above result shows that growth all has the obvious suppression effect to used carmustine to kinds of tumor cells, and its inhibitory action is relevant with dosage, can show significant potentiation when with carmustine synergist (O6-BG:O6-benzyl guanine) use in conjunction.This discovery constitutes the another key character of the present invention.
The tumor-inhibiting action of test seven, carmustine and carmustine synergist (slow releasing injection)
(Fisher344) is subjects with rat, with 2 * 10
5Individual prostate tumor cells subcutaneous injection is in its hypochondrium, treats that tumor growth after 14 days is divided into it negative control (blank), single therapy group (carmustine or carmustine synergist) and therapeutic alliance group (carmustine and carmustine synergist).Slow releasing injection is through intratumor injection.The treatment back was measured the gross tumor volume size on the 20th day, made relatively therapeutic effect (seeing Table 5) of index with inhibition rate of tumor growth.
Table 5
| Test group (n) | Suffered treatment | Tumor control rate (%) | The P value |
| 1(6) | Contrast | - | |
| 2(6) | Carmustine (5%) | 48 | <0.05 |
| 3(6) | Carmustine (10%) | 54 | <0.01 |
| 4(6) | Carmustine (15%) | 62 | <0.01 |
| 5(6) | Carmustine (20%) | 70 | <0.01 |
| 6(6) | 5-FU(10％) | 40 | <0.01 |
| 7(6) | Carmustine (5%)+5-FU | 68 | <0.001 |
| 8(6) | Carmustine (10%)+5-FU | 78 | <0.001 |
| 9(6) | Carmustine (15%)+5-FU | 86 | <0.001 |
| 10(6) | Carmustine (20%)+5-FU | 94 | <0.001 |
Above result shows that growth all has the obvious suppression effect to kinds of tumors when this concentration is used separately for used carmustine and carmustine synergist (5-FU), can show significant potentiation when use in conjunction, and be tangible dose-effect relationship.
The tumor-inhibiting action of test eight, carmustine and carmustine synergist (slow releasing injection)
(Fisher344) is subjects with rat, with 2 * 10
5Individual breast tumor cell subcutaneous injection is in its hypochondrium, treats that tumor growth after 14 days is divided into it negative control (blank), single therapy group, therapeutic alliance group.Slow releasing injection (adjuvant is that molecular weight is the PLA of 20000-40000) is through intratumor injection.The treatment back was measured the gross tumor volume size on the 20th day, made relatively therapeutic effect (seeing Table 6) of index with inhibition rate of tumor growth.
Table 6
| Test group (n) | Suffered treatment | Tumor control rate (%) | The P value |
| 1(6) | Contrast | - | |
| 2(6) | Carmustine (5%) | 48 | <0.05 |
| 3(6) | Carmustine (10%) | 56 | <0.01 |
| 4(6) | Carmustine (15%) | 62 | <0.01 |
| 5(6) | Carmustine (20%) | 70 | <0.01 |
| 6(6) | Cisplatin (5%) | 42 | <0.01 |
| 7(6) | Carmustine (5%)+cisplatin | 68 | <0.001 |
| 8(6) | Carmustine (10%)+cisplatin | 74 | <0.001 |
| 9(6) | Carmustine (15%)+cisplatin | 86 | <0.001 |
| 10(6) | Carmustine (20%)+cisplatin | 90 | <0.001 |
Above result shows that growth all has the obvious suppression effect to kinds of tumors when this concentration is used separately for used carmustine and carmustine synergist (cisplatin), can show significant potentiation when use in conjunction, and be tangible dose-effect relationship.This discovery constitutes the another key character of the present invention.
The tumor-inhibiting action of test nine, carmustine and carmustine synergist (slow releasing injection)
(Fisher344) is subjects with rat, with 2 * 10
5Individual rectal neoplasm cell subcutaneous injection is in its hypochondrium, treats that tumor growth after 14 days is divided into it following 10 groups (seeing Table 7).First group is contrast, and the 2nd to 10 group is the treatment group, and sustained-release implant is placed (contain 5-30%BCNU, molecular weight is that the PLGA (50:50) of 20000-40000 is an adjuvant) in tumor.The treatment back was measured gross tumor volume size, relatively therapeutic effect (seeing Table 7) on the 20th day.
Table 7
| Test group (n) | Therapeutic dose | Gross tumor volume (cm 3) | The P value |
| 1(6) | Contrast | 54±12 | |
| 2(6) | O6-BG(5％) | 48±8.8 | <0.05 |
| 3(6) | O6-BG(10％) | 42±8.0 | <0.01 |
| 4(6) | O6-BG(15％) | 38±4.8 | <0.001 |
| 5(6) | O6-BG(30) | 32±4.2 | <0.01 |
| 6(6) | Carmustine (10%) | 30±6.2 | <0.001 |
| 7(6) | (5%) O6-BG+ carmustine | 26±6.8 | <0.01 |
| 8(6) | (10%) O6-BG+ carmustine | 20±4.6 | <0.001 |
| 9(6) | (15%) O6-GB+ carmustine | 16±2.0 | <0.01 |
| 10(6) | (30%) O6-BG+ carmustine | 10±1.0 | <0.001 |
Above result shows that used carmustine synergist (O6-BG:O6-benzyl guanine) all has inhibitory action to growth of tumour cell, and its inhibitory action is relevant with dosage, can show significant potentiation when with the carmustine use in conjunction.This discovery constitutes the another key character of the present invention.
Release ratio in the body of the carmustine sustained-release implantation agent that test ten, different molecular weight polylactic acid are made
With rat (Fisher344) is subjects, grouping (3/group) and the equivalent carmustine sustained-release implantation agent that carries in the subcutaneous polylactic acid (PLA) that contains different molecular weight (MW).Survey the surplus of medicine in implant respectively at 1,3,7,14,21,28 and 35 day then, and then draw rate of release (%) in its body.The result shows, molecular weight is 20000 is released to: 1 day (10%), 3 (26%), 7 (54%), 14 (80%), 21 (90), 28 (92) and 35 (94%).Discharge in the body of the carmustine sustained-release implantation agent that comparison different molecular weight polylactic acid is made and find, slack-off with the molecular weight increase, with the 7th day was example, compare with whole body administration group, tumor control rate increases with the polylactic acid molecule amount and improves, and is followed successively by 66% (MW:5000), 64% (MW:15000), 58% (MW:25000), 54% (MW:40000) and 46 (MW:60000).
It is the medicinal slow release agent that adjuvant is made that same result also sees with polylactic acid, contains the combination of carmustine and synergist thereof.
That pays special attention to is simple to operation, the good reproducibility of slow releasing agent of the present invention, particularly slow releasing injection.Good effect not only, toxic and side effects is little.
Different drug packages is to want characteristic different with different Biodegradable high moleculars.Discover that further the slow-release auxiliary material that is most appropriate to medicament slow release of the present invention is a poly-dl-lactide, poly-dl-lactide/ethanol copolymer, the monomethyl polyethylene glycol, monomethyl polyethylene glycol copolymer, polyethylene glycol, the polyethylene glycol copolymer, end carboxyl polylactic acid, end carboxyl polylactic acid/ethanol copolymer, polifeprosan, bis-fatty acid and decanedioic acid copolymer, poly-(erucic acid dimer-decanedioic acid), poly-(fumaric acid-decanedioic acid), ethylene vinyl acetate copolymer, polylactic acid, the copolymer of polyglycolic acid and hydroxyacetic acid, xylitol, oligosaccharide, chrondroitin, chitin, hyaluronic acid, collagen protein, gelatin, one of albumin glue or its combination.The slow releasing preparation that above-mentioned slow-release auxiliary material is made does not have the prominent phenomenon of releasing of tangible medicine; Optimum suspending agent is one of methylcellulose, hydroxy methocel, sodium carboxymethyl cellulose, (iodine) glycerol, simethicone, propylene glycol, carbomer, mannitol, sorbitol, surfactant, soil temperature 20, soil temperature 40, soil temperature 80 or its combination.
In a word, growth all had the obvious suppression effect to kinds of tumor cells when used carmustine and various carmustine synergist were used separately, can show significant potentiation when use in conjunction.Therefore, effective ingredient of the present invention is carmustine and any one carmustine 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 one:
With the pharmaceutic adjuvant molecular weight of 90mg is that the polylactic acid (PLA) of 20000-40000 is put into container, adds 100 milliliters of dichloromethane dissolvings of organic solvent mixing, adds the 10mg carmustine, shakes up the dry organic solvent of removing of final vacuum again.Again shake up the dry organic solvent of removing of final vacuum.Dried pastille solid composite freezing and pulverizing is made the micropowder that contains percentage by weight 10% carmustine, 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).Subcutaneous drug release time is 30-35 days.
Embodiment two:
With the pharmaceutic adjuvant molecular weight of 75mg is that (PLGA 50:50) puts into container, adds 100 milliliters of dichloromethane dissolvings of organic solvent mixing, adds the 25mg carmustine, shakes up the dry organic solvent of removing of final vacuum again for the polylactic acid of 30000-50000.Dried solid composite is shaped immediately, and ray sterilizing after the packing obtains containing the Anticarcinogenic internal implant agent of the treatment entity tumor of percentage by weight 25% carmustine.Subcutaneous drug release time is 35-40 days.
Embodiment three:
The pharmaceutic adjuvant polifeprosan of 90mg (to carboxy phenyl propane: certain herbaceous plants with big flowers diacid weight ratio is 50:50) is put into container, add 100 milliliters of dichloromethane dissolvings of organic solvent mixing, add the 10mg carmustine, shake up the dry organic solvent of removing of final vacuum again.Dried solid composite is shaped immediately, and ray sterilizing after the packing obtains containing the Anticarcinogenic internal implant agent of the treatment entity tumor of weight hundred 10% carmustines.Subcutaneous drug release time is 15-20 days.
Embodiment four:
As the Anticarcinogenic internal implant agent that embodiment three described methods are made, different is that weight ratio and the drug disposition to carboxy phenyl propane (cPP) and certain herbaceous plants with big flowers diacid (SA) discharges following (table 8) in the used pharmaceutic adjuvant polifeprosan:
Table 8
| BCNU content (%) | cPP/SA | Drug release time in the body (my god) |
| 10 | 20/80 | 5-7 |
| 10 | 30/70 | 9-11 |
| 10 | 40/60 | 13-15 |
| 10 | 50/50 | 15-18 |
| 15 | 20/80 | 4-6 |
| 15 | 30/70 | 7-9 |
| 15 | 40/60 | 10-12 |
| 15 | 50/50 | 13-15 |
The result shows that the weight ratio to carboxy phenyl propane (cPP) and certain herbaceous plants with big flowers diacid (SA) in the polifeprosan is that 20-50/50-80 is suitable, and BCNU content is 10%-15%, optimal 10% the BCNU that contains for polifeprosan.
Embodiment five:
With the pharmaceutic adjuvant molecular weight of the 70mg that weighs is the polyglycolic acid of 15000-30000 and the copolymer (PLGA of hydroxyacetic acid, 50:50) put into container, add 100 milliliters of dichloromethane dissolvings of organic solvent mixing, add 15mg carmustine and 15mg5-FU, 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 percentage by weight 15% carmustine and 15%5-FU, be suspended in then in the normal saline that contains 1.0% sodium carboxymethyl cellulose and 5% mannitol, make corresponding suspension type slow releasing injection, viscosity is 400cp-480cp (25 ℃-30 ℃ time).The subcutaneous rat drug release time is 40-45 days.
Embodiment six:
With the pharmaceutic adjuvant molecular weight of the 80mg that weighs is that the PLGA (50:50) of 30000-50000 puts into container, adds 100 milliliters of dichloromethane dissolvings of organic solvent mixing, adds 15mg carmustine and 5mg5-FU, shakes up the dry organic solvent of removing of final vacuum again.Dried solid composite is shaped immediately, and ray sterilizing after the packing obtains containing the Anticarcinogenic internal implant agent of percentage by weight 15% carmustine and 5%5-FU.The subcutaneous rat drug release time is 25-30 days.
Embodiment seven:
With the pharmaceutic adjuvant molecular weight of the 70mg that weighs is that 40000 PLGA (75:25) puts into container, adds 100 milliliters of dichloromethane dissolvings of organic solvent mixing, adds 10mg carmustine and 20mg5-FU, shakes up the dry organic solvent of removing of final vacuum again.Dried solid composite is shaped immediately, and ray sterilizing after the packing obtains containing the Anticarcinogenic internal implant agent of percentage by weight 10% carmustine and 20%5-FU.The subcutaneous rat drug release time is 30-35 days.
Embodiment eight:
As described in embodiment five to seven, component that different is is one of following, all is weight percentage:
(A) 5% carmustine and 95% polyglycolic acid and the copolymer (50:50) of hydroxyacetic acid;
(B) 10% carmustine and 90% polyglycolic acid and the copolymer (50:50) of hydroxyacetic acid;
(C) 15% carmustine and 85% polyglycolic acid and the copolymer (70:30) of hydroxyacetic acid;
(D) 20% carmustine and 80% polyglycolic acid and the copolymer (70:30) of hydroxyacetic acid;
(E) 25% carmustine and 75% polyglycolic acid and the copolymer (75:25) of hydroxyacetic acid.
Embodiment nine:
As described in embodiment one to five, different is that anticancer effective component and percentage by weight are:
(1) O6-BG of the carmustine of 5-25% and 5-35%;
(2) cisplatin of the carmustine of 5-25% and 5-35%;
(3) 5-FU of the carmustine of 5-25% and 5-35%.
Embodiment ten:
With the pharmaceutic adjuvant molecular weight of the 10mg that weighs is that 15000 ethylene vinyl acetate copolymer (EVAc) is put into container, adds 100 milliliters of dichloromethane dissolvings of organic solvent mixing, adds the 10mg carmustine, shakes up the dry organic solvent of removing of final vacuum again.Dried solid composite is shaped immediately, and ray sterilizing after the packing obtains containing the pharmaceutical composition of the treatment entity tumor of percentage by weight 10% carmustine, as Anticarcinogenic internal implant agent.The subcutaneous rat drug release time is 20-25 days.
Embodiment 11:
As described in embodiment ten, the percentage by weight of different is anticancer effective component and adjuvant is:
(A) 10% carmustine and 90% EVAc;
(B) 15% carmustine and 85% EVAc;
(C) 20% carmustine and 80% EVAc;
(D) 25% carmustine and 75% EVAc;
(E) 30% carmustine and 70% EVAc;
Embodiment 12:
80mg polifeprosan (to carboxy phenyl propane: certain herbaceous plants with big flowers diacid weight ratio is 20:80) is put into container, add 100 milliliters of dichloromethane dissolving mixings after, add 10mg carmustine and 10mg O6-BG, 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 percentage by weight 10% carmustine and 10mg O6-BG, be suspended in then in the normal saline that contains 2.5% sodium carboxymethyl cellulose, make corresponding suspension type slow releasing injection, viscosity is 480cp-560cp (25 ℃-30 ℃ time), drug release time in external normal saline is 15-25 days, is 25-40 days at the subcutaneous drug release time of mice.
Embodiment 13:
As described in embodiment 12, different is that the anticancer effective component percentage by weight is:
(A) 5% carmustine and 35% O6-BG;
(B) 10% carmustine and 25% O6-BG;
(C) 15% carmustine and 15% O6-BG;
(D) 20% carmustine and 10% O6-BG;
(E) 25% carmustine and 5% O6-BG.
Embodiment 14:
With the pharmaceutic adjuvant molecular weight of the 80mg that weighs is that the PLGA (50:50) of 20000-40000 puts into container, add 100 milliliters of dichloromethane dissolving mixings after, add 10mg carmustine and 10mgO6-BG, shake up the dry organic solvent of removing of final vacuum again.Dried solid composite is shaped immediately, and ray sterilizing after the packing obtains containing the pharmaceutical composition of the treatment entity tumor of percentage by weight 10% carmustine and 10%O6-BG, as Anticarcinogenic internal implant agent.It is 15-25 days that this body is implanted into the drug release time of agent in external normal saline, is 25-40 days at the subcutaneous drug release time of mice.
Embodiment 15:
With the pharmaceutic adjuvant molecular weight of the 80mg that weighs is that the PLGA (75:25) of 40000-60000 puts into container, add 100 milliliters of dichloromethane dissolving mixings after, add 15mg carmustine and 5mgO6-BG, shake up the dry organic solvent of removing of final vacuum again.Dried solid composite is shaped immediately, and ray sterilizing after the packing obtains containing the pharmaceutical composition of the treatment entity tumor of percentage by weight 15% carmustine and 5%O6-BG, as Anticarcinogenic internal implant agent.It is 15-20 days that this body is implanted into the drug release time of agent in external normal saline, is 30-40 days at the subcutaneous drug release time of mice.
Embodiment 16:
With the pharmaceutic adjuvant molecular weight of the 80mg that weighs is that the PLA of 20000-40000 puts into container, add 100 milliliters of dichloromethane dissolving mixings after, add 5mg carmustine and 15mgO6-BG, shake up the dry organic solvent of removing of final vacuum again.Dried solid composite is shaped immediately, and ray sterilizing after the packing obtains containing the pharmaceutical composition of the treatment entity tumor of percentage by weight 5% carmustine and 15%O6-BG, as Anticarcinogenic internal implant agent.It is 15-20 days that this body is implanted into the drug release time of agent in external normal saline, is 30-40 days at the subcutaneous drug release time of mice.
Embodiment 17: as described in embodiment 13 to 16, component that different is is one of following, all is weight percentage:
(A) 5% carmustine and 35% O6-BG;
(B) 10% carmustine and 25% O6-BG;
(C) 15% carmustine and 15% O6-BG;
(D) 20% carmustine and 10% O6-BG;
(E) 25% carmustine and 5% O6-BG.
Embodiment 18:
With the pharmaceutic adjuvant molecular weight of the 80mg that weighs is that the PLGA (50:50) of 20000-40000 puts into container, add 100 milliliters of dichloromethane dissolving mixings after, add 10mg carmustine and 10mg cisplatin, shake up the dry organic solvent of removing of final vacuum again.Dried solid composite is shaped immediately, and ray sterilizing after the packing obtains containing the pharmaceutical composition of the treatment entity tumor of percentage by weight 10% carmustine and 10% cisplatin, as Anticarcinogenic internal implant agent.It is 15-25 days that this body is implanted into the drug release time of agent in external normal saline, is 25-40 days at the subcutaneous drug release time of mice.
Embodiment 19:
With the pharmaceutic adjuvant molecular weight of the 80mg that weighs is that the PLGA (75:25) of 40000-60000 puts into container, add 100 milliliters of dichloromethane dissolving mixings after, add 15mg carmustine and 5mg cisplatin, 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 percentage by weight 15% carmustine and 5% cisplatin, be suspended in then in the normal saline that contains 5% mannitol, make corresponding suspension type slow releasing injection, viscosity is 380cp-460cp (25 ℃-30 ℃ time), drug release time in external normal saline is 15-20 days, is 30-40 days at the subcutaneous drug release time of mice.
Embodiment 20:
With the pharmaceutic adjuvant molecular weight of the 80mg that weighs is that the PLA of 20000-40000 puts into container, add 100 milliliters of dichloromethane dissolving mixings after, add 5mg carmustine and 15mg cisplatin, shake up the dry organic solvent of removing of final vacuum again.Dried solid composite is shaped immediately, and ray sterilizing after the packing obtains containing the pharmaceutical composition of the treatment entity tumor of percentage by weight 5% carmustine and 15% cisplatin, as Anticarcinogenic internal implant agent.It is 15-20 days that this body is implanted into the drug release time of agent in external normal saline, is 30-40 days at the subcutaneous drug release time of mice.
Embodiment 21:
As described in embodiment 18 to 20, component that different is is one of following, all is weight percentage:
(A) 5% carmustine and 35% cisplatin;
(B) 10% carmustine and 25% cisplatin;
(C) 15% carmustine and 15% cisplatin;
(D) 20% carmustine and 10% cisplatin;
(E) 25% carmustine and 5% cisplatin.
Embodiment 22:
As embodiment one pharmaceutical composition to embodiment 21 described treatment entity tumors, used pharmaceutic adjuvant is selected from one of following or its combination that different is:
A) molecular weight is the polylactic acid (PLA) of 5000-15000,10000-20000,25000-35000 or 30000-50000;
B) molecular weight is the polyglycolic acid of 5000-15000,15000-35000,35000-45000 or 45000-80000 and the copolymer of hydroxyacetic acid (PLGA);
C) ethylene vinyl acetate copolymer (EVAc);
D) polifeprosan is (to carboxy phenyl propane (p-CPP): certain herbaceous plants with big flowers diacid (SA) copolymer), be 10:90,20:80,30:70,40:60,50:50 or 60:40 to the percentage by weight of carboxy phenyl propane (p-CPP) and certain herbaceous plants with big flowers diacid (SA);
E) xylitol, oligosaccharide, chitin, potassium salt, sodium salt, hyaluronic acid, collagen protein, gelatin or albumin.
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.
In addition, tumor is implanted into carmustine sustained-release implantation agent other entity tumors such as bone tumor, lymphoma, gastric cancer, bladder cancer, carcinoma of testis, colon cancer, rectal cancer, ovarian cancer, carcinoma of endometrium, cervical cancer, renal carcinoma and carcinoma of prostate is also had good therapeutical effect, and its effect obviously surpasses carmustine lumbar injection group and carmustine local injection group.This is unexpected finds to constitute major technique feature of the present invention, for the medicine of entity tumor provides another new selection.
Claims (3)
- [claim 1] a kind of with carry carmustine and and the anticancer sustained-release agent of carmustine synergist, be slow releasing injection, be grouped into by following one-tenth:Anticancer effective component is 10% carmustine and 10%O6-BG, and slow-release auxiliary material is 80% a pair of carboxy phenyl propane: certain herbaceous plants with big flowers diacid weight ratio is the polifeprosan of 20:80, and solvent is the normal saline that contains 2.5% sodium carboxymethyl cellulose;Described anticancer sustained-release agent is a sustained-release implant, is grouped into by following one-tenth:(1) anticancer effective component is 10% carmustine and 10%O6-BG, and slow-release auxiliary material is that 80% molecular weight is the PLGA of 20000-40000;(2) anticancer effective component is 15% carmustine and 5%O6-BG, and slow-release auxiliary material is that 80% molecular weight is the PLGA of 40000-60000;(3) anticancer effective component is 5% carmustine and 15%O6-BG, and slow-release auxiliary material is that 80% molecular weight is that molecular weight is the PLA of 20000-40000.
- [claim 2] slow releasing agent according to claim 1 is characterized in that anticancer effective component is used to prepare the slow releasing injection of the treatment cerebral tumor, glioma, osteosarcoma, lymphoma, hepatocarcinoma, pulmonary carcinoma, the esophageal carcinoma, gastric cancer, breast carcinoma, cancer of pancreas, thyroid carcinoma, nasopharyngeal carcinoma, ovarian cancer, carcinoma of endometrium, cervical cancer, renal carcinoma, carcinoma of prostate, bladder cancer, colon cancer, rectal cancer, carcinoma of testis, skin carcinoma or tumor of head and neck.
- [claim 3] slow releasing agent according to claim 1 is characterized in that anticancer effective component is used to prepare the sustained-release implant that treatment comes from cancer, sarcoma or the carcinosarcoma of nervous system, respiratory system, digestive system, genitourinary system, hormonal system, mucosa, body of gland, blood vessel, osseous tissue, lymph node, epithelium former or secondary.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA2008103045757A CN101390833A (en) | 2006-09-28 | 2006-09-28 | Anti-cancer slow-release formulation loaded with carmustine and synergist thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA2008103045757A CN101390833A (en) | 2006-09-28 | 2006-09-28 | Anti-cancer slow-release formulation loaded with carmustine and synergist thereof |
Related Parent Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA2006102009311A Division CN100998558A (en) | 2006-09-28 | 2006-09-28 | Slow-release anticarcinogen contg. carmustine and fluorouracil |
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| Publication Number | Publication Date |
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| CN101390833A true CN101390833A (en) | 2009-03-25 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA2008103045757A Pending CN101390833A (en) | 2006-09-28 | 2006-09-28 | Anti-cancer slow-release formulation loaded with carmustine and synergist thereof |
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| Country | Link |
|---|---|
| CN (1) | CN101390833A (en) |
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- 2006-09-28 CN CNA2008103045757A patent/CN101390833A/en active Pending
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