CN1973822A - Anticancer composition containing Sirolimus - Google Patents
Anticancer composition containing Sirolimus Download PDFInfo
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- CN1973822A CN1973822A CNA200610201343XA CN200610201343A CN1973822A CN 1973822 A CN1973822 A CN 1973822A CN A200610201343X A CNA200610201343X A CN A200610201343XA CN 200610201343 A CN200610201343 A CN 200610201343A CN 1973822 A CN1973822 A CN 1973822A
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Abstract
The anticancer composition containing sirolimus is one kind of slow releasing injection comprising slow released microsphere and special solvent containing suspending agent or slow releasing implant. The effective anticancer component is sirolimus, proteolytic enzyme selected from collagenase, hyaluornidase, etc and blood vessel inhibitor selected from gefitinib, thalidomide, etc. The slow releasing supplementary material is selected from polylactic acid, polyethylene glycol, polifeprosan, etc; the suspending agent is selected from sodium carboxymethyl cellulose, etc and has viscosity of 100cp-3000cp. The slow releasing injection and the slow releasing implant are used in treating tumor alone or in conjunction with chemotherapy.
Description
(1) technical field
The present invention relates to a kind of anti-cancer composition that contains rapamycin, belong to technical field of pharmaceuticals.Particularly, the invention provides a kind of slow releasing injection and sustained-release implant that contains rapamycin.This anticancer sustained-release agent can suppress or destroy matter and tumor vessel between entity tumor effectively, and can suppress the new vessels of tumor, effectively reduce tension force, a matter pressure, a matter viscosity in the tumor, and then improve its interstitial fluid conductance, help medicine and enter entity tumor and the effective diffusion in tumor.
(2) background technology
As new cancer therapy drug, rapamycin shows potential therapeutical effect to many kinds of cancerous cell.Yet traditional chemotherapy is not had a selectivity, be difficult to tumor by local and form effective drug level or therapeutic dose, and weak effect, toxicity is big, improves the restriction that medicine or radiological dose are subjected to general toxic reaction again merely.Referring to " placing cisplatin adding system carmustine treatment rat brain tumor in the tumor " " surgery tumor magazine " 69 phase 76-82 pages or leaves such as hole, (Kong Q et al., J Surg Oncol.1998Oct in 1998; 69 (2): 76-82).
The local placement of antitumor drug can overcome above defective preferably, not only can obviously improve the drug level of tumor by local, and can significantly reduce general toxic reaction.A large amount of internal and external tests have demonstrated the therapeutic effect to entity tumor, referring to " placing cisplatin adding system carmustine treatment rat brain tumor in the tumor " " surgery tumor magazine " 69 phase 76-82 pages or leaves such as Kong Qingzhongs, (Kong Q et al., J Surg Oncol.1998 Oct in 1998; 69 (2): 76-82) and Kong Qingzhong etc. " place cisplatin in the tumor and cure the former carbuncle in the occipital region tumor of rat " " surgery tumor magazine " 64 phase 268-273 pages or leaves (1997) (Kong Q et al., JSurg Oncol.1997 Oct; 64:268-273).Also can be referring to Chinese patent (ZL00111093.4; ZL96115937.5; Application number 001111264,001111272) and U.S.'s patent of invention (patent No. 6,376,525B1; 5,651,986; 5,626,862).
Yet, entity tumor is made up of tumor cell and mesenchyma stroma of tumors, wherein the blood vessel in the mesenchyma stroma of tumors not only provides support and requisite nutrient substance for the growth of tumor cell, also influenced chemotherapeutics around tumor and infiltration and diffusion in the tumor tissues, " situation of extracellular matrix is to the influence of medicine running in the entity tumor " " cancer research " 60 phase 2497-503 page or leaf such as carry referring to the Buddhist nun, (Netti PA, Cancer Res.2000,60 (9): 2497-503) in 2000.
The tumor cell of composition such as the blood vessel in the mesenchyma stroma of tumors and fibrin in the connective tissue and collagen protein and hyperplasia cause entity tumor between matter pressure (interstitial pressure) high, a matter viscosity (interstitialviscosity) is big, tissue tension coefficient (tissue tensile modulus) is big, (hydraulicconductance) is low for the interstitial fluid conductance.Above factors have limited medicine greatly and have entered entity tumor and the effective diffusion in tumor, therefore constitute the major obstacle of chemotherapy of tumors.
Moreover, the blood vessel in the mesenchyma stroma of tumors often causes the enhancing of tumor cell to the toleration of rapamycin to conventional chemotherapy medicine and insensitive, consequently treatment failure.
(3) summary of the invention
The present invention is directed to the deficiencies in the prior art, a kind of new pharmaceutical composition is provided, contain mesenchyme hydrolytic agent and/or rapamycin.More specifically, be the slow releasing agent of anti entity tumour, be mainly sustained-release implant and slow releasing injection.Topical application can suppress or destroy the blood vessel of tumor effectively and can suppress the new vessels of tumor; Decapacitation suppresses can also increase the sensitivity of tumor cell to rapamycin outside the tumor growth; This controlled release formulation for anti entity tumour also effectively reduces tension force, a matter pressure, the matter viscosity in the tumor, and then improves its interstitial fluid conductance, helps medicine and enters entity tumor and the effective diffusion in tumor.
In addition, mesenchyme hydrolytic agent and/or rapamycin are made drug level that slow releasing agent (being mainly slow releasing injection and sustained-release implant) not only can greatly improve tumor by local, reduce the drug level of medicine in blood circulation, are reduced the toxicity of medicine to normal structure, can also greatly make things convenient for the medicine injection, reduce operation technique complication, reduce patient's expense.The rapamycin decapacitation suppresses can also increase the sensitivity of tumor cell outside the tumor growth.The above unexpected main contents of the present invention of finding to constitute.
Controlled release formulation for anti entity tumour of the present invention comprises anticancer effective component and pharmaceutic adjuvant, and anticancer effective component is selected from rapamycin and mesenchyme hydrolytic agent.Mesenchyme hydrolytic agent is vasoinhibitor and/or proteolytic enzyme, vasoinhibitor is except that having the effect that suppresses growth of tumour cell, the blood vessel that can suppress or destroy tumor effectively also can suppress the formation of the new vessels of tumor, and then not only make tumor cell lose the required support of growth and the source of nutrient substance, share with proteolytic enzyme or use separately and also can obviously promote chemotherapeutics to enter tumor and around tumor and infiltration and diffusion in the tumor tissues; Proteolytic enzyme can effectively degrade blood vessel and compositions such as fibrin in the connective tissue and collagen protein in the mesenchyma stroma of tumors, effectively reduce tension force, a matter pressure, a matter viscosity in the tumor, and then improve its interstitial fluid conductance, help that medicine enters entity tumor and around the tumor and infiltration and diffusion in the tumor tissues.
Compound medicament composition of the present invention can be made into any dosage form, as, but be not limited to capsule, slow releasing agent, granule, pill, tablet, powder, injection, ointment, patch, implant, slow releasing agent implant, slow releasing agent injection etc.Wherein be preferred with the slow releasing agent, with slow releasing agent implant and slow releasing agent injection for most preferably.
A kind of preferred form of the present invention is a slow releasing injection, is made up of sustained-release micro-spheres and solvent.Particularly, this slow-releasing anticarcinogen injection is grouped into by following one-tenth:
(A) sustained-release micro-spheres comprises:
Anticancer effective component 0.01-60%
Slow-release auxiliary material 40-99.99%
Suspending agent 0.0-30%
More than be weight percentage
With
(B) solvent is for common solvent or contain the special solvent of suspending agent.
Wherein,
Anticancer effective component be mesenchyme hydrolytic agent or and rapamycin; Slow-release auxiliary material range of viscosities IV (dl/g) is 0.1～0.8, be selected from poly-dl-lactide (D, L-PLA), poly-dl-lactide/ethanol copolymer (D, L-PLGA), monomethyl polyethylene glycol (MPEG-PLA), monomethyl polyethylene glycol copolymer (MPEG-PLGA), polyethylene glycol (PLA-PEG-PLA), polyethylene glycol copolymer (PLGA-PEG-PLGA), end carboxyl polylactic acid (PLA-COOH), end carboxyl polylactic acid/ethanol copolymer (PLGA-COOH), polifeprosan, bis-fatty acid and decanedioic acid copolymer (PFAD-SA), poly-(erucic acid dimer-decanedioic acid) [P (EAD-SA)], poly-(fumaric acid-decanedioic acid) [P (FA-SA)], polylactic acid (PLA), the copolymer of polyglycolic acid and hydroxyacetic acid (PLGA), PPDO (PDO), PTMC (PTMC), xylitol, oligosaccharide, chrondroitin, chitin, chitosan, hyaluronic acid, collagen protein, gelatin, poloxamer, one of albumin glue or its combination; Suspending agent is selected from one of sodium carboxymethyl cellulose, (iodine) glycerol, simethicone, propylene glycol, carbomer, mannitol, sorbitol, surfactant, soil temperature 20, soil temperature 40 and soil temperature 80 or its combination.
In having the mesenchyme hydrolytic agent of active anticancer, be not all slow release effects that all can in slow-release auxiliary material of the present invention, reach effective release yet.Pharmaceutic adjuvant have hundreds of more than, pharmaceutic adjuvant with slow releasing function, it is not apparent particularly selected mesenchyme hydrolytic agent and rapamycin among the present invention slowly being discharged in the regular hour in human body or animal body, but specific slow-release auxiliary material need could be determined through a large amount of creative works with the selection of slow releasing pharmaceutical combination.Discharged and be not enough to obtain active drug concentration slowly, thereby effective tumor killing cell; Can cause prominent releasing if discharge, then cause general toxic reaction as conventional injection easily.The data of release characteristics need could obtain through a large amount of creationary experiments in inside and outside in the related data, particularly animal body, are not just can determine to have unobviousness through limited experiment.
Rapamycin (Rapamycin) shared ratio in compositions is decided because of concrete condition, can be 0.0001%-20%, is good with 0.01%-5%, and 0.1%-2% is best.Also optional its analog of rapamycin, as, but be not limited to, and Temsirolimus (Torisel, CCI-779), Sirolimus, Tacrolimus etc.
Proteolytic enzyme is selected from elastoser, pancreatic elastase, metalloproteases, trypsin, chymase, pepsin, pronase, Bacillus polymyxa Neutral proteinase, bromelain, Chymotrypsin, clostripain, thermolysin, subtilisin, carase, papain, chymopapain, fibrinolysin, house thunder sulfo-peptidase, pancreatin, cathepsin-G, cysteine proteinase, thioesterase, amide transferase, the transesterification enzymatic activity, plasminogen activator, collagenase, the polymorphonuclear leukocyte serine protease, nuclease, lipase, esterase, streptokinase, glycosidase, hyaluronidase, neuraminidase, amylase, Cervilaxin, a kind of or its combination in interferon (gamma interferon) and the brinase.
Serve as preferred wherein with elastoser, trypsin, pepsin, pronase, Bacillus polymyxa Neutral proteinase, bromelain, Chymotrypsin, clostripain, fibrinolysin, cathepsin-G, plasminogen activator, collagenase, streptokinase, glycosidase, hyaluronidase, lysozyme, Cervilaxin, interferon (gamma interferon) and brinase.
Vasoinhibitor is selected from a kind of or its combination among gefitinib, Erlotinib, Lapatinib, votaranib, WAY-EKB 569, NSC 609974, thalidomide, LS-2616, angiostatin, Endostatin, blood vessel endothelium chalone, imatinib mesylate, Sugen 5416, BMS 354825, Avastin, Cl 1033, Sorafenib, Sutent, TLK286, ABX-EGF, Marimastat, SU5416, SU6668, Amebacilin, the TNP-470.
Above newborn neovascularization inhibitor also comprises their salt, as, but be not limited to sulfate, phosphate, hydrochlorate, Lactobionate, acetate, aspat, nitrate, citrate, purine or pyrimidine salt, succinate and maleate etc.
Above-mentioned neovascularization inhibitor shared ratio in slow releasing agent is decided because of concrete condition, can be 0.1%-50%, is good with 1%-40%, and 5%-30% is best.
Medicine in medicament slow-release microsphere only is rapamycin or mesenchyme hydrolytic agent, and the application of slow-releasing anticarcinogen injection and potentiation mode are:
(1) contain the slow releasing injection local injection of rapamycin, mesenchyme hydrolytic agent is used through other approach;
(2) local injection contains the slow releasing injection of mesenchyme hydrolytic agent, and other approach are used rapamycin;
(3) local injection contains the slow releasing injection and the slow releasing injection that contains mesenchyme hydrolytic agent of rapamycin; Or
(4) local injection contains the slow releasing injection of rapamycin and synergist.
The slow-releasing anticarcinogen injection of topical application also is used for the potentiation to radiotherapy or other therapies.Other approach refer to, but are not limited to tremulous pulse, vein, abdominal cavity, subcutaneous, intracavitary administration.
Mesenchyme hydrolytic agent shared ratio in compositions is decided because of concrete condition, can be 0.1%-60%, is good with 2%-40%, and 5%-30% is best.
The weight ratio of rapamycin and mesenchyme hydrolytic agent is, but is not limited to 1-99: 1 to 1: 1-99.
Anticancer effective component in the slow-releasing anticarcinogen injection microsphere of the present invention is preferably as follows, and all is weight percentage:
Slow-release auxiliary material is selected from poly-dl-lactide, poly-dl-lactide/ethanol copolymer, the monomethyl polyethylene glycol, monomethyl polyethylene glycol copolymer, polyethylene glycol, the polyethylene glycol copolymer, end carboxyl polylactic acid, end carboxyl polylactic acid/ethanol copolymer, polifeprosan, bis-fatty acid and decanedioic acid copolymer, poly-(erucic acid dimer-decanedioic acid), poly-(fumaric acid-decanedioic acid), polylactic acid, the copolymer of polyglycolic acid and hydroxyacetic acid, xylitol, oligosaccharide, chrondroitin, chitin, chitosan, hyaluronic acid, collagen protein, gelatin, one of poloxamer and albumin glue or its combination.
Slow-release auxiliary material and percentage by weight thereof are most preferably as follows in the sustained-release micro-spheres of the present invention:
(1) PLA of 55-99%;
(2) PLGA of 50-99%;
(3) polifeprosan of 50-95%;
(4) bis-fatty acid of 55-98% and decanedioic acid copolymer;
(5) PLGA of the PLA of the polifeprosan of 45-80% and 45-80% or 45-80%;
(6) xylitol of 50-95%, oligosaccharide, chrondroitin, chitin, chitosan, hyaluronic acid, collagen protein, gelatin, poloxamer or white tempera; Or
(7) poly-dl-lactide of 50-95%, poly-dl-lactide/ethanol copolymer, monomethyl polyethylene glycol, monomethyl polyethylene glycol copolymer, polyethylene glycol, polyethylene glycol copolymer, end carboxyl polylactic acid or end carboxyl polylactic acid/ethanol copolymer.
In various high molecular polymers, with polylactic acid, decanedioic acid, the mixture or the copolymer that contain the macromolecule polymer of polylactic acid or decanedioic acid is first-selection, mixture and copolymer can be selected from, but be not limited to the mixture or the copolymer of the mixture of PLA, PLGA, glycolic and hydroxy carboxylic acid, decanedioic acid and fragrant polyanhydride or aliphatic polyanhydride.The blend ratio of glycolic and hydroxy carboxylic acid is 10/90-90/10 (weight), preferably 25/75-75/25 (weight).The method of blend is arbitrarily.Content when glycolic and hydroxy carboxylic acid copolymerization is respectively percentage by weight 10-90% and 90-10%.The representative of fragrance polyanhydride is polifeprosan [poly-(1,3-two (to the carboxyl phenoxy group) propane-decanedioic acid) (p (CPP-SA)), bis-fatty acid-decanedioic acid copolymer (PFAD-SA)], poly-(erucic acid dimer-decanedioic acid) [P (EAD-SA)] and poly-(fumaric acid-decanedioic acid) [P (FA-SA)] etc.Content during to carboxylic phenoxypropane (p-CPP) and decanedioic acid copolymerization is respectively percentage by weight 10-60% and 20-90%, and the blend weight ratio is 10-40: 50-90, preferably weight ratio 15-30: 65-85.
The molecular weight peak value of polylactic acid can be, but is not limited to, 5000-100, and 000, but with 20,000-60,000 is preferred, with 5,000-30,000 for most preferably; The molecular weight of polyglycolic acid can be, but is not limited to, 5000-100, and 000, but with 5,000-50,000 is preferred, with 10,000-30,000 for most preferably; Above polyhydroxy acid can singly select or multiselect.When singly selecting, serve as preferred with the copolymer (PLGA) of polylactic acid (PLA) or hydroxy carboxylic acid and glycolic, the molecular weight of copolymer can be, but is not limited to, 5000-100,000, but with 20,000-60,000 be preferably, with 30,000-50,000 for most preferably; When multiselect, compound polymer or the copolymer formed with macromolecule polymer or different macromolecule polymer serve as preferred, with the compound polymer that contains different molecular weight polylactic acid or decanedioic acid or copolymer for most preferably, as, but be not limited to, molecular weight is 1000 to 30000 polylactic acid with molecular weight is that 20000 to 50000 polylactic acid mixes, molecular weight is 10000 to 30000 polylactic acid with molecular weight is that 30000 to 80000 PLGA mixes, molecular weight is that 20000 to 30000 polylactic acid mixes with decanedioic acid, molecular weight is that 30000 to 80000 PLGA mixes with decanedioic acid.Used polylactic acid serves as preferred with Poly-L-lactic acid (L-PLA).Poly-L-lactic acid (L-PLA) range of viscosities IV (dl/g) is 0.2～0.8, and glass transition temperature range is 55～65 ℃, 175～185 ℃ of fusing points.
Except that above-mentioned 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, chitosan etc., and wherein salt can be, but is not limited to, potassium salt and sodium salt etc.
In the slow releasing injection, drug sustained release system can be made into microsphere, sub-micro ball, microemulsion, nanosphere, granule or spherical piller, makes the injection use then with after the injection solvent mixes.In various slow releasing injection, serve as preferred with the suspension type slow releasing injection, the suspension type slow releasing injection is the preparation that the drug sustained release system that will contain anticancer component is suspended in gained in the injection, used adjuvant is a kind of or its combination in the above-mentioned slow-release auxiliary material, and used solvent is common solvent or the special solvent that contains suspending agent.Common solvent is, but is not limited to the buffer that distilled water, water for injection, physiology are prepared towards liquid, dehydrated alcohol or various salt.The purpose of suspending agent is the pastille microsphere that effectively suspends, thereby is beneficial to the usefulness of injection.
Suspending agent is selected from one of sodium carboxymethyl cellulose, (iodine) glycerol, simethicone, propylene glycol, carbomer, mannitol, sorbitol, surfactant, soil temperature 20, soil temperature 40 and soil temperature 80 or its combination.
The content of suspending agent in common solvent is decided because of its characteristic, can be 0.1-30% and decides because of concrete condition.Consisting of of preferred suspending agent:
A) 0.5-5% sodium carboxymethyl cellulose+0.1-0.5% soil temperature 80; Or
B) 5-20% mannitol+0.1-0.5% soil temperature 80; Or.
C) 0.5-5% sodium carboxymethyl cellulose+5-20% sorbitol+0.1-0.5% soil temperature 80.
The kind of solvent is then depended in the preparation of solvent, and common solvent has commercially available, also can make by oneself, and as distilled water, water for injection, physiology buffer towards liquid, dehydrated alcohol or the preparation of various salt, but must be in strict accordance with related standards.Special solvent need be considered the kind of suspending agent and the medicine that composition, solvent suspended, composition, character and the requirement thereof of sustained-release micro-spheres (or microcapsule) and the preparation method of injection, as sodium carboxymethyl cellulose (1.5%)+mannitol and/or sorbitol (15%) and/or soil temperature 80 (0.1%) are dissolved in the normal saline corresponding solvent, viscosity is at 10cp-650cp (20 ℃-30 ℃ time).
The present invention finds to influence medicine and/or sustained-release micro-spheres suspends and/or the key factor of injection is the viscosity of solvent, and viscosity is big more, and suspension effect is good more, and syringeability is strong more.This unexpected one of main index characteristic of the present invention of finding to have constituted.The viscosity of solvent depends on the viscosity of suspending agent, and the viscosity of suspending agent is 100cp-3000cp (20 ℃-30 ℃ time), preferred 1000cp-3000cp (20 ℃-30 ℃ time), most preferably 1500cp-3000cp (20 ℃-30 ℃ time).According to the viscosity of the prepared solvent of this condition is 10cp-650cp (20 ℃-30 ℃ time), preferred 20cp-650cp (20 ℃-30 ℃ time), most preferably 60cp-650cp (20 ℃-30 ℃ time).
The preparation of injection has several different methods, and a kind of is that the sustained-release microparticle (A) of suspending agent for " 0 " directly mixed in special solvent, obtains corresponding sustained-release microparticle injection; Another kind is that suspending agent is not mixed in special solvent or common solvent for the sustained-release microparticle (A) of " 0 ", obtains corresponding sustained-release microparticle injection; Another is that sustained-release microparticle (A) is mixed in common solvent, adds the suspending agent mixing then, obtains corresponding sustained-release microparticle injection.Except, also can earlier sustained-release microparticle (A) be mixed and in special solvent, make corresponding suspension, with the moisture in ways such as the vacuum drying removal suspension, special solvent of reuse or common solvent suspendible obtain corresponding sustained-release microparticle injection afterwards then.Above method just is illustrative rather than definitive thereof the present invention.It should be noted that suspended drug or sustained-release micro-spheres (or microcapsule) concentration in injection decide because of specifically needing, can be, but be not limited to, 10-400mg/ml, but be preferably with 30-300mg/ml, with 50-200mg/ml most preferably.The viscosity of injection is 50cp-1000cp (20 ℃-30 ℃ time), preferred 100cp-1000cp (20 ℃-30 ℃ time), most preferably 200cp-650cp (20 ℃-30 ℃ time).This viscosity is applicable to 18-22 injection needle and special bigger (to 3 millimeters) injection needle of internal diameter.
The preparation method of slow releasing injection is arbitrarily, available some kinds of methods preparation: as, but be not limited to, mixing method, fusion method, dissolution method, spray drying method for preparation microsphere, dissolution method are made micropowder, liposome bag medicine method and emulsion process etc. in conjunction with freezing (drying) comminuting method.Serve as preferred wherein with dissolution method (being the solvent volatility process), seasoning, spray drying method and emulsion process.Microsphere then can be used for preparing above-mentioned various slow releasing injection, and its method is arbitrarily.The particle size range of used microsphere can be between 5-400um, serving as preferred between the 10-300um, with between the 20-200um for most preferably.
Microsphere also can be used for preparing other slow releasing injection, as gel injection, block copolymer micelle injection.Wherein, block copolymer micelle is formed in aqueous solution by hydrophobic-hydrophilic block copolymers, has spherical inner core-shell mechanism, and hydrophobic block forms kernel, and hydrophilic block forms shell.The carrier micelle injection enters the purpose that reaches control drug release or targeted therapy in the body.Used pharmaceutical carrier is above-mentioned any one or its combination.Wherein preferred molecular weight is the hydrophilic block of the Polyethylene Glycol (PEG) of 1000-15000 as the micelle copolymer, and preferred biological degradation polyalcohol (as PLA, polylactide, polycaprolactone and copolymer thereof (molecular weight 1500-25000)) is as the hydrophobic block of micelle copolymer.The particle size range of block copolymer micelle can be between 10-300um, between the 20-200um serving as preferred.Gel injection system is dissolved in some amphipathic solvent with biological degradation polyalcohol (as PLA, PLGA or DL-LA and epsilon-caprolactone copolymer), adds medicine miscible with it (or suspendible) back again and forms flowability gel preferably, can be through tumor week or intratumor injection.In case inject, amphipathic solvent diffuses to body fluid very soon, the moisture in the body fluid then infiltrates gel, makes polymer cure, slowly discharges medicine.
Sustained-release micro-spheres also can be used for preparing sustained-release implant, used pharmaceutic adjuvant can be any or multiple material in the above-mentioned pharmaceutic adjuvant, but with the high molecular weight water soluble polymer is main separation, in various high molecular polymers, with polylactic acid, decanedioic acid, the mixture or the copolymer that contain the macromolecule polymer of polylactic acid or decanedioic acid is first-selection, mixture and copolymer can be selected from, but be not limited to the mixture or the copolymer of the mixture of PLA, PLGA, PLA and PLGA, decanedioic acid and fragrant polyanhydride or aliphatic polyanhydride.Polylactic acid (PLA) is 10/90-90/10 (weight) with the blend ratio of polyglycolic acid, preferably 25/75-75/25 (weight).The method of blend is arbitrarily.Content when glycolic and lactic acid copolymerization is respectively percentage by weight 10-90% and 90-10%.The representative of fragrance polyanhydride is to carboxy phenyl propane (p-CPP), content during to carboxy phenyl propane (p-CPP) and decanedioic acid copolymerization is respectively percentage by weight 10-60% and 20-90%, the blend weight ratio is 10-40: 50-90, preferably weight ratio 15-30: 65-85.
Another form of slow releasing agent of the present invention is that slow releasing agent is a sustained-release implant.The effective ingredient of anticancer implant can be packaged in the whole pharmaceutic adjuvant equably, also can be packaged in carrier holder center or its surface; Can effective ingredient be discharged by direct diffusion and/or the mode of degrading through polymer.
The characteristics of sustained-release implant are that used slow-release auxiliary material removes the high molecular polymerization beyond the region of objective existence, also contain above-mentioned any one or multiple other adjuvant.The pharmaceutic adjuvant that adds is referred to as additive.Additive can be divided into filler, porogen, excipient, dispersant, isotonic agent, preservative agent, blocker, solubilizing agent, absorption enhancer, film former, gellant etc. according to its function.
The Main Ingredients and Appearance of sustained-release implant can be made into multiple dosage form.As, but be not limited to capsule, slow releasing agent, implant, slow releasing agent implant etc.; Be multiple shape, as, but be not limited to granule, pill, tablet, powder, sphere, bulk, needle-like, bar-shaped, column and membranaceous.In various dosage forms, serve as preferred slowly to discharge implant in the body.The volume size depends on factors such as the position, size of focus.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.
Anticancer effective component and percentage by weight in the sustained-release implant are preferably as follows:
(1) rapamycin of 0.01%-20%; Or
(2) elastoser of the rapamycin of 0.01%-20% and 1-40%, trypsin, pepsin, pronase, Bacillus polymyxa Neutral proteinase, bromelain, Chymotrypsin, clostripain, fibrinolysin, cathepsin-G, plasminogen activator, collagenase, streptokinase, glycosidase, hyaluronidase, lysozyme, Cervilaxin, gamma interferon, brinase, gefitinib, Erlotinib, Lapatinib, votaranib, WAY-EKB 569, NSC 609974, thalidomide, LS-2616, angiostatin, Endostatin, the blood vessel endothelium chalone, imatinib mesylate, Sugen 5416, BMS 354825, Avastin, Cl 1033, Sorafenib, Sutent, TLK286, ABX-EGF, Marimastat, SU5416, the combination of SU6668 or Amebacilin.
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 55-99%;
(2) PLGA of 50-99%;
(3) polifeprosan of 50-95%;
(4) bis-fatty acid of 55-98% and decanedioic acid copolymer;
(5) PLGA of the PLA of the polifeprosan of 30-80% and 30-80% or 30-80%;
(6) xylitol of 50-95%, oligosaccharide, chrondroitin, chitin, chitosan, hyaluronic acid, collagen protein, gelatin, poloxamer or white tempera; Or
(7) poly-dl-lactide of 50-95%, 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.
When the rapamycin in the medicament slow-release microsphere only is rapamycin or its synergist, the application of anti-cancer sustained-released implantation agent and the same slow releasing injection of potentiation mode.
Route of administration depends on multiple factor, for obtain valid density in former or position, metastatic tumour place, medicine can give through number of ways, as in subcutaneous, intracavity (in abdominal cavity, thoracic cavity and canalis spinalis), the tumor, in all injections of tumor or placement, selective arterial injection, the lymph node and injection in the bone marrow.With in selective arterial injection, intracavity, the tumor, tumor week injection or be placed as preferred.
The application of sustained-release implant and the same slow-releasing anticarcinogen injection of potentiation mode, the cancer therapy drug that place the associating of the chemical-therapy synergistic agent of the associating of the cancer therapy drug of the promptly local chemical-therapy synergistic agent of placing and other administration, the local cancer therapy drug of placing and other administration, part and the associating of the local chemical-therapy synergistic agent of placing.Wherein the cancer therapy drug of topical application and chemical-therapy synergistic agent can be separately or Joint Production, packing, sale, use.Packing refers to medicine carrying process and pastille slow-release agent the exterior and interior packing for transport and/or store of medicine for adjuvant.The medicine carrying process includes, but not limited to weighing, dissolving, mixing, drying, shaping, coating, spraying, granulation etc.
The 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, multiple myeloma, lungs, esophagus, stomach, mammary gland, pancreas, eyes, nasopharynx part, uterus, ovary, endometrium, cervix uteri, prostate, bladder, colon, rectum.
The clinical practice dosage of effective ingredient depends on patient's concrete condition, can be from 0.001 to 300mg/kg body weight, and 0.05 to 200mg/kg is preferred, 0.1 to 100mg/kg for there being most choosing.
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:
Test 1, contain tumor-inhibiting action in the body of slow releasing injection of rapamycin and mesenchyme hydrolytic agent
With the rat is subjects, with 2 * 10
5Individual pancreatic tumor cell subcutaneous injection is in its hypochondrium, treats that tumor growth after 14 days is divided into it following 10 groups (seeing Table 1).First group is contrast, and the 2nd to 10 group is the treatment group, and medicine is all through intratumor injection.The dosage of mesenchyme hydrolytic agent-vasoinhibitor is 1mg/kg, and rapamycin is 0.05mg/kg.The treatment back was measured gross tumor volume size, relatively therapeutic effect (seeing Table 1) on the 21st day.
Table 1
| Test group (n) | Suffered treatment | Gross tumor volume (cm 3) | The P value |
| 1(6) | Contrast | 58±10 | |
| 2(6) | Rapamycin | 48±5.0 | ＜0.05 |
| 3(6) | Collagenase | 42±6.0 | ＜0.01 |
| 4(6) | Gefitinib | 38±4.4 | ＜0.01 |
| 5(6) | Erlotinib | 36±5.0 | ＜0.01 |
| 6(6) | Lapatinib | 40±3.8 | ＜0.01 |
| 7(6) | Rapamycin+collagenase | 30±6.2 | ＜0.001 |
| 8(6) | Rapamycin+gefitinib | 22±3.6 | ＜0.001 |
| 9(6) | Rapamycin+Erlotinib | 26±5.2 | ＜0.001 |
| 10(6) | Rapamycin+Lapatinib | 20±2.4 | ＜0.001 |
Above result shows, growth all has the obvious suppression effect to kinds of tumor cells when this concentration is used separately for rapamycin and used mesenchyme hydrolytic agent (collagenase, gefitinib, Erlotinib, Lapatinib), can show significant potentiation when use in conjunction.
The tumor-inhibiting action of test 2, rapamycin and mesenchyme hydrolytic agent
Used tumor cell comprises CNS-1, C6, gastric gland epithelial cancer (SA), bone tumor (BC), breast carcinoma (BA), pulmonary carcinoma (LH), papillary adenocarcinoma of thyroid (PAT) etc.Medicine is through intratumor injection.Therapeutic effect (seeing Table 2).Neovascularization inhibitor dosage is 2.5mg/kg, and rapamycin is 0.01mg/kg.The treatment back was measured the gross tumor volume size on the 20th day, made relatively therapeutic effect (seeing Table 2) of index with inhibition rate of tumor growth (%).
Table 2
| Oncocyte | Votaranib | Hyaluronidase | WAY-EKB 569 | Rapamycin | Votaranib+rapamycin | Hyaluronidase+rapamycin | WAY-EKB 569+rapamycin |
| CNS | 40％ | 50％ | 62％ | 60％ | 86％ | 80％ | 78％ |
| C6 | 34％ | 64％ | 60％ | 64％ | 84％ | 80％ | 84％ |
| SA | 34％ | 40％ | 50％ | 62％ | 86％ | 82％ | 92％ |
| BC | 36％ | 62％ | 54％ | 64％ | 74％ | 82％ | 80％ |
| BA | 38％ | 60％ | 62％ | 60％ | 82％ | 72％ | 92％ |
| LH | 42％ | 56％ | 62％ | 58％ | 90％ | 86％ | 84％ |
| PAT | 48％ | 40％ | 66％ | 52％ | 80％ | 88％ | 88％ |
Above result shows, growth all has the obvious suppression effect to kinds of tumor cells when this concentration is used separately for used rapamycin and mesenchyme hydrolytic agent (hyaluronidase, votaranib, WAY-EKB 569), can show significant potentiation when use in conjunction.
The tumor-inhibiting action of test 3, rapamycin and mesenchyme hydrolytic agent
With the rat is subjects, with 2 * 10
5Individual tumor cell of liver subcutaneous injection is in its hypochondrium, treats that tumor growth after 14 days is divided into it following 10 groups (seeing Table 3).First group is contrast, and the 2nd to 10 group is the treatment group, and sustained-release implant is placed in tumor.Dosage is 0.5mg/kg.The treatment back was measured gross tumor volume size, relatively therapeutic effect (seeing Table 3) on the 14th day.
Table 3
| Test group (n) | Suffered treatment | Gross tumor volume (cm 3) | The P value |
| 1(6) | Contrast | 60±10 | |
| 2(6) | Rapamycin | 48±6.0 | ＜0.05 |
| 3(6) | Pancreatin | 50±6.2 | ＜0.01 |
| 4(6) | Imatinib | 36±4.6 | ＜0.001 |
| 5(6) | Sugen 5416 | 40±3.2 | ＜0.01 |
| 6(6) | BMS 354825 | 38±3.0 | ＜0.001 |
| 7(6) | Rapamycin+pancreatin | 34±4.6 | ＜0.01 |
| 8(6) | Rapamycin+imatinib | 20±2.4 | ＜0.001 |
| 9(6) | Rapamycin+Sugen 5416 | 22±3.4 | ＜0.01 |
| 10(6) | Rapamycin+BMS 354825 | 18±2.0 | ＜0.001 |
Above result shows, growth all has the obvious suppression effect to kinds of tumor cells when this concentration is used separately for used rapamycin and mesenchyme hydrolytic agent (pancreatin, imatinib, Sugen 5416, BMS 354825), can show significant potentiation when use in conjunction.
The tumor-inhibiting action of test 4, rapamycin and mesenchyme hydrolytic agent (slow releasing injection)
With the rat is subjects, with 2 * 10
5Individual pulmonary carcinoma 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 (rapamycin or mesenchyme hydrolytic agent) and therapeutic alliance group (rapamycin and mesenchyme hydrolytic agent).Rapamycin is through intratumor injection, and mesenchyme hydrolytic agent is through lumbar injection.Dosage is 0.25mg/kg.The treatment back was measured the gross tumor volume size on the 10th day, made relatively therapeutic effect (seeing Table 4) of index with inhibition rate of tumor growth.
Table 4
| Test group (n) | Suffered treatment | Suppression ratio (%) | The P value |
| 1(6) | Contrast | - | |
| 2(6) | Rapamycin | 42 | ＜0.05 |
| 3(6) | The blood vessel endothelium chalone | 38 | ＜0.01 |
| 4(6) | Imatinib mesylate | 36 | ＜0.01 |
| 5(6) | Sugen 5416 | 34 | ＜0.01 |
| 6(6) | BMS 354825 | 26 | ＜0.01 |
| 7(6) | Rapamycin+blood vessel endothelium chalone | 70 | ＜0.001 |
| 8(6) | Rapamycin+imatinib mesylate | 78 | ＜0.001 |
| 9(6) | Rapamycin+Sugen 5416 | 70 | ＜0.001 |
| 10(6) | Rapamycin+BMS 354825 | 68 | ＜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 rapamycin and mesenchyme hydrolytic agent (blood vessel endothelium chalone, imatinib mesylate, Sugen 5416, BMS 354825), can show significant potentiation when use in conjunction.
The tumor-inhibiting action of test 5, rapamycin and mesenchyme hydrolytic agent
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.Rapamycin is through lumbar injection, and mesenchyme hydrolytic agent is through the injection of tumor week.Mesenchyme hydrolytic agent dosage is 3mg/kg, and rapamycin is 0.5mg/kg.The treatment back was measured the gross tumor volume size on the 20th day, make relatively therapeutic effect of index with inhibition rate of tumor growth, above result shows, rapamycin obviously strengthens elastoser, trypsin, pepsin, pronase, Bacillus polymyxa Neutral proteinase, bromelain, Chymotrypsin, clostripain, fibrinolysin, cathepsin-G, plasminogen activator, collagenase, streptokinase, glycosidase, hyaluronidase, lysozyme, Cervilaxin, mesenchyme hydrolytic agents such as interferon (gamma interferon) and brinase are to the inhibitory action of kinds of tumors growth, wherein to trypsin, pepsin, pronase, Bacillus polymyxa Neutral proteinase, bromelain, Chymotrypsin, clostripain, fibrinolysin, cathepsin-G, the plasminogen activator lysozyme, the potentiation of Cervilaxin is (P＜0.01) the most obviously.
The tumor-inhibiting action of test 6, rapamycin and mesenchyme hydrolytic agent (sustained-release implant)
With the rat is subjects, with 2 * 10
5Individual pancreatic cancer 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 all placed in tumor.Dosage is 2.5mg/kg.The treatment back was measured the gross tumor volume size on the 20th day, made relatively therapeutic effect of index with inhibition rate of tumor growth.Above result shows that rapamycin obviously strengthens the inhibitory action (P＜0.01) of mesenchyme hydrolytic agents such as Cl 1033, Sorafenib, Sutent, TLK286, ABX-EGF, Marimastat, SU5416, SU6668 or Amebacilin to cancer of pancreas.
The tumor-inhibiting action of test 7, rapamycin and mesenchyme hydrolytic agent (sustained-release implant)
By testing 8 described methods mensuration rapamycins and mesenchyme hydrolytic agent (sustained-release implant) tumor-inhibiting action to colon cancer, above result shows that rapamycin obviously strengthens the tumor-inhibiting action (P＜0.01) of ovarian cancer to mesenchyme hydrolytic agent (Cervilaxin).
The test 8, the different molecular weight polylactic acid make according to release ratio in the body of platinum sustained-release implant
With the rat is subjects, grouping (3/group) and the equivalent fibrinolysin sustained-release implant 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 (8%), 3 (28%), 7 (56%), 14 (82%), 21 (90), 28 (94) and 35 (98%).Discharge in the body of the fibrinolysin sustained-release implant that comparison different molecular weight polylactic acid is made and find, slack-off with the molecular weight increase, with the 7th day was example, compare with whole body administration group, tumor control rate increases with the polylactic acid molecule amount and improves, and is followed successively by 68% (MW:5000), 66% (MW:15000), 54% (MW:25000), 50% (MW:40000) and 48 (MW:60000).
That pays special attention to is simple to operation, the good reproducibility of slow releasing agent of the present invention, particularly slow releasing injection.Good effect not only, toxic and side effects is little.
Different drug packages is to want characteristic different with different Biodegradable high moleculars.Discover that further the slow-release auxiliary material that is most appropriate to medicament slow release of the present invention is a poly-dl-lactide, poly-dl-lactide/ethanol copolymer, the monomethyl polyethylene glycol, monomethyl polyethylene glycol copolymer, polyethylene glycol, the polyethylene glycol copolymer, end carboxyl polylactic acid, end carboxyl polylactic acid/ethanol copolymer, polifeprosan, bis-fatty acid and decanedioic acid copolymer, poly-(erucic acid dimer-decanedioic acid), poly-(fumaric acid-decanedioic acid), polylactic acid, the copolymer of polyglycolic acid and hydroxyacetic acid, xylitol, oligosaccharide, chrondroitin, chitin, chitosan, hyaluronic acid, collagen protein, gelatin, poloxamer, one of albumin glue or its combination; 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 rapamycin and mesenchyme hydrolytic agent were used separately, can show significant potentiation when use in conjunction.Therefore, effective ingredient of the present invention is the combination of mesenchyme hydrolytic agent or any one (or more than one) rapamycin and mesenchyme hydrolytic agent.The medicine that contains above effective ingredient can be made into sustained-release micro-spheres, and then makes slow releasing injection and implant, serves as preferred with the suspensoid injectio that is combined to form with the special solvent that contains suspending agent wherein.
Slow releasing injection or sustained-release implant also can be further specified by following embodiment.Just the invention will be further described for the foregoing description and following examples, is not its content and use are imposed any restrictions.
(4) specific embodiment
Embodiment 1.
95mg 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 2mg rapamycin and 3mg gefitinib, shake up the back contains 2% rapamycin and 3% gefitinib 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.The viscosity of injection is 280cp-420cp (20 ℃-30 ℃ time), and the drug release time in external normal saline is 25-35 days, is about 30-35 days at the subcutaneous drug release time of mice.
Embodiment 2.
The method step that is processed into slow releasing injection is identical with embodiment 1, but different is that polifeprosan is 50: 50, and contained anticancer effective component and percentage by weight thereof are:
(1) rapamycin of 0.01%-5%; Or
(2) combination of the elastoser of the rapamycin of 0.01%-5% and 2-40%, trypsin, pepsin, pronase, Bacillus polymyxa Neutral proteinase, bromelain, Chymotrypsin, clostripain, fibrinolysin or Amebacilin.
Embodiment 3.
With 90mg molecular weight peak value is that the polylactic acid (PLA) of 10000-35000 is put into container, adds 100 milliliters of dichloromethane, behind the dissolving mixing, adds 5mg rapamycin and 5mg Erlotinib, 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 5% rapamycin and 5% Erlotinib, be suspended in then in the normal saline that contains 1.5% sodium carboxymethyl cellulose, make corresponding suspension type slow releasing injection.The viscosity of this slow releasing injection is 150cp-300cp (20 ℃-30 ℃ time), and the drug release time in external normal saline is 20-35 days, is about 35-50 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 the molecular weight peak value of different is polylactic acid is 30000-55000, and contained anticancer effective component and percentage by weight thereof are:
(1) rapamycin of 0.1%-10%; Or
(2) combination of the collagenase of the rapamycin of 0.1%-10% and 5-20%, streptokinase, glycosidase, hyaluronidase, lysozyme, Cervilaxin, gamma interferon, brinase, gefitinib, Erlotinib, Lapatinib, votaranib or WAY-EKB 569.
Embodiment 5.
With 80mg molecular weight peak value is the polylactic acid (PLGA of 10000-35000,50: 50) put into container, after adding 100 milliliters of dichloromethane dissolving mixings, add 0.2 milligram of rapamycin and 19.8 milligrams of plasminogen activators, shake up the back contains 0.2% rapamycin and 19.8% plasminogen activator with spray drying method for preparation injectable microsphere again.Then microsphere is suspended in the injection that contains the 5-15% sorbitol, makes corresponding suspension type slow releasing injection.The drug release time of this slow releasing injection in external normal saline is 14-18 days, is about 20-25 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 used adjuvant is that the contained anticancer effective component of polylactic acid (PLGA, 25: 75) of 30000-55000 is: the combination of the rapamycin of 1-10% and the collagenase of 1-20%, streptokinase, glycosidase, hyaluronidase, lysozyme, Cervilaxin, interferon or brinase for the molecular weight peak value.
Embodiment 7.
With 40mg polifeprosan (20: 80) and 50mg molecular weight peak value is the polylactic acid (PLGA of 20000-45000,50: 50) put into container, add 100 milliliters of dichloromethane, behind the dissolving mixing, add 1mg rapamycin and 9mg collagenase, shake up the back contains 1% rapamycin and 9% collagenase with spray drying method for preparation injectable microsphere again.Microsphere is suspended in the normal saline that contains 1.5% sodium carboxymethyl cellulose and 0.5% Tween 80 then, makes corresponding suspension type slow releasing injection.The drug release time of this slow releasing injection in external normal saline is 14-21 days, is about 20-25 days at the subcutaneous drug release time of mice.
Embodiment 8.
The method step that is processed into slow releasing injection is identical with embodiment 7, but different is that used adjuvant is the polylactic acid (PLGA of 30000-55000 for the molecular weight peak value, 50: 50), contained anticancer effective component is: the combination of the rapamycin of the collagenase of 2-10%, streptokinase, glycosidase, hyaluronidase, lysozyme, Cervilaxin, interferon or brinase and 1-5%.
Embodiment 9
With 50mg polifeprosan (20: 80) and 30mg molecular weight peak value is that the polylactic acid (PLA) of 10000-35000 is put into container, add 100 milliliters of dichloromethane, behind the dissolving mixing, add 5mg rapamycin and 15mg streptokinase, shake up the back contains 5% rapamycin and 15% streptokinase 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.The drug release time of this slow releasing injection in external normal saline is 18-25 days, is about 22-30 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 but different is that used adjuvant is that 30mg polifeprosan (50: 50) and 50mg molecular weight peak value are the polylactic acid (PLA) of 30000-45000, and contained anticancer effective component is: the collagenase of 2-40%, streptokinase, glycosidase, hyaluronidase, lysozyme, Cervilaxin, interferon or brinase and 1-10% combination.
Embodiment 11
70mg polifeprosan (to carboxy phenyl propane (p-CPP): decanedioic acid (SA) is 50: 50) copolymer is put into container, add 100 milliliters of dichloromethane, behind the dissolving mixing, add 10mg lysozyme and 20mg rapamycin, shake up the back contains 10% lysozyme and 20% rapamycin 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 24-28 days, is about 30-45 days at the subcutaneous drug release time of mice.
Embodiment 12
The method step that is processed into sustained-release implant is identical with embodiment 11, but different is that contained anticancer effective component is: the combination of 10% collagenase, streptokinase, glycosidase, hyaluronidase, lysozyme or Cervilaxin and 10% rapamycin.
Embodiment 13
With 70mg molecular weight peak value 80000 polylactic acid (PLGA, 50: 50) put into container, add 100 milliliters of dichloromethane, behind the dissolving mixing, add 10mg rapamycin and 10mg collagenase and 10mg hyaluronidase, shake up the back contains 10% rapamycin and 10% collagenase and 10% hyaluronidase 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 25-30 days, is about 35-50 days at the subcutaneous drug release time of mice.
Embodiment 14
The method step that is processed into sustained-release implant is identical with embodiment 11,13, but different is that contained anticancer effective component is: the combination of the rapamycin of 10% collagenase and 10% hyaluronidase and 15%.
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) the molecular weight peak value is the polylactic acid (PLA) of 5000-10000,10000-30000,30000-60000,60000-100000 or 100000-150000;
B) the molecular weight peak value is the polyglycolic acid of 5000-10000,10000-30000,30000-60000,60000-100000 or 100000-150000 and the copolymer of hydroxyacetic acid (PLGA), wherein, the ratio of polyglycolic acid and hydroxyacetic acid is 50-95: 50-50;
C) polifeprosan and PLA or PLGA;
D) 10: 90,20: 80,30: 70,40: 60,50: 50 or 60: 40 to carboxy phenyl propane (p-CPP): decanedioic acid (SA) copolymer (polifeprosan);
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, chitosan, potassium salt, sodium salt, hyaluronic acid, collagen protein, gelatin, poloxamer or albumin glue;
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 1-15, but different is used suspending agent is respectively one of following or its combination:
A) 0.5-3.0% carboxymethyl cellulose (sodium);
B) 5-15% mannitol;
C) 5-15% sorbitol;
D) 0.1-1.5% surfactant;
E) 0.1-0.5% polysorbas20.
Embodiment 17
The method step that is processed into slow releasing injection is identical with embodiment 11-15, but different is that contained anticancer effective component is:
(1) rapamycin of 1-10%; Or
(2) combination of the rapamycin of the collagenase of 1-10%, streptokinase, glycosidase, hyaluronidase, lysozyme or Cervilaxin and 1-5%; Or
(2) group of the gefitinib of the rapamycin of 1-10% and 1-15%, Erlotinib, Lapatinib, votaranib, WAY-EKB 569, NSC 609974, thalidomide, LS-2616, angiostatin, Endostatin, blood vessel endothelium chalone, imatinib mesylate, Sugen 5416, BMS 354825, Avastin, Cl 1033, Sorafenib, Sutent, TLK286, ABX-EGF, Marimastat, SU5416, SU6668, Amebacilin or TNP-470.
The foregoing description illustrates for example rather than will limit scope of the present invention.In fact, except that shown in this paper and the of the present invention various changes described, to those skilled in the art all can be from description and chart apparent.Certainly these changes should be in the scope of appended claim.
Therefore, to disclose some specific implementations of the present invention emphatically and its being equal to of making is changed or replaces all be in described design of appended claims and scope to the description that should be realized that the front.The present invention disclosed and the protection the content see claim.
Claims (10)
1. an anti-cancer composition that contains rapamycin is characterized in that the anticancer effective component that said composition contains is rapamycin and/or mesenchyme hydrolytic agent; Wherein mesenchyme hydrolytic agent is selected from proteolytic enzyme and/or vasoinhibitor.
2. the anti-cancer composition according to claim 1 is characterized in that the anticancer effective component of anti-cancer composition is used to prepare slow-releasing anticarcinogen injection or anti-cancer sustained-released implantation agent.
3. the slow releasing injection according to claim 2 is characterized in that slow releasing injection is grouped into by following one-tenth:
(A) sustained-release micro-spheres comprises:
Anticancer effective component 0.01-60%
Slow-release auxiliary material 40-99.99%
Suspending agent 0.0-30%
More than be weight percentage
With
(B) solvent is for common solvent or contain the special solvent of suspending agent.
Wherein, 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;
4. the slow-releasing anticarcinogen injection according to claim 3 is characterized in that described 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;
F) iodine glycerol, simethicone, propylene glycol or carbomer;
G) 0.5-5% sodium carboxymethyl cellulose+0.1-0.5% soil temperature 80;
H) 5-20% mannitol+0.1-0.5% soil temperature 80; Or
I) 0.5-5% sodium carboxymethyl cellulose+5-20% sorbitol+0.1-0.5% soil temperature 80.
5. the anti-cancer sustained-released implantation agent according to claim 3 is characterized in that anti-cancer sustained-released implantation agent is made up of anticancer effective component and slow-release auxiliary material.
6. the anti-cancer composition according to claim 1 is characterized in that the percentage by weight of rapamycin anticancer effective component in compositions is 0.0001%-50%; The weight ratio of rapamycin and mesenchyme hydrolytic agent is 1-99: 1 to 1: 1-99.
7. according to claim 3 and 5 described anticancer sustained-release agents, it is characterized in that slow-release auxiliary material is one of following or its combination:
A) polylactic acid, molecular weight peak value are 10000-30000,300000-60000,60000-100000 or 100000-150000;
B) copolymer of polyglycolic acid and hydroxyacetic acid, wherein, the ratio of polyglycolic acid and hydroxyacetic acid is 50-95: 50-50, the molecular weight peak value is 10000-30000,300000-60000,60000-100000 or 100000-150000;
C) polifeprosan and PLA or PLGA;
D) polifeprosan, to carboxy phenyl propane: decanedioic acid is 10: 90,20: 80,30: 70,40: 60,50: 50 or 60: 40;
E) bis-fatty acid and decanedioic acid copolymer;
F) poly-(erucic acid dimer-decanedioic acid);
G) poly-(fumaric acid-decanedioic acid);
H) xylitol, oligosaccharide, chrondroitin, chitin, chitosan, hyaluronic acid, collagen protein, gelatin, poloxamer or white tempera;
I) poly-dl-lactide, poly-dl-lactide/ethanol copolymer, monomethyl polyethylene glycol, monomethyl polyethylene glycol copolymer, polyethylene glycol, polyethylene glycol copolymer, end carboxyl polylactic acid or end carboxyl polylactic acid/ethanol copolymer.
8. the anti-cancer composition according to claim 1 is characterized in that vasoinhibitor is selected from a kind of or its combination among gefitinib, Erlotinib, Lapatinib, votaranib, WAY-EKB 569, NSC 609974, thalidomide, LS-2616, angiostatin, Endostatin, blood vessel endothelium chalone, imatinib mesylate, Sugen 5416, BMS 354825, Avastin, Cl 1033, Sorafenib, Sutent, TLK286, ABX-EGF, Marimastat, SU5416, SU6668, Amebacilin, the TNP-470.
9. the anti-cancer composition according to claim 1 is characterized in that proteolytic enzyme is selected from elastoser, pancreatic elastase, metalloproteases, trypsin, chymase, pepsin, pronase, Bacillus polymyxa Neutral proteinase, bromelain, Chymotrypsin, clostripain, thermolysin, subtilisin, carase, papain, chymopapain, fibrinolysin, house thunder sulfo-peptidase, pancreatin, cathepsin-G, cysteine proteinase, thioesterase, amide transferase, the transesterification enzymatic activity, plasminogen activator, collagenase, the polymorphonuclear leukocyte serine protease, nuclease, lipase, esterase, streptokinase, glycosidase, hyaluronidase, neuraminidase, amylase, Cervilaxin, a kind of or its combination in interferon (gamma interferon) and the brinase.
10. the anti-cancer composition according to claim 1 is characterized in that anticancer effective component and percentage by weight are:
(1) rapamycin of 0.01%-20%; Or
(2) elastoser of the rapamycin of 0.01%-20% and 1-40%, trypsin, pepsin, pronase, Bacillus polymyxa Neutral proteinase, bromelain, Chymotrypsin, clostripain, fibrinolysin, cathepsin-G, plasminogen activator, collagenase, streptokinase, glycosidase, hyaluronidase, lysozyme, Cervilaxin, gamma interferon, brinase, gefitinib, Erlotinib, Lapatinib, votaranib, WAY-EKB 569, NSC 609974, thalidomide, LS-2616, angiostatin, Endostatin, the blood vessel endothelium chalone, imatinib mesylate, Sugen 5416, BMS 354825, Avastin, Cl 1033, Sorafenib, Sutent, TLK286, ABX-EGF, Marimastat, SU5416, the combination of SU6668 or Amebacilin.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA200610201343XA CN1973822A (en) | 2006-12-20 | 2006-12-20 | Anticancer composition containing Sirolimus |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA200610201343XA CN1973822A (en) | 2006-12-20 | 2006-12-20 | Anticancer composition containing Sirolimus |
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| Publication Number | Publication Date |
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| CN1973822A true CN1973822A (en) | 2007-06-06 |
Family
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA200610201343XA Pending CN1973822A (en) | 2006-12-20 | 2006-12-20 | Anticancer composition containing Sirolimus |
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| CN (1) | CN1973822A (en) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110167555A (en) * | 2017-01-06 | 2019-08-23 | 参天制药株式会社 | It is bestowed in sirolimus tumor for treating prostate cancer |
| US10668011B2 (en) | 2016-06-30 | 2020-06-02 | Durect Corporation | Depot formulations |
| US10682340B2 (en) | 2016-06-30 | 2020-06-16 | Durect Corporation | Depot formulations |
| EP3984525A1 (en) * | 2014-06-12 | 2022-04-20 | Adare Pharmaceuticals USA, Inc. | Extended-release drug delivery compositions |
-
2006
- 2006-12-20 CN CNA200610201343XA patent/CN1973822A/en active Pending
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP3984525A1 (en) * | 2014-06-12 | 2022-04-20 | Adare Pharmaceuticals USA, Inc. | Extended-release drug delivery compositions |
| US10668011B2 (en) | 2016-06-30 | 2020-06-02 | Durect Corporation | Depot formulations |
| US10682340B2 (en) | 2016-06-30 | 2020-06-16 | Durect Corporation | Depot formulations |
| CN110167555A (en) * | 2017-01-06 | 2019-08-23 | 参天制药株式会社 | It is bestowed in sirolimus tumor for treating prostate cancer |
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